Archives: Cancer Types

Small Cell Lung Cancer Treatment (PDQ®)–Health Professional Version

Small Cell Lung Cancer Treatment (PDQ®)–Health Professional Version

General Information About Small Cell Lung Cancer (SCLC)

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SCLC accounts for approximately 15% of bronchogenic carcinomas.

At the time of diagnosis, approximately 30% of patients with SCLC have tumors confined to the hemithorax of origin, mediastinum, or supraclavicular lymph nodes. These patients have limited-stage disease (LD).[1] Patients with tumors that have spread beyond the supraclavicular areas have extensive-stage disease (ED).

SCLC is more responsive to chemotherapy and radiation therapy than other cell types of lung cancer. However, a cure is difficult to achieve because SCLC has a greater tendency to be widely disseminated by the time of diagnosis.

Incidence and Mortality

The overall incidence and mortality rates of SCLC in the United States have decreased during the past few decades.[2]

Estimated new cases and deaths from lung cancer (SCLC and non-small cell lung cancer [NSCLC] combined) in the United States in 2025:[3]

  • New cases: 226,650.
  • Deaths: 124,730.

Risk Factors

Increasing age is the most important risk factor for most cancers. Other risk factors for lung cancer include:

  • History of or current tobacco use: cigarettes, pipes, and cigars.[4]
  • Exposure to cancer-causing substances in secondhand smoke.[5,6]
  • Occupational exposure to asbestos, arsenic, chromium, beryllium, nickel, and other agents.[7]
  • Radiation exposure from any of the following sources:
    • Radiation therapy to the breast or chest.[8]
    • Radon exposure in the home or workplace.[9]
    • Medical imaging tests, such as computed tomography (CT) scans.[10]
    • Atomic bomb radiation.[11]
  • Living in an area with air pollution.[12–14]
  • Family history of lung cancer.[15]
  • HIV infection.[16]
  • Beta carotene supplements in heavy smokers.[17,18]

Clinical Features

Lung cancer may present with symptoms or be found incidentally on chest imaging. Symptoms and signs may result from the location of the primary local invasion or compression of adjacent thoracic structures, distant metastases, or paraneoplastic phenomena. The most common symptoms at presentation are worsening cough and dyspnea. Other presenting symptoms include:

  • Chest pain.
  • Hoarseness.
  • Malaise.
  • Anorexia.
  • Weight loss.
  • Hemoptysis.

Symptoms may result from local invasion or compression of adjacent thoracic structures, such as compression involving the esophagus causing dysphagia, compression involving the laryngeal nerves causing hoarseness, or compression involving the superior vena cava causing facial edema and distension of the superficial veins of the head and neck. Symptoms from distant metastases may also be present and include neurological defects or personality changes from brain metastases and pain from bone metastases.

Infrequently, patients with SCLC may present with symptoms and signs of one of the following paraneoplastic syndromes:

  • Inappropriate antidiuretic hormone secretion.
  • Cushing syndrome from secretion of adrenocorticotropic hormone.
  • Paraneoplastic cerebellar degeneration.
  • Lambert-Eaton myasthenic syndrome.[2]

Physical examination may identify enlarged supraclavicular lymphadenopathy, pleural effusion or lobar collapse, unresolved pneumonia, or signs of associated disease such as chronic obstructive pulmonary disease.

Diagnosis

Treatment options for patients are determined by histology, stage, and general health and comorbidities of the patient. Investigations of patients with suspected SCLC focus on confirming the diagnosis and determining the extent of the disease.

The procedures used to determine the presence of cancer include:

  • History.
  • Physical examination.
  • Routine laboratory evaluations.
  • Chest x-ray.
  • Chest CT scan with infusion of contrast material.
  • Biopsy.

Before a patient begins lung cancer treatment, an experienced lung cancer pathologist must review the pathological material. This is critical because SCLC, which responds well to chemotherapy and is generally not treated surgically, can be confused on microscopic examination with NSCLC.[19] Immunohistochemistry and electron microscopy are invaluable techniques for diagnosis and subclassification, but most lung tumors can be classified by light microscopic criteria.

For more information, see the Staging Evaluation section.

Prognosis and Survival

Regardless of stage, the prognosis for patients with SCLC is unsatisfactory despite improvements in diagnosis and therapy during the past 25 years. Without treatment, SCLC has the most aggressive clinical course of any type of pulmonary tumor, with a median survival from diagnosis of only 2 to 4 months. About 10% of people with SCLC remain free of disease during the 2 years from the start of therapy, which is the time period during which most relapses occur. However, even these patients are at risk of dying of lung cancer (both small and non-small cell types).[20] The overall survival rate at 5 years is 5% to 10%.[1,20–22]

An important prognostic factor for SCLC is the extent of disease. Patients with LD have a better prognosis than patients with ED. For patients with LD, the median survival is 16 to 24 months and the 5-year survival rates is 14% with current forms of treatment.[1,21,23,24] Patients diagnosed with LD who smoke should be encouraged to stop smoking before undergoing combined-modality therapy because continued smoking may compromise survival.[25]

Patients with LD have improved long-term survival with combined-modality therapy.[24,26][Level of evidence A1] Although long-term survivors have been reported among patients who received either surgery or chemotherapy alone, chemotherapy combined with thoracic radiation therapy (TRT) is considered the standard of care.[27] Adding TRT increases absolute survival by approximately 5% over chemotherapy alone.[26,28] Multiple trials and meta-analyses have evaluated the optimal timing of TRT relative to chemotherapy, with the weight of evidence suggesting a small benefit to early TRT.[1,29,30][Level of evidence A1]

In patients with ED, the median survival 6 to 12 months with currently available therapy, but long-term disease-free survival is rare.

Prophylactic cranial radiation prevents central nervous system recurrence and can improve survival in patients with good performance status who have had a complete response or a very good partial response to chemoradiation in LD or chemotherapy in ED.[31,32][Level of evidence A1]

Thoracic radiation may also improve long-term outcomes for these patients.[33]

All patients with this type of cancer may appropriately be considered for inclusion in clinical trials at the time of diagnosis. Information about ongoing clinical trials is available from the NCI website.

References
  1. Murray N, Coy P, Pater JL, et al.: Importance of timing for thoracic irradiation in the combined modality treatment of limited-stage small-cell lung cancer. The National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 11 (2): 336-44, 1993. [PUBMED Abstract]
  2. Govindan R, Page N, Morgensztern D, et al.: Changing epidemiology of small-cell lung cancer in the United States over the last 30 years: analysis of the surveillance, epidemiologic, and end results database. J Clin Oncol 24 (28): 4539-44, 2006. [PUBMED Abstract]
  3. American Cancer Society: Cancer Facts and Figures 2025. American Cancer Society, 2025. Available online. Last accessed January 16, 2025.
  4. Alberg AJ, Ford JG, Samet JM, et al.: Epidemiology of lung cancer: ACCP evidence-based clinical practice guidelines (2nd edition). Chest 132 (3 Suppl): 29S-55S, 2007. [PUBMED Abstract]
  5. Tulunay OE, Hecht SS, Carmella SG, et al.: Urinary metabolites of a tobacco-specific lung carcinogen in nonsmoking hospitality workers. Cancer Epidemiol Biomarkers Prev 14 (5): 1283-6, 2005. [PUBMED Abstract]
  6. Anderson KE, Kliris J, Murphy L, et al.: Metabolites of a tobacco-specific lung carcinogen in nonsmoking casino patrons. Cancer Epidemiol Biomarkers Prev 12 (12): 1544-6, 2003. [PUBMED Abstract]
  7. Straif K, Benbrahim-Tallaa L, Baan R, et al.: A review of human carcinogens–part C: metals, arsenic, dusts, and fibres. Lancet Oncol 10 (5): 453-4, 2009. [PUBMED Abstract]
  8. Friedman DL, Whitton J, Leisenring W, et al.: Subsequent neoplasms in 5-year survivors of childhood cancer: the Childhood Cancer Survivor Study. J Natl Cancer Inst 102 (14): 1083-95, 2010. [PUBMED Abstract]
  9. Gray A, Read S, McGale P, et al.: Lung cancer deaths from indoor radon and the cost effectiveness and potential of policies to reduce them. BMJ 338: a3110, 2009. [PUBMED Abstract]
  10. Berrington de González A, Kim KP, Berg CD: Low-dose lung computed tomography screening before age 55: estimates of the mortality reduction required to outweigh the radiation-induced cancer risk. J Med Screen 15 (3): 153-8, 2008. [PUBMED Abstract]
  11. Shimizu Y, Kato H, Schull WJ: Studies of the mortality of A-bomb survivors. 9. Mortality, 1950-1985: Part 2. Cancer mortality based on the recently revised doses (DS86). Radiat Res 121 (2): 120-41, 1990. [PUBMED Abstract]
  12. Katanoda K, Sobue T, Satoh H, et al.: An association between long-term exposure to ambient air pollution and mortality from lung cancer and respiratory diseases in Japan. J Epidemiol 21 (2): 132-43, 2011. [PUBMED Abstract]
  13. Cao J, Yang C, Li J, et al.: Association between long-term exposure to outdoor air pollution and mortality in China: a cohort study. J Hazard Mater 186 (2-3): 1594-600, 2011. [PUBMED Abstract]
  14. Hales S, Blakely T, Woodward A: Air pollution and mortality in New Zealand: cohort study. J Epidemiol Community Health 66 (5): 468-73, 2012. [PUBMED Abstract]
  15. Lissowska J, Foretova L, Dabek J, et al.: Family history and lung cancer risk: international multicentre case-control study in Eastern and Central Europe and meta-analyses. Cancer Causes Control 21 (7): 1091-104, 2010. [PUBMED Abstract]
  16. Shiels MS, Cole SR, Kirk GD, et al.: A meta-analysis of the incidence of non-AIDS cancers in HIV-infected individuals. J Acquir Immune Defic Syndr 52 (5): 611-22, 2009. [PUBMED Abstract]
  17. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. N Engl J Med 330 (15): 1029-35, 1994. [PUBMED Abstract]
  18. Omenn GS, Goodman GE, Thornquist MD, et al.: Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med 334 (18): 1150-5, 1996. [PUBMED Abstract]
  19. Travis WD, Colby TV, Corrin B, et al.: Histological typing of lung and pleural tumours. 3rd ed. Springer-Verlag, 1999.
  20. Johnson BE, Grayson J, Makuch RW, et al.: Ten-year survival of patients with small-cell lung cancer treated with combination chemotherapy with or without irradiation. J Clin Oncol 8 (3): 396-401, 1990. [PUBMED Abstract]
  21. Fry WA, Menck HR, Winchester DP: The National Cancer Data Base report on lung cancer. Cancer 77 (9): 1947-55, 1996. [PUBMED Abstract]
  22. Lassen U, Osterlind K, Hansen M, et al.: Long-term survival in small-cell lung cancer: posttreatment characteristics in patients surviving 5 to 18+ years–an analysis of 1,714 consecutive patients. J Clin Oncol 13 (5): 1215-20, 1995. [PUBMED Abstract]
  23. Turrisi AT, Kim K, Blum R, et al.: Twice-daily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide. N Engl J Med 340 (4): 265-71, 1999. [PUBMED Abstract]
  24. Jänne PA, Freidlin B, Saxman S, et al.: Twenty-five years of clinical research for patients with limited-stage small cell lung carcinoma in North America. Cancer 95 (7): 1528-38, 2002. [PUBMED Abstract]
  25. Videtic GM, Stitt LW, Dar AR, et al.: Continued cigarette smoking by patients receiving concurrent chemoradiotherapy for limited-stage small-cell lung cancer is associated with decreased survival. J Clin Oncol 21 (8): 1544-9, 2003. [PUBMED Abstract]
  26. Pignon JP, Arriagada R, Ihde DC, et al.: A meta-analysis of thoracic radiotherapy for small-cell lung cancer. N Engl J Med 327 (23): 1618-24, 1992. [PUBMED Abstract]
  27. Chandra V, Allen MS, Nichols FC, et al.: The role of pulmonary resection in small cell lung cancer. Mayo Clin Proc 81 (5): 619-24, 2006. [PUBMED Abstract]
  28. Warde P, Payne D: Does thoracic irradiation improve survival and local control in limited-stage small-cell carcinoma of the lung? A meta-analysis. J Clin Oncol 10 (6): 890-5, 1992. [PUBMED Abstract]
  29. Perry MC, Eaton WL, Propert KJ, et al.: Chemotherapy with or without radiation therapy in limited small-cell carcinoma of the lung. N Engl J Med 316 (15): 912-8, 1987. [PUBMED Abstract]
  30. Takada M, Fukuoka M, Kawahara M, et al.: Phase III study of concurrent versus sequential thoracic radiotherapy in combination with cisplatin and etoposide for limited-stage small-cell lung cancer: results of the Japan Clinical Oncology Group Study 9104. J Clin Oncol 20 (14): 3054-60, 2002. [PUBMED Abstract]
  31. Aupérin A, Arriagada R, Pignon JP, et al.: Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. Prophylactic Cranial Irradiation Overview Collaborative Group. N Engl J Med 341 (7): 476-84, 1999. [PUBMED Abstract]
  32. Slotman B, Faivre-Finn C, Kramer G, et al.: Prophylactic cranial irradiation in extensive small-cell lung cancer. N Engl J Med 357 (7): 664-72, 2007. [PUBMED Abstract]
  33. Slotman BJ, van Tinteren H, Praag JO, et al.: Use of thoracic radiotherapy for extensive stage small-cell lung cancer: a phase 3 randomised controlled trial. Lancet 385 (9962): 36-42, 2015. [PUBMED Abstract]

Cellular Classification of SCLC

Before initiating treatment for a patient with small cell lung cancer (SCLC), an experienced lung cancer pathologist should review the pathological material.

Pathological Classification

The current classification of subtypes of SCLC includes:[1]

  • Small cell carcinoma.
  • Combined small cell carcinoma (i.e., SCLC combined with additional components from any of the non-small cell lung carcinoma histological types).

SCLC arising from neuroendocrine cells forms one extreme of the spectrum of neuroendocrine carcinomas of the lung.

Neuroendocrine tumors include:

  • Low-grade typical carcinoid.
  • Intermediate-grade atypical carcinoid.
  • High-grade neuroendocrine tumors, including large-cell neuroendocrine carcinoma (LCNEC) and SCLC.

Because of differences in clinical behavior, therapy, and epidemiology, these tumors are classified separately in the World Health Organization (WHO) revised classification. The variant form of SCLC called mixed small cell/large cell carcinoma was not retained in the revised WHO classification. Instead, SCLC is now divided into SCLC and combined SCLC.[2] No minimum percentage of the additional component is required for a combined SCLC diagnosis with the exception of mixed LCNEC and SCLC, in which a 10% minimum LCNEC component is required.[3]

SCLC presents as a proliferation of small cells with the following morphological features:[4]

  • Scant cytoplasm.
  • Ill-defined borders.
  • Finely granular salt and pepper chromatin.
  • Absent or inconspicuous nucleoli.
  • Frequent nuclear molding.
  • A high mitotic count.

Nearly all SCLC are immunoreactive for keratin, thyroid transcription factor 1, and epithelial membrane antigen. Neuroendocrine and neural differentiation result in the expression of dopa decarboxylase, calcitonin, neuron-specific enolase, chromogranin A, CD56 (also known as nucleosomal histone kinase 1 or neural-cell adhesion molecule), gastrin-releasing peptide, and insulin-like growth factor 1. One or more markers of neuroendocrine differentiation can be found in approximately 75% of SCLC.[5]

Although preinvasive and in situ malignant changes are frequently found in patients with non-small cell lung cancer, these findings are rare in patients with SCLC.[6]

References
  1. Travis WD, Colby TV, Corrin B, et al.: Histological typing of lung and pleural tumours. 3rd ed. Springer-Verlag, 1999.
  2. Lei Y, Feng H, Qiang H, et al.: Clinical characteristics and prognostic factors of surgically resected combined small cell lung cancer: a retrospective study. Lung Cancer 146: 244-251, 2020. [PUBMED Abstract]
  3. Simbolo M, Centonze G, Ali G, et al.: Integrative molecular analysis of combined small-cell lung carcinomas identifies major subtypes with different therapeutic opportunities. ESMO Open 7 (1): 100308, 2022. [PUBMED Abstract]
  4. Brambilla E, Travis WD, Colby TV, et al.: The new World Health Organization classification of lung tumours. Eur Respir J 18 (6): 1059-68, 2001. [PUBMED Abstract]
  5. Guinee DG, Fishback NF, Koss MN, et al.: The spectrum of immunohistochemical staining of small-cell lung carcinoma in specimens from transbronchial and open-lung biopsies. Am J Clin Pathol 102 (4): 406-14, 1994. [PUBMED Abstract]
  6. Kumar V, Abbas A, Fausto N, eds.: Robins and Cotran Pathologic Basis of Disease. 7th ed. Elsevier Inc, 2005.

Stage Information for SCLC

Staging Systems

Several staging systems have been proposed for small cell lung cancer (SCLC).

  • American Joint Committee on Cancer (AJCC) Tumor, Node, and Metastasis (TNM).[1] The 8th edition of the AJCC Cancer Staging Manual recommends the use of the TNM to classify SCLC. For more information, see the AJCC Stage Groupings and TNM Definitions section in Non-Small Cell Lung Cancer Treatment.
  • Veterans Administration Lung Study Group (VALG).[2]
  • International Association for the Study of Lung Cancer (IASLC).[3]

Limited-Stage Disease

No universally accepted definition of this term is available. Limited-stage disease (LD) SCLC is confined to the hemithorax of origin, mediastinum, or supraclavicular nodes, which can be encompassed within a tolerable radiation therapy port.

Patients with pleural effusion, massive pulmonary tumor, and contralateral supraclavicular nodes have been both included in and excluded from LD by various groups.

Extensive-Stage Disease

Extensive-stage disease (ED) SCLC has spread beyond the supraclavicular areas and is too widespread to be included within the definition of LD. Patients with distant metastases (M1) are always considered to have ED.[3,4]

IASLC-AJCC TNM Staging System

The AJCC TNM defines LD as any T, except for T3–4, due to multiple lung nodules that do not fit in a tolerable radiation field, any N, and M0.[1] This corresponds to TNM stages I to IIIB. Extensive disease is TNM stage IV with distant metastases (M1), including malignant pleural effusions.[3,4] For more information, see the AJCC Stage Groupings and TNM Definitions section in Non-Small Cell Lung Cancer Treatment.

The IASLC conducted an analysis of clinical TNM staging for SCLC using the sixth edition of the AJCC TNM staging system for lung cancer. Survival rates for patients with clinical stages I and II disease are significantly different from those for patients with stage III disease with N2 or N3 involvement.[3] Patients with pleural effusion have an intermediate prognosis between LD and ED with hematogenous metastases and will be classified as having M1 disease (or ED). Application of the TNM system will not change how patients are managed; however, the analysis suggests that, in the context of clinical trials in LD, accurate TNM staging and stratification may be important.[3]

Staging Evaluation

Staging procedures for SCLC are important to distinguish patients with disease limited to their thorax from those with distant metastases. At the time of initial diagnosis, approximately two-thirds of patients with SCLC have clinical evidence of metastases; most of the remaining patients have clinical evidence of extensive nodal involvement in the hilar, mediastinal, and sometimes supraclavicular regions.

Determining the stage of cancer allows an assessment of prognosis and a determination of treatment, particularly when chest radiation therapy or surgical excision is added to chemotherapy for patients with LD. If ED is confirmed, further evaluation should be individualized according to the signs and symptoms unique to the individual patient. Standard staging procedures include:

  • A thorough physical examination.
  • Routine blood counts and serum chemistries.
  • Chest and upper abdominal computed tomography (CT) scanning.
  • A radionuclide bone scan.
  • A brain magnetic resonance imaging scan or CT scan.
  • Bone marrow aspirate or biopsy in selected patients in which treatment would change based on the results.

The role of positron emission tomography (PET) is still under study. SCLC is fluorine F 18-fludeoxyglucose (18F-FDG) avid at the primary site and at metastatic sites. PET may be used in staging patients with SCLC who are potential candidates for the addition of thoracic radiation therapy to chemotherapy, as PET may lead to upstaging or downstaging of patients and to alteration of radiation fields resulting from the identification of additional sites of nodal metastases.

Evidence (18F-FDG PET):

  1. In a study of 120 patients with LD SCLC or ED SCLC, FDG-PET led to restaging of ten patients to a higher stage and three patients to a lower stage.[5] FDG-PET was more sensitive and specific than CT scans for nonbrain distant metastases.
  2. In a small series of 24 patients with LD by conventional staging, two patients were restaged to ED.[2] Unsuspected nodal metastases were documented in 25% of patients, which altered the radiation plan in these patients. At this time, sensitivity, specificity, and positive- or negative-predictive value of PET scanning and its enhancement of staging accuracy are uncertain.
References
  1. Lung. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. Springer; 2017, pp. 431–56.
  2. Bradley JD, Dehdashti F, Mintun MA, et al.: Positron emission tomography in limited-stage small-cell lung cancer: a prospective study. J Clin Oncol 22 (16): 3248-54, 2004. [PUBMED Abstract]
  3. Shepherd FA, Crowley J, Van Houtte P, et al.: The International Association for the Study of Lung Cancer lung cancer staging project: proposals regarding the clinical staging of small cell lung cancer in the forthcoming (seventh) edition of the tumor, node, metastasis classification for lung cancer. J Thorac Oncol 2 (12): 1067-77, 2007. [PUBMED Abstract]
  4. Ihde D, Souhami B, Comis R, et al.: Small cell lung cancer. Lung Cancer 17 (Suppl 1): S19-21, 1997. [PUBMED Abstract]
  5. Brink I, Schumacher T, Mix M, et al.: Impact of [18F]FDG-PET on the primary staging of small-cell lung cancer. Eur J Nucl Med Mol Imaging 31 (12): 1614-20, 2004. [PUBMED Abstract]

Treatment Option Overview for SCLC

Chemotherapy and radiation therapy have been shown to improve survival for patients with small cell lung cancer (SCLC).

Chemotherapy

Chemotherapy improves the survival of patients with limited-stage disease (LD) or extensive-stage disease (ED), but it is curative in only a few patients.[1,2] Because patients with SCLC tend to develop distant metastases, localized forms of treatment, such as surgical resection or radiation therapy, rarely produce long-term survival.[3] Incorporating current chemotherapy regimens into the treatment program prolongs survival, with at least a fourfold to fivefold improvement in median survival compared with patients who are given no therapy.

The combination of platinum and etoposide is the most widely used standard chemotherapeutic regimen.[4–6][Level of evidence A1] No consistent survival benefit has resulted from platinum versus nonplatinum combinations, increased dose intensity or dose density, altered mode of administration (e.g., alternating or sequential administration) of various chemotherapeutic agents, or maintenance chemotherapy.[7–12][Level of evidence A1]

Radiation Therapy

SCLC is highly radiosensitive and thoracic radiation therapy improves survival of patients with LD and ED tumors.[13–16][Level of evidence A1] Prophylactic cranial irradiation prevents central nervous system recurrence and may improve the long-term survival of patients with good performance status who have responded to chemoradiation therapy.[17–19][Level of evidence A1] This type of irradiation also offers palliation of symptomatic metastatic disease.

Treatment options for patients with LD, ED, or recurrent SCLC are summarized in Table 1.

Table 1. Treatment Options for Patients With SCLC
Stage Treatment Options
ED = extensive-stage disease; LD = limited-stage disease.
LD Chemotherapy and radiation therapy
Adjuvant treatment after chemoradiation therapy
Combination chemotherapy alone
Surgery followed by chemotherapy or chemoradiation therapy
Prophylactic cranial irradiation
Clinical trials evaluating new drug regimens, surgical resection of the primary tumor, or new radiation therapy schedules and techniques (e.g., timing, three-dimensional treatment planning, and dose fractionation)
ED Immune checkpoint modulation and combination chemotherapy
Combination chemotherapy
Radiation therapy
Clinical trials evaluating new drug regimens or alternative drug doses and schedules
Recurrent disease Chemotherapy
Immunotherapy
Immune checkpoint modulation
Palliative therapy
Phase I and II clinical trials evaluating new drugs

Despite treatment advances, most patients with SCLC die of their tumor even with the best available therapy. Most of the improvements in survival of patients with SCLC are attributable to clinical trials that have attempted to improve on the best available and most accepted therapy. Patient entry into such studies is highly desirable.

Information about ongoing clinical trials is available from the NCI website.

References
  1. Comis RL, Friedland DM, Good BC: Small-cell lung cancer: a perspective on the past and a preview of the future. Oncology (Huntingt) 12 (1 Suppl 2): 44-50, 1998. [PUBMED Abstract]
  2. Agra Y, Pelayo M, Sacristan M, et al.: Chemotherapy versus best supportive care for extensive small cell lung cancer. Cochrane Database Syst Rev (4): CD001990, 2003. [PUBMED Abstract]
  3. Prasad US, Naylor AR, Walker WS, et al.: Long term survival after pulmonary resection for small cell carcinoma of the lung. Thorax 44 (10): 784-7, 1989. [PUBMED Abstract]
  4. Johnson BE, Grayson J, Makuch RW, et al.: Ten-year survival of patients with small-cell lung cancer treated with combination chemotherapy with or without irradiation. J Clin Oncol 8 (3): 396-401, 1990. [PUBMED Abstract]
  5. Lassen U, Osterlind K, Hansen M, et al.: Long-term survival in small-cell lung cancer: posttreatment characteristics in patients surviving 5 to 18+ years–an analysis of 1,714 consecutive patients. J Clin Oncol 13 (5): 1215-20, 1995. [PUBMED Abstract]
  6. Fry WA, Menck HR, Winchester DP: The National Cancer Data Base report on lung cancer. Cancer 77 (9): 1947-55, 1996. [PUBMED Abstract]
  7. Ihde DC, Mulshine JL, Kramer BS, et al.: Prospective randomized comparison of high-dose and standard-dose etoposide and cisplatin chemotherapy in patients with extensive-stage small-cell lung cancer. J Clin Oncol 12 (10): 2022-34, 1994. [PUBMED Abstract]
  8. Arriagada R, Le Chevalier T, Pignon JP, et al.: Initial chemotherapeutic doses and survival in patients with limited small-cell lung cancer. N Engl J Med 329 (25): 1848-52, 1993. [PUBMED Abstract]
  9. Klasa RJ, Murray N, Coldman AJ: Dose-intensity meta-analysis of chemotherapy regimens in small-cell carcinoma of the lung. J Clin Oncol 9 (3): 499-508, 1991. [PUBMED Abstract]
  10. Elias AD, Ayash L, Frei E, et al.: Intensive combined modality therapy for limited-stage small-cell lung cancer. J Natl Cancer Inst 85 (7): 559-66, 1993. [PUBMED Abstract]
  11. Murray N, Livingston RB, Shepherd FA, et al.: Randomized study of CODE versus alternating CAV/EP for extensive-stage small-cell lung cancer: an Intergroup Study of the National Cancer Institute of Canada Clinical Trials Group and the Southwest Oncology Group. J Clin Oncol 17 (8): 2300-8, 1999. [PUBMED Abstract]
  12. Amarasena IU, Walters JA, Wood-Baker R, et al.: Platinum versus non-platinum chemotherapy regimens for small cell lung cancer. Cochrane Database Syst Rev (4): CD006849, 2008. [PUBMED Abstract]
  13. Pignon JP, Arriagada R, Ihde DC, et al.: A meta-analysis of thoracic radiotherapy for small-cell lung cancer. N Engl J Med 327 (23): 1618-24, 1992. [PUBMED Abstract]
  14. Warde P, Payne D: Does thoracic irradiation improve survival and local control in limited-stage small-cell carcinoma of the lung? A meta-analysis. J Clin Oncol 10 (6): 890-5, 1992. [PUBMED Abstract]
  15. Murray N, Coy P, Pater JL, et al.: Importance of timing for thoracic irradiation in the combined modality treatment of limited-stage small-cell lung cancer. The National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 11 (2): 336-44, 1993. [PUBMED Abstract]
  16. Slotman BJ, van Tinteren H, Praag JO, et al.: Use of thoracic radiotherapy for extensive stage small-cell lung cancer: a phase 3 randomised controlled trial. Lancet 385 (9962): 36-42, 2015. [PUBMED Abstract]
  17. Turrisi AT, Glover DJ: Thoracic radiotherapy variables: influence on local control in small cell lung cancer limited disease. Int J Radiat Oncol Biol Phys 19 (6): 1473-9, 1990. [PUBMED Abstract]
  18. Aupérin A, Arriagada R, Pignon JP, et al.: Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. Prophylactic Cranial Irradiation Overview Collaborative Group. N Engl J Med 341 (7): 476-84, 1999. [PUBMED Abstract]
  19. Slotman B, Faivre-Finn C, Kramer G, et al.: Prophylactic cranial irradiation in extensive small-cell lung cancer. N Engl J Med 357 (7): 664-72, 2007. [PUBMED Abstract]

Treatment of Limited-Stage SCLC

Treatment Options for Patients With Limited-Stage SCLC

Treatment options for patients with limited-stage small cell lung cancer (SCLC) include:

  1. Chemotherapy and radiation therapy.
  2. Adjuvant treatment after chemoradiation therapy.
  3. Combination chemotherapy alone.
  4. Surgery followed by chemotherapy or chemoradiation therapy.
  5. Prophylactic cranial irradiation (PCI).
  6. Clinical trials evaluating new drug regimens, surgical resection of the primary tumor, or new radiation therapy schedules and techniques (e.g., timing, three-dimensional treatment planning, and dose fractionation).

Chemotherapy and radiation therapy

Combined-modality treatment with etoposide and cisplatin with thoracic radiation therapy (TRT) is the most widely used treatment for patients with limited-stage disease (LD) SCLC.

Evidence (combined-modality treatment):

  1. Survival. The following results have been reported in clinical trials:
    1. Mature results of prospective randomized trials suggest that combined-modality therapy produces a modest but significant improvement in survival of 5% at 3 years compared with chemotherapy alone.[1–3][Level of evidence A1]
    2. Clinical trials have consistently achieved median survivals of 18 to 24 months and 2-year survival rates of 40% to 50%, with a treatment-related mortality rate of less than 3%.[3–7][Level of evidence A1]
    3. No consistent survival benefit has resulted from the following treatment approaches:[8–16]
      • Increased dose intensity.
      • Increased dose density.
      • Administration of additional drugs or other (non–etoposide-containing) platinum-based combination regimens.
      • Altered modes of administration of various chemotherapeutic agents.
      • Maintenance chemotherapy.
  2. Length of treatment. The optimal duration of chemotherapy for patients with LD SCLC is not clearly defined, but no improvement exists in survival after the duration of drug administration exceeds 3 to 6 months. The preponderance of evidence available from randomized trials indicates that maintenance chemotherapy does not prolong survival for patients with LD SCLC.[8–15][Level of evidence A1]
  3. Dose and timing. The optimal dose and timing of TRT remain controversial.
    1. Multiple clinical trials and meta-analyses addressing the timing of TRT have been published, with the weight of evidence suggesting a small benefit to early TRT (i.e., TRT administered during the first or second cycle of chemotherapy administration).[3–6,8,9,15,17–20][Level of evidence A1]
    2. The amount of time from start to completion of TRT in LD SCLC may also affect overall survival (OS). In an analysis of four trials, the completion of therapy in less than 30 days was associated with an improved 5-year survival rate (relative risk, 0.62; 95% confidence interval [CI], 0.49–0.80; P = .0003).[20][Level of evidence A1]
    3. Both once-daily and twice-daily chest radiation schedules have been used in regimens with etoposide and cisplatin.
      • One randomized study showed a modest survival advantage in favor of twice-daily radiation therapy given for 3 weeks, compared with once-daily radiation therapy to 45 Gy given for 5 weeks (26% vs. 16% at 5 years; P = .04).[17][Level of evidence A1] Esophagitis was increased with twice-daily treatment.
      • The phase III CONVERT study (NCT00433563) randomly assigned patients to receive either 45 Gy radiation therapy in 30 twice-daily fractions of 1.5 Gy over 19 days or 66 Gy in 33 once-daily fractions of 2 Gy over 45 days, starting on day 22 after commencing cisplatin-etoposide chemotherapy (given as four to six cycles every 3 weeks in both groups).[21] The primary end point was OS, defined as time from randomization until death from any cause, analyzed by modified intention-to-treat. A 12% higher OS at 2 years in the once-daily group versus the twice-daily group was considered clinically significant to show superiority of the once-daily regimen.
        • At a median follow-up of 45 months (interquartile range [IQR], 35–58), median OS was 30 months (95% CI, 24–34) in the twice-daily group versus 25 months (95% CI, 21–31) in the once-daily group (hazard ratio for death in the once-daily group, 1.18 [95% CI, 0.95–1.45]; P = .14).
        • The two-year OS rate was 56% (95% CI, 50%–62%) in the twice-daily group and 51% (45%–57%) in the once-daily group (absolute difference between the treatment groups, 5.3% [95% CI, -3.2% to 13.7%]).
        • Most toxicities were similar between the groups, except there was significantly more grade 4 neutropenia with twice-daily radiation therapy (129 [49%] vs. 101 [38%]; P = .05). In contrast to the earlier study, there was no difference between the groups in terms of rates of grade 3 to 4 esophagitis or pneumonitis.
      • Twice-daily radiation therapy has not been broadly adopted. Once-daily fractions to doses higher than 60 Gy are feasible and commonly used; their clinical benefits are yet to be defined in phase III trials.[21][Level of evidence A1]

Adjuvant treatment after chemoradiation therapy

Evidence (adjuvant treatment after chemoradiation therapy):

  1. ADRIATIC (NCT03703297) was a phase III, randomized, double-blind, placebo-controlled, multicenter, global study, published in abstract form, that assessed durvalumab with or without tremelimumab as consolidation treatment for patients with LD SCLC. Patients had stage I to III disease (inoperable if stage I or II) that had not progressed after chemoradiation therapy. PCI was permitted before randomization. Patients were randomly assigned 1 to 42 days after concurrent chemoradiation therapy to receive durvalumab (1,500 mg) plus placebo, durvalumab (1,500 mg) plus tremelimumab (75 mg), or placebo plus placebo every 4 weeks for four cycles, followed by durvalumab or placebo every 4 weeks until investigator-determined progression or intolerable toxicity, or for a maximum of 24 months. The dual primary end points were OS and progression-free survival (PFS) per blinded independent central review for durvalumab versus placebo. The trial randomly assigned 730 patients, including 264 to receive durvalumab and 266 to receive placebo. The abstract was published after the first planned interim analysis of durvalumab versus placebo.[22]
    • The median duration of follow-up was 37.2 months for OS and 27.6 months for PFS.[22][Level of evidence A1]
    • The median OS was 55.9 months in the durvalumab arm (95% CI, 37.3–not estimable) and 33.4 months in the placebo arm (95% CI, 25.5–39.9). The 24-month OS rate was 68.0% in the durvalumab arm and 58.5% in the placebo arm. The 36-month OS rate was 56.5% in the durvalumab arm and 47.6% in the placebo arm.
    • The median PFS was 16.6 months in the durvalumab arm (95% CI, 10.2–28.2) and 9.2 months (95% CI, 7.4–12.9) in the placebo arm. The 18-month PFS rate was 48.8% in the durvalumab arm and 36.1% in the placebo arm. The 24-month PFS rate was 46.2% in the durvalumab arm and 34.2% in the placebo arm.
    • Grade 3 or 4 all-cause adverse events occurred in 24.3% of patients in the durvalumab arm and 24.2% of patients in the placebo arm. Adverse events led to treatment discontinuation in 16.3% of patients in the durvalumab arm and 10.6% of patients in the placebo arm, and to death in 2.7% of patients in the durvalumab arm and 1.9% of patients in the placebo arm. Any-grade pneumonitis/radiation pneumonitis was reported in 38.0% of patients who received durvalumab and 30.2% of patients who received the placebo.

    This is the first new treatment option for patients with LD SCLC in over 35 years.

Combination chemotherapy alone

Patients with a contraindication to radiation therapy may receive chemotherapy alone. Patients presenting with superior vena cava syndrome are treated immediately with combination chemotherapy, radiation therapy, or both, depending on the severity of presentation.[23,24] For more information, see Cardiopulmonary Syndromes.

Surgery followed by chemotherapy or chemoradiation therapy

The role of surgery in the management of patients with SCLC is unproven. Small case series and population studies have reported favorable outcomes for the minority of LD patients with very limited disease, with small tumors pathologically confined to the lung of origin or the lung and ipsilateral hilar lymph nodes from surgical resection with adjuvant chemotherapy.[25–29][Level of evidence C2] Patients who have undergone surgery and then been diagnosed with SCLC generally receive adjuvant chemotherapy with or without radiation therapy. In patients who receive chemotherapy with radiation therapy, there is no improvement in survival with the addition of surgery.[29][Level of evidence C2] Given the absence of data from randomized trials, the potential benefits and risks of surgery in the management of individual patients with SCLC must be considered.

Evidence (role of surgery):

  1. A randomized study evaluated the role of surgery in addition to chemoradiation therapy for 328 patients with LD SCLC. The study found no OS benefit with the addition of pulmonary resection.[30][Level of evidence A1]

PCI

Patients who have achieved a complete remission may receive PCI. Patients whose cancer can be controlled outside the brain have a 60% actuarial risk of developing central nervous system (CNS) metastases within 2 to 3 years after starting treatment.[29,31,32] Most of these patients have disease that relapses only in the brain, and nearly all of those with CNS relapse die of their cranial metastases. The risk of developing CNS metastases can be reduced by more than 50% with the administration of PCI.[31]

Evidence (role of PCI):

  1. A meta-analysis of seven randomized trials evaluated the value of PCI for patients in complete remission. The addition of PCI improved the rates of brain recurrence, disease-free survival, and OS. The 3-year OS rate increased from 15% to 21% with PCI.[31][Level of evidence A1]
  2. The randomized RTOG-0212 study (NCT00005062) included 720 patients with LD SCLC in complete remission after chemoradiation therapy. The trial demonstrated that standard-dose PCI (25 Gy in 10 fractions) was as effective as, and less toxic than, higher doses of brain radiation.[33]
  3. Randomized trials such as RTOG-0212 (NCT00005062) showed that doses higher than 25 Gy in 10 daily fractions do not improve long-term survival.[33–35]

Neurological sequelae

Retrospective studies have shown that long-term survivors of SCLC (>2 years from the start of treatment) have a high incidence of CNS impairment.[29,32,36–38] Prospective studies have shown that patients treated with PCI do not have significantly worse neuropsychological function than patients not treated with PCI.[38] Most patients with SCLC have neuropsychological abnormalities before the start of PCI and have no detectable neurological decline for as long as 2 years after the start of PCI.[38] Patients treated for SCLC continue to have declining neuropsychological function after 2 years from the start of treatment.[36–38] Additional neuropsychological testing of patients beyond 2 years from the start of treatment is needed before concluding that PCI does not contribute to the decline in intellectual function.

Treatment options for older patients

The optimal therapeutic approach in older patients remains unclear. A population analysis showed that increasing age was associated with decreased performance status and increased comorbidity.[39] Older patients were less likely to be treated with combined chemoradiation therapy, more intensive chemotherapy, and PCI. Older patients were also less likely to respond to therapy and had poorer survival outcomes. Whether these findings were a result of age and its associated comorbidities or suboptimal treatment delivery remains uncertain.

No specific phase III trial in older patients with LD SCLC has been reported. However, three secondary analyses of two cooperative group trials evaluating outcomes in patients aged 70 years or older have been published.[40–42] The survival outcomes for the older patients were identical to those of their younger counterparts in both trials. The older patients experienced more toxic effects, particularly hematological, compared with younger patients. There was a significant increase in treatment-related mortality in the EST-3588 trial that compared etoposide and cisplatin with either once-daily or twice-daily radiation therapy (1% for patients aged <70 years vs. 10% for patients aged ≥70 years; P = .01).[41] Because the older patients enrolled in these phase III trials may not be representative of LD SCLC patients in the general population, caution must be exercised in extrapolating these results to the general population of older patients.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References
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  16. Kubota K, Hida T, Ishikura S, et al.: Etoposide and cisplatin versus irinotecan and cisplatin in patients with limited-stage small-cell lung cancer treated with etoposide and cisplatin plus concurrent accelerated hyperfractionated thoracic radiotherapy (JCOG0202): a randomised phase 3 study. Lancet Oncol 15 (1): 106-13, 2014. [PUBMED Abstract]
  17. Turrisi AT, Kim K, Blum R, et al.: Twice-daily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide. N Engl J Med 340 (4): 265-71, 1999. [PUBMED Abstract]
  18. Huncharek M, McGarry R: A meta-analysis of the timing of chest irradiation in the combined modality treatment of limited-stage small cell lung cancer. Oncologist 9 (6): 665-72, 2004. [PUBMED Abstract]
  19. Pijls-Johannesma MC, De Ruysscher D, Lambin P, et al.: Early versus late chest radiotherapy for limited stage small cell lung cancer. Cochrane Database Syst Rev (1): CD004700, 2005. [PUBMED Abstract]
  20. De Ruysscher D, Pijls-Johannesma M, Bentzen SM, et al.: Time between the first day of chemotherapy and the last day of chest radiation is the most important predictor of survival in limited-disease small-cell lung cancer. J Clin Oncol 24 (7): 1057-63, 2006. [PUBMED Abstract]
  21. Faivre-Finn C, Snee M, Ashcroft L, et al.: Concurrent once-daily versus twice-daily chemoradiotherapy in patients with limited-stage small-cell lung cancer (CONVERT): an open-label, phase 3, randomised, superiority trial. Lancet Oncol 18 (8): 1116-1125, 2017. [PUBMED Abstract]
  22. Spigel DR, Cheng Y, Cho BC, et al.: ADRIATIC: Durvalumab (D) as consolidation treatment (tx) for patients (pts) with limited-stage small-cell lung cancer (LS-SCLC). [Abstract] J Clin Oncol 42 (Suppl 17): A-LBA5, 2024.
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  24. Würschmidt F, Bünemann H, Heilmann HP: Small cell lung cancer with and without superior vena cava syndrome: a multivariate analysis of prognostic factors in 408 cases. Int J Radiat Oncol Biol Phys 33 (1): 77-82, 1995. [PUBMED Abstract]
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  26. Shepherd FA, Ginsberg RJ, Patterson GA, et al.: A prospective study of adjuvant surgical resection after chemotherapy for limited small cell lung cancer. A University of Toronto Lung Oncology Group study. J Thorac Cardiovasc Surg 97 (2): 177-86, 1989. [PUBMED Abstract]
  27. Prasad US, Naylor AR, Walker WS, et al.: Long term survival after pulmonary resection for small cell carcinoma of the lung. Thorax 44 (10): 784-7, 1989. [PUBMED Abstract]
  28. Smit EF, Groen HJ, Timens W, et al.: Surgical resection for small cell carcinoma of the lung: a retrospective study. Thorax 49 (1): 20-2, 1994. [PUBMED Abstract]
  29. Chandra V, Allen MS, Nichols FC, et al.: The role of pulmonary resection in small cell lung cancer. Mayo Clin Proc 81 (5): 619-24, 2006. [PUBMED Abstract]
  30. Lad T, Piantadosi S, Thomas P, et al.: A prospective randomized trial to determine the benefit of surgical resection of residual disease following response of small cell lung cancer to combination chemotherapy. Chest 106 (6 Suppl): 320S-323S, 1994. [PUBMED Abstract]
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  32. Aupérin A, Arriagada R, Pignon JP, et al.: Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. Prophylactic Cranial Irradiation Overview Collaborative Group. N Engl J Med 341 (7): 476-84, 1999. [PUBMED Abstract]
  33. Le Péchoux C, Dunant A, Senan S, et al.: Standard-dose versus higher-dose prophylactic cranial irradiation (PCI) in patients with limited-stage small-cell lung cancer in complete remission after chemotherapy and thoracic radiotherapy (PCI 99-01, EORTC 22003-08004, RTOG 0212, and IFCT 99-01): a randomised clinical trial. Lancet Oncol 10 (5): 467-74, 2009. [PUBMED Abstract]
  34. Le Péchoux C, Laplanche A, Faivre-Finn C, et al.: Clinical neurological outcome and quality of life among patients with limited small-cell cancer treated with two different doses of prophylactic cranial irradiation in the intergroup phase III trial (PCI99-01, EORTC 22003-08004, RTOG 0212 and IFCT 99-01). Ann Oncol 22 (5): 1154-63, 2011. [PUBMED Abstract]
  35. Wolfson AH, Bae K, Komaki R, et al.: Primary analysis of a phase II randomized trial Radiation Therapy Oncology Group (RTOG) 0212: impact of different total doses and schedules of prophylactic cranial irradiation on chronic neurotoxicity and quality of life for patients with limited-disease small-cell lung cancer. Int J Radiat Oncol Biol Phys 81 (1): 77-84, 2011. [PUBMED Abstract]
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Treatment of Extensive-Stage SCLC

Treatment Options for Patients With Extensive-Stage SCLC

Treatment options for patients with extensive-stage disease (ED) small cell lung cancer (SCLC) include:

  1. Immune checkpoint modulation and combination chemotherapy.
  2. Combination chemotherapy.
  3. Radiation therapy.
  4. Clinical trials evaluating new drug regimens or alternative drug doses and schedules.

Immune checkpoint modulation and combination chemotherapy

Studies have evaluated the role of immune checkpoint inhibitors (programmed cell death-1 [PD-1] or programmed death-ligand 1 [PD-L1] inhibitors) in frontline treatment of patients with ED SCLC. Two PD-L1 inhibitors, atezolizumab and durvalumab, prolonged overall survival (OS) when combined with platinum and etoposide, compared with the same combination chemotherapy regimen alone. For more information, see the Combination chemotherapy section. Treatment with a PD-1 inhibitor, pembrolizumab, in combination with chemotherapy, did not meet statistical significance for the prespecified end point of OS in the KEYNOTE-604 (NCT03066778) phase III trial.[1][Level of evidence B1]

Evidence (immune checkpoint modulation and combination chemotherapy):

  1. Atezolizumab. IMpower133 (NCT02763579), a double-blind, placebo-controlled, randomized, phase III trial, compared four cycles of carboplatin and etoposide with either atezolizumab (n = 201) or placebo (n = 202), followed by maintenance with either atezolizumab or placebo (as per the original randomization) until unacceptable toxic effects, disease progression, or no additional benefit.[2]
    • At the planned interim analysis for OS, with a median follow-up of 22.9 months, the median OS was 12.3 months in the atezolizumab group and 10.3 months in the placebo group (hazard ratio [HR] for death, 0.76; 95% confidence interval [CI], 0.60−0.95; descriptive P = .0154).[2][Level of evidence A1]
    • The median progression-free survival (PFS) was 5.2 months for the atezolizumab group and 4.3 months for the placebo group (HR for disease progression or death, 0.77; 95% CI, 0.63−0.95; P = .02).
    • The toxicity event rate was similar for both arms, consistent with known adverse events of the individual agents. Grade 3 or 4 adverse events occurred in 56.6% of patients in the atezolizumab group and 56.1% of patients in the placebo group.
  2. Durvalumab. CASPIAN (NCT03043872) was a randomized, open-label, phase III trial that assigned patients to durvalumab plus platinum-etoposide (n = 268), durvalumab plus tremelimumab (a cytotoxic T lymphocyte antigen-4 [CTLA-4] inhibitor) plus platinum-etoposide (n = 268), or platinum-etoposide alone (n = 269). In the immunotherapy arms, patients received four cycles of platinum-etoposide plus durvalumab with or without tremelimumab, followed by durvalumab maintenance until intolerance or disease progression or until other discontinuation criteria were met. In the chemotherapy-alone arm, up to six cycles of chemotherapy could be given, as well as PCI, at the investigator’s discretion. At the time of planned interim OS analysis, the durvalumab plus platinum-etoposide group met the predefined threshold for statistical significance.[3]
    • The median OS was 12.9 months in the durvalumab plus platinum-etoposide group versus 10.5 months in the platinum-etoposide group (HR for OS, 0.75; 95% CI, 0.62−0.91; nominal P = .0032).[3][Level of evidence A1]
    • The toxicity event rate was similar in both arms, consistent with known adverse events of the individual agents. Grade 3 or 4 events occurred in 62% of patients in both study arms.

Combination chemotherapy

Chemotherapy for patients with ED SCLC is commonly given as a two-drug combination of platinum and etoposide in doses associated with at least moderate toxic effects (as in limited-stage [LD] SCLC).[4] Cisplatin is associated with significant toxic effects and requires fluid hydration, which can be problematic in patients with cardiovascular disease. Carboplatin is active in SCLC, is dosed according to renal function, and is associated with less nonhematological toxic effects.

Other regimens appear to produce similar survival outcomes but have been studied less extensively or are in less common use.

Table 2. Combination Chemotherapy for Extensive-Stage SCLC
Standard treatment Etoposide + cisplatin
Etoposide + carboplatin
Other regimens Cisplatin + irinotecan
Ifosfamide + cisplatin + etoposide
Cyclophosphamide + doxorubicin + etoposide
Cyclophosphamide + doxorubicin + etoposide + vincristine
Cyclophosphamide + etoposide + vincristine
Cyclophosphamide + doxorubicin + vincristine

Doses and schedules used in current programs yield overall response rates of 50% to 80% and complete response rates of 0% to 30% in patients with ED SCLC.[5,6][Level of evidence A1]

Intracranial metastases from small cell carcinoma may respond to chemotherapy as readily as metastases in other organs.[7,8]

Evidence (standard regimens):

  1. Two meta-analyses evaluated the role of platinum combinations versus nonplatinum combinations.
    • A Cochrane analysis did not identify a difference in 6-, 12-, or 24-month survival.[9]
    • A meta-analysis of 19 trials published between 1981 and 1999 showed a significant survival advantage for patients receiving platinum-based chemotherapy compared with those receiving a nonplatinum agent.[6][Level of evidence A1]
  2. The Hellenic Oncology Group conducted a phase III trial comparing cisplatin and etoposide with carboplatin plus etoposide.[10] The median survival was 11.8 months in the cisplatin arm and 12.5 months in the carboplatin arm.[10][Level of evidence A1] Although this difference was not statistically significant, the trial was underpowered to prove equivalence of the two treatment regimens in patients with either LD or ED.

Evidence (other combination chemotherapy regimens):

  1. Irinotecan. Five trials and two meta-analyses have evaluated the combination of etoposide and cisplatin versus irinotecan and cisplatin. Only one of the trials showed the superiority of the irinotecan-and-cisplatin combination.[11][Level of evidence A1] Subsequent trials and the meta-analyses support that the regimens provide equivalent clinical benefit with differing toxicity profiles.[12–17][Level of evidence A1] Irinotecan-and-cisplatin regimens led to less grade 3 to 4 anemia, neutropenia, and thrombocytopenia but more grade 3 to 4 vomiting and diarrhea than etoposide-and-cisplatin regimens. Treatment-related deaths were comparable between the two groups.
  2. Topotecan. In a randomized trial of 784 patients, the combination of oral topotecan given with cisplatin for 5 days was not superior to etoposide and cisplatin.[18] The 1-year survival rate was 31% (95% CI, 27%–36%) and was deemed to be noninferior, as the difference of -0.03 met the predefined criteria of no more than 10% absolute difference in 1-year survival.[18][Level of evidence A1]
  3. Paclitaxel. No consistent survival benefit has resulted from the addition of paclitaxel to etoposide and cisplatin.[19,20]

Evidence (duration of treatment):

  1. The optimal duration of chemotherapy is not clearly defined, but no obvious improvement in survival occurs when the duration of drug administration exceeds 6 months.[10,21,22]
  2. Reported data from randomized trials show no clear evidence that maintenance chemotherapy improves survival duration.[23–25][Level of evidence A1] However, a meta-analysis of 14 published randomized trials assessing the benefit of duration/maintenance therapy reported an odds ratio of 0.67 for both 1- and 2-year OS (95% CI, 0.56–0.79; P < .001 for 1-year OS and 0.53–0.86; P < .001 for 2-year OS). This corresponded to an increase of 9% in 1-year OS and 4% in 2-year OS.[26][Level of evidence A1]

Evidence (dose intensification):

  1. The role of dose intensification in patients with SCLC remains unclear.[27–31] Early studies showed that under-treatment compromised outcome and suggested that early dose intensification may improve survival.[27,28] A number of clinical trials have examined the use of colony-stimulating factors to support dose-intensified chemotherapy in SCLC.[29–37] These studies have yielded conflicting results.
    • Four studies have shown that a modest increase in dose intensity (25%–34%) was associated with a significant improvement in survival, with no compromise in quality of life (QOL).[29–32][Level of evidence A1]
    • Two of three studies that examined combinations of the variables of interval, dose per cycle, and number of cycles showed no advantage.[32–35][Level of evidence A1]
    • The European Organisation for Research and Treatment of Cancer trial (EORTC-08923) reported a randomized comparison of standard-dose cyclophosphamide, doxorubicin, and etoposide given every 3 weeks for five cycles versus intensified treatment given at 125% of the dose every 2 weeks for four cycles with granulocyte colony-stimulating factor (G-CSF) support.[35] The median dose intensity delivered was 70% higher in the experimental arm; the median cumulative dose was similar in both arms. There was no difference between treatment groups in median or 2-year survival.
    • A randomized phase III trial compared ifosfamide, cisplatin, and etoposide (ICE), which was given every 4 weeks, with twice weekly ICE with G-CSF and autologous blood support.[36] Despite achieving a relative dose intensity of 1.84 in the dose-accelerated arm, there was no difference in response rate (88% vs. 80%, respectively), median survival (14.4 vs. 13.9 months, respectively), or 2-year survival (19% vs. 22%, respectively) for dose-dense treatment compared with standard treatment.[36][Level of evidence A1] Patients who received dose-dense treatment spent less time on treatment and had fewer episodes of infection.
    • A randomized phase II study of identical design reported a significantly better median survival for the dose-dense arm (29.8 vs. 17.4 months, respectively; P = .02) and 2-year survival (62% vs. 36%, respectively; P = .05).[37] However, given the small study size (only 70 patients), these results should be viewed with caution.
Factors influencing treatment with chemotherapy
  1. Performance status.

    More patients with ED SCLC have greatly impaired performance status at the time of diagnosis than patients with LD. Such patients have a poor prognosis and tolerate aggressive chemotherapy or combined-modality therapy poorly. Single-agent intravenous, oral, and low-dose biweekly regimens have been developed for these patients.[33,38–44]

    Prospective randomized studies have shown that patients with a poor prognosis who are treated with conventional regimens live longer than those treated with single-agent, low-dose regimens or abbreviated courses of therapy. A study comparing chemotherapy every 3 weeks with treatment given as required for symptom control showed an improvement in QOL in patients receiving regular treatment.[41][Level of evidence B1]

    Other studies have tested intensive one-drug or two-drug regimens. A study conducted by the Medical Research Council demonstrated similar efficacy for an etoposide-plus-vincristine regimen and a four-drug regimen.[42] The latter regimen was associated with a greater risk of toxic effects and early death but was superior with respect to palliation of symptoms and psychological distress.[42][Level of evidence A3] Studies comparing a convenient oral treatment with single-agent oral etoposide versus combination therapy showed that the overall response rate and OS were significantly worse in the oral etoposide arm.[38,43][Level of evidence A1]

  2. Age.

    Subgroup analyses of phase II and III trials of patients with SCLC by age showed that myelosuppression and doxorubicin-induced cardiac toxic effects were more severe in older patients than in younger patients, and that the incidence of treatment-related death tended to be higher in older patients.[44] About 80% of older patients, however, received optimal treatment, and their survival was comparable with that of younger patients. The standard chemotherapy regimens for the general population could be applied to older patients in good general condition (i.e., performance status of 0–1, normal organ function, and no comorbidity). There is no evidence of a difference in response rate, disease-free survival (DFS), or OS in older patients compared with younger patients.

Radiation therapy

Radiation therapy to sites of metastatic disease unlikely to be immediately palliated by chemotherapy, especially brain, epidural, and bone metastases, is a standard treatment option for patients with ED SCLC. Brain metastases are treated with whole-brain radiation therapy.

Chest radiation therapy is sometimes given for superior vena cava syndrome, but chemotherapy alone, with radiation reserved for nonresponding patients, is appropriate initial treatment. For more information, see Cardiopulmonary Syndromes.

Thoracic radiation therapy for patients who respond to chemotherapy

Patients with ED SCLC treated with chemotherapy who have achieved a response may receive thoracic radiation therapy.

Evidence (thoracic radiation therapy):

  1. A randomized trial of 498 patients who responded after receiving four to six cycles of chemotherapy compared thoracic radiation therapy with 30 Gy in 10 fractions versus no radiation therapy. All patients received PCI.[45][Level of evidence A1]
    • OS was the primary study end point and not statistically different between the two groups at 1 year (33% for the thoracic radiation therapy group vs. 28% for the control group, P = .066).
    • However, in a secondary analysis, the 2-year OS rate was 13% in the thoracic radiation group (95% CI, 9%–19%) versus 3% in the control group (95% CI, 2%–8%; P = .004). The OS during the entire course of follow-up was not reported.
    • Thoracic radiation therapy resulted in a 6-month PFS rate of 24% in the thoracic radiation group (95% CI, 19%–30%) versus 7% in the control group (95% CI, 4%–11%; P = .001).
    • Intrathoracic recurrences, both isolated (19.8% vs. 46.0%) and in combination with recurrences at other sites (43.7% vs. 79.8%), were reduced by approximately 50%.
    • Thoracic radiation therapy was well tolerated.
PCI

Patients with ED treated with chemotherapy who have achieved a response can be considered for administration of PCI.

Evidence (PCI):

  1. A randomized trial of 286 patients who responded after four to six cycles of chemotherapy compared PCI with no further therapy.[46][Level of evidence B1 
    • The cumulative risk of brain metastases within 1 year was 14.6% in the radiation group (95% CI, 8.3%–20.9%) and 40.4% in the control group (95% CI, 32.1%– 48.6%).
    • Radiation was associated with an increase in median DFS from 12.0 weeks to 14.7 weeks and in median OS from 5.4 months to 6.7 months after randomization.
    • The 1-year survival rate was 27.1% (95% CI, 19.4%–35.5%) in the radiation group and 13.3% (95% CI, 8.1%–19.9%) in the control group.[46]
    • Radiation had side effects but did not have a clinically significant effect on global health status.[46]
    • Only 29% of the randomly assigned patients had brain imaging at diagnosis.[47]
Combination chemotherapy and radiation therapy

Combination chemotherapy plus chest radiation therapy does not appear to improve survival compared with chemotherapy alone in patients with ED SCLC.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References
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  13. Lara PN, Natale R, Crowley J, et al.: Phase III trial of irinotecan/cisplatin compared with etoposide/cisplatin in extensive-stage small-cell lung cancer: clinical and pharmacogenomic results from SWOG S0124. J Clin Oncol 27 (15): 2530-5, 2009. [PUBMED Abstract]
  14. Schmittel A, Sebastian M, Fischer von Weikersthal L, et al.: A German multicenter, randomized phase III trial comparing irinotecan-carboplatin with etoposide-carboplatin as first-line therapy for extensive-disease small-cell lung cancer. Ann Oncol 22 (8): 1798-804, 2011. [PUBMED Abstract]
  15. Zatloukal P, Cardenal F, Szczesna A, et al.: A multicenter international randomized phase III study comparing cisplatin in combination with irinotecan or etoposide in previously untreated small-cell lung cancer patients with extensive disease. Ann Oncol 21 (9): 1810-6, 2010. [PUBMED Abstract]
  16. Jiang J, Liang X, Zhou X, et al.: A meta-analysis of randomized controlled trials comparing irinotecan/platinum with etoposide/platinum in patients with previously untreated extensive-stage small cell lung cancer. J Thorac Oncol 5 (6): 867-73, 2010. [PUBMED Abstract]
  17. Guo S, Liang Y, Zhou Q: Complement and correction for meta-analysis of patients with extensive-stage small cell lung cancer managed with irinotecan/cisplatin versus etoposide/cisplatin as first-line chemotherapy. J Thorac Oncol 6 (2): 406-8; author reply 408, 2011. [PUBMED Abstract]
  18. Eckardt JR, von Pawel J, Papai Z, et al.: Open-label, multicenter, randomized, phase III study comparing oral topotecan/cisplatin versus etoposide/cisplatin as treatment for chemotherapy-naive patients with extensive-disease small-cell lung cancer. J Clin Oncol 24 (13): 2044-51, 2006. [PUBMED Abstract]
  19. Mavroudis D, Papadakis E, Veslemes M, et al.: A multicenter randomized clinical trial comparing paclitaxel-cisplatin-etoposide versus cisplatin-etoposide as first-line treatment in patients with small-cell lung cancer. Ann Oncol 12 (4): 463-70, 2001. [PUBMED Abstract]
  20. Niell HB, Herndon JE, Miller AA, et al.: Randomized phase III intergroup trial of etoposide and cisplatin with or without paclitaxel and granulocyte colony-stimulating factor in patients with extensive-stage small-cell lung cancer: Cancer and Leukemia Group B Trial 9732. J Clin Oncol 23 (16): 3752-9, 2005. [PUBMED Abstract]
  21. Spiro SG, Souhami RL, Geddes DM, et al.: Duration of chemotherapy in small cell lung cancer: a Cancer Research Campaign trial. Br J Cancer 59 (4): 578-83, 1989. [PUBMED Abstract]
  22. Bleehen NM, Girling DJ, Machin D, et al.: A randomised trial of three or six courses of etoposide cyclophosphamide methotrexate and vincristine or six courses of etoposide and ifosfamide in small cell lung cancer (SCLC). I: Survival and prognostic factors. Medical Research Council Lung Cancer Working Party. Br J Cancer 68 (6): 1150-6, 1993. [PUBMED Abstract]
  23. Giaccone G, Dalesio O, McVie GJ, et al.: Maintenance chemotherapy in small-cell lung cancer: long-term results of a randomized trial. European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group. J Clin Oncol 11 (7): 1230-40, 1993. [PUBMED Abstract]
  24. Sculier JP, Paesmans M, Bureau G, et al.: Randomized trial comparing induction chemotherapy versus induction chemotherapy followed by maintenance chemotherapy in small-cell lung cancer. European Lung Cancer Working Party. J Clin Oncol 14 (8): 2337-44, 1996. [PUBMED Abstract]
  25. Schiller JH, Adak S, Cella D, et al.: Topotecan versus observation after cisplatin plus etoposide in extensive-stage small-cell lung cancer: E7593–a phase III trial of the Eastern Cooperative Oncology Group. J Clin Oncol 19 (8): 2114-22, 2001. [PUBMED Abstract]
  26. Bozcuk H, Artac M, Ozdogan M, et al.: Does maintenance/consolidation chemotherapy have a role in the management of small cell lung cancer (SCLC)? A metaanalysis of the published controlled trials. Cancer 104 (12): 2650-7, 2005. [PUBMED Abstract]
  27. Cohen MH, Creaven PJ, Fossieck BE, et al.: Intensive chemotherapy of small cell bronchogenic carcinoma. Cancer Treat Rep 61 (3): 349-54, 1977 May-Jun. [PUBMED Abstract]
  28. Arriagada R, Le Chevalier T, Pignon JP, et al.: Initial chemotherapeutic doses and survival in patients with limited small-cell lung cancer. N Engl J Med 329 (25): 1848-52, 1993. [PUBMED Abstract]
  29. Fukuoka M, Masuda N, Negoro S, et al.: CODE chemotherapy with and without granulocyte colony-stimulating factor in small-cell lung cancer. Br J Cancer 75 (2): 306-9, 1997. [PUBMED Abstract]
  30. Woll PJ, Hodgetts J, Lomax L, et al.: Can cytotoxic dose-intensity be increased by using granulocyte colony-stimulating factor? A randomized controlled trial of lenograstim in small-cell lung cancer. J Clin Oncol 13 (3): 652-9, 1995. [PUBMED Abstract]
  31. Steward WP, von Pawel J, Gatzemeier U, et al.: Effects of granulocyte-macrophage colony-stimulating factor and dose intensification of V-ICE chemotherapy in small-cell lung cancer: a prospective randomized study of 300 patients. J Clin Oncol 16 (2): 642-50, 1998. [PUBMED Abstract]
  32. Thatcher N, Girling DJ, Hopwood P, et al.: Improving survival without reducing quality of life in small-cell lung cancer patients by increasing the dose-intensity of chemotherapy with granulocyte colony-stimulating factor support: results of a British Medical Research Council Multicenter Randomized Trial. Medical Research Council Lung Cancer Working Party. J Clin Oncol 18 (2): 395-404, 2000. [PUBMED Abstract]
  33. James LE, Gower NH, Rudd RM, et al.: A randomised trial of low-dose/high-frequency chemotherapy as palliative treatment of poor-prognosis small-cell lung cancer: a Cancer research Campaign trial. Br J Cancer 73 (12): 1563-8, 1996. [PUBMED Abstract]
  34. Pujol JL, Douillard JY, Rivière A, et al.: Dose-intensity of a four-drug chemotherapy regimen with or without recombinant human granulocyte-macrophage colony-stimulating factor in extensive-stage small-cell lung cancer: a multicenter randomized phase III study. J Clin Oncol 15 (5): 2082-9, 1997. [PUBMED Abstract]
  35. Ardizzoni A, Tjan-Heijnen VC, Postmus PE, et al.: Standard versus intensified chemotherapy with granulocyte colony-stimulating factor support in small-cell lung cancer: a prospective European Organization for Research and Treatment of Cancer-Lung Cancer Group Phase III Trial-08923. J Clin Oncol 20 (19): 3947-55, 2002. [PUBMED Abstract]
  36. Lorigan P, Woll PJ, O’Brien ME, et al.: Randomized phase III trial of dose-dense chemotherapy supported by whole-blood hematopoietic progenitors in better-prognosis small-cell lung cancer. J Natl Cancer Inst 97 (9): 666-74, 2005. [PUBMED Abstract]
  37. Buchholz E, Manegold C, Pilz L, et al.: Standard versus dose-intensified chemotherapy with sequential reinfusion of hematopoietic progenitor cells in small cell lung cancer patients with favorable prognosis. J Thorac Oncol 2 (1): 51-8, 2007. [PUBMED Abstract]
  38. Girling DJ: Comparison of oral etoposide and standard intravenous multidrug chemotherapy for small-cell lung cancer: a stopped multicentre randomised trial. Medical Research Council Lung Cancer Working Party. Lancet 348 (9027): 563-6, 1996. [PUBMED Abstract]
  39. Murray N, Grafton C, Shah A, et al.: Abbreviated treatment for elderly, infirm, or noncompliant patients with limited-stage small-cell lung cancer. J Clin Oncol 16 (10): 3323-8, 1998. [PUBMED Abstract]
  40. Westeel V, Murray N, Gelmon K, et al.: New combination of the old drugs for elderly patients with small-cell lung cancer: a phase II study of the PAVE regimen. J Clin Oncol 16 (5): 1940-7, 1998. [PUBMED Abstract]
  41. Earl HM, Rudd RM, Spiro SG, et al.: A randomised trial of planned versus as required chemotherapy in small cell lung cancer: a Cancer Research Campaign trial. Br J Cancer 64 (3): 566-72, 1991. [PUBMED Abstract]
  42. Randomised trial of four-drug vs less intensive two-drug chemotherapy in the palliative treatment of patients with small-cell lung cancer (SCLC) and poor prognosis. Medical Research Council Lung Cancer Working Party. Br J Cancer 73 (3): 406-13, 1996. [PUBMED Abstract]
  43. Souhami RL, Spiro SG, Rudd RM, et al.: Five-day oral etoposide treatment for advanced small-cell lung cancer: randomized comparison with intravenous chemotherapy. J Natl Cancer Inst 89 (8): 577-80, 1997. [PUBMED Abstract]
  44. Sekine I, Yamamoto N, Kunitoh H, et al.: Treatment of small cell lung cancer in the elderly based on a critical literature review of clinical trials. Cancer Treat Rev 30 (4): 359-68, 2004. [PUBMED Abstract]
  45. Slotman BJ, van Tinteren H, Praag JO, et al.: Use of thoracic radiotherapy for extensive stage small-cell lung cancer: a phase 3 randomised controlled trial. Lancet 385 (9962): 36-42, 2015. [PUBMED Abstract]
  46. Slotman B, Faivre-Finn C, Kramer G, et al.: Prophylactic cranial irradiation in extensive small-cell lung cancer. N Engl J Med 357 (7): 664-72, 2007. [PUBMED Abstract]
  47. Shivnani AT: Prophylactic cranial irradiation in small-cell lung cancer. N Engl J Med 357 (19): 1977; author reply 1978, 2007. [PUBMED Abstract]

Treatment of Recurrent SCLC

Treatment Options for Patients With Recurrent SCLC

Treatment options for patients with recurrent small cell lung cancer (SCLC) include:

  1. Chemotherapy.
  2. Immunotherapy.
  3. Immune checkpoint modulation.
  4. Palliative therapy.
  5. Phase I and II clinical trials evaluating new drugs, including bispecific T-cell engager (BiTE) immunotherapies.

At the time of recurrence, many patients with SCLC are potential candidates for further therapy.

For patients with recurrent SCLC, immune checkpoint modulation with anti–programmed death-ligand 1 (anti–PD-L1) antibodies may lead to durable responses either as single agents or in combination with cytotoxic T lymphocyte antigen-4 (anti–CTLA-4). Impacts on long-term survival from these approaches are being assessed in randomized trials.

Chemotherapy

Although second-line chemotherapy has produced tumor regression, responses are usually short lived. The median survival is rarely more than 12 months and usually less than 6 months after second-line therapy.[1] Response to first-line chemotherapy predicts subsequent response to second-line therapy.

As in other chemosensitive tumors (e.g., Hodgkin lymphoma and ovarian epithelial cancer), two main categories of patients receiving second-line chemotherapy have been described: sensitive and resistant. Sensitive patients have a first-line response that lasted more than 90 days after treatment was completed. These patients have the greatest benefit from second-line chemotherapy. Patients with sensitive disease respond to the same initial regimen in approximately 50% of cases; however, cumulative toxic effects may ensue.[2] Resistant patients either did not respond to first-line chemotherapy or responded initially but relapsed within 90 days of completion of their primary therapy.[3] Results from phase II studies of drugs such as topotecan, irinotecan, and gemcitabine indicate that response rates to agents vary depending on whether patients have sensitive, resistant, or refractory disease.[4–8][Level of evidence C2]

Topotecan is a standard chemotherapy for recurrent SCLC.[9,10] Lurbinectedin, a selective inhibitor of oncogenic transcription, is another option.[11] Patients with sensitive disease may achieve response to a number of agents including topotecan, irinotecan, taxanes, vinorelbine, paclitaxel, or gemcitabine.[4–8,12–14][Level of evidence C2] Response rates for combination agents are generally higher than those reported for single agents,[15,16] and one phase III study reported improved survival for patients with sensitive disease treated with combination cisplatin, etoposide, and irinotecan. However, higher rates of toxicity have been seen.[17]

Topotecan

Evidence (topotecan and other chemotherapy agents):

  1. A randomized comparison of second-line treatment with either cyclophosphamide, doxorubicin, and vincristine or topotecan in patients with sensitive disease reported no significant difference in response rates or survival. However, palliation of common lung cancer symptoms was better with topotecan.[9][Level of evidence A3]
  2. A phase III trial comparing chemotherapy with best supportive care (BSC) in patients with relapsed SCLC demonstrated that the addition of oral topotecan to BSC significantly increased overall survival (OS) and resulted in better symptom control compared with BSC alone.[10][Level of evidence A1] The study enrolled 141 patients with chemosensitive or chemoresistant relapsed SCLC who were unsuitable for further standard intravenous chemotherapy. The median survivals for patients receiving topotecan plus BSC were 25.9 weeks versus 13.9 weeks for BSC alone (P = .01).[10]
  3. A randomized phase III trial (CWRU-SKF-1598 [NCT00003917]) of 304 patients assessed the use of oral topotecan (2.3 mg/m2/day for 5 days every 21 days) or intravenous topotecan (1.5 mg/m2/day for 5 days every 21 days). Confirmed response rates were 18.3% and 21.9%, respectively.[12][Level of evidence B1] Secondary end points of median survival and 1-year survival rates were also similar (33 weeks vs. 35 weeks and 33% vs. 29%, respectively). Patients receiving oral topotecan experienced less grade 4 neutropenia (47% vs. 64.2%) but more diarrhea of all grades (35.9% vs. 19.9%) than with intravenous topotecan. Quality-of-life (QOL) analysis (using a nonvalidated QOL questionnaire) demonstrated no significant difference between the two arms.
Lurbinectedin

Evidence (lurbinectedin):

  1. A single-arm, open-label, phase II basket trial (NCT02454972) enrolled 105 patients with SCLC who had been previously treated with one line of a chemotherapy-containing regimen.[11]
    • The overall response rate after treatment with lurbinectedin was 35% (95% confidence interval [CI], 26%−45%), with a median response duration of 5.3 months (95% CI, 4.1−6.4).
    • The overall response rate was 45% (95% CI, 32%−58%) for patients with chemosensitive disease and 22% (95% CI, 11%−37%) for patients with chemoresistant disease.
    • The median duration of response was 6.2 months (95% CI, 3.5−7.3) for patients with chemosensitive disease and 4.7 months (95% CI, 2.6−5.6) for patients with chemoresistant disease.[11][Level of evidence C3]
Other chemotherapy agents

Evidence (other chemotherapy agents):

  1. A phase III trial (University Hospital Medical Information Network Clinical Trials Registry [UMIN000000828]) in Japan included 180 patients with extensive-stage SCLC, who had responded to first-line platinum-doublet chemotherapy but had their disease progress more than 90 days after completion of chemotherapy. Patients were randomly assigned 1:1 to receive intravenous topotecan for four cycles, which is the standard of care, or five 2-week cycles of cisplatin, etoposide, and irinotecan.[17]
    • The primary end point of OS was significantly prolonged with the combination of cisplatin, etoposide, and irinotecan (18.2 months; 95% CI, 15.7–20.6) compared with topotecan alone (12.5 months; 95% CI, 10.8–14.9; hazard ratio, 0.67; 90% CI, 0.51–0.88; P = .0079).
    • Rates of grade 3 to 4 toxicities were higher in patients treated with the combination regimen. Toxicities included febrile neutropenia (31% for the combination arm vs. 7% for topotecan alone) and thrombocytopenia (41% for the combination arm vs. 28% for topotecan alone).[17][Level of evidence A1]

Immunotherapy

Tarlatamab

Tarlatamab is a BiTE immunotherapy drug that targets delta-like ligand 3 (DLL3) and CD3. BiTE technology is a targeted immuno-oncology platform designed to engage a patient’s own T cells to any tumor-specific antigen, activating the cytotoxic potential of T cells to eliminate detectable cancer.

Evidence (tarlatamab):

  1. The phase II DeLLphi-301 trial (NCT05060016) evaluated the efficacy and safety of two doses of tarlatamab (10 mg or 100 mg every 2 weeks) in 220 patients with previously treated SCLC. Patients had previously received a median of two lines of treatment. The primary end point was objective response rate by blinded independent central review.[18]
    • The objective response rates were 40% (97.5% CI, 29%–52%) for patients who received 10 mg of tarlatamab and 32% (97.5% CI, 21%–44%) for patients who received 100 mg of tarlatamab. The median duration of response was not reached.
    • The median progression-free survival was 4.9 months (95% CI, 2.9–6.7) with 10 mg of tarlatamab and 3.9 months (95% CI, 2.6–4.4) with 100 mg of tarlatamab.
    • The most common adverse events were cytokine release syndrome (51% with 10 mg, 61% with 100 mg), decreased appetite, pyrexia, constipation, and anemia.
    • Cytokine release syndrome occurred after the first one to two doses and was managed with supportive care.
    • Neurological adverse events suggestive of immune effector cell–associated neurotoxicity syndrome were higher for patients who received 100 mg (28%) compared with patients who received 10 mg (8%).
    • The 10-mg dose showed improved tolerability over the 100-mg dose, with similar efficacy.

Immune checkpoint modulation

Early phase Ib and II trials showed objective response rates of 10% to 33% with nivolumab or pembrolizumab treatment in patients with disease progression after one or more lines of chemotherapy, resulting in accelerated approval from the U.S. Food and Drug Administration. However, both agents were voluntarily withdrawn after subsequent trials failed to confirm benefit.[19,20]

Palliative therapy

Patients with central nervous system (CNS) recurrences can often obtain palliation of symptoms with additional chemotherapy and/or radiation therapy. A retrospective review showed that 43% of patients had disease response when treated with additional chemotherapy at the time of CNS relapse.[21] Most patients treated with radiation therapy obtain objective responses and improvement after radiation therapy.[22]

Some patients with intrinsic endobronchial obstructing lesions or extrinsic compression caused by the tumor have achieved successful palliation with endobronchial laser therapy (for endobronchial lesions only) and/or brachytherapy.[23] Expandable metal stents can be safely inserted under local anesthesia via the bronchoscope, which results in improved symptoms and pulmonary function in patients with malignant airways obstruction.[24]

Patients with progressive intrathoracic tumor after failing initial chemotherapy can achieve significant tumor responses, palliation of symptoms, and short-term local control with external-beam radiation therapy. Only the rare patient, however, will experience long-term survival after receiving salvage radiation therapy.[25]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References
  1. Davies AM, Evans WK, Mackay JA, et al.: Treatment of recurrent small cell lung cancer. Hematol Oncol Clin North Am 18 (2): 387-416, 2004. [PUBMED Abstract]
  2. Postmus PE, Berendsen HH, van Zandwijk N, et al.: Retreatment with the induction regimen in small cell lung cancer relapsing after an initial response to short term chemotherapy. Eur J Cancer Clin Oncol 23 (9): 1409-11, 1987. [PUBMED Abstract]
  3. Giaccone G, Donadio M, Bonardi G, et al.: Teniposide in the treatment of small-cell lung cancer: the influence of prior chemotherapy. J Clin Oncol 6 (8): 1264-70, 1988. [PUBMED Abstract]
  4. Sandler AB: Irinotecan in small-cell lung cancer: the US experience. Oncology (Williston Park) 15 (1 Suppl 1): 11-2, 2001. [PUBMED Abstract]
  5. van der Lee I, Smit EF, van Putten JW, et al.: Single-agent gemcitabine in patients with resistant small-cell lung cancer. Ann Oncol 12 (4): 557-61, 2001. [PUBMED Abstract]
  6. Masuda N, Fukuoka M, Kusunoki Y, et al.: CPT-11: a new derivative of camptothecin for the treatment of refractory or relapsed small-cell lung cancer. J Clin Oncol 10 (8): 1225-9, 1992. [PUBMED Abstract]
  7. Perez-Soler R, Glisson BS, Lee JS, et al.: Treatment of patients with small-cell lung cancer refractory to etoposide and cisplatin with the topoisomerase I poison topotecan. J Clin Oncol 14 (10): 2785-90, 1996. [PUBMED Abstract]
  8. Masters GA, Declerck L, Blanke C, et al.: Phase II trial of gemcitabine in refractory or relapsed small-cell lung cancer: Eastern Cooperative Oncology Group Trial 1597. J Clin Oncol 21 (8): 1550-5, 2003. [PUBMED Abstract]
  9. von Pawel J, Schiller JH, Shepherd FA, et al.: Topotecan versus cyclophosphamide, doxorubicin, and vincristine for the treatment of recurrent small-cell lung cancer. J Clin Oncol 17 (2): 658-67, 1999. [PUBMED Abstract]
  10. O’Brien ME, Ciuleanu TE, Tsekov H, et al.: Phase III trial comparing supportive care alone with supportive care with oral topotecan in patients with relapsed small-cell lung cancer. J Clin Oncol 24 (34): 5441-7, 2006. [PUBMED Abstract]
  11. Trigo J, Subbiah V, Besse B, et al.: Lurbinectedin as second-line treatment for patients with small-cell lung cancer: a single-arm, open-label, phase 2 basket trial. Lancet Oncol 21 (5): 645-654, 2020. [PUBMED Abstract]
  12. Eckardt JR, von Pawel J, Pujol JL, et al.: Phase III study of oral compared with intravenous topotecan as second-line therapy in small-cell lung cancer. J Clin Oncol 25 (15): 2086-92, 2007. [PUBMED Abstract]
  13. Ardizzoni A, Hansen H, Dombernowsky P, et al.: Topotecan, a new active drug in the second-line treatment of small-cell lung cancer: a phase II study in patients with refractory and sensitive disease. The European Organization for Research and Treatment of Cancer Early Clinical Studies Group and New Drug Development Office, and the Lung Cancer Cooperative Group. J Clin Oncol 15 (5): 2090-6, 1997. [PUBMED Abstract]
  14. Furuse K, Kubota K, Kawahara M, et al.: Phase II study of vinorelbine in heavily previously treated small cell lung cancer. Japan Lung Cancer Vinorelbine Study Group. Oncology 53 (2): 169-72, 1996 Mar-Apr. [PUBMED Abstract]
  15. Smit EF, Fokkema E, Biesma B, et al.: A phase II study of paclitaxel in heavily pretreated patients with small-cell lung cancer. Br J Cancer 77 (2): 347-51, 1998. [PUBMED Abstract]
  16. Rocha-Lima CM, Herndon JE, Lee ME, et al.: Phase II trial of irinotecan/gemcitabine as second-line therapy for relapsed and refractory small-cell lung cancer: Cancer and Leukemia Group B Study 39902. Ann Oncol 18 (2): 331-7, 2007. [PUBMED Abstract]
  17. Goto K, Ohe Y, Shibata T, et al.: Combined chemotherapy with cisplatin, etoposide, and irinotecan versus topotecan alone as second-line treatment for patients with sensitive relapsed small-cell lung cancer (JCOG0605): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol 17 (8): 1147-1157, 2016. [PUBMED Abstract]
  18. Ahn MJ, Cho BC, Felip E, et al.: Tarlatamab for Patients with Previously Treated Small-Cell Lung Cancer. N Engl J Med 389 (22): 2063-2075, 2023. [PUBMED Abstract]
  19. Antonia SJ, López-Martin JA, Bendell J, et al.: Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial. Lancet Oncol 17 (7): 883-895, 2016. [PUBMED Abstract]
  20. Ott PA, Elez E, Hiret S, et al.: Pembrolizumab in Patients With Extensive-Stage Small-Cell Lung Cancer: Results From the Phase Ib KEYNOTE-028 Study. J Clin Oncol 35 (34): 3823-3829, 2017. [PUBMED Abstract]
  21. Kristensen CA, Kristjansen PE, Hansen HH: Systemic chemotherapy of brain metastases from small-cell lung cancer: a review. J Clin Oncol 10 (9): 1498-502, 1992. [PUBMED Abstract]
  22. Carmichael J, Crane JM, Bunn PA, et al.: Results of therapeutic cranial irradiation in small cell lung cancer. Int J Radiat Oncol Biol Phys 14 (3): 455-9, 1988. [PUBMED Abstract]
  23. Miller JI, Phillips TW: Neodymium:YAG laser and brachytherapy in the management of inoperable bronchogenic carcinoma. Ann Thorac Surg 50 (2): 190-5; discussion 195-6, 1990. [PUBMED Abstract]
  24. Wilson GE, Walshaw MJ, Hind CR: Treatment of large airway obstruction in lung cancer using expandable metal stents inserted under direct vision via the fibreoptic bronchoscope. Thorax 51 (3): 248-52, 1996. [PUBMED Abstract]
  25. Ochs JJ, Tester WJ, Cohen MH, et al.: “Salvage” radiation therapy for intrathoracic small cell carcinoma of the lung progressing on combination chemotherapy. Cancer Treat Rep 67 (12): 1123-6, 1983. [PUBMED Abstract]

Latest Updates to This Summary (05/14/2025)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Editorial changes were made to this summary.

This summary is written and maintained by the PDQ Adult Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of small cell lung cancer. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

  • be discussed at a meeting,
  • be cited with text, or
  • replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Small Cell Lung Cancer Treatment are:

  • Janet Dancey, MD, FRCPC (Ontario Institute for Cancer Research & NCIC Clinical Trials Group)
  • Monaliben Patel, MD (University of Rochester Medical Center)
  • Arun Rajan, MD (National Cancer Institute)
  • Eva Szabo, MD (National Cancer Institute)

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website’s Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

Permission to Use This Summary

PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”

The preferred citation for this PDQ summary is:

PDQ® Adult Treatment Editorial Board. PDQ Small Cell Lung Cancer Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/lung/hp/small-cell-lung-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389347]

Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.

Disclaimer

Based on the strength of the available evidence, treatment options may be described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

Contact Us

More information about contacting us or receiving help with the Cancer.gov website can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the website’s Email Us.

Lung Cancer Screening (PDQ®)–Patient Version

Lung Cancer Screening (PDQ®)–Patient Version

What Is Screening?

Go to Health Professional Version

Screening is looking for cancer before a person has any symptoms. This can help find cancer at an early stage. When abnormal tissue or cancer is found early, it may be easier to treat. By the time symptoms appear, cancer may have begun to spread.

Scientists are trying to better understand which people are more likely to get certain types of cancer. They also study the things we do and the things around us to see if they cause cancer. This information helps doctors recommend who should be screened for cancer, which screening tests should be used, and how often the tests should be done.

It is important to remember that your doctor does not necessarily think you have cancer if he or she suggests a screening test. Screening tests are given when you have no cancer symptoms.

If a screening test result is abnormal, you may need to have more tests done to find out if you have cancer. These are called diagnostic tests.

General Information About Lung Cancer

Key Points

  • Lung cancer is a disease in which malignant (cancer) cells form in the tissues of the lung.
  • Lung cancer is the leading cause of cancer death in the United States.
  • Different factors increase or decrease the risk of lung cancer.

Lung cancer is a disease in which malignant (cancer) cells form in the tissues of the lung.

The lungs are a pair of cone-shaped breathing organs in the chest. The lungs bring oxygen into the body as you breathe in. They release carbon dioxide, a waste product of the body’s cells, as you breathe out. Each lung has sections called lobes. The left lung has two lobes. The right lung is slightly larger, and has three lobes. A thin membrane called the pleura surrounds the lungs. Two tubes called bronchi lead from the trachea (windpipe) to the right and left lungs. The bronchi are sometimes also involved in lung cancer. Tiny air sacs called alveoli and small tubes called bronchioles make up the inside of the lungs.

EnlargeRespiratory system anatomy; drawing shows the right lung with the upper, middle, and lower lobes, the left lung with the upper and lower lobes, and the trachea, bronchi, lymph nodes, and diaphragm. An inset shows the bronchioles, alveoli, artery, and vein.
Anatomy of the respiratory system showing the trachea, the right and left lungs and their lobes, and the bronchi. The lymph nodes and the diaphragm are also shown. Oxygen is inhaled into the lungs and passes through the alveoli (the tiny air sacs at the end of the bronchioles) and into the bloodstream (see inset), where it travels to the tissues throughout the body.

There are two main types of lung cancer: small cell lung cancer and non-small cell lung cancer.

Other PDQ summaries containing information related to lung cancer include:

Lung cancer is the leading cause of cancer death in the United States.

Lung cancer is the second most common type of non-skin cancer in the United States. Lung cancer is the leading cause of cancer death in men and in women.

Different factors increase or decrease the risk of lung cancer.

Anything that increases your chance of getting a disease is called a risk factor. Anything that decreases your chance of getting a disease is called a protective factor.

Tobacco smoking is the most important risk factor for lung cancer. Cigarette, cigar, and pipe smoking all increase the risk of lung cancer. Tobacco smoking causes about 9 out of 10 cases of lung cancer in men and about 8 out of 10 cases of lung cancer in women. The best way to prevent lung cancer is to not smoke.

For information about risk factors and protective factors for lung cancer, see Lung Cancer Prevention.

Lung Cancer Screening

Key Points

  • Tests are used to screen for different types of cancer when a person does not have symptoms.
  • Three screening tests have been studied to see if they decrease the risk of dying from lung cancer.
  • Screening with LDCT scans has been shown to decrease the risk of dying from lung cancer in heavy smokers.
  • Screening with chest x-rays and/or sputum cytology does not decrease the risk of dying from lung cancer.
  • Screening tests for lung cancer are being studied in clinical trials.

Tests are used to screen for different types of cancer when a person does not have symptoms.

Scientists study screening tests to find those with the fewest harms and most benefits. Cancer screening trials also are meant to show whether early detection (finding cancer before it causes symptoms) helps a person live longer or decreases a person’s chance of dying from the disease. For some types of cancer, the chance of recovery is better if the disease is found and treated at an early stage.

Three screening tests have been studied to see if they decrease the risk of dying from lung cancer.

The following screening tests have been studied to see if they decrease the risk of dying from lung cancer:

  • Low-dose computed tomography (LDCT): A procedure that uses low-dose radiation to make a series of very detailed pictures of areas inside the body using an x-ray machine that scans the body in a spiral path. This procedure is also called spiral scan or helical scan.
  • Chest x-ray: An x-ray of the organs and bones inside the chest. An x-ray is a type of energy beam that can go through the body and onto film, making a picture of areas inside the body.
  • Sputum cytology: Sputum cytology is a procedure in which a sample of sputum (mucus that is coughed up from the lungs) is viewed under a microscope to check for cancer cells.

Screening with LDCT scans has been shown to decrease the risk of dying from lung cancer in heavy smokers.

The National Lung Screening Trial studied people aged 55 years to 74 years who had smoked at least 1 pack of cigarettes per day for 30 years or more. Participants were either current smokers or former smokers who had quit within the last 15 years. The trial used chest x-rays or LDCT scans to check for signs of lung cancer.

Screening with LDCT once a year for three years was better than chest x-rays at finding early-stage lung cancer and decreased the risk of dying from lung cancer in current and former heavy smokers.

Current smokers whose LDCT scan result shows possible signs of cancer may be more likely to quit smoking.

Screening with LDCT can cause possible harms, including:

For more information about these possible harms, see the Risks of Lung Cancer Screening below.

A Guide is available for patients and doctors to learn more about the benefits and harms of screening for lung cancer.

Screening with chest x-rays and/or sputum cytology does not decrease the risk of dying from lung cancer.

Chest x-ray and sputum cytology are two screening tests that have been used to check for signs of lung cancer. Screening with chest x-ray, sputum cytology, or both of these tests does not decrease the risk of dying from lung cancer.

Screening tests for lung cancer are being studied in clinical trials.

Information about clinical trials supported by NCI can be found on NCI’s clinical trials search webpage. Clinical trials supported by other organizations can be found on the ClinicalTrials.gov website.

Risks of Lung Cancer Screening

Key Points

  • Screening tests have risks.
  • The risks of lung cancer screening tests include the following:
    • Finding lung cancer may not improve health or help you live longer.
    • False-negative test results can occur.
    • False-positive test results can occur.
    • Chest x-rays and CT scans expose the chest to radiation.
    • Talk to your doctor about your risk for lung cancer and your need for screening tests.

Screening tests have risks.

Decisions about screening tests can be difficult. Not all screening tests are helpful and most have risks. Before having any screening test, you may want to discuss the test with your doctor. It is important to know the risks of the test and whether it has been proven to reduce the risk of dying from cancer.

The risks of lung cancer screening tests include the following:

Finding lung cancer may not improve health or help you live longer.

Screening may not improve your health or help you live longer if you have lung cancer that has already spread to other places in your body.

When a screening test result leads to the diagnosis and treatment of a disease that may never have caused symptoms or become life-threatening, it is called overdiagnosis. It is not known if treatment of these cancers would help you live longer than if no treatment were given, and treatments for cancer may have serious side effects. Harms of treatment may happen more often in people who have medical problems caused by heavy or long-term smoking.

False-negative test results can occur.

Screening test results may appear to be normal even though lung cancer is present. A person who receives a false-negative test result (one that shows there is no cancer when there really is) may delay seeking medical care even if there are symptoms.

False-positive test results can occur.

Screening test results may appear to be abnormal even though no cancer is present. A false-positive test result (one that shows there is cancer when there really isn’t) can cause anxiety and is usually followed by more tests (such as biopsy), which also have risks. A biopsy to diagnose lung cancer can cause part of the lung to collapse. Sometimes surgery is needed to reinflate the lung. Harms of diagnostic tests may happen more often in patients who have medical problems caused by heavy or long-term smoking.

Chest x-rays and CT scans expose the chest to radiation.

Radiation exposure from chest x-rays and low-dose CT scans may increase the risk of cancer. Younger people and people at low risk for lung cancer are more likely to develop lung cancer caused by radiation exposure from screening than to be spared death from lung cancer.

Talk to your doctor about your risk for lung cancer and your need for screening tests.

Talk to your doctor or other health care provider about your risk for lung cancer, whether a screening test is right for you, and about the benefits and harms of the screening test. You should take part in the decision about whether a screening test is right for you. For more information, see Cancer Screening Overview.

About This PDQ Summary

About PDQ

Physician Data Query (PDQ) is the National Cancer Institute’s (NCI’s) comprehensive cancer information database. The PDQ database contains summaries of the latest published information on cancer prevention, detection, genetics, treatment, supportive care, and complementary and alternative medicine. Most summaries come in two versions. The health professional versions have detailed information written in technical language. The patient versions are written in easy-to-understand, nontechnical language. Both versions have cancer information that is accurate and up to date and most versions are also available in Spanish.

PDQ is a service of the NCI. The NCI is part of the National Institutes of Health (NIH). NIH is the federal government’s center of biomedical research. The PDQ summaries are based on an independent review of the medical literature. They are not policy statements of the NCI or the NIH.

Purpose of This Summary

This PDQ cancer information summary has current information about lung cancer screening. It is meant to inform and help patients, families, and caregivers. It does not give formal guidelines or recommendations for making decisions about health care.

Reviewers and Updates

Editorial Boards write the PDQ cancer information summaries and keep them up to date. These Boards are made up of experts in cancer treatment and other specialties related to cancer. The summaries are reviewed regularly and changes are made when there is new information. The date on each summary (“Updated”) is the date of the most recent change.

The information in this patient summary was taken from the health professional version, which is reviewed regularly and updated as needed, by the PDQ Screening and Prevention Editorial Board.

Clinical Trial Information

A clinical trial is a study to answer a scientific question, such as whether one treatment is better than another. Trials are based on past studies and what has been learned in the laboratory. Each trial answers certain scientific questions in order to find new and better ways to help cancer patients. During treatment clinical trials, information is collected about the effects of a new treatment and how well it works. If a clinical trial shows that a new treatment is better than one currently being used, the new treatment may become “standard.” Patients may want to think about taking part in a clinical trial. Some clinical trials are open only to patients who have not started treatment.

Clinical trials can be found online at NCI’s website. For more information, call the Cancer Information Service (CIS), NCI’s contact center, at 1-800-4-CANCER (1-800-422-6237).

Permission to Use This Summary

PDQ is a registered trademark. The content of PDQ documents can be used freely as text. It cannot be identified as an NCI PDQ cancer information summary unless the whole summary is shown and it is updated regularly. However, a user would be allowed to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks in the following way: [include excerpt from the summary].”

The best way to cite this PDQ summary is:

PDQ® Screening and Prevention Editorial Board. PDQ Lung Cancer Screening. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/lung/patient/lung-screening-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389428]

Images in this summary are used with permission of the author(s), artist, and/or publisher for use in the PDQ summaries only. If you want to use an image from a PDQ summary and you are not using the whole summary, you must get permission from the owner. It cannot be given by the National Cancer Institute. Information about using the images in this summary, along with many other images related to cancer can be found in Visuals Online. Visuals Online is a collection of more than 3,000 scientific images.

Disclaimer

The information in these summaries should not be used to make decisions about insurance reimbursement. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

Contact Us

More information about contacting us or receiving help with the Cancer.gov website can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the website’s E-mail Us.

Lung Cancer Prevention (PDQ®)–Health Professional Version

Lung Cancer Prevention (PDQ®)–Health Professional Version

Overview

Go to Patient Version

Note: The Overview section summarizes the published evidence on this topic. The rest of the summary describes the evidence in more detail.

Other PDQ summaries containing information related to lung cancer prevention include the following:

Who Is at Risk?

Lung cancer risk is largely a function of older age combined with extensive cigarette smoking history. Lung cancer is more common in men than women and in those of lower socioeconomic status. Patterns of lung cancer according to demographic characteristics tend to be strongly correlated with historical patterns of cigarette smoking prevalence. An exception is the very high rate of lung cancer in African American men, a group whose very high lung cancer death rate is not explainable simply by historical smoking patterns.[1]

In nonsmokers, important lung cancer risk factors are exposure to secondhand smoke, exposure to ionizing radiation, and occupational exposure to lung carcinogens, such as asbestos. Radiation exposures relevant to the general population include environmental exposure to radon and radiation exposures administered in the medical care setting, particularly when administered at high doses, such as radiation therapy to the chest or breast.[2] Cigarette smoking often interacts with these other factors. There are several examples, including radon exposure and asbestos exposure, in which the combined exposure to cigarette smoke plus another risk factor results in an increase in risk that is much greater than the sum of the risks associated with each factor alone.

Factors associated with increased risk of lung cancer

Cigarette smoking

Starting with the 1964 Surgeon General’s Report and followed by each subsequent Surgeon General’s Report that has included a review of the evidence on smoking and lung cancer, an enormous body of scientific evidence clearly documents that cigarette smoking causes lung cancer, and that cigarette smoking is the major cause of lung cancer.

Based on solid evidence, cigarette smoking causes lung cancer. The risks of lung cancer associated with cigarette smoking are dose-dependent and increase markedly according to the number of cigarettes smoked per day and the number of years smoked. On average, current smokers have approximately 20 times the risk of lung cancer as nonsmokers.

Magnitude of Effect: Increased risk, very large.

  • Study Design: Numerous prospective cohort and case-control studies, combined with quasi-experimental evidence showing population-level smoking prevalence predicts the population-level burden of lung cancer.
  • Internal Validity: Good.
  • Consistency: Good.
  • External Validity: Good.
Exposure to secondhand smoke

Based on solid evidence, exposure to secondhand smoke is an established cause of lung cancer.

Magnitude of Effect: Increased risk, small magnitude. Compared with nonsmokers not exposed to secondhand smoke, nonsmokers exposed to secondhand smoke have approximately a 20% increased risk of lung cancer.

  • Study Design: Prospective cohort and case-control studies.
  • Internal Validity: Good.
  • Consistency: Good.
  • External Validity: Good.
Radiation exposure

Based on solid evidence, exposure to radiation increases lung cancer incidence and mortality. Cigarette smoking greatly potentiates this effect.

Magnitude of Effect: Increased risk that follows a dose-response gradient, with smaller increases in risk for low levels of exposure and greater increases in risk for high levels of exposure.

  • Study Design: Cohort and case-control studies.
  • Internal Validity: Fair.
  • Consistency: Good.
  • External Validity: Good.
Occupational exposure to lung carcinogens

Based on solid evidence, workplace exposure to asbestos, arsenic, beryllium, cadmium, chromium, and nickel increases lung cancer incidence and mortality.

Magnitude of Effect: Increased risk, large magnitude (more than fivefold). Risks follow a dose-response gradient, with high-level exposures associated with large increases in risk. Cigarette smoking also potentiates the effect of many of these lung carcinogens so that the risks are even greater in smokers.

  • Study Design: Cohort and case-control studies.
  • Internal Validity: Good.
  • Consistency: Good.
  • External Validity: Good.
Air pollution

Based on solid evidence, exposure to outdoor air pollution, specifically small particles, increases lung cancer incidence and mortality.

Magnitude of Effect: Increased risk; compared with the lowest exposure categories, those in the highest exposure categories have approximately a 40% increased risk of lung cancer.

  • Study Design: Cohort and case-control studies.
  • Internal Validity: Good.
  • Consistency: Good.
  • External Validity: Good.

Factors of uncertain association with risk

Dietary factors

Based on equivocal evidence, the observed inverse associations between lung cancer and dietary factors, such as fruit and vegetable consumption, are difficult to disentangle from cigarette smoking.

Magnitude of Effect: Inverse association, moderate magnitude, but difficult to determine if true cause-effect association or due to confounding by cigarette smoking.

  • Study Design: Numerous cohort and case-control studies, and meta-analyses.
  • Internal Validity: Fair.
  • Consistency: Fair.
  • External Validity: Good.
Physical activity

Based on equivocal evidence, the observed inverse associations between lung cancer and higher levels of physical activity are difficult to disentangle from cigarette smoking.

Magnitude of Effect: Inverse association, moderate magnitude, but difficult to determine if true cause-effect association or due to confounding by cigarette smoking.

  • Study Design: Numerous cohort and case-control studies, and meta-analyses.
  • Internal Validity: Fair.
  • Consistency: Fair.
  • External Validity: Good.

Interventions Associated With Decreased Risk of Lung Cancer

Smoking avoidance

Based on solid evidence, cigarette smoking causes lung cancer and therefore, smoking avoidance results in decreased mortality from primary lung cancers.

Magnitude of Effect: Decreased risk, substantial magnitude.

  • Study Design: Cohort and case-control studies.
  • Internal Validity: Good.
  • Consistency: Good.
  • External Validity: Good.

Smoking cessation

Based on solid evidence, long-term sustained smoking cessation results in decreased incidence of lung cancer and of second primary lung tumors.

Magnitude of Effect: Decreased risk, moderate magnitude.

  • Study Design: Cohort and case-control studies.
  • Internal Validity: Good.
  • Consistency: Good.
  • External Validity: Good.

Eliminating secondhand smoke

Based on solid evidence, exposure to secondhand smoke causes lung cancer and therefore, preventing exposure to secondhand smoke results in decreased incidence and mortality from primary lung cancers.

Magnitude of Effect: Decreased risk, small magnitude.

  • Study Design: Cohort and case-control studies.
  • Internal Validity: Good.
  • Consistency: Good.
  • External Validity: Good.

Reducing or eliminating occupational exposure to lung carcinogens

Based on solid evidence, occupational exposures such as asbestos, arsenic, nickel, and chromium are causally associated with lung cancer. Reducing or eliminating workplace exposures to known lung carcinogens would be expected to result in a corresponding decrease in the risk of lung cancer.

Magnitude of Effect: Decreased risk, with a larger effect, the greater the reduction in exposure.

  • Study Design: Cohort and case-control studies.
  • Internal Validity: Good.
  • Consistency: Good.
  • External Validity: Good.

Reducing or eliminating exposure to radon

Based on solid evidence, indoor exposure to radon increases lung cancer incidence and mortality, particularly among cigarette smokers. In homes with high radon concentrations, taking steps to prevent radon from entering homes by sealing the basement would be expected to result in a corresponding decrease in the risk of lung cancer.

Magnitude of Effect: Increased risk that follows a dose-response gradient, with small increases in risk for levels experienced in most at-risk homes to greater increases in risk for high-level exposures.

  • Study Design: Cohort and case-control studies.
  • Internal Validity: Fair.
  • Consistency: Good.
  • External Validity: Fair.

Interventions Associated With an Increased Risk of Lung Cancer

Beta-carotene supplementation in current smokers

Based on solid evidence, high-intensity smokers who take pharmacological doses of beta-carotene have an increased lung cancer incidence and mortality that is associated with taking the supplement.

Magnitude of Effect: Increased risk, small magnitude.

  • Study Design: Two randomized controlled trials (RCTs) with consistent results.
  • Internal Validity: Good.
  • Consistency: Good.
  • External Validity: Good.

Interventions That Do Not Decrease Risk of Lung Cancer

Beta-carotene in nonsmokers

Based on solid evidence, nonsmokers who take pharmacological doses of beta-carotene do not experience significantly different lung cancer incidence or mortality compared with taking a placebo.

Magnitude of Effect: No substantive effect.

  • Study Design: RCT.
  • Internal Validity: Good.
  • Consistency: Good.
  • External Validity: Fair.

Vitamin E (Tocopherol)

Based on solid evidence, taking vitamin E supplements does not affect the risk of lung cancer.

Magnitude of Effect: Strong evidence of no association.

  • Study Design: RCTs.
  • Internal Validity: Good.
  • Consistency: Fair.
  • External Validity: Good.
References
  1. Pinsky PF: Racial and ethnic differences in lung cancer incidence: how much is explained by differences in smoking patterns? (United States). Cancer Causes Control 17 (8): 1017-24, 2006. [PUBMED Abstract]
  2. Friedman DL, Whitton J, Leisenring W, et al.: Subsequent neoplasms in 5-year survivors of childhood cancer: the Childhood Cancer Survivor Study. J Natl Cancer Inst 102 (14): 1083-95, 2010. [PUBMED Abstract]

Incidence and Mortality

Lung cancer has a tremendous impact on the health of the American public, with an estimated 226,650 new cases and 124,730 deaths predicted in 2025 in men and women combined.[1] Lung cancer incidence and mortality rates increased markedly throughout most of the 20th century, first in men and then in women. The trends in lung cancer incidence and mortality rates have closely mirrored historical patterns of smoking prevalence, after accounting for an appropriate latency period. Because of historical differences in smoking prevalence between men and women, lung cancer rates in men have consistently declined since the mid-1980s, but rates in women have only declined since the mid-2000s.[2] The incidence rate in men declined from a high of 96.57 cases per 100,000 men in 1984 to 46.68 cases per 100,000 men in 2021. The incidence rate in women declined from a high of 51.01 cases per 100,000 women in 2005 to 41.58 cases per 100,000 women in 2021.[3] In the United States, lung cancer will account for about 11% of new cancer cases and about 20% of all cancer deaths in 2025. Lung cancer is the leading cause of cancer deaths in both men and women. In 2025, an estimated 60,540 deaths due to lung cancer will occur among U.S. women, compared with an estimated 42,170 deaths due to breast cancer.[1]

Lung cancer incidence and mortality are highest in Black men compared with other racial and ethnic groups in the United States.[4] Between 2017 and 2021, the incidence rate in Black men was higher than in White men (66.5 vs. 60.0 cases per 100,000 men, respectively), whereas among women, the incidence rate in Black women was lower than in White women (43.2 vs. 52.2 cases per 100,000 women, respectively). Similarly, between 2018 and 2022, the mortality rate in Black men was higher than in White men (46.7 vs. 41.2 deaths per 100,000 men, respectively), whereas the mortality rate in Black women was lower than in White women (25.9 vs. 31.0 deaths per 100,000 women, respectively).[4]

Surgical treatment or radiation therapy is the treatment of choice for early stages of cancer.[5] The overall 5-year relative survival rate from lung cancer was 26.7% from 2014 to 2020. Lung cancer survival is worse for men compared with women and for Black individuals compared with White individuals. For example, 5-year lung cancer survival rates were lower in Black men than in White men (20.1% vs. 22.6%, respectively) and lower in Black women than in White women (28.2% vs. 30.8%, respectively).[3]

The hypothesis has been proposed that women may be more susceptible than men to lung cancer caused by smoking. However, the results of studies that compared the association between smoking and lung cancer in men and women using appropriate comparisons do not support this hypothesis.[6]

The results of the Multi-Ethnic Cohort Study indicated that for a given degree of cigarette smoking, African American individuals had a higher risk of lung cancer than other racial and ethnic groups.[7] Menthol cigarettes have been hypothesized as one potential factor contributing to the observed greater susceptibility to smoking-caused lung cancer in African American individuals, but menthol cigarettes have not been observed to be associated with a higher risk of lung cancer than nonmenthol cigarettes.[8,9]

References
  1. American Cancer Society: Cancer Facts and Figures 2025. American Cancer Society, 2025. Available online. Last accessed January 16, 2025.
  2. Edwards BK, Brown ML, Wingo PA, et al.: Annual report to the nation on the status of cancer, 1975-2002, featuring population-based trends in cancer treatment. J Natl Cancer Inst 97 (19): 1407-27, 2005. [PUBMED Abstract]
  3. Surveillance Research Program, National Cancer Institute: SEER*Explorer: An interactive website for SEER cancer statistics. Bethesda, MD: National Cancer Institute. Available online. Last accessed December 30, 2024.
  4. National Cancer Institute: SEER Stat Fact Sheets: Lung and Bronchus. Bethesda, Md: National Institutes of Health. Available online. Last accessed December 12, 2024.
  5. Spira A, Ettinger DS: Multidisciplinary management of lung cancer. N Engl J Med 350 (4): 379-92, 2004. [PUBMED Abstract]
  6. Bain C, Feskanich D, Speizer FE, et al.: Lung cancer rates in men and women with comparable histories of smoking. J Natl Cancer Inst 96 (11): 826-34, 2004. [PUBMED Abstract]
  7. Haiman CA, Stram DO, Wilkens LR, et al.: Ethnic and racial differences in the smoking-related risk of lung cancer. N Engl J Med 354 (4): 333-42, 2006. [PUBMED Abstract]
  8. Blot WJ, Cohen SS, Aldrich M, et al.: Lung cancer risk among smokers of menthol cigarettes. J Natl Cancer Inst 103 (10): 810-6, 2011. [PUBMED Abstract]
  9. Alberg AJ, Ford JG, Samet JM, et al.: Epidemiology of lung cancer: ACCP evidence-based clinical practice guidelines (2nd edition). Chest 132 (3 Suppl): 29S-55S, 2007. [PUBMED Abstract]

Cigarette Smoking Is the Primary Risk Factor

The epidemic of lung cancer in the 20th century was primarily due to increases in cigarette smoking, the predominant cause of lung cancer. The threefold variation in lung cancer mortality rates across the United States more or less parallels long-standing state-specific differences in the prevalence of cigarette smoking. For example, average annual age-adjusted lung cancer death rates for 1996 to 2000 were highest in Kentucky (78 deaths per 100,000 individuals), where 31% of residents were current smokers in 2001. Lung cancer death rates were lowest in Utah (26 deaths per 100,000 individuals), which had the lowest prevalence of cigarette smoking (13%).[1]

References
  1. Weir HK, Thun MJ, Hankey BF, et al.: Annual report to the nation on the status of cancer, 1975-2000, featuring the uses of surveillance data for cancer prevention and control. J Natl Cancer Inst 95 (17): 1276-99, 2003. [PUBMED Abstract]

The Biology of Carcinogenesis

Understanding the biology of carcinogenesis is crucial to the development of effective prevention and treatment strategies. Two important concepts in this regard are the multistep nature of carcinogenesis and the diffuse field-wide carcinogenic process. Epithelial cancers in the lung appear to develop in a series of steps extending over years. Epithelial carcinogenesis is conceptually divided into three phases: initiation, promotion, and progression. This process has been inferred from human studies identifying clinical-histological premalignant lesions (e.g., metaplasia and dysplasia). The concept of field carcinogenesis is that multiple independent neoplastic lesions occurring within the lung can result from repeated exposure to carcinogens, primarily tobacco. Patients developing cancers of the aerodigestive tract secondary to cigarette smoke also are likely to have multiple premalignant lesions of independent origin within the carcinogen-exposed field. The concepts of multistep and field carcinogenesis provide a model for prevention studies.[1]

References
  1. Lippman SM, Benner SE, Hong WK: Cancer chemoprevention. J Clin Oncol 12 (4): 851-73, 1994. [PUBMED Abstract]

Risk Factors

Factors Associated With Increased Risk of Lung Cancer

Cigarette smoking

The most important risk factor for lung cancer (and for many other cancers) is cigarette smoking.[1–3] Epidemiological data have established that cigarette smoking is the predominant cause of lung cancer. This causative link has been widely recognized since the 1960s, when national reports in Great Britain and the United States brought the cancer risk of smoking prominently to the public’s attention.[2] The lifetime risk of lung cancer was estimated in a Swiss population to be 15% in men who smoke and 12% in women who smoke, compared with 2% or less in nonsmokers.[4] The percentages of lung cancers estimated to be caused by tobacco smoking in males and females are 90% and 78%, respectively. The manufactured cigarette has changed over time, but there is no evidence to suggest that changes such as low tar or low nicotine cigarettes have resulted in reduced lung cancer risks.[5,6] Cigarette smoking is the most important contributor to the lung cancer burden because of its high prevalence of use and because cigarette smokers tend to smoke frequently, but cigar and pipe smoking have also been associated independently in case-control and cohort studies with increased lung cancer risk.[7,8] The cigar risks are of particular concern because of the increased prevalence of cigar use in the United States.[9]

The development of lung cancer is the culmination of multistep carcinogenesis. Genetic damage caused by chronic exposure to carcinogens, such as those in cigarette smoke, is the driving force behind the multistep process. Evidence of genetic damage is the association of cigarette smoking with the formation of the DNA adducts in human lung tissue. A strong link between tobacco smoke and lung carcinogenesis has been established by molecular data.[10,11]

Secondhand tobacco smoke

Secondhand tobacco smoke is also an established cause of lung cancer.[12] Secondhand smoke has the same components as inhaled mainstream smoke, though in lower absolute concentrations, between 1% and 10% depending on the constituent. Elevated biomarkers of tobacco exposure, including urinary cotinine, urinary 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) metabolites, and carcinogen-protein adducts, are seen in those who are exposed to secondhand cigarette smoke.[13–15]

Family history

A positive family history of lung cancer is a risk factor for lung cancer. The results of a meta-analysis of epidemiological studies indicated that those with a positive family history of lung cancer were at approximately twice the risk of lung cancer compared with those with no affected relatives.[16,17] Cigarette smoking behavior tends to run in families and family members are exposed to secondhand smoke, so the extent to which measured family history represents a genetic predisposition to lung cancer independent of the shared risk factor of cigarette smoking is uncertain.

Human immunodeficiency virus (HIV) infection

HIV infection has been observed to be statistically associated with an increased lung cancer risk; for example, the results of a meta-analysis of 13 studies indicated HIV-infected individuals had a 2.6-fold higher risk of lung cancer than non-HIV-infected individuals (standard incidence ratio, 2.6; 95% confidence interval [CI], 2.1–3.1).[18] The clinical significance of this association remains to be elucidated, as it raises the possibility that HIV infection increases susceptibility to lung cancer, but may merely reflect the high smoking prevalence (study estimates ranged from 59% to 96%) among those infected with HIV compared with the general population (smoking prevalence approximately 20%).

Other environmental causes of lung cancer

Occupational exposures to lung carcinogens

Several environmental exposures other than tobacco smoke are causally associated with lung cancer, but the proportion of the lung cancer burden due to these exposures is small compared with cigarette smoking. Many lung carcinogens have been identified in studies of high occupational exposures. Considered in total, occupational exposures have been estimated to account for approximately 10% of lung cancers.[19] These carcinogens include asbestos, radon, tar and soot (sources of polycyclic aromatic hydrocarbons), arsenic, chromium, nickel, beryllium, and cadmium.[20] For many of these workplace carcinogens, cigarette smoking interacts synergistically to increase the risk.[21] In developed countries, workplace exposures to these agents have largely been controlled.

Radiation exposure

Based on studies of populations exposed to high doses of radiation, lung cancer has been determined to be one of the cancers that is causally associated with exposure to ionizing radiation.[22] Two types of radiation that are relevant to lung cancer include high-energy ionizing electromagnetic radiation (such as x-rays and gamma rays) and particles (such as alpha particles and neutrons).

An important early source of data about radiation exposure came from studies of atomic bomb survivors in Japan; these studies demonstrated that a single high-dose exposure to gamma rays is sufficient to increase the risk of lung cancer in a dose-dependent fashion.[23] Lung cancer risk in patients treated with radiation for a number of medical conditions has also been evaluated. Studies of patients with tuberculosis who were treated with pneumothorax and monitored with frequent fluoroscopy, with resulting cumulative radiation doses of about 85 rads (0.85 Gy) staggered over time, indicated that any lung cancer risks associated with this exposure pattern, if they exist, are difficult to detect.[24,25] In contrast, the results of many studies provide clear-cut evidence that radiation therapy to the chest to treat cancer results in an increased risk of lung cancer in a dose-dependent manner. The evidence is most abundant for breast cancer [26–29] and Hodgkin lymphoma.[30] The risk of lung cancer after radiation therapy is amplified among patients who smoke cigarettes, compared with nonsmokers.[26,27,29,30]

The association between radiation exposure and lung cancer has implications for the general population in countries such as the United States, where computed tomography (CT) scans are relatively common and may contribute to an excess of cancer at the population level.[31] In light of the established association between exposure to ionizing radiation and lung cancer risk, researchers have urged caution to minimize risks when cancer screening involves ionizing radiation exposure, such as using of low-dose spiral CT screening for lung cancer instead of higher-dose techniques.[32,33]

Because they deposit concentrated energy in tissue, particles (e.g., alpha particles) produce more biological damage at an equivalent dose than radiation (e.g., x-rays).[34] A public health concern is radon, the primary source of alpha particles. Radon is an inert gas produced naturally in the decay series of uranium. Along with other supportive scientific evidence, studies of underground uranium miners exposed to very high levels of radon have demonstrated that radon exposure causes lung cancer.[22] This effect is amplified considerably in miners who smoke.[35] Radon has broader societal interest because it can enter buildings as a soil-derived gas and is a prevalent population-level exposure.

Estimates of the proportion of lung cancer deaths attributable to indoor exposure to radon vary by method of estimation and by the levels of radon exposure in a country, but the median estimates are 26% for lifelong nonsmokers (range, 13%–50%) and 10% for ever smokers (range, 7%–13%).[36–38] Because of a synergistic interaction between cigarette smoking and radon exposure, the radon-associated risk of lung cancer among smokers is considerably greater than for nonsmokers.[39] The prevention strategy for residents of homes with high radon concentrations is to have the basement sealed to prevent radon gas from leaking into the home.[40]

Air pollution

Although early evidence from case-control and cohort studies did not support an association between air pollution and lung cancer, the evidence now points to a genuine association.[41] In particular, two prospective cohort studies provide evidence to suggest that air pollution is weakly associated with the risk of lung cancer. In an extended follow-up of a study of six U.S. cities, the adjusted relative risk (RR) of lung cancer mortality for each 10 µg/m3 increase in concentration of fine-particulate was 1.27 (95% CI, 0.96–1.69).[42] Using data from the American Cancer Society’s Cancer Prevention Study II, it was observed that compared with the least polluted areas, residence in areas with high sulfate concentrations was associated with an increased risk of lung cancer (adjusted RR, 1.4; 95% CI, 1.1–1.7) after adjustment for occupational exposures and the factors mentioned above.[43] In a subsequent update to this report, the risk of lung cancer was observed to increase 14% for each 10 μg/m3 increase in concentration of fine particles.[44] The evidence indicating an association between constituents of ambient air pollution and increased lung cancer mortality continues to strengthen, with reports from Asia,[45,46] New Zealand,[47] and Europe,[48] documenting increased risks with exposure to certain components of particulate matter.

Factors of Uncertain Association With Risk

Dietary factors

Studies of dietary factors have yielded intriguing findings, but because the diets of smokers tend to be less healthy than those of nonsmokers, it is challenging to separate the influence of dietary factors from the effects of smoking. When considering the relationships between lung cancer and dietary factors, confounding factors related to cigarette smoking cannot be dismissed as a possible explanation.

While the focus has been on fruit and vegetable consumption and micronutrients, a wide range of dietary and anthropometric factors have been investigated. Anthropometric measures have been studied, indicating a tendency for leaner persons to have increased lung cancer risk relative to those with greater body mass index.[49,50] The results of a meta-analysis showed that alcohol drinking in the highest consumption categories only (in excess of about a drink a day) was associated with an increased risk of lung cancer.

Physical activity

A meta-analysis of leisure-time physical activity and lung cancer risk revealed that higher levels of physical activity protect against lung cancer.[51] The overall evidence for physical activity has been mixed, but several studies have reported that individuals who are more physically active have a lower risk of lung cancer than those who are more sedentary,[52–54] even after adjustment for cigarette smoking. The WCRF evidence review rated the inverse association between physical activity and lung cancer as limited suggestive evidence.[55]

Studies of physical activity yield findings consistent with an inverse association, but because physical activity behaviors differ between smokers and nonsmokers, it is difficult to infer that there is a direct relationship between physical activity and lung cancer risk.

Lung cancer in never smokers

In countries where cigarette smoking is common, about 10% to 20% of lung cancer cases occur in never smokers.[56] Radon and secondhand smoke exposure are established causes of lung cancer in never smokers. An increase in lung cancer risk among never smokers also has been observed with exposure to asbestos, ionizing radiation from sources other than radon, and indoor air pollution caused by combustion of coal or other solid fuel.[57] Limited data are available about the association of lung cancer in never smokers with physical activity, diet, alcohol, and anthropometry, yet they typically suggest that the relationships do not differ markedly from those in ever smokers.[49,52–54,58–60] Nevertheless, the inability to fully control for confounding by smoking in epidemiological analyses of ever smokers and the possibility of different lung cancer causal pathways from never and ever smokers warrants care when extrapolating results for ever smokers to never smokers.

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  29. Kaufman EL, Jacobson JS, Hershman DL, et al.: Effect of breast cancer radiotherapy and cigarette smoking on risk of second primary lung cancer. J Clin Oncol 26 (3): 392-8, 2008. [PUBMED Abstract]
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Interventions Associated With Decreased Risk of Lung Cancer

Smoking Avoidance and Cessation

Substantial harm to public health accrues from addiction to cigarette smoking. Compared with nonsmokers, smokers experience a dose-dependent increase in the risk of developing lung cancer (and many other malignancies).[1,2]

Approximately 85% of all lung cancer deaths are estimated to be attributed to cigarette smoking. Substantial benefits accrue to the smoker by quitting smoking. For more information, see Cigarette Smoking: Health Risks and How to Quit. Avoidance of tobacco use is the most effective measure to prevent lung cancer. The preventive effect of smoking cessation depends on the duration and intensity of prior smoking and upon time since cessation. Compared with the risk in persistent smokers, a 30% to 60% reduction in lung cancer mortality risk has been noted after 10 years of cessation.[2–6] Although lung cancer mortality risk can be greatly reduced by quitting for a long period of time, the risk will never be as low as the risk in nonsmokers.[6] This emphasizes the importance of discouraging smoking initiation in younger people.

The benefits of tobacco control at the population level provide strong quasi-experimental evidence that reducing population-level exposure to cigarettes has resulted in population-level declines in the occurrence of lung cancer. Reduced tobacco consumption, resulting from decreases in smoking initiation and increases in smoking cessation, led to a decline in overall age-adjusted lung cancer mortality among men since the mid-1980s, consistent with reductions in smoking prevalence among men since the 1960s.[7] Gender differences in time trends for lung cancer are a reflection of (1) the later adoption of cigarette smoking in women compared with men and (2) the later reduction in smoking prevalence among women compared with men.

Smoking cessation guidelines

Nicotine dependence exposes smokers in a dose-dependent fashion to carcinogenic and genotoxic elements that cause lung cancer.[4] Overcoming nicotine dependence is often extremely difficult. The Agency for Healthcare Research and Quality (formerly the Agency for Health Care Policy and Research [AHCPR]) developed a set of clinical smoking-cessation guidelines for helping nicotine-dependent patients and health care providers.[5] The six major elements of the guidelines include the following:

  1. Clinicians must document the tobacco-use status of every patient.
  2. Every patient using tobacco should be offered one or more of the effective smoking cessation treatments that are available.
  3. Every patient using tobacco should be provided with at least one of the effective brief cessation interventions that are available.
  4. More intense interventions are more effective than less intense interventions in producing long-term tobacco abstinence, reflecting the dose-response relationship between the intervention and its outcome.
  5. One or more of the three treatment elements identified as being particularly effective should be included in smoking-cessation treatment:
    1. Nicotine-replacement (e.g., nicotine patches and gum) or other evidence-based smoking cessation pharmacotherapy (e.g., varenicline or bupropion).
    2. Social support from clinician in the form of encouragement and assistance.
    3. Skills training and problem solving (cessation and abstinence techniques).
  6. To be effective, health care systems must make institutional changes resulting in systematic identification of tobacco users and intervention with these patients at every visit.

Pharmacotherapy for smoking cessation

Many pharmacotherapies for smoking cessation, including nicotine replacement therapies (e.g., gum, patch, spray, lozenge, and inhaler) and other smoking cessation pharmacotherapies (e.g., varenicline and bupropion), result in statistically significant increases in smoking cessation rates compared with placebo. Based on a synthesis of the results of 110 randomized trials, nicotine replacement therapy treatments, alone or in combination, improve cessation rates over placebos after 6 months (relative risk, 1.58; 95% confidence interval, 1.50–1.66).[8] Since the AHCPR guidelines were published, additional evidence of the effectiveness of such pharmacotherapies for smoking cessation has been published.[9–11] The choice of therapy should be individualized based on a number of factors, including past experience, preference, and potential agent side effects. For more information on pharmacotherapy for smoking cessation, see Cigarette Smoking: Health Risks and How to Quit.

Population-level interventions

In addition to individually focused cessation efforts, a number of tobacco control strategies at the community, state, and national level have been credited with reducing the prevalence of smoking. Strategies include the following:[12,13]

  • Reducing minors’ access to tobacco products.
  • Disseminating effective school-based prevention curricula together with media strategies.
  • Raising the cost of tobacco products by raising taxes.
  • Using tobacco excise taxes to fund community-level interventions including mass media.
  • Providing proven quitting strategies through health care organizations.
  • Adopting smoke-free laws and policies.

Smoke-free workplace legislation

A review of more than 50 studies found that smoke-free workplace legislation was consistently associated with reduced secondhand smoke exposure, whether measured in reduced time of exposure (71%–100% reduction) or prevalence of persons exposed to secondhand smoke (22%–85% reduction), with particularly marked reductions among hospitality workers.[14] Smoke-free workplace legislation was associated with consistent and statistically significant reductions in levels of nicotine, dust, benzene, and particulate matter. Health indicators including respiratory systems, sensory symptoms, and hospital admissions were reported as outcomes in 25 studies. With respect to health outcomes, a consistent finding was reduced hospital admissions for cardiac events. Evidence suggested that smoke-free workplace legislation may also result in reduced prevalence of active cigarette smoking; for example, one study observed a 32% decreased smoking prevalence in a county that enacted smoke-free workplace legislation compared with a 2.8% decrease in nearby counties with no smoke-free workplace legislation.

Preventing Occupational Exposure to Lung Carcinogens

After cigarette smoking and exposure to secondhand smoke, occupational exposure to lung carcinogens, such as asbestos, arsenic, nickel, and chromium, is the most important contributor to the lung cancer burden. When occupational exposure to lung carcinogens are all considered together, 9% to 15% of all lung cancer deaths can be attributed to occupational exposure to lung carcinogens.[15] Reducing or eliminating workplace exposures to known lung carcinogens would be expected to result in a corresponding decrease in the risk of lung cancer. Consequently, the proportion of the lung cancer burden attributable to occupational exposures is declining over time in countries like the United States that have taken steps to protect the workforce from exposure to known lung carcinogens.

References
  1. The Health Consequences of Smoking: A Report of the Surgeon General. U.S. Department of Health and Human Services, CDC, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health, 2004. Also available online. Last accessed April 9, 2025.
  2. The Health Benefits of Smoking Cessation: a report of the Surgeon General. US Department of Health and Human Services, Public Health Service, Centers for Disease Control, Centers for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health, DHHS Publ No (CDC) 90-8416, 1990.
  3. Schottenfeld D, Fraumeni JF Jr, eds.: Cancer Epidemiology and Prevention. 2nd ed. Oxford University Press, 1996.
  4. Cinciripini PM, Hecht SS, Henningfield JE, et al.: Tobacco addiction: implications for treatment and cancer prevention. J Natl Cancer Inst 89 (24): 1852-67, 1997. [PUBMED Abstract]
  5. Fiore MC, Bailey WC, Cohen SJ, et al.: Smoking Cessation: Clinical Practice Guideline No 18. US Department of Health and Human Services, Public Health Service, Agency for Health Care Policy and Research, 1996. AHCPR Publ No 96-0692.
  6. Tindle HA, Stevenson Duncan M, Greevy RA, et al.: Lifetime Smoking History and Risk of Lung Cancer: Results From the Framingham Heart Study. J Natl Cancer Inst 110 (11): 1201-1207, 2018. [PUBMED Abstract]
  7. Greenlee RT, Murray T, Bolden S, et al.: Cancer statistics, 2000. CA Cancer J Clin 50 (1): 7-33, 2000 Jan-Feb. [PUBMED Abstract]
  8. Silagy C, Lancaster T, Stead L, et al.: Nicotine replacement therapy for smoking cessation. Cochrane Database Syst Rev (3): CD000146, 2004. [PUBMED Abstract]
  9. Hurt RD, Sachs DP, Glover ED, et al.: A comparison of sustained-release bupropion and placebo for smoking cessation. N Engl J Med 337 (17): 1195-202, 1997. [PUBMED Abstract]
  10. Jorenby DE, Leischow SJ, Nides MA, et al.: A controlled trial of sustained-release bupropion, a nicotine patch, or both for smoking cessation. N Engl J Med 340 (9): 685-91, 1999. [PUBMED Abstract]
  11. Hughes JR, Goldstein MG, Hurt RD, et al.: Recent advances in the pharmacotherapy of smoking. JAMA 281 (1): 72-6, 1999. [PUBMED Abstract]
  12. Wingo PA, Ries LA, Giovino GA, et al.: Annual report to the nation on the status of cancer, 1973-1996, with a special section on lung cancer and tobacco smoking. J Natl Cancer Inst 91 (8): 675-90, 1999. [PUBMED Abstract]
  13. Koh HK: The end of the “tobacco and cancer” century. J Natl Cancer Inst 91 (8): 660-1, 1999. [PUBMED Abstract]
  14. Callinan JE, Clarke A, Doherty K, et al.: Legislative smoking bans for reducing secondhand smoke exposure, smoking prevalence and tobacco consumption. Cochrane Database Syst Rev (4): CD005992, 2010. [PUBMED Abstract]
  15. Alberg AJ, Ford JG, Samet JM, et al.: Epidemiology of lung cancer: ACCP evidence-based clinical practice guidelines (2nd edition). Chest 132 (3 Suppl): 29S-55S, 2007. [PUBMED Abstract]

Interventions Associated With Increased Risk of Lung Cancer

Beta-Carotene Supplementation in Smokers

Results of the National Cancer Institute (NCI) Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) trial were first published in 1994.[1] This trial included 29,133 Finnish male chronic smokers aged 50 to 69 years in a 2 × 2 factorial design of alpha-tocopherol (50 mg/day) and beta-carotene (20 mg/day). Participants were randomly assigned to one of the following four groups for 5 to 8 years: beta-carotene alone, alpha-tocopherol alone, beta-carotene plus alpha-tocopherol, or placebo. Participants who received beta-carotene (alone or with alpha-tocopherol) had a higher incidence of lung cancer (relative risk [RR], 1.18; 95% confidence interval [CI], 1.03–1.36) and higher total mortality (RR, 1.08; 95% CI, 1.01–1.16). This effect appeared to be associated with heavier smoking (one or more packs/day) and alcohol intake (at least one drink/day).[2] Supplementation with alpha-tocopherol produced no overall effect on lung cancer (RR, 0.99; 95% CI, 0.87–1.13).

In 1996, the results of the U.S. Beta-Carotene and Retinol Efficacy Trial (CARET) were published.[3] This multicenter trial involved 18,314 smokers, former smokers, and asbestos-exposed workers who were randomly assigned to beta-carotene (at a higher dose than the ATBC trial, 30 mg/day) plus retinyl palmitate (25,000 IU/day) or placebo. The primary endpoint was lung cancer incidence. The trial was terminated early by the Data Monitoring Committee and NCI because its results confirmed the ATBC finding of a harmful effect of beta-carotene over that of placebo, which increased lung cancer incidence (RR, 1.28; 95% CI, 1.04–1.57) and total mortality (RR, 1.17; 95% CI, 1.03–1.33). In a follow-up study of CARET participants after the intervention discontinued, these effects attenuated for a period of time. After 6 years of postintervention follow-up, the postintervention RR for lung cancer incidence was 1.12 (95% CI, 0.97–1.31) and for total mortality was 1.08 (95% CI, 0.99–1.71). During the postintervention phase a larger RR among women, rather than men, emerged for both outcomes in subgroup analyses; the reason for this observation, if reliable, is not known.[4]

The overall findings from the ATBC [1,2] and CARET [3,5] studies, which include over 47,000 participants, demonstrated that pharmacological doses of beta-carotene increase lung cancer risk in relatively high-intensity smokers. The mechanism of this adverse effect is not known. Lung cancer risks were not increased in subsets of moderate-intensity smokers (less than a pack per day) in the ATBC study, or in former smokers in the CARET study. Evidence from other studies, such as the Physicians’ Health Study,[6] does not indicate that beta-carotene supplementation increases lung cancer risk in nonsmokers. Subsequent analyses of participants in these trials and cohorts suggest that the beneficial outcomes associated with high beta-carotene plasma levels may be due to increased dietary intake of fruits and vegetables. These findings show the importance of randomized controlled trials to confirm epidemiological studies.

References
  1. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. N Engl J Med 330 (15): 1029-35, 1994. [PUBMED Abstract]
  2. Albanes D, Heinonen OP, Taylor PR, et al.: Alpha-Tocopherol and beta-carotene supplements and lung cancer incidence in the alpha-tocopherol, beta-carotene cancer prevention study: effects of base-line characteristics and study compliance. J Natl Cancer Inst 88 (21): 1560-70, 1996. [PUBMED Abstract]
  3. Omenn GS, Goodman GE, Thornquist MD, et al.: Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med 334 (18): 1150-5, 1996. [PUBMED Abstract]
  4. Goodman GE, Thornquist MD, Balmes J, et al.: The Beta-Carotene and Retinol Efficacy Trial: incidence of lung cancer and cardiovascular disease mortality during 6-year follow-up after stopping beta-carotene and retinol supplements. J Natl Cancer Inst 96 (23): 1743-50, 2004. [PUBMED Abstract]
  5. Omenn GS, Goodman GE, Thornquist MD, et al.: Risk factors for lung cancer and for intervention effects in CARET, the Beta-Carotene and Retinol Efficacy Trial. J Natl Cancer Inst 88 (21): 1550-9, 1996. [PUBMED Abstract]
  6. Hennekens CH, Buring JE, Manson JE, et al.: Lack of effect of long-term supplementation with beta carotene on the incidence of malignant neoplasms and cardiovascular disease. N Engl J Med 334 (18): 1145-9, 1996. [PUBMED Abstract]

Interventions With Adequate Evidence That They Do Not Reduce Risk

Chemoprevention

Studies have examined whether it is possible to prevent cancer development in the lung using chemopreventive agents. Chemoprevention is defined as the use of specific natural or synthetic chemical agents to reverse, suppress, or prevent carcinogenesis before the development of invasive malignancy. So far, agents tested for efficacy in lung cancer chemoprevention have been micronutrients, such as beta-carotene and vitamin E.

Beta-carotene supplementation in nonsmokers

Two other randomized controlled trials of beta-carotene were carried out in populations that were not at excess risk of lung cancer. The Physicians’ Health Study was designed to study the effects of beta-carotene and aspirin in cancer and cardiovascular disease. The study was a randomized, double-blind, placebo-controlled trial begun in 1982 involving 22,071 male physicians aged 40 to 84 years. After 12 years of follow-up, beta-carotene was not associated with overall risk of cancer (relative risk [RR], 0.98) or lung cancer among current (11% of study population) or former (39% of study population) smokers.[1]

In the Women’s Health Study (WHS) approximately 40,000 female health professionals were randomly assigned to 50 mg beta carotene on alternate days or placebo. After a median of 2.1 years of beta-carotene treatment and 2 additional years of follow-up, there was no evidence that beta-carotene protected against lung cancer, as there were more lung cancer cases observed in the beta-carotene (n = 30) than placebo (n = 21) group.[2] The strong evidence from rigorous randomized, placebo-controlled trials clearly indicated that beta-carotene supplementation does not lower the risk of lung cancer in populations that are not high-risk for lung cancer.

Vitamin E supplementation

The Heart Outcomes Prevention Evaluation (HOPE) trial began in 1993 and continued follow-up as the HOPE-The Ongoing Outcomes (HOPE-TOO) through 2003. In this randomized, placebo-controlled trial, patients aged 55 years or older with vascular disease or diabetes were assigned to 400 IU vitamin E or placebo. With a median follow-up of 7 years, the group randomly assigned to vitamin E had a significantly lower lung cancer incidence rate (1.4%) than the placebo group (2.0%) (RR, 0.72; 95% confidence interval [CI], 0.53–0.98).[3] However, the protective association between vitamin E supplements and lung cancer in the HOPE-TOO study needs to be interpreted in the context of evidence from other randomized trials. In the National Cancer Institute Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) study, supplementation with alpha-tocopherol produced no overall effect on lung cancer (RR, 0.99; 95% CI, 0.87–1.13). In the WHS of 40,000 female health professionals, using 600 IU of vitamin E every other day showed no evidence of protection against lung cancer in women (RR, 1.09; 95% CI, 0.83–1.44).[4] The Medical Research Council/British Heart Foundation Heart Protection Study (HPS) is a randomized, placebo-controlled trial to test antioxidant vitamin supplementation with vitamin E, vitamin C, and beta-carotene among 20,536 United Kingdom adults with coronary disease, other occlusive arterial disease, or diabetes. The trial began recruitment in 1994, and as of the 2001 follow-up the results showed a slightly higher rate of lung cancer in the vitamin group compared with the placebo group (1.6% vs. 1.4%, respectively).[5]

Looking at the vitamin E results for the ATBC, HPS, and HOPE-TOO studies combined, the summary odds ratio was 0.97 (95% CI, 0.87–1.08),[3] and adding the results from the WHS to this would bring the association even closer to the null. The combined evidence for vitamin E supplementation thus continues to be consistent with no effect on lung cancer risk.

References
  1. Hennekens CH, Buring JE, Manson JE, et al.: Lack of effect of long-term supplementation with beta carotene on the incidence of malignant neoplasms and cardiovascular disease. N Engl J Med 334 (18): 1145-9, 1996. [PUBMED Abstract]
  2. Lee IM, Cook NR, Manson JE, et al.: Beta-carotene supplementation and incidence of cancer and cardiovascular disease: the Women’s Health Study. J Natl Cancer Inst 91 (24): 2102-6, 1999. [PUBMED Abstract]
  3. Lonn E, Bosch J, Yusuf S, et al.: Effects of long-term vitamin E supplementation on cardiovascular events and cancer: a randomized controlled trial. JAMA 293 (11): 1338-47, 2005. [PUBMED Abstract]
  4. Lee IM, Cook NR, Gaziano JM, et al.: Vitamin E in the primary prevention of cardiovascular disease and cancer: the Women’s Health Study: a randomized controlled trial. JAMA 294 (1): 56-65, 2005. [PUBMED Abstract]
  5. Heart Protection Study Collaborative Group: MRC/BHF Heart Protection Study of antioxidant vitamin supplementation in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 360 (9326): 23-33, 2002. [PUBMED Abstract]

Latest Updates to This Summary (04/17/2025)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Incidence and Mortality

Updated statistics with estimated new cases and deaths for 2025 (cited American Cancer Society as reference 1).

This summary is written and maintained by the PDQ Screening and Prevention Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about lung cancer prevention. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Screening and Prevention Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

  • be discussed at a meeting,
  • be cited with text, or
  • replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website’s Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Screening and Prevention Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

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PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”

The preferred citation for this PDQ summary is:

PDQ® Screening and Prevention Editorial Board. PDQ Lung Cancer Prevention. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/lung/hp/lung-prevention-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389452]

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Lung Cancer Screening (PDQ®)–Health Professional Version

Lung Cancer Screening (PDQ®)–Health Professional Version

Overview

Go to Patient Version

Note: The Overview section summarizes the published evidence on this topic. The rest of the summary describes the evidence in more detail.

Other PDQ summaries containing information related to lung cancer screening include the following:

Evidence of Benefit Associated With Screening

Screening by low-dose computed tomography (LDCT): Benefit

Two randomized trials have reported statistically significant reductions in lung cancer mortality associated with low-dose computed tomography (LDCT) screening. One trial reported that screening higher-risk individuals (30+ pack-years and either current smokers or quit within the past 15 years) aged 55 to 74 years three times, once annually, with LDCT reduced lung cancer mortality by 20% (95% confidence interval [CI], 6.8%–26.7%; P = .004) and all-cause mortality by 6.7% (95% CI, 1.2%–13.6%; P = .02) over screening with chest radiographs.[1] An updated analysis showed that the estimated reduction in lung cancer mortality was 16% (95% CI, 5%–25%).[2] The other trial reported that among high-risk current and former smokers, men who were randomly assigned to four rounds of LDCT screening had a 24% reduction (95% CI, 6%–39%) in lung cancer mortality, compared with men who were randomly assigned to no screening.[3]

Magnitude of Effect: About 20% to 24% relative reduction in lung cancer–specific mortality.

  • Study Design: Evidence obtained from randomized controlled trials (RCTs).
  • Internal Validity: Good.
  • Consistency: Good.
  • External Validity: Fair.

Screening by LDCT: Harms

False-positive exams

False-positive rates with LDCT screening have been high, although the magnitude of the rates varies with the definition of a positive screen.[1,4] False-positive exams may result in unnecessary invasive diagnostic procedures.

Magnitude of Effect: Two large randomized trials, the National Lung Screening Trial (NLST) and the Nederlands–Leuvens Longkanker Screenings Onderzoek Trial (NELSON), found that the average false-positive rate per screening round was 23.3% and 10.4%, respectively.[1,3,4] Using a more recent definition of a positive LDCT screening on the basis of the Lung-RADS criteria yields a false-positive rate that may be somewhat lower than that seen in the NLST.[4] A total of 0.06% of all false-positive screening results in the NLST led to a major complication after an invasive procedure was performed as a diagnostic follow-up to the screening. Over three screening rounds, 1.8% of NLST participants who did not have lung cancer had an invasive procedure after a positive screening result.

  • Study Design: Evidence obtained from an RCT.
  • Internal Validity: Good.
  • Consistency: Good.
  • External Validity: Fair.
Overdiagnosis from LDCT

Based on fair evidence, some lung cancers detected by LDCT screening appear to represent overdiagnosed cancer. However, estimates of overdiagnosis rates, derived typically by using data from randomized trials of LDCT screening, vary greatly. Therefore, the magnitude of overdiagnosis with LDCT screening is not clear. Overdiagnosed cancers result in unnecessary diagnostic procedures and also lead to unnecessary treatment. The harms of diagnostic procedures and treatment occur at the highest rate among long-term and/or heavy smokers because of smoking-associated comorbidities that increase risk propagation.

Magnitude of Effect: Uncertain.

  • Study Design: RCTs.
  • Internal Validity: Good.
  • Consistency: Evidence is consistent for the overall existence of overdiagnosis but is poor for determining the exact magnitude of effect.
  • External Validity: Fair.

Evidence of No Benefit Associated With Screening

Screening by chest x-ray and/or sputum cytology: Benefits

Based on solid evidence, screening with chest x-ray and/or sputum cytology does not reduce mortality from lung cancer in the general population or in ever-smokers.

Magnitude of Effect: Not applicable.

  • Study Design: RCTs.
  • Internal Validity: Good.
  • Consistency: Good.
  • External Validity: Good.

Screening by chest x-ray and/or sputum cytology: Harms

False-positive exams

Based on solid evidence, false-positive rates with chest x-rays are in the range of 5% to 10% per exam. False-positive exams may result in unnecessary invasive diagnostic procedures.

  • Study Design: RCTs.
  • Internal Validity: Good.
  • Consistency: Good.
  • External Validity: Good.
Overdiagnosis from chest x-ray and/or sputum cytology

Based on fair evidence, some of the lung cancers detected by screening chest x-ray and/or sputum cytology appear to represent overdiagnosed cancer; however, the magnitude of overdiagnosis is not clear. These cancers result in unnecessary diagnostic procedures and also lead to unnecessary treatment. The harms of diagnostic procedures and treatment occur at the highest rate among long-term and/or heavy smokers because of smoking-associated comorbidities that increase risk propagation.

Magnitude of Effect: Uncertain.

  • Study Design: RCTs.
  • Internal Validity: Good.
  • Consistency: Evidence is consistent for the overall existence of overdiagnosis but is poor for determining the exact magnitude of effect.
  • External Validity: Good.
References
  1. Aberle DR, Adams AM, Berg CD, et al.: Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med 365 (5): 395-409, 2011. [PUBMED Abstract]
  2. Pinsky PF, Church TR, Izmirlian G, et al.: The National Lung Screening Trial: results stratified by demographics, smoking history, and lung cancer histology. Cancer 119 (22): 3976-83, 2013. [PUBMED Abstract]
  3. de Koning HJ, van der Aalst CM, de Jong PA, et al.: Reduced Lung-Cancer Mortality with Volume CT Screening in a Randomized Trial. N Engl J Med 382 (6): 503-513, 2020. [PUBMED Abstract]
  4. Pinsky PF, Gierada DS, Black W, et al.: Performance of Lung-RADS in the National Lung Screening Trial: a retrospective assessment. Ann Intern Med 162 (7): 485-91, 2015. [PUBMED Abstract]

Incidence and Mortality

Lung cancer is the second most common form of noncutaneous cancer in the United States and is the leading cause of cancer death in both men and women. In 2025 alone, an estimated 110,680 men and 115,970 women will be diagnosed with lung cancer, and 64,190 men and 60,540 women will die of this disease. After rising rapidly over several decades in both sexes, the lung cancer death rate declined by 61% for men starting in 1990 and by 38% for women starting in 2002. From 2013 to 2022, death rates decreased by 4.8% per year in men and 3.7% per year in women.[1]

References
  1. American Cancer Society: Cancer Facts and Figures 2025. American Cancer Society, 2025. Available online. Last accessed January 16, 2025.

Risk Factors

The most important risk factor for lung cancer (as for many other cancers) is tobacco use.[1,2] Cigarette smoking has been definitively established by epidemiological and preclinical animal experimental data as the primary cause of lung cancer. This causative link has been widely recognized since the 1960s, when national reports in Great Britain and the United States brought the cancer risk of smoking prominently to public attention.[2] The percentages of lung cancers estimated to be caused by tobacco smoking in men and women are 90% and 78%, respectively.

For a complete description of factors associated with an increased or decreased risk of lung cancer, see Lung Cancer Prevention.

References
  1. The Health Consequences of Smoking: A Report of the Surgeon General. U.S. Department of Health and Human Services, CDC, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health, 2004. Also available online. Last accessed April 9, 2025.
  2. Smoking and Health: Report of the Advisory Committee to the Surgeon General of the Public Health Service. US Department of Health, Education, and Welfare, 1965. PHS Publ No 1103.

Evidence of Benefit Associated With Screening

Screening by Low-Dose Computed Tomography

There have been intensive efforts to improve lung cancer screening with newer technologies, including low-dose computed tomography (LDCT).[1,2] LDCT was shown to be more sensitive than chest radiography. In the Early Lung Cancer Action Project (ELCAP),[2] LDCT detected almost six times as many stage I lung cancers as chest radiography, and most of these tumors were no larger than 1 cm in diameter.

A systematic analysis [3] summarized 13 observational studies of LDCT, which included 60 to 5,201 participants and were conducted between 1993 and 2004. Some Japanese studies included nonsmokers, but the other studies were limited to current and former smokers. Variability in detection of nodules—between 3% and 51%—may be attributed to several factors:

  • The definition of nodules (some studies required a size threshold).
  • The computed tomography (CT) technology (thin slice detects more and smaller nodules).
  • Geographic variation in endemic granulomatous disease.

Overall, lung cancer was diagnosed in 1.1% to 4.7% of screened participants. Most of these diagnoses were early-stage disease.[3]

The National Lung Screening Trial (NLST) provided the first solid evidence that screening with LDCT can reduce lung cancer mortality risk in ever-smokers who have smoked 30 pack-years or longer and in former smokers who have quit within the past 15 years. The NLST included 33 centers across the United States. Eligible participants were aged of 55 years to 74 years at randomization, had a history of at least 30 pack-years of cigarette smoking, and, if former smokers, had quit within the past 15 years. A total of 53,454 individuals were enrolled; 26,722 participants were randomly assigned to receive screening with LDCT, and 26,732 participants were randomly assigned to receive screening with chest x-ray. Any noncalcified nodule found with LDCT that measured at least 4 mm in any diameter and any noncalcified nodule or mass identified on x-ray images were classified as positive. Radiologists, however, had the option of calling a final screen negative if a noncalcified nodule had been stable on the three screening exams. The LDCT group had a substantially higher rate of positive screening tests than did the radiography group (round 1, 27.3% vs. 9.2%; round 2, 27.9% vs. 6.2%; and round 3, 16.8% vs. 5.0%). Overall, 39.1% of participants in the LDCT group and 16.0% in the radiography group had at least one positive screening result. Of those who screened positive, the proportion with lung cancer (i.e., positive predictive value) was 3.6% in the LDCT group and 5.5% in the radiography group.[4]

In the LDCT group, 649 cancers were diagnosed after a positive screening test, 44 after a negative screening test, and 367 among participants who either missed the screening or received the diagnosis after the completion of the screening phase. In the radiography group, 279 cancers were diagnosed after a positive screening test, 137 after a negative screening test, and 525 among participants who either missed the screening or received the diagnosis after the completion of the screening phase. Three hundred fifty-six deaths from lung cancer occurred in the LDCT group, and 443 deaths from lung cancer occurred in the chest x-ray group; the relative reduction in the rate of death from lung cancer was 20% (95% confidence interval [CI], 6.8%–26.7%) with LDCT screening at a median duration of follow-up of 6.5 years.[4] An updated analysis showed that the estimated reduction in lung cancer mortality was 16% (95% CI, 5%–25%).[5] Overall, mortality was reduced by 6.7% (95% CI, 1.2%–13.6%). The number needed to screen with LDCT to prevent one death from lung cancer was 320.[4]

An extended follow-up analysis of the NLST reported mortality data after a median of 12.3 years of follow-up. The estimated number needed to screen with LDCT to prevent one lung cancer death was 303.[6]

Since the publication of the results of the NLST, more has been learned about who may benefit the most from screening for lung cancer using LDCT.[7–9] One group of investigators developed an individual risk model to assess who might benefit from screening. The model used additional factors not used as inclusion criteria in the NLST, such as a history of chronic obstructive pulmonary disease, personal or family history of lung cancer, and a more detailed smoking history. More individuals would have been eligible to be screened using the trial’s criteria as opposed to the inclusion criteria of the NLST without missing patients with cancer.[8] A second group performed a reanalysis of the NLST data, calculated each patient’s risk of developing lung cancer, and estimated each patient’s lung cancer mortality.[9] The investigators then divided the NLST participants into five groups on the basis of risk. The number needed to screen to avoid a lung cancer death in the low-risk group was 5,276; 161 screens were needed in the high-risk group to avoid a lung cancer death. Furthermore, the number of false-positive screens decreased from 1,648 in the lowest quintile of risk to 65 in the highest-risk group. The three highest quintiles of risk accounted for 88% of the mortality reduction from screening, whereas the lowest quintile accounted for only a 1% reduction in mortality. These studies illustrate possible improvements for determining the population of patients who may benefit the most from screening, potentially reducing the number of false positives and reducing the potential harm related to the adverse events associated with their evaluation. One other benefit of calculating individual risk is the ability to incorporate the findings into a shared decision-making process so that patients can decide whether to undergo screening.[9] However, a comparison of ten models used for predicting lung cancer or lung cancer mortality risk found that four of the models were well calibrated with reasonable discrimination, but none of these models were considered superior to the others for identifying lung cancer risk among individuals who had ever smoked. Additional work is needed to address modeling weaknesses.[10]

The NELSON trial (Nederlands–Leuvens Longkanker Screenings Onderzoek) conducted in Belgium and the Netherlands examined screening for lung cancer in smokers (13,195 men, 2,594 women, and 3 unknown) with CT, using a volume criterion for positivity.[11] Participants were recruited from population registries in the two countries based on responses to questionnaires about their smoking history and other data. Those who either smoked currently or had quit for fewer than 10 years and had smoked more than 15 cigarettes a day for over 25 years or more than 10 cigarettes a day for over 30 years were eligible. Those with serious comorbidities or previous cancers were excluded. All participants were randomly assigned equally to either usual care or an initial screen and three subsequent screens at intervals of 1, 2, and 2.5 years. The screening test was LDCT, which was retrospectively analyzed by supervised software to determine nodule segmentation and volume. After a minimum follow-up of 10 years, 90% of men assigned to screening complied with each opportunity on average, with a 2.1% rate of being referred for diagnosis. These men experienced a lung cancer incidence rate of 5.58 per 1,000 person-years and a lung cancer–specific mortality rate of 2.5 per 1,000 person-years, compared with 4.91 cases and 3.3 deaths per 1,000 person-years in men assigned to usual care. The mortality rate ratio for screening was 0.76 (95% CI, 0.61–0.94).[11]

Although the NELSON study used a usual-care arm instead of a chest x-ray arm, the results are consistent with the main NLST results discussed above, both in the impact on lung cancer mortality and in overdiagnosis. The mortality results were even more similar when the NELSON cohort was constrained to the NLST smoking eligibility subgroup. The two studies diverged in several ways, however. The NLST observed an all-cause mortality reduction consistent with the dominant effect of lung cancer on mortality among smokers. NELSON did not find such an effect. In addition, no healthy volunteer effect was observed in NELSON, while the NLST reported a substantial effect. However, these differences between the studies do not cast doubt on the main effect on lung cancer mortality but may invite further analyses to understand the inconsistencies better.

Other, smaller randomized clinical trials (RCTs) of LDCT that compare a nonscreening arm with LDCT are under way or are already completed in a number of countries.[12–18] These smaller trials are not powered to assess mortality as an endpoint, but there is an effort to combine the findings from these studies with the NELSON data, once the data are fully mature. These studies may also assess consistency with the NLST findings. In addition to the data gleaned from ongoing trials, data from the NLST, NELSON, and other completed trials are being analyzed to examine other important issues in lung cancer screening, including cost-effectiveness, quality of life, and whether screening would benefit individuals younger than those enrolled in the NLST and those with fewer than 30 pack-years of smoking exposure. Data from the U.S. Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial suggest that, in the absence of screening, the risk of lung cancer death for current smokers who have a smoking history of 20 to 29 pack-years is no different from that of former smokers who have quit within 15 years and have a smoking history of more than 30 pack-years (hazard ratio, 1.07; CI, 0.75–1.5).[19] Although the risk for the 20-to-29-pack-years current-smokers group is no different from that of the former-smokers group (for whom LDCT screening is recommended by the U.S. Preventive Services Task Force), the efficacy of screening is unknown in the 20-to-29-pack-years current-smokers group.[19]

[Note: A Guide has been developed to help patients and physicians assess the benefits and harms of LDCT screening for lung cancer.20]

Screening and Smoking Cessation

The target population for lung cancer screening has a high prevalence of current smokers compared with the general population. A lung cancer screening program could potentially impact the likelihood of smoking cessation, theoretically promoting cessation among those screened who have lung abnormalities detected on their screen. Conversely, screening could also be a deterrent to cessation among those with no evidence of lung abnormalities on their screen. The Danish Lung Cancer Screening Trial is a randomized trial that compared LDCT with no intervention among participants aged 50 to 70 years who had at least a 20 pack-year smoking history.[21] The proportion of participants who had quit smoking was monitored every year for 5 years of follow-up and remained virtually identical in the two groups from baseline (CT group and control group each had 23% ex-smokers) until the 5-year follow-up (43% ex-smokers in both groups). The comparison of these two randomized groups indicates that the CT screening program had zero net effect on the likelihood of smoking cessation.

Another report used data from the NLST to address the question of whether the screening result influenced the likelihood of smoking cessation.[22] The NLST compared CT with chest x-ray, and data from both arms were pooled to examine the impact of abnormal findings on the likelihood of smoking cessation. Compared with those who did not have abnormal findings, current smokers who had a screening examination that was suspicious for lung cancer (but was not lung cancer) were significantly more likely to have stopped smoking 1 year later. The associations with quitting smoking among those who had a major lung abnormality that was not suspicious for lung cancer, or those who had a minor abnormality, were weaker and not uniformly statistically significant.

A third study from the U.K. Lung Cancer Screening pilot trial of an LDCT scan found that screening was associated with a statistically significant increase in short- and long-term cessation, and this effect was greatest among those whose initial screening test was positive, warranting additional clinical investigation.[23]

The results of these studies suggest that the net impact of a CT program on smoking cessation varied,[21] but there appears to be a higher likelihood of smoking cessation among current smokers who have findings suspicious for lung cancer.[22] This is an important research area that needs to be clarified.

A meta-analysis that includes 85 RCTs published between 2010 and 2017 [24] concluded that electronic/Web-based, in-person counseling, and pharmacotherapy treatment interventions significantly increased the odds of successful smoking cessation among populations eligible for lung cancer screening.

References
  1. Ahrendt SA, Chow JT, Xu LH, et al.: Molecular detection of tumor cells in bronchoalveolar lavage fluid from patients with early stage lung cancer. J Natl Cancer Inst 91 (4): 332-9, 1999. [PUBMED Abstract]
  2. Henschke CI, McCauley DI, Yankelevitz DF, et al.: Early Lung Cancer Action Project: overall design and findings from baseline screening. Lancet 354 (9173): 99-105, 1999. [PUBMED Abstract]
  3. Bach PB, Mirkin JN, Oliver TK, et al.: Benefits and harms of CT screening for lung cancer: a systematic review. JAMA 307 (22): 2418-29, 2012. [PUBMED Abstract]
  4. Aberle DR, Adams AM, Berg CD, et al.: Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med 365 (5): 395-409, 2011. [PUBMED Abstract]
  5. Pinsky PF, Church TR, Izmirlian G, et al.: The National Lung Screening Trial: results stratified by demographics, smoking history, and lung cancer histology. Cancer 119 (22): 3976-83, 2013. [PUBMED Abstract]
  6. National Lung Screening Trial Research Team: Lung Cancer Incidence and Mortality with Extended Follow-up in the National Lung Screening Trial. J Thorac Oncol 14 (10): 1732-1742, 2019. [PUBMED Abstract]
  7. Moyer VA; U.S. Preventive Services Task Force: Screening for lung cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 160 (5): 330-8, 2014. [PUBMED Abstract]
  8. Tammemägi MC, Katki HA, Hocking WG, et al.: Selection criteria for lung-cancer screening. N Engl J Med 368 (8): 728-36, 2013. [PUBMED Abstract]
  9. Kovalchik SA, Tammemagi M, Berg CD, et al.: Targeting of low-dose CT screening according to the risk of lung-cancer death. N Engl J Med 369 (3): 245-54, 2013. [PUBMED Abstract]
  10. Katki HA, Kovalchik SA, Petito LC, et al.: Implications of Nine Risk Prediction Models for Selecting Ever-Smokers for Computed Tomography Lung Cancer Screening. Ann Intern Med 169 (1): 10-19, 2018. [PUBMED Abstract]
  11. de Koning HJ, van der Aalst CM, de Jong PA, et al.: Reduced Lung-Cancer Mortality with Volume CT Screening in a Randomized Trial. N Engl J Med 382 (6): 503-513, 2020. [PUBMED Abstract]
  12. Paci E, Puliti D, Lopes Pegna A, et al.: Mortality, survival and incidence rates in the ITALUNG randomised lung cancer screening trial. Thorax 72 (9): 825-831, 2017. [PUBMED Abstract]
  13. Wille MM, Dirksen A, Ashraf H, et al.: Results of the Randomized Danish Lung Cancer Screening Trial with Focus on High-Risk Profiling. Am J Respir Crit Care Med 193 (5): 542-51, 2016. [PUBMED Abstract]
  14. Infante M, Cavuto S, Lutman FR, et al.: Long-Term Follow-up Results of the DANTE Trial, a Randomized Study of Lung Cancer Screening with Spiral Computed Tomography. Am J Respir Crit Care Med 191 (10): 1166-75, 2015. [PUBMED Abstract]
  15. Pastorino U, Rossi M, Rosato V, et al.: Annual or biennial CT screening versus observation in heavy smokers: 5-year results of the MILD trial. Eur J Cancer Prev 21 (3): 308-15, 2012. [PUBMED Abstract]
  16. Pastorino U, Silva M, Sestini S, et al.: Prolonged lung cancer screening reduced 10-year mortality in the MILD trial: new confirmation of lung cancer screening efficacy. Ann Oncol 30 (7): 1162-1169, 2019. [PUBMED Abstract]
  17. Doria-Rose VP, Szabo E: Screening and prevention of lung cancer. In: Kernstine KH, Reckamp KL, eds.: Lung Cancer: A Multidisciplinary Approach to Diagnosis and Management. Demos Medical, 2011, pp 53-72.
  18. Becker N, Motsch E, Trotter A, et al.: Lung cancer mortality reduction by LDCT screening-Results from the randomized German LUSI trial. Int J Cancer 146 (6): 1503-1513, 2020. [PUBMED Abstract]
  19. Pinsky PF, Kramer BS: Lung Cancer Risk and Demographic Characteristics of Current 20-29 Pack-year Smokers: Implications for Screening. J Natl Cancer Inst 107 (11): , 2015. [PUBMED Abstract]
  20. Woloshin S, Schwartz LM, Black WC, et al.: Cancer screening campaigns–getting past uninformative persuasion. N Engl J Med 367 (18): 1677-9, 2012. [PUBMED Abstract]
  21. Ashraf H, Saghir Z, Dirksen A, et al.: Smoking habits in the randomised Danish Lung Cancer Screening Trial with low-dose CT: final results after a 5-year screening programme. Thorax 69 (6): 574-9, 2014. [PUBMED Abstract]
  22. Tammemägi MC, Berg CD, Riley TL, et al.: Impact of lung cancer screening results on smoking cessation. J Natl Cancer Inst 106 (6): dju084, 2014. [PUBMED Abstract]
  23. Brain K, Carter B, Lifford KJ, et al.: Impact of low-dose CT screening on smoking cessation among high-risk participants in the UK Lung Cancer Screening Trial. Thorax 72 (10): 912-918, 2017. [PUBMED Abstract]
  24. Cadham CJ, Jayasekera JC, Advani SM, et al.: Smoking cessation interventions for potential use in the lung cancer screening setting: A systematic review and meta-analysis. Lung Cancer 135: 205-216, 2019. [PUBMED Abstract]

Evidence of No Benefit Associated With Screening

Screening by Chest X-ray and/or Sputum Cytology

The question of lung cancer screening dates back to the 1950s, when rising lung cancer incidence and mortality rates indicated a need for intervention. In response to the emerging lung cancer problem, five studies of chest imaging, two of which were controlled, were undertaken during the 1950s and 1960s.[1–8] Two studies also included sputum cytology.[1–5] The results of these studies suggested no overall benefit of screening, although design limitations prevented the studies from providing definitive evidence.

In the early 1970s, the National Cancer Institute funded the Cooperative Early Lung Cancer Detection Program,[9] which was designed to assess the ability of screening with radiologic chest imaging and sputum cytology to reduce lung cancer mortality in male smokers. The program comprised three separate randomized controlled trials (RCTs), each enrolling about 10,000 male participants aged 45 years and older who smoked at least one pack of cigarettes a day in the previous year. One study was conducted at the Mayo Clinic,[10–12] one at Johns Hopkins University,[13–15] and one at Memorial Sloan-Kettering Cancer Center.[15–18] The Hopkins and Sloan-Kettering studies employed the same design: participants randomly assigned to the intervention arm received sputum cytology every 4 months and annual chest imaging, while participants randomly assigned to the control arm received annual chest imaging. Neither study observed a reduction in lung cancer mortality with screening.[15] The two studies were interpreted as showing no benefit of frequent sputum cytology when added to an annual regimen of chest x-ray.

The design of the Mayo Clinic study (known as the Mayo Lung Project, or MLP), was different. All potential participants were screened with chest imaging and sputum cytology, and those known or suspected to have lung cancer, as well as those in poor health, were excluded. Remaining participants were randomly assigned to either an intervention arm that received chest imaging and sputum cytology every 4 months for 6 years, or to a control arm that received a one-time recommendation at trial entry to receive the same tests on an annual basis. No reduction in lung cancer mortality was observed. The MLP was interpreted in the 1970s as showing no benefit of an intense screening regimen with chest x-ray and sputum cytology.

One RCT of lung cancer screening with chest imaging was conducted in Europe in the 1970s. This Czechoslovakian study began with a prevalence screen (chest imaging and sputum cytology) of 6,364 men aged 40 to 64 years who were current smokers with a lifetime consumption of at least 150,000 cigarettes.[19,20] All participants except the 18 diagnosed with lung cancer as a result of the prevalence screen were randomly assigned to either an intervention arm or a control arm. Participants in the intervention arm received semiannual screening for 3 years. Participants in the control arm received screening during the third year only. The investigators reported 19 lung cancer deaths in the intervention arm and 13 in the control arm. They concluded that frequent screening was not necessary.

By 1990, the medical community was still unsure about the relationship between screening with chest imaging (using traditional chest x-ray) and lung cancer mortality. Although previous studies showed no benefit, findings were not definitive because of a lack of statistical power. A multiphasic trial with ample statistical power, the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial,[21] began in 1992. PLCO enrolled 154,901 participants aged 55 to 74 years, including women (50%) and never-smokers (45%). One-half of the participants were randomly assigned to screening, and the other half of them were advised to receive their usual medical care. PLCO had 90% power to detect a 20% reduction in lung cancer mortality.

The lung component of PLCO addressed the question of whether annual single-view (posterior-anterior) chest x-ray was capable of reducing lung cancer mortality as compared with usual medical care. When the study began, all participants randomly assigned to screening were invited to receive a baseline and three annual chest x-ray screens, although the protocol ultimately was changed to screen never-smokers only three times. At 13 years of follow-up, 1,213 lung cancer deaths were observed in the intervention group, compared with 1,230 lung cancer deaths in the usual-care group (mortality relative risk, 0.99; 95% confidence interval, 0.87–1.22). Subanalyses suggested no differential effect by sex or smoking status.[21]

Given the abundance and consistency of evidence, as well as the lack of benefit observed in the PLCO trial, it is appropriate to conclude that lung cancer screening with chest x-ray and/or sputum cytology, regardless of sex or smoking status, does not reduce lung cancer mortality.

References
  1. An evaluation of radiologic and cytologic screening for the early detection of lung cancer: a cooperative pilot study of the American Cancer Society and the Veterans Administration. Cancer Res 26 (10): 2083-121, 1966. [PUBMED Abstract]
  2. Boucot KR, Weiss W: Is curable lung cancer detected by semiannual screening? JAMA 224 (10): 1361-5, 1973. [PUBMED Abstract]
  3. Brett GZ: The value of lung cancer detection by six-monthly chest radiographs. Thorax 23 (4): 414-20, 1968. [PUBMED Abstract]
  4. Brett GZ: Earlier diagnosis and survival in lung cancer. Br Med J 4 (678): 260-2, 1969. [PUBMED Abstract]
  5. Dales LG, Friedman GD, Collen MF: Evaluating periodic multiphasic health checkups: a controlled trial. J Chronic Dis 32 (5): 385-404, 1979. [PUBMED Abstract]
  6. Nash FA, Morgan JM, Tomkins JG: South London Lung Cancer Study. Br Med J 2 (607): 715-21, 1968. [PUBMED Abstract]
  7. Weiss W, Boucot KR, Cooper DA: The Philadelphia pulmonary neoplasm research project. Survival factors in bronchogenic carcinoma. JAMA 216 (13): 2119-23, 1971. [PUBMED Abstract]
  8. Weiss W, Boucot KR: The Philadelphia Pulmonary Neoplasm Research Project. Early roentgenographic appearance of bronchogenic carcinoma. Arch Intern Med 134 (2): 306-11, 1974. [PUBMED Abstract]
  9. Berlin NI: Overview of the NCI Cooperative Early Lung Cancer Detection Program. Cancer 89 (11 Suppl): 2349-51, 2000. [PUBMED Abstract]
  10. Fontana RS, Sanderson DR, Taylor WF, et al.: Early lung cancer detection: results of the initial (prevalence) radiologic and cytologic screening in the Mayo Clinic study. Am Rev Respir Dis 130 (4): 561-5, 1984. [PUBMED Abstract]
  11. Fontana RS, Sanderson DR, Woolner LB, et al.: Lung cancer screening: the Mayo program. J Occup Med 28 (8): 746-50, 1986. [PUBMED Abstract]
  12. Fontana RS, Sanderson DR, Woolner LB, et al.: Screening for lung cancer. A critique of the Mayo Lung Project. Cancer 67 (4 Suppl): 1155-64, 1991. [PUBMED Abstract]
  13. Frost JK, Ball WC, Levin ML, et al.: Early lung cancer detection: results of the initial (prevalence) radiologic and cytologic screening in the Johns Hopkins study. Am Rev Respir Dis 130 (4): 549-54, 1984. [PUBMED Abstract]
  14. Levin ML, Tockman MS, Frost JK, et al.: Lung cancer mortality in males screened by chest X-ray and cytologic sputum examination: a preliminary report. Recent Results Cancer Res 82: 138-46, 1982. [PUBMED Abstract]
  15. Doria-Rose VP, Marcus PM, Szabo E, et al.: Randomized controlled trials of the efficacy of lung cancer screening by sputum cytology revisited: a combined mortality analysis from the Johns Hopkins Lung Project and the Memorial Sloan-Kettering Lung Study. Cancer 115 (21): 5007-17, 2009. [PUBMED Abstract]
  16. Flehinger BJ, Kimmel M, Polyak T, et al.: Screening for lung cancer. The Mayo Lung Project revisited. Cancer 72 (5): 1573-80, 1993. [PUBMED Abstract]
  17. Melamed M, Flehinger B, Miller D, et al.: Preliminary report of the lung cancer detection program in New York. Cancer 39 (2): 369-82, 1977. [PUBMED Abstract]
  18. Melamed MR, Flehinger BJ, Zaman MB, et al.: Screening for early lung cancer. Results of the Memorial Sloan-Kettering study in New York. Chest 86 (1): 44-53, 1984. [PUBMED Abstract]
  19. Kubík A, Polák J: Lung cancer detection. Results of a randomized prospective study in Czechoslovakia. Cancer 57 (12): 2427-37, 1986. [PUBMED Abstract]
  20. Kubik A, Parkin DM, Khlat M, et al.: Lack of benefit from semi-annual screening for cancer of the lung: follow-up report of a randomized controlled trial on a population of high-risk males in Czechoslovakia. Int J Cancer 45 (1): 26-33, 1990. [PUBMED Abstract]
  21. Oken MM, Hocking WG, Kvale PA, et al.: Screening by chest radiograph and lung cancer mortality: the Prostate, Lung, Colorectal, and Ovarian (PLCO) randomized trial. JAMA 306 (17): 1865-73, 2011. [PUBMED Abstract]

Harms of Screening

Screening by Low-Dose Computed Tomography

False-positive exams

False-positive exams are particularly problematic in the context of lung cancer screening. The individuals most likely to be screened for lung cancer, (i.e., heavy smokers) have comorbidities, such as chronic obstructive pulmonary disease and heart disease, that make them poor candidates for certain diagnostic procedures.

False-positive test results must be considered when lung cancer screening with low-dose computed tomography (LDCT) is being evaluated. A false-positive test may lead to anxiety and invasive diagnostic procedures, such as percutaneous needle biopsy or thoracotomy. The percentage of false-positive findings varies substantially among studies and is primarily attributable to differences in how a positive scan is defined (the size criteria), the thickness of the slice used between cuts (smaller slice thicknesses lead to detection of more nodules), and whether the subject resides in a geographic location where granulomatous disease is highly prevalent.

In the National Lung Screening Trial (NLST), the false-positive rate was 24% at baseline, and 27% and 16% for the two subsequent screening rounds.[1] In a systematic review of 20 studies (including the NLST), the median false-positive rate was 20.5% (range, 1%–49%) on baseline screens and 9.5% (range, 1%–42%) on postbaseline screens.[2] False-positive rates are generally lower on postbaseline screens because a nodule’s growth rate can be assessed when there is a previous screen available, and stable (nongrowing) nodules are often denoted as negative screens. The Lung-RADs criteria for assessing LDCT findings, which are in wide use in the United States, are stricter than the NLST criteria for defining a positive screen, and have the potential to lower the false-positive rate from that seen in the NLST.[3]

Diagnostic evaluations and downstream complications

A systematic review of the benefits and harms of computed tomography (CT) screening for lung cancer summarized 21 studies with respect to various diagnostic outcomes, although not all studies reported on all outcomes.[2] The rate of diagnostic CT imaging after a reported nodule varied from 0% to 45% of all individuals who were screened. Positron emission tomography scanning was performed in 2.5% to 5.5% of individuals who were screened. The frequency of nonsurgical biopsies or procedures ranged from 0.7% to 4.4% of individuals who were screened, with the finding of a benign result on biopsy ranging from 6% to 79%. The rate of surgical resection for screen-detected nodules was between 0.9% and 5.6% of individuals who were screened; the proportion among these with a benign result ranged from 6% to 45%.

In the NLST, most major complications were related to invasive procedures and surgeries performed on patients diagnosed with lung cancer, with a major complication rate of 11.8%. The rates of complications from the NLST may not be generalizable to a community setting; participants in the NLST were younger, better educated, and less likely to be current smokers (therefore, healthier) than the population of smokers and former smokers in the general U.S. population who would be eligible for screening. Of note, 82% of the participants were enrolled at large academic medical centers, and 76% of the participants were enrolled at National Cancer Institute–designated cancer centers. However, diagnostic follow-up did not necessarily occur at the NLST screening centers and could have been carried out in community settings. This may account for the low complication rate and surgical mortality rate (1%) found in the NLST. These findings led the multisociety position paper to strongly recommend that screening be carried out at centers with the same patient-management resources as those in the NLST.[4]

A retrospective cohort study of community practices indirectly estimated the complication rates and downstream medical costs of invasive diagnostic procedures performed for lung abnormalities identified through lung cancer screening.[5] The observed complications rates of 22.2% (in patients aged 55–64 years) and 23.8% (in patients aged 65–77 years) were more than twice that reported in the NLST (8.5%–9.8%). The mean costs of managing complications ranged from $6,320 (minor complication) to $56,845 (major complication). These data suggest that the NLST, which was conducted in the context of a controlled clinical trial, may have underestimated the potential for adverse events and high downstream costs in the community setting. Study limitations include a lack of information about patient eligibility for lung cancer screening, the fact that the diagnostic procedures were not generally performed as follow-up to screening, and the extent to which complications were affected by poorer patient health and lower quality of care. Despite limitations, these results reinforce the need for the discussion about risks, benefits, and shared decision making.[5]

Overdiagnosis

A less familiar harm is overdiagnosis, which means the diagnosis of a condition that would not have become clinically significant had it not been detected by screening [6]—that is, had the patient not been diagnosed with the cancer, the patient would have died of other causes. In the case of screening with LDCT, overdiagnosis could lead to unnecessary diagnosis of lung cancer requiring some combination of therapy (e.g., lobectomy, chemotherapy, and radiation therapy). Autopsy studies suggest that a significant number of individuals die with lung cancer rather than die of lung cancer. In one study, about one-sixth of all lung cancers found at autopsy had not been clinically recognized before death.[7] This may be an underestimate; depending on the extent of the autopsy, many small lung cancers that are detectable by CT may go unrecorded in an autopsy record.[8] Studies in Japan provided additional evidence that screening with LDCT could lead to a substantial amount of overdiagnosis.[9]

One approach to assessing overdiagnosis involves examining the volume-doubling time of lung tumors detected on LDCT. In one study, the volume-doubling times of 61 lung cancers were estimated by using an exponential model and successive CT images. Lesions were classified into the three following types: type G (ground glass opacity), type GS (focal glass opacity with a solid central component), and type S (solid nodule).

The mean volume-doubling times were 813 days, 457 days, and 149 days for types G, GS, and S, respectively. In this study, annual CT screening identified a large number of slowly growing adenocarcinomas that were not visible on chest x-ray, suggesting overdiagnosis.[10]

In a screening cohort with more than 5,000 participants, volume-doubling time was used as a surrogate for overdiagnosis. Patients with a calculated volume-doubling time of more than 400 days before surgical resection were considered to have a slow-growing or indolent cancer.[11] The investigators discovered that 25% of incident cancers (31 of 120) met the criteria of a slow-growing or indolent tumor.[11] This rate is consistent with previous chest radiograph screening studies and for other solid tumors.

Another approach to assessing overdiagnosis is to compare lung cancer incidence rates across arms in randomized trials of LDCT screening. Data from the NLST showed a gap of about 120 excess lung cancer cases in the LDCT group compared with the chest radiograph group after a medium follow-up of 6.5 years (i.e., 4.5 years after the last scheduled screen). This suggests that 18% of screen-detected lung cancers (N = 649) were overdiagnosed.[12] However, an extended follow-up analysis of the NLST based on a median of 11.3 years of follow-up for incident cancer found a much smaller, and nonstatistically significant, excess of only 20 cancers in the LDCT group, resulting in an estimate of the percentage of overdiagnosed LDCT screen-detected cancers of 3%. Note that the NLST control group was screened with chest x-rays, so technically the above overdiagnosis estimates were in comparison with what would have been diagnosed with chest x-ray screening, not with what would have been diagnosed with no screening.

Additional evidence of overdiagnosis with LDCT screening was observed in the randomized Danish Lung Cancer Screening Trial. At 10 years of follow-up (5 years after the last screening exam), almost twice as many lung cancers had been diagnosed in the screening group as in the control group: 5.1 vs. 2.7 cases per 1,000 person-years or 100 vs. 53 lung cancer cases in 4,104 total participants, respectively. Most of the lung cancers were early-stage adenocarcinomas, with no statistically significant difference in the number of stage III and IV cancers between the two groups.[13] Overdiagnosis was estimated at 67%.[14] In three other small trials of LDCT screening, one showed a borderline significant increase in lung cancer incidence in the LDCT versus the control arm (P = .04), suggesting overdiagnosis, while there was no significant difference in lung cancer incidence across arms in the other two trials.[15–17] In the NELSON trial (Nederlands–Leuvens Longkanker Screenings Onderzoek), with 4.5 years follow-up after the last screen, the overdiagnosis rate was 19.7% (95% confidence interval [CI], -5% to 42%).[18]

The overdiagnosis estimates from the NLST are compared with what would have been diagnosed with chest x-ray screening; therefore, in order to interpret them, it is necessary to have an estimate of the level of overdiagnosis using chest x-ray screening, preferably, covering a time period and population similar to those in the NLST. Such an estimate comes from the U.S. Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial of chest x-ray screening versus usual care, specifically in the subset of PLCO trial participants who met the NLST eligibility criteria. These data showed no evidence of overdiagnosis, with essentially equivalent numbers of diagnosed lung cancers in the chest x-ray and usual-care arms after 3 years of follow-up after the last scheduled screen (rate ratio, 1.00).[19]

A meta-analysis of overdiagnosis from six randomized controlled trials, including the NLST and the NELSON, showed an aggregate overdiagnosis rate of 0.30 (95% CI, 0.06–0.55). The overdiagnosis rate was defined as the difference across arms in incident lung cancers divided by the number of screen-detected cases in the LDCT arm. However, there was significant heterogeneity (P = .0001) in the overdiagnosis rate across trials, with two small trials showing rates around 0.65 and the NLST showing a low rate of 0.04.[20]

Radiation exposure

Another potential risk from screening with LDCT is radiation exposure. The average exposure is low; the mean effective dose for LDCT in the NLST was 1.4 (SD = 0.5) mSv. It is estimated that over a 3-year period of screening, NLST participants were exposed to an average of 8 mSv of radiation (which accounts for radiation from screens and additional imaging for screen-detected nodules). A study of LDCT screens that were performed on more than 12,000 patients from 2016 to 2017 at 72 U.S. institutions found a mean effective dose of 1.2 (SD = 1.1) mSv. Almost two-thirds (65%) of the institutions had a median effective dose higher than the American College of Radiology guideline of 1 mSv. Modeling from previous work on radiation exposure and the development of cancer suggests that there could be one death per 2,500 screens in those participating in a screening program such as the NLST, although the benefit of screening of about one death avoided per 960 screens substantially outweighs the risk. Younger individuals and those without a significant risk of lung cancer may be more likely to suffer a radiation-induced lung cancer from screening than to be spared a lung cancer death.[2]

Screening by Chest X-ray and/or Sputum Cytology

False-positive exams

In the PLCO Cancer Screening Trial, the false-positive rate with chest x-ray screening ranged from 6.8% to 8.7% per exam over the four screening rounds.[21] In the NLST chest x-ray arm, false-positive rates were generally similar (range, 4.7%–8.7% over three rounds).[1]

Diagnostic evaluation and downstream complications

In the NLST chest x-ray arm, among subjects with positive screens at baseline, 86% received imaging as diagnostic follow-up, 5% received a bronchoscopy, and 5% underwent a surgical procedure. Diagnostic imaging rates were modestly lower after postbaseline positive screens, while bronchoscopy and surgery rates were similar. A total of 0.3% of false-positive screens were associated with a complication of an invasive diagnostic procedure.[1]

In the PLCO trial, 0.4% of participants with at least one false-positive screen who had a diagnostic evaluation had a complication associated with a diagnostic procedure.[19] The most common of the 69 complications were pneumothorax (29%), atelectasis (15%), and infection (10%).

Overdiagnosis

In the Mayo Lung Project trial of screening with chest x-ray and sputum cytology, after 5 years of follow-up after the last scheduled screen, 206 cancers were diagnosed in the screening arm compared with 160 cancers in the control arm.[22] Based on 90 screen-detected cancers in the screened arm, the overdiagnosis rate would be computed as 51% (i.e., [206–160]/90). After 13 years of follow-up in the PLCO trial, 1,696 lung cancers had been diagnosed in the intervention arm as compared with 1,620 cancers diagnosed in the usual-care arm, suggesting that about 25% of the 307 chest x-ray screen-detected cancers in the trial were overdiagnosed.[19] However, the incidence of lung cancer was not statistically different between the intervention and usual-care arms in the PLCO trial (rate ratio, 1.05; 95% CI, 0.98–1.12), indicating that the null hypothesis of no overdiagnosis could not be rejected.

References
  1. Aberle DR, Adams AM, Berg CD, et al.: Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med 365 (5): 395-409, 2011. [PUBMED Abstract]
  2. Bach PB, Mirkin JN, Oliver TK, et al.: Benefits and harms of CT screening for lung cancer: a systematic review. JAMA 307 (22): 2418-29, 2012. [PUBMED Abstract]
  3. Pinsky PF, Gierada DS, Black W, et al.: Performance of Lung-RADS in the National Lung Screening Trial: a retrospective assessment. Ann Intern Med 162 (7): 485-91, 2015. [PUBMED Abstract]
  4. Mazzone P, Powell CA, Arenberg D, et al.: Components necessary for high-quality lung cancer screening: American College of Chest Physicians and American Thoracic Society Policy Statement. Chest 147 (2): 295-303, 2015. [PUBMED Abstract]
  5. Huo J, Xu Y, Sheu T, et al.: Complication Rates and Downstream Medical Costs Associated With Invasive Diagnostic Procedures for Lung Abnormalities in the Community Setting. JAMA Intern Med 179 (3): 324-332, 2019. [PUBMED Abstract]
  6. Black WC: Overdiagnosis: An underrecognized cause of confusion and harm in cancer screening. J Natl Cancer Inst 92 (16): 1280-2, 2000. [PUBMED Abstract]
  7. Chan CK, Wells CK, McFarlane MJ, et al.: More lung cancer but better survival. Implications of secular trends in “necropsy surprise” rates. Chest 96 (2): 291-6, 1989. [PUBMED Abstract]
  8. Dammas S, Patz EF, Goodman PC: Identification of small lung nodules at autopsy: implications for lung cancer screening and overdiagnosis bias. Lung Cancer 33 (1): 11-6, 2001. [PUBMED Abstract]
  9. Marcus PM, Fagerstrom RM, Prorok PC, et al.: Screening for lung cancer with helical CT scanning. Clinical Pulmonary Medicine 9 (6): 323-9, 2002.
  10. Hasegawa M, Sone S, Takashima S, et al.: Growth rate of small lung cancers detected on mass CT screening. Br J Radiol 73 (876): 1252-9, 2000. [PUBMED Abstract]
  11. Veronesi G, Maisonneuve P, Bellomi M, et al.: Estimating overdiagnosis in low-dose computed tomography screening for lung cancer: a cohort study. Ann Intern Med 157 (11): 776-84, 2012. [PUBMED Abstract]
  12. Patz EF, Pinsky P, Gatsonis C, et al.: Overdiagnosis in low-dose computed tomography screening for lung cancer. JAMA Intern Med 174 (2): 269-74, 2014. [PUBMED Abstract]
  13. Wille MM, Dirksen A, Ashraf H, et al.: Results of the Randomized Danish Lung Cancer Screening Trial with Focus on High-Risk Profiling. Am J Respir Crit Care Med 193 (5): 542-51, 2016. [PUBMED Abstract]
  14. Heleno B, Siersma V, Brodersen J: Estimation of Overdiagnosis of Lung Cancer in Low-Dose Computed Tomography Screening: A Secondary Analysis of the Danish Lung Cancer Screening Trial. JAMA Intern Med 178 (10): 1420-1422, 2018. [PUBMED Abstract]
  15. Paci E, Puliti D, Lopes Pegna A, et al.: Mortality, survival and incidence rates in the ITALUNG randomised lung cancer screening trial. Thorax 72 (9): 825-831, 2017. [PUBMED Abstract]
  16. Infante M, Cavuto S, Lutman FR, et al.: Long-Term Follow-up Results of the DANTE Trial, a Randomized Study of Lung Cancer Screening with Spiral Computed Tomography. Am J Respir Crit Care Med 191 (10): 1166-75, 2015. [PUBMED Abstract]
  17. Pastorino U, Silva M, Sestini S, et al.: Prolonged lung cancer screening reduced 10-year mortality in the MILD trial: new confirmation of lung cancer screening efficacy. Ann Oncol 30 (7): 1162-1169, 2019. [PUBMED Abstract]
  18. de Koning HJ, van der Aalst CM, de Jong PA, et al.: Reduced Lung-Cancer Mortality with Volume CT Screening in a Randomized Trial. N Engl J Med 382 (6): 503-513, 2020. [PUBMED Abstract]
  19. Oken MM, Hocking WG, Kvale PA, et al.: Screening by chest radiograph and lung cancer mortality: the Prostate, Lung, Colorectal, and Ovarian (PLCO) randomized trial. JAMA 306 (17): 1865-73, 2011. [PUBMED Abstract]
  20. Passiglia F, Cinquini M, Bertolaccini L, et al.: Benefits and Harms of Lung Cancer Screening by Chest Computed Tomography: A Systematic Review and Meta-Analysis. J Clin Oncol 39 (23): 2574-2585, 2021. [PUBMED Abstract]
  21. Hocking WG, Hu P, Oken MM, et al.: Lung cancer screening in the randomized Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. J Natl Cancer Inst 102 (10): 722-31, 2010. [PUBMED Abstract]
  22. Fontana RS, Sanderson DR, Woolner LB, et al.: Screening for lung cancer. A critique of the Mayo Lung Project. Cancer 67 (4 Suppl): 1155-64, 1991. [PUBMED Abstract]

Informed Medical Decision Making

Informed medical decision making is increasingly recommended for individuals who are considering cancer screening. Many different types and formats of decision aids have been studied. For more information, see Cancer Screening Overview.

Latest Updates to This Summary (04/17/2025)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Incidence and Mortality

Updated statistics with estimated new cases and deaths for 2025 (cited American Cancer Society as reference 1). Also revised text to state that after rising rapidly over several decades in both sexes, the lung cancer death rate declined by 61% for men starting in 1990 and by 38% for women starting in 2002. From 2013 to 2022, death rates decreased by 4.8% per year in men and 3.7% per year in women.

This summary is written and maintained by the PDQ Screening and Prevention Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about lung cancer screening. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Screening and Prevention Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

  • be discussed at a meeting,
  • be cited with text, or
  • replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website’s Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Screening and Prevention Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

Permission to Use This Summary

PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”

The preferred citation for this PDQ summary is:

PDQ® Screening and Prevention Editorial Board. PDQ Lung Cancer Screening. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/lung/hp/lung-screening-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389268]

Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.

Disclaimer

The information in these summaries should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

Contact Us

More information about contacting us or receiving help with the Cancer.gov website can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the website’s Email Us.

Lung Cancer Prevention (PDQ®)–Patient Version

Lung Cancer Prevention (PDQ®)–Patient Version

What Is Prevention?

Go to Health Professional Version

Cancer prevention is action taken to lower the chance of getting cancer. By preventing cancer, the number of new cases of cancer in a group or population is lowered. Hopefully, this will lower the number of deaths caused by cancer.

To prevent new cancers from starting, scientists look at risk factors and protective factors. Anything that increases your chance of developing cancer is called a cancer risk factor; anything that decreases your chance of developing cancer is called a cancer protective factor.

Some risk factors for cancer can be avoided, but many cannot. For example, both smoking and inheriting certain genes are risk factors for some types of cancer, but only smoking can be avoided. Regular exercise and a healthy diet may be protective factors for some types of cancer. Avoiding risk factors and increasing protective factors may lower your risk, but it does not mean that you will not get cancer.

Different ways to prevent cancer are being studied, including:

  • changing lifestyle or eating habits
  • avoiding things known to cause cancer
  • taking medicines to treat a precancerous condition or to keep cancer from starting

General Information About Lung Cancer

Key Points

  • Lung cancer is a disease in which malignant (cancer) cells form in the tissues of the lung.
  • Lung cancer is the leading cause of cancer death in both men and women.

Lung cancer is a disease in which malignant (cancer) cells form in the tissues of the lung.

The lungs are a pair of cone-shaped breathing organs in the chest. The lungs bring oxygen into the body as you breathe in. They release carbon dioxide, a waste product of the body’s cells, as you breathe out. Each lung has sections called lobes. The left lung has two lobes. The right lung is slightly larger, and has three lobes. A thin membrane called the pleura surrounds the lungs. Two tubes called bronchi lead from the trachea (windpipe) to the right and left lungs. The bronchi are sometimes also involved in lung cancer. Tiny air sacs called alveoli and small tubes called bronchioles make up the inside of the lungs.

EnlargeRespiratory system anatomy; drawing shows the right lung with the upper, middle, and lower lobes, the left lung with the upper and lower lobes, and the trachea, bronchi, lymph nodes, and diaphragm. An inset shows the bronchioles, alveoli, artery, and vein.
Anatomy of the respiratory system showing the trachea, the right and left lungs and their lobes, and the bronchi. The lymph nodes and the diaphragm are also shown. Oxygen is inhaled into the lungs and passes through the alveoli (the tiny air sacs at the end of the bronchioles) and into the bloodstream (see inset), where it travels to the tissues throughout the body.

There are two main types of lung cancer: small cell lung cancer and non-small cell lung cancer.

Other PDQ summaries containing information related to lung cancer include:

Lung cancer is the leading cause of cancer death in both men and women.

Lung cancer rates and deaths are higher in Black men than in other racial and ethnic group in the United States.

Lung Cancer Prevention

Key Points

  • Avoiding risk factors and increasing protective factors may help prevent lung cancer.
  • The following are risk factors for lung cancer:
    • Cigarette, cigar, and pipe smoking
    • Secondhand smoke
    • Family history
    • HIV infection
    • Environmental risk factors
    • Beta carotene supplements in heavy smokers
  • The following are protective factors for lung cancer:
    • Not smoking
    • Quitting smoking
    • Lower exposure to workplace risk factors
    • Lower exposure to radon
  • It is not clear if the following decrease the risk of lung cancer:
    • Diet
    • Physical activity
  • The following do not decrease the risk of lung cancer:
    • Beta carotene supplements in nonsmokers
    • Vitamin E supplements
  • Cancer prevention clinical trials are used to study ways to prevent cancer.
  • New ways to prevent lung cancer are being studied in clinical trials.

Avoiding risk factors and increasing protective factors may help prevent lung cancer.

Avoiding cancer risk factors may help prevent certain cancers. Risk factors include smoking, having overweight, and not getting enough exercise. Increasing protective factors such as quitting smoking and exercising may also help prevent some cancers. Talk to your doctor or other health care professional about how you might lower your risk of cancer.

The following are risk factors for lung cancer:

Cigarette, cigar, and pipe smoking

Tobacco smoking is the most important risk factor for lung cancer. Cigarette, cigar, and pipe smoking all increase the risk of lung cancer. Tobacco smoking causes about 9 out of 10 cases of lung cancer in men and about 8 out of 10 cases of lung cancer in women.

Studies have shown that smoking low tar or low nicotine cigarettes does not lower the risk of lung cancer.

Studies also show that the risk of lung cancer from smoking cigarettes increases with the number of cigarettes smoked per day and the number of years smoked. People who smoke have about 20 times the risk of lung cancer compared to those who do not smoke.

Secondhand smoke

Being exposed to secondhand tobacco smoke is also a risk factor for lung cancer. Secondhand smoke is the smoke that comes from a burning cigarette or other tobacco product, or that is exhaled by smokers. People who inhale secondhand smoke are exposed to the same cancer-causing agents as smokers, although in smaller amounts. Inhaling secondhand smoke is called involuntary or passive smoking.

Family history

Having a family history of lung cancer is a risk factor for lung cancer. People with a relative who has had lung cancer may be twice as likely to have lung cancer as people who do not have a relative who has had lung cancer. Because cigarette smoking tends to run in families and family members are exposed to secondhand smoke, it is hard to know whether the increased risk of lung cancer is from the family history of lung cancer or from being exposed to cigarette smoke.

HIV infection

Being infected with the human immunodeficiency virus (HIV), the cause of acquired immunodeficiency syndrome (AIDS), is linked with a higher risk of lung cancer. People infected with HIV may have more than twice the risk of lung cancer than those who are not infected. Since smoking rates are higher in those infected with HIV than in those not infected, it is not clear whether the increased risk of lung cancer is from HIV infection or from being exposed to cigarette smoke.

Environmental risk factors

  • Radiation exposure: Being exposed to radiation is a risk factor for lung cancer. Atomic bomb radiation, radiation therapy, imaging tests, and radon are sources of radiation exposure:
    • Atomic bomb radiation: Being exposed to radiation after an atomic bomb explosion increases the risk of lung cancer.
    • Radiation therapy: Radiation therapy to the chest may be used to treat certain cancers, including breast cancer and Hodgkin lymphoma. Radiation therapy uses x-rays, gamma rays, or other types of radiation that may increase the risk of lung cancer. The higher the dose of radiation received, the higher the risk. The risk of lung cancer following radiation therapy is higher in patients who smoke than in nonsmokers.
    • Imaging tests: Imaging tests, such as CT scans, expose patients to radiation. Low-dose spiral CT scans expose patients to less radiation than higher dose CT scans. In lung cancer screening, the use of low-dose spiral CT scans can lessen the harmful effects of radiation.
    • Radon: Radon is a radioactive gas that comes from the breakdown of uranium in rocks and soil. It seeps up through the ground, and leaks into the air or water supply. Radon can enter homes through cracks in floors, walls, or the foundation, and levels of radon can build up over time.

    Studies show that high levels of radon gas inside the home or workplace increase the number of new cases of lung cancer and the number of deaths caused by lung cancer. The risk of lung cancer is higher in smokers exposed to radon than in nonsmokers who are exposed to it. In people who have never smoked, about 26% of deaths caused by lung cancer have been linked to being exposed to radon.

  • Workplace exposure: Studies show that being exposed to the following substances increases the risk of lung cancer:

    These substances can cause lung cancer in people who are exposed to them in the workplace and have never smoked. As the level of exposure to these substances increases, the risk of lung cancer also increases. The risk of lung cancer is even higher in people who are exposed and also smoke.

  • Air pollution: Studies show that living in areas with higher levels of air pollution increases the risk of lung cancer.

Beta carotene supplements in heavy smokers

Taking beta carotene supplements (pills) increases the risk of lung cancer, especially in smokers who smoke one or more packs a day. The risk is higher in smokers who have at least one alcoholic drink every day.

The following are protective factors for lung cancer:

Not smoking

The best way to prevent lung cancer is to not smoke.

Quitting smoking

Smokers can decrease their risk of lung cancer by quitting. In smokers who have been treated for lung cancer, quitting smoking lowers the risk of new lung cancers. Counseling, the use of nicotine replacement products, and antidepressant therapy have helped smokers quit for good.

In a person who has quit smoking, the chance of preventing lung cancer depends on how many years and how much the person smoked and the length of time since quitting. After a person has quit smoking for 10 years, the risk of lung cancer decreases 30% to 60%.

Although the risk of dying from lung cancer can be greatly decreased by quitting smoking for a long period of time, the risk will never be as low as the risk in nonsmokers. This is why it is important for young people not to start smoking.

See the following for more information on quitting smoking:

Lower exposure to workplace risk factors

Laws that protect workers from being exposed to cancer-causing substances, such as asbestos, arsenic, nickel, and chromium, may help lower their risk of developing lung cancer. Laws that prevent smoking in the workplace help lower the risk of lung cancer caused by secondhand smoke.

Lower exposure to radon

Lowering radon levels may lower the risk of lung cancer, especially among cigarette smokers. High levels of radon in homes may be reduced by taking steps to prevent radon leakage, such as sealing basements.

It is not clear if the following decrease the risk of lung cancer:

Diet

Some studies show that people who eat high amounts of fruits or vegetables have a lower risk of lung cancer than those who eat low amounts. However, since smokers tend to have less healthy diets than nonsmokers, it is hard to know whether the decreased risk is from having a healthy diet or from not smoking.

Physical activity

Some studies show that people who are physically active have a lower risk of lung cancer than people who are not. However, since smokers tend to have different levels of physical activity than nonsmokers, it is hard to know if physical activity affects the risk of lung cancer.

The following do not decrease the risk of lung cancer:

Beta carotene supplements in nonsmokers

Studies of nonsmokers show that taking beta carotene supplements does not lower their risk of lung cancer.

Vitamin E supplements

Studies show that taking vitamin E supplements does not affect the risk of lung cancer.

Cancer prevention clinical trials are used to study ways to prevent cancer.

Cancer prevention clinical trials are used to study ways to lower the risk of developing certain types of cancer. Some cancer prevention trials include healthy people who may or may not have an increased risk of cancer. Other prevention trials include people who have had cancer and are trying to prevent recurrence or a second cancer.

The purpose of some cancer prevention clinical trials is to find out whether actions people take can prevent cancer. These may include eating fruits and vegetables, exercising, quitting smoking, or taking certain medicines, vitamins, minerals, or food supplements.

New ways to prevent lung cancer are being studied in clinical trials.

Information about clinical trials supported by NCI can be found on NCI’s clinical trials search webpage. Clinical trials supported by other organizations can be found on the ClinicalTrials.gov website.

About This PDQ Summary

About PDQ

Physician Data Query (PDQ) is the National Cancer Institute’s (NCI’s) comprehensive cancer information database. The PDQ database contains summaries of the latest published information on cancer prevention, detection, genetics, treatment, supportive care, and complementary and alternative medicine. Most summaries come in two versions. The health professional versions have detailed information written in technical language. The patient versions are written in easy-to-understand, nontechnical language. Both versions have cancer information that is accurate and up to date and most versions are also available in Spanish.

PDQ is a service of the NCI. The NCI is part of the National Institutes of Health (NIH). NIH is the federal government’s center of biomedical research. The PDQ summaries are based on an independent review of the medical literature. They are not policy statements of the NCI or the NIH.

Purpose of This Summary

This PDQ cancer information summary has current information about lung cancer prevention. It is meant to inform and help patients, families, and caregivers. It does not give formal guidelines or recommendations for making decisions about health care.

Reviewers and Updates

Editorial Boards write the PDQ cancer information summaries and keep them up to date. These Boards are made up of experts in cancer treatment and other specialties related to cancer. The summaries are reviewed regularly and changes are made when there is new information. The date on each summary (“Updated”) is the date of the most recent change.

The information in this patient summary was taken from the health professional version, which is reviewed regularly and updated as needed, by the PDQ Screening and Prevention Editorial Board.

Clinical Trial Information

A clinical trial is a study to answer a scientific question, such as whether one treatment is better than another. Trials are based on past studies and what has been learned in the laboratory. Each trial answers certain scientific questions in order to find new and better ways to help cancer patients. During treatment clinical trials, information is collected about the effects of a new treatment and how well it works. If a clinical trial shows that a new treatment is better than one currently being used, the new treatment may become “standard.” Patients may want to think about taking part in a clinical trial. Some clinical trials are open only to patients who have not started treatment.

Clinical trials can be found online at NCI’s website. For more information, call the Cancer Information Service (CIS), NCI’s contact center, at 1-800-4-CANCER (1-800-422-6237).

Permission to Use This Summary

PDQ is a registered trademark. The content of PDQ documents can be used freely as text. It cannot be identified as an NCI PDQ cancer information summary unless the whole summary is shown and it is updated regularly. However, a user would be allowed to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks in the following way: [include excerpt from the summary].”

The best way to cite this PDQ summary is:

PDQ® Screening and Prevention Editorial Board. PDQ Lung Cancer Prevention. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/lung/patient/lung-prevention-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389497]

Images in this summary are used with permission of the author(s), artist, and/or publisher for use in the PDQ summaries only. If you want to use an image from a PDQ summary and you are not using the whole summary, you must get permission from the owner. It cannot be given by the National Cancer Institute. Information about using the images in this summary, along with many other images related to cancer can be found in Visuals Online. Visuals Online is a collection of more than 3,000 scientific images.

Disclaimer

The information in these summaries should not be used to make decisions about insurance reimbursement. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

Contact Us

More information about contacting us or receiving help with the Cancer.gov website can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the website’s E-mail Us.

Non-Small Cell Lung Cancer Treatment (PDQ®)–Patient Version

Non-Small Cell Lung Cancer Treatment (PDQ®)–Patient Version

General Information About Non-Small Cell Lung Cancer

Go to Health Professional Version

Key Points

  • Non-small cell lung cancer is a type of cancer that forms in the tissues of the lung.
  • There are several types of non-small cell lung cancer.
  • Smoking is the major risk factor for non-small cell lung cancer.
  • Signs and symptoms of non-small cell lung cancer include coughing and shortness of breath.
  • Tests that examine the lungs are used to diagnose and stage non-small cell lung cancer.
  • If lung cancer is suspected, you will have a biopsy.
  • After non-small cell lung cancer has been diagnosed, tests are done to find out if cancer cells have spread within the chest or to other parts of the body.
  • Some people decide to get a second opinion.
  • Certain factors affect the prognosis (chance of recovery) and treatment options.

Non-small cell lung cancer is a type of cancer that forms in the tissues of the lung.

The lungs are a pair of cone-shaped breathing organs in the chest. The lungs bring oxygen into the body as you breathe in. They release carbon dioxide, a waste product of the body’s cells, as you breathe out. Each lung has sections called lobes. The left lung has two lobes. The right lung is slightly larger and has three lobes. Two tubes called bronchi lead from the trachea (windpipe) to the right and left lungs. Lung cancer may also form in the bronchi. Tiny air sacs called alveoli and small tubes called bronchioles make up the inside of the lungs.

EnlargeRespiratory system anatomy; drawing shows the right lung with the upper, middle, and lower lobes, the left lung with the upper and lower lobes, and the trachea, bronchi, lymph nodes, and diaphragm. An inset shows the bronchioles, alveoli, artery, and vein.
Anatomy of the respiratory system showing the trachea, the right and left lungs and their lobes, and the bronchi. The lymph nodes and the diaphragm are also shown. Oxygen is inhaled into the lungs and passes through the alveoli (the tiny air sacs at the end of the bronchioles) and into the bloodstream (see inset), where it travels to the tissues throughout the body.

A thin membrane called the pleura covers the outside of each lung and lines the inside wall of the chest cavity. This creates a sac called the pleural cavity. The pleural cavity normally contains a small amount of fluid that helps the lungs move smoothly in the chest when you breathe.

There are two main types of lung cancer: non-small cell lung cancer and small cell lung cancer. Non-small cell lung cancer is more common than small cell lung cancer.

There are several types of non-small cell lung cancer.

Each type of non-small cell lung cancer has different kinds of cancer cells. The cancer cells of each type grow and spread in different ways. The types of non-small cell lung cancer are named for the kinds of cells found in the cancer and how the cells look under a microscope:

  • Squamous cell carcinoma is a type of lung cancer that forms in the thin, flat cells lining the inside of the lungs. This is also called epidermoid carcinoma.
  • Large cell carcinoma is a type of lung cancer that may begin in several types of large cells.
  • Adenocarcinoma is a type of lung cancer that begins in the cells that line the alveoli and make substances such as mucus.

Less common types of non-small cell lung cancer include adenosquamous carcinoma, sarcomatoid carcinoma, salivary gland carcinoma, carcinoid tumor, and unclassified carcinoma.

Smoking is the major risk factor for non-small cell lung cancer.

Lung cancer is caused by certain changes to the way lung cells function, especially how they grow and divide into new cells. There are many risk factors for lung cancer, but many do not directly cause cancer. Instead, they increase the chance of DNA damage in cells that may lead to lung cancer. Learn more about how cancer develops at What Is Cancer?

A risk factor is anything that increases the chance of getting a disease. Some risk factors for lung cancer, like smoking, can be changed. However, risk factors also include things you cannot change, like your genetics, age, and family history. Learning about risk factors for lung cancer can help you make changes that might lower your risk of getting it.

Smoking tobacco now or in the past is the most important risk factor for lung cancer. Smoking cigarettes, pipes, or cigars increases the risk of lung cancer. The earlier in life a person starts smoking, the more often a person smokes, and the more years a person smokes, the greater the risk of lung cancer.

Other risk factors for lung cancer include:

Older age is the main risk factor for most cancers. The chance of getting cancer increases as you get older.

Having one or more of these risk factors does not necessarily mean you will get lung cancer. Many people with risk factors never develop lung cancer, whereas others with no known risk factors do. Talk with your doctor if you think you might be at increased risk.

When smoking is combined with other risk factors, the risk of lung cancer is increased.

Signs and symptoms of non-small cell lung cancer include coughing and shortness of breath.

Sometimes lung cancer does not cause any signs or symptoms. It may be found during a chest x-ray done for another condition. Signs and symptoms may be caused by lung cancer or by other conditions. Check with your doctor if you have:

  • chest discomfort or pain
  • a cough that doesn’t go away or gets worse over time
  • trouble breathing
  • wheezing
  • blood in sputum (mucus coughed up from the lungs)
  • hoarseness
  • loss of appetite
  • weight loss for no known reason
  • fatigue
  • trouble swallowing
  • swelling in the face and/or veins in the neck

Tests that examine the lungs are used to diagnose and stage non-small cell lung cancer.

Non-small cell lung cancer is usually diagnosed with tests and procedures that make pictures of the lung and the area around it. The process used to find out if cancer cells have spread within and around the lung is called staging. Tests and procedures to detect, diagnose, and stage non-small cell lung cancer are usually done at the same time. To plan treatment, it is important to know the stage of the disease and whether the cancer can be removed by surgery.

In addition to asking about your personal and family health history and doing a physical exam, your doctor may perform the following tests and procedures:

  • Laboratory tests are medical procedures that test samples of tissue, blood, urine, or other substances in the body. These tests help to diagnose disease, plan and check treatment, or monitor the disease over time.
  • Chest x-ray is a type of radiation that can go through the body and make pictures of the organs and bones inside the chest.
    EnlargeChest x-ray; drawing shows a patient standing with their back to the x-ray machine. X-rays pass through the patient's body onto film or a computer and take pictures of the structures and organs inside the chest.
    A chest x-ray is used to take pictures of the structures and organs inside the chest. X-rays pass through the patient’s body onto film or a computer.
  • CT scan (CAT scan) of the brain, chest, and abdomen uses a computer linked to an x-ray machine to make a series of detailed pictures of areas inside the body. The pictures are taken from different angles and are used to create 3-D views of tissues and organs. A dye may be injected into a vein or swallowed to help the organs or tissues show up more clearly. This procedure is also called computed tomography, computerized tomography, or computerized axial tomography.

If lung cancer is suspected, you will have a biopsy.

You may have one of the following types of biopsies:

  • Fine-needle aspiration (FNA) biopsy of the lung is the removal of tissue or fluid from the lung using a thin needle. A CT scan, ultrasound, or other imaging procedure is used to locate the abnormal tissue or fluid in the lung. A small incision may be made in the skin where the biopsy needle is inserted into the abnormal tissue or fluid. A sample is removed with the needle and sent to the laboratory. A pathologist then views the sample under a microscope to look for cancer cells. A chest x-ray is done after the procedure to make sure no air is leaking from the lung into the chest.
    EnlargeFine-needle aspiration biopsy of the lung; drawing shows a patient lying on a table that slides through the computed tomography (CT) machine with an x-ray picture of a cross-section of the lung on a monitor above the patient. Drawing also shows a doctor using the x-ray picture to help place the biopsy needle through the chest wall and into the area of abnormal lung tissue. Inset shows a side view of the chest cavity and lungs with the biopsy needle inserted into the area of abnormal tissue.
    Fine-needle aspiration biopsy of the lung. The patient lies on a table that slides through the computed tomography (CT) machine, which takes x-ray pictures of the inside of the body. The x-ray pictures help the doctor see where the abnormal tissue is in the lung. A biopsy needle is inserted through the chest wall and into the area of abnormal lung tissue. A small piece of tissue is removed through the needle and checked under the microscope for signs of cancer.

    An endoscopic ultrasound (EUS) is a type of ultrasound that may be used to guide an FNA biopsy of the lung, lymph nodes, or other areas. EUS is a procedure in which an endoscope is inserted into the body. An endoscope is a thin, tube-like instrument with a light and a lens for viewing. A probe at the end of the endoscope is used to bounce high-energy sound waves (ultrasound) off internal tissues or organs and make echoes. The echoes form a picture of body tissues called a sonogram.

    EnlargeEndoscopic ultrasound-guided fine-needle aspiration biopsy; drawing shows an endoscope with an ultrasound probe and biopsy needle inserted through the mouth and into the esophagus. Also shown are the lymph nodes near the esophagus and cancer in one lung. An inset shows the ultrasound probe locating the lymph nodes with cancer and the biopsy needle removing tissue from one of the lymph nodes near the esophagus.
    Endoscopic ultrasound-guided fine-needle aspiration biopsy. An endoscope that has an ultrasound probe and a biopsy needle is inserted through the mouth and into the esophagus. The probe bounces sound waves off body tissues to make echoes that form a sonogram (computer picture) of the lymph nodes near the esophagus. The sonogram helps the doctor see where to place the biopsy needle to remove tissue from the lymph nodes. This tissue is checked under a microscope for signs of cancer.
  • Bronchoscopy is a procedure to look inside the trachea and large airways in the lung for abnormal areas. A bronchoscope is inserted through the nose or mouth into the trachea and lungs. A bronchoscope is a thin, tube-like instrument with a light and a lens for viewing. It may also have a tool to remove tissue samples, which are checked under a microscope for signs of cancer.
    EnlargeBronchoscopy; drawing shows a bronchoscope inserted through the mouth, trachea, and bronchus into the lung; lymph nodes along trachea and bronchi; and cancer in one lung. Inset shows patient lying on a table having a bronchoscopy.
    Bronchoscopy. A bronchoscope is inserted through the mouth, trachea, and major bronchi into the lung, to look for abnormal areas. A bronchoscope is a thin, tube-like instrument with a light and a lens for viewing. It may also have a cutting tool. Tissue samples may be taken to be checked under a microscope for signs of disease.
  • Thoracoscopy is a surgical procedure to look at the organs inside the chest to check for abnormal areas. An incision (cut) is made between two ribs, and a thoracoscope is inserted into the chest. A thoracoscope is a thin, tube-like instrument with a light and a lens for viewing. It may also have a tool to remove tissue or lymph node samples, which are checked under a microscope for signs of cancer. In some cases, this procedure is used to remove part of the esophagus or lung. If certain tissues, organs, or lymph nodes can’t be reached, a thoracotomy may be done. In this procedure, a larger incision is made between the ribs and the chest is opened.
  • Thoracentesis is the removal of fluid from the space between the lining of the chest and the lung using a needle. A pathologist views the fluid under a microscope to look for cancer cells.
  • Mediastinoscopy is a surgical procedure to look at the organs, tissues, and lymph nodes between the lungs for abnormal areas. An incision (cut) is made at the top of the breastbone and a mediastinoscope is inserted into the chest. A mediastinoscope is a thin, tube-like instrument with a light and a lens for viewing. It may also have a tool to remove tissue or lymph node samples, which are checked under a microscope for signs of cancer.
  • Anterior mediastinotomy is a surgical procedure to look at the organs and tissues between the lungs and between the breastbone and heart for abnormal areas. An incision (cut) is made next to the breastbone and a mediastinoscope is inserted into the chest. A mediastinoscope is a thin, tube-like instrument with a light and a lens for viewing. It may also have a tool to remove tissue or lymph node samples, which are checked under a microscope for signs of cancer. This is also called the Chamberlain procedure.
  • Lymph node biopsy is the removal of all or part of a lymph node. A pathologist views the lymph node tissue under a microscope to check for cancer cells. A lymph node biopsy may be done at the same time as other types of biopsies.

One or more of the following laboratory tests may be done to study the tissue from the biopsy:

  • Molecular tests check for certain genes, proteins, or other molecules in a sample of tissue, blood, or other body fluid. Molecular tests check for certain gene or chromosome changes that occur in non-small cell lung cancer.
  • Immunohistochemistry uses antibodies to check for certain antigens (markers) in a sample of a patient’s tissue. The antibodies are usually linked to an enzyme or a fluorescent dye. After the antibodies bind to a specific antigen in the tissue sample, the enzyme or dye is activated, and the antigen can then be seen under a microscope. This type of test is used to help diagnose cancer and to help tell one type of cancer from another type of cancer.

After non-small cell lung cancer has been diagnosed, tests are done to find out if cancer cells have spread within the chest or to other parts of the body.

The process used to find out if cancer has spread within the chest or to other parts of the body is called staging. The information gathered from the staging process determines the stage of the disease. It is important to know the stage in order to plan treatment. Some of the tests used to diagnose non-small cell lung cancer are also used to stage the disease.

Imaging tests that may be used in the staging process include:

  • MRI (magnetic resonance imaging) of the brain uses a magnet, radio waves, and a computer to make a series of detailed pictures of areas inside the brain. This procedure is also called nuclear magnetic resonance imaging (NMRI).
  • PET scan (positron emission tomography scan) uses a small amount of radioactive glucose (sugar) that is injected into a vein. Then a scanner rotates around the body to make detailed, computerized pictures of areas inside the body where the glucose is taken up. Because cancer cells often take up more glucose than normal cells, the pictures can be used to find cancer cells in the body. A PET scan and CT scan may be done at the same time. This is called a PET-CT.
  • Bone scan checks for cancer cells in the bone. A very small amount of radioactive material is injected into a vein and travels through the bloodstream. The radioactive material collects in the bones with cancer and is detected by a scanner.
  • Pulmonary function test (PFT) checks how well the lungs are working. It measures how much air the lungs can hold and how quickly air moves into and out of the lungs. It also measures how much oxygen is used and how much carbon dioxide is given off during breathing. This is also called lung function test.
  • Bone marrow aspiration and biopsy is the removal of bone marrow, blood, and a small piece of bone by inserting a hollow needle into the hipbone or breastbone. A pathologist views the bone marrow, blood, and bone under a microscope to look for signs of cancer.

Some people decide to get a second opinion.

You may want to get a second opinion to confirm your non-small cell lung cancer diagnosis and treatment plan. If you seek a second opinion, you will need to get medical test results and reports from the first doctor to share with the second doctor. The second doctor will review the pathology report, slides, and scans. They may agree with the first doctor, suggest changes or another treatment approach, or provide more information about your cancer.

Learn more about choosing a doctor and getting a second opinion at Finding Cancer Care. You can contact NCI’s Cancer Information Service via chat, email, or phone (both in English and Spanish) for help finding a doctor, hospital, or getting a second opinion. For questions you might want to ask at your appointments, visit Questions to Ask Your Doctor About Cancer.

Certain factors affect the prognosis (chance of recovery) and treatment options.

The prognosis and treatment options depend on:

For most people with non-small cell lung cancer, current treatments do not cure the cancer. If lung cancer is found, you may want to think about taking part in one of the many clinical trials being done to improve treatment or quality of life. Clinical trials are taking place in most parts of the country for people with all stages of non-small cell lung cancer. Information about ongoing clinical trials is available at Clinical Trials Information for Patients and Caregivers.

Stages of Non-Small Cell Lung Cancer

Key Points

  • The following stages are used for non-small cell lung cancer:
    • Occult (hidden) stage non-small cell lung cancer
    • Stage 0 (carcinoma in situ)
    • Stage I (also called stage 1) non-small cell lung cancer
    • Stage II (also called stage 2) non-small cell lung cancer
    • Stage III (also called stage 3) non-small cell lung cancer
    • Stage IV (also called stage 4) non-small cell lung cancer
  • Non-small cell lung cancer can recur (come back) after it has been treated.

Cancer stage describes the extent of cancer in the body, such as the size of the tumor, whether it has spread, and how far it has spread from where it first formed. It is important to know the stage of non-small cell lung cancer to plan the best treatment.

There are several staging systems for cancer that describe the extent of the cancer. Non-small cell lung cancer staging usually uses the TNM staging system. The cancer may be described by this staging system in your pathology report. Based on the TNM results, a stage (I, II, III, or IV, also written as 1, 2, 3, or 4) is assigned to your cancer. When talking to you about your diagnosis, your doctor may describe the cancer as one of these stages.

Learn about tests to stage non-small lung cell cancer. Learn more about Cancer Staging.

The following stages are used for non-small cell lung cancer:

Occult (hidden) stage non-small cell lung cancer

In the occult (hidden) stage, cancer cannot be seen by imaging or bronchoscopy. Cancer cells are found in sputum or bronchial washings (a sample of cells taken from inside the airways that lead to the lungs). Cancer may have spread to other parts of the body.

Stage 0 (carcinoma in situ)

In stage 0, abnormal cells are found in the lining of the airways. These abnormal cells may become cancer and spread into nearby normal tissue. Stage 0 may be adenocarcinoma in situ (AIS) or squamous cell carcinoma in situ (SCIS).

Stage I (also called stage 1) non-small cell lung cancer

In stage I, cancer has formed. Stage I is divided into stages IA and IB.

  • Stage IA:
    EnlargeStage IA lung cancer; drawing shows a tumor (3 cm or smaller) in the right lung. Also shown are the lymph nodes, trachea, pleura, and diaphragm.
    Stage IA lung cancer. The tumor is in the lung only and is 3 centimeters or smaller. Cancer has not spread to the lymph nodes.

    The tumor is in the lung only and is 3 centimeters or smaller. Cancer has not spread to the lymph nodes.

  • Stage IB:
    EnlargeTwo-panel drawing of stage IB lung cancer; the panel on the left shows a tumor (larger than 3 cm but not larger than 4 cm) in the right lung. Also shown are the pleura and diaphragm. The panel on the right shows a primary tumor (4 cm or smaller) in the left lung and cancer in (a) the left main bronchus and (b) the inner membrane covering the lung (inset). Also shown is (c) part or all of the lung has collapsed or has pneumonitis (inflammation). The carina and a rib (inset) are also shown.
    Stage IB lung cancer. The tumor is larger than 3 centimeters but not larger than 4 centimeters. Cancer has not spread to the lymph nodes; OR the tumor is 4 centimeters or smaller. Cancer has not spread to the lymph nodes and one or more of the following is found: (a) cancer has spread to the main bronchus, but has not spread to the carina; and/or (b) cancer has spread to the inner membrane that covers the lung; and/or (c) part of the lung or the whole lung has collapsed or has pneumonitis (inflammation of the lung).

    The tumor is larger than 3 centimeters but not larger than 4 centimeters. Cancer has not spread to the lymph nodes.

    or

    The tumor is 4 centimeters or smaller and one or more of the following is found:

    • Cancer has spread to the main bronchus, but has not spread to the carina.
    • Cancer has spread to the innermost layer of the membrane that covers the lung.
    • Part of the lung or the whole lung has collapsed or has developed pneumonitis.

    Cancer has not spread to the lymph nodes.

Stage II (also called stage 2) non-small cell lung cancer

Stage II is divided into stages IIA and IIB.

  • Stage IIA:
    EnlargeStage IIA lung cancer; drawing shows a primary tumor (larger than 4 cm but not larger than 5 cm) in the left lung and cancer in (a) the left main bronchus and (b) the inner membrane covering the lung (inset). Also shown is (c) part or all of the lung has collapsed or has pneumonitis (inflammation). The carina, pleura, and a rib (inset) are also shown.
    Stage IIA lung cancer. The tumor is larger than 4 centimeters but not larger than 5 centimeters. Cancer has not spread to the lymph nodes and one or more of the following may be found: (a) cancer has spread to the main bronchus, but has not spread to the carina; and/or (b) cancer has spread to the inner membrane that covers the lung; and/or (c) part of the lung or the whole lung has collapsed or has pneumonitis (inflammation of the lung).

    The tumor is larger than 4 centimeters but not larger than 5 centimeters. Cancer has not spread to the lymph nodes and one or more of the following may be found:

    • Cancer has spread to the main bronchus, but has not spread to the carina.
    • Cancer has spread to the innermost layer of the membrane that covers the lung.
    • Part of the lung or the whole lung has collapsed or has developed pneumonitis.
  • Stage IIB:
    EnlargeStage IIB lung cancer (1); drawing shows a primary tumor (5 cm or smaller) in the right lung and cancer in lymph nodes in the same lung as the primary tumor. Also shown are the trachea, main bronchus, pleura, and diaphragm.
    Stage IIB lung cancer (1). The primary tumor is 5 centimeters or smaller and cancer has spread to the lymph nodes on the same side of the chest as the primary tumor. The lymph nodes with cancer are in the lung or near the bronchus.

    The tumor is 5 centimeters or smaller and cancer has spread to lymph nodes on the same side of the chest as the primary tumor. The lymph nodes with cancer are in the lung or near the bronchus. Also, one or more of the following may be found:

    • Cancer has spread to the main bronchus, but has not spread to the carina.
    • Cancer has spread to the innermost layer of the membrane that covers the lung.
    • Part of the lung or the whole lung has collapsed or has developed pneumonitis.

    or

    EnlargeStage IIB lung cancer (2); drawing shows (a) a primary tumor (larger than 5 cm but not larger than 7 cm) in the left lung (top inset) and (b) a separate tumor in the same lobe of the lung as the primary tumor. Also shown is cancer that has spread to (c) the chest wall and the membranes covering the lung and chest wall (middle inset); (d) the nerve that controls the diaphragm; and (e) the sac around the heart (bottom inset). The pleura, diaphragm, heart, and a rib (middle inset) are also shown.
    Stage IIB lung cancer (2). Cancer has not spread to lymph nodes and one or more of the following is found: (a) the primary tumor is larger than 5 centimeters but not larger than 7 centimeters; and/or (b) there are one or more separate tumors in the same lobe of the lung as the primary tumor; and/or cancer has spread to any of the following: (c) the chest wall and/or the membrane that lines the inside of the chest wall, (d) the nerve that controls the diaphragm, and/or (e) the outer layer of tissue of the sac around the heart.

    Cancer has not spread to the lymph nodes and one or more of the following is found:

    • The tumor is larger than 5 centimeters but not larger than 7 centimeters.
    • There are one or more separate tumors in the same lobe of the lung as the primary tumor.
    • Cancer has spread to any of the following:
      • the membrane that lines the inside of the chest wall
      • the chest wall
      • the nerve that controls the diaphragm
      • the outer layer of tissue of the sac around the heart

Stage III (also called stage 3) non-small cell lung cancer

Stage III is divided into stages IIIA, IIIB, and IIIC.

  • Stage IIIA:
    EnlargeStage IIIA lung cancer (1); drawing shows a primary tumor (5 cm or smaller) in the left lung (top inset) and cancer in lymph nodes around the trachea. Also shown is cancer that has spread to (a) the left main bronchus and (b) the membrane covering the lung (bottom inset). Also shown is (c) part or all of the lung has collapsed or has pneumonitis (inflammation). The carina, pleura, and a rib (bottom inset) are also shown.
    Stage IIIA lung cancer (1). The tumor is 5 centimeters or smaller and cancer has spread to lymph nodes on the same side of the chest as the primary tumor. The lymph nodes with cancer are around the trachea or aorta (not shown), or where the trachea divides into the bronchi. Also, one or more of the following may be found: (a) cancer has spread to the main bronchus, but has not spread to the carina; and/or (b) cancer has spread to the inner membrane that covers the lung; and/or (c) part of the lung or the whole lung has collapsed or has pneumonitis (inflammation of the lung).

    The tumor is 5 centimeters or smaller and cancer has spread to lymph nodes on the same side of the chest as the primary tumor. The lymph nodes with cancer are around the trachea or aorta, or where the trachea divides into the bronchi. Also, one or more of the following may be found:

    • Cancer has spread to the main bronchus, but has not spread to the carina.
    • Cancer has spread to the innermost layer of the membrane that covers the lung.
    • Part of the lung or the whole lung has collapsed or has developed pneumonitis.

    or

    EnlargeStage IIIA lung cancer (2); drawing shows (a) a primary tumor (larger than 5 cm but not larger than 7 cm) in the left lung and cancer in lymph nodes in the lung or near the bronchus on the same side of the chest as the primary tumor. Also shown is (b) separate tumors in the same lobe of the lung as the primary tumor and cancer that has spread to (c) the chest wall and the membranes covering the lung and chest wall (top right inset); (d) the nerve that controls the diaphragm; and (e) the sac around the heart (bottom right inset). The trachea, left main bronchus, diaphragm, heart, and a rib (top right inset) are also shown.
    Stage IIIA lung cancer (2). Cancer has spread to lymph nodes on the same side of the chest as the primary tumor. The lymph nodes with cancer are in the lung or near the bronchus. Also, one or more of the following is found: (a) the tumor is larger than 5 centimeters but not larger than 7 centimeters; and/or (b) there are one or more separate tumors in the same lobe of the lung as the primary tumor; and/or cancer has spread to any of the following: (c) the chest wall and/or the membrane that lines the inside of the chest wall, (d) the nerve that controls the diaphragm, and/or (e) the outer layer of tissue of the sac around the heart.

    Cancer has spread to lymph nodes on the same side of the chest as the primary tumor. The lymph nodes with cancer are in the lung or near the bronchus. Also, one or more of the following is found:

    • The tumor is larger than 5 centimeters but not larger than 7 centimeters.
    • There are one or more separate tumors in the same lobe of the lung as the primary tumor.
    • Cancer has spread to any of the following:
      • the membrane that lines the inside of the chest wall
      • the chest wall
      • the nerve that controls the diaphragm
      • the outer layer of tissue of the sac around the heart

    or

    EnlargeStage IIIA lung cancer (3); drawing shows (a) a primary tumor (larger than 7 cm) in the left lung and (b) separate tumors in a different lobe of the lung with the primary tumor. Also shown is cancer that has spread to the (c) trachea, (d) carina, (e) esophagus, (f) breastbone, (g) diaphragm, (h) heart, and (i) the aorta and vena cava.
    Stage IIIA lung cancer (3). Cancer may have spread to lymph nodes on the same side of the chest as the primary tumor. The lymph nodes with cancer are in the lung or near the bronchus. Also, one or more of the following is found: (a) the primary tumor is larger than 7 centimeters; and/or (b) there are one or more separate tumors in a different lobe of the lung with the primary tumor; and/or the tumor is any size and cancer has spread to any of the following: (c) trachea, (d) carina, (e) esophagus, (f) breastbone or backbone, (g) diaphragm, (h) heart, (i) major blood vessels that lead to or from the heart (aorta or vena cava), or the nerve that controls the larynx (not shown).

    Cancer may have spread to lymph nodes on the same side of the chest as the primary tumor. The lymph nodes with cancer are in the lung or near the bronchus. Also, one or more of the following is found:

    • The tumor is larger than 7 centimeters.
    • There are one or more separate tumors in a different lobe of the lung with the primary tumor.
    • The tumor is any size and cancer has spread to any of the following:
  • Stage IIIB:
    EnlargeStage IIIB lung cancer (1); drawing shows a primary tumor (5 cm or smaller) in the left lung and cancer in lymph nodes above the collarbone on the same side of the chest as the primary tumor and in lymph nodes on the opposite side of the chest as the primary tumor. Also shown is cancer that has spread to (a) the left main bronchus and (b) the membrane covering the lung. Also shown is (c) part or all of the lung has collapsed or has pneumonitis (inflammation). The carina, pleura, and a rib (inset) are also shown.
    Stage IIIB lung cancer (1). The primary tumor is 5 centimeters or smaller and cancer has spread to lymph nodes above the collarbone on the same side of the chest as the primary tumor or to any lymph nodes on the opposite side of the chest as the primary tumor. Also, one or more of the following may be found: (a) cancer has spread to the main bronchus, but has not spread to the carina; and/or (b) cancer has spread to the inner membrane that covers the lung; and/or (c) part of the lung or the whole lung has collapsed or has pneumonitis (inflammation of the lung).

    The tumor is 5 centimeters or smaller and cancer has spread to lymph nodes above the collarbone on the same side of the chest as the primary tumor or to any lymph nodes on the opposite side of the chest as the primary tumor. Also, one or more of the following may be found:

    • Cancer has spread to the main bronchus, but has not spread to the carina.
    • Cancer has spread to the innermost layer of the membrane that covers the lung.
    • Part of the lung or the whole lung has collapsed or has developed pneumonitis.

    or

    EnlargeStage IIIB lung cancer (2); drawing shows a primary tumor in the left lung and (a) a separate tumor in a different lobe of the lung with the primary tumor. Also shown is cancer in lymph nodes on the same side of the chest as the primary tumor. The lymph nodes with cancer are around the trachea or where the trachea divides into the bronchi. Also shown is (b) cancer that has spread to the following: the chest wall and the lining of the chest wall and lung, the nerve that controls the voice box, the trachea, the carina, the esophagus, the breastbone, the diaphragm, the nerve that controls the diaphragm, the aorta and vena cava, the heart, and the sac around the heart.
    Stage IIIB lung cancer (2). The tumor may be any size and cancer has spread to lymph nodes on the same side of the chest as the primary tumor. The lymph nodes with cancer are around the trachea or aorta (not shown), or where the trachea divides into the bronchi. Also, one or more of the following is found: (a) there are one or more separate tumors in the same lobe or a different lobe of the lung with the primary tumor; and/or (b) cancer has spread to any of the following: the chest wall or the membrane that lines the inside of the chest wall, the nerve that controls the voice box, the trachea, the carina, the esophagus, the breastbone or backbone (not shown), the diaphragm, the nerve that controls the diaphragm, the heart, the major blood vessels that lead to or from the heart (aorta or vena cava), or the outer layer of tissue of the sac around the heart.

    The tumor may be any size and cancer has spread to lymph nodes on the same side of the chest as the primary tumor. The lymph nodes with cancer are around the trachea or aorta, or where the trachea divides into the bronchi. Also, one or more of the following is found:

    • There are one or more separate tumors in the same lobe or a different lobe of the lung with the primary tumor.
    • Cancer has spread to any of the following:
      • the membrane that lines the inside of the chest wall
      • the chest wall
      • the nerve that controls the diaphragm
      • the outer layer of tissue of the sac around the heart
      • the trachea
      • the carina
      • the esophagus
      • the breastbone or backbone
      • the diaphragm
      • the heart
      • the major blood vessels that lead to or from the heart (aorta or vena cava)
      • the nerve that controls the larynx (voice box)
  • Stage IIIC:
    EnlargeStage IIIC lung cancer; drawing shows a primary tumor in the left lung and (a) separate tumors in the same lobe of the lung with the primary tumor. Also shown is cancer in lymph nodes above the collarbone on the same side and opposite side of the chest as the primary tumor. Also shown is (b) cancer that has spread to the following: the chest wall and the lining of the chest wall and lung, the nerve that controls the voice box, the trachea, the carina, the esophagus, the breastbone, the diaphragm, the nerve that controls the diaphragm, the heart, the aorta and vena cava, and the sac around the heart.
    Stage IIIC lung cancer. The tumor may be any size and cancer has spread to lymph nodes above the collarbone on the same side of the chest as the primary tumor or to any lymph nodes on the opposite side of the chest as the primary tumor. Also, one or more of the following is found: (a) there are one or more separate tumors in the same lobe or a different lobe of the lung with the primary tumor; and/or (b) cancer has spread to any of the following: the chest wall or the membrane that lines the inside of the chest wall, the nerve that controls the voice box, the trachea, the carina, the esophagus, the breastbone or backbone (not shown), the diaphragm, the nerve that controls the diaphragm, the heart, the major blood vessels that lead to or from the heart (aorta or vena cava), or the outer layer of tissue of the sac around the heart.

    The tumor may be any size and cancer has spread to lymph nodes above the collarbone on the same side of the chest as the primary tumor or to any lymph nodes on the opposite side of the chest as the primary tumor. Also, one or more of the following is found:

    • There are one or more separate tumors in the same lobe or a different lobe of the lung with the primary tumor.
    • Cancer has spread to any of the following:
      • the membrane that lines the inside of the chest wall
      • the chest wall
      • the nerve that controls the diaphragm
      • the outer layer of tissue of the sac around the heart
      • the trachea
      • the carina
      • the esophagus
      • the breastbone or backbone
      • the diaphragm
      • the heart
      • the major blood vessels that lead to or from the heart (aorta or vena cava)
      • the nerve that controls the larynx (voice box)

Stage IV (also called stage 4) non-small cell lung cancer

Stage IV is divided into stages IVA and IVB.

  • Stage IVA:
    EnlargeStage IVA lung cancer; drawing shows a primary tumor in the right lung and (a) a tumor in the left lung. Also shown is (b) fluid or cancer nodules around the lungs or heart (inset), and (c) other organs or tissues where lung cancer may spread, including the brain, adrenal gland, kidney, liver, bone, and distant lymph nodes.
    Stage IVA lung cancer. The tumor may be any size and cancer may have spread to the lymph nodes. One or more of the following is found: (a) there are one or more tumors in the lung that does not have the primary tumor; and/or (b) cancer is found in fluid around the lungs or heart or there are cancer nodules in the lining around the lungs or the sac around the heart; and/or (c) cancer has spread to one place in an organ or tissue not near the lung, such as the brain, adrenal gland, kidney, liver, or bone, or to a lymph node that is not near the lung.

    The tumor may be any size and cancer may have spread to the lymph nodes. One or more of the following is found:

    • There are one or more tumors in the lung that does not have the primary tumor.
    • Cancer is found in the lining around the lungs or the sac around the heart.
    • Cancer is found in fluid around the lungs or the heart.
    • Cancer has spread to one place in an organ not near the lung, such as the brain, liver, adrenal gland, kidney, bone, or to a lymph node that is not near the lung.
  • Stage IVB:
    EnlargeStage IVB lung cancer; drawing shows a primary cancer in the right lung and other parts of the body where lung cancer may spread, including the brain, adrenal gland, kidney, liver, distant lymph nodes, and bone. An inset shows cancer cells spreading from the lung, through the blood and lymph system, to another part of the body where metastatic cancer has formed.
    Stage IVB lung cancer. The cancer has spread to multiple places in one or more organs that are not near the lung, such as the brain, adrenal gland, kidney, liver, distant lymph nodes, or bone.

    Cancer has spread to multiple places in one or more organs that are not near the lung.

Non-small cell lung cancer can recur (come back) after it has been treated.

Recurrent non-small cell lung cancer is cancer that has come back after it has been treated. If non-small cell lung cancer comes back, it may come back in the brain, lung, chest, or in other parts of the body. Tests will be done to help determine where the cancer has returned. The type of treatment for non-small cell lung cancer will depend on where it has come back.

Learn more in Recurrent Cancer: When Cancer Comes Back.

Treatment Option Overview

Key Points

  • There are different types of treatment for people with non-small cell lung cancer.
  • The following types of treatment are used:
    • Surgery
    • Radiation therapy
    • Chemotherapy
    • Targeted therapy
    • Immunotherapy
    • Laser therapy
    • Photodynamic therapy (PDT)
    • Cryosurgery
    • Electrocautery
  • New types of treatment are being tested in clinical trials.
  • Treatment for non-small cell lung cancer may cause side effects.
  • Follow-up care may be needed.

There are different types of treatment for people with non-small cell lung cancer.

Different types of treatments are available for people with non-small cell lung cancer. You and your cancer care team will work together to decide your treatment plan, which may include more than one type of treatment. Many factors will be considered, such as the stage of the cancer, your overall health, and your preferences. Your plan will include information about your cancer, the goals of treatment, your treatment options and the possible side effects, and the expected length of treatment.

Talking with your cancer care team before treatment begins about what to expect will be helpful. You’ll want to learn what you need to do before treatment begins, how you’ll feel while going through it, and what kind of help you will need. To learn more, visit Questions to Ask Your Doctor About Treatment. 

The following types of treatment are used:

Surgery

Four types of surgery are used to treat lung cancer:

  • Wedge resection is surgery to remove a tumor and some of the normal tissue around it. When a slightly larger amount of tissue is taken, it is called a segmental resection.
    EnlargeWedge resection of the lung; shows trachea and lungs with cancer in a lung lobe. The removed lung tissue with the cancer and small amount of healthy tissue around it is shown next to the lung lobe it was removed from.
    Wedge resection of the lung. Part of the lung lobe containing the cancer and a small amount of healthy tissue around it is removed.
  • Lobectomy is surgery to remove a whole lobe (section) of the lung.
    EnlargeLobectomy; drawing shows lobes of both lungs, trachea, bronchi, bronchioles, and lymph nodes. Cancer is shown in one lobe. The removed lobe is shown next to the lung from which it was removed.
    Lobectomy. A lobe of the lung is removed.
  • Pneumonectomy is surgery to remove one whole lung.
    EnlargePneumonectomy; drawing shows the trachea, lymph nodes, and lungs, with cancer in one lung. The removed lung with the cancer is shown.
    Pneumonectomy. The whole lung is removed.
  • Sleeve resection is surgery to remove part of the bronchus.

After the doctor removes all the cancer that can be seen at the time of the surgery, some people may be given chemotherapy or radiation therapy after surgery to kill any cancer cells that are left. Treatment given after the surgery to lower the risk that the cancer will come back is called adjuvant therapy.

Radiation therapy

Radiation therapy is a cancer treatment that uses high-energy x-rays or other types of radiation to kill cancer cells or keep them from growing. There are two types of radiation therapy:

  • External radiation therapy uses a machine outside the body to send radiation toward the area of the body with cancer. Certain ways of giving external radiation therapy can help keep radiation from damaging nearby healthy tissue:
    • Stereotactic body radiation therapy uses special equipment to ensure you are in the same position for each radiation treatment. Once a day for several days, a radiation machine aims a larger than usual dose of radiation directly at the tumor. By having you in the same position for each treatment, there is less damage to nearby healthy tissue. This procedure is also called stereotactic external beam radiation therapy and stereotaxic radiation therapy.
    • Stereotactic radiosurgery is used to treat lung cancer that has spread to the brain. A rigid head frame is attached to the skull to keep the head still during the radiation treatment. A machine aims a single large dose of radiation directly at the tumor in the brain. This procedure does not involve surgery. It is also called stereotaxic radiosurgery, radiosurgery, and radiation surgery.
  • Internal radiation therapy uses a radioactive substance sealed in needles, seeds, wires, or catheters that are placed directly into or near the cancer.

For tumors in the airways, radiation is given directly to the tumor through an endoscope.

The way the radiation therapy is given depends on the type and stage of the cancer being treated. It also depends on where the cancer is found. External and internal radiation therapy are used to treat non-small cell lung cancer.

Chemotherapy

Chemotherapy (also called chemo) uses drugs to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing.

Chemotherapy for non-small cell lung cancer is usually systemic, meaning it is injected into a vein or given by mouth. When given this way, the drugs enter the bloodstream to reach cancer cells throughout the body. 

Chemotherapy drugs used to treat non-small cell lung cancer may include:

Combinations of these chemotherapy drugs may be used. Other chemotherapy drugs not listed here may also be used.

Chemotherapy may also be combined with other kinds of treatment. For example, it may be combined with radiation therapy or immunotherapy drugs.

Learn more about how chemotherapy works, how it is given, common side effects, and more at Chemotherapy to Treat Cancer and Chemotherapy and You: Support for People With Cancer.

Targeted therapy

Targeted therapy uses drugs or other substances to identify and attack specific cancer cells. Your doctor may suggest biomarker tests to help predict your response to certain targeted therapy drugs. Learn more about Biomarker Testing for Cancer Treatment.

Targeted therapies used to treat non-small cell lung cancer include:

Learn more about Targeted Therapy to Treat Cancer.

Immunotherapy

Immunotherapy helps a person’s immune system fight cancer. Your doctor may suggest biomarker tests to help predict your response to certain immunotherapy drugs. Learn more about Biomarker Testing for Cancer Treatment.

Immunotherapy drugs used to treat non-small cell lung cancer include:

Learn more about Immunotherapy to Treat Cancer.

Laser therapy

Laser therapy is a cancer treatment that uses a laser beam (a narrow beam of intense light) to kill cancer cells.

Learn more about Lasers to Treat Cancer.

Photodynamic therapy (PDT)

Photodynamic therapy (PDT) is a cancer treatment that uses a drug and a certain type of laser light to kill cancer cells. A drug that is not active until it is exposed to light is injected into a vein. The drug collects more in cancer cells than in normal cells. Fiberoptic tubes are then used to carry the laser light to the cancer cells, where the drug becomes active and kills the cells. Photodynamic therapy causes little damage to healthy tissue. It is used mainly to treat tumors on or just under the skin or in the lining of internal organs. When the tumor is in the airways, PDT is given directly to the tumor through an endoscope.

Learn more about Photodynamic Therapy to Treat Cancer.

Cryosurgery

Cryosurgery is a treatment that uses an instrument to freeze and destroy abnormal tissue, such as carcinoma in situ. This type of treatment is also called cryotherapy. For tumors in the airways, cryosurgery is done through an endoscope.

Learn more about Cryosurgery to Treat Cancer.

Electrocautery

Electrocautery is a treatment that uses a probe or needle heated by an electric current to destroy abnormal tissue. For tumors in the airways, electrocautery is done through an endoscope.

New types of treatment are being tested in clinical trials.

For some people, joining a clinical trial may be an option. There are different types of clinical trials for people with cancer. For example, a treatment trial tests new treatments or new ways of using current treatments. Supportive care and palliative care trials look at ways to improve quality of life, especially for those who have side effects from cancer and its treatment.

You can use the clinical trial search to find NCI-supported cancer clinical trials accepting participants. The search allows you to filter trials based on the type of cancer, your age, and where the trials are being done. Clinical trials supported by other organizations can be found on the ClinicalTrials.gov website.

Learn more about clinical trials, including how to find and join one, at Clinical Trials Information for Patients and Caregivers.

Treatment for non-small cell lung cancer may cause side effects.

For information about side effects caused by treatment for cancer, visit our Side Effects page.

Follow-up care may be needed.

As you go through treatment, you will have follow-up tests or check-ups. Some tests that were done to diagnose or stage the cancer may be repeated to see how well the treatment is working. Decisions about whether to continue, change, or stop treatment may be based on the results of these tests.

Some of the tests will continue to be done from time to time after treatment has ended. The results of these tests can show if your condition has changed or if the cancer has recurred (come back).

Treatment of Occult Non-Small Cell Lung Cancer

Treatment of occult non-small cell lung cancer depends on the stage of the disease. Occult tumors are often found at an early stage (the tumor is in the lung only) and sometimes can be cured by surgery.

Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.

Treatment of Stage 0 (carcinoma in situ)

Treatment of stage 0 may include:

Learn more about these treatments in the Treatment Option Overview.

Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.

Treatment of Stage I Non-Small Cell Lung Cancer

Treatment of stage IA non-small cell lung cancer and stage IB non-small cell lung cancer may include:

Learn more about these treatments and find a list of chemotherapy, targeted therapy, and immunotherapy drugs for lung cancer in the Treatment Option Overview.

Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.

Treatment of Stage II Non-Small Cell Lung Cancer

Treatment of stage IIA non-small cell lung cancer and stage IIB non-small cell lung cancer may include:

Learn more about these treatments and find a list of chemotherapy, targeted therapy, and immunotherapy drugs for lung cancer in the Treatment Option Overview.

Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.

Treatment of Stage IIIA Non-Small Cell Lung Cancer

Treatment of stage IIIA non-small cell lung cancer that can be removed with surgery may include:

  • chemotherapy followed by surgery
  • chemotherapy and radiation therapy followed by surgery
  • immunotherapy and chemotherapy followed by surgery
  • immunotherapy and chemotherapy followed by surgery and more immunotherapy
  • surgery followed by chemotherapy
  • surgery followed by targeted therapy
  • surgery followed by chemotherapy and immunotherapy
  • surgery followed by immunotherapy
  • surgery followed by chemotherapy and radiation therapy
  • surgery followed by radiation therapy

Treatment of stage IIIA non-small cell lung cancer that cannot be removed with surgery may include:

Learn more about supportive care for signs and symptoms including cough, shortness of breath, and chest pain at Cardiopulmonary Syndromes and Cancer Pain.

Non-small cell lung cancer of the superior sulcus, often called Pancoast tumor, begins in the upper part of the lung and spreads to nearby tissues such as the chest wall, large blood vessels, and spine. Treatment of Pancoast tumors may include:

  • surgery
  • chemotherapy and radiation therapy followed by surgery
  • radiation therapy alone

Some stage IIIA non-small cell lung tumors that have grown into the chest wall may be completely removed. Treatment of chest wall tumors may include:

  • surgery
  • surgery and radiation therapy
  • radiation therapy alone
  • chemotherapy combined with radiation therapy and/or surgery

Learn more about these treatments and find a list of chemotherapy drugs for lung cancer in the Treatment Option Overview.

Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.

Treatment of Stage IIIB and Stage IIIC Non-Small Cell Lung Cancer

Treatment of stage IIIB non-small cell lung cancer and stage IIIC non-small cell lung cancer may include:

Learn more about these treatments and find a list of chemotherapy, targeted therapy, and immunotherapy drugs for lung cancer in the Treatment Option Overview.

Learn more about supportive care for signs and symptoms such as cough, shortness of breath, and chest pain at Cardiopulmonary Syndromes and Cancer Pain.

Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.

Treatment of Newly Diagnosed Stage IV, Relapsed, and Recurrent Non-Small Cell Lung Cancer

Treatment of newly stage IV, relapsed, and recurrent non-small cell lung cancer may include:

Learn more about these treatments and find a list of chemotherapy, targeted therapy, and immunotherapy drugs for lung cancer in the Treatment Option Overview.

Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.

Treatment of Progressive Stage IV, Relapsed, and Recurrent Non-Small Cell Lung Cancer

Treatment of progressive stage IV, relapsed, and recurrent non-small cell lung cancer may include:

Learn more about these treatments and find a list of chemotherapy, targeted therapy, and immunotherapy drugs for lung cancer in the Treatment Option Overview.

Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.

To Learn More About Non-Small Cell Lung Cancer

For more information from the National Cancer Institute about non-small cell lung cancer, visit:

For general cancer information and other resources from the National Cancer Institute, visit:

About This PDQ Summary

About PDQ

Physician Data Query (PDQ) is the National Cancer Institute’s (NCI’s) comprehensive cancer information database. The PDQ database contains summaries of the latest published information on cancer prevention, detection, genetics, treatment, supportive care, and complementary and alternative medicine. Most summaries come in two versions. The health professional versions have detailed information written in technical language. The patient versions are written in easy-to-understand, nontechnical language. Both versions have cancer information that is accurate and up to date and most versions are also available in Spanish.

PDQ is a service of the NCI. The NCI is part of the National Institutes of Health (NIH). NIH is the federal government’s center of biomedical research. The PDQ summaries are based on an independent review of the medical literature. They are not policy statements of the NCI or the NIH.

Purpose of This Summary

This PDQ cancer information summary has current information about the treatment of non-small cell lung cancer. It is meant to inform and help patients, families, and caregivers. It does not give formal guidelines or recommendations for making decisions about health care.

Reviewers and Updates

Editorial Boards write the PDQ cancer information summaries and keep them up to date. These Boards are made up of experts in cancer treatment and other specialties related to cancer. The summaries are reviewed regularly and changes are made when there is new information. The date on each summary (“Updated”) is the date of the most recent change.

The information in this patient summary was taken from the health professional version, which is reviewed regularly and updated as needed, by the PDQ Adult Treatment Editorial Board.

Clinical Trial Information

A clinical trial is a study to answer a scientific question, such as whether one treatment is better than another. Trials are based on past studies and what has been learned in the laboratory. Each trial answers certain scientific questions in order to find new and better ways to help cancer patients. During treatment clinical trials, information is collected about the effects of a new treatment and how well it works. If a clinical trial shows that a new treatment is better than one currently being used, the new treatment may become “standard.” Patients may want to think about taking part in a clinical trial. Some clinical trials are open only to patients who have not started treatment.

Clinical trials can be found online at NCI’s website. For more information, call the Cancer Information Service (CIS), NCI’s contact center, at 1-800-4-CANCER (1-800-422-6237).

Permission to Use This Summary

PDQ is a registered trademark. The content of PDQ documents can be used freely as text. It cannot be identified as an NCI PDQ cancer information summary unless the whole summary is shown and it is updated regularly. However, a user would be allowed to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks in the following way: [include excerpt from the summary].”

The best way to cite this PDQ summary is:

PDQ® Adult Treatment Editorial Board. PDQ Non-Small Cell Lung Cancer Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/lung/patient/non-small-cell-lung-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389355]

Images in this summary are used with permission of the author(s), artist, and/or publisher for use in the PDQ summaries only. If you want to use an image from a PDQ summary and you are not using the whole summary, you must get permission from the owner. It cannot be given by the National Cancer Institute. Information about using the images in this summary, along with many other images related to cancer can be found in Visuals Online. Visuals Online is a collection of more than 3,000 scientific images.

Disclaimer

The information in these summaries should not be used to make decisions about insurance reimbursement. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

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More information about contacting us or receiving help with the Cancer.gov website can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the website’s E-mail Us.

Non-Small Cell Lung Cancer Treatment (PDQ®)–Health Professional Version

Non-Small Cell Lung Cancer Treatment (PDQ®)–Health Professional Version

General Information About Non-Small Cell Lung Cancer (NSCLC)

Go to Patient Version

NSCLC is any type of epithelial lung cancer other than small cell lung cancer (SCLC). The most common types of NSCLC are squamous cell carcinoma, large cell carcinoma, and adenocarcinoma, but there are several other types that occur less frequently, and all types can occur in unusual histological variants. Although NSCLCs are associated with cigarette smoke, adenocarcinomas may be found in patients who never smoked.

As a class, NSCLC is usually less sensitive to chemotherapy and radiation therapy than SCLC. Patients with resectable disease may be cured by surgery or surgery followed by chemotherapy. Local control can be achieved with radiation therapy in many patients with unresectable disease, but cure is seen in relatively few patients. Patients with locally advanced unresectable disease may achieve long-term survival with radiation therapy combined with chemotherapy. Patients with advanced metastatic disease may achieve improved survival and palliation of symptoms with chemotherapy, targeted agents, and other supportive measures.

Incidence and Mortality

Estimated new cases and deaths from lung cancer (NSCLC and SCLC combined) in the United States in 2025:[1]

  • New cases: 226,650.
  • Deaths: 124,730.

Lung cancer is the leading cause of cancer-related mortality in the United States. The 5-year relative survival rate from 2014 to 2020 for patients with lung cancer was 27%. The 5-year relative survival rate varies markedly for patients diagnosed at local stage (64%), regional stage (36%), or distant stage (9%).[1]

Anatomy

NSCLC arises from the epithelial cells of the lung of the central bronchi to terminal alveoli. The histological type of NSCLC correlates with site of origin, reflecting the variation in respiratory tract epithelium of the bronchi to alveoli. Squamous cell carcinoma usually starts near a central bronchus. Adenocarcinoma and bronchioloalveolar carcinoma usually originate in peripheral lung tissue.

EnlargeRespiratory system anatomy; drawing shows the right lung with the upper, middle, and lower lobes, the left lung with the upper and lower lobes, and the trachea, bronchi, lymph nodes, and diaphragm. An inset shows the bronchioles, alveoli, artery, and vein.
Anatomy of the respiratory system.

Pathogenesis

Smoking-related lung carcinogenesis is a multistep process. Squamous cell carcinoma and adenocarcinoma have defined premalignant precursor lesions. Before becoming invasive, lung epithelium may undergo morphological changes that include:

  • Hyperplasia.
  • Metaplasia.
  • Dysplasia.
  • Carcinoma in situ.

Dysplasia and carcinoma in situ are considered the principal premalignant lesions because they are more likely to progress to invasive cancer and less likely to spontaneously regress.

Risk Factors

Increasing age is the most important risk factor for most cancers. Other risk factors for lung cancer include:

  • History of or current tobacco use: cigarettes, pipes, and cigars.[2]
  • Exposure to cancer-causing substances in secondhand smoke.[3,4]
  • Occupational exposure to asbestos, arsenic, chromium, beryllium, nickel, and other agents.[5]
  • Radiation exposure from any of the following sources:
    • Radiation therapy to the breast or chest.[6]
    • Radon exposure in the home or workplace.[7]
    • Medical imaging tests, such as computed tomography (CT) scans.[8]
    • Atomic bomb radiation.[9]
  • Living in an area with air pollution.[10–12]
  • Family history of lung cancer.[13]
  • HIV infection.[14]
  • Beta carotene supplements in heavy smokers.[15,16]

The single most important risk factor for the development of lung cancer is smoking. For a smoker, the risk of lung cancer is, on average, tenfold higher than in a lifetime nonsmoker (defined as a person who has smoked <100 cigarettes in his or her lifetime). The risk increases with the quantity of cigarettes, duration of smoking, and starting age.

Smoking cessation results in a decrease in precancerous lesions and a reduction in lung cancer risk. Former smokers continue to have an elevated risk of lung cancer for years after quitting. Asbestos exposure may exert a synergistic effect of cigarette smoking on lung cancer risk.[17]

In addition, after resection of a lung cancer, there is a 1% to 2% risk per patient per year that a second lung cancer will occur.[18]

A significant number of patients cured of their smoking-related lung cancer may develop a second malignancy. In the Lung Cancer Study Group trial of 907 patients with stage T1, N0 resected tumors, the rate was 1.8% per year for nonpulmonary second cancers and 1.6% per year for new lung cancers.[19] Other studies have reported even higher risks of second tumors in long-term survivors, including rates of 10% for second lung cancers and 20% for all second cancers.[20]

Because of the persistent risk of developing second lung cancers in former smokers, various chemoprevention strategies have been evaluated in randomized control trials. None of the phase III trials using the agents beta carotene, retinol, 13-cis-retinoic acid, [alpha]-tocopherol, N-acetylcysteine, or acetylsalicylic acid has demonstrated beneficial, reproducible results.[16,21–24][Level of evidence A1] Chemoprevention of second primary cancers of the upper aerodigestive tract is undergoing clinical evaluation in patients with early-stage lung cancer.

For more information, see Lung Cancer Prevention.

Screening

In patients considered at high risk of developing lung cancer, the only screening modality for early detection that has been shown to alter mortality is low-dose helical CT scanning.[25] Studies have failed to demonstrate that screening with chest radiography and sputum cytology lowers lung cancer mortality rates.

For more information, see the Screening by low-dose computed tomography: benefit section in Lung Cancer Screening.

Clinical Presentation

Lung cancer may present with symptoms or be found incidentally on chest imaging. The most common symptoms at presentation include:

  • Worsening cough.
  • Chest pain.
  • Hemoptysis.
  • Malaise.
  • Weight loss.
  • Dyspnea.
  • Hoarseness.

Symptoms may result from local invasion or compression of adjacent thoracic structures, such as compression involving the esophagus causing dysphagia, compression involving the laryngeal nerves causing hoarseness, or compression involving the superior vena cava causing facial edema and distension of the superficial veins of the head and neck.

Symptoms from distant metastases may also be present and include neurological defect or personality change from brain metastases or pain from bone metastases. Infrequently, patients may present with symptoms and signs of paraneoplastic diseases such as hypertrophic osteoarthropathy with digital clubbing or hypercalcemia from parathyroid hormone-related protein.

Physical examination may identify enlarged supraclavicular lymphadenopathy, pleural effusion or lobar collapse, unresolved pneumonia, or signs of associated disease such as chronic obstructive pulmonary disease or pulmonary fibrosis.

Diagnosis

Investigations of patients with suspected NSCLC focus on confirming the diagnosis and determining the extent of the disease. Treatment options are determined by histology, stage, and general health and comorbidities of the patient.

The procedures used to determine the presence of cancer include:

  • History.
  • Physical examination.
  • Routine laboratory evaluations.
  • Chest x-ray.
  • Chest CT scan with infusion of contrast material.
  • Biopsy.

Before a patient begins lung cancer treatment, an experienced lung cancer pathologist must review the pathological material. This is critical because SCLC, which responds well to chemotherapy and is generally not treated surgically, can be confused on microscopic examination with NSCLC.[26] Immunohistochemistry and electron microscopy are invaluable techniques for diagnosis and subclassification, but most lung tumors can be classified by light microscopic criteria.

For more information on tests and procedures used for staging, see the General Staging Evaluation section.

Prognostic Factors

Multiple studies have attempted to identify the prognostic importance of a variety of clinicopathological factors.[20,27–30] Factors that have correlated with adverse prognosis include:

  • Increasing stage.
  • Presence of pulmonary or constitutional symptoms.
  • Large tumor size (>3 cm).
  • Metastases to multiple lymph nodes within a TNM-defined nodal station.[31–41] For more information, see the Evaluation of mediastinal lymph node metastasis section.
  • Vascular invasion.[28,42–44]

For patients with inoperable disease, prognosis is adversely affected by poor performance status and weight loss of more than 10%. These patients have been excluded from clinical trials evaluating aggressive multimodality interventions.

In multiple retrospective analyses of clinical trial data, advanced age alone has not been shown to influence response or survival with therapy.[45]

Because treatment is not satisfactory for almost all patients with NSCLC, eligible patients should consider clinical trials. Information about ongoing clinical trials is available from the NCI website.

References
  1. American Cancer Society: Cancer Facts and Figures 2025. American Cancer Society, 2025. Available online. Last accessed January 16, 2025.
  2. Alberg AJ, Ford JG, Samet JM, et al.: Epidemiology of lung cancer: ACCP evidence-based clinical practice guidelines (2nd edition). Chest 132 (3 Suppl): 29S-55S, 2007. [PUBMED Abstract]
  3. Tulunay OE, Hecht SS, Carmella SG, et al.: Urinary metabolites of a tobacco-specific lung carcinogen in nonsmoking hospitality workers. Cancer Epidemiol Biomarkers Prev 14 (5): 1283-6, 2005. [PUBMED Abstract]
  4. Anderson KE, Kliris J, Murphy L, et al.: Metabolites of a tobacco-specific lung carcinogen in nonsmoking casino patrons. Cancer Epidemiol Biomarkers Prev 12 (12): 1544-6, 2003. [PUBMED Abstract]
  5. Straif K, Benbrahim-Tallaa L, Baan R, et al.: A review of human carcinogens–part C: metals, arsenic, dusts, and fibres. Lancet Oncol 10 (5): 453-4, 2009. [PUBMED Abstract]
  6. Friedman DL, Whitton J, Leisenring W, et al.: Subsequent neoplasms in 5-year survivors of childhood cancer: the Childhood Cancer Survivor Study. J Natl Cancer Inst 102 (14): 1083-95, 2010. [PUBMED Abstract]
  7. Gray A, Read S, McGale P, et al.: Lung cancer deaths from indoor radon and the cost effectiveness and potential of policies to reduce them. BMJ 338: a3110, 2009. [PUBMED Abstract]
  8. Berrington de González A, Kim KP, Berg CD: Low-dose lung computed tomography screening before age 55: estimates of the mortality reduction required to outweigh the radiation-induced cancer risk. J Med Screen 15 (3): 153-8, 2008. [PUBMED Abstract]
  9. Shimizu Y, Kato H, Schull WJ: Studies of the mortality of A-bomb survivors. 9. Mortality, 1950-1985: Part 2. Cancer mortality based on the recently revised doses (DS86). Radiat Res 121 (2): 120-41, 1990. [PUBMED Abstract]
  10. Katanoda K, Sobue T, Satoh H, et al.: An association between long-term exposure to ambient air pollution and mortality from lung cancer and respiratory diseases in Japan. J Epidemiol 21 (2): 132-43, 2011. [PUBMED Abstract]
  11. Cao J, Yang C, Li J, et al.: Association between long-term exposure to outdoor air pollution and mortality in China: a cohort study. J Hazard Mater 186 (2-3): 1594-600, 2011. [PUBMED Abstract]
  12. Hales S, Blakely T, Woodward A: Air pollution and mortality in New Zealand: cohort study. J Epidemiol Community Health 66 (5): 468-73, 2012. [PUBMED Abstract]
  13. Lissowska J, Foretova L, Dabek J, et al.: Family history and lung cancer risk: international multicentre case-control study in Eastern and Central Europe and meta-analyses. Cancer Causes Control 21 (7): 1091-104, 2010. [PUBMED Abstract]
  14. Shiels MS, Cole SR, Kirk GD, et al.: A meta-analysis of the incidence of non-AIDS cancers in HIV-infected individuals. J Acquir Immune Defic Syndr 52 (5): 611-22, 2009. [PUBMED Abstract]
  15. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. N Engl J Med 330 (15): 1029-35, 1994. [PUBMED Abstract]
  16. Omenn GS, Goodman GE, Thornquist MD, et al.: Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med 334 (18): 1150-5, 1996. [PUBMED Abstract]
  17. Wingo PA, Ries LA, Giovino GA, et al.: Annual report to the nation on the status of cancer, 1973-1996, with a special section on lung cancer and tobacco smoking. J Natl Cancer Inst 91 (8): 675-90, 1999. [PUBMED Abstract]
  18. Johnson BE: Second lung cancers in patients after treatment for an initial lung cancer. J Natl Cancer Inst 90 (18): 1335-45, 1998. [PUBMED Abstract]
  19. Thomas P, Rubinstein L: Cancer recurrence after resection: T1 N0 non-small cell lung cancer. Lung Cancer Study Group. Ann Thorac Surg 49 (2): 242-6; discussion 246-7, 1990. [PUBMED Abstract]
  20. Martini N, Bains MS, Burt ME, et al.: Incidence of local recurrence and second primary tumors in resected stage I lung cancer. J Thorac Cardiovasc Surg 109 (1): 120-9, 1995. [PUBMED Abstract]
  21. van Boxem AJ, Westerga J, Venmans BJ, et al.: Photodynamic therapy, Nd-YAG laser and electrocautery for treating early-stage intraluminal cancer: which to choose? Lung Cancer 31 (1): 31-6, 2001. [PUBMED Abstract]
  22. Blumberg J, Block G: The Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study in Finland. Nutr Rev 52 (7): 242-5, 1994. [PUBMED Abstract]
  23. Lippman SM, Lee JJ, Karp DD, et al.: Randomized phase III intergroup trial of isotretinoin to prevent second primary tumors in stage I non-small-cell lung cancer. J Natl Cancer Inst 93 (8): 605-18, 2001. [PUBMED Abstract]
  24. van Zandwijk N, Dalesio O, Pastorino U, et al.: EUROSCAN, a randomized trial of vitamin A and N-acetylcysteine in patients with head and neck cancer or lung cancer. For the EUropean Organization for Research and Treatment of Cancer Head and Neck and Lung Cancer Cooperative Groups. J Natl Cancer Inst 92 (12): 977-86, 2000. [PUBMED Abstract]
  25. Aberle DR, Adams AM, Berg CD, et al.: Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med 365 (5): 395-409, 2011. [PUBMED Abstract]
  26. Travis WD, Colby TV, Corrin B, et al.: Histological typing of lung and pleural tumours. 3rd ed. Springer-Verlag, 1999.
  27. Albain KS, Crowley JJ, LeBlanc M, et al.: Survival determinants in extensive-stage non-small-cell lung cancer: the Southwest Oncology Group experience. J Clin Oncol 9 (9): 1618-26, 1991. [PUBMED Abstract]
  28. Macchiarini P, Fontanini G, Hardin MJ, et al.: Blood vessel invasion by tumor cells predicts recurrence in completely resected T1 N0 M0 non-small-cell lung cancer. J Thorac Cardiovasc Surg 106 (1): 80-9, 1993. [PUBMED Abstract]
  29. Ichinose Y, Yano T, Asoh H, et al.: Prognostic factors obtained by a pathologic examination in completely resected non-small-cell lung cancer. An analysis in each pathologic stage. J Thorac Cardiovasc Surg 110 (3): 601-5, 1995. [PUBMED Abstract]
  30. Fontanini G, Bigini D, Vignati S, et al.: Microvessel count predicts metastatic disease and survival in non-small cell lung cancer. J Pathol 177 (1): 57-63, 1995. [PUBMED Abstract]
  31. Sayar A, Turna A, Kiliçgün A, et al.: Prognostic significance of surgical-pathologic multiple-station N1 disease in non-small cell carcinoma of the lung. Eur J Cardiothorac Surg 25 (3): 434-8, 2004. [PUBMED Abstract]
  32. Osaki T, Nagashima A, Yoshimatsu T, et al.: Survival and characteristics of lymph node involvement in patients with N1 non-small cell lung cancer. Lung Cancer 43 (2): 151-7, 2004. [PUBMED Abstract]
  33. Ichinose Y, Kato H, Koike T, et al.: Overall survival and local recurrence of 406 completely resected stage IIIa-N2 non-small cell lung cancer patients: questionnaire survey of the Japan Clinical Oncology Group to plan for clinical trials. Lung Cancer 34 (1): 29-36, 2001. [PUBMED Abstract]
  34. Tanaka F, Yanagihara K, Otake Y, et al.: Prognostic factors in patients with resected pathologic (p-) T1-2N1M0 non-small cell lung cancer (NSCLC). Eur J Cardiothorac Surg 19 (5): 555-61, 2001. [PUBMED Abstract]
  35. Asamura H, Suzuki K, Kondo H, et al.: Where is the boundary between N1 and N2 stations in lung cancer? Ann Thorac Surg 70 (6): 1839-45; discussion 1845-6, 2000. [PUBMED Abstract]
  36. Riquet M, Manac’h D, Le Pimpec-Barthes F, et al.: Prognostic significance of surgical-pathologic N1 disease in non-small cell carcinoma of the lung. Ann Thorac Surg 67 (6): 1572-6, 1999. [PUBMED Abstract]
  37. van Velzen E, Snijder RJ, Brutel de la Rivière A, et al.: Lymph node type as a prognostic factor for survival in T2 N1 M0 non-small cell lung carcinoma. Ann Thorac Surg 63 (5): 1436-40, 1997. [PUBMED Abstract]
  38. Vansteenkiste JF, De Leyn PR, Deneffe GJ, et al.: Survival and prognostic factors in resected N2 non-small cell lung cancer: a study of 140 cases. Leuven Lung Cancer Group. Ann Thorac Surg 63 (5): 1441-50, 1997. [PUBMED Abstract]
  39. Izbicki JR, Passlick B, Karg O, et al.: Impact of radical systematic mediastinal lymphadenectomy on tumor staging in lung cancer. Ann Thorac Surg 59 (1): 209-14, 1995. [PUBMED Abstract]
  40. Martini N, Burt ME, Bains MS, et al.: Survival after resection of stage II non-small cell lung cancer. Ann Thorac Surg 54 (3): 460-5; discussion 466, 1992. [PUBMED Abstract]
  41. Naruke T, Goya T, Tsuchiya R, et al.: Prognosis and survival in resected lung carcinoma based on the new international staging system. J Thorac Cardiovasc Surg 96 (3): 440-7, 1988. [PUBMED Abstract]
  42. Thomas P, Doddoli C, Thirion X, et al.: Stage I non-small cell lung cancer: a pragmatic approach to prognosis after complete resection. Ann Thorac Surg 73 (4): 1065-70, 2002. [PUBMED Abstract]
  43. Macchiarini P, Fontanini G, Hardin MJ, et al.: Relation of neovascularisation to metastasis of non-small-cell lung cancer. Lancet 340 (8812): 145-6, 1992. [PUBMED Abstract]
  44. Khan OA, Fitzgerald JJ, Field ML, et al.: Histological determinants of survival in completely resected T1-2N1M0 nonsmall cell cancer of the lung. Ann Thorac Surg 77 (4): 1173-8, 2004. [PUBMED Abstract]
  45. Earle CC, Tsai JS, Gelber RD, et al.: Effectiveness of chemotherapy for advanced lung cancer in the elderly: instrumental variable and propensity analysis. J Clin Oncol 19 (4): 1064-70, 2001. [PUBMED Abstract]

Cellular and Molecular Classification of NSCLC

Malignant non-small cell epithelial tumors of the lung are classified by the World Health Organization (WHO)/International Association for the Study of Lung Cancer (IASLC). The three main subtypes of non-small cell lung cancer (NSCLC) include:

  • Squamous cell carcinoma (25% of lung cancers).
  • Adenocarcinoma (40% of lung cancers).
  • Large cell carcinoma (10% of lung cancers).

Additional types include adenosquamous carcinoma, sarcomatoid carcinomas, salivary gland type tumors, carcinoid tumors, and other unclassified carcinomas. There are many subtypes in these categories.[1]

Tumor Types

Squamous cell carcinoma

Most squamous cell carcinomas of the lung are located centrally, in the larger bronchi of the lung. Squamous cell carcinomas are linked more strongly with smoking than other forms of NSCLC. The incidence of squamous cell carcinoma of the lung has been decreasing in recent years.

Adenocarcinoma

Adenocarcinoma is now the most common histological subtype in many countries, and subclassification of adenocarcinoma is important. One of the biggest problems with lung adenocarcinomas is the frequent histological heterogeneity. Mixtures of adenocarcinoma histological subtypes are more common than tumors consisting purely of a single pattern of acinar, papillary, bronchioloalveolar, and solid adenocarcinoma with mucin formation.

Criteria for the diagnosis of bronchioloalveolar carcinoma have varied widely in the past. The current WHO/IASLC definition is much more restrictive than that previously used by many pathologists because it is limited to only noninvasive tumors.

If stromal, vascular, or pleural invasion are identified in an adenocarcinoma that has an extensive bronchioloalveolar carcinoma component, the classification would be an adenocarcinoma of mixed subtype with predominant bronchioloalveolar pattern and a focal acinar, solid, or papillary pattern, depending on which pattern is seen in the invasive component. However, the future of bronchioloalveolar carcinoma as a distinct clinical entity is unclear; a multidisciplinary expert panel representing the IASLC, the American Thoracic Society, and the European Respiratory Society proposed a major revision of the classification of adenocarcinomas in 2011 that entails a reclassification of what was called bronchioloalveolar carcinoma into newly defined histological subgroups.

The following variants of adenocarcinoma are recognized in the WHO/IASLC classification:

  • Well-differentiated fetal adenocarcinoma.
  • Mucinous (colloid) adenocarcinoma.
  • Mucinous cystadenocarcinoma.
  • Signet ring adenocarcinoma.
  • Clear cell adenocarcinoma.

Large cell carcinoma

In addition to the general category of large cell carcinoma, several uncommon variants are recognized in the WHO/IASLC classification, including:

  • Large cell neuroendocrine carcinoma (LCNEC).
  • Basaloid carcinoma.
  • Lymphoepithelioma-like carcinoma.
  • Clear cell carcinoma.
  • Large cell carcinoma with rhabdoid phenotype.

Basaloid carcinoma is also recognized as a variant of squamous cell carcinoma, and rarely, adenocarcinomas may have a basaloid pattern; however, in tumors without either of these features, they are regarded as a variant of large cell carcinoma.

Neuroendocrine tumors

LCNEC is recognized as a histologically high-grade non-small cell carcinoma. It has a very poor prognosis similar to that of small cell lung cancer (SCLC). Atypical carcinoid is recognized as an intermediate-grade neuroendocrine tumor with a prognosis that falls between typical carcinoid and high-grade SCLC and LCNEC.

Neuroendocrine differentiation can be demonstrated by immunohistochemistry or electron microscopy in 10% to 20% of common NSCLCs that do not have any neuroendocrine morphology. These tumors are not formally recognized within the WHO/IASLC classification scheme because the clinical and therapeutic significance of neuroendocrine differentiation in NSCLC is not firmly established. These tumors are referred to collectively as NSCLC with neuroendocrine differentiation.

Carcinomas with pleomorphic, sarcomatoid, or sarcomatous elements

This is a group of rare tumors. Spindle cell carcinomas and giant cell carcinomas comprise only 0.4% of all lung malignancies, and carcinosarcomas comprise only 0.1% of all lung malignancies. In addition, this group of tumors reflects a continuum in histological heterogeneity, as well as epithelial and mesenchymal differentiation. On the basis of clinical and molecular data, biphasic pulmonary blastoma is regarded as part of the spectrum of carcinomas with pleomorphic, sarcomatoid, or sarcomatous elements.

Molecular Features

The identification of genetic variants in lung cancer has led to the development of molecularly targeted therapies to improve the survival of subsets of patients with metastatic disease.[2] In particular, subsets of adenocarcinoma now have been associated with specific variants in genes encoding components of the EGFR, MAPK, and PI3K signaling pathways. These variants may affect drug sensitivity and primary or acquired resistance to kinase inhibitors. Genomic alterations that can be targeted with approved therapies or for which treatments are under development include:

  • EGFR.
  • ALK.
  • BRAF.
  • ROS1.
  • RET.
  • NTRK1, NTRK2, and NTRK3.
  • MET.
  • KRAS.
  • HER2.

EGFR and ALK variants predominate in adenocarcinomas that develop in nonsmokers, and KRAS and BRAF variants are more common in smokers or former smokers. EGFR variants strongly predict the improved response rate and progression-free survival of patients who take EGFR inhibitors. In a set of 2,142 lung adenocarcinoma specimens from patients treated at Memorial Sloan Kettering Cancer Center, EGFR exon 19 deletions and L858R were found in 15% of tumors from former smokers (181 of 1,218; 95% confidence interval [CI], 13%–17%), 6% from current smokers (20 of 344; 95% CI, 4%–9%), and 52% from never-smokers (302 of 580; 95% CI, 48%–56%; P < .001 for ever- vs. never-smokers).[3]

ALK::EML4 fusion genes form translocation products that occur in 3% to 7% of unselected NSCLC cases and are responsive to pharmacological inhibition of ALK by agents like crizotinib. Sensitizing fusions of ALK with other genes have also been reported.

References
  1. Travis WD, Brambilla E, Nicholson AG, et al.: The 2015 World Health Organization Classification of Lung Tumors: Impact of Genetic, Clinical and Radiologic Advances Since the 2004 Classification. J Thorac Oncol 10 (9): 1243-1260, 2015. [PUBMED Abstract]
  2. Pao W, Girard N: New driver mutations in non-small-cell lung cancer. Lancet Oncol 12 (2): 175-80, 2011. [PUBMED Abstract]
  3. D’Angelo SP, Pietanza MC, Johnson ML, et al.: Incidence of EGFR exon 19 deletions and L858R in tumor specimens from men and cigarette smokers with lung adenocarcinomas. J Clin Oncol 29 (15): 2066-70, 2011. [PUBMED Abstract]

Stage Information for NSCLC

General Staging Evaluation

In non-small cell lung cancer (NSCLC), the determination of stage has important therapeutic and prognostic implications. Careful initial diagnostic evaluation to define the location and to determine the extent of primary and metastatic tumor involvement is critical for the appropriate care of patients.

In general, symptoms, physical signs, laboratory findings, and perceived risk of distant metastasis lead to an evaluation for distant metastatic disease. Additional tests such as bone scans and computed tomography (CT)/magnetic resonance imaging (MRI) of the brain may be performed if initial assessments suggest metastases or if patients with stage III disease are being evaluated for aggressive local and combined modality treatments.

Stage has a critical role in the selection of therapy. The stage of disease is based on a combination of clinical factors and pathological factors.[1] The distinction between clinical stage and pathological stage should be considered when evaluating reports of survival outcome.

Procedures used to determine stage include:

  • History.
  • Physical examination.
  • Routine laboratory evaluations.
  • Chest x-ray.
  • Chest CT scan with infusion of contrast material.
  • Fluorine F 18-fludeoxyglucose positron emission tomography (18F-FDG PET) scanning.

Procedures used to obtain tissue samples include bronchoscopy, mediastinoscopy, or anterior mediastinotomy.

Pathological staging of NSCLC requires examination of the tumor, knowledge of resection margins, and determination of lymph node status.

At diagnosis, patients with NSCLC can be divided into the following three groups that reflect both the extent of the disease and the treatment approach:

  1. Surgically resectable disease (generally stage I, stage II, and selected stage III tumors).
    • Has the best prognosis, which depends on a variety of tumor and host factors.
    • Patients with resectable disease who have medical contraindications to surgery are candidates for curative radiation therapy.
    • Postoperative cisplatin-based combination chemotherapy may provide a survival advantage for patients with resected stage II or stage IIIA NSCLC.
  2. Locally (T3–T4) and/or regionally (N2–N3) advanced disease.
    • Has a diverse natural history.
    • Selected patients with locally advanced tumors may benefit from combined modality treatments.
    • Patients with unresectable or N2–N3 disease are treated with radiation therapy in combination with chemotherapy.
    • Selected patients with T3 or N2 disease can be treated effectively with surgical resection and either preoperative or postoperative chemotherapy or chemoradiation therapy.
  3. Distant metastatic disease (includes distant metastases [M1] that were found at the time of diagnosis).
    • May be treated with systemic therapy (chemotherapy and/or immunotherapy or targeted therapy). Radiation therapy can be used for palliation.

Evaluation of mediastinal lymph node metastasis

Surgical evaluation

Surgical staging of the mediastinum is considered standard if accurate evaluation of the nodal status is needed to determine therapy.

Accurate staging of the mediastinal lymph nodes provides important prognostic information.

Evidence (nodal status):

  1. The association between survival and the number of examined lymph nodes during surgery for patients with stage I NSCLC treated with definitive surgical resection was assessed from the population-based Surveillance, Epidemiology, and End Results (SEER) Program database for the period from 1990 to 2000.[2] A total of 16,800 patients were included in the study.
    1. The overall survival analysis for patients without radiation therapy was done by comparing the reference group (one to four lymph nodes) with the following groups:
      • Patients with five to eight lymph nodes examined during surgery had a modest but statistically significant increase in survival, with a proportionate hazard ratio (HR) of 0.90 (95% confidence interval [CI], 0.84–0.97).
      • For patients with 9 to 12 examined lymph nodes, the HR was 0.86 (95% CI, 0.79–0.95).
      • For patients with 13 to 16 examined lymph nodes, the HR was 0.78 (95% CI, 0.68–0.90).
      • There appeared to be no incremental improvement after evaluating more than 16 lymph nodes.

      The corresponding results for lung cancer–specific mortality and for patients who received radiation therapy were not substantially different.

    2. These results indicate that patient survival following resection for NSCLC is associated with the number of lymph nodes evaluated during surgery. Because this is most likely the result of a reduction-of-staging error, namely, a decreased likelihood of missing positive lymph nodes with an increasing number of lymph nodes sampled, it suggests that an evaluation of nodal status should include 11 to 16 lymph nodes.
CT imaging

CT scanning is primarily used for determining the size of the tumor. The CT scan should extend inferiorly to include the liver and adrenal glands. MRI scans of the thorax and upper abdomen do not appear to yield advantages over CT scans.[3]

Evidence (CT scan):

  1. A systematic review of the medical literature relating to the accuracy of CT scanning for noninvasive staging of the mediastinum in patients with lung cancer was conducted. In the 35 studies published between 1991 and June 2006, 5,111 evaluable patients were identified. Almost all studies specified that CT scanning was performed following the administration of intravenous contrast material and that a positive test result was defined as the presence of one or more lymph nodes that measured larger than 1 cm on the short-axis diameter.[4]
    • The median prevalence of mediastinal metastasis was 28% (range, 18%–56%).
    • The pooled estimates of sensitivity and specificity of CT scanning for identifying mediastinal lymph node metastasis were 51% (95% CI, 47%–54%) for sensitivity and 86% (95% CI, 84%–88%) for specificity. Corresponding positive (3.4%) and negative (0.6%) likelihood ratios were provided.
  2. The results from the systematic review are similar to those of a large meta-analysis that reported the median sensitivity and specificity of CT scanning for identifying malignant mediastinal nodes as 61% for sensitivity and 79% for specificity.[5]
  3. An earlier meta-analysis reported an average sensitivity rate of 64% and specificity rate of 74%.[6]
18F-FDG PET scanning

The wider availability and use of 18F-FDG PET scanning for staging has modified the approach to staging mediastinal lymph nodes and distant metastases.

Randomized trials evaluating the utility of 18F-FDG PET scanning in potentially resectable NSCLC patients reported conflicting results in terms of the relative reduction in the number of noncurative thoracotomies.

Although the current evidence is conflicting, 18F-FDG PET scanning may improve results of early-stage lung cancer by identifying patients who have evidence of metastatic disease that is beyond the scope of surgical resection and that is not evident by standard preoperative staging procedures.

Evidence (18F-FDG PET scan):

  1. A systematic review, an expansion of a health technology assessment conducted in 2001 by the Institute for Clinical and Evaluative Sciences, evaluated the accuracy and utility of 18F-FDG PET scanning in the diagnosis and staging of lung cancer.[7] Through a systematic search of the literature, 12 evidence summary reports and 15 prospective studies of the diagnostic accuracy of 18F-FDG PET scanning were identified.
    • 18F-FDG PET scanning appears to be superior to CT imaging for mediastinal staging in NSCLC.
    • 18F-FDG PET scanning also appears to have high sensitivity and reasonable specificity for differentiating benign from malignant lesions as small as 1 cm.
  2. A systematic review of the medical literature relating to the accuracy of 18F-FDG PET scanning for noninvasive staging of the mediastinum in patients with lung cancer identified 44 studies published between 1994 and 2006 with 2,865 evaluable patients.[4]
    • The median prevalence of mediastinal metastases was 29% (range, 5%–64%).
    • Pooled estimates of sensitivity and specificity for identifying mediastinal metastasis were 74% (95% CI, 69%–79%) for sensitivity and 85% (95% CI, 82%–88%) for specificity.
    • Corresponding positive (4.9%) and negative (0.3%) likelihood ratios were provided for mediastinal staging with 18F-FDG PET scanning.
    • These findings demonstrated that 18F-FDG PET scanning is more accurate than CT scanning for staging of the mediastinum in patients with lung cancer.

Decision analyses demonstrate that 18F-FDG PET scanning may reduce the overall costs of medical care by identifying patients with falsely negative CT scans in the mediastinum or otherwise undetected sites of metastases.[8–10] Studies concluded that the money saved by forgoing mediastinoscopy in 18F-FDG PET-positive mediastinal lesions was not justified because of the unacceptably high number of false-positive results.[8–10] A randomized study found that the addition of 18F-FDG PET scanning to conventional staging was associated with significantly fewer thoracotomies.[11] A second randomized trial evaluating the impact of 18F-FDG PET scanning on clinical management found that 18F-FDG PET scanning provided additional information regarding appropriate stage but did not lead to significantly fewer thoracotomies.[12]

Combination of CT imaging and 18F-FDG PET scanning

The combination of CT imaging and 18F-FDG PET scanning has greater sensitivity and specificity than CT imaging alone.[13]

Evidence (CT/18F-FDG PET scan):

  1. If there is no evidence of distant metastatic disease on CT scan, 18F-FDG PET scanning complements CT scan staging of the mediastinum. Numerous nonrandomized studies of 18F-FDG PET scanning have evaluated mediastinal lymph nodes using surgery (i.e., mediastinoscopy and/or thoracotomy with mediastinal lymph node dissection) as the gold standard of comparison.
  2. A meta-analysis evaluated the conditional test performance of 18F-FDG PET scanning and CT scanning.
    • The median sensitivity and specificity of 18F-FDG PET scans were reported as 100% for sensitivity and 78% for specificity in patients with enlarged lymph nodes.[5]
    • 18F-FDG PET scanning is considered very accurate in identifying malignant nodal involvement when lymph nodes are enlarged. However, 18F-FDG PET scanning will falsely identify a malignancy in approximately one-fourth of patients with lymph nodes that are enlarged for other reasons, usually as a result of inflammation or infection.[14,15]
  3. The median sensitivity and specificity of 18F-FDG PET scanning in patients with normal-sized mediastinal lymph nodes were 82% for sensitivity and 93% for specificity.[5] These data indicate that nearly 20% of patients with normal-sized lymph nodes but with malignant involvement had falsely negative 18F-FDG PET scan findings.

For patients with clinically operable NSCLC, the evidence supports performing a biopsy of mediastinal lymph nodes that are found to be larger than 1 cm in shortest transverse axis on chest CT scan or are found to be positive on 18F-FDG PET scan. Negative 18F-FDG PET scanning does not preclude biopsy of radiographically enlarged mediastinal lymph nodes. Mediastinoscopy is necessary for the detection of cancer in mediastinal lymph nodes when the results of the CT scan and 18F-FDG PET scan do not corroborate each other.

Evaluation of brain metastasis

Patients at risk of brain metastases may be staged with CT or MRI scans.

Evidence (staging with CT or MRI):

  1. One study randomly assigned 332 patients with potentially operable NSCLC and no neurological symptoms to brain CT or MRI imaging to detect occult brain metastasis before lung surgery.[16]
    • MRI showed a trend towards a higher preoperative detection rate than CT scan (P = .069), with an overall detection rate of approximately 7% from pretreatment to 12 months after surgery.
    • Patients with stage I or stage II disease had a detection rate of 4% (i.e., 8 detections out of 200 patients); however, individuals with stage III disease had a detection rate of 11.4% (i.e., 15 detections out of 132 patients).
    • The mean maximal diameter of the brain metastases was significantly smaller in the MRI group.

    Whether the improved detection rate of MRI translates into improved outcome remains unknown. Not all patients are able to tolerate MRI, and for these patients contrast-enhanced CT scan is a reasonable substitute.

Evaluation of distant metastasis to sites other than the brain

Numerous nonrandomized, prospective, and retrospective studies have demonstrated that 18F-FDG PET scanning offers diagnostic advantages over conventional imaging in staging distant metastatic disease; however, standard 18F-FDG PET scans have limitations. 18F-FDG PET scans may not extend below the pelvis and may not detect bone metastases in the long bones of the lower extremities. Because the metabolic tracer used in 18F-FDG PET scanning accumulates in the brain and urinary tract, 18F-FDG PET scanning is not reliable for detection of metastases in these sites.[16]

The Revised International System for Staging Lung Cancer

The Revised International System for Staging Lung Cancer, based on information from a clinical database of more than 5,000 patients, was adopted in 2010 by the American Joint Committee on Cancer (AJCC) and the Union Internationale Contre le Cancer.[17,18] These revisions provide greater prognostic specificity for patient groups; however, the correlation between stage and prognosis predates the widespread availability of PET imaging.

AJCC Stage Groupings and TNM Definitions

The AJCC has designated staging by TNM (tumor, node, metastasis) classification to define NSCLC.[18]

Table 1. Definitions of Primary Tumor (T) for Lung Cancera
T Category T Criteria
aReprinted with permission from AJCC: Lung. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 431–56.
TX Primary tumor cannot be assessed, or tumor proven by the presence of malignant cells in sputum or bronchial washings but not visualized by imaging or bronchoscopy.
T0 No evidence of primary tumor.
Tis Carcinoma in situ; SCIS =Squamous cell carcinoma in situ; AIS: Adenocarcinoma in situ; Adenocarcinoma with pure lepidic pattern, ≤3 cm in greatest dimension.
T1 Tumor ≤3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the main bronchus).
  T1mi Minimally invasive adenocarcinoma: adenocarcinoma (≤3 cm in greatest dimension) with a predominantly lepidic pattern and ≤5 mm invasion in greatest dimension.
  T1a Tumor ≤1 cm in greatest dimension. A superficial, spreading tumor of any size whose invasive component is limited to the bronchial wall and may extend proximal to the main bronchus also is classified as T1a, but these tumors are uncommon.
  T1b Tumor >1 cm but ≤2 cm in greatest dimension.
  T1c Tumor >2 cm but ≤3 cm in greatest dimension.
T2 Tumor >3 cm but ≤5 cm or having any of the following features: involves the main bronchus regardless of distance to the carina, but without involvement of the carina; invades visceral pleura (PL1 or PL2); associated with atelectasis or obstructive pneumonitis that extends to the hilar region, involving part or all of the lung. T2 tumors with these features are classified as T2a if ≤4 cm or if the size cannot be determined and T2b if >4 cm but ≤5 cm.
  T2a Tumor >3 cm but ≤4 cm in greatest dimension.
  T2b Tumor >4 cm but ≤5 cm in greatest dimension.
T3 Tumor >5 cm but ≤7 cm in greatest dimension or directly invading any of the following: parietal pleura (PL3), chest wall (including superior sulcus tumors), phrenic nerve, parietal pericardium; or separate tumor nodule(s) in the same lobe as the primary.
T4 Tumor >7 cm or tumor of any size invading one or more of the following: diaphragm, mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, or carina; separate tumor nodule(s) in an ipsilateral lobe different from that of the primary.
Table 2. Definitions of Regional Lymph Node (N) for Lung Cancera
N Category N Criteria
aReprinted with permission from AJCC: Lung. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 431–56.
NX Regional lymph nodes cannot be assessed.
N0 No regional lymph node metastasis.
N1 Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes, including involvement by direct extension.
N2 Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s).
N3 Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s).
Table 3. Definitions of Distant Metastasis (M) for Lung Cancera
M Category M Criteria
aReprinted with permission from AJCC: Lung. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 431–56.
M0 No distant metastasis.
M1 Distant metastasis.
  M1a Separate tumor nodule(s) in a contralateral lobe; tumor with pleural or pericardial nodules or malignant pleural or pericardial effusion. Most pleural (pericardial) effusions with lung cancer are a result of the tumor. In a few patients, however, multiple microscopic examinations of pleural (pericardial) fluid are negative for tumor, and the fluid is nonbloody and not an exudate. If these elements and clinical judgment dictate that the effusion is not related to the tumor, the effusion should be excluded as a staging descriptor.
  M1b Single extrathoracic metastases in a single organ (including involvement of a single nonregional node).
  M1c Multiple extrathoracic metastases in a single organ or in multiple organs.
Table 4. AJCC Prognostic Stage Groups for Lung Cancera
Stage TNM Classification Illustration
T = primary tumor; N = regional lymph node; M = distant metastasis.
aReprinted with permission from AJCC: Lung. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 431–56.
Occult carcinoma TX, N0, M0  
0 Tis, N0, M0  
IA1 T1mi, N0, M0
EnlargeStage IA lung cancer; drawing shows a tumor (3 cm or smaller) in the right lung. Also shown are the lymph nodes, trachea, pleura, and diaphragm.
T1a, N0, M0
IA2 T1b, N0, M0
IA3 T1c, N0, M0
IB T2a, N0, M0
EnlargeTwo-panel drawing of stage IB lung cancer; the panel on the left shows a tumor (larger than 3 cm but not larger than 4 cm) in the right lung. Also shown are the pleura and diaphragm. The panel on the right shows a primary tumor (4 cm or smaller) in the left lung and cancer in (a) the left main bronchus and (b) the inner membrane covering the lung (inset). Also shown is (c) part or all of the lung has collapsed or has pneumonitis (inflammation). The carina and a rib (inset) are also shown.
IIA T2b, N0, M0
EnlargeStage IIA lung cancer; drawing shows a primary tumor (larger than 4 cm but not larger than 5 cm) in the left lung and cancer in (a) the left main bronchus and (b) the inner membrane covering the lung (inset). Also shown is (c) part or all of the lung has collapsed or has pneumonitis (inflammation). The carina, pleura, and a rib (inset) are also shown.
IIB T1a, N1, M0
EnlargeStage IIB lung cancer (1); drawing shows a primary tumor (5 cm or smaller) in the right lung and cancer in lymph nodes in the same lung as the primary tumor. Also shown are the trachea, main bronchus, pleura, and diaphragm.
EnlargeStage IIB lung cancer (2); drawing shows (a) a primary tumor (larger than 5 cm but not larger than 7 cm) in the left lung (top inset) and (b) a separate tumor in the same lobe of the lung as the primary tumor. Also shown is cancer that has spread to (c) the chest wall and the membranes covering the lung and chest wall (middle inset); (d) the nerve that controls the diaphragm; and (e) the sac around the heart (bottom inset). The pleura, diaphragm, heart, and a rib (middle inset) are also shown.
T1b, N1, M0
T1c, N1, M0
T2a, N1, M0
T2b, N1, M0
T3, N0, M0
IIIA T1a, N2, M0
EnlargeStage IIIA lung cancer (1); drawing shows a primary tumor (5 cm or smaller) in the left lung (top inset) and cancer in lymph nodes around the trachea. Also shown is cancer that has spread to (a) the left main bronchus and (b) the membrane covering the lung (bottom inset). Also shown is (c) part or all of the lung has collapsed or has pneumonitis (inflammation). The carina, pleura, and a rib (bottom inset) are also shown.
EnlargeStage IIIA lung cancer (2); drawing shows (a) a primary tumor (larger than 5 cm but not larger than 7 cm) in the left lung and cancer in lymph nodes in the lung or near the bronchus on the same side of the chest as the primary tumor. Also shown is (b) separate tumors in the same lobe of the lung as the primary tumor and cancer that has spread to (c) the chest wall and the membranes covering the lung and chest wall (top right inset); (d) the nerve that controls the diaphragm; and (e) the sac around the heart (bottom right inset). The trachea, left main bronchus, diaphragm, heart, and a rib (top right inset) are also shown.
EnlargeStage IIIA lung cancer (3); drawing shows (a) a primary tumor (larger than 7 cm) in the left lung and (b) separate tumors in a different lobe of the lung with the primary tumor. Also shown is cancer that has spread to the (c) trachea, (d) carina, (e) esophagus, (f) breastbone, (g) diaphragm, (h) heart, and (i) the aorta and vena cava.
T1b, N2, M0
T1c, N2, M0
T2a, N2, M0
T2b, N2, M0
T3, N1, M0
T4, N0, M0
T4, N1, M0
IIIB T1a, N3, M0
EnlargeStage IIIB lung cancer (1); drawing shows a primary tumor (5 cm or smaller) in the left lung and cancer in lymph nodes above the collarbone on the same side of the chest as the primary tumor and in lymph nodes on the opposite side of the chest as the primary tumor. Also shown is cancer that has spread to (a) the left main bronchus and (b) the membrane covering the lung. Also shown is (c) part or all of the lung has collapsed or has pneumonitis (inflammation). The carina, pleura, and a rib (inset) are also shown.
EnlargeStage IIIB lung cancer (2); drawing shows a primary tumor in the left lung and (a) a separate tumor in a different lobe of the lung with the primary tumor. Also shown is cancer in lymph nodes on the same side of the chest as the primary tumor. The lymph nodes with cancer are around the trachea or where the trachea divides into the bronchi. Also shown is (b) cancer that has spread to the following: the chest wall and the lining of the chest wall and lung, the nerve that controls the voice box, the trachea, the carina, the esophagus, the breastbone, the diaphragm, the nerve that controls the diaphragm, the aorta and vena cava, the heart, and the sac around the heart.
T1b, N3, M0
T1c, N3, M0
T2a, N3, M0
T2b, N3, M0
T3, N2, M0
T4, N2, M0
IIIC T3, N3, M0
EnlargeStage IIIC lung cancer; drawing shows a primary tumor in the left lung and (a) separate tumors in the same lobe of the lung with the primary tumor. Also shown is cancer in lymph nodes above the collarbone on the same side and opposite side of the chest as the primary tumor. Also shown is (b) cancer that has spread to the following: the chest wall and the lining of the chest wall and lung, the nerve that controls the voice box, the trachea, the carina, the esophagus, the breastbone, the diaphragm, the nerve that controls the diaphragm, the heart, the aorta and vena cava, and the sac around the heart.
T4, N3, M0
IV Any T, Any N, M1  
IVA Any T, Any N, M1a
EnlargeStage IVA lung cancer; drawing shows a primary tumor in the right lung and (a) a tumor in the left lung. Also shown is (b) fluid or cancer nodules around the lungs or heart (inset), and (c) other organs or tissues where lung cancer may spread, including the brain, adrenal gland, kidney, liver, bone, and distant lymph nodes.
Any T, Any N, M1b
IVB Any T, Any N, M1c
EnlargeStage IVB lung cancer; drawing shows a primary cancer in the right lung and other parts of the body where lung cancer may spread, including the brain, adrenal gland, kidney, liver, distant lymph nodes, and bone. An inset shows cancer cells spreading from the lung, through the blood and lymph system, to another part of the body where metastatic cancer has formed.
References
  1. Pfister DG, Johnson DH, Azzoli CG, et al.: American Society of Clinical Oncology treatment of unresectable non-small-cell lung cancer guideline: update 2003. J Clin Oncol 22 (2): 330-53, 2004. [PUBMED Abstract]
  2. Ludwig MS, Goodman M, Miller DL, et al.: Postoperative survival and the number of lymph nodes sampled during resection of node-negative non-small cell lung cancer. Chest 128 (3): 1545-50, 2005. [PUBMED Abstract]
  3. Webb WR, Gatsonis C, Zerhouni EA, et al.: CT and MR imaging in staging non-small cell bronchogenic carcinoma: report of the Radiologic Diagnostic Oncology Group. Radiology 178 (3): 705-13, 1991. [PUBMED Abstract]
  4. Toloza EM, Harpole L, McCrory DC: Noninvasive staging of non-small cell lung cancer: a review of the current evidence. Chest 123 (1 Suppl): 137S-146S, 2003. [PUBMED Abstract]
  5. Gould MK, Kuschner WG, Rydzak CE, et al.: Test performance of positron emission tomography and computed tomography for mediastinal staging in patients with non-small-cell lung cancer: a meta-analysis. Ann Intern Med 139 (11): 879-92, 2003. [PUBMED Abstract]
  6. Dwamena BA, Sonnad SS, Angobaldo JO, et al.: Metastases from non-small cell lung cancer: mediastinal staging in the 1990s–meta-analytic comparison of PET and CT. Radiology 213 (2): 530-6, 1999. [PUBMED Abstract]
  7. Ung YC, Maziak DE, Vanderveen JA, et al.: 18Fluorodeoxyglucose positron emission tomography in the diagnosis and staging of lung cancer: a systematic review. J Natl Cancer Inst 99 (23): 1753-67, 2007. [PUBMED Abstract]
  8. Dietlein M, Weber K, Gandjour A, et al.: Cost-effectiveness of FDG-PET for the management of potentially operable non-small cell lung cancer: priority for a PET-based strategy after nodal-negative CT results. Eur J Nucl Med 27 (11): 1598-609, 2000. [PUBMED Abstract]
  9. Scott WJ, Shepherd J, Gambhir SS: Cost-effectiveness of FDG-PET for staging non-small cell lung cancer: a decision analysis. Ann Thorac Surg 66 (6): 1876-83; discussion 1883-5, 1998. [PUBMED Abstract]
  10. Gambhir SS, Hoh CK, Phelps ME, et al.: Decision tree sensitivity analysis for cost-effectiveness of FDG-PET in the staging and management of non-small-cell lung carcinoma. J Nucl Med 37 (9): 1428-36, 1996. [PUBMED Abstract]
  11. van Tinteren H, Hoekstra OS, Smit EF, et al.: Effectiveness of positron emission tomography in the preoperative assessment of patients with suspected non-small-cell lung cancer: the PLUS multicentre randomised trial. Lancet 359 (9315): 1388-93, 2002. [PUBMED Abstract]
  12. Viney RC, Boyer MJ, King MT, et al.: Randomized controlled trial of the role of positron emission tomography in the management of stage I and II non-small-cell lung cancer. J Clin Oncol 22 (12): 2357-62, 2004. [PUBMED Abstract]
  13. Vansteenkiste JF, Stroobants SG, De Leyn PR, et al.: Lymph node staging in non-small-cell lung cancer with FDG-PET scan: a prospective study on 690 lymph node stations from 68 patients. J Clin Oncol 16 (6): 2142-9, 1998. [PUBMED Abstract]
  14. Roberts PF, Follette DM, von Haag D, et al.: Factors associated with false-positive staging of lung cancer by positron emission tomography. Ann Thorac Surg 70 (4): 1154-9; discussion 1159-60, 2000. [PUBMED Abstract]
  15. Liewald F, Grosse S, Storck M, et al.: How useful is positron emission tomography for lymphnode staging in non-small-cell lung cancer? Thorac Cardiovasc Surg 48 (2): 93-6, 2000. [PUBMED Abstract]
  16. Yokoi K, Kamiya N, Matsuguma H, et al.: Detection of brain metastasis in potentially operable non-small cell lung cancer: a comparison of CT and MRI. Chest 115 (3): 714-9, 1999. [PUBMED Abstract]
  17. Mountain CF: Revisions in the International System for Staging Lung Cancer. Chest 111 (6): 1710-7, 1997. [PUBMED Abstract]
  18. Lung. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. Springer; 2017, pp. 431–56.

Treatment Option Overview for NSCLC

In non-small cell lung cancer (NSCLC), results of standard treatment are poor except for the most localized cancers. All newly diagnosed patients with NSCLC are potential candidates for studies evaluating new forms of treatment.

Treatment decisions are based on some of the following factors:

  • Knowledge of histological type and molecular features.
  • Tumor size and location.
  • Involvement of pleura.
  • Surgical margins.
  • Status and location of lymph nodes by station.
  • Tumor grade.
  • Lymphovascular invasion.

Surgery is potentially the most curative therapeutic option for this disease. Postoperative chemotherapy may provide an additional benefit to patients with resected NSCLC. Radiation therapy combined with chemotherapy can produce a cure in a small number of patients and can provide palliation in most patients. Prophylactic cranial irradiation may reduce the incidence of brain metastases, but there is no evidence of a survival benefit and the effect of prophylactic cranial irradiation on quality of life is not known.[1,2] In patients with advanced-stage disease, chemotherapy or EGFR kinase inhibitors offer modest improvements in median survival, although overall survival is poor.[3,4]

Chemotherapy has produced short-term improvement in disease-related symptoms in patients with advanced NSCLC. Several clinical trials have attempted to assess the impact of chemotherapy on tumor-related symptoms and quality of life. In total, these studies suggest that tumor-related symptoms may be controlled by chemotherapy without adversely affecting overall quality of life;[5,6] however, the impact of chemotherapy on quality of life requires more study. In general, medically eligible older patients with good performance status obtain the same benefits from treatment as younger patients.

The identification of pathogenic variants has led to the development of molecularly targeted therapies for lung cancer that have improved the survival of some patients with metastatic disease.[7] In particular, genetic abnormalities in EGFR, MAPK, and PI3K signaling pathways in subsets of NSCLC may affect drug sensitivity and primary or acquired resistance to kinase inhibitors. EGFR variants strongly predict the improved response rate and progression-free survival in patients who receive EGFR inhibitors. ALK::EML4 fusion genes and other genes form translocation products that occur in 3% to 7% of unselected NSCLC cases and are responsive to pharmacological inhibition of ALK by agents like alectinib. The MET oncogene encodes hepatocyte growth factor receptor. Amplification of this gene has been associated with secondary resistance to EGFR tyrosine kinase inhibitors. Recurrent fusions involving the ROS1 gene are observed in up to 2% of NSCLCs and are responsive to treatment with crizotinib and entrectinib. NTRK gene fusions can occur in up to 1% of NSCLCs and can be treated with the TRK inhibitors, larotrectinib and entrectinib. For more information, see the Molecular Features section.

The treatment options for each stage of NSCLC are presented in Table 5.

Table 5. Treatment Options for NSCLC
Stage (TNM Definitions) Treatment Options
NSCLC = non-small cell lung cancer; TKIs = tyrosine kinase inhibitors; TNM = tumor, node, metastasis.
Occult NSCLC Surgery
Stage 0 NSCLC Surgery
Endobronchial therapies
Stages IA and IB NSCLC Surgery
Adjuvant therapy
Radiation therapy
Stages IIA and IIB NSCLC Surgery with or without adjuvant and/or neoadjuvant therapy
Radiation therapy
Stage IIIA NSCLC Resected or resectable disease Surgery with neoadjuvant and/or adjuvant therapy
Neoadjuvant therapy
Perioperative (neoadjuvant and adjuvant) immunotherapy with chemotherapy
Adjuvant therapy
Unresectable disease Chemoradiation therapy
Radiation therapy
Superior sulcus tumors Surgery
Chemoradiation therapy followed by surgery
Radiation therapy alone
Tumors that invade the chest wall Surgery
Surgery and radiation therapy
Radiation therapy alone
Chemotherapy combined with radiation therapy and/or surgery
Stages IIIB and IIIC NSCLC Sequential or concurrent chemotherapy and radiation therapy
Radiation therapy alone
Newly Diagnosed Stage IV, Relapsed, and Recurrent NSCLC Cytotoxic combination chemotherapy
Combination chemotherapy with monoclonal antibodies
Maintenance therapy after first-line chemotherapy (for patients with stable or responding disease after four cycles of platinum-based combination chemotherapy)
EGFR TKIs with or without chemotherapy (for patients with EGFR variants)
EGFR-directed therapy (for patients with EGFR exon 20 insertions)
ALK inhibitors (for patients with ALK translocations)
BRAF V600E and MEK inhibitors (for patients with BRAF V600E variants)
ROS1 inhibitors (for patients with ROS1 rearrangements)
NTRK inhibitors (for patients with NTRK fusions)
RET inhibitors (for patients with RET fusions)
MET inhibitors (for patients with MET exon 14-skipping variants)
Immune checkpoint inhibitors with or without chemotherapy
mTOR inhibitors (for patients with unresectable, locally advanced or metastatic, progressive, well-differentiated, nonfunctional, neuroendocrine tumors)
Local therapies and special considerations
Progressive Stage IV, Relapsed, and Recurrent NSCLC Chemotherapy
EGFR-directed therapy
ALK-directed TKIs
BRAF V600E and MEK inhibitors (for patients with BRAF V600E variants)
ROS1-directed therapy
NTRK inhibitors (for patients with NTRK fusions)
RET inhibitors (for patients with RET fusions)
MET inhibitors (for patients with MET exon 14-skipping variants)
KRAS G12C inhibitors (for patients with KRAS G12C variants)
HER2-targeted therapy (for patients with HER2 variants)
Immunotherapy
mTOR inhibitors (for patients with unresectable, locally advanced or metastatic, progressive, well-differentiated, nonfunctional, neuroendocrine tumors)

In addition to the treatment options presented in Table 5, treatment options under clinical evaluation include:

  • Combining local treatment (surgery).
  • Regional treatment (radiation therapy).
  • Systemic treatments (chemotherapy, immunotherapy, and targeted agents).
  • Developing more effective systemic therapy.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References
  1. Lester JF, MacBeth FR, Coles B: Prophylactic cranial irradiation for preventing brain metastases in patients undergoing radical treatment for non-small-cell lung cancer: a Cochrane Review. Int J Radiat Oncol Biol Phys 63 (3): 690-4, 2005. [PUBMED Abstract]
  2. Pöttgen C, Eberhardt W, Grannass A, et al.: Prophylactic cranial irradiation in operable stage IIIA non small-cell lung cancer treated with neoadjuvant chemoradiotherapy: results from a German multicenter randomized trial. J Clin Oncol 25 (31): 4987-92, 2007. [PUBMED Abstract]
  3. Chemotherapy for non-small cell lung cancer. Non-small Cell Lung Cancer Collaborative Group. Cochrane Database Syst Rev (2): CD002139, 2000. [PUBMED Abstract]
  4. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. Non-small Cell Lung Cancer Collaborative Group. BMJ 311 (7010): 899-909, 1995. [PUBMED Abstract]
  5. Spiro SG, Rudd RM, Souhami RL, et al.: Chemotherapy versus supportive care in advanced non-small cell lung cancer: improved survival without detriment to quality of life. Thorax 59 (10): 828-36, 2004. [PUBMED Abstract]
  6. Clegg A, Scott DA, Hewitson P, et al.: Clinical and cost effectiveness of paclitaxel, docetaxel, gemcitabine, and vinorelbine in non-small cell lung cancer: a systematic review. Thorax 57 (1): 20-8, 2002. [PUBMED Abstract]
  7. Pao W, Girard N: New driver mutations in non-small-cell lung cancer. Lancet Oncol 12 (2): 175-80, 2011. [PUBMED Abstract]

Treatment of Occult NSCLC

In occult lung cancer, a diagnostic evaluation often includes chest x-ray and selective bronchoscopy with close follow-up (e.g., computed tomography scan), when needed, to define the site and nature of the primary tumor; tumors discovered in this fashion are generally early stage and curable by surgery.

After discovery of the primary tumor, treatment involves establishing the stage of the tumor. Therapy is identical to that recommended for other non-small cell lung cancer (NSCLC) patients with similar-stage disease.

Treatment Options for Occult NSCLC

Treatment options for occult NSCLC include:

  1. Surgery.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

Treatment of Stage 0 NSCLC

Stage 0 non-small cell lung cancer (NSCLC) frequently progresses to invasive cancer.[1–3] Patients may be offered surveillance bronchoscopies and, if lesions are detected, potentially curative therapies.

Treatment Options for Stage 0 NSCLC

Treatment options for stage 0 NSCLC include:

  1. Surgery.
  2. Endobronchial therapies, including photodynamic therapy, electrocautery, cryotherapy, and neodymium-doped yttrium aluminum garnet (Nd-YAG) laser therapy.

Surgery

Segmentectomy or wedge resection are used to preserve maximum normal pulmonary tissue because patients with stage 0 NSCLC are at a high risk of second lung cancers. Because these tumors are, by definition, noninvasive and incapable of metastasizing, they should be curable with surgical resection; however, such lesions, when identified, are often centrally located and may require a lobectomy.

Endobronchial therapies

Patients with central lesions may be candidates for curative endobronchial therapy. Endobronchial therapies that preserve lung function include photodynamic therapy, electrocautery, cryotherapy, and Nd-YAG laser therapy.[3–6]

Evidence (endobronchial therapies):

  1. Small case series have reported high complete response rates and long-term survival in selected patients.[7,8][Level of evidence C2]

Efficacy of these treatment modalities in the management of patients with early NSCLC remains to be proven in definitive randomized controlled trials.

A high incidence of second primary cancers develop in these patients.[1,2]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References
  1. Woolner LB, Fontana RS, Cortese DA, et al.: Roentgenographically occult lung cancer: pathologic findings and frequency of multicentricity during a 10-year period. Mayo Clin Proc 59 (7): 453-66, 1984. [PUBMED Abstract]
  2. Venmans BJ, van Boxem TJ, Smit EF, et al.: Outcome of bronchial carcinoma in situ. Chest 117 (6): 1572-6, 2000. [PUBMED Abstract]
  3. Jeremy George P, Banerjee AK, Read CA, et al.: Surveillance for the detection of early lung cancer in patients with bronchial dysplasia. Thorax 62 (1): 43-50, 2007. [PUBMED Abstract]
  4. Kennedy TC, McWilliams A, Edell E, et al.: Bronchial intraepithelial neoplasia/early central airways lung cancer: ACCP evidence-based clinical practice guidelines (2nd edition). Chest 132 (3 Suppl): 221S-233S, 2007. [PUBMED Abstract]
  5. Corti L, Toniolo L, Boso C, et al.: Long-term survival of patients treated with photodynamic therapy for carcinoma in situ and early non-small-cell lung carcinoma. Lasers Surg Med 39 (5): 394-402, 2007. [PUBMED Abstract]
  6. Deygas N, Froudarakis M, Ozenne G, et al.: Cryotherapy in early superficial bronchogenic carcinoma. Chest 120 (1): 26-31, 2001. [PUBMED Abstract]
  7. van Boxem TJ, Venmans BJ, Schramel FM, et al.: Radiographically occult lung cancer treated with fibreoptic bronchoscopic electrocautery: a pilot study of a simple and inexpensive technique. Eur Respir J 11 (1): 169-72, 1998. [PUBMED Abstract]
  8. van Boxem AJ, Westerga J, Venmans BJ, et al.: Photodynamic therapy, Nd-YAG laser and electrocautery for treating early-stage intraluminal cancer: which to choose? Lung Cancer 31 (1): 31-6, 2001. [PUBMED Abstract]

Treatment of Stages IA and IB NSCLC

Treatment Options for Stages IA and IB NSCLC

Treatment options for stages IA non-small cell lung cancer (NSCLC) and IB NSCLC include:

  1. Surgery.
  2. Adjuvant therapy.
  3. Radiation therapy (for patients who cannot have surgery or choose not to have surgery).

Chemotherapy and radiation therapy have not been shown to improve survival in patients with stage I NSCLC that has been completely resected.

Surgery

Surgery is the treatment of choice for patients with stage I NSCLC. A lobectomy or segmental, wedge, or sleeve resection may be performed as appropriate. Patients with impaired pulmonary function are candidates for segmental or wedge resection of the primary tumor. Careful preoperative assessment of the patient’s overall medical condition, especially the patient’s pulmonary reserve, is critical in considering the benefits of surgery. The immediate postoperative mortality rate is age related, but a 3% to 5% mortality rate with lobectomy can be expected.[1]

Evidence (surgery):

  1. The Lung Cancer Study Group conducted a randomized study (LCSG-821) that compared lobectomy with limited resection for patients with stage I lung cancer. Results of the study showed:[2]
    • A reduction in local recurrence for patients treated with lobectomy compared with those treated with limited excision.
    • No significant difference in overall survival (OS).
  2. Similar results were reported from a nonrandomized comparison of anatomical segmentectomy and lobectomy.[3]
    • A survival advantage was noted with lobectomy for patients with tumors larger than 3 cm but not for those with tumors smaller than 3 cm.
    • The rate of locoregional recurrence was significantly less after lobectomy, regardless of primary tumor size.
  3. A study of stage I patients showed:[4]
    • Those treated with wedge or segmental resections had a local recurrence rate of 50% (i.e., 31 recurrences out of 62 patients) despite having undergone complete resections.[4]
  4. A multicenter, noninferiority, phase III trial (NCT00499330) evaluated lobar or sublobar resection in patients with peripheral stage IA NSCLC. A total of 697 patients with clinical stage T1a, N0 tumors (tumor size <2 cm) were randomly assigned to undergo sublobar resection or lobar resection after intraoperative confirmation of node-negative disease in the hilar and mediastinal lymph nodes. The primary end point was disease-free survival (DFS).[5][Level of evidence B1]
    • After a median follow-up of 7 years, sublobar resection was noninferior to lobar resection for DFS (hazard ratio [HR], 1.01; 90% confidence interval [CI], 0.83–1.24; one-sided P = .02 for noninferiority).
    • OS was similar after sublobar resection or lobar resection (HR, 0.95; 95% CI, 0.72–1.26).
    • No substantial differences were noted in the incidence of locoregional or distant disease recurrence between the two groups.
    • At 6 months after surgery, the magnitude of reduction from baseline in the percentage of predicted FEV1 (forced expiratory volume in first second of expiration) was greater in the lobectomy group (-6%; 95% CI, -8% to -5%) versus the sublobar resection group (-4%; 95% CI, -5% to -2%). The magnitude of reduction in the percentage of predicted FVC (forced vital capacity) was also greater after lobectomy (-5%; 95% CI, -7% to -3%) than after sublobar resection (-3%; 95% CI, -4% to -1%).

    These results suggest that sublobar resection by anatomical segmentectomy or wedge resection is effective for management of clinical stage T1a, N0 NSCLC when intraoperative sampling of hilar and mediastinal lymph nodes is negative.

  5. The Cochrane Collaboration reviewed 11 randomized trials with a total of 1,910 patients who underwent surgical interventions for early-stage (I–IIIA) lung cancer.[6] A pooled analysis of three trials reported the following:
    • Four-year survival was superior in patients with resectable stage I, II, or IIIA NSCLC who underwent resection and complete ipsilateral mediastinal lymph node dissection (CMLND), compared with those who underwent resection and lymph node sampling; the HR was estimated to be 0.78 (95% CI, 0.65–0.93, P = .005).[6][Level of evidence A1]
    • There was a significant reduction in any cancer recurrence (local or distant) in the CMLND group (relative risk [RR], 0.79; 95% CI, 0.66–0.95; P = .01) that appeared mainly because of a reduction in the number of distant recurrences (RR, 0.78; 95% CI, 0.61–1.00; P = .05).
    • There was no difference in operative mortality.
    • Air leak lasting more than 5 days was significantly more common in patients assigned to CMLND (RR, 2.94; 95% CI, 1.01–8.54; P = .05).
  6. CMLND versus lymph node sampling was evaluated in a large, randomized, phase III trial (ACOSOG-Z0030 [NCT00003831]).[7,8]
    • Preliminary analyses of operative morbidity and mortality showed comparable rates from the procedures.[7,8]
    • There was no difference in OS, DFS, local recurrence, and regional recurrence.[8][Level of evidence A1]

Current evidence suggests that lung cancer resection combined with CMLND is not associated with improvement in survival compared with lung cancer resection combined with systematic sampling of mediastinal lymph nodes in patients with stage I, II, or IIIA NSCLC.[8][Level of evidence A1]

Conclusions about the efficacy of surgery for patients with local and locoregional NSCLC are limited by the small number of participants studied to date and the potential methodological weaknesses of the trials.

Adjuvant therapy

Many patients who have surgery subsequently develop regional or distant metastases.[9] Such patients are candidates for entry into clinical trials evaluating postoperative treatment with chemotherapy or radiation therapy following surgery. At present, neither chemotherapy nor radiation therapy has been found to improve survival in patients with stage I NSCLC that has been completely resected.

Adjuvant chemotherapy

Based on a meta-analysis, postoperative chemotherapy is not recommended outside of a clinical trial for patients with completely resected stage I NSCLC.[10] However, there may be some benefit of adjuvant chemotherapy in patients with stage IB tumors that are larger than 4 cm.

Evidence (adjuvant chemotherapy for patients with stage IB NSCLC):

  1. The Cancer and Leukemia Group B study (CALGB-9633 [NCT00002852]) addressed the results of adjuvant carboplatin and paclitaxel versus observation for OS in 344 patients with resected stage IB (i.e., pathological T2, N0) NSCLC. Within 4 to 8 weeks of resection, patients were randomly assigned to postoperative chemotherapy or observation.[11]
    • Survival was not significantly different (HR, 0.83; 90% CI, 0.64–1.08; P = .12) at a median follow-up of 74 months.
    • Grades 3 to 4 neutropenia were the predominant toxicity; there were no treatment-related deaths.
    • A post-hoc exploratory analysis demonstrated a significant survival difference in favor of postoperative chemotherapy for patients who had tumors 4 cm or larger in diameter (HR, 0.69; 90% CI, 0.48–0.99; P = .043).

Given the magnitude of observed survival differences, CALGB-9633 may have been underpowered to detect small but clinically meaningful improvements in survival. In addition, the use of a carboplatin versus a cisplatin combination might have affected the results. At present, there is no reliable evidence that postoperative chemotherapy improves survival of patients with stage IB NSCLC.[11][Level of evidence A1]

Adjuvant targeted therapy (for patients with stage IB NSCLC and EGFR variants)

Adjuvant targeted therapy with osimertinib for patients with resected stage IB to IIIA NSCLC and an EGFR pathogenic variant was studied in a phase III clinical trial and showed improved OS.

Evidence (adjuvant targeted therapy with osimertinib for patients with stage IB NSCLC and EGFR variants):

  1. The phase III, double-blind, placebo-controlled ADAURA (NCT02511106) trial included 682 patients with surgically resected stage IB to stage IIIA NSCLC and EGFR pathogenic variants (centrally determined, deletion in exon 19 or L858R variant). Patients were randomly assigned to receive either 80 mg of osimertinib by mouth daily (n = 399) or a placebo (n = 342) for 3 years. Standard postoperative adjuvant chemotherapy was allowed but not mandatory; decisions regarding adjuvant chemotherapy were made by the physician and patient before trial enrollment.[12][Level of evidence A1]
    • In the overall population, the 5-year OS rate was 88% in the osimertinib group and 78% in the placebo group (overall HRdeath, 0.49; 95.03% CI, 0.34–0.70; P < .001).
    • Among patients with stage II to IIIA disease, the 5-year OS rate was 85% in the osimertinib group and 73% in the placebo group (overall HRdeath, 0.49; 95.03% CI, 0.33–0.73; P < .001).
    • The adverse event profile is consistent with other studies that used osimertinib except for pneumonia related to COVID-19, which was reported later.

The U.S. Food and Drug Administration (FDA) approved osimertinib as adjuvant therapy for patients with stage IB to IIIA NSCLC with EGFR exon 19 deletions or EGFR L858R variants.

Adjuvant targeted therapy (for patients with stage IB tumors and ALK variants)

Evidence (adjuvant targeted therapy for patients with stage IB tumors with ALK variants):

  1. The global, phase III, open-label ALINA trial (NCT03456076) included 257 patients with completely resected stage IB (tumors ≥4 cm), II, or IIIA (American Joint Committee on Cancer 7th edition staging criteria) NSCLC and an ALK variant. Patients were randomly assigned in a 1:1 ratio to receive either oral alectinib (600 mg twice daily) for 24 months or intravenous platinum-based chemotherapy in four 21-day cycles. The primary end point was DFS, tested hierarchically among patients with stage II or IIIA disease and then in the intention-to-treat (ITT) population. Secondary end points included central nervous system (CNS) DFS, OS, and safety.[13]
    • The median duration of follow-up for survival was 27.8 months (27.8 months in the alectinib group and 28.4 months in the chemotherapy group).
    • The 2-year DFS rate was 93.8% in the alectinib group and 63.0% in the chemotherapy group (stage II/IIIA) (HRdisease recurrence or death, 0.24; 95% CI, 0.13–0.45; P < .001).[13][Level of evidence B1]
    • The ITT population included patients with stage IB, II, or IIIA disease who had been randomly assigned. The DFS rate in the ITT population was 93.6% for patients who received alectinib and 63.7% for patients who received chemotherapy (HR, 0.24; 95% CI, 0.13–0.43; P < .001).
    • The HRCNS disease recurrence or death was 0.22 (95% CI, 0.08–0.58) in favor of alectinib.
    • OS data are immature.

The FDA approved alectinib for adjuvant treatment following tumor resection in patients with NSCLC and an ALK variant.

Adjuvant immunotherapy

Evidence (adjuvant immunotherapy with pembrolizumab for patients with stage IB tumors >4 cm):

  1. The phase III, multicenter, open-label PEARLS/KEYNOTE-091 trial (NCT02504372) randomly assigned 1,177 patients with completely resected stage IB (tumor >4 cm) to stage IIIA NSCLC to receive pembrolizumab (200 mg every 3 weeks) or placebo for up to 18 cycles, or until disease progression or unacceptable toxicity. Patients started study treatment after resection or, if indicated, after adjuvant chemotherapy (maximum of four cycles). The dual primary end points were DFS in the overall study population and DFS in patients with a programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) of 50% or greater, as determined using the PD-L1 IHC 22C3 pharmDx assay. These end points were reported in a prespecified interim analysis after a median follow-up of 35.6 months (interquartile range, 27.1–45.5).[14][Level of evidence B1]
    • In the overall study population, the median DFS was 53.6 months (95% CI, 39.2–not reached [NR]) in the pembrolizumab group and 42.0 months (95% CI, 31.3–NR) in the placebo group (HR, 0.76; 95% CI, 0.63–0.91; P = .0014).
    • In the PD-L1 TPS ≥50% population, the median DFS was not reached with either pembrolizumab (95% CI, 44.3–NR) or placebo (95% CI, 35.8–NR) (HR, 0.82; 95% CI, 0.57–1.18; P = .14).
    • OS data were immature at the time of the prespecified interim analysis.
    • No new safety signals were identified in this study.

The FDA approved pembrolizumab as a single agent for adjuvant treatment following resection and platinum-based chemotherapy for patients with stage IB (T2a ≥4 cm), II, or IIIA NSCLC. Of note, the FDA label specifies that pembrolizumab can be used as adjuvant therapy after platinum-based chemotherapy. However, chemotherapy was not required in the overall study patient population evaluated in KEYNOTE-091.

Adjuvant external radiation therapy

The value of postoperative (adjuvant) radiation therapy (PORT) has been evaluated and has not been found to improve the outcome of patients with completely resected stage I NSCLC.[15]

Adjuvant brachytherapy

The value of intraoperative (adjuvant) brachytherapy applied to the suture line has been evaluated in patients undergoing sublobar resections for stage I NSCLC to improve local control; it has not been found to improve outcomes.

Evidence (adjuvant brachytherapy):

  1. A phase III trial that randomly assigned 222 patients to undergo sublobar resection with or without suture line brachytherapy reported the following:[16]
    • No difference in the primary end point of local recurrence (5-year estimate, 14.0% vs. 16.7%; P = .59).
    • No difference in OS rates (5-year estimate, 61.4% vs. 55.6%; P = .38).[16][Level of evidence B1] vs. [Level of evidence A1]

Radiation therapy

A substantial number of patients are ineligible for standard surgical resection because of comorbid conditions that are associated with unacceptably high perioperative risk. Patients with potentially resectable tumors with medical contraindications to surgery or those with inoperable stage I disease and with sufficient pulmonary reserve may be candidates for radiation therapy with curative intent.[17–19] Nonrandomized observational studies comparing treatment outcomes associated with resection, radiation therapy, and observation have demonstrated shorter survival times and higher mortality for patients who undergo observation only.[17,20]

Conventional radiation therapy

Historically, conventional primary radiation therapy consisted of approximately 60 Gy to 70 Gy delivered with megavoltage equipment to the midplane of the known tumor volume using conventional fractionation (1.8–2.0 Gy per day).

Improvements in radiation techniques include planning techniques to account for tumor motion, more conformal planning techniques (e.g., 3-D conformal radiation therapy and intensity-modulated radiation therapy), and image guidance during treatment. Modern approaches to delivery of external-beam radiation therapy (EBRT) include hypofractionated radiation therapy and stereotactic body radiation therapy (SBRT). However, there are limited reliable data from comparative trials to determine which approaches yield superior outcomes.[18,19]

Evidence (conventional radiation therapy):

  1. In the largest retrospective conventional radiation therapy series, patients with inoperable disease were treated with definitive radiation therapy.[21–23]
    • Patients achieved 5-year survival rates of 10% to 30%.[21–23]
    • Several series demonstrated that patients with T1, N0 tumors had better outcomes, and 5-year survival rates of 30% to 60% were found in this subgroup.[21,22,24]
    • However, local-only failure occurs in as many as 50% of patients treated with conventional radiation therapy to doses in the range of 60 Gy to 65 Gy.[25,26]
  2. A single report of patients older than 70 years who had resectable lesions smaller than 4 cm but who had medically inoperable disease or who refused surgery reported the following:[24]
    • Survival at 5 years after radiation therapy with curative intent was comparable with a historical control group of patients of similar age who were resected with curative intent.
  3. A small case series using matched controls reported the following:[4]
    • The addition of endobronchial brachytherapy improved local disease control compared with EBRT.[4][Level of evidence C2]
Hypofractionated radiation therapy

Hypofractionated radiation therapy involves the delivery of a slightly higher dose of radiation therapy per day (e.g., 2.4–4.0 Gy) over a shorter period of time compared with conventionally fractionated radiation therapy. Multiple prospective phase I/II trials have demonstrated that hypofractionated radiation therapy to a dose of 60 Gy to 70 Gy delivered over 3 to 4 weeks with 2.4 Gy to 4.0 Gy per day resulted in a low incidence of moderate to severe toxicity, 2-year OS rates of 50% to 60%, and 2-year tumor local control of 80% to 90%.[27–29][Level of evidence C1]

Stereotactic body radiation therapy (SBRT)

SBRT involves the delivery of highly conformal, high-dose radiation therapy over an extremely hypofractionated course (e.g., one to five treatments) delivered over 1 to 2 weeks. Commonly used regimens include 18 Gy × 3, 12 Gy to 12.5 Gy × 4, and 10 Gy to 12 Gy × 5, and deliver a substantially higher biologically effective dose compared with historic conventional radiation therapy regimens.

Multiple prospective phase I/II trials and institutional series have demonstrated that SBRT results in a low incidence of pulmonary toxicity (<10% risk of symptomatic radiation pneumonitis), 2-year OS rates of 50% to 60%, and 2-year tumor control of 90% to 95%.[30–36][Level of evidence C1]

Evidence (SBRT):

  1. Early phase I/II trials from Indiana University identified the maximum tolerated dose of three-fraction SBRT at 18 Gy × 3 for T1 tumors.
    • This regimen resulted in a 2-year OS rate of 55% and 2-year local tumor control of 95%.
    • An unacceptably high incidence (8.6%) of grade 5 toxicity was observed in patients with central tumors (defined as within 2 cm of the tracheobronchial tree from the trachea to the level of the lobar bronchi).[31]
  2. A subsequent multicenter trial (RTOG-0236 [NCT00087438]) studied the 18 Gy × 3 regimen in 55 patients with peripheral T1 to T2 tumors only.
    • This trial demonstrated a 3-year OS rate of 56% and 3-year primary tumor control of 98%.
    • The incidence of moderate to severe toxicity was low, with grade 3 toxicity in 24% of patients, grade 4 toxicity in 4% of patients, and no grade 5 toxicity, with a 4% incidence of grade 3 radiation pneumonitis.[35]
  3. In the largest reported series from VU University Medical Center Amsterdam, 676 patients with T1 to T2 tumors were treated with three-, five-, and eight-fraction SBRT using a risk-adapted approach (a tailored fractionation regimen based on tumor proximity to critical organs).
    • With a median follow-up of 32.9 months, the median OS was 40.7 months, and 2-year local tumor control was 95%.[36]
  4. While central location is a contraindication to three-fraction SBRT based on data from the Indiana phase II study, a subsequent systematic review of published reports of 315 patients with 563 central tumors demonstrated a much lower incidence of severe toxicity, including a 1% to 5% risk of grade 5 events with more protracted SBRT regimens (e.g., four to ten fractions).[37]
  5. A multicenter phase I/II trial (RTOG-0813 [NCT00750269]) is ongoing to identify the maximum tolerated dose for a five-fraction SBRT regimen for central tumors.

A randomized trial of hypofractionated radiation therapy versus SBRT (LUSTRE [NCT01968941]) is ongoing to determine the optimal radiation therapy regimen, but SBRT has been widely adopted for patients with medically inoperable stage I NSCLC.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References
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  2. Ginsberg RJ, Rubinstein LV: Randomized trial of lobectomy versus limited resection for T1 N0 non-small cell lung cancer. Lung Cancer Study Group. Ann Thorac Surg 60 (3): 615-22; discussion 622-3, 1995. [PUBMED Abstract]
  3. Warren WH, Faber LP: Segmentectomy versus lobectomy in patients with stage I pulmonary carcinoma. Five-year survival and patterns of intrathoracic recurrence. J Thorac Cardiovasc Surg 107 (4): 1087-93; discussion 1093-4, 1994. [PUBMED Abstract]
  4. Mantz CA, Dosoretz DE, Rubenstein JH, et al.: Endobronchial brachytherapy and optimization of local disease control in medically inoperable non-small cell lung carcinoma: a matched-pair analysis. Brachytherapy 3 (4): 183-90, 2004. [PUBMED Abstract]
  5. Altorki N, Wang X, Kozono D, et al.: Lobar or Sublobar Resection for Peripheral Stage IA Non-Small-Cell Lung Cancer. N Engl J Med 388 (6): 489-498, 2023. [PUBMED Abstract]
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  10. Pignon JP, Tribodet H, Scagliotti GV, et al.: Lung adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative Group. J Clin Oncol 26 (21): 3552-9, 2008. [PUBMED Abstract]
  11. Strauss GM, Herndon JE, Maddaus MA, et al.: Adjuvant paclitaxel plus carboplatin compared with observation in stage IB non-small-cell lung cancer: CALGB 9633 with the Cancer and Leukemia Group B, Radiation Therapy Oncology Group, and North Central Cancer Treatment Group Study Groups. J Clin Oncol 26 (31): 5043-51, 2008. [PUBMED Abstract]
  12. Tsuboi M, Herbst RS, John T, et al.: Overall Survival with Osimertinib in Resected EGFR-Mutated NSCLC. N Engl J Med 389 (2): 137-147, 2023. [PUBMED Abstract]
  13. Wu YL, Dziadziuszko R, Ahn JS, et al.: Alectinib in Resected ALK-Positive Non-Small-Cell Lung Cancer. N Engl J Med 390 (14): 1265-1276, 2024. [PUBMED Abstract]
  14. O’Brien M, Paz-Ares L, Marreaud S, et al.: Pembrolizumab versus placebo as adjuvant therapy for completely resected stage IB-IIIA non-small-cell lung cancer (PEARLS/KEYNOTE-091): an interim analysis of a randomised, triple-blind, phase 3 trial. Lancet Oncol 23 (10): 1274-1286, 2022. [PUBMED Abstract]
  15. PORT Meta-analysis Trialists Group: Postoperative radiotherapy for non-small cell lung cancer. Cochrane Database Syst Rev (2): CD002142, 2005. [PUBMED Abstract]
  16. Fernando HC, Landreneau RJ, Mandrekar SJ, et al.: Impact of brachytherapy on local recurrence rates after sublobar resection: results from ACOSOG Z4032 (Alliance), a phase III randomized trial for high-risk operable non-small-cell lung cancer. J Clin Oncol 32 (23): 2456-62, 2014. [PUBMED Abstract]
  17. McGarry RC, Song G, des Rosiers P, et al.: Observation-only management of early stage, medically inoperable lung cancer: poor outcome. Chest 121 (4): 1155-8, 2002. [PUBMED Abstract]
  18. Lanni TB, Grills IS, Kestin LL, et al.: Stereotactic radiotherapy reduces treatment cost while improving overall survival and local control over standard fractionated radiation therapy for medically inoperable non-small-cell lung cancer. Am J Clin Oncol 34 (5): 494-8, 2011. [PUBMED Abstract]
  19. Grutters JP, Kessels AG, Pijls-Johannesma M, et al.: Comparison of the effectiveness of radiotherapy with photons, protons and carbon-ions for non-small cell lung cancer: a meta-analysis. Radiother Oncol 95 (1): 32-40, 2010. [PUBMED Abstract]
  20. Raz DJ, Zell JA, Ou SH, et al.: Natural history of stage I non-small cell lung cancer: implications for early detection. Chest 132 (1): 193-9, 2007. [PUBMED Abstract]
  21. Dosoretz DE, Katin MJ, Blitzer PH, et al.: Radiation therapy in the management of medically inoperable carcinoma of the lung: results and implications for future treatment strategies. Int J Radiat Oncol Biol Phys 24 (1): 3-9, 1992. [PUBMED Abstract]
  22. Gauden S, Ramsay J, Tripcony L: The curative treatment by radiotherapy alone of stage I non-small cell carcinoma of the lung. Chest 108 (5): 1278-82, 1995. [PUBMED Abstract]
  23. Sibley GS, Jamieson TA, Marks LB, et al.: Radiotherapy alone for medically inoperable stage I non-small-cell lung cancer: the Duke experience. Int J Radiat Oncol Biol Phys 40 (1): 149-54, 1998. [PUBMED Abstract]
  24. Noordijk EM, vd Poest Clement E, Hermans J, et al.: Radiotherapy as an alternative to surgery in elderly patients with resectable lung cancer. Radiother Oncol 13 (2): 83-9, 1988. [PUBMED Abstract]
  25. Dosoretz DE, Galmarini D, Rubenstein JH, et al.: Local control in medically inoperable lung cancer: an analysis of its importance in outcome and factors determining the probability of tumor eradication. Int J Radiat Oncol Biol Phys 27 (3): 507-16, 1993. [PUBMED Abstract]
  26. Kaskowitz L, Graham MV, Emami B, et al.: Radiation therapy alone for stage I non-small cell lung cancer. Int J Radiat Oncol Biol Phys 27 (3): 517-23, 1993. [PUBMED Abstract]
  27. Bradley J, Graham MV, Winter K, et al.: Toxicity and outcome results of RTOG 9311: a phase I-II dose-escalation study using three-dimensional conformal radiotherapy in patients with inoperable non-small-cell lung carcinoma. Int J Radiat Oncol Biol Phys 61 (2): 318-28, 2005. [PUBMED Abstract]
  28. Bogart JA, Hodgson L, Seagren SL, et al.: Phase I study of accelerated conformal radiotherapy for stage I non-small-cell lung cancer in patients with pulmonary dysfunction: CALGB 39904. J Clin Oncol 28 (2): 202-6, 2010. [PUBMED Abstract]
  29. Cheung P, Faria S, Ahmed S, et al.: Phase II study of accelerated hypofractionated three-dimensional conformal radiotherapy for stage T1-3 N0 M0 non-small cell lung cancer: NCIC CTG BR.25. J Natl Cancer Inst 106 (8): , 2014. [PUBMED Abstract]
  30. Timmerman R, Papiez L, McGarry R, et al.: Extracranial stereotactic radioablation: results of a phase I study in medically inoperable stage I non-small cell lung cancer. Chest 124 (5): 1946-55, 2003. [PUBMED Abstract]
  31. Timmerman R, McGarry R, Yiannoutsos C, et al.: Excessive toxicity when treating central tumors in a phase II study of stereotactic body radiation therapy for medically inoperable early-stage lung cancer. J Clin Oncol 24 (30): 4833-9, 2006. [PUBMED Abstract]
  32. Lagerwaard FJ, Haasbeek CJ, Smit EF, et al.: Outcomes of risk-adapted fractionated stereotactic radiotherapy for stage I non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 70 (3): 685-92, 2008. [PUBMED Abstract]
  33. Baumann P, Nyman J, Hoyer M, et al.: Outcome in a prospective phase II trial of medically inoperable stage I non-small-cell lung cancer patients treated with stereotactic body radiotherapy. J Clin Oncol 27 (20): 3290-6, 2009. [PUBMED Abstract]
  34. Fakiris AJ, McGarry RC, Yiannoutsos CT, et al.: Stereotactic body radiation therapy for early-stage non-small-cell lung carcinoma: four-year results of a prospective phase II study. Int J Radiat Oncol Biol Phys 75 (3): 677-82, 2009. [PUBMED Abstract]
  35. Timmerman R, Paulus R, Galvin J, et al.: Stereotactic body radiation therapy for inoperable early stage lung cancer. JAMA 303 (11): 1070-6, 2010. [PUBMED Abstract]
  36. Senthi S, Lagerwaard FJ, Haasbeek CJ, et al.: Patterns of disease recurrence after stereotactic ablative radiotherapy for early stage non-small-cell lung cancer: a retrospective analysis. Lancet Oncol 13 (8): 802-9, 2012. [PUBMED Abstract]
  37. Senthi S, Haasbeek CJ, Slotman BJ, et al.: Outcomes of stereotactic ablative radiotherapy for central lung tumours: a systematic review. Radiother Oncol 106 (3): 276-82, 2013. [PUBMED Abstract]

Treatment of Stages IIA and IIB NSCLC

Treatment Options for Stages IIA and IIB NSCLC

Treatment options for stages IIA non-small cell lung cancer (NSCLC) and IIB NSCLC include:

  1. Surgery with or without adjuvant and/or neoadjuvant therapy.
    1. Surgery alone.
    2. Adjuvant chemotherapy.
    3. Adjuvant targeted therapy (for patients with EGFR variants).
    4. Adjuvant targeted therapy (for patients with ALK variants).
    5. Adjuvant immunotherapy.
    6. Adjuvant radiation therapy.
    7. Neoadjuvant chemotherapy.
    8. Neoadjuvant immunotherapy with chemotherapy.
    9. Perioperative (neoadjuvant and adjuvant) immunotherapy with neoadjuvant chemotherapy.
  2. Radiation therapy (for patients who cannot have surgery).
  3. Clinical trials of radiation therapy after curative surgery.

Adjuvant radiation therapy has not been shown to improve outcomes in patients with stage II NSCLC.

Surgery with or without adjuvant or neoadjuvant therapy

Surgery alone

Surgery is the treatment of choice for patients with stage II NSCLC. A lobectomy, pneumonectomy, segmental resection, wedge resection, or sleeve resection may be performed as appropriate. Careful preoperative assessment of the patient’s overall medical condition, especially the patient’s pulmonary reserve, is critical in considering the benefits of surgery. In addition to the immediate and age-related postoperative mortality rate, a 5% to 8% mortality rate with pneumonectomy or a 3% to 5% mortality rate with lobectomy can be expected.

Evidence (surgery):

  1. The Cochrane Collaboration reviewed 11 randomized trials with a total of 1,910 patients who underwent surgical interventions for early-stage (I–IIIA) lung cancer.[1] A pooled analysis of three trials reported the following:
    • Four-year survival was superior in patients with resectable stage I, II, or IIIA NSCLC who underwent resection and complete ipsilateral mediastinal lymph node dissection (CMLND), compared with those who underwent resection and lymph node sampling; the hazard ratio (HR) was estimated to be 0.78 (95% confidence interval [CI], 0.65–0.93; P = .005).[1][Level of evidence A1]
    • There was a significant reduction in any cancer recurrence (local or distant) in the CMLND group (relative risk [RR], 0.79; 95% CI, 0.66–0.95; P = .01) that appeared mainly as the result of a reduction in the number of distant recurrences (RR, 0.78; 95% CI, 0.61–1.00; P = .05).
    • There was no difference in operative mortality.
    • Air leak lasting more than 5 days was significantly more common in patients assigned to CMLND (RR, 2.94; 95% CI, 1.01–8.54; P = .05).
  2. CMLND versus lymph node sampling was evaluated in a large randomized phase III trial (ACOSOG-Z0030 [NCT00003831]).[2]
    • Preliminary analyses of operative morbidity and mortality showed comparable rates from the procedures.[2]
    • There was no difference in overall survival (OS), disease-free survival (DFS), local recurrence, and regional recurrence.[3][Level of evidence A1]

Evidence suggests that lung cancer resection combined with CMLND is not associated with improvement in survival compared with lung cancer resection combined with systematic sampling of mediastinal lymph nodes in patients with stage I, II, or IIIA NSCLC.[3][Level of evidence A1]

Conclusions about the efficacy of surgery for patients with local and locoregional NSCLC are limited by the small number of participants studied and potential methodological weaknesses of the trials.

Adjuvant chemotherapy

The preponderance of evidence indicates that postoperative cisplatin combination chemotherapy provides a significant survival advantage to patients with resected stage II NSCLC. Preoperative chemotherapy may also provide survival benefit. The optimal sequence of surgery and chemotherapy and the benefits and risks of postoperative radiation therapy in patients with resectable NSCLC remain to be determined.

After surgery, many patients develop regional or distant metastases.[4] Several randomized controlled trials and meta-analyses have evaluated the use of postoperative chemotherapy in patients with stage I, II, and IIIA NSCLC.[5–11]

Evidence (adjuvant chemotherapy):

  1. Data on individual patient outcomes were collected and pooled into a meta-analysis from the five largest trials (4,584 patients) of cisplatin-based chemotherapy in patients with completely resected NSCLC that were conducted after 1995.[7]
    • With a median follow-up time of 5.2 years, the overall HRdeath was 0.89 (95% CI, 0.82–0.96; P = .005), corresponding to a 5-year absolute benefit of 5.4% from chemotherapy.
    • The benefit varied with stage (test for trend, P = .04; HR for stage IA, 1.40; 95% CI, 0.95–2.06; HR for stage IB, 0.93; 95% CI, 0.78–1.10; HR for stage II, 0.83; 95% CI, 0.73–0.95; and HR for stage III, 0.83; 95% CI, 0.72–0.94).
    • The effect of chemotherapy did not vary significantly (test for interaction, P = .11) with the associated drugs, including vinorelbine (HR, 0.80; 95% CI, 0.70–0.91), etoposide or vinca alkaloid (HR, 0.92; 95% CI, 0.80–1.07), or other drugs (HR, 0.97; 95% CI, 0.84–1.13).
    • The greater effect on survival observed with the doublet of cisplatin plus vinorelbine compared with other regimens should be interpreted cautiously as the total dose of cisplatin received was significantly higher in patients treated with vinorelbine.
  2. The meta-analysis [7] and the individual studies [5,12] support the administration of postoperative cisplatin-based chemotherapy in combination with vinorelbine.
    1. Superior OS for the trial population and patients with stage II disease was reported for the Lung Adjuvant Cisplatin Evaluation (LACE) pooled analysis (pooled HR, 0.83; 95% CI, 0.73–0.95); the Adjuvant Navelbine International Trialist Association (ANITA) trial (HR, 0.71; 95% CI, 0.49–1.03); and the National Cancer Institute of Canada Clinical Trials Group JBR.10 trial (HR, 0.59; 95% CI, 0.42–0.85).
    2. Chemotherapy effect was higher in patients with better performance status.
    3. There was no interaction between chemotherapy effect and any of the following:
      • Sex.
      • Age.
      • Histology.
      • Type of surgery.
      • Planned radiation therapy.
      • Planned total dose of cisplatin.
  3. In a retrospective analysis of a phase III trial of postoperative cisplatin and vinorelbine, patients older than 65 years were found to benefit from treatment.[13]
    • Chemotherapy significantly prolonged OS for patients older than 65 years (HR, 0.61; 95% CI, 0.38–0.98; P = .04).
    • There were no significant differences in toxic effects, hospitalization, or treatment-related death by age group, although patients older than 65 years received less treatment.[13]
  4. Several other randomized controlled trials and meta-analyses have evaluated the use of postoperative chemotherapy in patients with stages I, II, and IIIA NSCLC.[5–11]

Based on these data, patients with completely resected stage II lung cancer may benefit from postoperative cisplatin-based chemotherapy.[13][Level of evidence A1]

Adjuvant targeted therapy (for patients with EGFR variants)

Adjuvant targeted therapy with osimertinib for patients with resected stage IB to IIIA NSCLC and an EGFR pathogenic variant was studied in a phase III clinical trial and showed improved OS.

Evidence (adjuvant targeted therapy with osimertinib for patients with stages IIA and IIB NSCLC and an EGFR variant):

  1. The phase III, double-blind, placebo-controlled ADAURA (NCT02511106) trial included 682 patients with surgically resected stage IB to stage IIIA NSCLC and EGFR pathogenic variants (centrally determined, deletion in exon 19 or L858R variant). Patients were randomly assigned to receive 80 mg of osimertinib by mouth daily (n = 399) or a placebo (n = 342) for 3 years. Standard postoperative adjuvant chemotherapy was allowed but not mandatory; decisions regarding adjuvant chemotherapy were made by the physician and patient before trial enrollment.[14][Level of evidence A1]
    • In the overall population, the 5-year OS rate was 88% in the osimertinib group and 78% in the placebo group (overall HRdeath, 0.49; 95.03% CI, 0.34–0.70; P < .001).
    • Among patients with stage II to IIIA disease, the 5-year OS rate was 85% in the osimertinib group and 73% in the placebo group (overall HRdeath, 0.49; 95.03% CI, 0.33–0.73; P < .001).
    • The adverse event profile is consistent with other studies that used osimertinib except for pneumonia related to COVID-19, which was reported later.

The U.S. Food and Drug Administration (FDA) approved osimertinib as adjuvant therapy for patients with stage IB to IIIA NSCLC with EGFR exon 19 deletions or EGFR L858R variants.

Adjuvant targeted therapy (for patients with ALK variants)

Evidence (adjuvant targeted therapy (for patients with ALK variants).

  1. The global, phase III, open-label ALINA trial (NCT03456076) included 257 patients with completely resected stage IB (tumors ≥4 cm), II, or IIIA (American Joint Committee on Cancer 7th edition staging criteria) NSCLC and an ALK variant. Patients were randomly assigned in a 1:1 ratio to receive either oral alectinib (600 mg twice daily) for 24 months or intravenous platinum-based chemotherapy in four 21-day cycles. The primary end point was DFS, tested hierarchically among patients with stage II or IIIA disease and then in the intention-to-treat (ITT) population. Secondary end points included central nervous system (CNS) DFS, OS, and safety.[15]
    • The median duration of follow-up for survival was 27.8 months (27.8 months in the alectinib group and 28.4 months in the chemotherapy group).
    • The 2-year DFS rate was 93.8% in the alectinib group and 63.0% in the chemotherapy group (stage II/IIIA) (HRdisease recurrence or death, 0.24; 95% CI, 0.13–0.45; P < .001).[15][Level of evidence B1]
    • The ITT population included patients with stage IB, II, or IIIA disease who had been randomly assigned. The DFS rate in the ITT population was 93.6% for patients who received alectinib and 63.7% for patients who received chemotherapy (HR, 0.24; 95% CI, 0.13–0.43; P < .001).
    • The HRCNS disease recurrence or death was 0.22 (95% CI, 0.08–0.58) in favor of alectinib.
    • OS data are immature.

The FDA approved alectinib for adjuvant treatment following tumor resection in patients with NSCLC and an ALK variant.

Adjuvant immunotherapy

Adjuvant immunotherapy for patients with resected stage IB to IIIA NSCLC has been found to significantly increase DFS.[16,17]

Evidence (adjuvant immunotherapy with pembrolizumab for patients with stage IIA and IIB tumors >4 cm):

  1. The phase III, multicenter, open-label PEARLS/KEYNOTE-091 trial (NCT02504372) randomly assigned 1,177 patients with completely resected stage IB (tumor >4 cm) to stage IIIA NSCLC to receive pembrolizumab (200 mg every 3 weeks) or placebo for up to 18 cycles, or until disease progression or unacceptable toxicity. Patients started study treatment after resection or, if indicated, after adjuvant chemotherapy (maximum of four cycles). The dual primary end points were DFS in the overall study population and DFS in patients with a programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) of 50% or greater, as determined using the PD-L1 IHC 22C3 pharmDx assay. These end points were reported in a prespecified interim analysis after a median follow-up of 35.6 months (interquartile range [IQR], 27.1–45.5).[16][Level of evidence B1]
    • In the overall study population, the median DFS was 53.6 months (95% CI, 39.2–not reached [NR]) in the pembrolizumab group and 42.0 months (95% CI, 31.3–NR) in the placebo group (HR, 0.76; 95% CI, 0.63–0.91; P = .0014).
    • In the PD-L1 TPS ≥50% population, the median DFS was not reached with either pembrolizumab (95% CI, 44.3–NR) or placebo (95% CI, 35.8–NR) (HR, 0.82; 95% CI, 0.57–1.18; P = .14).
    • OS data were immature at the time of the prespecified interim analysis.
    • No new safety signals were identified in this study.

The FDA approved pembrolizumab as a single agent for adjuvant treatment following resection and platinum-based chemotherapy for patients with stage IB (T2a ≥4 cm), II, or IIIA NSCLC. Of note, the FDA label specifies that pembrolizumab can be used as adjuvant therapy after platinum-based chemotherapy. However, chemotherapy was not required in the overall study patient population evaluated in KEYNOTE-091.

Evidence (adjuvant immunotherapy with atezolizumab for patients with stages IIA and IIB NSCLC):

  1. IMpower010 (NCT02486718) was a phase III, multicenter, open-label trial that randomly assigned 1,005 patients with surgically resected stage IB (tumor >4 cm) to stage IIIA NSCLC. Patients received atezolizumab (1,200 mg every 21 days intravenously) or best supportive care for 16 cycles or 1 year after standard adjuvant platinum-based chemotherapy. Patients were enrolled after resection if they were eligible for cisplatin-based chemotherapy and were randomized after completion of chemotherapy if they remained eligible and did not experience disease progression. The primary end point was investigator-assessed DFS.[17]
    • The primary end point was tested hierarchically, first in the stage II to IIIA population subgroup whose tumors expressed PD-L1 on at least 1% of tumor cells (using the SP263 antibody), then in all patients in the stage II to IIIA population, and finally in the ITT population (stage IB to IIIA). Of the 882 patients who were randomly assigned and had stage II to IIIA disease, 476 had tumors expressing PD-L1 on at least 1% of tumor cells per SP263.[17][Level of evidence B1]
    • After a median follow-up of 32.2 months, atezolizumab treatment improved DFS compared with best supportive care in patients in the stage II to IIIA population whose tumors expressed PD-L1 on at least 1% of tumor cells (HR, 0.66; 95% CI, 0.50–0.88; P = .0039). At 24 months, the DFS rate was 74.6% for the atezolizumab group and 61.0% for the best supportive care group.
    • Atezolizumab also improved DFS in all patients in the stage II to IIIA population (HR, 0.79; 95% CI, 0.64–0.96; P = .020). At 24 months, the DFS rate was 70.2% for the atezolizumab group and 61.6% for the best supportive care group.
    • In the ITT population, which included patients with stage IB to IIIA disease, HRDFS was 0.81 (95% CI, 0.67–0.99; P = .040). However, the boundary for statistical significance for DFS was not crossed.
    • OS data are immature.
    • No new safety signals were noted.

The FDA approved atezolizumab for adjuvant treatment of patients with stage II to IIIA NSCLC whose tumors express PD-L1 on at least 1% of tumor cells.

Adjuvant radiation therapy

The value of postoperative (adjuvant) radiation therapy (PORT) has been evaluated.[18]

Evidence (adjuvant radiation therapy):

  1. A meta-analysis, based on the results of ten randomized controlled trials and 2,232 individuals, reported the following:[18]
    • An 18% relative increase in the risk of death for patients who received PORT compared with surgery alone (HR, 1.18; P = .002). This is equivalent to an absolute detriment of 6% at 2 years (95% CI, 2%–9%), reducing OS from 58% to 52%. Exploratory subgroup analyses suggested that this detrimental effect was most pronounced for patients with stage I/II, N0 to N1 disease, whereas for patients with stage III, N2 disease there was no clear evidence of an adverse effect.
    • Results for local (HR, 1.13; P = .02), distant (HR, 1.14; P = .02), and overall (HR, 1.10; P = .06) recurrence-free survival similarly showed a detriment of PORT.[18][Level of evidence A1]

Further analysis is needed to determine whether these outcomes can potentially be modified with technical improvements, better definitions of target volumes, and limitation of cardiac volume in the radiation portals.

Neoadjuvant chemotherapy

The role of chemotherapy before surgery was tested in clinical trials. The proposed benefits of preoperative chemotherapy include:

  • A reduction in tumor size that may facilitate surgical resection.
  • Early eradication of micrometastases.
  • Better tolerability.

Preoperative chemotherapy may, however, delay potentially curative surgery.

Evidence (neoadjuvant chemotherapy):

  1. The Cochrane Collaboration reported a systematic review and meta-analysis of seven randomized controlled trials that included 988 patients and evaluated the addition of preoperative chemotherapy to surgery versus surgery alone. These trials evaluated patients with stages I, II, and IIIA NSCLC.[19]
    • Preoperative chemotherapy provided an absolute benefit in survival of 6% across all stages of disease, from 14% to 20% at 5 years (HR, 0.82; 95% CI, 0.69–0.97; P = .022).[19][Level of evidence A1]
    • This analysis was unable to address questions such as whether particular types of patients may benefit more or less from preoperative chemotherapy.
  2. In the largest trial reported to date, 519 patients were randomly assigned to receive either surgery alone or three cycles of platinum-based chemotherapy followed by surgery. Most patients (61%) had clinical stage I disease; 31% had stage II disease; and 7% had stage III disease.[20]
    • No survival advantage was seen.[20]
    • Postoperative complications were similar between groups, and no impairment of quality of life was observed.
    • There was no evidence of a benefit in terms of OS (HR, 1.02; 95% CI, 0.80–1.31; P = .86).
    • Updating the systematic review by addition of the present result suggests a 12% relative survival benefit with the addition of neoadjuvant (preoperative) chemotherapy (1,507 patients; HR, 0.88; 95% CI, 0.76–1.01; P = .07), equivalent to an absolute improvement in survival of 5% at 5 years.
Neoadjuvant immunotherapy with chemotherapy
Nivolumab plus platinum-based chemotherapy

Evidence (nivolumab plus platinum-based chemotherapy):

  1. Checkmate 77T (NCT04025879) was a phase III double-blind trial that enrolled 735 patients with resectable stage IIA (>4 cm) to IIIB (N2 node stage, single- or multistation) NSCLC. Patients had no EGFR variants or known ALK translocations. Patients were randomly assigned to receive either neoadjuvant nivolumab plus chemotherapy or neoadjuvant chemotherapy plus placebo every 3 weeks for four cycles, followed by surgery and adjuvant nivolumab or placebo every 4 weeks for 1 year. The primary end point was event-free survival (EFS) according to blinded independent review. Secondary end points were pathological complete response and major pathological response according to blinded independent review, OS, and safety.[21]
    • At median follow-up of 25.4 months (range, 15.7–44.2), the 18-month EFS rate was 70.2% in the nivolumab group and 50.0% in the chemotherapy group (HRdisease progression or recurrence, abandoned surgery, or death, 0.58; 97.36% CI, 0.42–0.81; P < .001).[21][Level of evidence B1]
    • The pathological complete response rate was 25.3% in the nivolumab group and 4.7% in the chemotherapy group (odds ratio [OR], 6.64; 95% CI, 3.40–12.97).
    • The major pathological response rate (≤10% residual viable tumor cells after surgery in the primary tumor and sampled lymph nodes) was 35.4% in the nivolumab group and 12.1% in the chemotherapy group (OR, 4.01; 95% CI, 2.48–6.49).
    • Grade 3 or 4 treatment-related adverse events occurred in 32.5% of patients in the nivolumab group and 25.2% of patients in the chemotherapy group.

The FDA approved nivolumab with platinum-doublet chemotherapy as neoadjuvant treatment, followed by single-agent nivolumab after surgery as adjuvant treatment, for adults with resectable (tumors ≥4 cm and/or node positive) NSCLC and no EGFR variants or ALK rearrangements.

Perioperative (neoadjuvant and adjuvant) immunotherapy with chemotherapy

Several immune checkpoint inhibitors have been approved by the FDA for select patient populations with potentially resectable NSCLC, either in the neoadjuvant setting (nivolumab) or adjuvant setting (atezolizumab, durvalumab, or pembrolizumab). Ongoing phase III trials are evaluating the role of perioperative immune checkpoint inhibitors. These regimens for patients with potentially resectable stages II to III NSCLC include neoadjuvant immune checkpoint inhibitors with chemotherapy followed by surgery and adjuvant immune checkpoint inhibitors. Compared with neoadjuvant chemotherapy alone, early results from studies of perioperative immune checkpoint inhibitor regimens have shown improvements in several key outcomes including EFS, major pathological response, pathological complete response, and OS.

Perioperative pembrolizumab plus platinum-based chemotherapy

Evidence (neoadjuvant pembrolizumab plus chemotherapy and adjuvant pembrolizumab):

  1. The phase III double-blind KEYNOTE-671 (NCT03425643) trial included 797 patients with untreated stage II, IIIA, or IIIB (≥1 ipsilateral mediastinal node or subcarinal node) NSCLC. Patients were randomly assigned to receive neoadjuvant pembrolizumab (200 mg every 3 weeks) or placebo with cisplatin-based chemotherapy for four cycles, followed by surgery and adjuvant pembrolizumab or placebo for up to 13 cycles, or until disease progression or unacceptable toxicity. The dual primary end points were EFS (defined as the time from randomization to local progression precluding surgery, unresectable tumor, progression or recurrence, or death) and OS. At the second interim analysis, the median follow-up was 36.6 months (range, 27.6–47.8).[22][Level of evidence A1]
    1. The median EFS was 47.2 months (95% CI, 32.9–NR) in the pembrolizumab group and 18.3 months (95% CI, 14.8–22.1) in the placebo group (HR, 0.59; 95% CI, 0.48–0.72).
    2. The 36-month OS rate estimates were 71% (95% CI, 66%–76%) in the pembrolizumab group and 64% (95% CI, 58%–69%) in the placebo group (HR, 0.72; 95% CI, 0.56–0.93; one-sided P = .0052; threshold, one-sided P = .0054).
    3. Secondary end points were reported as follows:
      • Major pathological response occurred in 30.2% of patients in the pembrolizumab group and 11.0% of patients in the placebo group (P < .0001).
      • Pathological complete response occurred in 18.1% of patients in the pembrolizumab group and 4.0% of patients in the placebo group (P < .0001).
    4. Grade 3 to 5 treatment-related adverse events occurred in 179 of 396 patients (45%) in the pembrolizumab group and in 151 of 399 patients (38%) in the placebo group. Treatment-related adverse events led to death in four patients (1%) in the pembrolizumab group and three patients (1%) in the placebo group.
Perioperative durvalumab plus platinum-based chemotherapy

Evidence (durvalumab plus platinum-based chemotherapy):

  1. The phase III AEGEAN trial (NCT03800134) investigated perioperative durvalumab plus neoadjuvant chemotherapy compared with neoadjuvant chemotherapy alone in patients with resectable (stage II to IIIB [N2]) NSCLC. Patients received four cycles of treatment every 3 weeks before surgery, followed by adjuvant durvalumab or placebo intravenously every 4 weeks for 12 cycles. The modified intention-to-treat population (740 patients) included all patients who were randomly assigned, excluding patients with documented EGFR or ALK alterations. The first planned interim analysis occurred with 31.9% data maturity and at a median follow-up of 1 year. The primary end points were EFS and pathological complete response.[23][Level of evidence B1]
    • At 12 months, the EFS rate was 73.4% for patients who received durvalumab (95% CI, 67.9%–78.1%), and 64.5% for patients who received chemotherapy alone (95% CI, 58.8%–69.6%).
    • Pathological complete response was significantly higher with perioperative durvalumab (17.2%), compared with chemotherapy alone (4.3%, P < .001).
    • The EFS and pathological complete response benefit were observed regardless of stage and PD-L1 expression.
    • The safety profile was consistent with known profiles of durvalumab and chemotherapy.
Perioperative nivolumab plus platinum-based chemotherapy

Evidence (neoadjuvant nivolumab plus chemotherapy and adjuvant nivolumab):

  1. Checkmate 77T (NCT04025879) was a phase III double-blind trial that enrolled 735 patients with resectable stage IIA (>4 cm) to IIIB (N2 node stage, single- or multistation) NSCLC. Patients had no EGFR variants or known ALK translocations. Patients were randomly assigned to receive either neoadjuvant nivolumab plus chemotherapy or neoadjuvant chemotherapy plus placebo every 3 weeks for four cycles, followed by surgery and adjuvant nivolumab or placebo every 4 weeks for 1 year. The primary end point was EFS according to blinded independent review. Secondary end points were pathological complete response and major pathological response according to blinded independent review, OS, and safety.[21]
    • At median follow-up of 25.4 months (range, 15.7–44.2), the 18-month EFS rate was 70.2% in the nivolumab group and 50.0% in the chemotherapy group (HRdisease progression or recurrence, abandoned surgery, or death, 0.58; 97.36% CI, 0.42–0.81; P < .001).[21][Level of evidence B1]
    • The pathological complete response rate was 25.3% in the nivolumab group and 4.7% in the chemotherapy group (OR, 6.64; 95% CI, 3.40–12.97).
    • The major pathological response rate (≤10% residual viable tumor cells after surgery in the primary tumor and sampled lymph nodes) was 35.4% in the nivolumab group and 12.1% in the chemotherapy group (OR, 4.01; 95% CI, 2.48–6.49).
    • Grade 3 or 4 treatment-related adverse events occurred in 32.5% of patients in the nivolumab group and 25.2% of patients in the chemotherapy group.
Perioperative toripalimab plus platinum-based chemotherapy

Evidence (toripalimab plus platinum-based chemotherapy):

  1. A phase III randomized trial (Neotorch [NCT04158440]) evaluated the efficacy and safety of toripalimab in combination with neoadjuvant platinum-based chemotherapy followed by maintenance toripalimab versus chemotherapy alone in patients with resectable stage II, IIIA, or IIIB (N2) NSCLC without EGFR or ALK alterations. Patients were stratified by disease stage (II, IIIA, or IIIB), PD-L1 tumor expression status (≥1%, <1%, or not evaluable using the JS311IHC staining assay), planned surgical approach (pneumonectomy or lobectomy), and histological subtype (squamous vs. nonsquamous). A total of 501 patients with stage II to III resectable NSCLC were randomly assigned to receive either (1) toripalimab plus platinum-based chemotherapy for three cycles before surgery and one cycle after surgery followed by single-agent maintenance toripalimab for up to 13 cycles or (2) platinum-based chemotherapy alone for three cycles before surgery and one cycle after surgery. Coprimary end points were EFS (defined as time from randomization to the first documentation of disease progression leading to the inability to operate, postoperative progression, or local or distant recurrence/death from any cause) and major pathological response (≤10% or less viable tumor cells in the tumor bed). Secondary end points included OS, pathological complete response, DFS after surgery, and safety.[24]
    • In a prespecified interim analysis of EFS in patients with stage III NSCLC (n = 404) after a median follow-up of 18.3 months (IQR, 12.7–22.5 months), the median EFS was not reached (95% CI, 24.4 months–NR) in the toripalimab group and was 15.1 months (95% CI, 10.6–21.9) in the placebo group (HR, 0.40; 95% CI, 0.28–0.57; P < .001).
    • The 1- and 2-year EFS rates were 84.4% and 64.7%, respectively, in the toripalimab group and 57.0% and 38.7%, respectively, in the placebo group. A consistent effect on EFS, favoring toripalimab, was observed in all subgroups.
    • After surgical resection, a major pathological response occurred in 98 patients (48.5%) in the toripalimab group and 17 patients (8.4%) in the placebo group (between group difference, 40.2%; 95% CI, 32.2%–48.1%; P < .001).

The FDA has not approved this drug for patients with lung cancer.

Radiation therapy

Patients with potentially operable tumors with medical contraindications to surgery or those with inoperable stage II disease and with sufficient pulmonary reserve are candidates for radiation therapy with curative intent.[25] Primary radiation therapy often consists of approximately 60 Gy delivered with megavoltage equipment to the midplane of the volume of the known tumor using conventional fractionation. A boost to the cone down field of the primary tumor is frequently used to enhance local control. Careful treatment planning with precise definition of target volume and avoidance of critical normal structures, to the extent possible, is needed for optimal results; this requires the use of a simulator.

Among patients with excellent performance status, a 3-year survival rate of 20% may be expected if a course of radiation therapy with curative intent can be completed.

Evidence (radiation therapy):

  1. In the largest retrospective series reported to date, 152 patients with medically inoperable NSCLC were treated with definitive radiation therapy. The study reported the following:[26]
    • A 5-year OS rate of 10%.
    • Forty-four patients with T1 tumors achieved an actuarial DFS rate of 60%.
    • This retrospective study also suggested that improved DFS was obtained with radiation therapy doses greater than 60 Gy.[26]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References
  1. Manser R, Wright G, Hart D, et al.: Surgery for early stage non-small cell lung cancer. Cochrane Database Syst Rev (1): CD004699, 2005. [PUBMED Abstract]
  2. Allen MS, Darling GE, Pechet TT, et al.: Morbidity and mortality of major pulmonary resections in patients with early-stage lung cancer: initial results of the randomized, prospective ACOSOG Z0030 trial. Ann Thorac Surg 81 (3): 1013-9; discussion 1019-20, 2006. [PUBMED Abstract]
  3. Darling GE, Allen MS, Decker PA, et al.: Randomized trial of mediastinal lymph node sampling versus complete lymphadenectomy during pulmonary resection in the patient with N0 or N1 (less than hilar) non-small cell carcinoma: results of the American College of Surgery Oncology Group Z0030 Trial. J Thorac Cardiovasc Surg 141 (3): 662-70, 2011. [PUBMED Abstract]
  4. Martini N, Bains MS, Burt ME, et al.: Incidence of local recurrence and second primary tumors in resected stage I lung cancer. J Thorac Cardiovasc Surg 109 (1): 120-9, 1995. [PUBMED Abstract]
  5. Winton T, Livingston R, Johnson D, et al.: Vinorelbine plus cisplatin vs. observation in resected non-small-cell lung cancer. N Engl J Med 352 (25): 2589-97, 2005. [PUBMED Abstract]
  6. Arriagada R, Bergman B, Dunant A, et al.: Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med 350 (4): 351-60, 2004. [PUBMED Abstract]
  7. Pignon JP, Tribodet H, Scagliotti GV, et al.: Lung adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative Group. J Clin Oncol 26 (21): 3552-9, 2008. [PUBMED Abstract]
  8. Scagliotti GV, Fossati R, Torri V, et al.: Randomized study of adjuvant chemotherapy for completely resected stage I, II, or IIIA non-small-cell Lung cancer. J Natl Cancer Inst 95 (19): 1453-61, 2003. [PUBMED Abstract]
  9. Hotta K, Matsuo K, Ueoka H, et al.: Role of adjuvant chemotherapy in patients with resected non-small-cell lung cancer: reappraisal with a meta-analysis of randomized controlled trials. J Clin Oncol 22 (19): 3860-7, 2004. [PUBMED Abstract]
  10. Edell ES, Cortese DA: Photodynamic therapy in the management of early superficial squamous cell carcinoma as an alternative to surgical resection. Chest 102 (5): 1319-22, 1992. [PUBMED Abstract]
  11. Corti L, Toniolo L, Boso C, et al.: Long-term survival of patients treated with photodynamic therapy for carcinoma in situ and early non-small-cell lung carcinoma. Lasers Surg Med 39 (5): 394-402, 2007. [PUBMED Abstract]
  12. Douillard JY, Rosell R, De Lena M, et al.: Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB-IIIA non-small-cell lung cancer (Adjuvant Navelbine International Trialist Association [ANITA]): a randomised controlled trial. Lancet Oncol 7 (9): 719-27, 2006. [PUBMED Abstract]
  13. Pepe C, Hasan B, Winton TL, et al.: Adjuvant vinorelbine and cisplatin in elderly patients: National Cancer Institute of Canada and Intergroup Study JBR.10. J Clin Oncol 25 (12): 1553-61, 2007. [PUBMED Abstract]
  14. Tsuboi M, Herbst RS, John T, et al.: Overall Survival with Osimertinib in Resected EGFR-Mutated NSCLC. N Engl J Med 389 (2): 137-147, 2023. [PUBMED Abstract]
  15. Wu YL, Dziadziuszko R, Ahn JS, et al.: Alectinib in Resected ALK-Positive Non-Small-Cell Lung Cancer. N Engl J Med 390 (14): 1265-1276, 2024. [PUBMED Abstract]
  16. O’Brien M, Paz-Ares L, Marreaud S, et al.: Pembrolizumab versus placebo as adjuvant therapy for completely resected stage IB-IIIA non-small-cell lung cancer (PEARLS/KEYNOTE-091): an interim analysis of a randomised, triple-blind, phase 3 trial. Lancet Oncol 23 (10): 1274-1286, 2022. [PUBMED Abstract]
  17. Felip E, Altorki N, Zhou C, et al.: Adjuvant atezolizumab after adjuvant chemotherapy in resected stage IB-IIIA non-small-cell lung cancer (IMpower010): a randomised, multicentre, open-label, phase 3 trial. Lancet 398 (10308): 1344-1357, 2021. [PUBMED Abstract]
  18. PORT Meta-analysis Trialists Group: Postoperative radiotherapy for non-small cell lung cancer. Cochrane Database Syst Rev (2): CD002142, 2005. [PUBMED Abstract]
  19. Burdett SS, Stewart LA, Rydzewska L: Chemotherapy and surgery versus surgery alone in non-small cell lung cancer. Cochrane Database Syst Rev (3): CD006157, 2007. [PUBMED Abstract]
  20. Gilligan D, Nicolson M, Smith I, et al.: Preoperative chemotherapy in patients with resectable non-small cell lung cancer: results of the MRC LU22/NVALT 2/EORTC 08012 multicentre randomised trial and update of systematic review. Lancet 369 (9577): 1929-37, 2007. [PUBMED Abstract]
  21. Cascone T, Awad MM, Spicer JD, et al.: Perioperative Nivolumab in Resectable Lung Cancer. N Engl J Med 390 (19): 1756-1769, 2024. [PUBMED Abstract]
  22. Spicer JD, Garassino MC, Wakelee H, et al.: Neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab compared with neoadjuvant chemotherapy alone in patients with early-stage non-small-cell lung cancer (KEYNOTE-671): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 404 (10459): 1240-1252, 2024. [PUBMED Abstract]
  23. Heymach JV, Harpole D, Mitsudomi T, et al.: Perioperative Durvalumab for Resectable Non-Small-Cell Lung Cancer. N Engl J Med 389 (18): 1672-1684, 2023. [PUBMED Abstract]
  24. Lu S, Zhang W, Wu L, et al.: Perioperative Toripalimab Plus Chemotherapy for Patients With Resectable Non-Small Cell Lung Cancer: The Neotorch Randomized Clinical Trial. JAMA 331 (3): 201-211, 2024. [PUBMED Abstract]
  25. Komaki R, Cox JD, Hartz AJ, et al.: Characteristics of long-term survivors after treatment for inoperable carcinoma of the lung. Am J Clin Oncol 8 (5): 362-70, 1985. [PUBMED Abstract]
  26. Dosoretz DE, Katin MJ, Blitzer PH, et al.: Radiation therapy in the management of medically inoperable carcinoma of the lung: results and implications for future treatment strategies. Int J Radiat Oncol Biol Phys 24 (1): 3-9, 1992. [PUBMED Abstract]

Treatment of Stage IIIA NSCLC

Patients with stage IIIA non-small cell lung cancer (NSCLC) are a heterogenous group. Patients may have metastases to ipsilateral mediastinal nodes, potentially resectable T3 tumors invading the chest wall, or mediastinal involvement with metastases to peribronchial or hilar lymph nodes (N1). Presentations of disease range from resectable tumors with microscopic metastases to lymph nodes to unresectable, bulky disease involving multiple nodal stations.

Patients with clinical stage IIIA N2 disease have a 5-year overall survival (OS) rate of 10% to 15%; however, patients with bulky mediastinal involvement (i.e., visible on chest radiography) have a 5-year survival rate of 2% to 5%. Depending on clinical circumstances, the principal forms of treatment that are considered for patients with stage IIIA NSCLC are radiation therapy, chemotherapy, surgery, and combinations of these modalities.

Treatment options vary according to the location of the tumor and whether it is resectable.

Treatment Options for Resected/Resectable Stage IIIA NSCLC

Treatment options for resected/resectable disease include:

  1. Surgery with neoadjuvant or adjuvant therapy.
  2. Neoadjuvant therapy.
    1. Neoadjuvant chemotherapy.
    2. Neoadjuvant chemoradiation therapy.
    3. Neoadjuvant immunotherapy with chemotherapy.
  3. Perioperative (neoadjuvant and adjuvant) immunotherapy with chemotherapy.
    1. Perioperative pembrolizumab plus platinum-based chemotherapy.
    2. Perioperative durvalumab plus platinum-based chemotherapy.
    3. Perioperative nivolumab plus platinum-based chemotherapy.
    4. Perioperative toripalimab plus platinum-based chemotherapy.
  4. Adjuvant therapy.
    1. Adjuvant chemotherapy.
    2. Adjuvant targeted therapy (for patients with EGFR variants).
    3. Adjuvant targeted therapy (for patients with ALK variants).
    4. Adjuvant immunotherapy.
    5. Adjuvant chemoradiation therapy.
    6. Adjuvant radiation therapy.

Despite careful preoperative staging, some patients will be found to have metastases to mediastinal N2 lymph nodes at thoracotomy.

The preponderance of evidence indicates that postoperative cisplatin combination chemotherapy provides a significant survival advantage to patients with resected NSCLC with occult N2 disease discovered at surgery. The optimal sequence of surgery and chemotherapy and the benefits and risks of postoperative radiation therapy in patients with resectable NSCLC are yet to be determined.

Surgery

If complete resection of tumor and lymph nodes is possible, such patients may benefit from surgery followed by postoperative chemotherapy. Current evidence suggests that lung cancer resection combined with complete ipsilateral mediastinal lymph node dissection (CMLND) is not associated with improvement in survival compared with lung cancer resection combined with systematic sampling of mediastinal lymph nodes in patients with stage I, II, or IIIA NSCLC.[1][Level of evidence A1]

The addition of surgery to chemoradiation therapy for patients with stage IIIA NSCLC did not result in improved OS in a phase III trial but did improve progression-free survival (PFS) and local control.[2][Level of evidence B1]

Evidence (surgery):

  1. The Cochrane Collaboration reviewed 11 randomized trials with a total of 1,910 patients who underwent surgical interventions for early-stage (I–IIIA) lung cancer.[3] A pooled analysis of three trials reported the following:
    • Four-year survival was superior in patients with resectable stage I, II, or IIIA NSCLC who underwent resection and CMLND, compared with those who underwent resection and lymph node sampling; the hazard ratio (HR) was estimated to be 0.78 (95% confidence interval [CI], 0.65–0.93; P = .005).[3][Level of evidence A1]
  2. CMLND versus lymph node sampling was evaluated in a large randomized phase III trial (ACOSOG-Z0030). Preliminary analyses of operative morbidity and mortality showed comparable rates from the procedures.[4]
    • There was no difference in OS, disease-free survival (DFS), local recurrence, and regional recurrence.[1][Level of evidence A1]

Conclusions about the efficacy of surgery for patients with local and locoregional NSCLC are limited by the small number of participants studied to date and by the potential methodological weaknesses of the trials.

Neoadjuvant therapy

Neoadjuvant chemotherapy

The role of chemotherapy before surgery in patients with stage IIIA NSCLC has been extensively tested in clinical trials. The proposed benefits of preoperative (neoadjuvant) chemotherapy include:

  • A reduction in tumor size that may facilitate surgical resection.
  • Early eradication of micrometastases.
  • Better tolerability.

Evidence (neoadjuvant chemotherapy):

  1. The Cochrane Collaboration provided a systematic review and meta-analysis of seven randomized controlled trials that included 988 patients and evaluated the addition of preoperative chemotherapy to surgery versus surgery alone.[5] These trials evaluated patients with stages I, II, and IIIA NSCLC.
    • Preoperative chemotherapy provided an absolute benefit in survival of 6% across all stages of disease, from 14% to 20% at 5 years (HR, 0.82; 95% CI, 0.69–0.97; P = .022).[5][Level of evidence A1]
    • This analysis was unable to address questions such as whether particular types of patients may benefit more or less from preoperative chemotherapy.[6]
  2. In the largest trial reported to date, 519 patients were randomly assigned to receive either surgery alone or three cycles of platinum-based chemotherapy followed by surgery.[7] Most patients (61%) had clinical stage I disease, 31% had stage II disease, and 7% had stage III disease.
    • Postoperative complications were similar between groups, and no impairment of quality of life was observed.
    • There was no evidence of a benefit in terms of OS (HR, 1.02; 95% CI, 0.80–1.31; P = .86).
    • Updating the systematic review by addition of the present result suggests a 12% relative survival benefit with the addition of preoperative chemotherapy (1,507 patients; HR, 0.88; 95% CI, 0.76–1.01; P = .07), equivalent to an absolute improvement in survival of 5% at 5 years.[7]
Neoadjuvant chemoradiation therapy

Administering concurrent neoadjuvant chemotherapy and radiation therapy before surgery may intensify treatment and increase the likelihood of downstaging the tumor burden. Commonly used regimens that have been tested in the phase II setting include cisplatin/etoposide (EP5050) and weekly carboplatin/paclitaxel.[8,9] In a randomized trial of neoadjuvant chemoradiation therapy and surgery versus concurrent chemoradiation therapy alone, there was no difference in OS, but surgery improved PFS and local control.[2][Level of evidence B1]

Evidence (neoadjuvant chemoradiation therapy):

  1. The Intergroup-0139 trial (NCT00002550) compared chemoradiation therapy alone with neoadjuvant chemoradiation followed by surgery in 396 patients with stage IIIA (N2) NSCLC.[2]
    • Surgery did not improve OS (5-year OS rate, 27% vs. 20%; HR, 0.87; 0.70–1.10; P = .24).
    • Surgery improved PFS (5-year PFS rate, 22% vs. 11%; HR, 0.77; 0.62–0.96; P = .017) and decreased the risk of local recurrence (10% vs. 22%; P = .002).
    • There was increased treatment mortality with neoadjuvant chemoradiation with surgery (8% vs. 2%), particularly in the subset of patients who underwent pneumonectomy.

A direct comparison of neoadjuvant chemotherapy versus neoadjuvant chemoradiation therapy using modern treatment regimens has not been performed to date; the optimal neoadjuvant approach remains unclear.

Neoadjuvant immunotherapy with chemotherapy
Nivolumab plus platinum-based chemotherapy

The CheckMate 816 trial evaluated the combination of nivolumab (an anti-programmed death 1 antibody) and platinum-based chemotherapy as neoadjuvant therapy in patients with resectable (≥4 cm or node positive) NSCLC. Nivolumab therapy improved event-free survival (EFS) and pathological complete response rates compared with chemotherapy alone.

Evidence (nivolumab plus platinum-based chemotherapy):

  1. CheckMate 816 (NCT02998528) was a phase III open-label trial that enrolled 358 patients with resectable stage IB to stage IIIA NSCLC. Notably, patients with stage IB disease had tumors measuring at least 4 cm and were classified according to the American Joint Committee on Cancer (AJCC) 7th edition staging criteria used for this trial; these tumors are now classified as stage IIA according to the AJCC 8th edition staging criteria. Patients were randomly assigned to receive nivolumab (360 mg) in combination with platinum-doublet chemotherapy or platinum-doublet chemotherapy alone every 3 weeks for three cycles before undergoing definitive surgery. The primary end points were EFS (defined as the time from randomization to any progression of disease precluding surgery, progression or recurrence of disease after surgery, progression of disease in the absence of surgery, or death from any cause) and pathological complete response (defined as 0% residual viable tumor cells in the primary tumor and sampled lymph nodes) according to blinded independent central review.[10][Level of evidence B1]
    • With a minimum follow-up of 21 months, the median EFS was 31.6 months (95% CI, 30.2–not reached [NR]) in the nivolumab-plus-chemotherapy group and 20.8 months (95% CI, 14.0–26.7) in the chemotherapy-alone group (HR, 0.63; 97.38% CI, 0.43–0.91; P = .005).
    • The estimated percentage of patients surviving without disease progression or disease recurrence at 1 year was 76.1% for patients who received nivolumab plus chemotherapy and 63.4% for patients who received chemotherapy alone. The magnitude of benefit was greater in 1) patients with stage IIIA disease versus patients with stage IB or II disease (HR, 0.54; 95% CI, 0.37–0.80 vs. HR, 0.87; 95% CI, 0.48–1.56), 2) patients with tumor programmed death-ligand 1 (PD-L1) expression ≥1% versus <1% (HR, 0.41; 95% CI, 0.24–0.70 vs. HR, 0.85; 95% CI, 0.54–1.32), and 3) patients with nonsquamous histology versus squamous histology.
    • Pathological complete response was observed in 24% (95% CI, 18.0%– 31.0%) of patients who received nivolumab plus chemotherapy and 2.2% (95% CI, 0.6%–5.6%) of patients who received chemotherapy alone (odds ratio, 13.94; 99% CI, 3.49–55.75; P < .001).
    • Median OS was not reached in either group (HRdeath, 0.57; 99.67% CI, 0.30–1.07; P = .008).
    • Grade 3 or 4 treatment-related adverse events occurred in 33.5% of patients in the nivolumab-plus-chemotherapy group and in 36.9% of patients in the chemotherapy-alone group. Treatment-related adverse events led to treatment discontinuation in 10.2% of patients in the nivolumab-plus-chemotherapy group and in 9.7% of patients in the chemotherapy-alone group.
  2. NADIM (NCT03081689) was an open-label, multicenter, single-arm trial for patients with stage IIIA NSCLC with surgically resectable disease. Patients received neoadjuvant paclitaxel and carboplatin plus nivolumab (360 mg) every 21 days for three cycles, followed by adjuvant nivolumab monotherapy for 1 year (240 mg once every 2 weeks for 4 months, followed by 480 mg once every 4 weeks for 8 months). The intention-to-treat (ITT) population included all patients who received neoadjuvant treatment. The per-protocol population included all patients who underwent tumor resection and received at least one cycle of adjuvant therapy. The median follow-up time was 60 months.[11,12]
    • In the ITT population, the 5-year PFS rate was 65.0% (95% CI, 49.4%–76.9%), and the OS rate was 69.3% (53.7%–80.6%).[12][Level of evidence C1]
    • Major pathological response was defined as the presence of 10% or fewer tumor cells in the primary tumor. A total of 82.9% of patients had a major pathological response, including 63.4% of patients who had a complete pathological response. A total of 17.1% patients had an incomplete response.
    • Disease progression occurred in 11 patients (24%).
    • A total of 14 patients (30%) died, including 9 (20%) of disease relapse and 5 (11%) of causes not related to the tumor.
    • Tumor mutational burden and PD-L1 status were not predictive of survival.

    Circulating tumor DNA (ctDNA) from plasma samples obtained before and after neoadjuvant treatment (but before surgery) was analyzed with the hybridization capture–based TruSight Oncology 500 ctDNA next-generation sequencing assay on a NovaSeq sequencer (Illumina).

    • Low pretreatment levels of ctDNA were significantly associated with improved PFS (HR, 0.20; 95% CI, 0.06–0.63) and OS (HR, 0.07; 95% CI, 0.01–0.39).
    • Undetectable ctDNA levels after neoadjuvant treatment were significantly associated with PFS (HR, 0.26; 95% CI, 0.07–0.93) and OS (HR, 0.04; 95% CI, 0.00–0.55).

The U.S. Food and Drug Administration (FDA) approved nivolumab in combination with platinum-doublet chemotherapy for neoadjuvant treatment of patients with resectable (tumors ≥4 cm or node positive) NSCLC.

Perioperative (neoadjuvant and adjuvant) immunotherapy with chemotherapy

Several immune checkpoint inhibitors have been approved by the FDA for select patient populations with potentially resectable NSCLC, either in the neoadjuvant setting (nivolumab) or adjuvant setting (atezolizumab, durvalumab, or pembrolizumab). Ongoing phase III trials are evaluating the role of perioperative immune checkpoint inhibitors. These regimens for patients with potentially resectable stages II to III NSCLC include neoadjuvant immune checkpoint inhibitors with chemotherapy followed by surgery and adjuvant immune checkpoint inhibitors. Compared with neoadjuvant chemotherapy alone, early results from studies of perioperative immune checkpoint inhibitor regimens have shown improvements in several key outcomes including EFS, major pathological response, pathological complete response, and OS.

Perioperative pembrolizumab plus platinum-based chemotherapy

Evidence (neoadjuvant pembrolizumab plus chemotherapy and adjuvant pembrolizumab):

  1. The phase III double-blind KEYNOTE-671 (NCT03425643) trial included 797 patients with untreated stage II, IIIA, or IIIB (≥1 ipsilateral mediastinal node or subcarinal node) NSCLC. Patients were randomly assigned to receive neoadjuvant pembrolizumab (200 mg every 3 weeks) or placebo with cisplatin-based chemotherapy for four cycles, followed by surgery and adjuvant pembrolizumab or placebo for up to 13 cycles, or until disease progression or unacceptable toxicity. The dual primary end points were EFS (defined as the time from randomization to local progression precluding surgery, unresectable tumor, progression or recurrence, or death) and OS. At the second interim analysis, the median follow-up was 36.6 months (range, 27.6–47.8).[13][Level of evidence A1]
    1. The median EFS was 47.2 months (95% CI, 32.9–NR) in the pembrolizumab group and 18.3 months (95% CI, 14.8–22.1) in the placebo group (HR, 0.59; 95% CI, 0.48–0.72).
    2. The 36-month OS rate estimates were 71% (95% CI, 66%–76%) in the pembrolizumab group and 64% (95% CI, 58%–69%) in the placebo group (HR, 0.72; 95% CI, 0.56–0.93; one-sided P = .0052; threshold, one-sided P = .0054).
    3. Secondary end points were reported as follows:
      • Major pathological response occurred in 30.2% of patients in the pembrolizumab group and 11.0% of patients in the placebo group (P < .0001).
      • Pathological complete response occurred in 18.1% of patients in the pembrolizumab group and 4.0% of patients in the placebo group (P < .0001).
    4. Grade 3 to 5 treatment-related adverse events occurred in 179 of 396 patients (45%) in the pembrolizumab group and in 151 of 399 patients (38%) in the placebo group. Treatment-related adverse events led to death in four patients (1%) in the pembrolizumab group and three patients (1%) in the placebo group.
Perioperative durvalumab plus platinum-based chemotherapy

Evidence (durvalumab plus platinum-based chemotherapy):

  1. The phase III AEGEAN trial (NCT03800134) investigated perioperative durvalumab plus neoadjuvant chemotherapy compared with neoadjuvant chemotherapy alone in patients with resectable (stage II to IIIB [N2]) NSCLC. Patients received four cycles of treatment every 3 weeks before surgery, followed by adjuvant durvalumab or placebo intravenously every 4 weeks for 12 cycles. The modified intention-to-treat population (740 patients) included all patients who were randomly assigned, excluding patients with documented EGFR or ALK alterations. The first planned interim analysis occurred with 31.9% data maturity and at a median follow-up of 1 year. The primary end points were EFS and pathological complete response.[14][Level of evidence B1]
    • At 12 months, the EFS rate was 73.4% for patients who received durvalumab (95% CI, 67.9%–78.1%), and 64.5% for patients who received chemotherapy alone (95% CI, 58.8%–69.6%).
    • Pathological complete response was significantly higher with perioperative durvalumab (17.2%), compared with chemotherapy alone (4.3%, P < .001).
    • The EFS and pathological complete response benefit were observed regardless of stage and PD-L1 expression.
    • The safety profile was consistent with known profiles of durvalumab and chemotherapy.
Perioperative nivolumab plus platinum-based chemotherapy

Evidence (neoadjuvant nivolumab plus chemotherapy and adjuvant nivolumab):

  1. Checkmate 77T (NCT04025879) was a phase III double-blind trial that enrolled 735 patients with resectable stage IIA (>4 cm) to IIIB (N2 node stage, single- or multistation) NSCLC. Patients had no EGFR variants or known ALK translocations. Patients were randomly assigned to receive either neoadjuvant nivolumab plus chemotherapy or neoadjuvant chemotherapy plus placebo every 3 weeks for four cycles, followed by surgery and adjuvant nivolumab or placebo every 4 weeks for 1 year. The primary end point was EFS according to blinded independent review. Secondary end points were pathological complete response and major pathological response according to blinded independent review, OS, and safety.[15]
    • At median follow-up of 25.4 months (range, 15.7–44.2), the 18-month EFS rate was 70.2% in the nivolumab group and 50.0% in the chemotherapy group (HRdisease progression or recurrence, abandoned surgery, or death, 0.58; 97.36% CI, 0.42–0.81; P < .001).[15][Level of evidence B1]
    • The pathological complete response rate was 25.3% in the nivolumab group and 4.7% in the chemotherapy group (OR, 6.64; 95% CI, 3.40–12.97).
    • The major pathological response rate (≤10% residual viable tumor cells after surgery in the primary tumor and sampled lymph nodes) was 35.4% in the nivolumab group and 12.1% in the chemotherapy group (OR, 4.01; 95% CI, 2.48–6.49).
    • Grade 3 or 4 treatment-related adverse events occurred in 32.5% of patients in the nivolumab group and 25.2% of patients in the chemotherapy group.
Perioperative toripalimab plus platinum-based chemotherapy

Evidence (toripalimab plus platinum-based chemotherapy):

  1. A phase III randomized trial (Neotorch [NCT04158440]) evaluated the efficacy and safety of toripalimab in combination with neoadjuvant platinum-based chemotherapy followed by maintenance toripalimab versus chemotherapy alone in patients with resectable stage II, IIIA, or IIIB (N2) NSCLC without EGFR or ALK alterations. Patients were stratified by disease stage (II, IIIA, or IIIB), PD-L1 tumor expression status (≥1%, <1%, or not evaluable using the JS311IHC staining assay), planned surgical approach (pneumonectomy or lobectomy), and histological subtype (squamous vs. nonsquamous). A total of 501 patients with stage II to III resectable NSCLC were randomly assigned to receive either (1) toripalimab plus platinum-based chemotherapy for three cycles before surgery and one cycle after surgery followed by single-agent maintenance toripalimab for up to 13 cycles or (2) platinum-based chemotherapy alone for three cycles before surgery and one cycle after surgery. Coprimary end points were EFS (defined as time from randomization to the first documentation of disease progression leading to the inability to operate, postoperative progression, or local or distant recurrence/death from any cause) and major pathological response (≤10% or less viable tumor cells in the tumor bed). Secondary end points included OS, pathological complete response, DFS after surgery, and safety.[16]
    • In a prespecified interim analysis of EFS in patients with stage III NSCLC (n = 404) after a median follow-up of 18.3 months (IQR, 12.7–22.5 months), the median EFS was not reached (95% CI, 24.4 months–NR) in the toripalimab group and was 15.1 months (95% CI, 10.6–21.9) in the placebo group (HR, 0.40; 95% CI, 0.28–0.57; P < .001).
    • The 1- and 2-year EFS rates were 84.4% and 64.7%, respectively, in the toripalimab group and 57.0% and 38.7%, respectively, in the placebo group. A consistent effect on EFS, favoring toripalimab, was observed in all subgroups.
    • After surgical resection, a major pathological response occurred in 98 patients (48.5%) in the toripalimab group and 17 patients (8.4%) in the placebo group (between group difference, 40.2%; 95% CI, 32.2%–48.1%; P < .001).

The FDA has not approved this drug for patients with lung cancer.

Adjuvant therapy

Adjuvant chemotherapy

Patients with completely resected stage IIIA NSCLC may benefit from postoperative cisplatin-based chemotherapy.[17][Level of evidence A1]

Evidence (adjuvant chemotherapy):

Evidence from randomized controlled clinical trials indicates that when stage IIIA NSCLC is encountered unexpectedly at surgery, chemotherapy given after complete resection improves survival.

Several randomized, controlled trials and meta-analyses have evaluated the use of postoperative chemotherapy in patients with stages I, II, and IIIA NSCLC.[17–23]

  1. Data on individual patient outcomes from the five largest trials (4,584 patients) that were conducted after 1995 of cisplatin-based chemotherapy in patients with completely resected NSCLC were collected and pooled into a meta-analysis.[17]
    • With a median follow-up of 5.2 years, the overall HRdeath was 0.89 (95% CI, 0.82–0.96; P = .005), corresponding to a 5-year absolute benefit of 5.4% from chemotherapy.
    • The effect of chemotherapy did not vary significantly (test for interaction, P = .11) with the associated drugs, including vinorelbine (HR, 0.80; 95% CI, 0.70–0.91), etoposide or vinca alkaloid (HR, 0.92; 95% CI, 0.80–1.07), or other drugs (HR, 0.97; 95% CI, 0.84–1.13).
    • The benefit varied with stage (HR for stage IIIA, 0.83; 95% CI, 0.72–0.94).
    • The greater effect on survival observed with the doublet of cisplatin plus vinorelbine compared with other regimens should be interpreted with caution as the total dose of cisplatin received was significantly higher in patients treated with vinorelbine.
  2. Two trials (FRE-IALT and the Adjuvant Navelbine International Trialist Association [ANITA] trial) reported significant OS benefits associated with postoperative chemotherapy in stage IIIA disease.[6,19]
    1. For the subgroup of stage IIIA patients in the ANITA trial (n = 325), the HR was 0.69 (95% CI, 0.53–0.90), and the result for the FRE-IALT trial (n = 728) was HR, 0.79 (95% CI, 0.66–0.95).
    2. The chemotherapy effect was higher in patients with a better performance status.
    3. There was no interaction between the chemotherapy effect and any of the following:
      • Sex.
      • Age.
      • Histology.
      • Type of surgery.
      • Planned radiation therapy.
      • Planned total dose of cisplatin.
  3. In a retrospective analysis of a phase III trial of postoperative cisplatin and vinorelbine, patients older than 65 years were found to benefit from treatment.[24]
    • Chemotherapy significantly prolonged OS for patients older than 65 years (HR, 0.61; 95% CI, 0.38–0.98; P = .04).
    • There were no significant differences in toxic effects, hospitalization, or treatment-related death by age group, although patients older than 65 years received less treatment.
Adjuvant targeted therapy (for patients with EGFR variants)

Adjuvant targeted therapy with osimertinib for patients with resected stage IB to IIIA NSCLC and an EGFR pathogenic variant was studied in a phase III clinical trial and showed improved OS.

Evidence (adjuvant targeted therapy with osimertinib for patients with stage IIIA NSCLC and an EGFR variant):

  1. The phase III, double-blind, placebo-controlled ADAURA (NCT02511106) trial included 682 patients with surgically resected stage IB to stage IIIA NSCLC and EGFR pathogenic variants (centrally determined, deletion in exon 19 or L858R variant). Patients were randomly assigned to receive 80 mg of osimertinib by mouth daily (n = 399) or a placebo (n = 342) for 3 years. Standard postoperative adjuvant chemotherapy was allowed but not mandatory; decisions regarding adjuvant chemotherapy were made by the physician and patient before trial enrollment.[25][Level of evidence A1]
    • In the overall population, the 5-year OS rate was 88% in the osimertinib group and 78% in the placebo group (overall HRdeath, 0.49; 95.03% CI, 0.34–0.70; P < .001).
    • Among patients with stage II to IIIA disease, the 5-year OS rate was 85% in the osimertinib group and 73% in the placebo group (overall HRdeath, 0.49; 95.03% CI, 0.33–0.73; P < .001).
    • The adverse event profile is consistent with other studies that used osimertinib except for pneumonia related to COVID-19, which was reported later.

The FDA approved osimertinib as adjuvant therapy for patients with stage IB to IIIA NSCLC with EGFR exon 19 deletions or EGFR L858R variants.

Adjuvant targeted therapy (for patients with ALK variants)

Evidence (adjuvant targeted therapy for patients with ALK variants).

  1. The global, phase III, open-label ALINA trial (NCT03456076) included 257 patients with completely resected stage IB (tumors ≥4 cm), II, or IIIA (AJCC 7th edition staging criteria) NSCLC and an ALK variant. Patients were randomly assigned in a 1:1 ratio to receive either oral alectinib (600 mg twice daily) for 24 months or intravenous platinum-based chemotherapy in four 21-day cycles. The primary end point was DFS, tested hierarchically among patients with stage II or IIIA disease and then in the ITT population. Secondary end points included central nervous system (CNS) DFS, OS, and safety.[26]
    • The median duration of follow-up for survival was 27.8 months (27.8 months in the alectinib group and 28.4 months in the chemotherapy group).
    • The 2-year DFS rate was 93.8% in the alectinib group and 63.0% in the chemotherapy group (stage II/IIIA) (HRdisease recurrence or death, 0.24; 95% CI, 0.13–0.45; P < .001).[26][Level of evidence B1]
    • The ITT population included patients with stage IB, II, or IIIA disease who had been randomly assigned. The DFS rate in the ITT population was 93.6% for patients who received alectinib and 63.7% for patients who received chemotherapy (HR, 0.24; 95% CI, 0.13–0.43; P < .001).
    • The HRCNS disease recurrence or death was 0.22 (95% CI, 0.08–0.58) in favor of alectinib.
    • OS data are immature.

The FDA approved alectinib for adjuvant treatment following tumor resection in patients with NSCLC and an ALK variant.

Adjuvant immunotherapy

Adjuvant immunotherapy for patients with resected stage IB to IIIA NSCLC has been found to significantly increase DFS.[27,28]

Evidence (adjuvant immunotherapy with pembrolizumab for patients with stage IIIA NSCLC):

  1. The phase III, multicenter, open-label PEARLS/KEYNOTE-091 trial (NCT02504372) randomly assigned 1,177 patients with completely resected stage IB (tumor >4 cm) to stage IIIA NSCLC to receive pembrolizumab (200 mg every 3 weeks) or placebo for up to 18 cycles, or until disease progression, or unacceptable toxicity. Patients started study treatment after resection or, if indicated, after adjuvant chemotherapy (maximum of four cycles). The dual primary end points were DFS in the overall study population and DFS in patients with a PD-L1 tumor proportion score (TPS) of 50% or greater, as determined using the PD-L1 IHC 22C3 pharmDx assay. These end points were reported in a prespecified interim analysis after a median follow-up of 35.6 months (interquartile range, 27.1–45.5).[27][Level of evidence B1]
    • In the overall study population, the median DFS was 53.6 months (95% CI, 39.2 to NR) in the pembrolizumab group and 42.0 months (95% CI, 31.3–NR) in the placebo group (HR, 0.76; 95% CI, 0.63–0.91, P = .0014).
    • In the PD-L1 TPS ≥50% population, the median DFS was not reached with either pembrolizumab (95% CI, 44.3–NR) or placebo (95% CI, 35.8–NR) (HR, 0.82; 95% CI, 0.57–1.18; P = .14).
    • OS data were immature at the time of prespecified interim analysis.
    • No new safety signals were identified in this study.

The FDA approved pembrolizumab as a single agent for adjuvant treatment following resection and platinum-based chemotherapy for patients with stage IB (T2a ≥4 cm), II, or IIIA NSCLC. Of note, the FDA label specifies that pembrolizumab can be used as adjuvant therapy after platinum-based chemotherapy. However, chemotherapy was not required in the overall study patient population evaluated in KEYNOTE-091.

Evidence (adjuvant immunotherapy with atezolizumab for patients with resected stage IIIA NSCLC):

  1. IMpower010 (NCT02486718) was a phase III, multicenter, open-label trial that randomly assigned 1,005 patients with surgically resected stage IB (tumor >4 cm) to stage IIIA NSCLC. Patients received atezolizumab (1,200 mg every 21 days intravenously) or best supportive care for 16 cycles or 1 year after standard adjuvant platinum-based chemotherapy. Patients were enrolled after resection if they were eligible for cisplatin-based chemotherapy and were randomized after completion of chemotherapy if they remained eligible and did not experience disease progression. The primary end point was investigator-assessed DFS.[28]
    • The primary end point was tested hierarchically, first in the stage II to IIIA population subgroup whose tumors expressed PD-L1 on at least 1% of tumor cells (using the SP263 antibody), then in all patients in the stage II to IIIA population, and finally in the ITT population (stage IB to IIIA). Of the 882 patients who were randomly assigned and had stage II to IIIA disease, 476 had tumors expressing PD-L1 on at least 1% of tumor cells per SP263.[28][Level of evidence B1]
    • After a median follow-up of 32.2 months, atezolizumab treatment improved DFS compared with best supportive care in patients in the stage II to IIIA population whose tumors expressed PD-L1 on at least 1% of tumor cells (HR, 0.66; 95% CI, 0.50–0.88; P = .0039). At 24 months, the DFS rate was 74.6% for the atezolizumab group and 61.0% for the best supportive care group.
    • Atezolizumab also improved DFS in all patients in the stage II to IIIA population (HR, 0.79; 95% CI, 0.64–0.96; P = .020). At 24 months, the DFS rate was 70.2% for the atezolizumab group and 61.6% for the best supportive care group.
    • In the ITT population, which included patients with stage IB to IIIA disease, HRDFS was 0.81 (95% CI, 0.67–0.99; P = .040). However, the boundary for statistical significance for DFS was not crossed.
    • OS data are immature.
    • No new safety signals were noted.

The FDA approved atezolizumab for adjuvant treatment of patients with stage II to IIIA NSCLC whose tumors express PD-L1 on at least 1% of tumor cells.

Adjuvant chemoradiation therapy

Combination chemotherapy and radiation therapy administered before or following surgery should be viewed as investigational and requiring evaluation in future clinical trials.

Evidence (adjuvant chemoradiation therapy):

  1. Five randomized trials have assessed the value of postoperative combination chemoradiation therapy versus radiation therapy following surgical resection.[5,7,29–31][Level of evidence A1]
    • Only one trial reported improved DFS, and no trial reported improved OS.
  2. Three trials have evaluated platinum-based combination chemotherapy followed by surgery versus platinum-based chemotherapy followed by radiation therapy (60–69.6 Gy) alone to determine whether surgery or radiation therapy was most efficacious.[31–33] Although the studies were small, enrolling 73 (Radiation Therapy Oncology Group [RTOG]) (RTOG 89-01), 107 (The University of Texas M.D. Anderson Cancer Center), and 333 (European Organisation for Research and Treatment of Cancer [EORTC-08941; NCT00002623]) patients with stage IIIA (N2) disease, no trial reported a difference in local control or survival.[31–33][Level of evidence A1]
    1. In the largest series (EORTC-08941), 579 patients with histologically- or cytologically-proven stage IIIA (N2) NSCLC were given three cycles of platinum-based induction chemotherapy.[33] The 333 responding patients were subsequently randomly assigned to surgical resection or radiation therapy. Of the 154 patients (92%) who underwent surgery, 50% had a radical resection, 42% had a pathological downstaging, and 5% had a pathological complete response; 4% died after surgery. Postoperative (adjuvant) radiation therapy (PORT) was administered to 62 patients (40%) in the surgery arm. Among the 154 patients (93%) who received radiation therapy, overall compliance to the radiation therapy prescription was 55%, and grade 3 to 4 acute and late esophageal and pulmonary toxic effects occurred in 4% and 7% of patients; one patient died of radiation pneumonitis.
      • Median OS was 16.4 months for patients assigned to resection versus 17.5 months for patients assigned to radiation therapy; the 5-year OS rate was 15.7% for patients assigned to resection versus 14% for patients assigned to radiation therapy (HR, 1.06; 95% CI, 0.84–1.35).[33]
      • Rates of PFS were also similar in both groups. In view of its low morbidity and mortality, it was concluded that radiation therapy should be considered the preferred locoregional treatment for these patients.[33]
Adjuvant radiation therapy

The value of PORT has been assessed.[29] Although some studies suggest that PORT can improve local control for node-positive patients whose tumors were resected, it remains controversial whether it can improve survival. The optimal dose of thoracic PORT is not known at this time. Most studies cited used doses ranging from 30 Gy to 60 Gy, typically provided in 2 Gy to 2.5 Gy fractions.[29]

As referred to in the National Cancer Institute of Canada (NCIC) Clinical Trials Group JBR.10 study (NCT00002583), PORT may be considered in selected patients to reduce the risk of local recurrence, if any of the following are present:[24]

  • Involvement of multiple nodal stations.
  • Extracapsular tumor spread.
  • Close or microscopically positive resection margins.

Evidence (adjuvant radiation therapy):

Evidence from one large meta-analysis, subset analyses of randomized trials, and one large population study suggest that PORT may reduce local recurrence. Results from these studies on the effect of PORT on OS are conflicting.

  1. A meta-analysis of ten randomized trials that evaluated PORT versus surgery alone showed the following:
  2. Results from a nonrandomized subanalysis of the ANITA trial, comparing 5-year OS in N2 patients who did or did not receive PORT, found the following:[6]
    • Higher survival rates in patients who received radiation therapy in the observation arm (21% in patients who received PORT vs. 17% in patients who did not receive PORT) and in the chemotherapy arm (47% with PORT vs. 34% without PORT); however, statistical tests of comparison were not conducted.[6]
  3. Results from the Surveillance, Epidemiology, and End Results (SEER) Program [30] suggest the following:
    • The large SEER retrospective study (N = 7,465) found superior survival rates associated with radiation therapy in N2 disease (HR, 0.855; 95% CI, 0.762–0.959).

There is benefit of PORT in stage IIIA (N2) disease, and the role of PORT in early stages of NSCLC should be clarified in ongoing phase III trials. Further analysis is needed to determine whether these outcomes can be modified with technical improvements, better definitions of target volumes, and limitation of cardiac volume in the radiation portals.[19]

Treatment Options for Unresectable Stage IIIA NSCLC

Treatment options for patients with unresectable stage IIIA NSCLC include:

  1. Chemoradiation therapy.
  2. Radiation therapy.

Chemoradiation therapy

The addition of sequential and concurrent chemotherapy to radiation therapy has been evaluated in prospective randomized trials and meta-analyses. Overall, concurrent treatment may provide the greatest benefit in survival with an increase in toxic effects.

Concomitant platinum-based radiation chemotherapy may improve survival of patients with locally advanced NSCLC. However, the available data are insufficient to accurately define the size of such a potential treatment benefit and the optimal schedule of chemotherapy.[34]

Evidence (chemoradiation therapy):

  1. A meta-analysis of patient data from 11 randomized clinical trials showed the following:[35]
    • Cisplatin-based combinations plus radiation therapy resulted in a 10% reduction in the risk of death compared with radiation therapy alone.[35][Level of evidence A1]
  2. A meta-analysis of 13 trials (based on 2,214 evaluable patients) showed the following:[36]
    • The addition of concurrent chemotherapy to radical radiation therapy reduced the risk of death at 2 years (relative risk [RR], 0.93; 95% CI, 0.88–0.98; P = .01).
    • For the 11 trials with platinum-based chemotherapy, RR was 0.93 (95% CI, 0.87–0.99; P = .02).[36]
  3. A meta-analysis of individual data from 1,764 patients was based on nine trials and showed the following:[34]
    • The HRdeath among patients treated with radiation therapy and chemotherapy compared with radiation therapy alone was 0.89 (95% CI, 0.81–0.98; P = .02), corresponding to an absolute benefit of chemotherapy of 4% at 2 years.
    • The combination of platinum with etoposide appeared to be more effective than platinum alone.
Concurrent versus sequential chemoradiation therapy

The results from two randomized trials (including RTOG-9410 [NCT01134861]) and a meta-analysis indicate that concurrent chemotherapy and radiation therapy may provide greater survival benefit, albeit with more toxic effects, than sequential chemotherapy and radiation therapy.[37–39][Level of evidence A1]

Evidence (concurrent vs. sequential chemoradiation therapy):

  1. In the first trial, the combination of mitomycin C, vindesine, and cisplatin were given concurrently with split-course daily radiation therapy to 56 Gy compared with chemotherapy followed by continuous daily radiation therapy to 56 Gy.[37]
    • Five-year OS rates favored concurrent therapy (27% vs. 9%).
    • Myelosuppression was greater among patients in the concurrent arm, but treatment-related mortality was less than 1% in both arms.[37]
  2. In the second trial, 610 patients were randomly assigned to sequential chemotherapy with cisplatin and vinblastine followed by 63 Gy of radiation therapy, concurrent chemoradiation therapy using the same regimen, or concurrent chemotherapy with cisplatin and etoposide with twice-daily radiation therapy.[39]
    • Median and 5-year survival were superior in the concurrent chemotherapy with daily radiation therapy arm (17 months vs. 14.6 months and 16% vs. 10% for sequential regimen; P = .046).[39]
  3. Two smaller studies also reported OS results that favored concurrent over sequential chemotherapy and radiation, although the results did not reach statistical significance.[38,40][Level of evidence A1]
  4. A meta-analysis of three trials evaluated concurrent versus sequential treatment (711 patients).[36]
    • The analysis indicated a significant benefit of concurrent over sequential treatment (RR, 0.86; 95% CI, 0.78–0.95; P = .003). All studies used cisplatin-based regimens and once-daily radiation therapy.[36]
    • More deaths (3% OS rate) were reported in the concurrent arm, but this did not reach statistical significance (RR, 1.60; 0.75–3.44; P = .2).
    • There was more acute esophagitis (grade 3 or worse) with concurrent treatment (range, 17%–26%) compared with sequential treatment (range, 0%–4%; RR, 6.77; P = .001). Overall, the incidence of neutropenia (grade 3 or worse) was similar in both arms.
Radiation therapy dose escalation for concurrent chemoradiation

With improvement in radiation therapy–delivery technology in the 1990s, including tumor-motion management and image guidance, phase I/II trials demonstrated the feasibility of dose-escalation radiation therapy to 74 Gy with concurrent chemotherapy.[41–43] However, a phase III trial of a conventional dose of 60 Gy versus dose escalation to 74 Gy with concurrent weekly carboplatin/paclitaxel did not demonstrate improved local control or PFS, and OS was worse with dose escalation (HR, 1.38; 95% CI, 1.09–1.76; P = .004). There was a nonsignificant increase in grade 5 events with dose escalation (10% vs. 2%) and higher incidence of grade 3 esophagitis (21% vs. 7%; P = .0003). Thus, there is no clear benefit in radiation dose escalation beyond 60 Gy for stage III NSCLC.[44][Level of evidence A1]

Consolidation therapy following concurrent chemoradiation

Evidence (consolidation therapy following concurrent chemoradiation):

  1. The randomized phase III PROCLAIM study [NCT00686959] enrolled 598 patients with newly diagnosed, stage IIIA/B, unresectable, nonsquamous NSCLC.[45] Patients were randomly assigned on a 1:1 ratio to either of two arms:
    • Arm A: Pemetrexed (500 mg/m2) and cisplatin (75 mg/m2) intravenously every 3 weeks for three cycles plus concurrent thoracic radiation therapy (60 to 66 Gy) followed by pemetrexed consolidation every 3 weeks for four cycles.
    • Arm B: Standard therapy with etoposide (50 mg/m2) and cisplatin (50 mg/m2) intravenously every 4 weeks for two cycles plus concurrent thoracic radiation therapy (60 to 66 Gy) followed by two cycles of consolidation platinum-based doublet chemotherapy.

    The primary objective was OS. The study was designed as a superiority trial with 80% power to detect an OS HR of 0.74 with a type 1 error of .05. This study randomly assigned 598 patients (arm A, 301; arm B, 297) and treated 555 patients (arm A, 283; arm B, 272).

    • Enrollment was stopped early because of futility.
    • OS in arm A was not superior to arm B (HR, 0.98; 95% CI, 0.79–1.20; median, 26.8 vs. 25.0 months; P = .831).
    • Arm A had a significantly lower incidence of any drug-related grade 3 to 4 adverse events (64.0% vs. 76.8%; P = .001), including neutropenia (24.4% vs. 44.5%; P < .001), during the overall treatment period.
Consolidation immunotherapy
Durvalumab

Durvalumab is a selective human IgG1 monoclonal antibody that blocks PD-L1 binding to programmed death 1 (PD-1) and CD80, allowing T cells to recognize and kill tumor cells.[46]

Evidence (durvalumab following concurrent chemoradiation):

  1. The phase III PACIFIC trial (NCT02125461) enrolled 713 patients with stage III NSCLC whose disease had not progressed after two or more cycles of platinum-based chemoradiation therapy. Patients were randomly assigned in a 2:1 ratio to receive durvalumab (10 mg/kg intravenously) or placebo (every 2 weeks for up to 12 months).[46]
    • At a median follow-up of 34.2 months for all patients and 61.6 months for censored patients, the median OS was 47.5 months for all patients and 29.1 months for censored patients (stratified HR, 0.72; 95% CI, 0.59–0.89). The median PFS was 16.9 months in the durvalumab group and 5.6 months in the placebo group (stratified HR, 0.55; 95% CI, 0.45–0.68).
    • The estimated 5-year OS rates were 42.9% (95% CI, 38.2%–47.4%) in the durvalumab group and 33.4% (95% CI, 27.3%–39.6%) in the placebo group.[47][Level of evidence A1]
    • The estimated 5-year PFS rates were 33.1% (95% CI, 28.0%–38.2%) in the durvalumab group and 19% (95% CI, 13.6%–25.2%) in the placebo group.
    • Grade 3 or 4 adverse events occurred in 29.9% of patients treated with durvalumab and in 26.1% of patients treated with placebo. The most common adverse event of grade 3 or 4 was pneumonia in 4.4% of the patients who received durvalumab and in 3.8% of the patients who received placebo.
Osimertinib (for patients with EGFR variants)

Evidence (osimertinib following concurrent chemoradiation therapy):

  1. The phase III, double-blind, placebo-controlled LAURA trial (NCT03521154) included patients with unresectable stage III NSCLC and EGFR variants. Patients had not progressed during or after definitive chemoradiation therapy. A total of 216 patients who had undergone chemoradiation therapy were randomly assigned to receive either osimertinib (n = 143) or placebo (n = 73). The primary end point was PFS as assessed by blinded independent central review.[48]
    • The median PFS was 39.1 months with osimertinib and 5.6 months with placebo (HRdisease progression or death, 0.16; 95% CI, 0.10–0.24; P < .001).
    • At 36 months, the OS rate was 84% for patients in the osimertinib group (95% CI, 75%–89%) and 74% for patients in the placebo group (95% CI, 57%–85%) (HRdeath, 0.81; 95% CI, 0.42–1.56; P = .53) (at 20% data maturity).[48][Level of evidence A1]
    • Grade 3 or higher adverse events occurred in 35% of patients in the osimertinib group and 12% of patients in the placebo group. Radiation pneumonitis was reported in 48% of patients in the osimertinib group and 38% of patients in the placebo group.
Other systemic consolidation therapies

The addition of induction chemotherapy before concurrent chemotherapy and radiation therapy has not been shown to improve survival.[49][Level of evidence A1]

Randomized trials of other consolidation systemic therapies, including docetaxel,[50] gefitinib,[51] and tecemotide (MUC1 antigen-specific immunotherapy) [52] have not shown an improvement in OS.[Level of evidence A1]

Radiation therapy

Locally advanced unresectable tumors

Radiation therapy alone may provide benefit to patients with locally advanced unresectable stage IIIA NSCLC.

Radiation therapy with traditional dose and fractionation schedules (1.8–2.0 Gy per fraction per day to 60–70 Gy in 6–7 weeks) results in reproducible long-term survival benefit in 5% to 10% of patients and significant palliation of symptoms.[53]

Evidence (radiation therapy for locally advanced unresectable tumor):

  1. One prospective randomized clinical study showed the following:[54]
    • Radiation therapy given continuously (including weekends) as three daily fractions (continuous hyperfractionated accelerated radiation therapy) improved OS compared with radiation therapy given as one daily fraction.[54][Level of evidence A1]
    • Patterns of failure for patients treated with radiation therapy alone included both locoregional and distant failures.

Although patients with unresectable stage IIIA disease may benefit from radiation therapy, long-term outcomes have generally been poor because of local and systemic relapse.

Palliative treatment

Radiation therapy may be effective in palliating symptomatic local involvement with NSCLC, such as:

  • Tracheal, esophageal, or bronchial compression.
  • Pain.
  • Vocal cord paralysis.
  • Hemoptysis.
  • Superior vena cava syndrome.

In some cases, endobronchial laser therapy and/or brachytherapy has been used to alleviate proximal obstructing lesions.[55]

Evidence (radiation therapy for palliative treatment):

  1. A systematic review identified six randomized trials of high-dose rate endobronchial brachytherapy (HDREB) alone or with external-beam radiation therapy (EBRT) or laser therapy.[56]
    • Better overall symptom palliation and fewer re-treatments were required in previously untreated patients using EBRT alone.[56][Level of evidence A3]
    • Although EBRT is frequently prescribed for symptom palliation, there is no consensus about when the fractionation scheme should be used.
    • For EBRT, different multifraction regimens appear to provide similar symptom relief;[57–62] however, single-fraction radiation therapy may be insufficient for symptom relief compared with hypofractionated or standard regimens, as seen in the NCIC Clinical Trials Group trial (NCT00003685).[59][Level of evidence A3]
    • Evidence of a modest increase in survival in patients with better performance status given high-dose EBRT is available.[57,58][Level of evidence A1]
    • HDREB provided palliation of symptomatic patients with recurrent endobronchial obstruction previously treated by EBRT, when it was technically feasible.

Treatment Options for Superior Sulcus Tumors

Treatment options for superior sulcus tumors include:

  1. Surgery.
  2. Chemoradiation therapy followed by surgery.
  3. Radiation therapy alone.

NSCLC of the superior sulcus, frequently termed Pancoast tumors, occurs in less than 5% of patients.[63,64] Superior sulcus tumors usually arise from the apex of the lung and are challenging to treat because of their proximity to structures at the thoracic inlet. At this location, tumors may invade the parietal pleura, chest wall, brachial plexus, subclavian vessels, stellate ganglion, and adjacent vertebral bodies. However, Pancoast tumors are amenable to curative treatment, especially in patients with T3, N0 disease.

Adverse prognostic factors include the presence of mediastinal nodal metastases (N2 disease), spine or subclavian-vessel involvement (T4 disease), and limited resection (R1 or R2).

Surgery

Evidence (surgery):

  1. Retrospective case series have reported that complete resection was achieved in only 64% of T3, N0 tumors and 39% of T4, N0 tumors.[65]

Chemoradiation therapy followed by surgery

Evidence (chemoradiation therapy):

  1. Two large, prospective, multicenter phase II trials have evaluated induction chemoradiation therapy followed by resection.[66,67]
    1. In the first trial (NCT00002642), 110 eligible patients were enrolled with mediastinoscopy negative, clinical T3–4, N0–1 tumors of the superior sulcus.[67] Induction treatment was two cycles of etoposide and cisplatin with 45 Gy of concurrent radiation therapy.
      • The induction regimen was well tolerated, and only five participants had grade 3 or higher toxic effects.
      • Induction chemoradiation therapy could sterilize the primary lesion. Induction therapy was completed by 104 patients (95%). Of the 95 patients eligible for surgery, 88 (80%) underwent thoracotomy, two (1.8%) died postoperatively, and 83 (76%) had complete resections.
      • Pathological complete response or minimal microscopic disease was seen in 61 (56%) resection specimens. Pathological complete response led to better survival than when any residual disease was present (P = .02).
      • Five-year survival was 44% for all patients and 54% after complete resection, with no difference between T3 and T4 tumors. Disease progression occurred mainly in distant sites.
    2. In the second trial, 75 patients were enrolled and treated with induction therapy with mitomycin C, vindesine, and cisplatin combined with 45 Gy of radiation therapy.[66] Fifty-seven patients (76%) underwent surgical resection, and complete resection was achieved in 51 patients (68%).
      • There were 12 patients with pathological complete response.
      • Major postoperative morbidity, including chylothorax, empyema, pneumonitis, adult respiratory distress syndrome, and bleeding, was observed in eight patients. There were three treatment-related deaths.
      • At 3 years, the DFS rate was 49%, and the OS rate was 61%; at 5 years, the DFS rate was 45%, and the OS rate was 56%.[66][Level of evidence C2]
Radiation therapy dose escalation for concurrent chemoradiation

With improvement in radiation therapy–delivery technology in the 1990s, including tumor-motion management and image guidance, phase I/II trials demonstrated the feasibility of dose-escalation radiation therapy to 74 Gy with concurrent chemotherapy.[41–43] However, a phase III trial of a conventional dose of 60 Gy versus dose escalation to 74 Gy with concurrent weekly carboplatin/paclitaxel did not demonstrate improved local control or PFS, and OS was worse with dose escalation (HR, 1.38 [1.09–1.76]; P = .004). There was a nonsignificant increase in grade 5 events with dose escalation (10% vs. 2%) and higher incidence of grade 3 esophagitis (21% vs. 7%; P = .0003). Thus, there is no clear benefit in radiation dose escalation beyond 60 Gy for stage III NSCLC.[44][Level of evidence A1]

Radiation therapy alone

While radiation therapy is an integral part of the treatment of Pancoast tumors, variations in dose, treatment technique, and staging that were used in various published series make it difficult to determine its effectiveness.[63,64]

Small, retrospective series of radiation therapy in patients who were only clinically staged have reported 5-year survival rates of 0% to 40%, depending on T stage, total radiation dose, and other prognostic factors. Induction radiation therapy and en bloc resection was shown to be potentially curative.

Evidence (radiation therapy):

  1. In the preoperative setting, a dose of 45 Gy over 5 weeks is generally recommended, while a dose of approximately 61 Gy is required when using definitive radiation therapy as the primary modality.[63,64]

Treatment Options for Tumors That Invade the Chest Wall

Treatment options for tumors that invade the chest wall include:

  1. Surgery.
  2. Surgery and radiation therapy.
  3. Radiation therapy alone.
  4. Chemotherapy combined with radiation therapy and/or surgery.

Selected patients with bulky primary tumors that directly invade the chest wall can obtain long-term survival with surgical management provided that their tumor is completely resected.

Evidence (radical surgery):

  1. In a small case series of 97 patients, the 5-year survival rate of patients who had completely resected T3, N0, M0 disease was 44.2%. For patients with completely resected T3, N1, M0 disease, the 5-year survival rate was 40.0%. In patients with completely resected T3, N2, M0 disease, the 5-year survival rate was 6.2%.[68][Level of evidence C2]
  2. In a small case series of 104 patients, the 5-year survival rate of patients who had completely resected T3, N0, M0 disease was 67.3%. For patients with completely resected T3, N1, M0 disease, the 5-year survival rate was 100.0%. In patients with completely resected T3, N2, M0 disease, the 5-year survival rate was 17.9%.[69][Level of evidence C2]
  3. In a case series of 309 patients treated at three centers, patients who underwent en bloc resection had superior outcomes compared with patients who underwent extrapleural resections (60.3% vs. 39.1%; P = .03).[70][Level of evidence C2]

Adjuvant chemotherapy is recommended, and radiation therapy is reserved for cases with unclear resection margins. Survival rates were lower in patients who underwent incomplete resection and had mediastinal lymph node involvement. Combined-modality approaches have been evaluated to improve ability to achieve complete resection.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

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  69. Facciolo F, Cardillo G, Lopergolo M, et al.: Chest wall invasion in non-small cell lung carcinoma: a rationale for en bloc resection. J Thorac Cardiovasc Surg 121 (4): 649-56, 2001. [PUBMED Abstract]
  70. Doddoli C, D’Journo B, Le Pimpec-Barthes F, et al.: Lung cancer invading the chest wall: a plea for en-bloc resection but the need for new treatment strategies. Ann Thorac Surg 80 (6): 2032-40, 2005. [PUBMED Abstract]

Treatment of Stages IIIB and IIIC NSCLC

On the basis of the Surveillance, Epidemiology, and End Results (SEER) Program registry, the estimated incidence of stage IIIB non-small cell lung cancer (NSCLC) is 17.6%.[1] The anticipated 5-year survival rate for most patients who present with clinical stage IIIB NSCLC is 3% to 7%.[2] In small case series, selected patients with T4, N0–1 disease, solely as the result of satellite tumor nodule(s) within the primary lobe, had 5-year survival rates of 20%.[3,4][Level of evidence C1]

Treatment Options for Stages IIIB and IIIC NSCLC

Treatment options for stages IIIB NSCLC and IIIC NSCLC include:

  1. Sequential or concurrent chemotherapy and radiation therapy.
    1. Radiation therapy dose escalation for concurrent chemoradiation.
    2. Systemic consolidation therapy before or after concurrent chemoradiation therapy.
  2. Radiation therapy alone.
  3. New fractionation schedules (under clinical evaluation).
  4. Radiosensitizers (NCT02186847) (under clinical evaluation).
  5. Combined-modality approaches (under clinical evaluation).
  6. Incorporation of targeted agents into combined modality therapy in patients with EGFR variants or ALK translocations (RTOG-1306 [NCT01822496]; 11-464 [NCT01553942]) (under clinical evaluation).
  7. Adaptive radiation therapy using positron emission tomography–based response assessment during treatment (RTOG-1106/ACRIN-6697) (under clinical evaluation).

In general, patients with stages IIIB and IIIC NSCLC do not benefit from surgery alone and are best managed by initial chemotherapy, chemotherapy plus radiation therapy, or radiation therapy alone, depending on:

  • Sites of tumor involvement.
  • The patient’s performance status.

Most patients with excellent performance status are candidates for combined-modality chemotherapy and radiation therapy with the following exceptions:

  • Selected patients with T4, N0 disease may be treated with combined-modality therapy and surgery similar to patients with superior sulcus tumors.

Patients with stages IIIB or IIIC NSCLC are candidates for clinical trials, which may lead to improvement in the control of disease.

Sequential or concurrent chemotherapy and radiation therapy

Many randomized studies of patients with unresectable stage III NSCLC show that treatment with preoperative or concurrent cisplatin-based chemotherapy and radiation therapy to the chest is associated with improved survival compared with treatment that uses radiation therapy alone. Although patients with unresectable stages IIIB or IIIC disease may benefit from radiation therapy, long-term outcomes have generally been poor, often the result of local and systemic relapse. The addition of sequential and concurrent chemotherapy to radiation therapy has been evaluated in prospective randomized trials.

Evidence (sequential or concurrent chemotherapy and radiation therapy):

  1. A meta-analysis of patient data from 11 randomized clinical trials showed the following:[5]
    • Cisplatin-based combinations plus radiation therapy resulted in a 10% reduction in the risk of death compared with radiation therapy alone.[5][Level of evidence A1]
  2. A meta-analysis of 13 trials (based on 2,214 evaluable patients) showed the following:[6]
    • The addition of concurrent chemotherapy to radical radiation therapy reduced the risk of death at 2 years (relative risk [RR], 0.93; 95% confidence interval [CI], 0.88–0.98; P = .01).
    • For the 11 trials with platinum-based chemotherapy, RR was 0.93 (95% CI, 0.87–0.99; P = .02).[6]
  3. A meta-analysis of individual data from 1,764 patients evaluated nine trials.[7]
    • The hazard ratio (HR)death among patients treated with radiation therapy and chemotherapy compared with radiation therapy alone was 0.89 (95% CI, 0.81–0.98; P = .02) corresponding to an absolute benefit of chemotherapy of 4% at 2 years.
    • The combination of platinum with etoposide appeared to be more effective than platinum alone. Concomitant platinum-based chemotherapy and radiation therapy may improve survival of patients with locally advanced NSCLC. However, the available data are insufficient to accurately define the size of such a potential treatment benefit and the optimal schedule of chemotherapy.[7]
  4. The results from two randomized trials (including RTOG-9410 [NCT01134861]) and a meta-analysis indicate that concurrent chemotherapy and radiation therapy provide greater survival benefit, albeit with more toxic effects, than sequential chemotherapy and radiation therapy.[8–10][Level of evidence A1]
    1. In the first trial, the combination of mitomycin C, vindesine, and cisplatin were given concurrently with split-course daily radiation therapy to 56 Gy compared with chemotherapy followed by continuous daily radiation therapy to 56 Gy.[8]
      • Five-year overall survival (OS) rates favored concurrent therapy (27% vs. 9%).
      • Myelosuppression was greater among patients in the concurrent arm, but treatment-related mortality was less than 1% in both arms.[8]
    2. In the second trial, 610 patients were randomly assigned to sequential chemotherapy with cisplatin and vinblastine followed by 63 Gy of radiation therapy, concurrent chemoradiation therapy using the same regimen, or concurrent chemotherapy with cisplatin and etoposide with twice-daily radiation therapy.[9,10]
      • Median and 5-year survival were superior in the concurrent chemotherapy with daily radiation therapy arm (17 months vs. 14.6 months and 16% vs. 10% for sequential regimen [P = .046]).
    3. Two smaller studies also reported OS results that favored concurrent over sequential chemotherapy and radiation, although the results did not reach statistical significance.[10][Level of evidence A1]; [11]
  5. A meta-analysis of three trials evaluated concurrent versus sequential treatment (711 patients).[6]
    • The analysis indicated a significant benefit of concurrent versus sequential treatment (RR, 0.86; 95% CI, 0.78–0.95; P = .003). All used cisplatin-based regimens and once-daily radiation therapy.[6]
    • More deaths (3% overall) were reported in the concurrent arm, but this did not reach statistical significance (RR, 1.60; 0.75–3.44; P = .2).
    • There was more acute esophagitis (grade 3 or worse) with concurrent treatment (range, 17%–26%) compared with sequential treatment (range, 0%–4%; RR, 6.77; P = .001). Overall, the incidence of neutropenia (grade 3 or worse) was similar in both arms.
Radiation therapy dose escalation for concurrent chemoradiation

With improvement in radiation therapy–delivery technology in the 1990s, including tumor-motion management and image guidance, phase I/II trials demonstrated the feasibility of dose-escalation radiation therapy to 74 Gy with concurrent chemotherapy.[12–14] However, a phase III trial of a conventional dose of 60 Gy versus dose escalation to 74 Gy with concurrent weekly carboplatin/paclitaxel did not demonstrate improved local control or progression-free survival (PFS), and OS was worse with dose escalation (HR, 1.38 [1.09–1.76]; P = .004). There was a nonsignificant increase in grade 5 events with dose escalation (10% vs. 2%) and higher incidence of grade 3 esophagitis (21% vs. 7%; P = .0003).[15][Level of evidence A1]

Systemic consolidation therapy before or after concurrent chemoradiation therapy
Consolidation immunotherapy
Durvalumab

Durvalumab is a selective human IgG1 monoclonal antibody that blocks programmed death-ligand 1 (PD-L1) binding to programmed death 1 (PD-1) and CD80, allowing T cells to recognize and kill tumor cells.[16]

Evidence (durvalumab):

  1. The phase III PACIFIC trial (NCT02125461) enrolled 713 patients with stage III NSCLC whose disease had not progressed after two or more cycles of platinum-based chemoradiation therapy. Patients were randomly assigned in a 2:1 ratio to receive durvalumab (10 mg/kg intravenously) or placebo (every 2 weeks for up to 12 months).[16] The coprimary end points were PFS assessed by blinded independent central review and OS (unplanned for the interim analysis).
    • At the interim analysis, the coprimary end point of PFS was met. The median PFS was 16.8 months with durvalumab versus 5.6 months with placebo (HR, 0.52; 95% CI, 0.42–0.65; P < .001).[16][Level of evidence B1] The 18-month PFS rate was 44.2% with durvalumab versus 27% with placebo.
    • PFS benefit was seen across all prespecified subgroups and was irrespective of PD-L1 expression before chemoradiation therapy or smoking status. EGFR variants were observed in 6% of patients (29 treated with durvalumab vs. 14 treated with placebo). The unstratified HR for the subgroup with EGFR variants was 0.76 (95% CI, 0.35–1.64).
    • Grade 3 or 4 adverse events occurred in 29.9% of patients treated with durvalumab and in 26.1% of patients treated with placebo. The most common adverse event of grade 3 or 4 was pneumonia in 4.4% of patients treated with durvalumab and in 3.8% of patients treated with placebo.
    • OS was not assessed at the interim analysis.
Osimertinib (for patients with EGFR variants)

Evidence (osimertinib following concurrent chemoradiation therapy):

  1. The phase III, double-blind, placebo-controlled LAURA trial (NCT03521154) included patients with unresectable stage III NSCLC and EGFR variants . Patients had not progressed during or after definitive chemoradiation therapy. A total of 216 patients who had undergone chemoradiation therapy were randomly assigned to receive either osimertinib (n = 143) or placebo (n = 73). The primary end point was PFS as assessed by blinded independent central review.[17]
    • The median PFS was 39.1 months with osimertinib and 5.6 months with placebo (HRdisease progression or death, 0.16; 95% CI, 0.10–0.24; P < .001).
    • At 36 months, the OS rate was 84% for patients in the osimertinib group (95% CI, 75%–89%) and 74% for patients in the placebo group (95% CI, 57%–85%) (HRdeath, 0.81; 95% CI, 0.42–1.56; P = .53) (at 20% data maturity).[17][Level of evidence A1]
    • Grade 3 or higher adverse events occurred in 35% of patients in the osimertinib group and 12% of patients in the placebo group. Radiation pneumonitis was reported in 48% of patients in the osimertinib group and 38% of patients in the placebo group.
Other systemic consolidation therapies

The addition of induction chemotherapy before concurrent chemotherapy and radiation therapy has not been shown to improve survival.[18][Level of evidence A1]

Randomized trials of other consolidation systemic therapies, including docetaxel,[19] gefitinib,[20] and tecemotide (MUC1 antigen-specific immunotherapy) [21] have not shown an improvement in OS.[Level of evidence A1]

The role of consolidation systemic therapy after concurrent chemotherapy and radiation therapy for unresectable NSCLC remains unclear. Phase III trials of consolidation systemic therapy including conventional chemotherapy (docetaxel),[19] tyrosine kinase inhibitors (gefitinib),[20] and immunotherapy (tecemotide: MUC1 antigen-specific immunotherapy) [21] have not shown an improvement in OS.[Level of evidence A1]

Radiation therapy alone

For treatment of locally advanced unresectable tumor in patients who are not candidates for chemotherapy

Radiation therapy alone may provide benefit to patients with locally advanced unresectable stage III NSCLC.

Radiation therapy with traditional dose and fractionation schedules (1.8–2.0 Gy per fraction per day to 60–70 Gy in 6–7 weeks) results in reproducible long-term survival benefit in 5% to 10% of patients and significant palliation of symptoms.[22]

Evidence (radiation therapy for locally advanced unresectable tumor):

  1. One prospective randomized clinical study showed the following:
    • Radiation therapy given as three daily fractions improved OS compared with radiation therapy given as one daily fraction.[23][Level of evidence A1]
    • Patterns of failure for patients treated with radiation therapy alone included both locoregional and distant failures.
For patients requiring palliative treatment

Radiation therapy may be effective in palliating symptomatic local involvement with NSCLC, such as:

  • Tracheal, esophageal, or bronchial compression.
  • Pain.
  • Vocal cord paralysis.
  • Hemoptysis.
  • Superior vena cava syndrome.

In some cases, endobronchial laser therapy and/or brachytherapy has been used to alleviate proximal obstructing lesions.[24]

Evidence (radiation therapy for palliative treatment):

  1. A systematic review identified six randomized trials of high-dose rate endobronchial brachytherapy (HDREB) alone or with external-beam radiation therapy (EBRT) or laser therapy.[25]
    • Better overall symptom palliation and fewer re-treatments were required in previously untreated patients using EBRT alone.[25][Level of evidence A3]
    • HDREB provided palliation of symptomatic patients with recurrent endobronchial obstruction previously treated by EBRT, when it was technically feasible.
    • Although EBRT is frequently prescribed for symptom palliation, there is no consensus about when the fractionation scheme should be used.
    • Although different multifraction regimens appear to provide similar symptom relief,[26–31] single-fraction radiation may be insufficient for symptom relief compared with hypofractionated or standard regimens, as shown in the National Cancer Institute of Canada Clinical Trials Group trial (NCT00003685).[28][Level of evidence A3]
    • Evidence of a modest increase in survival in patients with better performance status given high-dose radiation therapy is available.[26,27][Level of evidence A1]

Patients with stages IIIB or IIIC disease with poor performance status are candidates for chest radiation therapy to palliate pulmonary symptoms (e.g., cough, shortness of breath, hemoptysis, or pain).[22][Level of evidence C1] For more information, see Cardiopulmonary Syndromes and Cancer Pain.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References
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  2. Mountain CF: Revisions in the International System for Staging Lung Cancer. Chest 111 (6): 1710-7, 1997. [PUBMED Abstract]
  3. Deslauriers J, Brisson J, Cartier R, et al.: Carcinoma of the lung. Evaluation of satellite nodules as a factor influencing prognosis after resection. J Thorac Cardiovasc Surg 97 (4): 504-12, 1989. [PUBMED Abstract]
  4. Urschel JD, Urschel DM, Anderson TM, et al.: Prognostic implications of pulmonary satellite nodules: are the 1997 staging revisions appropriate? Lung Cancer 21 (2): 83-7; discussion 89-91, 1998. [PUBMED Abstract]
  5. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. Non-small Cell Lung Cancer Collaborative Group. BMJ 311 (7010): 899-909, 1995. [PUBMED Abstract]
  6. Rowell NP, O’rourke NP: Concurrent chemoradiotherapy in non-small cell lung cancer. Cochrane Database Syst Rev (4): CD002140, 2004. [PUBMED Abstract]
  7. Aupérin A, Le Péchoux C, Pignon JP, et al.: Concomitant radio-chemotherapy based on platin compounds in patients with locally advanced non-small cell lung cancer (NSCLC): a meta-analysis of individual data from 1764 patients. Ann Oncol 17 (3): 473-83, 2006. [PUBMED Abstract]
  8. Furuse K, Fukuoka M, Kawahara M, et al.: Phase III study of concurrent versus sequential thoracic radiotherapy in combination with mitomycin, vindesine, and cisplatin in unresectable stage III non-small-cell lung cancer. J Clin Oncol 17 (9): 2692-9, 1999. [PUBMED Abstract]
  9. Curran WJ, Paulus R, Langer CJ, et al.: Sequential vs. concurrent chemoradiation for stage III non-small cell lung cancer: randomized phase III trial RTOG 9410. J Natl Cancer Inst 103 (19): 1452-60, 2011. [PUBMED Abstract]
  10. Fournel P, Robinet G, Thomas P, et al.: Randomized phase III trial of sequential chemoradiotherapy compared with concurrent chemoradiotherapy in locally advanced non-small-cell lung cancer: Groupe Lyon-Saint-Etienne d’Oncologie Thoracique-Groupe Français de Pneumo-Cancérologie NPC 95-01 Study. J Clin Oncol 23 (25): 5910-7, 2005. [PUBMED Abstract]
  11. Zatloukal P, Petruzelka L, Zemanova M, et al.: Concurrent versus sequential chemoradiotherapy with cisplatin and vinorelbine in locally advanced non-small cell lung cancer: a randomized study. Lung Cancer 46 (1): 87-98, 2004. [PUBMED Abstract]
  12. Rosenman JG, Halle JS, Socinski MA, et al.: High-dose conformal radiotherapy for treatment of stage IIIA/IIIB non-small-cell lung cancer: technical issues and results of a phase I/II trial. Int J Radiat Oncol Biol Phys 54 (2): 348-56, 2002. [PUBMED Abstract]
  13. Socinski MA, Blackstock AW, Bogart JA, et al.: Randomized phase II trial of induction chemotherapy followed by concurrent chemotherapy and dose-escalated thoracic conformal radiotherapy (74 Gy) in stage III non-small-cell lung cancer: CALGB 30105. J Clin Oncol 26 (15): 2457-63, 2008. [PUBMED Abstract]
  14. Bradley JD, Bae K, Graham MV, et al.: Primary analysis of the phase II component of a phase I/II dose intensification study using three-dimensional conformal radiation therapy and concurrent chemotherapy for patients with inoperable non-small-cell lung cancer: RTOG 0117. J Clin Oncol 28 (14): 2475-80, 2010. [PUBMED Abstract]
  15. Bradley JD, Paulus R, Komaki R, et al.: Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 study. Lancet Oncol 16 (2): 187-99, 2015. [PUBMED Abstract]
  16. Antonia SJ, Villegas A, Daniel D, et al.: Durvalumab after Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer. N Engl J Med 377 (20): 1919-1929, 2017. [PUBMED Abstract]
  17. Lu S, Kato T, Dong X, et al.: Osimertinib after Chemoradiotherapy in Stage III EGFR-Mutated NSCLC. N Engl J Med 391 (7): 585-597, 2024. [PUBMED Abstract]
  18. Vokes EE, Herndon JE, Kelley MJ, et al.: Induction chemotherapy followed by chemoradiotherapy compared with chemoradiotherapy alone for regionally advanced unresectable stage III Non-small-cell lung cancer: Cancer and Leukemia Group B. J Clin Oncol 25 (13): 1698-704, 2007. [PUBMED Abstract]
  19. Hanna N, Neubauer M, Yiannoutsos C, et al.: Phase III study of cisplatin, etoposide, and concurrent chest radiation with or without consolidation docetaxel in patients with inoperable stage III non-small-cell lung cancer: the Hoosier Oncology Group and U.S. Oncology. J Clin Oncol 26 (35): 5755-60, 2008. [PUBMED Abstract]
  20. Kelly K, Chansky K, Gaspar LE, et al.: Phase III trial of maintenance gefitinib or placebo after concurrent chemoradiotherapy and docetaxel consolidation in inoperable stage III non-small-cell lung cancer: SWOG S0023. J Clin Oncol 26 (15): 2450-6, 2008. [PUBMED Abstract]
  21. Butts C, Socinski MA, Mitchell PL, et al.: Tecemotide (L-BLP25) versus placebo after chemoradiotherapy for stage III non-small-cell lung cancer (START): a randomised, double-blind, phase 3 trial. Lancet Oncol 15 (1): 59-68, 2014. [PUBMED Abstract]
  22. Langendijk JA, ten Velde GP, Aaronson NK, et al.: Quality of life after palliative radiotherapy in non-small cell lung cancer: a prospective study. Int J Radiat Oncol Biol Phys 47 (1): 149-55, 2000. [PUBMED Abstract]
  23. Komaki R, Cox JD, Hartz AJ, et al.: Characteristics of long-term survivors after treatment for inoperable carcinoma of the lung. Am J Clin Oncol 8 (5): 362-70, 1985. [PUBMED Abstract]
  24. Miller JI, Phillips TW: Neodymium:YAG laser and brachytherapy in the management of inoperable bronchogenic carcinoma. Ann Thorac Surg 50 (2): 190-5; discussion 195-6, 1990. [PUBMED Abstract]
  25. Ung YC, Yu E, Falkson C, et al.: The role of high-dose-rate brachytherapy in the palliation of symptoms in patients with non-small-cell lung cancer: a systematic review. Brachytherapy 5 (3): 189-202, 2006 Jul-Sep. [PUBMED Abstract]
  26. Sundstrøm S, Bremnes R, Aasebø U, et al.: Hypofractionated palliative radiotherapy (17 Gy per two fractions) in advanced non-small-cell lung carcinoma is comparable to standard fractionation for symptom control and survival: a national phase III trial. J Clin Oncol 22 (5): 801-10, 2004. [PUBMED Abstract]
  27. Lester JF, Macbeth FR, Toy E, et al.: Palliative radiotherapy regimens for non-small cell lung cancer. Cochrane Database Syst Rev (4): CD002143, 2006. [PUBMED Abstract]
  28. Bezjak A, Dixon P, Brundage M, et al.: Randomized phase III trial of single versus fractionated thoracic radiation in the palliation of patients with lung cancer (NCIC CTG SC.15). Int J Radiat Oncol Biol Phys 54 (3): 719-28, 2002. [PUBMED Abstract]
  29. Erridge SC, Gaze MN, Price A, et al.: Symptom control and quality of life in people with lung cancer: a randomised trial of two palliative radiotherapy fractionation schedules. Clin Oncol (R Coll Radiol) 17 (1): 61-7, 2005. [PUBMED Abstract]
  30. Kramer GW, Wanders SL, Noordijk EM, et al.: Results of the Dutch National study of the palliative effect of irradiation using two different treatment schemes for non-small-cell lung cancer. J Clin Oncol 23 (13): 2962-70, 2005. [PUBMED Abstract]
  31. Senkus-Konefka E, Dziadziuszko R, Bednaruk-Młyński E, et al.: A prospective, randomised study to compare two palliative radiotherapy schedules for non-small-cell lung cancer (NSCLC). Br J Cancer 92 (6): 1038-45, 2005. [PUBMED Abstract]

Treatment of Newly Diagnosed Stage IV, Relapsed, and Recurrent NSCLC

Factors Affecting Treatment Selection

Forty percent of patients with newly diagnosed non-small cell lung cancer (NSCLC) have stage IV disease. Treatment goals are to prolong survival and control disease-related symptoms. Treatment options include cytotoxic chemotherapy, targeted agents, and immunotherapy. Factors influencing treatment selection include comorbidity, performance status, histology, and molecular and immunologic features of the cancer. Therefore, assessment of tumor-genomic changes and programmed death-ligand 1 (PD-L1) expression is critical before initiating therapy. Radiation therapy and surgery are generally used in selective cases for symptom palliation.

Factors that affect selection of treatment include:

History and molecular features

Patients with nonsquamous cell histology, good performance status, no history of hemoptysis or other bleeding, or recent history of cardiovascular events may benefit from the addition of bevacizumab to paclitaxel and carboplatin. Patients with sensitizing variants in exon 19 or exon 21 of EGFR (particularly those from East Asia, never smokers, and those with adenocarcinoma) may benefit from EGFR tyrosine kinase inhibitors (TKIs) as an alternative to first- or second-line chemotherapy. Patients with tumors harboring ALK translocations, ROS1 rearrangements, or NTRK fusions may benefit from ALK, ROS1, or NTRK inhibitors as an alternative to first- or second-line chemotherapy.

Patients with tumors expressing PD-L1 (>50% by immunohistochemistry) have improved survival with pembrolizumab. The addition of pembrolizumab to carboplatin-plus-pemetrexed chemotherapy for nonsquamous advanced lung cancer improves survival irrespective of PD-L1 expression.[1][Level of evidence A1] For patients with stage IV or recurrent NSCLC and PD-L1 expression on at least 1% of tumor cells, frontline combination immunotherapy with nivolumab and ipilimumab increases overall survival (OS).[2][Level of evidence A1] Second-line systemic therapy with nivolumab, docetaxel, pemetrexed, or pembrolizumab for PD-L1−positive tumors also improves survival in patients with good performance status (who have not received the same or a similar agent in the first-line setting).[3][Level of evidence A1]

The role of systemic therapy in patients with an Eastern Cooperative Oncology Group (ECOG) performance status below 2 is less certain.

Patients with adenocarcinoma may benefit from pemetrexed [4] and bevacizumab, as well as from combination chemotherapy with pembrolizumab. Patients with unresectable, locally advanced or metastatic, well-differentiated, nonfunctional, neuroendocrine tumors benefit from the mTOR inhibitor, everolimus.

Age and comorbidity

Evidence supports the concept that older patients with good performance status and limited comorbidity may benefit from combination chemotherapy. Age alone should not dictate treatment-related decisions in patients with advanced NSCLC. Older patients with a good performance status enjoy longer survival and a better quality of life when treated with chemotherapy compared with supportive care alone. Caution should be exercised when extrapolating data for patients aged 70 to 79 years to patients aged 80 years or older because only a very small number of patients aged 80 years or older have been enrolled in clinical trials, and the benefit in this group is uncertain.[5,6]

Evidence (age and comorbidity):

  1. Platinum-containing combination chemotherapy regimens provide clinical benefit when compared with supportive care or single-agent therapy; however, such treatment may be contraindicated in some older patients because of the age-related reduction in the functional reserve of many organs and/or comorbid conditions. Approximately two-thirds of patients with NSCLC are aged 65 years or older, and approximately 40% are aged 70 years or older.[7] Surveillance, Epidemiology, and End Results (SEER) Program data suggest that the percentage of patients older than 70 years is closer to 50%.
  2. A review of the SEER Medicare data from 1994 to 1999 found a much lower rate of chemotherapy use than expected for the overall population.[8] The same data suggested that older patients may have more comorbidities or a higher rate of functional compromise that would make study participation difficult, if not contraindicated; lack of clinical trial data may influence decisions to treat individual patients with standard chemotherapy.
  3. Single-agent chemotherapy and combination chemotherapy clearly benefit at least some older patients. In the Elderly Lung Cancer Vinorelbine Italian Study, 154 patients who were older than 70 years were randomly assigned to vinorelbine or supportive care.[9]
    • Patients who were treated with vinorelbine had a 1-year survival rate of 32%, compared with 14% for those who were treated with supportive care alone. Quality-of-life parameters were also significantly improved in the chemotherapy arm, and toxic effects were acceptable.
  4. A trial from Japan compared single-agent docetaxel with vinorelbine in 180 patients older than 70 years with good performance status.[10]
    • Response rates (22% vs. 10%) and progression-free survival (PFS) (5.4 months vs. 3.1 months) were significantly better with docetaxel, but median survival (14.3 months vs. 9.9 months) and 1-year survival rates (59% vs. 37%) did not reach statistical significance.
  5. Retrospective data analyzing and comparing younger (age <70 years) patients with older (age ≥70 years) patients who participated in large randomized trials of doublet combinations have also shown that older patients may derive the same survival benefit, but with a higher risk of toxic effects in the bone marrow.[5,6,11–14]

Performance status

Performance status is among the most important prognostic factors for survival of patients with NSCLC.[15] The benefit of therapy for this group of patients has been evaluated through retrospective analyses and prospective clinical trials.

The results support further evaluation of chemotherapeutic approaches for both metastatic and locally advanced NSCLC; however, the efficacy of current platinum-based chemotherapy combinations is such that no specific regimen can be regarded as standard therapy. Outside of a clinical trial setting, chemotherapy should only be given to patients with good performance status and evaluable tumor lesions, who desire this treatment after being fully informed of its anticipated risks and limited benefits.

Randomized controlled trials of patients with stage IV disease and good performance status have shown that cisplatin-based chemotherapy improves survival and palliates disease-related symptoms.[3][Level of evidence A1]

Evidence (performance status):

  1. The Cancer and Leukemia Group B trial (CLB-9730 [NCT00003117]), which compared carboplatin and paclitaxel with single-agent paclitaxel, enrolled 99 patients with a performance status of 2 (18% of the study’s population).[13]
    • When compared with patients with a performance status of 0 to 1, who had a median survival of 8.8 months and a 1-year survival rate of 38%, the corresponding median survival figures for patients with a performance status of 2 were 3.0 months and a 1-year survival rate of 14%; this demonstrates the poor prognosis conferred by a lower performance status. These differences were statistically significant.
    • When patients with a performance status of 2 were analyzed by treatment arm, those who received combination chemotherapy had a significantly higher response rate (24% vs. 10%), longer median survival (4.7 months vs. 2.4 months), and a superior 1-year survival rate (18% vs. 10%), compared with those who were treated with single-agent paclitaxel.[13]
  2. A phase III trial compared single-agent pemetrexed with the combination of carboplatin and pemetrexed in 205 patients with a performance status of 2 who had not had any previous chemotherapy.[16][Level of evidence A1]
    • Median OS was 5.3 months for the pemetrexed-alone group and 9.3 months for the carboplatin-and-pemetrexed group (hazard ratio [HR], 0.62; 95% confidence interval [CI], 0.46–0.83; P = .001).
    • Median PFS was 2.8 months for the pemetrexed-alone group and 5.8 months for the carboplatin-and-pemetrexed group (P < .001).
    • The response rates were 10.3% for the pemetrexed-alone group and 23.8% for the carboplatin-and-pemetrexed group (P = .032).
    • Side effects were more frequent in the combination arm, as expected.

    This study, which was performed in eight centers in Brazil and one center in the United States, reported rates of OS and PFS that were higher than has historically been noted in most, although not all, other published studies. This may indicate differences in patient selection.

  3. A subset analysis of 68 patients with a performance status of 2 from a trial that randomly assigned more than 1,200 patients to four platinum-based regimens has been published.
    • Despite a high incidence of adverse events, including five deaths, the final analysis showed that the overall toxic effects experienced by patients with a performance status of 2 was not significantly different from that experienced by patients with a performance status of 0 to 1.
    • An efficacy analysis demonstrated an overall response rate of 14%, median survival time of 4.1 months, and a 1-year survival rate of 19%; all were substantially inferior to the patients with performance status of 0 to 1.
  4. A phase II randomized trial (E-1599 [NCT00006004]) of attenuated dosages of cisplatin plus gemcitabine and carboplatin plus paclitaxel included 102 patients with a performance status of 2.[17]
    • Response rates were 25% in the cisplatin-plus-gemcitabine arm and 16% in the carboplatin-plus-paclitaxel arm; median survival times were 6.8 months in the cisplatin-plus-gemcitabine arm and 6.1 months in the carboplatin-plus-paclitaxel arm; 1-year survival rates were 25% in the cisplatin-plus-gemcitabine arm and 19% in the carboplatin-plus-paclitaxel arm. None of these differences was statistically significant, but the survival figures were longer than expected, based on historical controls.
  5. Results from two trials suggest that patients with a performance status of 2 may experience symptom improvement.[18,19]

Treatment Options for Newly Diagnosed Stage IV, Relapsed, and Recurrent NSCLC (First-Line Therapy)

Treatment options for patients with newly diagnosed stage IV, relapsed, and recurrent disease include:

  1. Cytotoxic combination chemotherapy with platinum (cisplatin or carboplatin) and paclitaxel, gemcitabine, docetaxel, vinorelbine, irinotecan, protein-bound paclitaxel, or pemetrexed.
  2. Combination chemotherapy with monoclonal antibodies.
  3. Maintenance therapy after first-line chemotherapy (for patients with stable or responding disease after four cycles of platinum-based combination chemotherapy).
    • Maintenance therapy following first-line chemotherapy.
    • Pemetrexed following first-line platinum-based combination chemotherapy.
  4. EGFR tyrosine kinase inhibitors (TKIs) with or without chemotherapy (for patients with EGFR variants).
  5. EGFR-directed therapy (for patients with EGFR exon 20 insertions).
  6. ALK inhibitors (for patients with ALK translocations).
  7. BRAF V600E and MEK inhibitors (for patients with BRAF V600E variants).
  8. ROS1 inhibitors (for patients with ROS1 rearrangements).
  9. NTRK inhibitors (for patients with NTRK fusions).
  10. RET inhibitors (for patients with RET fusions).
  11. MET inhibitors (for patients with MET exon 14-skipping variants).
  12. Immune checkpoint inhibitors with or without chemotherapy.
  13. mTOR inhibitors (for patients with unresectable, locally advanced or metastatic, progressive, well-differentiated, nonfunctional, neuroendocrine tumors).
  14. Local therapies and special considerations.
  15. Clinical trials can be considered as first-line therapy.

Cytotoxic combination chemotherapy

Combination chemotherapy

The type and number of chemotherapy drugs to be used for the treatment of patients with advanced NSCLC has been extensively evaluated in randomized controlled trials and meta-analyses.

Several randomized trials have evaluated various drugs combined with either cisplatin or carboplatin in previously untreated patients with advanced NSCLC. On the basis of meta-analyses of the trials, the following conclusions can be drawn:

  • Certain three-drug combinations that add so-called targeted agents may result in superior survival.
  • EGFR inhibitors may benefit selected patients with EGFR variants.
  • Maintenance chemotherapy after four cycles of platinum combination chemotherapy may improve PFS and OS.
  • Platinum combinations with vinorelbine, paclitaxel, docetaxel, gemcitabine, irinotecan, protein-bound paclitaxel, and pemetrexed yield similar improvements in survival. Types and frequencies of toxic effects differ, and these may determine the preferred regimen for an individual patient. Patients with adenocarcinoma may benefit from pemetrexed.
  • Cisplatin and carboplatin yield similar improvements in outcome with different toxic effects. Some, but not all, trials and meta-analyses of trials suggest that outcomes with cisplatin may be superior, although with a higher risk of certain toxicities such as nausea and vomiting.
  • Nonplatinum combinations offer no advantage to platinum-based chemotherapy, and some studies demonstrate inferiority.
  • Three-drug combinations of the commonly used chemotherapy drugs do not result in superior survival and are more toxic than two-drug combinations.

Evidence (combination chemotherapy):

  1. The Cochrane Collaboration reviewed data from all randomized controlled trials published between January 1980 and June 2006, comparing a doublet regimen with a single-agent regimen or comparing a triplet regimen with a doublet regimen in patients with advanced NSCLC.[24] Sixty-five trials (13,601 patients) were identified.
    • In the trials that compared a doublet regimen with a single-agent regimen, a significant increase was observed in tumor response (odds ratio [OR], 0.42; 95% CI, 0.37–0.47; P < .001) and 1-year survival (OR, 0.80; 95% CI, 0.70–0.91; P < .001) in favor of the doublet regimen. The absolute benefit in 1-year survival was 5%, which corresponds to an increase in 1-year survival from 30% with a single-agent regimen to 35% with a doublet regimen. The rates of grades 3 and 4 toxic effects caused by doublet regimens were statistically increased compared with rates after single-agent therapy, with ORs ranging from 1.2 to 6.2. Infection rates did not increase in doublet regimens.
    • There was no increase in 1-year survival (OR, 1.01; 95% CI, 0.85–1.21; P = .88) for triplet regimens versus doublet regimens. The median survival ratio was 1.00 (95% CI, 0.94–1.06; P = .97).
  2. Several meta-analyses have evaluated whether cisplatin or carboplatin regimens are superior, with variable results.[25–27] One meta-analysis reported individual patient data for 2,968 patients entered in nine randomized trials.[25]
    • The objective response rate was higher for patients treated with cisplatin (30%) than for patients treated with carboplatin (24%); (OR, 1.37; 95% CI, 1.16–1.61; P < .001).
    • Carboplatin treatment was associated with a nonstatistically significant increase in the hazard of mortality relative to treatment with cisplatin (HR, 1.07; 95% CI, 0.99–1.15; P = .100).
    • In patients with nonsquamous cell tumors and in patients treated with third-generation chemotherapy, carboplatin-based chemotherapy was associated with a statistically significant increase in mortality (HR, 1.12; 95% CI, 1.01–1.23 in patients with nonsquamous cell tumors and HR, 1.11; 95% CI, 1.01–1.21 in patients treated with third-generation chemotherapy).
    • Treatment-related toxic effects were also assessed in the meta-analysis. More thrombocytopenia was seen with carboplatin than with cisplatin (12% vs. 6%; OR, 2.27; 95% CI, 1.71–3.01; P < .001), but cisplatin caused more nausea and vomiting (8% vs. 18%; OR, 0.42; 95% CI, 0.33–0.53; P < .001) and renal toxic effects (0.5% vs. 1.5%; OR, 0.37; 95% CI, 0.15–0.88; P = .018).
    • The authors concluded that treatment with cisplatin was not associated with a substantial increase in the overall risk of severe toxic effects. This comprehensive individual-patient meta-analysis is consistent with the conclusions of other meta-analyses that were based on essentially the same clinical trials, but which used only published data.
  3. Three literature-based meta-analyses have trials that compared platinum with nonplatinum combinations.[28–30]
    1. The first meta-analysis identified 37 assessable trials that included 7,633 patients.[28]
      • A 62% increase in the OR for response was attributable to platinum-based therapy (OR, 1.62; 95% CI, 1.46–1.8; P < .001). The 1-year survival rate was increased by 5% with platinum-based regimens (34% vs. 29%; OR, 1.21; 95% CI, 1.09–1.35; P = .003).
      • No statistically significant increase in 1-year survival was found when platinum therapies were compared with third-generation-based combination regimens (OR, 1.11; 95% CI, 0.96–1.28; P = .17).
      • The toxic effects of platinum-based regimens was significantly higher for hematologic toxic effects, nephrotoxic effects, and nausea and vomiting but not for neurological toxic effects, febrile neutropenia rate, or toxic death rate. These results are consistent with the second literature-based meta-analysis.
    2. The second meta-analysis identified 17 trials that included 4,920 patients.[29]
      • The use of platinum-based doublet regimens was associated with a slightly higher survival at 1 year (relative risk [RR], 1.08; 95% CI, 1.01%–1.16%; P = .03) and a better partial response (RR, 1.11; 95% CI, 1.02–1.21; P = .02), with a higher risk of anemia, nausea, and neurological toxic effects.
      • In subanalyses, cisplatin-based doublet regimens improved survival at 1 year (RR, 1.16%; 95% CI, 1.06–1.27; P = .001), complete response (RR, 2.29; 95% CI, 1.08–4.88; P = .03), and partial response (RR, 1.19; 95% CI, 1.07–1.32; P = .002), with an increased risk of anemia, neutropenia, neurological toxic effects, and nausea.
      • Conversely, carboplatin-based doublet regimens did not increase survival at 1 year (RR, 0.95; 95% CI, 0.85–1.07; P = .43).
    3. The third meta-analysis of phase III trials randomizing platinum-based versus nonplatinum combinations as first-line chemotherapy identified 14 trials.[30] Experimental arms were gemcitabine and vinorelbine (n = 4), gemcitabine and taxane (n = 7), gemcitabine and epirubicin (n = 1), paclitaxel and vinorelbine (n = 1), and gemcitabine and ifosfamide (n = 1). This meta-analysis was limited to the set of 11 phase III studies that used a platinum-based doublet (2,298 patients in the platinum-based arm and 2,304 patients in the nonplatinum arm).
      • Patients treated with a platinum-based regimen benefited from a statistically significant reduction in the risk of death at 1 year (OR, 0.88; 95% CI, 0.78–0.99; P = .044) and a lower risk of being refractory to chemotherapy (OR, 0.87; CI, 0.73–0.99; P = .049).
      • Forty-four (1.9%) toxic-related deaths were reported for platinum-based regimens and 29 (1.3%) toxic-related deaths were reported for nonplatinum regimens (OR, 1.53; CI, 0.96–2.49; P = .08). An increased risk of grade 3 to 4 gastrointestinal and hematologic toxic effects for patients treated with platinum-based chemotherapy was statistically demonstrated. There was no statistically significant increase in the risk of febrile neutropenia (OR, 1.23; CI, 0.94–1.60; P = .063).
Drug and dose schedule

Among the active combinations, definitive recommendations regarding drug dose and schedule cannot be made, except for carboplatin, pemetrexed, and pembrolizumab for patients with nonsquamous tumor histology.

Evidence (drug and dose schedule):

  1. One meta-analysis of seven trials that included 2,867 patients assessed the benefit of docetaxel versus vinorelbine.[31] Docetaxel was administered with a platinum agent in three trials, with gemcitabine in two trials, or as monotherapy in two trials. Vinca alkaloid (vinorelbine in six trials and vindesine in one trial) was administered with cisplatin in six trials or alone in one trial.
    • The pooled estimate for OS showed an 11% improvement in favor of docetaxel (HR, 0.89; 95% CI, 0.82–0.96; P = .004). Sensitivity analyses that considered only vinorelbine as a comparator or only the doublet regimens showed similar improvements.
    • Grade 3 to 4 neutropenia and grade 3 to 4 serious adverse events were less frequent with docetaxel-based regimens (OR, 0.59; 95% CI, 0.38–0.89; P = .013) versus vinca alkaloid-based regimens (OR, 0.68; 95% CI, 0.55–0.84; P < .001).
  2. Two randomized trials compared weekly versus every-3-week dosing of paclitaxel and carboplatin, which reported no significant difference in efficacy and better tolerability for weekly administration.[32,33] Although meta-analyses of randomized controlled trials suggest that cisplatin combinations may be superior to carboplatin or nonplatinum combinations, the clinical relevance of the differences in efficacy must be balanced against the anticipated tolerability, logistics of administration, and familiarity of the medical staff in making treatment decisions for individual patients.
  3. A large, noninferiority, phase III randomized study compared the OS in 1,725 chemotherapy-naïve patients with stage IIIB/IV NSCLC and a performance status of 0 to 1.[4] Patients received cisplatin 75 mg/m2 on day 1 and gemcitabine 1,250 mg/m2 on days 1 and 8 (n = 863) or cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 on day 1 (n = 862) every 3 weeks for up to six cycles.
    • OS for cisplatin and pemetrexed (median survival, 10.3 months) was noninferior to cisplatin and gemcitabine (median survival, 10.3 months; HR, 0.94; 95% CI, 0.84%–1.05%).
    • In patients with adenocarcinoma (n = 847), OS was statistically superior for cisplatin and pemetrexed (12.6 months) versus cisplatin and gemcitabine (10.9 months); in patients with large cell carcinoma (n = 153), OS was statistically superior for cisplatin and pemetrexed (10.4 months) versus cisplatin and gemcitabine (6.7 months).
    • In contrast, in patients with squamous cell histology (n = 473), there was a significant improvement in survival with cisplatin and gemcitabine (10.8 months) versus cisplatin and pemetrexed (9.4 months). For cisplatin and pemetrexed, rates of grade 3 or 4 neutropenia, anemia, and thrombocytopenia (P ≤ .001); febrile neutropenia (P = .002); and alopecia (P < .001) were significantly lower, whereas grade 3 or 4 nausea (P = .004) was more common.
    • The results of this study suggested that the cisplatin and pemetrexed doublet is another alternative doublet for first-line chemotherapy for advanced NSCLC. The results also suggested that there may be differences in outcome depending on histology.

Combination chemotherapy with monoclonal antibodies

Bevacizumab

Evidence (bevacizumab):

  1. Two randomized trials have evaluated the addition of bevacizumab, an antibody targeting vascular endothelial growth factor, to standard first-line combination chemotherapy.
    1. In a randomized study of 878 patients with recurrent or advanced stage IIIB/IV NSCLC, 444 patients received paclitaxel and carboplatin alone, and 434 patients received paclitaxel and carboplatin plus bevacizumab.[34] Chemotherapy was administered every 3 weeks for six cycles, and bevacizumab was administered every 3 weeks until disease progression was evident or toxic effects were intolerable. Patients with squamous cell tumors, brain metastases, clinically significant hemoptysis, or inadequate organ function or performance status (ECOG performance status >1) were excluded.
      • Median survival was 12.3 months in the group assigned to chemotherapy plus bevacizumab, as compared with 10.3 months in the chemotherapy-alone group (HRdeath, 0.79; P = .003).
      • Median PFS was 6.2 months in the group assigned to chemotherapy plus bevacizumab (HRdisease progression, 0.66; P < .001), with a 35% response rate (P < .001), and 4.5 months in the chemotherapy-alone group (HRdisease progression, 0.66; P < .001), with a 15% response rate (P < .001).
      • Rates of clinically significant bleeding were 4.4% in the group assigned to chemotherapy plus bevacizumab and 0.7% in the chemotherapy-alone group (P < .001). There were 15 treatment-related deaths in the chemotherapy-plus-bevacizumab group, including five from pulmonary hemorrhage.
      • For this subgroup of patients with NSCLC, the addition of bevacizumab to paclitaxel and carboplatin may provide survival benefit.[34][Level of evidence A1]
    2. Another randomized, phase III trial investigated the efficacy and safety of cisplatin-gemcitabine plus bevacizumab.[35] Patients were randomly assigned to receive cisplatin (80 mg/m2) and gemcitabine (1,250 mg/m2) for up to six cycles, plus low-dose bevacizumab (7.5 mg/kg), high-dose bevacizumab (15 mg/kg), or placebo every 3 weeks until disease progression. The primary end point was amended from OS to PFS during the course of the study. A total of 1,043 patients were accrued (placebo group, n = 347; low-dose group, n = 345; high-dose group, n = 351).
      • PFS was significantly prolonged with the addition of bevacizumab; the HRs for PFS were 0.75 in the low-dose group (median PFS, 6.7 months vs. 6.1 months for the placebo group; P = .03) and 0.82 in the high-dose group compared with the placebo group (median PFS, 6.5 months vs. 6.1 months for the placebo group; P = .03).[35][Level of evidence A1]
      • Objective response rates were also improved with the addition of bevacizumab, and they were 20.1% for placebo, 34.1% for low-dose bevacizumab, and 30.4% for high-dose bevacizumab plus cisplatin/gemcitabine.
      • Incidence of grade 3 or greater adverse events was similar across arms.
      • Grade 3 or greater pulmonary hemorrhage rates were 1.5% or less for all arms, despite 9% of patients receiving therapeutic anticoagulation.
      • These results support the addition of bevacizumab to platinum-containing chemotherapy, but the results are far less impressive than when the carboplatin-paclitaxel combination was used.
      • Furthermore, no significant difference in survival was shown in this study, as reported in abstract form.
      • Altogether, these findings may suggest that the backbone of chemotherapy may be important when bevacizumab is added.
Cetuximab

Evidence (cetuximab):

  1. Two trials have evaluated the addition of cetuximab to first-line combination chemotherapy.[36,37]
    1. In the first trial, 676 chemotherapy-naïve patients with stage IIIB (pleural effusion) or stage IV NSCLC, without restrictions by histology or EGFR expression, received cetuximab with taxane (paclitaxel or docetaxel with carboplatin) or combination chemotherapy.[36]
      • The addition of cetuximab did not result in a statistically significant improvement in PFS, the primary study end point, or OS.
      • Median PFS was 4.40 months for patients in the cetuximab-chemotherapy arm versus 4.24 months for patients in the taxane-carboplatin arm (HR, 0.902; 95% CI, 0.761–1.069; P = .236).
      • Median OS was 9.69 months for patients in the cetuximab-chemotherapy arm versus 8.38 months for patients in the chemotherapy-alone arm (HR, 0.890; 95% CI, 0.754–1.051; P = .169).
      • In treatment-specific analyses, PFS, OS, and response were not significantly associated with EGFR expression, EGFR variants, EGFR copy number, or KRAS variants.[38]
    2. The second trial was composed of 1,125 chemotherapy-naïve patients with advanced EGFR-expressing stage IIIB/IV NSCLC treated with cisplatin-vinorelbine chemotherapy plus cetuximab or chemotherapy alone.[37]
      • The primary study end point, OS, was longer for patients treated with cetuximab and chemotherapy (median 11.3 months vs. 10.1 months; HRdeath, 0.871; 95% CI, 0.762–0.996; P = .044).
      • A survival benefit was seen in all histological subgroups; however, survival benefit was not seen in non-White or Asian patients. Only the interaction between the treatment and the ethnic origin was significant (P = .011).
      • The main cetuximab-related adverse event was acne-like rash (grade 3, 10%).
    3. It is not clear whether the differences in outcome in these two studies are the result of differences in the study populations, tumor characterization for EGFR expression, or chemotherapy regimens.
Necitumumab

Evidence (necitumumab):

  1. Two phase III trials have evaluated the addition of the second-generation, recombinant, human immunoglobulin G1 EGFR antibody, necitumumab, to platinum-doublet chemotherapy in the first-line treatment of patients with advanced nonsquamous cell and squamous cell NSCLC.[39,40]
    1. The SQUIRE trial (NCT00981058) randomly assigned 1,093 patients with advanced squamous NSCLC to receive either first-line chemotherapy with cisplatin and gemcitabine or the same regimen with the addition of necitumumab (800 mg on day 1 and day 8 of each cycle).[40]
      • Median OS was prolonged with the addition of necitumumab (11.5 months vs. 9.9 months; P = .01).
      • PFS was also prolonged with the addition of necitumumab (5.7 months vs. 5.5 months); however, the overall response rate was similar in both groups (31% vs. 28%).
      • Grades 3 and 4 adverse events were higher in the necitumumab-containing arm (72% vs. 62%).
      • Necitumumab is associated with higher toxicity and relatively modest benefit.
    2. The INSPIRE trial (NCT00982111) randomly assigned 633 patients with advanced nonsquamous NSCLC to receive either first-line chemotherapy with cisplatin and pemetrexed or to cisplatin and pemetrexed with the addition of necitumumab (800 mg on day 1 and day 8 of each cycle).[39]
      • This study showed no benefit from the addition of necitumumab to standard first-line chemotherapy for advanced nonsquamous NSCLC.
      • OS was 11.3 months (95% CI, 9.5–13.4) for patients in the necitumumab-containing arm versus 11.5 months (95% CI, 10.1–13.1) for patients in the chemotherapy alone arm; P = .96. Similarly, there was no difference between the arms in terms of objective response or PFS.
      • Serious adverse events and rates of grades 3 and 4 adverse events, including thromboembolic events, were higher in patients in the necitumumab-containing arm; the incidence of treatment-related deaths was also higher (5% vs. 3%).
      • On the basis of these results, necitumumab is not recommended as combination therapy with standard first-line chemotherapy for patients with advanced nonsquamous NSCLC.

Maintenance therapy after first-line chemotherapy (for patients with stable or responding disease after four cycles of platinum-based combination chemotherapy)

One extensively investigated treatment strategy in NSCLC is maintenance therapy after initial response to chemotherapy. Options for maintenance therapy that have been investigated include:

  • Continuing the initial combination chemotherapy regimen.
  • Continuing only single-agent chemotherapy.
  • Introducing a new agent as maintenance.

Multiple randomized trials have evaluated the efficacy of continuing first-line combination cytotoxic chemotherapy beyond three to four cycles.

Evidence (maintenance therapy following first-line chemotherapy):

  1. None of the trials of continued cytotoxic combinations showed a significant OS advantage with additional or longer durations beyond four cycles. For patients with nonsquamous NSCLC, two studies have demonstrated improved PFS and OS with either switch or continuous maintenance chemotherapy (e.g., maintenance pemetrexed after initial cisplatin and gemcitabine or maintenance pemetrexed after initial cisplatin and pemetrexed).[41]
  2. Three trials found statistically significantly improved PFS or time to progression with additional chemotherapy.[42–44]
  3. No consistent improvement in quality of life was reported.[43,45,46]
  4. Chemotherapy-related toxicities were greater with prolonged chemotherapy.[45,46]

These data suggest that PFS and OS for patients with nonsquamous NSCLC may be improved either by continuing an effective chemotherapy beyond four cycles or by immediate initiation of alternative chemotherapy. The improvement in PFS, however, is tempered by an increase in adverse events including additional cytotoxic chemotherapy and no consistent improvement in quality of life. For patients who have stable disease or who respond to first-line therapy, evidence does not support the continuation of combination cytotoxic chemotherapy until disease progression or the initiation of a different chemotherapy before disease progression. Collectively, these trials suggest that first-line cytotoxic combination chemotherapy should be stopped at disease progression or after four cycles in patients whose disease is not responding to treatment; it can be administered for no more than six cycles.[42,43,45,46] For patients with nonsquamous NSCLC who have a response or stable disease after four to six cycles of platinum combination chemotherapy, maintenance chemotherapy with pemetrexed should be considered.[41]

Evidence (first-line platinum-based combination chemotherapy followed by pemetrexed):

The findings of two randomized trials (NCT00102804 and NCT00789373) have shown improved outcomes with the addition of pemetrexed after standard first-line platinum-based combination chemotherapy.[44,47]

  1. In the first trial, 663 patients with stage IIIB/IV disease who had not progressed during four cycles of nonpemetrexed platinum–based chemotherapy were randomly assigned (in a 2:1 ratio) to receive pemetrexed or placebo until disease progression.[47]
    • Both the primary end point of PFS and the secondary end point of OS were statistically significantly prolonged with the addition of maintenance pemetrexed (median PFS, 4.3 months vs. 2.6 months; HR, 0.50; 95% CI, 0.42–0.61; P < .0001; median OS, 13.4 months vs. 10.6 months; HR, 0.79; 95% CI, 0.65–0.95; P = .012).
    • Benefit was not seen in patients with squamous histology.
    • Higher than grade 3 toxicity and treatment discontinuations that resulted from drug-related toxic effects were higher in the pemetrexed group than in the placebo group.
    • No pemetrexed-related deaths occurred.
    • Relatively fewer patients in the pemetrexed group than in the placebo group received systemic postdiscontinuation therapy (227 [51%] vs. 149 [67%]; P = .0001).
    • Quality of life during maintenance therapy with pemetrexed was similar to placebo, except for a small increase in loss of appetite and significantly delayed worsening of pain and hemoptysis as assessed using the Lung Cancer Symptom Scale.[48] The quality-of-life results require cautious evaluation because there was a high degree of censoring (>50%) with the primary quality-of-life end point, which was time to worsening of symptoms.
    • Trials have not evaluated maintenance pemetrexed versus pemetrexed at progression.
  2. In the second trial, 539 patients with nonsquamous NSCLC with nonprogression after treatment with pemetrexed and cisplatin were randomly assigned to continued pemetrexed or placebo.[44]
    • There was a statistically significant improvement in the primary end point of PFS (4.1 months vs. 2.8 months, HR, 0.62; 95% CI, 0.49–0.79) and in the secondary end point of OS (13.9 months vs. 11 months, HR, 0.78; 95% CI, 0.64–0.96).[41,44][Level of evidence B1]

EGFR tyrosine kinase inhibitors (TKIs) with or without chemotherapy (for patients with EGFR variants)

Select patients with activating EGFR variants may benefit from single-agent EGFR TKIs. Randomized controlled trials of patients with chemotherapy-naïve NSCLC and EGFR variants have shown that EGFR inhibitors alone improved both PFS and OS and have favorable toxicity profiles compared with combination chemotherapy. The combination of EGFR TKIs with chemotherapy showed improved PFS compared with EGFR TKI monotherapy and represents another treatment option.

Osimertinib alone

Evidence (osimertinib alone):

  1. A phase III, multicenter, randomized, double-blind, controlled trial (FLAURA [NCT02296125]) compared osimertinib, an oral, third-generation, irreversible EGFR TKI that inhibits both EGFR-TKI–sensitizing variants and the EGFR T790M resistance variant, with standard of care EGFR TKIs (gefitinib or erlotinib) as first-line treatment of patients with previously untreated, EGFR-positive (exon 19 deletion or L858R), advanced NSCLC, as detected by a U.S. Food and Drug Administration (FDA)-approved test.[49] The 556 patients were randomly assigned in a 1:1 ratio.
    • The primary end point of PFS was significantly longer with osimertinib (18.9 months vs. 10.2 months; HR, 0.46; 95% CI, 0.37–0.57, P < .001).[49][Level of evidence B1]
    • The objective response rate was similar for both groups (80% for the osimertinib group vs. 76% for the standard EGFR TKI group).
    • Central nervous system (CNS) progression was observed less often in the osimertinib group compared with the standard EGFR TKI group (6% vs. 15%).
    • The median duration of response (DOR) was 17.2 months (95% CI, 13.8–22.0) with osimertinib versus 8.5 months (95% CI, 7.3–9.8) with standard EGFR TKIs.
    • OS was a key secondary end point. With a follow-up of at least 39 months in each group, the median OS was 38.6 months (95% CI, 34.5–41.8) in the osimertinib group and 31.8 months (95% CI, 26.6–36.0) in the standard EGFR TKI group (HRdeath 0.80; 95.05% CI, 0.64–1.00; P = .046).[50][Level of evidence A1]
    • The crossover rate from the standard EGFR TKI group to the osimertinib group was 31% (85 of 277) among patients assigned to the standard EGFR TKI group and 47% (85 of 180) among patients discontinuing the EGFR TKI. The authors noted that this crossover probably contributed to the duration of OS in the EGFR TKI (31.8 months).
    • No new safety signals were observed. Rates of adverse events of grade 3 or higher and adverse events leading treatment discontinuations were similar between groups. Adverse events leading to dose interruptions, reductions, or permanent discontinuations were 43%, 5%, and 15%, respectively, in the osimertinib group and 41%, 4%, and 18%, respectively, in the EGFR TKI group.

The FDA approved osimertinib for first-line treatment of NSCLC with an EGFR variant (EGFR exon 19 deletion or EGFR L858R variant).

Longer PFS and OS, activity against the EGFR T790M variant and the EGFR-TKI−sensitizing variant, decreased frequency of CNS progression, and good tolerability make osimertinib the preferred choice for treatment of patients with advanced EGFR-positive NSCLC compared with first- and second-generation EGFR TKIs.

Osimertinib plus chemotherapy

Evidence (osimertinib plus chemotherapy):

  1. A multicenter, randomized, open-label, phase III trial (FLAURA2 [NCT04035486]) compared osimertinib plus chemotherapy with osimertinib alone in patients with advanced NSCLC and EGFR variants (EGFR exon 19 deletion or EGFR L858R variant). Patients had not previously received treatment for advanced disease. Patients received osimertinib (80 mg once daily) with chemotherapy (pemetrexed [500 mg/m2 of body-surface area] plus either cisplatin [75 mg/m2] or carboplatin [pharmacologically guided dose, area under the curve (AUC) = 5]) or osimertinib monotherapy (80 mg once daily). Chemotherapy in the combination arm was given for four 21-day cycles and was followed by osimertinib and pemetrexed (500 mg/m2) maintenance every 3 weeks. A total of 557 eligible patients were randomly assigned in a 1:1 ratio. The primary end point was investigator-assessed PFS.[51]
    • PFS was 25.5 months (24.7–not calculable) for patients in the osimertinib-plus-chemotherapy group and 16.7 months (14.1–21.3) for patients in the osimertinib-monotherapy group (HR, 0.62; 95% CI, 0.49–0.79; P < .001).[51][Level of evidence B1] PFS was assessed according to blinded independent central review and was consistent with the primary analysis (HR, 0.62; 95% CI, 0.48–0.80).
    • At 24 months, 57% (95% CI, 50%–63%) of the patients in the osimertinib-plus-chemotherapy group and 41% (95% CI, 35%–47%) of those in the osimertinib-alone group were alive and progression-free.
    • An objective response (complete or partial) occurred in 83% of patients who received osimertinib plus chemotherapy and 76% of patients who received osimertinib alone.
    • The median DOR was 24.0 months (95% CI, 20.9–27.8) in the osimertinib-plus-chemotherapy group and 15.3 months (95% CI, 12.7–19.4), in the osimertinib-alone group.
    • Grade 3 or higher adverse events from any cause were more common with the combination (64%) than with monotherapy (27%); this is consistent with known chemotherapy-related adverse events. Osimertinib plus pemetrexed with a platinum-based agent had a safety profile that was consistent with the established profiles of these agents.

    Analysis of OS, a secondary end point, requires further follow-up (data maturity, 27%).

Amivantamab plus lazertinib

The FDA previously approved amivantamab for patients with locally advanced or metastatic NSCLC and EGFR exon 20 insertions whose disease progressed during or after platinum-based chemotherapy. Lazertinib is a third-generation EGFR TKI.

Evidence (amivantamab plus lazertinib):

  1. The international phase III MARIPOSA trial (NCT04487080) included 1,074 patients with untreated advanced or metastatic NSCLC and EGFR variants (EGFR exon 19 deletion or EGFR L858R). Patients were randomly assigned in a 2:2:1 ratio to receive amivantamab plus lazertinib (429 patients, in an open-label fashion), osimertinib (429 patients, in a blinded fashion), or lazertinib (216 patients, in a blinded fashion). The primary end point of the study was PFS for the amivantamab-lazertinib group compared with the osimertinib group, as assessed by blinded independent central review. At a median follow-up of 22.0 months, the median duration of treatment was 18.5 months (range, 0.2–31.4) in the amivantamab-lazertinib group and 18.0 months (range, 0.2–32.7) in the osimertinib group.[52]
    • The median PFS was 23.7 months in the amivantamab-lazertinib group and 16.6 months in the osimertinib group (HRdisease progression or death, 0.70; 95% CI, 0.58–0.85; P < .001).[52][Level of evidence B1]
    • The objective response rate was 86% in the amivantamab-lazertinib group (95% CI, 83%–89%) and 85% in the osimertinib group (95% CI, 81%–88%).
    • The median DOR was 25.8 months (95% CI, 20.1–not estimable [NE]) in the amivantamab-lazertinib group and 16.8 months (95% CI, 14.8-18.5) in the osimertinib group.
    • The HRdeath was 0.80 (95% CI, 0.61–1.05).
    • The treatment discontinuation rate due to adverse events was 10% in the amivantamab-lazertinib group and 3% in the osimertinib group.

The FDA approved the amivantamab-lazertinib combination as first-line treatment for patients with locally advanced or metastatic NSCLC and EGFR exon 19 or EGFR L858R variants.

Dacomitinib

Evidence (dacomitinib):

  1. A multicenter open-label, phase III trial (ARCHER 1050 [NCT01774721]) compared dacomitinib, a second-generation, irreversible EGFR TKI, administered orally at a dose of 45 mg per day with gefitinib administered orally at a dose of 250 mg per day, as first-line therapy in patients with newly diagnosed advanced NSCLC and the following EGFR variants: EGFR exon 19 deletion or EGFR L858R variants, as detected by an FDA-approved test.[53] Four hundred and fifty-two eligible patients were randomly assigned in a 1:1 ratio. The primary end point was PFS assessed by masked independent review in the intention-to-treat (ITT) population.
    • Median PFS was 14.7 months in the dacomitinib group and 9.2 months in the gefitinib group (HR, 0.59; 95% CI, 0.47−0.74; P < .0001).[53][Level of evidence B1]
    • The objective response rate was similar between the two groups (75% for the dacomitinib group vs. 72% for the gefitinib group; P = 0.42).
    • The median DOR was longer in the dacomitinib group (14.8 months vs. 8.3 months; HR, 0.4; 95% CI, 0.31−0.53; P < .0001).
    • The median OS was 34.1 months with dacomitinib vs. 26.8 months with gefitinib (HR, 0.76; 95% CI, 0.58−0.99; P = .44).[53]
    • Grade 3 or higher adverse events of any cause occurred in 63% of patients who received dacomitinib and 41% of patients who received gefitinib. The most common grade 3 or 4 adverse events were dermatitis acneiform (14% in the dacomitinib group vs. none in the gefitinib group), diarrhea (8% vs. 1%), and raised alanine aminotransferase (ALT) levels (1% vs. 8%). Serious treatment-related adverse events were more frequent in the dacomitinib group (9% vs. 4%). Permanent discontinuation of the study drug because of treatment-related adverse events occurred more often in the dacomitinib group (10% vs. 7%). Dose reductions were also more frequent in the dacomitinib group (66% vs. 8%).

The FDA approved dacomitinib for first-line treatment of patients with metastatic NSCLC with EGFR exon 19 deletion or exon 21 L858R substitution variants as detected by an FDA-approved test.

Gefitinib

Evidence (gefitinib):

  1. A phase III, multicenter, randomized trial compared gefitinib with carboplatin plus paclitaxel as first-line treatment in clinically selected patients in East Asia who had advanced adenocarcinoma of the lung and had never smoked or were former light smokers.[54]
    • The study met its primary objective of demonstrating the superiority of gefitinib compared with the carboplatin-paclitaxel combination for PFS (HRprogression or death, 0.74; 95% CI, 0.65–0.85; P < .001).
    • The median PFS was 5.7 months in the gefitinib group and 5.8 months in the carboplatin-paclitaxel group.[54][Level of evidence B1]
    • Following the time that chemotherapy was discontinued and while gefitinib was continued, the PFS curves clearly separated and favored gefitinib.
    • The 12-month PFS rates were 24.9% with the gefitinib group and 6.7% with the carboplatin-paclitaxel group.
    • More than 90% of the patients in the trial with variants had either EGFR del19 or L858R variants, which have been shown to be sensitive to EGFR inhibitors. In the subgroup of patients with these variants, PFS was significantly longer among those who received gefitinib (HR, 0.48; 95% CI, 0.36–0.64; P < .001); however, in the subgroup of patients who were negative for EGFR variants, PFS was significantly longer in those who received the carboplatin-paclitaxel combination (HR with gefitinib, 2.85; 95% CI, 2.05–3.98; P < .001). There was a significant interaction between treatment and EGFR variants with respect to PFS (P < .001).[54]
    • OS was similar for patients who received gefitinib and carboplatin-paclitaxel, with no significant difference in treatments (HR, 0.90; 95% CI, 0.79–1.02; P = .109) or in EGFR variant–positive (HR, 1.00; 95% CI, 0.76–1.33; P = .990) or EGFR variant–negative (HR, 1.18; 95% CI, 0.86–1.63; P = .309; treatment by EGFR variant interaction P = .480) subgroups. A high proportion (64.3%) of EGFR variant–positive patients randomly assigned to the carboplatin-paclitaxel regimen received subsequent EGFR TKIs. PFS was significantly longer with gefitinib for patients who had both high EGFR gene copy number and EGFR variants (HR, 0.48; 95% CI, 0.34–0.67) but significantly shorter when high EGFR gene copy number was not accompanied by an EGFR variant (HR, 3.85; 95% CI, 2.09–7.09).
  2. A phase III trial from Japan prospectively confirmed that patients with NSCLC and EGFR variants have improved PFS but not OS when treated with gefitinib. The trial included 230 chemotherapy-naïve patients with metastatic NSCLC and EGFR variants who were randomly assigned to receive gefitinib or carboplatin-paclitaxel.[55]
    • In the planned interim analysis of data for the first 200 patients, PFS was significantly longer in the gefitinib group than in the standard-chemotherapy group (HRdeath or disease progression with gefitinib, 0.36; P < .001), resulting in early termination of the study.
    • The gefitinib group had a significantly longer median PFS (10.8 months vs. 5.4 months in the chemotherapy group; HR, 0.30; 95% CI, 0.22–0.41; P < .001).[55][Level of evidence B1] The median OS was 30.5 months in the gefitinib group and 23.6 months in the standard chemotherapy group (P = .31).
  3. Another phase III trial from Japan also prospectively confirmed that patients with NSCLC and EGFR variants have improved PFS but not OS when treated with gefitinib. In the second trial, the West Japanese Oncology Group conducted a phase III study (WJTOG3405) in 177 chemotherapy-naïve patients aged 75 years or younger and diagnosed with stage IIIB/IV NSCLC or postoperative recurrence and EGFR variants (either the EGFR exon 19 deletion or EGFR L858R single nucleotide variant). Patients were randomly assigned to receive either gefitinib or cisplatin plus docetaxel (given every 21 days for three to six cycles). The primary end point was PFS.[56]
    • The gefitinib group had significantly longer PFS than the cisplatin-plus-docetaxel group, with a median PFS of 9.2 months (95% CI, 8.0–13.9) versus 6.3 months (range, 5.8–7.8 months; HR, 0.489; 95% CI, 0.336–0.710; log-rank P < .0001).[56][Level of evidence B1]
Erlotinib

Evidence (erlotinib):

  1. An open-label phase III trial (NCT00874419) from China included 165 patients older than 18 years with histologically confirmed stage IIIB/IV NSCLC and confirmed activating EGFR variants (i.e., EGFR exon 19 deletion or EGFR L858R single nucleotide variant). Patients were randomly assigned to receive either oral erlotinib (150 mg/day) until they experienced disease progression or unacceptable toxic effects, or up to four cycles of gemcitabine plus carboplatin.[57]
    • The median PFS was significantly longer in patients who received erlotinib than in patients who received chemotherapy (13.1 months [95% CI, 10.58–16.53] vs. 4.6 months [range, 4.21–5.42 months]; HR, 0.16; 95% CI, 0.10–0.26; P < .0001).[57][Level of evidence B1]
  2. In a European study (EURTAC [NCT00446225]), 1,227 patients with advanced NSCLC were screened for EGFR variants. Of these, 174 patients with EGFR variants were randomly assigned to receive erlotinib or platinum-based chemotherapy.[58] The primary end point was PFS.
    • In an interim analysis of the first 153 patients, PFS in the chemotherapy arm was 5.2 months (95% CI, 4.5–5.8) compared with 9.7 months (95% CI, 8.4–12.3) in the erlotinib arm (HR, 0.37; P < .0001). Median survival was 19.3 months in patients in the chemotherapy arm and 19.5 months in patients in the erlotinib arm (HR, 0.80; P = .42).[59][Level of evidence B1]
Afatinib

Evidence (afatinib):

  1. An open-label, randomized, phase III study (LUX-Lung 3 [NCT00949650]) included 345 Asian (72%) and White (26%) patients with stage IIIB/IV NSCLC and confirmed EGFR variants (i.e., EGFR exon 19 deletion, EGFR L858R variant, or other [38 of 345 patients had other less-common EGFR variants]). Patients were screened, and 340 patients received at least one dose of study medication, which was either 40 mg of oral afatinib, an irreversible EGFR/human epidermal receptor TKI, daily or up to six cycles of cisplatin and pemetrexed for first-line treatment.[60]
    1. The primary end point was PFS. In this study, the afatinib group had significantly longer PFS than the cisplatin-plus-pemetrexed group, with a median PFS of 11.1 months for afatinib and 6.9 months for chemotherapy (HR, 0.58; 95% CI, 0.43–0.78; P = .001).[60][Level of evidence B1]
    2. Assessment of OS was a secondary end point and was reported separately.[61] Similar to the PFS analysis, OS was stratified based on EGFR variant type and the patient’s ethnic origin.
      • With a median follow-up of 41 months, median OS was 28.2 months in patients in both arms (HR, 0.88; 95% CI, 0.66–1.17; P = .39).
      • In patients with common EGFR variants (i.e., EGFR exon 19 deletion or EGFR L858R variant), survival did not differ significantly between treatment arms (HR, 0.78; 95% CI, 0.58–1.06; P = .11). However, prespecified subgroup analyses demonstrated a survival advantage with afatinib compared with chemotherapy in patients with EGFR del19 variants (median OS, 33.3 months vs. 21.1 months; HR, 0.54; 95% CI, 0.36–0.79; P = .0015) but no significant difference between treatment arms in patients with EGFR L858R variants (median OS, 27.6 months vs. 40.3 months; HR, 1.30; 95% CI, 0.80–2.11; P = .29).
      • First-line afatinib was associated with a significant survival advantage compared with chemotherapy in patients with NSCLC and EGFR del19 variants, but not in patients with EGFR L858R variants or in the overall EGFR-positive patient population.[61][Level of evidence A1]
  2. An open-label phase III study (LUX-Lung 6 [NCT01121393]) included 364 East Asian patients with stage IIIB/IV NSCLC and confirmed EGFR variants (i.e., EGFR exon 19 deletion, EGFR L858R variant, or other EGFR variants). Patients were randomly assigned in a 2:1 ratio to receive 40 mg of afatinib daily or gemcitabine and cisplatin for up to six cycles for first-line treatment.[62]
    1. The primary end point was PFS. Median PFS was significantly longer in the afatinib group (11.0 months; 95% CI, 9.7–13.7) than in the gemcitabine and cisplatin group (5.6 months, [range, 5.1–6.7 months]; HR, 0.28; 95% CI, 0.20–0.39; P < .0001).[62][Level of evidence B1]
    2. Assessment of OS was a prespecified secondary end point and was reported separately.[61] Similar to the PFS analysis, OS was stratified on the basis of EGFR variant type and the patient’s ethnic origin.
      • With a median follow-up of 33 months, median OS was 23.1 months in patients in the afatinib arm and 23.5 months in patients in the chemotherapy arm (HR, 0.93; 95% CI, 0.72–1.22; P = .61).
      • In patients with common EGFR variants (i.e., EGFR exon 19 deletion or EGFR L858R variant), survival did not differ significantly between treatment arms (HR, 0.83; 95% CI, 0.62–1.09; P = .18). However, prespecified subgroup analyses demonstrated a survival advantage with afatinib compared with chemotherapy in patients with EGFR del19 variants (median OS, 31.4 months vs. 18.4 months; HR, 0.64; 95% CI, 0.44–0.94; P = .023), but no significant difference between treatment arms was seen in patients with EGFR L858R variants (median OS, 19.6 months vs. 24.3 months; HR, 1.22; 95% CI, 0.81–1.83; P = .34).
      • First-line afatinib was associated with a significant survival advantage compared with chemotherapy in patients with NSCLC and EGFR del19 variants but not in patients with EGFR L858R variants or in the overall EGFR-positive patient population.[61][Level of evidence A1]

EGFR-directed therapy (for patients with EGFR exon 20 insertions)

Amivantamab

Amivantamab has been previously approved for patients with locally advanced or metastatic NSCLC and EGFR exon 20 insertions whose disease has progressed during or after platinum-based chemotherapy.

Evidence (amivantamab plus chemotherapy):

  1. PAPILLON (NCT04538664) was a phase III randomized trial that compared amivantamab plus chemotherapy with chemotherapy alone as first-line treatment for patients with advanced NSCLC and EGFR exon 20 insertions. Patients in the chemotherapy-alone group who had disease progression were allowed to cross over to receive amivantamab monotherapy. A total of 308 patients were randomly assigned 1:1 to receive either amivantamab plus carboplatin and pemetrexed or carboplatin plus pemetrexed. The primary end point was PFS according to blinded independent central review. The median follow-up was 14.9 months.[63][Level of evidence B1]
    • At 18 months, the PFS rate was 31% for patients who received amivantamab plus chemotherapy, and 3% for patients who received chemotherapy alone.
    • The objective response rate was higher in the amivantamab-plus-chemotherapy group (73%) than the chemotherapy-alone group (47%).
    • In an interim OS analysis, there was no statistically significant difference.
    • The most common adverse events with amivantamab plus chemotherapy were hematologic toxicities, rash, and paronychia. Infusion reactions occurred in 42% of patients.

    The study supports amivantamab plus chemotherapy as an effective first-line treatment option for patients with NSCLC and EGFR exon 20 insertions based on superior PFS when compared with chemotherapy alone.[63]

ALK inhibitors (for patients with ALK translocations)

Alectinib

Evidence (alectinib):

  1. In an open-label, randomized, phase III study (the ALEX trial [NCT02075840]), 303 patients with previously untreated, advanced ALK-rearranged NSCLC received either alectinib (600 mg twice a day) or crizotinib (250 mg twice a day).[64] The primary end point was investigator-assessed PFS.
    • The rate of PFS was significantly higher with alectinib than crizotinib; the 12-month event-free survival rate was 68.4% for the alectinib group (95% CI, 61.0%–75.9%) compared with 48.7% for the crizotinib group (95% CI, 40.4%–56.9%) (HR, 0.47; 95% CI, 0.34–0.65; P < .001). The median PFS was not reached with alectinib. The results of independent review committee-assessed PFS were consistent.[64][Level of evidence B1]
    • CNS progression events were less frequent with alectinib (12%) than with crizotinib (45%) (HR, 0.16; 95% CI, 0.10–0.28; P <.001).
    • The response rate was similar for both groups, 82.9% for the alectinib group compared with 75.5% for the crizotinib group (P = .09).
    • Grade 3 to 5 adverse events were less frequent with alectinib (41%) than with crizotinib (50%).
  2. A second, open-label, randomized, phase III trial (J-ALEX) recruited 207 ALK-inhibitor–naïve Japanese patients with ALK-positive NSCLC who were chemotherapy-naïve or had received one previous chemotherapy regimen. Patients were randomly assigned in a 1:1 ratio to receive alectinib (300 mg twice daily, which is the dose approved in Japan and is lower than the 600 mg twice daily dose approved elsewhere) versus crizotinib (250 mg twice daily).[65] The primary end point was PFS-assessed by an independent review committee.
    • At data cutoff for the second primary interim analysis, the independent data monitoring committee determined that the primary end point was met (HR, 0.34; 99.7% CI, 0.17–0.71; P <.0001) and recommended immediate release of the data. Median PFS had not been reached with alectinib but was reached at 10.2 months with crizotinib.
    • Grade 3 or 4 adverse events occurred less frequently with alectinib (26% occurrence rate) than with crizotinib (52% occurrence rate).
Lorlatinib

Evidence (lorlatinib):

  1. The phase III CROWN trial (NCT03052608) included patients with advanced ALK-rearranged NSCLC who had received no prior systemic therapy for metastatic disease. The trial randomly assigned 296 patients to receive either lorlatinib (100 mg daily) or crizotinib (250 mg twice daily). The primary end point was PFS as determined by blinded independent central review.[66][Level of evidence B1]
    • With a median follow-up of 60.2 months, the median PFS was not reached (NR) (95% CI, 64.3–NR) in patients who received lorlatinib. With a median follow-up of 55.1 months, the median PFS was 9.1 months (95% CI, 7.4–10.9) in patients who received crizotinib (HR, 0.19; 95% CI, 0.13–0.27).[67]
    • The 5-year PFS rate was 60% (95% CI, 51%–68%) in patients who received lorlatinib and 8% (95% CI, 3%–14%) in patients who received crizotinib.
    • The median time to intracranial progression was not reached (95% CI, NR–NR) in the lorlatinib group and was 16.4 months (95% CI, 12.7–21.9) in the crizotinib group (HR, 0.06; 95% CI, 0.03–0.12).
    • Lorlatinib was associated with more grade 3 to 4 adverse events than crizotinib (72% vs. 56%), the most common being altered lipid levels. Treatment discontinuation occurred in 7% of patients who received lorlatinib and 9% of patients who received crizotinib.[66]

The FDA approved lorlatinib for patients with metastatic NSCLC whose tumors are ALK-positive, as detected by an FDA-approved test.

Crizotinib

Evidence (crizotinib):

  1. In an open-label, randomized, phase III study, 343 patients with stage IIIB/IV NSCLC harboring translocations in ALK received either 250 mg of crizotinib orally twice a day or the combination of pemetrexed and cisplatin or carboplatin for up to six cycles.[68] At the time of disease progression, patients on the chemotherapy arm were allowed to cross over to crizotinib; 60% of patients in the chemotherapy arm subsequently received crizotinib. The primary end point of this study was PFS.
    • The study met its primary end point and demonstrated that crizotinib is superior to chemotherapy in prolonging PFS (median, 10.9 months vs. 7.0 months; HR, 0.454; 95% CI, 0.346–0.596; P < .0001).[69][Level of evidence B1]
Ceritinib

Evidence (ceritinib):

  1. In an open-label, randomized, phase III study, 376 patients with stage IIIB/IV ALK-rearranged nonsquamous NSCLC received either oral ceritinib 750 mg daily or platinum-based chemotherapy (cisplatin or carboplatin and pemetrexed) every 3 weeks for four cycles, followed by maintenance pemetrexed.[70] The primary end point was PFS and crossover from chemotherapy to ceritinib was allowed upon documented progression.
    • Median PFS, assessed by blinded independent review, was 16.6 months in the ceritinib group and 8.1 months in the chemotherapy group (HR, 0.55; 95% CI, 0.42–0.73; P < .00001).
    • The median OS was not reached with ceritinib, and it was 26.2 months with chemotherapy (HR, 0.73; 95% CI, 0.50–1.08; P = .056).[70][Level of evidence B1]
Brigatinib

Evidence (brigatinib):

  1. A phase II, open-label trial (NCT02094573) enrolled 222 patients with ALK-translocated locally advanced or metastatic NSCLC who had disease progression after crizotinib treatment. Patients were randomly assigned to receive 90 mg every day (n = 112; 109 treated) or 180 mg every day with a 7-day lead-in at 90 mg every day (n = 110).[71]
    • The primary end point assessed by the investigators was objective response rate. The objective response rate was 45% (97.5% CI, 34%–56%) for patients who received the 90 mg dose and 54% (97.5% CI, 43%–65%) for patients who received the 180 mg dose.
    • Median PFS was 9.2 months (95% CI, 7.4–15.6) for patients who received the 90 mg dose and 12.9 months (95% CI, 11.1–NR) for patients who received the 180 mg dose.
    • At data cutoff, the median DOR was 13.8 months (95% CI, 5.6–13.8) for patients who received the 90 mg dose and 11.1 months (95% CI, 9.2–13.8) for patients who received the 180 mg dose.[71][Level of evidence B3]
    • The CNS objective response rate in patients with measurable CNS lesions was 42% in patients who received 90 mg every day (n = 26) and 67% in patients who received 180 mg every day (n = 18).
    • Common adverse events, which were mainly grade 1 or 2 and occurred in 27% to 38% of patients at the higher dose, were nausea, diarrhea, headache, and cough. A subset of pulmonary adverse events with early onset (median onset, day 2) occurred in 14 of 219 treated patients (all grades, 6%; grade ≥3, 3%); none occurred after escalation to 180 mg. These events included dyspnea, hypoxia, cough, pneumonia, or pneumonitis. They were managed with dose interruption. Seven of the 14 patients were successfully retreated with brigatinib.
    • The FDA-approved dose of brigatinib is 90 mg every day for 7 days; if tolerated, the dose is increased to 180 mg every day.

BRAF V600E and MEK inhibitors (for patients with BRAF V600E variants)

BRAF V600E variants occur in 1% to 2% of lung adenocarcinomas.

Dabrafenib and trametinib

Evidence (dabrafenib and trametinib):

  1. In a phase II, multicenter, nonrandomized, open-label study (NCT01336634), 36 patients with previously untreated metastatic NSCLC who tested positive for BRAF V600E variants were treated with dabrafenib (a BRAF inhibitor) 150 mg twice a day and trametinib (a MEK inhibitor) 2 mg every day.[72] BRAF V600E variants were identified by the Oncomine Dx Target Test (ThermoFisher Scientific). The primary end point was investigator-assessed overall response.
    • The overall response rate was 64% (95% CI, 46%–79%). Six percent of patients had a complete response, and 58% of patients had a partial response.
    • The median investigator-assessed PFS was 10.9 months (95% CI, 7.0–16.6). The estimated median DOR was 10.4 months (95% CI, 8.3–17.9). At data cutoff, 47% of patients had died, and the median OS was 24.6 months (95% CI, 12.3–NE).
    • Sixty-nine percent of patients had at least one grade 3 or 4 adverse event, of which the most common were pyrexia, ALT increase, hypertension, or vomiting. Adverse events led to permanent discontinuation in 22% of patients, dose interruption or delay in 75% of patients, and dose reduction in 39% of patients.[72][Level of evidence C3]

The FDA approved the combination of dabrafenib and trametinib in the treatment of patients with NSCLC and BRAF V600E variants as detected by an FDA-approved test.

ROS1 inhibitors (for patients with ROS1 rearrangements)

ROS1 rearrangements occur in approximately 1% to 2% of patients with NSCLC.[73] ROS1 TKI therapy is the current standard of care for patients with locally advanced or metastatic NSCLC and a ROS1 variant. Crizotinib, entrectinib, and repotrectinib are all approved by the FDA for patients with NSCLC and ROS1 fusions. Notably, repotrectinib is the only ROS1 TKI that is approved by the FDA for patients previously treated with a ROS1 TKI. Entrectinib and repotrectinib have both shown intracranial activity, while repotrectinib also appears to be active in patients with known ROS1 resistance variants, including G2032R.

Entrectinib

The FDA approved entrectinib for treatment of patients with metastatic NSCLC and ROS1 variants.

Evidence (entrectinib):

  1. The safety and clinical activity of entrectinib in ROS1 fusion–positive metastatic NSCLC was determined by integrated analysis of three multicenter, single-arm, open-label clinical trials (ALKA-372-001/EudraCT, 2012-000148-88, STARTRK-1 [NCT02097810], and STARTRK-2 [NCT02568267]).[74] Entrectinib was given orally at a dose of at least 600 mg once daily. Primary end points were objective response rate and the DOR determined by blinded independent central review. Of note, time-to-event end points are difficult to interpret in the absence of a control arm. Evaluation of tumor samples for the ROS1 gene fusion was conducted prospectively in local laboratories using either a FISH or next-generation sequencing (NGS) laboratory-developed test.

    Seventeen (32%) patients had received no previous systemic therapy, 23 (43%) had received one previous therapy, and 13 (25%) had received two or more lines of treatment. CNS disease was present in 23 (43%) patients at baseline. Thirty-one (59%) patients were never-smokers and 52 (98%) patients had adenocarcinoma histology.

    • The objective response rate in 53 efficacy-evaluable patients was 77% (95% CI, 64%−88%). Six percent of patients had a complete response and 72% had a partial response. Among patients with CNS disease at baseline, the objective response rate was 74% (95% CI, 52%−90%) and all patients had a partial response. Among patients without CNS disease at baseline, the overall response rate was 80% (95% CI, 61%−92%) (10% had a complete response and 70% had a partial response).[74][Level of evidence C3]
    • The median DOR was 24.6 months (95% CI, 11.4−34.8) in efficacy-evaluable patients; 12.6 months (95% CI, 6.5−NE) in patients with baseline CNS disease, and 24.6 months (95% CI, 11.4−34.8) in those without CNS disease at baseline.
    • Treatment-related adverse events were assessed in 134 patients in the safety-evaluable population. Grade 1 or 2 treatment-related adverse events were observed in 79 patients (59%). Grade 3 or 4 treatment-related adverse events were observed in 46 patients (34%). Fifteen patients (11%) had serious treatment-related adverse events. There were no treatment-related deaths.
    • The median PFS was 19 months (95% CI, 12.2−36.6) in efficacy-evaluable patients; 13.6 months (95% CI, 4.5−NE) in patients with baseline CNS disease, and 26.3 months (95% CI, 15.7−36.6) in patients with no baseline CNS disease.
Crizotinib

Crizotinib is approved by the FDA for patients with metastatic NSCLC and ROS1 variants.

Evidence (crizotinib):

  1. In an expansion cohort of a phase I study of crizotinib, 50 patients with advanced NSCLC who tested positive for ROS1 rearrangement were treated with oral crizotinib 250 mg twice daily.[75] ROS1 rearrangements were identified using break-apart FISH or reverse transcriptase−polymerase chain reaction assay. Seven patients (14%) had not had any previous treatment for advanced disease, 21 patients (42%) had one prior treatment, and 22 patients (44%) had more than one prior treatment. The primary end point was response rate.
    • The overall response rate was 72% (95% CI, 58%–84%). Six percent of patients had a complete response, 66% had a partial response, and 18% had stable disease as their best response.
    • Median PFS was 19.2 months (95% CI, 14.4–NR). The estimated DOR was 17.6 months (95% CI, 14.5–NR).[75][Level of evidence C3]
  2. In a phase II, open-label, single-arm trial, 127 East Asian patients with ROS1-positive NSCLC were treated with crizotinib 250 mg twice daily.[76] Twenty-four patients (18.9%) had not had any previous treatment for advanced disease, 53 patients (41.7%) had one previous treatment, and 50 patients (39%) had two or three previous treatments. The primary end point was objective response rate by independent review.
    • The objective response rate was 71.7% (95% CI, 63.0%–79.3%). Response rates were similar, irrespective of the number of previous therapies. Complete responses occurred in 13.4% of patients, while 58.3% of patients had partial responses, and 16.5% of patients had stable disease as their best response.[76][Level of evidence C3]
    • Median PFS was 15.9 months (95% CI, 12.9–24). The DOR was 19.7 months (95% CI, 14.1–NR).
    • OS was 32.5 months (95% CI, 32.5–NR).
Repotrectinib (for both ROS1 TKI-naïve and ROS1 TKI-treated patients)

Repotrectinib is approved by the FDA for patients with locally advanced or metastatic ROS1 fusion–positive NSCLC. This approval specifically includes patients who have previously received a ROS1 TKI.[77]

Evidence (repotrectinib for both ROS1 TKI-naïve and ROS1 TKI-treated patients):

  1. The phase I/II, single-arm TRIDENT-1 trial (NCT03093116) evaluated the safety and efficacy of repotrectinib in patients with advanced solid tumors with ALK, ROS1, NTRK1, NTRK2, or NTRK3 rearrangements. In total, 352 patients with ROS1 fusion–positive NSCLC were assigned to one of four cohorts based on previous exposure to a ROS1 TKI (yes vs. no) and/or to chemotherapy or immunotherapy (yes vs. no). The primary efficacy end point was objective response rate in two cohorts (n = 127): patients who had not previously received either a ROS1 TKI or chemotherapy/immunotherapy and patients who had previously received one ROS1 TKI but had not received chemotherapy/immunotherapy. Secondary end points included PFS, DOR, OS, and intracranial response.[78]
    • Among ROS1 TKI-naïve patients (n = 71), the objective response rate was 79% (95% CI, 68%–88%). Among patients who had received one prior ROS1 TKI and never received chemotherapy/immunotherapy (n = 56), the objective response rate was 38% (95% CI, 25%–52%). Responses were seen in six of eight pretreated patients with detectable TKI-resistance variants.[78][Level of evidence C3]
    • Among ROS1 TKI-naïve patients, the median PFS was 35.7 months (95% CI, 27.4–NE), and the median DOR was 34.1 months (95% CI, 26–NE). Among ROS1 TKI-treated patients, the median PFS was 9.0 months (95% CI, 6.8–19.6) and the median DOR was 14.8 months (95% CI, 7.6–NE). The median time to response was 1.8 months in both cohorts.
    • Among all patients with advanced solid tumors treated at the phase II recommended dose (n = 426), adverse events of grade 3 or higher occurred in 29% of patients. The most common grade 3 or higher adverse events were anemia (4%) and increased blood creatine kinase (4%). Adverse events led to dose reductions in 38% of patients, dose interruptions in 50% of patients, and treatment discontinuation in 7% of patients.

NTRK inhibitors (for patients with NTRK fusions)

Somatic gene fusions in NTRK occur across a range of solid tumors including in fewer than 0.5% of NSCLC tumors.[79,80] These fusions appear to occur more frequently in nonsmokers with lung adenocarcinoma.

Larotrectinib

Evidence (larotrectinib):

  1. Larotrectinib was studied in three protocols: a phase I study involving adults, a phase I/II study involving children, and a phase II study involving adolescents and adults.[81] Fusions were confirmed in the tumors using either FISH or NGS methods. The primary end point for the combined analysis was objective response rate by independent review and was conducted with input from regulators with the goal of excluding a lower bound of less than 30% for response rate. In total, 55 patients with a median age of 45 years (range, 4 months‒76 years) were enrolled across 17 different NTRK fusion-positive tumor types. All patients had either metastatic disease (82%) or locally advanced unresectable disease (18%). Enrolled patients had received a median of two previous systemic therapies.
    • The objective response rate was 75% (95% CI, 61%‒75%) and 73% of these responses lasted at least 6 months.[81][Level of evidence C3]
    • Treatment was well tolerated with 93% of adverse events being grade 1 to 2; the most common grade 3 to 4 adverse events were anemia (11% of patients), transaminitis (7%), and neutropenia (7%).

The FDA approved larotrectinib for the treatment of patients with locally advanced or metastatic tumors and NTRK gene fusions without a known acquired resistance variant, and who have no satisfactory alternative treatments or whose cancer has progressed following treatment.

Entrectinib

The FDA granted accelerated approval to entrectinib for the treatment of solid tumors that have an NTRK gene fusion without a known acquired resistance variant, are metastatic, have progressed after treatment, have no satisfactory alternative therapy, or for cases in which surgical resection is likely to result in severe morbidity.

Evidence (entrectinib):

  1. The safety and clinical activity of entrectinib in NTRK inhibitor-naïve patients with metastatic or locally-advanced solid tumors (including NSCLC) and NTRK1, NTRK2, or NTRK3 gene fusions was determined by integrated analysis of three early-phase, multicenter, single-arm, open-label clinical trials (ALKA-372-001/EudraCT, 2012-000148-88, STARTRK-1 [NCT02097810], and STARTRK-2 [NCT02568267]).[82] Treatment consisted of entrectinib administered orally at a dose of at least 600 mg once per day. The primary end points were objective response rate and median DOR, which were assessed by blinded independent central review. Of note, time-to-event end points are difficult to interpret in the absence of a control arm. Identification of positive NTRK gene fusion status was conducted prospectively in local laboratories or a central laboratory using various nucleic acid–based tests.

    Of 54 patients in the NTRK gene fusion–positive efficacy-evaluable population, 20 (37%) had received no previous systemic therapy, 11 (20%) had received one previous systemic therapy, and 23 (43%) had received two or more systemic therapies. Twelve (22%) patients had CNS disease at baseline. Ten (19%) patients had NSCLC. Fifty-two (96%) patients had NTRK gene fusions detected by NGS and 2 (4%) had NTRK gene fusions detected by other nucleic acid–based tests.

    • The objective response rate in 54 patients was 57% (95% CI, 43.2%−70.8%). Seven percent of patients had a complete response and 50% had a partial response. In patients with baseline CNS disease, 50% achieved a response (all partial responses), whereas in patients without baseline CNS disease, 60% achieved a response (10% complete response; 50% partial response).[82][Level of evidence C3]
    • The median DOR in efficacy-evaluable patients was 10.4 months (95% CI, 7.1−NE). In patients with baseline CNS disease DOR was not estimable, and in patients with no baseline CNS disease it was 12.9 months (95% CI, 7.1−NE).
    • Among 10 patients with NSCLC, the response rate was 70% (95% CI, 35%−93%) and DOR ranged between 1.9 months and 20.1 months. For more information, see the prescribing information.
    • The safety-evaluable population consisted of 68 patients with NTRK fusion–positive tumors. Most treatment-related adverse events were grade 1 or 2 and reversible. The most frequent grade 3 or 4 treatment-related adverse events were increased weight gain (10%) and anemia (12%). Serious treatment-related adverse events were reported in 7 (10%) patients. Three (4%) patients had dose interruptions and 27 (40%) patients had dose reductions due to treatment-related adverse events. There were no treatment-related deaths.
    • Median PFS was 11.2 months (95% CI, 8.0−14.9). In patients with baseline CNS disease, median PFS was 7.7 months (95% CI, 4.7−NE), and it was 12 months (95% CI, 8.7−15.7) in patients with no baseline CNS disease.

RET inhibitors (for patients with RET fusions)

Somatic gene fusions of RET occur in 1% to 2% of patients with NSCLC and in patients with thyroid cancer.[83]

Selpercatinib

Evidence (selpercatinib):

  1. A phase I/II study (LIBRETTO-001 [NCT03157128]) enrolled patients with RET fusion−positive solid tumors. RET fusion status was determined by local molecular testing (NGS, FISH, or polymerase chain reaction assay) without central confirmation. The primary end point was objective response.[84][Level of evidence C3]
    • Updated analysis was conducted in 316 patients with RET fusion–positive NSCLC.[84]
    • Among the 69 treatment-naïve patients, the objective response rate was 84% (95% CI, 73%–92%), and 6% achieved complete responses. The median DOR was 20.2 months (95% CI, 13.0–could not be evaluated); 40% of responses were ongoing at the data cutoff (median follow-up, 20.3 months). The median PFS was 22.0 months; 35% of patients were alive and progression-free at the data cutoff (median follow-up, 21.9 months).
    • Among the 247 patients who had received prior platinum-based chemotherapy, the objective response rate was 61% (95% CI, 55%–67%), and 7% achieved complete responses. The median DOR was 28.6 months (95% CI, 20.4–could not be evaluated); 49% of responses were ongoing (median follow-up, 21.2 months). The median PFS was 24.9 months; 38% of patients were alive and progression-free at the data cutoff (median follow-up, 24.7 months).
    • Among the 26 patients with measurable baseline CNS metastasis by the independent review committee, the intracranial objective response rate was 85% (95% CI, 65%–96%), and 27% had complete responses.
    • In the full safety population (n = 796), the median treatment duration was 36.1 months.
    • There was no significant change in the safety profile. Most adverse events were grade 1 to 2. The most common adverse events were edema, diarrhea, fatigue, dry mouth, hypertension, increased ALT and aspartate aminotransferase (AST), and rash.

The FDA approved selpercatinib to treat adults with locally advanced or metastatic NSCLC with RET gene fusions, as detected by an FDA-approved test.

Pralsetinib

Evidence (pralsetinib):

  1. A phase I/II study (ARROW [NCT03037385]) enrolled patients with RET fusion−positive solid tumors. Two hundred thirty-three patients had RET fusion−positive NSCLC. RET fusion status was determined by local molecular testing of tumor or circulating tumor nucleic acid (ctDNA) in blood, without central confirmation. The primary end point was objective response.[85][Level of evidence C3]
    • Ninety-two patients who had received platinum-based chemotherapy and 29 patients who were treatment-naïve (and not candidates for standard platinum-based treatment) received pralsetinib before the efficacy enrollment cutoff (July 11, 2019). Eighty-seven previously treated patients and 27 treatment-naïve patients had centrally adjudicated baseline measurable disease, and thus formed the efficacy cohort.
    • The overall response rate was 61% (95% CI, 50%–71%) in the 87 patients who had received platinum-based chemotherapy, including complete responses in 6%. The median DOR was not reached (15.2 months–NE).
    • The overall response rate was 70% (95% CI, 50%–86%) in the 27 treatment-naïve patients, including complete responses in 11%. The median DOR was 9.0 months (6.3–NE).
    • In the 233-patient safety cohort, 93% had treatment-related adverse events, including 48% with grade 3 or worse events. The most common grade 3 or worse treatment-related adverse events were neutropenia (18%), hypertension (11%), and anemia (10%). Dose reductions occurred in 38% of patients, and 6% discontinued treatment because of adverse events.

MET inhibitors (for patients with MET exon 14-skipping variants)

Dysregulation of the MET proto-oncogene resulting from disruption of distinct splice sites leads to loss of MET exon 14 and enhanced MET signaling. These MET variants drive tumor proliferation, survival, invasion, and metastasis, and occur in 3% to 4% of patients with NSCLC.[86]

Tepotinib

Evidence (tepotinib):

  1. An open-label phase II study (VISION [NCT02864992]) enrolled patients with MET exon 14-skipping variants. The trial included 152 patients who received tepotinib (500 mg orally once daily). MET status was determined centrally, either via liquid biopsy (from circulating free DNA obtained from plasma; n = 66) or via tissue biopsy (n = 60). Twenty-seven patients had positive results from both methods. The primary end point was objective response.[87][Level of evidence C3]
    • Among the 99 patients who had been followed for at least 9 months (i.e., the efficacy population), the objective response rate as assessed by independent review was 46% (95% CI, 36%–57%), with a median DOR of 11.1 months (95% CI, 7.2–NE). Response rates were similar in the liquid biopsy and tissue biopsy groups.
    • Responses were similar regardless of prior therapy.
    • Grade 3 or higher adverse events occurred in 28% of patients, including peripheral edema in 7% of patients. Adverse events led to therapy discontinuation in 11% of patients.
Capmatinib

Evidence (capmatinib):

  1. A phase II study (GEOMETRY [NCT02414139]) evaluated capmatinib (400 mg orally twice daily) in patients with MET exon 14-skipping variants or MET amplification. MET status was performed centrally. A total of 373 patients were enrolled and treated. Of those patients, 160 had NSCLC with MET exon 14-skipping variants. Patients were assigned to cohorts based on MET status and previous treatments (cohorts 1a–7). There were 60 treatment-naïve patients (cohorts 5b and 7) and 100 previously treated patients (cohorts 4 and 6). The primary end point was overall response rate.[88][Level of evidence B3]
    • The overall median follow-up was 46.4 months (interquartile range [IQR], 41.8–65.4) for treatment-naïve patients and 66.9 months (IQR, 56.7–73.9) for previously treated patients.
    • The overall response rate was 68% (95% CI, 55.0%–79.7%) in treatment-naïve patients and 44% (95% CI, 34.1%–54.3%) in previously treated patients.
    • The most common treatment-related adverse events were peripheral edema (n = 174; 47%), nausea (n = 130; 35%), increased blood creatinine (n = 78; 21%), and vomiting (n = 74; 20%). Grade 3 to 4 serious adverse events occurred in 44% of patients, with dyspnea as the most common (occurring in 5% of patients).

    The FDA approved capmatinib for patients with metastatic NSCLC and MET exon 14-skipping variants.

Immune checkpoint inhibitors with or without chemotherapy

Pembrolizumab is a humanized monoclonal antibody that inhibits the interaction between the programmed death protein 1 (PD-1) coinhibitory immune checkpoint expressed on tumor cells and infiltrating immune cells and its ligands, PD-L1 and PD-L2.[89]

Pembrolizumab plus chemotherapy

Evidence (pembrolizumab plus chemotherapy):

  1. A phase III double-blind trial (KEYNOTE-189 [NCT02578680]) randomly assigned, in a 2:1 ratio, 616 patients with metastatic nonsquamous NSCLC without sensitizing EGFR variants or ALK rearrangements who had received no previous treatment for metastatic disease. Patients received pemetrexed and a platinum-based drug plus either 200 mg of pembrolizumab or placebo every 3 weeks for 4 cycles, followed by pembrolizumab or placebo for up to a total of 35 cycles plus pemetrexed maintenance.[1] Crossover to pembrolizumab monotherapy was permitted after verified progression among patients in the placebo-containing combination group. The primary end points were OS and PFS as assessed by blinded independent central committee radiological review.
    • In the 5-year updated analysis, the median time from random assignment to data cutoff was 64.6 months (range, 60.1–72.4).[90]
    • After 5 years, pembrolizumab plus pemetrexed-platinum was associated with improved OS and PFS, compared with placebo plus pemetrexed-platinum in patients with metastatic nonsquamous NSCLC, regardless of PD-L1 expression. In the ITT population, 5-year OS rates were 19.4% in the pembrolizumab plus pemetrexed-platinum group, compared with 11.3% in the placebo plus pemetrexed-platinum group.
    • Survival was higher in patients with a higher PD-L1 tumor proportion score (TPS), especially in the TPS >50% subgroup (29.6% vs. 21.4%).
    • There were 57 patients who completed 35 cycles of pembrolizumab. For these patients, the objective response rate was 86.0% and the 3-year OS rate after completing 35 cycles (approximately 5 years after random assignment) was 71.9%.[90]
    • Immune-mediated adverse events and infusion reactions occurred in 113 (27.9%) and 27 (13.4%) patients.
    • Adverse events of grade 3 or higher occurred with similar frequency in both treatment groups (71.9% in the pembrolizumab combination group vs. 66.8% in the placebo combination group).
  2. A phase III, randomized, double-blind study (KEYNOTE-407 [NCT02775435]) included previously untreated patients with metastatic squamous cell NSCLC. Patients were randomly assigned 1:1 to receive pembrolizumab 200 mg or placebo plus carboplatin and paclitaxel/nab-paclitaxel once every 3 weeks for four cycles, followed by pembrolizumab or placebo for up to 35 cycles (pembrolizumab-plus-chemotherapy, n = 5,278; placebo-plus-chemotherapy, n = 5,281). Primary end points were OS and PFS per RECIST version 1.1 by blinded independent central review.[91]
    • The median time from random assignment to data cutoff was 56.9 months (range, 49.9–66.2). OS and PFS were improved with pembrolizumab-plus-chemotherapy versus placebo-plus-chemotherapy (HR, 0.71 [0.59–0.85] and 0.62 [0.52–0.74]), respectively; 95% CI). The 5-year OS rates were 18.4% and 9.7%, respectively.[91][Level of evidence A1]
    • A total of 55 patients completed 35 cycles of pembrolizumab. The objective response rate was 90.9% and the 3-year OS rate after completion of 35 cycles (approximately 5 years after random assignment) was 69.5%.
Pembrolizumab alone

Evidence (pembrolizumab alone):

  1. A phase III open-label study (KEYNOTE-024) randomly assigned 305 patients with previously untreated, advanced NSCLC with PD-L1 expression on 50% or more tumor cells and no sensitizing EGFR variants or ALK translocations to either intravenous pembrolizumab (200 mg every 3 weeks for up to 35 cycles) or platinum-based chemotherapy (four to six cycles, investigator’s choice; pemetrexed maintenance was allowed for nonsquamous tumors).[89] The primary end point was PFS.
    1. PD-L1 expression was centrally assessed using the PD-L1 immunohistochemistry 22C3 pharmDx assay. PD-L1 tumor expression of 50% or more was found in 30.2% of 1,653 patient samples that were examined.
    2. Pembrolizumab demonstrated significant improvement in median PFS (10.3 months vs. 6.0 months; HR, 0.50; 95% CI, 0.37–0.68; P < .001). The overall response rate (44.8% vs. 27.8%), the median DOR (NR, [range, 1.9–14.5 months] vs. 6.3 months [range, 2.1–12.6 months]), and the estimated rate of OS at 6 months (80.2% vs. 72.4%; HR, 0.60; 95% CI, 0.41–0.89; P = .005) were all higher with pembrolizumab than with chemotherapy.
    3. Further follow-up of this study confirmed an OS advantage in favor of pembrolizumab; the median OS for patients who received pembrolizumab was 30 months (95% CI, 18.3 months–NR) versus 14.2 months for patients who received chemotherapy, with a 75% crossover to immunotherapy afterwards, suggesting the crossover did not impact survival.[92]
    4. Adverse events (any grade) were less frequent with pembrolizumab than with chemotherapy (73.4% vs. 90.0%).
      • Grade 3 to 5 adverse events occurred in 26.6% of patients treated with pembrolizumab and 53.3% of patients treated with chemotherapy.
      • Grade 3 or 4 immune-related events occurred in 9.7% of patients treated with pembrolizumab and 0.7% of patients treated with chemotherapy.
      • The most common grade 3 or 4 immune-related events associated with pembrolizumab were severe skin reactions (3.9%), pneumonitis (2.6%), and colitis (1.3%).
      • There were no grade 5 immune-related events.
    5. Pembrolizumab treatment demonstrated significant improvement in PFS, OS, and DOR with less frequent adverse events compared with chemotherapy treatment.[89][Level of evidence B1]
  2. A phase III open-label study (KEYNOTE-042 [NCT02220894]) included patients with locally advanced or metastatic NSCLC without EGFR or ALK alterations and with a PD-L1 TPS score of greater than 1%. Patients were randomly assigned to receive either pembrolizumab 200 mg once every 3 weeks for 35 cycles or chemotherapy (carboplatin plus paclitaxel or pemetrexed) for four to six cycles with optional maintenance pemetrexed (pembrolizumab, n = 637; chemotherapy, n = 637). The primary end points were OS in the populations with a PD-L1 TPS greater than 50%, greater than 20%, and greater than 1%.[93]
    1. The median follow-up was 61.1 months (range, 50.0–76.3).
    2. OS outcomes favored pembrolizumab versus chemotherapy, regardless of the PD-L1 TPS.
      • The HR was 0.68 (95% CI, 0.57–0.81) for the TPS >50% group, 0.75 (95% CI, 0.64–0.87) for the TPS >20% group, and 0.79 (95% CI, 0.70–0.89) for the TPS >1% group.
      • The OS rates for patients who received pembrolizumab were 21.9% (TPS >50%), 19.4% (TPS >1%), and 16.6% (TPS >1%).
    3. The most common adverse reactions reported in at least 10% of patients who received pembrolizumab as a single agent in KEYNOTE-042 included fatigue, decreased appetite, dyspnea, cough, rash, constipation, diarrhea, nausea, hypothyroidism, pneumonia, pyrexia, and weight loss.

The FDA approved pembrolizumab in combination with pemetrexed and carboplatin as first-line treatment of patients with metastatic nonsquamous NSCLC, regardless of PD-L1 expression. The FDA also approved pembrolizumab as a first-line monotherapy for patients with NSCLC whose tumors express PD-L1 (>1%) (staining as determined by an FDA-approved test). Patients with EGFR or ALK genomic tumor aberrations should have disease progression while receiving FDA-approved therapies before receiving pembrolizumab (see the FDA label for pembrolizumab).

Cemiplimab-rwlc plus chemotherapy

Evidence (cemiplimab-rwlc plus chemotherapy):

  1. A phase III, double-blind, placebo-controlled trial (EMPOWER-Lung 3 [NCT03409614]) examined cemiplimab-rwlc plus platinum-doublet chemotherapy in 466 patients with stage III or IV advanced NSCLC. Patients had not received previous chemotherapy and had no EGFR, ALK, or ROS1 genomic tumor aberrations. Patients were randomly assigned (2:1) to receive cemiplimab-rwlc 350 mg (n = 312) or placebo (n = 154) every 3 weeks for up to 108 weeks along with four cycles of platinum-doublet chemotherapy. Patients also received pemetrexed maintenance as indicated. The primary end point was OS. The trial met preset OS efficacy criteria and was stopped early on the recommendation of the independent data monitoring committee.[94][Level of evidence A1]
    • The median OS was 21.9 months (95% CI, 15.5–not evaluable [NE]) in the cemiplimab-rwlc-plus-chemotherapy group and 13 months (95% CI, 11.9–16.1) in the placebo-plus-chemotherapy group (HR, 0.71; 95% CI, 0.53–0.93; P = .014).
    • The secondary end point of median PFS was 8.2 months (95% CI, 6.4–9.3) in the cemiplimab-rwlc-plus-chemotherapy group and 5.0 months (95% CI, 4.3–6.2) in the placebo-plus-chemotherapy group (HR, 0.56; 95% CI, 0.44–0.70; P < .0001).
    • Another secondary end point, the estimated proportion of patients alive at 12 months, was 65.7% (95% CI, 59.9%–70.9%) in the cemiplimab-rwlc-plus-chemotherapy group and 56.1% (95% CI, 47.5%–63.8%) in the placebo-plus-chemotherapy group.
    • Grade 3 or greater adverse events occurred in 43.6% (136 of 312) of patients who received cemiplimab-rwlc plus chemotherapy and 31.4% (48 of 153) of patients who received placebo plus chemotherapy.
    • The most common (≥15%) adverse reactions were alopecia, musculoskeletal pain, nausea, fatigue, peripheral neuropathy, and decreased appetite.

The FDA approved cemiplimab-rwlc in combination with platinum-based chemotherapy for adult patients with advanced NSCLC and no EGFR, ALK, or ROS1 aberrations.

Cemiplimab-rwlc alone

Evidence (cemiplimab-rwlc alone):

  1. A phase III open-label study (EMPOWER-Lung 1 [NCT03088540]) enrolled 710 patients with advanced NSCLC and PD-L1 tumor expression of at least 50%. Patients were randomly assigned (1:1) to receive cemiplimab-rwlc 350mg every 3 weeks for up to 108 weeks or platinum-doublet chemotherapy. Patients could cross over from chemotherapy to cemiplimab-rwlc in the event of disease progression. There was also the option to cross over to continue cemiplimab-rwlc plus four cycles of chemotherapy in the event of progression with cemiplimab alone. Primary end points were OS and PFS per blinded independent central review. The median follow-up was 37 months for the ITT population.[95,96][Level of evidence A1]
    • At 35 months of follow-up, in patients with PD-L1 expression ≥50%, the median OS was 26.1 months with cemiplimab-rwlc and 13.3 months with chemotherapy (HR, 0.57; P < .0001).
    • The median PFS was 8.1 months for patients who received cemiplimab-rwlc and 5.3 months for patients who received chemotherapy (HR, 0.51; P < .0001).
    • The objective response rate was 46% for patients who received cemiplimab-rwlc and 21% for patients who received chemotherapy (OR, 3.264; P < .0001).
    • Benefits were greater in patients with PD-L1 expression ≥90% versus 50% to 89%.
    • Among 64 patients who received cemiplimab-rwlc plus chemotherapy after initial progression while receiving cemiplimab-rwlc alone, the median PFS was 6.6 months, the objective response rate was 31%, and the OS was 15.1 months.
    • The most common adverse reactions (>10%) with cemiplimab-rwlc were musculoskeletal pain, rash, anemia, fatigue, decreased appetite, pneumonia, and cough. The safety profile of cemiplimab-rwlc was consistent over longer follow-up.

The FDA approved cemiplimab-rwlc for patients with advanced NSCLC (locally advanced who are not candidates for surgical resection or definitive chemoradiation or metastatic) and PD-L1 tumor expression of at least 50% with no EGFR, ALK, or ROS1 genomic aberrations.

Tremelimumab

Tremelimumab is a fully human monoclonal antibody against cytotoxic T-lymphocyte associated antigen 4 (CTLA-4). It is an immune checkpoint blocker.

Durvalumab plus tremelimumab plus chemotherapy

Evidence (durvalumab plus tremelimumab plus chemotherapy):

  1. POSEIDON (NCT03164616), a phase III open-label trial, studied tremelimumab plus durvalumab and chemotherapy, durvalumab plus chemotherapy, and chemotherapy alone as first-line therapy in patients with metastatic NSCLC. The primary end points were PFS and OS for durvalumab plus chemotherapy versus chemotherapy. Key alpha-controlled secondary end points were PFS and OS for tremelimumab plus durvalumab and chemotherapy versus chemotherapy. Patients were randomly assigned (1:1:1) to one of the following three arms:[97][Level of evidence B1]
    1. Arm 1: Tremelimumab 75 mg plus durvalumab 1,500 mg with platinum-based chemotherapy for up to four 21-day cycles followed by durvalumab once every 4 weeks until progression and one additional tremelimumab dose at week 16.
    2. Arm 2: Durvalumab plus chemotherapy for up to four 21-day cycles followed by durvalumab once every 4 weeks until progression.
    3. Arm 3: Platinum-based chemotherapy for up to six 21-day cycles (with or without maintenance pemetrexed).

    The following results were observed:

    • Treatment with durvalumab significantly improved PFS compared with chemotherapy alone. The median PFS was 5.5 months for patients who received durvalumab plus chemotherapy and 4.8 months for patients who received chemotherapy alone (HR, 0.74; 95% CI, 0.62–0.89; P = .0009).
    • A trend for improved OS did not reach statistical significance for patients in arms 2 and 3. The median OS was 13.3 months for patients who received durvalumab plus chemotherapy and 11.7 months for patients who received chemotherapy alone. (HR, 0.86; 95% CI, 0.72–1.02; P = .0758). The 24-month OS rate was 29.6% in the durvalumab-plus-chemotherapy arm and 22.1% in the chemotherapy-alone arm.
    • Both PFS and OS were significantly improved when tremelimumab therapy was added to durvalumab and chemotherapy compared with chemotherapy alone. The median PFS was 6.2 months for patients who received tremelimumab plus durvalumab and chemotherapy and 4.8 months for patients who received chemotherapy alone (HR, 0.72; 95% CI, 0.60–0.86; P = .0003). The median OS was 14.0 months in the tremelimumab arm and 11.7 months in the chemotherapy-alone arm (HR, 0.77; 95% CI, 0.65–0.92; P = .0030). The 24-month OS rate was 32.9% in the tremelimumab-plus durvalumab-and-chemotherapy arm and 22.1% in the chemotherapy-alone arm. In addition, this combination demonstrated consistent OS results across levels of PD-L1 expression.
    • Grade 3 to 4 treatment-related events occurred in 51.8% of patients who received tremelimumab plus durvalumab and chemotherapy, 14.1% of patients who received durvalumab and chemotherapy, and 9.9% of patients who received chemotherapy alone.

The FDA approved tremelimumab in combination with durvalumab and platinum-based chemotherapy for adult patients with metastatic NSCLC with no sensitizing EGFR or ALK genomic tumor aberrations. The approval is based on a comparison of treatment arms one and three.

Atezolizumab alone

Evidence (atezolizumab alone):

  1. A phase III open-label study (IMpower110 [NCT02409342]) included 572 patients with previously untreated metastatic nonsquamous or squamous NSCLC. Patients had PD-L1 expression on at least 1% of tumor cells or on at least 1% of tumor-infiltrating immune cells. Patients were randomly assigned to receive either atezolizumab (1,200 mg intravenously) or platinum-based chemotherapy (4 or 6 cycles) once every 3 weeks. The primary end point was OS in the PD-L1–selected population that excluded sensitizing EGFR variants or ALK translocations.[98][Level of evidence A1]
    • PD-L1 expression was assessed by the SP142 immunohistochemical assay. High expression was defined as more than 50% of tumor cells or more than 10% of tumor-infiltrating immune cells expressing PD-L1.
    • In the 205 patients with high PD-L1 expression, the median OS was 20.2 months for patients who received atezolizumab and 13.1 months for patients who received chemotherapy (HRdeath, 0.59; P = .01).
    • Grade 3 to 4 adverse events occurred in 30.1% of patients who received atezolizumab and 52.5% of patients who received chemotherapy.

Atezolizumab monotherapy is approved for first-line treatment of patients with high PD-L1 expression (PD-L1 staining ≥50% of tumor cells or PD-L1 stained tumor-infiltrating immune cells covering ≥10% of the tumor area), as determined by an FDA-approved test, in the absence of EGFR or ALK genomic aberrations.

Atezolizumab plus chemotherapy

Evidence (atezolizumab in combination with carboplatin and nab-paclitaxel chemotherapy):

  1. A phase III open-label study (IMpower130 [NCT02367781]) included 724 patients with previously untreated, stage IV, nonsquamous NSCLC. Patients were randomly assigned 2:1 to receive atezolizumab (1,200 mg intravenously every 3 weeks) plus chemotherapy (carboplatin, AUC 6 mg/mL per minute every 3 weeks with nab-paclitaxel 100 mg/m2 intravenously every week), or chemotherapy alone given once every 3 weeks for four or six cycles. All patients received maintenance therapy as follows: (1) patients in the atezolizumab-plus-chemotherapy group received atezolizumab 1,200 mg intravenously every 3 weeks until investigator-assessed loss of clinical benefit or toxicity, and (2) patients in the chemotherapy-alone group received best supportive care or pemetrexed switch maintenance therapy until disease progression or toxicity. Coprimary end points were investigator-assessed PFS and OS in the ITT population with EGFR wild-type and ALK wild-type tumors.[99][Level of evidence A1]
    • In the ITT wild-type population, the median OS was 18.6 months (95% CI, 16.0–21.2) in the atezolizumab-plus-chemotherapy group and 13.9 months (95% CI, 12.0–18.7) in the chemotherapy group (stratified HR, 0.79; 95% CI, 0.64–0.98; P = .033).
    • The median PFS was 7 months (95% CI, 6.2–7.3) in the atezolizumab-plus-chemotherapy group and 5.5 months (95% CI, 4.4–5.9) in the chemotherapy group (stratified HR, 0.64; 95% CI, 0.54–0.77; P < .0001).
    • Subgroup analyses showed OS and PFS benefit with atezolizumab across several clinical subgroups, with the exception of patients with liver metastases where the additional of atezolizumab did not improve OS versus chemotherapy alone, and for patients with EGFR and ALK genomic alterations.
    • OS and PFS benefit with atezolizumab was also observed in the ITT wild-type population independent of PD-L1 expression.
    • Grade 3 or 4 adverse events occurred in 81% of patients who received atezolizumab plus chemotherapy versus 71% of patients who received chemotherapy alone. Immune-related adverse events occurred in 45% of patients treated with atezolizumab plus chemotherapy and most were grade 1 or 2 in severity. The most common immune-related adverse events were rash (24%), hypothyroidism (15%), and hepatitis (10%).

Atezolizumab in combination with nab-paclitaxel and carboplatin is approved for the first-line treatment of patients with metastatic nonsquamous NSCLC with no EGFR or ALK genomic aberrations.

Atezolizumab plus bevacizumab plus chemotherapy

Evidence (atezolizumab in combination with carboplatin, paclitaxel, and bevacizumab):

  1. In a phase III open-label study (IMpower150 [NCT02366143]),1,202 patients with stage IV or recurrent metastatic nonsquamous NSCLC were randomly assigned in a 1:1:1 ratio to receive either atezolizumab plus carboplatin plus paclitaxel (ACP group), atezolizumab plus bevacizumab plus carboplatin plus paclitaxel (ABCP group), or bevacizumab plus carboplatin plus paclitaxel (BCP group). Treatment consisted of four or six 21-day cycles. Atezolizumab was given intravenously at a dose of 1,200 mg, bevacizumab at a dose of 15 mg per kilogram of body weight, carboplatin at an area under the concentration-time curve of 6 mg/mL per minute and paclitaxel at a dose of 200 mg/m2 (175 mg/m2 for Asian patients). Patients continued to receive atezolizumab, bevacizumab, or both until disease progression or development of intolerable toxicity. Coprimary end points were PFS, both in the ITT population with EGFR wild-type and ALK wild-type tumors and among patients with wild-type tumors who had high expression of an effector T-cell (Teff) gene signature in the tumor, and OS in the wild-type population.[100][Level of evidence A1]
    • Median PFS was longer in the ABCP group (8.3 months) than the BCP group (6.8 months) (HR, 0.62; 95% CI, 0.52–0.74; P < .001). In the Teff-high wild-type population, PFS was 11.3 months versus 6.8 months (HR, 0.51; 95% CI, 0.38–0.68; P .001). PFS was also longer in the ABCP group versus the BCP group in the ITT population with EGFR and ALK genomic alterations, among patients with low or negative PD-L1 expression, low Teff gene-signature expression, and in patients with liver metastases.
    • Median OS among patients with wild-type tumors was longer in the ABCP group (19.2 months), compared with the BCP group (14.7 months) (HR, 0.78; 95% CI, 0.64–0.96; P = .02).
    • Grade 3 or 4 treatment-related adverse events occurred in 56% of patients in the ABCP group versus 48% of patients in the BCP group. Most immune-related adverse events in the ABCP group were grade 1 or 2, and rash, hypothyroidism, hyperthyroidism, hepatitis, pneumonitis, and colitis were most common. Treatment-related deaths occurred in 11 patients (2.8%) in the ABCP group and 9 patients (2.3%) in the BCP group. Five deaths in the ABCP group were caused by pulmonary hemorrhage or hemoptysis, and four of five occurred in patients with high-risk features, including tumors infiltrating great vessels or tumor cavitation.

Atezolizumab in combination with bevacizumab, paclitaxel, and carboplatin is approved for the first-line treatment of patients with metastatic nonsquamous NSCLC with no EGFR or ALK genomic aberrations.

Nivolumab plus ipilimumab

Nivolumab, a fully human anti–PD-1 antibody, and ipilimumab, a fully human anti–CTLA-4 antibody, are immune checkpoint inhibitors with distinct but complementary mechanisms of action.[101]

Evidence (nivolumab plus ipilimumab):

  1. A phase III open-label study (CheckMate 227 [NCT02477826]) evaluated nivolumab in combination with ipilimumab versus chemotherapy as first-line treatment for stage IV or recurrent NSCLC without sensitizing EGFR variants or ALK translocations. Patients (n = 1,739) were grouped by PD-L1 tumor status (either ≥1% or <1%). Patients with PD-L1 expression of at least 1% were randomly assigned to receive either nivolumab (3 mg/kg every 2 weeks) plus ipilimumab (1 mg/kg every 6 weeks), nivolumab (240 mg every 2 weeks) alone, or platinum-doublet chemotherapy every 3 weeks for up to four cycles. Patients with PD-L1 expression less than 1% were randomly assigned to receive nivolumab with ipilimumab, nivolumab with platinum-doublet chemotherapy, or platinum-doublet chemotherapy (every 3 weeks). Patients were treated until disease progression or unacceptable toxicity or up to 2 years for immunotherapy. Coprimary end points were OS with nivolumab-plus-ipilimumab compared with chemotherapy in patients with tumor PD-L1 expression of at least 1%, and PFS with nivolumab-plus-ipilimumab compared with chemotherapy in patients with high tumor mutational burden (TMB) (≥10 mutations per megabase).[2,102][Level of evidence A1]
    • Among patients with tumor PD-L1 ≥1% (n = 1,189), the median OS was 17.1 months (95% CI, 15.0–20.2) with nivolumab-plus-ipilimumab and 14.9 months (95% CI, 12.7–16.7) with chemotherapy (HR, 0.77; 95% CI, 0.66–0.91; P = .007). Five-year outcomes with nivolumab-plus-ipilimumab versus chemotherapy showed durable clinical benefit, with an OS rate of 24% with nivolumab-plus-ipilimumab and 14% for chemotherapy alone.[101]
    • In patients with TMB-high NSCLC, the median PFS was 7.2 months (95% CI, 5.5–13.2) with nivolumab-plus-ipilimumab, versus 5.5 months (95% CI, 4.4–5.8) with chemotherapy alone (HR, 0.58; 97.5% CI, 0.41–0.81; P < .001).
    • Among patients with tumor PD-L1 <1% (n = 550), the median OS was 17.4 months (95% CI, 13.2–22.0) with nivolumab-plus-ipilimumab, and 12.2 months (95% CI, 9.2–14.3) with chemotherapy alone (HR, 0.65; 95% CI, 0.52–0.81). Five-year outcomes with nivolumab-plus-ipilimumab versus chemotherapy alone showed durable clinical benefit, with an OS rate of 19% for nivolumab-plus-ipilimumab and 7% for chemotherapy alone.[101]
    • The frequency of grade 3 to 4 treatment-related adverse events was similar in both groups (32.8% with nivolumab-plus-ipilimumab vs. 36.0% with chemotherapy alone). Treatment-related adverse events leading to therapy discontinuation were more common with nivolumab-plus-ipilimumab than with chemotherapy alone (24.5% vs. 13.9%).
    • Treatment-related deaths occurred in eight patients who received nivolumab-plus-ipilimumab (pneumonitis in four patients; shock, myocarditis, acute tubular necrosis, and cardiac tamponade in one patient each) and in six patients who received chemotherapy (sepsis in two patients; febrile neutropenia, multifocal brain infarctions, interstitial lung disease, and thrombocytopenia in one patient each).

The FDA approved nivolumab-plus-ipilimumab as first-line therapy for patients with advanced NSCLC with PD-L1 expression of at least 1% and no EGFR or ALK genomic aberrations. While this regimen is not FDA-approved for patients with PD-L1 expression less than 1%, these patients were noted to have durable clinical benefit in CheckMate 227.

mTOR inhibitors

Everolimus

Everolimus is used for patients with unresectable, locally advanced or metastatic, progressive, well-differentiated, nonfunctional, neuroendocrine tumors.

Everolimus, an oral mTOR inhibitor, is clinically active against advanced pancreatic and nonpancreatic neuroendocrine tumors.[103] Based on the results of the RADIANT-4 clinical trial,[103] the FDA approved everolimus for the treatment of adult patients with unresectable, locally advanced or metastatic, progressive, well-differentiated (low or intermediate grade), nonfunctional neuroendocrine tumors of lung or gastrointestinal origin.

Evidence (everolimus):

  1. A randomized, double-blind, placebo-controlled, phase III trial (RADIANT-4 [NCT01524783]) evaluated everolimus in patients older than 18 years with advanced, progressive, well-differentiated, nonfunctional neuroendocrine tumors of lung or gastrointestinal origin.[103] Eligible patients were randomly assigned in a 2:1 ratio to received everolimus 10 mg daily orally or placebo, both with best supportive care. A total of 302 patients were enrolled (205 in the everolimus arm and 97 in the placebo arm), including 90 patients with neuroendocrine tumors of lung origin (63 in the everolimus arm and 27 in the placebo arm). The primary end point was PFS assessed by central radiology review in the ITT population.
    • Median PFS was 11.0 months in the everolimus arm and 3.9 months in the placebo group (HR, 0.48; 95% CI, 0.35−0.67; P < .00001).[103][Level of evidence B1]
    • In a post hoc analysis of the lung subgroup, median PFS by central review was 9.2 months in the everolimus arm and 3.6 months in the placebo arm (HR, 0.50; 95% CI, 0.28−0.88).[103]
    • The objective response rate was 2% in patients who received everolimus and 1% in patients who received placebo. Disease stabilization was observed in 81% of patients in the everolimus arm and 64% of patients in the placebo arm.
    • The median duration of treatment was longer in the patients who received everolimus compared with those who received placebo (40.4 weeks vs. 19.6 weeks).
    • A planned interim analysis of OS showed a 36% reduction in the estimated risk of death with everolimus relative to placebo (HR, 0.64; 95% CI, 0.40−1.05). These results were not statistically significant.
    • The most common treatment-related adverse events were stomatitis, diarrhea, fatigue, infections, rash, and peripheral edema. The most common drug-related grade 3 or 4 adverse events were stomatitis, diarrhea, infections, anemia, and fatigue. Grade 3 or 4 adverse events resulted in treatment discontinuation in 12% of patients in the everolimus group and 3% of patients in the placebo group.

Local therapies and special considerations

Endobronchial laser therapy and/or brachytherapy (for obstruction lesions)

Radiation therapy may be effective in palliating symptomatic patients with local involvement of NSCLC with any of the following:

  • Tracheal, esophageal, or bronchial compression.
  • Pain.
  • Vocal cord paralysis.
  • Hemoptysis.
  • Superior vena cava syndrome.

In some cases, endobronchial laser therapy and/or brachytherapy have been used to alleviate proximal obstructing lesions.[20]

EBRT (primarily for palliation of local symptomatic tumor growth)

Although EBRT is frequently prescribed for symptom palliation, there is no consensus on which fractionation scheme should be used. Although different multifraction regimens appear to provide similar symptom relief,[104–109] single-fraction radiation may be insufficient for symptom relief compared with hypofractionated or standard regimens, as evidenced in the NCT00003685 trial.[21][Level of evidence A3] Evidence of a modest increase in survival in patients with a better performance status given high-dose radiation therapy is available.[23,110][Level of evidence A1] In closely observed asymptomatic patients, treatment may often be appropriately deferred until symptoms or signs of a progressive tumor develop.

Evidence (radiation therapy):

  1. A systematic review identified six randomized trials of high-dose rate endobronchial brachytherapy (HDREB) alone or with EBRT or laser therapy.[111]
    • Better overall symptom palliation and fewer re-treatments were required in previously untreated patients using EBRT alone.[111][Level of evidence A3]
    • HDREB provided palliation of symptomatic patients with recurrent endobronchial obstruction previously treated by EBRT, when it was technically feasible.
Treatment of second primary tumor

A solitary pulmonary metastasis from an initially resected bronchogenic carcinoma is unusual. The lung is frequently the site of second primary malignancies in patients with primary lung cancers. Whether the new lesion is a new primary cancer or a metastasis may be difficult to determine. Studies have indicated that in most patients the new lesion is a second primary tumor, and after its resection, some patients may achieve long-term survival. Thus, if the first primary tumor has been controlled, the second primary tumor should be resected, if possible.[112,113]

Treatment of brain metastases

Patients who present with a solitary cerebral metastasis after resection of a primary NSCLC lesion and who have no evidence of extracranial tumor can achieve prolonged disease-free survival with surgical excision of the brain metastasis and postoperative whole-brain radiation therapy.[114,115] Unresectable brain metastases in this setting may be treated with stereotactic radiosurgery.[116]

Approximately 50% of patients treated with resection and postoperative radiation therapy will develop recurrence in the brain; some of these patients will be suitable for additional treatment.[117] In those selected patients with good performance status and without progressive metastases outside of the brain, treatment options include reoperation or stereotactic radiation surgery.[116,117] For most patients, additional radiation therapy can be considered; however, the palliative benefit of this treatment is limited.[118][Level of evidence C2]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References
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Lung Cancer—Health Professional Version

Lung Cancer—Health Professional Version

Treatment

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Supportive & Palliative Care

We offer evidence-based supportive and palliative care information for health professionals on the assessment and management of cancer-related symptoms and conditions.

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Kidney Cancer in Children (PDQ®)–Patient Version

Kidney Cancer in Children (PDQ®)–Patient Version

What is kidney cancer in children?

Kidney cancer occurs when cells in one or both kidneys start to grow without control and form a tumor. There are many types of kidney tumors that can occur in children and adolescents. Some are benign (not cancer), and others are cancerous. Most kidney tumors in children are cancer. Even though benign tumors don’t spread like cancer, they can affect a child’s health and kidney function. Treatment is usually needed for benign and cancerous tumors.

The kidneys are two bean-shaped organs located on either side of the spine, just above the waist. Their main job is to remove waste and extra fluids from the body to make urine:

  • Tiny tubules in the kidneys filter and clean the blood.
  • Urine passes from each kidney through a thin tube called a ureter into the bladder.
  • The bladder stores the urine until it leaves the body through a tube called the urethra.
EnlargeAnatomy of the urinary system; drawing showing the right and left kidneys, the ureters, the bladder filled with urine, and the urethra. The inside of the left kidney shows the renal pelvis. An inset shows the renal tubules and urine. The spine and adrenal glands are also shown.
Anatomy of the urinary system showing the kidneys, ureters, bladder, and urethra. The inside of the left kidney shows the renal pelvis. An inset shows the renal tubules and urine. Also shown is the spine and adrenal glands. Urine is made in the renal tubules and collects in the renal pelvis of each kidney. The urine flows from the kidneys through the ureters to the bladder. The urine is stored in the bladder until it leaves the body through the urethra.

Symptoms of kidney cancer in children

Sometimes childhood kidney cancer causes symptoms. But sometimes a parent finds a tumor in the abdomen by chance. Or a doctor finds a tumor during a well-child health check-up. It’s important to check with your child’s doctor if your child has:

  • a lump, swelling, or pain in the abdomen
  • blood in the urine
  • back pain
  • fever for no known reason
  • weight loss for no known reason
  • infection
  • anemia
  • hypercalcemia with symptoms of loss of appetite, nausea and vomiting, weakness, or feeling very tired

These symptoms may also be caused by other problems. The only way to know is for your child to see a doctor.

Tests to diagnose kidney cancer in children

If your child has symptoms that suggest kidney cancer, the doctor will need to find out if these are due to cancer or another problem. The doctor will ask when the symptoms started and how often your child has been having them. The doctor will also ask about your child’s personal and family medical history and do a physical exam. Depending on these results, they may recommend other tests. If your child is diagnosed with kidney cancer, the results of these tests will help plan treatment.

The tests used to diagnose kidney cancer may include:

Complete blood count (CBC)

A CBC checks a sample of blood for:

Blood chemistry studies

Blood chemistry studies use a blood sample to measure the amounts of certain substances released into the blood by organs and tissues. An unusual amount of a substance can be a sign that the liver and kidneys are not working as they should.

Renal function test

A renal function test uses blood or urine samples to measure the amounts of certain substances released into the blood or urine by the kidneys. An unusual amount of a substance can be a sign that the kidneys are not working as they should.

Urinalysis

A urinalysis checks the color of urine and its contents, such as sugar, protein, blood, and bacteria.

Ultrasound exam

Ultrasound exam uses high-energy sound waves that bounce off internal tissues or organs and make echoes. The echoes form a picture of body tissues called a sonogram.

EnlargeAbdominal ultrasound; drawing shows a child lying on an exam table during an abdominal ultrasound procedure. A technician is shown pressing a transducer (a device that makes sound waves that bounce off tissues inside the body) against the skin of the abdomen. A computer screen shows a sonogram (picture).
Abdominal ultrasound. An ultrasound transducer connected to a computer is pressed against the skin of the abdomen. The transducer bounces sound waves off internal organs and tissues to make echoes that form a sonogram (computer picture).

CT scan (CAT scan)

CT scan uses a computer linked to an x-ray machine to make a series of detailed pictures of areas inside the body, such as the chest, abdomen, and pelvis. The pictures are taken from different angles and are used to create 3-D views of tissue and organs. A dye is injected into a vein or swallowed to help the organs or tissues show up more clearly. This procedure is also called computed tomography, computerized tomography, or computerized axial tomography. Learn more about Computed Tomography (CT) Scans and Cancer.

EnlargeComputed tomography (CT) scan; drawing shows a child lying on a table that slides through the CT scanner, which takes a series of detailed x-ray pictures of areas inside the body.
Computed tomography (CT) scan. The child lies on a table that slides through the CT scanner, which takes a series of detailed x-ray pictures of areas inside the body.

Magnetic resonance imaging (MRI) with gadolinium

MRI uses a magnet, radio waves, and a computer to make a series of detailed pictures of areas inside the body, such as the abdomen or pelvis. A substance called gadolinium is injected into a vein. The gadolinium collects around the cancer cells so they show up brighter in the picture. This procedure is also called nuclear magnetic resonance imaging (NMRI).

EnlargeMagnetic resonance imaging (MRI) scan; drawing shows a child lying on a table that slides into the MRI machine, which takes a series of detailed pictures of areas inside the body.
Magnetic resonance imaging (MRI) scan. The child lies on a table that slides into the MRI machine, which takes a series of detailed pictures of areas inside the body. The positioning of the child on the table depends on the part of the body being imaged.

X-ray

An x-ray is a type of radiation that can go through the body and make pictures of areas inside the body.

PET-CT Scan

PET-CT scan combines the pictures from a positron emission tomography (PET) scan and a computed tomography (CT) scan. The PET and CT scans are done at the same time on the same machine. The combined scans make more detailed pictures than either test would make by itself.

  • For the PET scan, a small amount of radioactive sugar (also called radioactive glucose) is injected into a vein. The PET scanner rotates around the body and makes a picture of where sugar is being used in the body. Cancer cells show up brighter in the picture because they are more active and take up more sugar than normal cells.
  • For the CT scan (CAT scan), a series of detailed x-ray pictures of areas inside the body is taken from different angles to create 3-D views of tissues and organs. A dye may be injected into a vein or swallowed to help the organs or tissues show up more clearly. Learn more about Computed Tomography (CT) Scans and Cancer.

Biopsy

Biopsy is the removal of a sample of cells or tissue from the tumor so that a pathologist can view it under a microscope to check for cancer. Whether your child will have a biopsy is based on:

  • The size of the tumor.
  • The stage of the cancer. There will not be a biopsy if the tumor looks like it can be removed with surgery or it is stage 1 or stage 2. The reason for not doing a biopsy is to avoid the spread of tumor cells during the procedure.
  • Whether cancer is in one or both kidneys.
  • Whether imaging tests clearly show the cancer.

Your child may have a biopsy before they receive any treatment, after chemotherapy to shrink the tumor, or during surgery to remove the tumor.

Getting a second opinion

You may want to get a second opinion to confirm your child’s diagnosis and treatment plan. If you seek a second opinion, you will need to get medical test results and reports from the first doctor to share with the second doctor. The second doctor will review the pathology report, slides, and scans. They may agree with the first doctor, suggest changes to the treatment plan, or provide more information about your child’s tumor.

To learn more about choosing a doctor and getting a second opinion, visit Finding Cancer Care. You can contact NCI’s Cancer Information Service via chat, email, or phone (both in English and Spanish) for help finding a doctor or hospital that can provide a second opinion. For questions you might want to ask at your child’s doctor visits, visit Questions to Ask Your Doctor about Cancer. 

Genetic counseling for children with kidney cancer

If your child is diagnosed with kidney cancer, it may not be clear from the family medical history whether it was caused by an inherited condition that increased their risk. Genetic counseling can assess the likelihood that your child’s cancer is inherited and whether genetic testing is needed. Genetic counselors and other specially trained health professionals can discuss your child’s diagnosis and your family’s medical history to help you understand the:

Genetic counselors can also help you cope with your child’s genetic testing results. This can include how to discuss the results with family members. They can advise you about whether other members in your family should receive genetic testing.

Learn more about genetic testing at Genetic Testing for Inherited Cancer Risk.

Stages of kidney cancer in children

After your child is diagnosed with kidney cancer, they will be referred to a pediatric oncologist. This is a doctor who specializes in staging and treating cancer in children.

Staging is the process of learning the extent of the cancer in the body. Sometimes cancer is found only in the kidney. Or, it may have spread to other parts of the body. The doctor will recommend tests to see if the cancer has spread, and if so, how far.

To learn about the TNM staging system used for adults and children with renal cell cancer, visit Stages of Renal Cell Cancer.

To learn more about the Children’s Oncology Group staging system used for rhabdoid tumor of the kidney, clear cell sarcoma of the kidney, or anaplastic sarcoma of the kidney, visit Stages of Wilms tumor.

When kidney cancer comes back after treatment, it is called recurrent kidney cancer. If there are signs that the cancer has returned, your child will have tests to find out where the cancer is in your child’s body and if it has spread. The type of treatment will depend on the type of kidney cancer and where in the body it has come back.

Types of kidney cancer in children

There are many types of kidney cancer that occur in children. The type of kidney cancer is often based on how the cancer cells look under a microscope, certain genetic changes that may be present in the tumor, and other tests.

Wilms tumor

Wilms tumor is the most common kidney cancer in children younger than 15 years. It can occur in one or both kidneys. This cancer can spread to the lungs, liver, bone, brain, or nearby lymph nodes. Learn more at Wilms Tumor.

Renal cell cancer (RCC)

Renal cell cancer is the most common type of kidney cancer in adolescents aged 15 to 19 years and in adults. This cancer is rare in children younger than 15 years. RCC is often diagnosed at a later stage in children and adolescents. When the cancer is found, it may already have spread to the lungs, liver, bone, brain, or lymph nodes.

Renal medullary cancer is a rare subtype of renal cell cancer that grows and spreads quickly.

Causes and risk factors for RCC

Childhood RCC is caused by certain changes in the way kidney cells function, especially how they grow and divide into new cells. The exact cause of these changes is often unknown. Learn more about how cancer develops at What Is Cancer?

A risk factor is anything that increases the chance of getting a disease. Not every child with one or more of these risk factors will develop RCC. And it will develop in some children who don’t have a known risk factor.

RCC may be related to certain inherited conditions or prior cancer treatment, such as chemotherapy or radiation therapy for childhood cancers like neuroblastoma, soft tissue sarcoma, leukemia, or Wilms tumor.

Inherited conditions linked to RCC include:

  • Von Hippel-Lindau disease (VHL), an inherited condition that can increase the risk of kidney tumors
  • tuberous sclerosis, a genetic disorder that causes fatty cysts in the kidney and other parts of the body
  • familial RCC, a condition that occurs when certain changes in the genes that cause kidney cancer are passed down from the parent to the child
  • sickle cell hemoglobinopathy, a genetic disorder that causes sickle cell disease and may be associated with renal medullary cancer (a rare subtype of renal cell carcinoma)
  • hereditary leiomyomatosis, an inherited disorder that increases the risk of having cancer of the kidney, skin, and uterus

Talk with your child’s doctor if you think your child may be at risk.

Monitoring children at risk of RCC

If your child has VHL disease, they have a higher risk of developing RCC. Your child may be monitored with yearly check-ups, including an abdominal ultrasound and MRI, starting between the ages of 8 to 11 years to look for kidney tumors.

Treatment of RCC

Treatment of renal cell cancer may include:

Learn more about these treatments in the Types of treatment section.

If the cancer comes back after treatment, your child’s doctor will talk with you about what to expect and next steps. There might be treatment options that shrink the cancer or control its growth. If there are no treatment options, your child can receive care to control their cancer symptoms so they can be as comfortable as possible.

Rhabdoid tumor of the kidney

Rhabdoid tumor of the kidney is a type of cancer that occurs mostly in infants and young children. It is often advanced at the time of diagnosis and grows and spreads quickly, often to the lungs or brain.

Children with a certain change in the SMARCB1 or SMARCA4 genes can have cancer grow in the kidney, brain, or soft tissues. Children with SMARCB1 are checked regularly to see if a rhabdoid tumor has formed in the kidney or the brain.

Causes and risk factors for rhabdoid tumor of the kidney

Rhabdoid tumor of the kidney is caused by certain changes in the way kidney cells function, especially how they grow and divide into new cells. The exact cause of these changes is often unknown. Learn more about how cancer develops at What Is Cancer?

A risk factor is anything that increases the chance of getting a disease. Children with a certain change in the SMARCB1 or SMARCA4 gene may have an increased risk of developing cancer in the kidney, brain, or soft tissues. Not every child with these risk factors will develop rhabdoid tumor of the kidney. And it will develop in some children who don’t have a known risk factor.

Talk with your child’s doctor if you think your child may be at risk.

Monitoring children at risk of rhabdoid tumor of the kidney

If your child has an inherited change to the SMARCB1 gene, they may have a higher risk of developing rhabdoid tumor of the kidney and other types of cancer. Your child may have check-ups from birth until age 5 years, including a brain MRI and an abdominal ultrasound every 3 months, to look for cancer.

Treatment of rhabdoid tumor of the kidney

There is no standard treatment for rhabdoid tumor of the kidney. Treatment may include:

  • a combination of surgery, chemotherapy, or radiation therapy
  • high-dose chemotherapy with or without stem cell transplant

Learn more about these treatments in the Types of treatment section.

If the cancer comes back after treatment, your child’s doctor will talk with you about what to expect and possible next steps. There might be treatment options that may shrink the cancer or control its growth. If there are no treatments, your child can receive care to control symptoms from cancer so they can be as comfortable as possible.

Clear cell sarcoma of the kidney

Clear cell sarcoma of the kidney is a rare cancer that occurs most often before age 3 years. It may spread to the bone, lungs, brain, liver, or soft tissue. Most relapses occur within 3 years of treatment. But it may come back up to 14 years after treatment, though this is rare. Clear cell sarcoma often comes back in the brain or lungs.

Treatment of stage I clear cell sarcoma of the kidney may include:

  • surgery with removal of lymph nodes to test them for cancer cells followed by chemotherapy

Treatment of stages II, III, and IV clear cell sarcoma of the kidney may include:

  • surgery with removal of lymph nodes to test them for cancer cells followed by combination chemotherapy and radiation therapy

Treatment of recurrent clear cell sarcoma of the kidney may include chemotherapy, surgical resection (if possible), and radiation therapy.

Learn about these treatments in the Types of treatment section.

Congenital mesoblastic nephroma

Congenital mesoblastic nephroma is a tumor of the kidney that is often diagnosed during the first year of life or before birth. It is the most common kidney tumor found in infants younger than 6 months old and is found more often in males than in females.

Some of these tumors have cells with a certain genetic change called a translocation. This means that part of one chromosome switches places with part of another chromosome. In congenital mesoblastic nephroma an abnormal gene is formed when the ETV6 gene on chromosome 12 switches places with the NTRK3 gene on another chromosome.

Treatment of stages I, II, and some children with stage III congenital mesoblastic nephroma may include surgery.

Treatment for some children with stage III congenital mesoblastic nephroma may include surgery followed by chemotherapy.

Treatment of recurrent congenital mesoblastic nephroma may include:

Learn about these treatments in the Types of treatment section.

Ewing sarcoma of the kidney

Ewing sarcoma of the kidney is a rare cancer that usually occurs in young adults. Young adults are usually diagnosed with large tumors that grow and spread to other parts of the body quickly. The cancer may spread to the lungs, liver or bone.

There is no standard treatment for Ewing sarcoma of the kidney. Treatment may include a combination of surgery, chemotherapy, and radiation therapy.

It may also be treated in the same way that Ewing sarcoma is treated. To learn more, visit Ewing Sarcoma Treatment.

Primary renal myoepithelial carcinoma

Primary renal myoepithelial carcinoma is a rare cancer that grows and spreads quickly. It usually affects soft tissues, but it sometimes forms in the internal organs, such as the kidney.

There is no standard treatment for primary renal myoepithelial carcinoma. Treatment may include a combination of surgery, chemotherapy, and radiation therapy.

Learn about these treatments in the Types of treatment section.

If the cancer comes back after treatment, your child’s doctor will talk with you about what to expect and possible next steps. There might be treatment options that may shrink the cancer or control its growth. If there are no treatments, your child can receive care to control symptoms from cancer so they can be as comfortable as possible.

Multilocular cystic nephroma

Multilocular cystic nephromas are benign tumors made up of cysts. They are most common in infants, young children, and adult women. These tumors can occur in one or both kidneys.

Multilocular cystic nephroma is caused by certain changes in the way kidney cells function, especially how they grow and divide into new cells. The exact cause of these changes is often unknown. Learn more about how cancer develops at What Is Cancer?

A risk factor is anything that increases the chance of getting a disease. Multilocular cystic nephroma may be an inherited condition that is caused by a change in the DICER1 gene. Not every child with this risk factor will develop multilocular cystic nephroma. And it will develop in some children who don’t have a known risk factor. Talk with your child’s doctor if you think your child may be at risk.

Children with a change in the DICER1 gene may have imaging tests to check the lungs for cysts or solid tumors called pleuropulmonary blastoma. To learn more, visit Pleuropulmonary Blastoma.

Treatment of multilocular cystic nephroma includes surgery. Learn more about this treatment in the Types of treatment section.

If the cancer comes back after treatment, your child’s doctor will talk with you about what to expect and possible next steps. There might be treatment options that may shrink the cancer or control its growth. If there are no treatments, your child can receive care to control symptoms from cancer so they can be as comfortable as possible.

Anaplastic sarcoma of the kidney

Anaplastic sarcoma of the kidney is a rare cancer that is most common in children or adolescents younger than age 15 years. Anaplastic sarcoma of the kidney often spreads to the lungs, liver, or bones.

Anaplastic sarcoma of the kidney is caused by certain changes in the way kidney cells function, especially how they grow and divide into new cells. The exact cause of these changes is often unknown. Learn more about how cancer develops at What Is Cancer?

A risk factor is anything that increases the chance of getting a disease. Anaplastic sarcoma of the kidney may be an inherited condition that is caused by a change in the DICER1 gene. Not every child with this risk factor will develop anaplastic sarcoma of the kidney. And it will develop in some children who don’t have a known risk factor. Talk with your child’s doctor if you think your child may be at risk.

Children with a change in the DICER1 gene may also have imaging tests to check the lungs for cysts or solid tumors called pleuropulmonary blastoma. To learn more, visit Pleuropulmonary Blastoma.

There is no standard treatment for anaplastic sarcoma of the kidney. Treatment is usually the same treatment given for anaplastic Wilms tumor or Ewing sarcoma. To learn more, visit Wilms Tumor or Ewing Sarcoma Treatment.

Primary renal synovial sarcoma

Primary renal synovial sarcoma is a cyst-like cancer that is often found in the right kidney of young adults. These tumors grow and spread quickly.

Some tumors have cells with a certain genetic change called a translocation. This means that part of one chromosome switches places with part of another chromosome. In primary renal synovial sarcoma, the SS18 gene on chromosome 18 switches places with the SSX gene on another chromosome to make an abnormal gene. To diagnose primary renal synovial sarcoma, the tumor cells may be checked for this genetic change.

Treatment of primary renal synovial sarcoma usually includes surgery and maybe chemotherapy. Learn more about these treatments in the Types of treatment section.

If the cancer comes back after treatment, your child’s doctor will talk with you about what to expect and possible next steps. There might be treatment options that may shrink the cancer or control its growth. If there are no treatments, your child can receive care to control symptoms from cancer so they can be as comfortable as possible.

Nephroblastomatosis

Nephroblastomatosis (also called diffuse hyperplastic perilobar nephroblastomatosis) is not cancer. But if untreated, it can become a Wilms tumor, which is cancer.

Sometimes, after the kidneys form in the fetus, abnormal groups of kidney cells remain. These abnormal groups of cells may grow in many places inside the kidney or make a thick layer around the kidney. They most often occur in both kidneys. If these cells are found in one kidney after surgery for Wilms tumor, the child has an increased risk of Wilms tumor in the other kidney.

Treatment of nephroblastomatosis may include chemotherapy followed by nephrectomy. Sometimes a partial nephrectomy may be done to keep as much kidney function as possible. Learn more about these treatments in the Types of treatment section.

Types of treatment for kidney cancer in children

Who treats children with kidney cancer?

A pediatric oncologist, a doctor who specializes in treating children with cancer, oversees treatment of kidney cancer. The pediatric oncologist works with other health care providers who are experts in treating children with childhood kidney tumors and also specialize in other areas of medicine. Other specialists may include:

Treatment options

There are different types of treatment for children and adolescents with kidney cancer. You and your child’s cancer team will work together to decide treatment. Treatment will depend on factors such as your child’s overall health and whether the cancer is newly diagnosed or has come back.

Your child’s treatment plan will include information about the cancer, the goals for treatment, treatment options, and the possible side effects. It will be helpful to talk with your child’s cancer care team before treatment begins about what to expect. For help every step of the way, visit our booklet, Children with Cancer: A Guide for Parents.

Types of treatment your child might have include:

Surgery

Children with kidney cancer may have surgery to obtain a biopsy sample or to remove the cancer. There are two types of surgery used to treat kidney cancer:

  • Nephrectomy is surgery to remove the whole kidney. This surgery is the most common treatment for kidney cancer. Nearby lymph nodes may also be removed and checked for cancer.

    If the cancer is in both kidneys and they are not working well, your child may have a kidney transplant. A transplant is surgery to remove a kidney and replace it with one from a donor.

  • Partial nephrectomy is the removal of the cancer in the kidney and a small amount of normal tissue around it. Your child may have this surgery if cancer is found in both kidneys or is likely to spread to both kidneys. The goal of the surgery is to keep as much of the kidney as possible. A partial nephrectomy is also called renal-sparing surgery.

After the doctor removes all the cancer that can be seen at the time of the surgery, your child may have chemotherapy, radiation therapy, or both to kill any cancer cells that are left. Sometimes after chemotherapy or radiation therapy, doctors will do a second-look surgery to see if cancer remains.

Sometimes kidney cancer cannot be removed for one of these reasons:

  • the tumor is too close to important organs or blood vessels
  • the tumor is too large to remove
  • the cancer is in both kidneys, unless the tumors are very small
  • there is a blood clot in the vessels near the liver
  • your child has trouble breathing because cancer has spread to the lungs

In this case, your child will have a biopsy first. Then they will receive chemotherapy to reduce the size of the tumor before surgery. The goal of this approach is to save as much healthy tissue as possible and reduce problems after surgery.

Radiation therapy

Radiation therapy uses high-energy x-rays or other types of radiation to kill cancer cells or keep them from growing. A type of radiation therapy called external beam radiation is used to treat childhood kidney tumors. It uses a machine outside the body to send radiation toward the area of the body with cancer. Radiation therapy may be given alone or with other treatments, such as chemotherapy.

To learn more, visit External Beam Radiation Therapy for Cancer and Radiation Therapy Side Effects.

Chemotherapy

Chemotherapy (also called chemo) uses drugs to kill cancer cells or stop them from dividing. Chemotherapy may be given alone or with other types of treatment, such as radiation therapy.

For children with kidney cancer, chemotherapy is taken by mouth or injected into a vein. When given this way, chemotherapy enters the bloodstream and can reach cancer cells throughout the body. Chemotherapy that is used alone or in combination to treat kidney cancer include:

Other chemotherapy not listed here may also be used.

Sometimes chemotherapy is given before surgery to reduce the size of the tumor. Shrinking the tumor before surgery can help save as much healthy tissue as possible and reduce problems after surgery. This is called neoadjuvant chemotherapy.

Learn more about how chemotherapy works, how it is given, common side effects, and more at Chemotherapy to Treat Cancer.

Immunotherapy

Immunotherapy uses your child’s immune system to fight cancer. Immunotherapy that may be used to treat kidney cancer in children includes interleukin-2 (IL-2).

To learn more about immunotherapy, visit Immunotherapy to Treat Cancer.

Stem cell transplant

Stem cell transplant (stem cell rescue) is a procedure to replace the blood-forming stem cells that are destroyed when high doses of chemotherapy are given to kill cancer cells. Before high-dose chemotherapy, stem cells (immature blood cells) are removed from the blood or bone marrow of your child and stored in a freezer. After your child completes chemotherapy, the frozen stem cells are thawed and given back to them through an infusion. These stem cells grow into new blood cells.

Targeted therapy

Targeted therapy uses drugs or other substances to identify and attack specific cancer cells. Targeted therapy that is used or being studied to treat childhood kidney cancer may include:

To learn more, visit Targeted Therapy to Treat Cancer.

Clinical trials

For some children, joining a clinical trial may be an option. There are different types of clinical trials for childhood cancer. For example, a treatment trial tests new treatments or new ways of using current treatments. Supportive care and palliative care trials look at ways to improve quality of life, especially for those who have side effects from cancer and its treatment.

You can use the clinical trial search to find NCI-supported cancer clinical trials accepting participants. The search allows you to filter trials based on the type of cancer, your child’s age, and where the trials are being done. Clinical trials supported by other organizations can be found on the ClinicalTrials.gov website.

Learn more about clinical trials, including how to find and join one, at Clinical Trials Information for Patients and Caregivers.

Prognostic factors for kidney cancer in children

If your child has been diagnosed with kidney cancer, you likely have questions about how serious the cancer is and your child’s chances of survival. The likely outcome or course of a disease is called prognosis.

The prognosis for renal cell cancer depends on:

  • the stage of the cancer
  • whether the cancer has spread to the lymph nodes

The prognosis for rhabdoid tumor of the kidney depends on:

  • your child’s age at the time of diagnosis
  • the stage of the cancer
  • whether the cancer has spread to the brain or spinal cord

The prognosis for clear cell sarcoma of the kidney depends on:

  • your child’s age at the time of diagnosis
  • the stage of the cancer

No two people are alike, and responses to treatment can vary greatly. Your child’s cancer care team is in the best position to talk with you about your child’s prognosis.

Side effects and late effects of treatment

Cancer treatments can cause side effects. Which side effects your child has depends on the type of treatment they receive, the dose, and how their body reacts. Talk with your child’s treatment team about which side effects to look for and ways to manage them.

To learn more about side effects that begin during treatment for cancer, visit Side Effects.

Problems from cancer treatment that begin 6 months or later after treatment and continue for months or years are called late effects. Late effects of cancer treatment may include:

  • physical problems, such as trouble with exercise, mobility, strength, and flexibility
  • chronic health conditions that could affect the heart, lungs, kidneys, intestines, and hormone levels
  • infertility or problems during pregnancy including high blood pressure, early labor, or the baby being in an unusual position as birth approaches
  • neurological symptoms, such as changes in mood, feelings, thinking, learning, or memory
  • second cancers (new types of cancer), such as leukemias, thyroid cancer, cancer of the gastrointestinal tract, breast cancer, or skin cancer

Some late effects may be treated or controlled. It is important to talk with your child’s doctors about the effects cancer treatment can have on your child. Learn more about Late Effects of Treatment for Childhood Cancer.

Follow-up care

As your child goes through treatment, they will have follow-up tests or check-ups. Some of the tests that they had to diagnose the cancer may be repeated. Some tests will be repeated to see how well the treatment is working. Decisions about whether to continue, change, or stop treatment may be based on the results of these tests.

Your child will continue to have some tests from time to time after treatment has ended. The results of these tests can show if your child’s condition has changed or if the cancer has come back.

To learn more about follow-up tests, visit Tests to diagnose kidney cancer in children.

Coping with your child's kidney tumor

When your child has a kidney tumor, every member of the family needs support. Taking care of yourself during this difficult time is important. Reach out to your child’s treatment team and to people in your family and community for support. To learn more, visit Support for Families: Childhood Cancer and the booklet Children with Cancer: A Guide for Parents.

Related resources

For more childhood cancer information and other general cancer resources, visit:

About This PDQ Summary

About PDQ

Physician Data Query (PDQ) is the National Cancer Institute’s (NCI’s) comprehensive cancer information database. The PDQ database contains summaries of the latest published information on cancer prevention, detection, genetics, treatment, supportive care, and complementary and alternative medicine. Most summaries come in two versions. The health professional versions have detailed information written in technical language. The patient versions are written in easy-to-understand, nontechnical language. Both versions have cancer information that is accurate and up to date and most versions are also available in Spanish.

PDQ is a service of the NCI. The NCI is part of the National Institutes of Health (NIH). NIH is the federal government’s center of biomedical research. The PDQ summaries are based on an independent review of the medical literature. They are not policy statements of the NCI or the NIH.

Purpose of This Summary

This PDQ cancer information summary has current information about the treatment of kidney cancer in children. It is meant to inform and help patients, families, and caregivers. It does not give formal guidelines or recommendations for making decisions about health care.

Reviewers and Updates

Editorial Boards write the PDQ cancer information summaries and keep them up to date. These Boards are made up of experts in cancer treatment and other specialties related to cancer. The summaries are reviewed regularly and changes are made when there is new information. The date on each summary (“Updated”) is the date of the most recent change.

The information in this patient summary was taken from the health professional version, which is reviewed regularly and updated as needed, by the PDQ Pediatric Treatment Editorial Board.

Clinical Trial Information

A clinical trial is a study to answer a scientific question, such as whether one treatment is better than another. Trials are based on past studies and what has been learned in the laboratory. Each trial answers certain scientific questions in order to find new and better ways to help cancer patients. During treatment clinical trials, information is collected about the effects of a new treatment and how well it works. If a clinical trial shows that a new treatment is better than one currently being used, the new treatment may become “standard.” Patients may want to think about taking part in a clinical trial. Some clinical trials are open only to patients who have not started treatment.

Clinical trials can be found online at NCI’s website. For more information, call the Cancer Information Service (CIS), NCI’s contact center, at 1-800-4-CANCER (1-800-422-6237).

Permission to Use This Summary

PDQ is a registered trademark. The content of PDQ documents can be used freely as text. It cannot be identified as an NCI PDQ cancer information summary unless the whole summary is shown and it is updated regularly. However, a user would be allowed to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks in the following way: [include excerpt from the summary].”

The best way to cite this PDQ summary is:

PDQ® Pediatric Treatment Editorial Board. PDQ Kidney Cancer in Children. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/kidney/patient/childhood-kidney-cancer. Accessed <MM/DD/YYYY>.

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The information in these summaries should not be used to make decisions about insurance reimbursement. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

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Wilms Tumor (PDQ®)–Patient Version

Wilms Tumor (PDQ®)–Patient Version

What is Wilms tumor?

Go to Health Professional Version

Wilms tumor (also called nephroblastoma) is the most common type of kidney cancer in children younger than 15 years. In the United States, about 650 children are diagnosed with it each year, and most are between the ages of 2 and 5 years. Wilms tumor can occur in older adolescents and adults, but this is rare.

The kidneys are bean-shaped organs located on either side of the spine, above the waist. Their main job is to remove waste and extra fluids from the body to make urine:

  • Tiny tubules in the kidneys filter and clean the blood.
  • Urine passes from each kidney through a thin tube called a ureter into the bladder.
  • The bladder stores the urine until it leaves the body through a tube called the urethra.
EnlargeAnatomy of the urinary system; drawing showing the right and left kidneys, the ureters, the bladder filled with urine, and the urethra. The inside of the left kidney shows the renal pelvis. An inset shows the renal tubules and urine. The spine and adrenal glands are also shown.
Anatomy of the urinary system showing the kidneys, ureters, bladder, and urethra. The inside of the left kidney shows the renal pelvis. An inset shows the renal tubules and urine. Also shown is the spine and adrenal glands. Urine is made in the renal tubules and collects in the renal pelvis of each kidney. The urine flows from the kidneys through the ureters to the bladder. The urine is stored in the bladder until it leaves the body through the urethra.

Wilms tumor can affect one or both kidneys. It may spread to other parts of the body, such as the lungs, liver, bone, brain, or lymph nodes.

A rare type of Wilms tumor called cystic partially differentiated nephroblastoma is made of cysts and usually occurs in young children.

During fetal development, some kidney cells may not develop normally. These abnormal groups of kidney cells may remain in one or both kidneys after birth, and in some cases, may lead to nephroblastomatosis (also called diffuse hyperplastic perilobar nephroblastomatosis) or Wilms tumor. In nephroblastomatosis (a non-cancerous kidney condition), these abnormal groups of cells may grow in many places inside the kidney or make a thick layer around the kidney. These abnormal groups of cells most often occur in both kidneys. Although nephroblastomatosis is not cancer, it can develop into Wilms tumor if left untreated. If a child has one kidney removed because of Wilms tumor and doctors find nephroblastomatosis in the removed kidney, the child has a higher risk of Wilms tumor in the remaining kidney.

Causes and risk factors for Wilms tumor

Wilms tumor is caused by certain changes to the way the kidney cells function, especially how they grow and divide into new cells. The exact cause of these changes is often unknown. Learn more about how cancer develops at What Is Cancer?

A risk factor is anything that increases the chance of getting a disease. Not every child with one or more of these risk factors will develop a kidney tumor. And it will develop in some children who don’t have a known risk factor.

Wilms tumor may be part of a genetic syndrome that affects growth or development. A genetic syndrome is a set of signs and symptoms or conditions that occur together and is caused by certain changes in the genes. Certain conditions or environmental exposures can also increase your child’s risk of developing Wilms tumor. The following have been linked to Wilms tumor:

Talk with your child’s doctor if you think your child may be at risk.

Monitoring children at risk of Wilms tumor

Some children have a higher risk of Wilms tumor. Regular testing can help find cancer at an earlier stage and improve your child’s chance of survival. If your child has a higher risk of Wilms tumor, they may have an abdominal ultrasound for Wilms tumor every 3 months until they are at least 8 years old. This test can find small Wilms tumors before symptoms occur.

Testing for children with Beckwith-Wiedemann syndrome or hemihypertrophy

Children with Beckwith-Wiedemann syndrome or hemihypertrophy are at risk of tumors in the liver, adrenal glands, and kidneys. These children may receive testing to find Wilms tumor before symptoms occur. The testing schedule may include:

  • Until age 4 years, a blood test to check for alpha-fetoprotein (AFP) levels and an abdominal ultrasound.
  • For ages 4 to 8 years, an ultrasound of the kidneys and a physical exam by a geneticist or pediatric oncologist twice a year. Some children with certain gene changes may have a different schedule for an abdominal ultrasound.

Testing for children with aniridia

Children with aniridia and a certain gene change may have an abdominal ultrasound every 3 months until age 8 years to look for Wilms tumor.

Testing for children at risk of Wilms tumor in the second kidney

Some children are diagnosed with Wilms tumor in both kidneys at the same time. Wilms tumor may also occur in the second kidney after your child is successfully treated for Wilms tumor in one kidney. If your child is at risk of developing Wilms tumor in the second kidney, they should have an abdominal ultrasound every 3 months for up to 8 years to monitor for any new tumors.

Symptoms of Wilms tumor

Sometimes Wilms tumor causes symptoms. But sometimes a parent may notice a lump in their child’s abdomen or notice that their child’s stomach looks bigger than before. In some cases, a doctor finds the tumor during a routine check-up. It’s important to check with your child’s doctor if your child has:

  • a lump, swelling, or pain in the abdomen
  • blood in the urine
  • high blood pressure
  • fever for no known reason
  • loss of appetite
  • weight loss for no known reason
  • a cough
  • blood in the sputum
  • trouble breathing
  • chest pain
  • pain in the abdomen
  • fever

These symptoms may also be caused by other problems. The only way to know is for your child to see a doctor.

Diagnosis of Wilms tumor

If your child has symptoms that suggest Wilms tumor, the doctor will need to find out if these are due to cancer or another problem. The doctor will ask when the symptoms started and how often your child has been having them. The doctor will also ask about your child’s personal and family medical history and do a physical exam. Depending on these results, they may recommend tests to find out if your child has Wilms tumor, and if so, its extent (stage).

Tests to diagnose Wilms tumor

The following tests may be used to diagnose Wilms tumor. The results of these tests will help plan treatment.

Lab tests

  • Complete blood count (CBC) checks a sample of blood for:
  • Blood chemistry study uses a blood sample to measure the amounts of certain substances released into the blood by organs and tissues in the body. An unusual amount of a substance can be a sign that the liver and kidneys are not working as they should.
  • Renal function test uses a blood sample to measure the amounts of certain substances released into the blood by the kidneys. An unusual amount of a substance can be a sign that the kidneys are not working as they should.
  • Urinalysis checks the color of urine and its contents, such as sugar, protein, blood, and bacteria. An unusual amount of a substance can be a sign that the kidneys are not working as they should.

Imaging tests and procedures

  • Ultrasound uses high-energy sound waves (ultrasound) that bounce off internal tissues or organs and make echoes. The echoes form a picture of body tissues called a sonogram. An ultrasound of the abdomen is done to diagnose a kidney tumor.
    EnlargeAbdominal ultrasound; drawing shows a child lying on an exam table during an abdominal ultrasound procedure. A technician is shown pressing a transducer (a device that makes sound waves that bounce off tissues inside the body) against the skin of the abdomen. A computer screen shows a sonogram (picture).
    Abdominal ultrasound. An ultrasound transducer connected to a computer is pressed against the skin of the abdomen. The transducer bounces sound waves off internal organs and tissues to make echoes that form a sonogram (computer picture).
  • CT scan (CAT scan) uses a computer linked to an x-ray machine to make a series of detailed pictures of areas inside the body, such as the chest, abdomen, and pelvis. The pictures are taken from different angles and are used to create 3-D views of tissues and organs. A dye may be injected into a vein or swallowed to help the organs or tissues show up more clearly. This procedure is also called computed tomography, computerized tomography, or computerized axial tomography. Learn more about Computed Tomography (CT) Scans and Cancer.
    EnlargeComputed tomography (CT) scan; drawing shows a child lying on a table that slides through the CT scanner, which takes a series of detailed x-ray pictures of areas inside the body.
    Computed tomography (CT) scan. The child lies on a table that slides through the CT scanner, which takes a series of detailed x-ray pictures of areas inside the body.
  • Magnetic resonance imaging (MRI) with gadolinium uses a magnet, radio waves, and a computer to make a series of detailed pictures of areas inside the body, such as the abdomen or pelvis. A substance called gadolinium is injected into a vein. The gadolinium collects around the cancer cells so they show up brighter in the picture. This procedure is also called nuclear magnetic resonance imaging (NMRI).
    EnlargeMagnetic resonance imaging (MRI) scan; drawing shows a child lying on a table that slides into the MRI machine, which takes a series of detailed pictures of areas inside the body.
    Magnetic resonance imaging (MRI) scan. The child lies on a table that slides into the MRI machine, which takes a series of detailed pictures of areas inside the body. The positioning of the child on the table depends on the part of the body being imaged.
  • X-ray is a type of radiation that can go through the body and make pictures of areas inside the body, such as the chest and abdomen.
  • PET-CT scan combines the pictures from a positron emission tomography (PET) scan and a computed tomography (CT) scan. The PET and CT scans are done at the same time on the same machine. The combined scans make more detailed pictures than either test would make by itself.
    • For the PET scan, a small amount of radioactive sugar (also called radioactive glucose) is injected into a vein. The PET scanner rotates around the body and makes pictures of where sugar is being used in the body. Cancer cells show up brighter in the picture because they are more active and take up more sugar than normal cells do.
    • For the CT scan (CAT scan), a series of detailed x-ray pictures are taken from different angles to create 3-D views of tissues and organs. A dye may be injected into a vein or swallowed to help the organs or tissues show up more clearly.
  • Biopsy is the removal of a sample of cells or tissue from the tumor so that a pathologist can view it under a microscope to check for cancer. The decision of whether to do a biopsy is based on:
    • The size of the tumor.
    • The stage of the cancer. There will not be a biopsy if the tumor can be removed with surgery or is stage I or stage II Wilms tumor. The reason for not doing a biopsy is to avoid the spread of tumor cells during the procedure.
    • Where in the kidney the tumor is and whether cancer is in one or both kidneys.
    • Whether imaging tests clearly show the cancer.
    • Whether the child is participating in a clinical trial.

    A biopsy may be done before your child has any treatment, after chemotherapy, or during surgery.

Tests to stage Wilms tumor

If your child is diagnosed with a Wilms tumor, you will be referred to a pediatric oncologist. This is a doctor who specializes in childhood cancers. They will recommend tests to determine the extent of the cancer. The cancer may only be in one spot, but sometimes it spreads to other parts of the body. The process of learning the extent of the cancer in the body is called staging. It is important to know the stage of the tumor to plan the best treatment.

The following tests and procedures may be used to determine the stage of the Wilms tumor:

Lab tests

  • Renal function test.
  • Liver function test uses a blood sample to check how the liver is functioning. The blood sample is used to check the liver enzymes and to measure the amounts of certain substances (such as bilirubin) that are released into the blood by the liver. A higher-than-normal amount of a substance can be a sign that the liver is not working as it should.

Imaging tests and procedures

  • Lymph node biopsy is the removal of all or part of a lymph node in the abdomen. A pathologist views the lymph node tissue under a microscope to check for cancer cells. This procedure is also called lymph node sampling.
  • X-ray of the chest and bones.
  • CT scan (CAT scan).
  • PET-CT scan.
  • MRI (magnetic resonance imaging).
  • Bone scan checks if there are rapidly dividing cells, such as cancer cells, in the bone. A very small amount of radioactive material is injected into a vein and travels through the bloodstream. The radioactive material collects in the areas of the bones with cancer and is detected by a scanner.
  • Ultrasound of the major blood vessels of the heart is done to see if the tumor has started to grow in a blood vessel that returns the blood to the heart.

Getting a second opinion

You may want to get a second opinion to confirm your child’s diagnosis and treatment plan. If you seek a second opinion, you will need to get medical test results and reports from the first doctor to share with the second doctor. The second doctor will review the genetic testing report, pathology report, slides, and scans. This doctor may agree with the first doctor, suggest changes to the treatment plan, or provide more information about your child’s tumor.

To learn more about choosing a doctor and getting a second opinion, visit Finding Cancer Care. You can contact NCI’s Cancer Information Service via chat, email, or phone (both in English and Spanish) for help finding a doctor or hospital that can provide a second opinion. For questions you might want to ask at your child’s appointments, visit Questions to Ask Your Doctor About Cancer. 

Genetic counseling for children with Wilms tumor

It is not always clear from the family medical history whether a child with Wilms tumor has an inherited condition that increased their risk. Genetic counseling can assess the likelihood that your child’s cancer is inherited and whether genetic testing is needed. Genetic counselors and other specially trained health professionals can discuss your child’s diagnosis and your family’s medical history to help you understand the:

  • options for testing for syndromes that may increase the risk of cancer
  • risk of your child developing other types of cancer
  • risk of kidney tumors and other cancers for your child’s siblings
  • risks and benefits of learning genetic information

Genetic counselors can also help you cope with your child’s genetic testing results, including how to discuss the results with family members. They can advise you about whether other members in your family should receive genetic testing.

Genetic counseling may be done if your child has:

  • a genetic syndrome or condition that increases the risk of Wilms tumor
  • Wilms tumors in both kidneys
  • Wilms tumor that is diagnosed before age 2 years

To learn more, visit Genetic Testing for Inherited Cancer Risk.

Stages of Wilms tumor

Staging is the process of learning the extent of the cancer in the body. Sometimes cancer is only in the kidney. Or, it may have spread to other parts of the body.

Besides stages, Wilms tumors are described by their histology, which refers to how the cells look under a microscope. The histology affects the prognosis and the treatment of Wilms tumor.

The histology may be favorable or anaplastic (unfavorable):

  • Tumors with a favorable histology have a better prognosis and respond better to chemotherapy and radiation therapy than anaplastic tumors.
  • Tumor cells that are anaplastic divide quickly and do not look like the type of cells they came from when viewed under a microscope. Anaplastic tumors are harder to treat with chemotherapy than other Wilms tumors at the same stage.

Stage I

In stage I, the tumor was completely removed by surgery and all of the following are true:

  • cancer was found only in the kidney and did not spread to blood vessels in the renal sinus (the part of the kidney where it joins the ureter) or to the lymph nodes
  • no cancer cells were found at the edges of the area where the tumor was removed
  • the outer layer of the kidney did not break open
  • the tumor did not break open
  • a biopsy was not done before the tumor was removed

Stage II

In stage II, the tumor was completely removed by surgery and no cancer cells were found at the edges of the area where the cancer was removed. Cancer has not spread to the lymph nodes. Before the tumor was removed, one of the following was also true:

  • cancer had spread to the renal sinus (the part of the kidney where it joins the ureter)
  • cancer had spread to blood vessels outside the area of the kidney where urine is made, such as the renal sinus

Stage III

In stage III, cancer remains in the abdomen after surgery and at least one of the following is true:

  • cancer has spread to the lymph nodes in the abdomen or pelvis (the part of the body between the hips)
  • cancer has spread to or through the surface of the peritoneum (the tissue that lines the abdominal cavity and covers most organs in the abdomen)
  • a biopsy of the tumor was done before it was removed
  • the tumor broke open before or during surgery to remove it
  • the tumor was removed in more than one piece
  • cancer cells are found at the edges of the area where the tumor was removed
  • the entire tumor could not be removed because important organs or tissues in the body would be damaged

Stage IV

In stage IV, cancer has spread through the blood to other parts of the body such as the lungs, liver, bone, or brain, or to lymph nodes outside the abdomen and pelvis.

Stage V

In stage V (bilateral) Wilms tumor, cancer cells are found in both kidneys when the cancer is first diagnosed. The cancer in each kidney is staged separately as stage I, II, III, or IV.

Recurrent Wilms tumor

Recurrent Wilms tumor is cancer that has come back after it has been treated. If there are signs that the cancer has returned, your child will have tests to find out where the cancer is in your child’s body and if it has spread.

The type of treatment that your child will have depends on whether the Wilms tumor came back in the kidney or came back in other places in the body, such as the lungs, abdomen, or liver.

Learn more about Treatment of recurrent Wilms tumor.

Types of treatment for Wilms tumor

Who treats children with Wilms tumor?

A pediatric oncologist, a doctor who specializes in treating children with cancer, oversees treatment of Wilms tumor. The pediatric oncologist works with other health care providers who are experts in treating children and specialize in certain areas of medicine. Other specialists may include:

Treatment options

There are different types of treatment for children and adolescents with Wilms tumor. You and your child’s care team will work together to decide treatment. Many factors will be considered, such as:

  • your child’s overall health
  • the stage of your child’s tumor
  • the histology (favorable or anaplastic)
  • the risk of cancer coming back after treatment
  • whether the cancer has spread to other areas in the body
  • whether both kidneys have cancer
  • whether your child has an inherited cancer syndrome
  • whether the cancer is newly diagnosed or has come back

The goal of treatment is to kill the cancer cells and decrease the risk of late effects from treatment.

Your child’s treatment plan will include information about the cancer, the goals of treatment, treatment options, and possible side effects. It will be helpful to talk with your child’s care team before treatment begins about what to expect. For help every step of the way, visit our booklet, Children with Cancer: A Guide for Parents.

Types of treatment your child might have include:

Surgery

Children with Wilms tumor may have surgery to obtain a biopsy sample or to remove the cancer. There are two types of surgery used to treat Wilms tumors:

  • Nephrectomy is surgery to remove the whole kidney. This is the most common treatment for Wilms tumor. Nearby lymph nodes may also be removed and checked for cancer. If the cancer is in both kidneys and they are not working well, your child may need a kidney transplant. A transplant is surgery to remove the kidney and replace it with one from a donor.
  • Partial nephrectomy is the removal of the cancer in the kidney and a small amount of normal tissue around it. Your child may have this surgery if cancer is found in both kidneys or if it is likely to spread to both kidneys. The goal of the surgery is to keep as much of the kidney as possible. A partial nephrectomy is also called renal-sparing surgery.

After the doctor removes all the cancer that can be seen at the time of the surgery, your child may have chemotherapy or radiation therapy to kill any cancer cells that are left.

Sometimes, the tumor cannot be removed because:

  • the tumor is too close to important organs or blood vessels or is growing in important blood vessels (such as the inferior vena cava)
  • the tumor is too large to remove
  • the cancer is in both kidneys, unless the tumors are very small
  • there is a blood clot in the vessels near the liver
  • the cancer has spread to the lungs, and your child has trouble breathing

If the tumor cannot be removed, your child will have a biopsy first. Then, they will receive chemotherapy to reduce the size of the tumor to make surgery possible. The goal of this approach is to save as much healthy kidney tissue as possible and reduce problems after surgery. Chemotherapy given before surgery is called neoadjuvant chemotherapy.

Radiation therapy

Radiation therapy uses high-energy x-rays or other types of radiation to kill cancer cells or keep them from growing. Wilms tumor is treated with external beam radiation therapy. This type of therapy uses a machine outside the body to send radiation toward the area of the body with cancer. Radiation therapy may be given alone or with other treatments, such as chemotherapy.

Learn more about External Beam Radiation Therapy for Cancer and Radiation Therapy Side Effects.

Chemotherapy

Chemotherapy (also called chemo) uses drugs to stop the growth of cancer cells. Chemotherapy either kills the cells or stops them from dividing. Chemotherapy may be given alone or with other types of treatment, such as radiation therapy.

For children with Wilms tumor, chemotherapy is injected into a vein. When given this way, chemotherapy enters the bloodstream and can reach cancer cells throughout the body.

Chemotherapy drugs used alone or in combination to treat Wilms tumor include:

Other chemotherapy not listed here may also be used.

Chemotherapy may be given before or after surgery. Chemotherapy given after surgery to kill any cancer cells that remain is called adjuvant therapy.

Learn more about how chemotherapy works, how it is given, common side effects, and more at Chemotherapy to Treat Cancer.

Stem cell transplant

Stem cell transplant (or stem cell rescue) is a procedure to replace the blood-forming stem cells that are destroyed when high doses of chemotherapy are given to kill cancer cells. Before high-dose chemotherapy, stem cells (immature blood cells) are removed from the blood or bone marrow of your child and are stored in a freezer. After your child completes chemotherapy, the frozen stem cells are thawed and given back to them through an infusion. These stem cells grow into new blood cells.

Clinical trials

For some children, joining a clinical trial may be an option. There are different types of clinical trials for childhood cancer. For example, a treatment trial tests new treatments or new ways of using current treatments. Supportive care and palliative care trials look at ways to improve quality of life, especially for those who have side effects from cancer and its treatment.

You can use the clinical trial search to find NCI-supported cancer clinical trials accepting participants. The search allows you to filter trials based on the type of cancer, your child’s age, and where the trials are being done. Clinical trials supported by other organizations can be found on the ClinicalTrials.gov website.

Learn more about clinical trials, including how to find and join one, at Clinical Trials Information for Patients and Caregivers.

Clinical trials have led to improvements in the treatment of Wilms tumor, including the number of children who are cured.

Treatment of Wilms tumor by stage and histology

To learn more about the treatments listed below, visit Types of treatment for Wilms tumor.

Stage I Wilms tumor

Treatment of stage I Wilms tumor with favorable histology may include:

  • nephrectomy with removal of lymph nodes, followed by combination chemotherapy
  • nephrectomy with removal of lymph nodes for children younger than 2 years and who have a certain weight

Treatment of stage I anaplastic Wilms tumor is nephrectomy with removal of lymph nodes, followed by combination chemotherapy and radiation therapy to the flank area (either side of the body between the ribs and hipbone).

Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.

Stage II Wilms tumor

Treatment of stage II Wilms tumor with favorable histology is nephrectomy with removal of lymph nodes, followed by combination chemotherapy.

Treatment of stage II anaplastic Wilms tumor is nephrectomy with removal of lymph nodes, followed by radiation therapy to the abdomen and combination chemotherapy.

Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.

Stage III Wilms tumor

Treatment of stage III Wilms tumor with favorable histology is nephrectomy with removal of lymph nodes, followed by radiation therapy to the abdomen and combination chemotherapy.

Treatment of stage III anaplastic Wilms tumor may include:

  • nephrectomy with removal of lymph nodes, followed by radiation therapy to the abdomen and combination chemotherapy
  • combination chemotherapy, followed by nephrectomy with removal of lymph nodes, followed by radiation therapy to the abdomen

Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.

Stage IV Wilms tumor

Treatment of stage IV Wilms tumor with favorable histology may include:

  • Nephrectomy with removal of lymph nodes, followed by combination chemotherapy. Radiation therapy may be given to the area where the tumor was or to other parts of the abdomen.
  • Radiation therapy to treat cancer that has spread to other parts of the body.

Treatment of stage IV anaplastic Wilms tumor may include:

  • nephrectomy with removal of lymph nodes, followed by radiation therapy to the abdomen and combination chemotherapy
  • chemotherapy given before nephrectomy with removal of lymph nodes, followed by radiation therapy to the abdomen
  • radiation therapy to treat cancer that has spread to other parts of the body

Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.

Stage V Wilms tumor and children at high risk of developing bilateral Wilms tumor

Treatment of stage V Wilms tumor or bilateral Wilms tumor may be different for each child and may include:

  • Combination chemotherapy to shrink the tumor, followed by repeat imaging at 6 to 12 weeks to decide on further treatment. A biopsy may be done or treatment may be given, including partial nephrectomy, continued chemotherapy, or radiation therapy.
  • A biopsy of the kidneys, followed by combination chemotherapy to shrink the tumor. Then, surgery is done to remove as much of the cancer as possible. If cancer remains after surgery, your child may have chemotherapy and possibly radiation therapy.

If a kidney transplant is needed because of kidney problems, it is usually delayed until 1 to 2 years after treatment is completed and there are no signs of cancer.

Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.

Treatment of cystic partially differentiated nephroblastoma

Treatment of cystic partially differentiated nephroblastoma is surgery that may be followed by chemotherapy.

Treatment of recurrent Wilms tumor

To learn about the treatments listed below, visit Types of treatment for Wilms tumor.

Treatment of recurrent Wilms tumor may include:

  • a combination of chemotherapy, surgery, and radiation therapy
  • high-dose chemotherapy followed by a stem cell transplant using your child’s own blood stem cells

Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.

Prognostic factors for Wilms tumor

If your child has been diagnosed with Wilms tumor, you likely have questions about how serious the cancer is and your child’s chances of survival. The likely outcome or course of a disease is called prognosis.

The prognosis for Wilms tumor depends on:

  • how different the tumor cells are from normal kidney cells when looked at under a microscope (favorable histology or anaplastic)
  • the stage of the cancer
  • your child’s age
  • whether there are certain changes in chromosomes or genes
  • whether the cancer has just been diagnosed or has come back after treatment
  • whether the cancer has spread to the lymph nodes

Newly diagnosed Wilms tumor with favorable histology can often be cured.

No two people are alike, and responses to treatment can vary greatly. Your child’s care team is in the best position to talk with you about your child’s prognosis.

Side effects and late effects of treatment

Cancer treatments can cause side effects. Which side effects your child might have depends on the type of treatment they receive, the dose, and how their body reacts. Talk with your child’s treatment team about which side effects to look for and ways to manage them.

To learn more about side effects that begin during treatment for cancer, visit Side Effects.

Problems from cancer treatment that begin 6 months or later after treatment and continue for months or years are called late effects. Late effects of cancer treatment may include:

  • physical problems, such as trouble with exercise, mobility, strength, and flexibility
  • chronic health conditions that affect the heart, lungs, kidneys, intestines, and hormone levels
  • infertility or problems during pregnancy, including high blood pressure, early labor, or the baby being in an unusual position as birth approaches
  • neurological symptoms, such as changes in mood, feelings, thinking, learning, or memory
  • second cancers (new types of cancer), such as leukemias, thyroid cancer, cancer of the gastrointestinal tract, breast cancer, or skin cancer

Some late effects may be treated or controlled. It is important to talk with your child’s doctors about the effects cancer treatment can have on your child. Learn more about Late Effects of Treatment for Childhood Cancer.

Children with Wilms tumor and related problems may be monitored for late effects involving the kidneys.

  • Children with WAGR syndrome are monitored throughout their lives because they are at increased risk of developing hypertension and kidney disease.
  • Children with Wilms tumor and an abnormal genitourinary system are monitored because they are at increased risk of late kidney failure.
  • Children with Wilms tumor and aniridia without an abnormal genitourinary system are at lower risk but are monitored for kidney disease or kidney failure.

Clinical trials are being done to find out if lower doses of chemotherapy and radiation can be used to lessen the late effects of treatment without changing how well the treatment works.

Follow-up care

As your child goes through treatment, they will have follow-up tests or check-ups. Some of the tests that were done to diagnose the cancer or to find out the stage of the cancer may be repeated. Some tests will be repeated to see how well the treatment is working. Decisions about whether to continue, change, or stop treatment may be based on the results of these tests.

Some of the tests will continue to be done for years after treatment has ended. The results of these tests can show if your child’s condition has changed, the health of your child’s kidney or other organs, or if the cancer has come back.

To learn more about follow-up tests, visit Tests to diagnose Wilms tumor.

Coping with your child's cancer

When your child has cancer, every member of the family needs support. Taking care of yourself during this difficult time is important. Reach out to your child’s treatment team and to people in your family and community for support. To learn more, visit Support for Families: Childhood Cancer and the booklet Children with Cancer: A Guide for Parents.

Related resources

For more childhood cancer information and other general cancer resources, visit:

About This PDQ Summary

About PDQ

Physician Data Query (PDQ) is the National Cancer Institute’s (NCI’s) comprehensive cancer information database. The PDQ database contains summaries of the latest published information on cancer prevention, detection, genetics, treatment, supportive care, and complementary and alternative medicine. Most summaries come in two versions. The health professional versions have detailed information written in technical language. The patient versions are written in easy-to-understand, nontechnical language. Both versions have cancer information that is accurate and up to date and most versions are also available in Spanish.

PDQ is a service of the NCI. The NCI is part of the National Institutes of Health (NIH). NIH is the federal government’s center of biomedical research. The PDQ summaries are based on an independent review of the medical literature. They are not policy statements of the NCI or the NIH.

Purpose of This Summary

This PDQ cancer information summary has current information about the treatment of Wilms tumor and other childhood kidney tumors. It is meant to inform and help patients, families, and caregivers. It does not give formal guidelines or recommendations for making decisions about health care.

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Editorial Boards write the PDQ cancer information summaries and keep them up to date. These Boards are made up of experts in cancer treatment and other specialties related to cancer. The summaries are reviewed regularly and changes are made when there is new information. The date on each summary (“Updated”) is the date of the most recent change.

The information in this patient summary was taken from the health professional version, which is reviewed regularly and updated as needed, by the PDQ Pediatric Treatment Editorial Board.

Clinical Trial Information

A clinical trial is a study to answer a scientific question, such as whether one treatment is better than another. Trials are based on past studies and what has been learned in the laboratory. Each trial answers certain scientific questions in order to find new and better ways to help cancer patients. During treatment clinical trials, information is collected about the effects of a new treatment and how well it works. If a clinical trial shows that a new treatment is better than one currently being used, the new treatment may become “standard.” Patients may want to think about taking part in a clinical trial. Some clinical trials are open only to patients who have not started treatment.

Clinical trials can be found online at NCI’s website. For more information, call the Cancer Information Service (CIS), NCI’s contact center, at 1-800-4-CANCER (1-800-422-6237).

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The best way to cite this PDQ summary is:

PDQ® Pediatric Treatment Editorial Board. PDQ Wilms Tumor. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/kidney/patient/wilms-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389390]

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