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Malignant Mesothelioma Treatment (PDQ®)–Health Professional Version

Malignant Mesothelioma Treatment (PDQ®)–Health Professional Version

General Information About Malignant Mesothelioma Treatment

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Diagnosis and Prognostic Factors

The time to confirm a diagnosis of malignant mesothelioma and the rate of disease progression both vary greatly. This makes it difficult to assess prognosis for these patients. In large retrospective series of patients with pleural mesothelioma, the following important prognostic factors were identified:[1,2][Level of evidence C1]

  • Stage.
  • Age.
  • Performance status (PS).
  • Histology.

Prognostic scoring systems

Two prognostic scoring systems have been developed for advanced unresectable mesothelioma and are used to stratify patients enrolling in clinical trials: the Cancer and Leukemia Group B (CALGB) index and the European Organisation for the Research and Treatment of Cancer (EORTC) index.

CALGB index

The CALGB index was developed retrospectively using the clinical characteristics of 337 patients treated in clinical trials of chemotherapy for advanced mesothelioma during a 10-year period.[3][Level of evidence C1] These characteristics were used collectively to define six prognostic groups with median survivals ranging from 13.9 months (Eastern Cooperative Oncology Group [ECOG] PS = 0, age <49 years; or PS = 0, age ≥49 years and hemoglobin ≥14.6 g/dL) to 1.4 months (PS = 1 or 2 and white blood cell [WBC] count ≥15.6 × 109/L).

The prognostic value of the CALGB index was evaluated retrospectively in a phase II clinical trial of 105 patients.[4][Level of evidence C1] Median survival in this study for patients in the best CALGB prognostic group was 29.9 months, compared with 1.8 months for patients in the worst prognostic group. However, the intermediate groups 2 to 4 overlapped in their survival times.

EORTC index

The EORTC index was also developed retrospectively using the characteristics of 181 patients from five phase II clinical trials of chemotherapy during a 9-year period.[5][Level of evidence C1] In a multivariate analysis, the following characteristics were associated with poorer survival:

  • WBC count >8.3 × 109/L.
  • ECOG PS ≥1.
  • Unconfirmed histology on central review.
  • Nonepithelioid histology.
  • Male sex.

Patients were allocated a numerical prognostic score based on each of these variables (+0.55 if WBC >8.3 × 109/L, +0.60 if ECOG PS ≥1, +0.52 if unconfirmed histology, and +0.60 if male sex). Subsequently, patients were classified into two prognostic groups that included low-risk patients with a prognostic score of 1.27 or lower (0–2 risk factors) and high-risk patients with a prognostic score higher than 1.27 (3–5 risk factors). High-risk patients had a relative risk of death of 2.9 compared with low-risk patients (P < .001). The 1-year survival rate was 40% for the low-risk group compared with 12% for the high-risk group.

Follow-Up and Survivorship

Patients with limited disease may consider multimodality therapy incorporating radical surgery (extrapulmonary pneumonectomy or radical pleurectomy with decortication) given with or without chemotherapy and/or radiation therapy. Multimodality therapy has been associated with a relatively long survival in observational series.[6][Level of evidence C1] For patients treated with aggressive surgical approaches, the following factors are associated with improved long-term survival:[7,8][Level of evidence C2]

  • Epithelioid histology.
  • Negative lymph nodes.
  • Negative surgical margins.

For patients treated with aggressive surgical approaches, nodal status is an important prognostic factor.[7] Median survival has been reported as 16 months for patients with malignant pleural disease and 5 months for patients with extensive disease. In some instances, the tumor grows through the diaphragm, making the site of origin difficult to assess. Cautious interpretation of treatment results with this disease is imperative because of the selection differences among series. Effusions, both pleural and peritoneal, represent major symptomatic problems for at least 66% of patients. For more information, see Cardiopulmonary Syndromes.

Carcinogenesis

A history of asbestos exposure is reported in about 70% to 80% of mesothelioma cases.[1,9,10]

References
  1. Ruffie P, Feld R, Minkin S, et al.: Diffuse malignant mesothelioma of the pleura in Ontario and Quebec: a retrospective study of 332 patients. J Clin Oncol 7 (8): 1157-68, 1989. [PUBMED Abstract]
  2. Tammilehto L, Maasilta P, Kostiainen S, et al.: Diagnosis and prognostic factors in malignant pleural mesothelioma: a retrospective analysis of sixty-five patients. Respiration 59 (3): 129-35, 1992. [PUBMED Abstract]
  3. Herndon JE, Green MR, Chahinian AP, et al.: Factors predictive of survival among 337 patients with mesothelioma treated between 1984 and 1994 by the Cancer and Leukemia Group B. Chest 113 (3): 723-31, 1998. [PUBMED Abstract]
  4. Mikulski SM, Costanzi JJ, Vogelzang NJ, et al.: Phase II trial of a single weekly intravenous dose of ranpirnase in patients with unresectable malignant mesothelioma. J Clin Oncol 20 (1): 274-81, 2002. [PUBMED Abstract]
  5. Curran D, Sahmoud T, Therasse P, et al.: Prognostic factors in patients with pleural mesothelioma: the European Organization for Research and Treatment of Cancer experience. J Clin Oncol 16 (1): 145-52, 1998. [PUBMED Abstract]
  6. Flores RM, Pass HI, Seshan VE, et al.: Extrapleural pneumonectomy versus pleurectomy/decortication in the surgical management of malignant pleural mesothelioma: results in 663 patients. J Thorac Cardiovasc Surg 135 (3): 620-6, 626.e1-3, 2008. [PUBMED Abstract]
  7. Sugarbaker DJ, Strauss GM, Lynch TJ, et al.: Node status has prognostic significance in the multimodality therapy of diffuse, malignant mesothelioma. J Clin Oncol 11 (6): 1172-8, 1993. [PUBMED Abstract]
  8. de Perrot M, Feld R, Cho BC, et al.: Trimodality therapy with induction chemotherapy followed by extrapleural pneumonectomy and adjuvant high-dose hemithoracic radiation for malignant pleural mesothelioma. J Clin Oncol 27 (9): 1413-8, 2009. [PUBMED Abstract]
  9. Chailleux E, Dabouis G, Pioche D, et al.: Prognostic factors in diffuse malignant pleural mesothelioma. A study of 167 patients. Chest 93 (1): 159-62, 1988. [PUBMED Abstract]
  10. Adams VI, Unni KK, Muhm JR, et al.: Diffuse malignant mesothelioma of pleura. Diagnosis and survival in 92 cases. Cancer 58 (7): 1540-51, 1986. [PUBMED Abstract]

Cellular Classification of Malignant Mesothelioma

Histologically, malignant mesothelioma tumors are composed of spindle cells (sarcomatoid), epithelial elements, or both (biphasic). Desmoplastic mesothelioma, consisting of bland tumor cells between dense bands of stroma, is a subtype of sarcomatoid mesothelioma. The epithelioid form is occasionally confused with lung adenocarcinoma or metastatic carcinomas. Epithelioid tumors account for approximately 60% of mesothelioma diagnoses.[1] Attempts to diagnose by cytology or needle biopsy of the pleura are often unsuccessful. It can be especially difficult to differentiate mesothelioma from adenocarcinoma in small tissue specimens. Thoracoscopy can be valuable in obtaining adequate tissue specimens for diagnostic purposes.[2]

Examination of the gross tumor at surgery and use of special stains or electron microscopy can often help to determine diagnosis. Pancytokeratin stains are positive in nearly all mesotheliomas.[1] Cytokeratin 5 and 6, calretinin, WT-1, and D2-40 are particularly useful immunohistochemical stains for the differential diagnosis of epithelioid mesothelioma. Calretinin and D2-40 positivity in combination with pancytokeratin positivity is most useful to distinguish sarcomatoid mesothelioma from sarcoma and other histologies.[1] Histological appearance seems to be of prognostic value, and most clinical studies show that patients with epithelial mesotheliomas have a better prognosis than patients with sarcomatoid or biphasic mesotheliomas.[3–5]

References
  1. Travis W, Brambilla E, Müller-Hermelink H, et al., eds.: Pathology and Genetics of Tumours of the Lung, Pleura, and Thymus. IARC Press, 2004. World Health Organization Classification of Tumours.
  2. Boutin C, Rey F: Thoracoscopy in pleural malignant mesothelioma: a prospective study of 188 consecutive patients. Part 1: Diagnosis. Cancer 72 (2): 389-93, 1993. [PUBMED Abstract]
  3. Chahinian AP, Pass HI: Malignant mesothelioma. In: Holland JC, Frei E, eds.: Cancer Medicine e.5. 5th ed. B.C. Decker Inc, 2000, pp 1293-1312.
  4. Nauta RJ, Osteen RT, Antman KH, et al.: Clinical staging and the tendency of malignant pleural mesotheliomas to remain localized. Ann Thorac Surg 34 (1): 66-70, 1982. [PUBMED Abstract]
  5. Sugarbaker DJ, Strauss GM, Lynch TJ, et al.: Node status has prognostic significance in the multimodality therapy of diffuse, malignant mesothelioma. J Clin Oncol 11 (6): 1172-8, 1993. [PUBMED Abstract]

Stage Information for Malignant Mesothelioma

American Joint Committee on Cancer (AJCC) Stage Groupings and Definitions of TNM

The AJCC has designated staging by TNM (tumor, node, metastasis) classification to define malignant mesothelioma.[1]

Cancers staged using the AJCC cancer staging system include classifications for diffuse malignant pleural mesotheliomas but do not include localized malignant pleural mesotheliomas or other primary tumors of the pleura.[1]

Patients with stage I disease have a significantly better prognosis than patients with advanced stages. Because this disease is rare, exact survival information based on stage is limited.[2]

Table 1. Definitions of TNM Stages IA and IBa
Stage TNM Description
T = primary tumor; N = regional lymph node; M = metastasis.
aReprinted with permission from AJCC: Malignant Pleural Mesothelioma. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 457–68.
IA T1, N0, M0 T1 = Tumor limited to the ipsilateral parietal pleura with or without involvement of:
–visceral pleura.
–mediastinal pleura.
–diaphragmatic pleura.
N0 = No regional lymph node metastases.
M0 = No distant metastasis.
IB T2 or T3, N0, M0 T2 = Tumor involving each of the ipsilateral pleural surfaces (parietal, mediastinal, diaphragmatic, and visceral pleura) with at least one of the following features:
–involvement of diaphragmatic muscle.
–extension of tumor from visceral pleura into the underlying pulmonary parenchyma.
T3 = Describes locally advanced but potentially resectable tumor.
Tumor involving all the ipsilateral pleural surfaces (parietal, mediastinal, diaphragmatic, and visceral pleura) with at least one of the following features:
–involvement of the endothoracic fascia.
–extension into the mediastinal fat.
–solitary, completely resectable focus of tumor extending into the soft tissues of the chest wall.
–nontransmural involvement of the pericardium.
N0 = No regional lymph node metastases.
M0 = No distant metastasis.
Table 2. Definitions of TNM Stage IIa
Stage TNM Description
T = primary tumor; N = regional lymph node; M = metastasis.
aReprinted with permission from AJCC: Malignant Pleural Mesothelioma. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 457–68.
II T1, N1, M0 T1 = Tumor limited to the ipsilateral parietal pleura with or without involvement of:
–visceral pleura.
–mediastinal pleura.
–diaphragmatic pleura.
N1 = Metastases in the ipsilateral bronchopulmonary, hilar, or mediastinal (including the internal mammary, peridiaphragmatic, pericardial fat pad, or intercostal) lymph nodes.
M0 = No distant metastasis.
T2, N1, M0 T2 = Tumor involving each of the ipsilateral pleural surfaces (parietal, mediastinal, diaphragmatic, and visceral pleura) with at least one of the following features:
–involvement of diaphragmatic muscle.
–extension of tumor from visceral pleura into the underlying pulmonary parenchyma.
N1 = Metastases in the ipsilateral bronchopulmonary, hilar, or mediastinal (including the internal mammary, peridiaphragmatic, pericardial fat pad, or intercostal) lymph nodes.
M0 = No distant metastasis.
Table 3. Definitions of TNM Stages IIIA and IIIBa
Stage TNM Description
T = primary tumor; N = regional lymph node; M = metastasis.
aReprinted with permission from AJCC: Malignant Pleural Mesothelioma. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 457–68.
IIIA T3, N1, M0 T3 = Describes locally advanced but potentially resectable tumor.
Tumor involving all of the ipsilateral pleural surfaces (parietal, mediastinal, diaphragmatic, and visceral pleura) with at least one of the following features:
–involvement of the endothoracic fascia.
–extension into the mediastinal fat.
–solitary, completely resectable focus of tumor extending into the soft tissues of the chest wall.
–nontransmural involvement of the pericardium.
N1 = Metastases in the ipsilateral bronchopulmonary, hilar, or mediastinal (including the internal mammary, peridiaphragmatic, pericardial fat pad, or intercostal) lymph nodes.
M0 = No distant metastasis.
IIIB T1–3, N2, M0 T1 = Tumor limited to the ipsilateral parietal pleura with or without involvement of:
–visceral pleura.
–mediastinal pleura.
–diaphragmatic pleura.
T2 = Tumor involving each of the ipsilateral pleural surfaces (parietal, mediastinal, diaphragmatic, and visceral pleura) with at least one of the following features:
–involvement of diaphragmatic muscle.
–extension of tumor from visceral pleura into the underlying pulmonary parenchyma.
T3 = Describes locally advanced but potentially resectable tumor.
Tumor involving all of the ipsilateral pleural surfaces (parietal, mediastinal, diaphragmatic, and visceral pleura) with at least one of the following features:
–involvement of the endothoracic fascia.
–extension into the mediastinal fat.
–solitary, completely resectable focus of tumor extending into the soft tissues of the chest wall.
–nontransmural involvement of the pericardium.
N2 = Metastases in the contralateral mediastinal, ipsilateral, or contralateral supraclavicular lymph nodes.
M0 = No distant metastasis.
T4, Any N, M0 T4 = Describes locally advanced technically unresectable tumor. Tumor involving all of the ipsilateral pleural surfaces (parietal, mediastinal, diaphragmatic, and visceral pleura) with at least one of the following features:
–diffuse extension or multifocal masses of the tumor in the chest wall, with or without associated rib destruction.
–direct transdiaphragmatic extension of the tumor to the peritoneum.
–direct extension of the tumor to the contralateral pleura.
–direct extension of the tumor to the mediastinal organs.
–direct extension of the tumor into the spine.
–tumor extending through to the internal surface of the pericardium with or without a pericardial effusion; or tumor involving the myocardium.
NX = Regional lymph nodes cannot be assessed.
N0 = No regional lymph node metastases.
N1 = Metastases in the ipsilateral bronchopulmonary, hilar, or mediastinal (including the internal mammary, peridiaphragmatic, pericardial fat pad, or intercostal) lymph nodes.
N2 = Metastases in the contralateral mediastinal, ipsilateral, or contralateral supraclavicular lymph nodes.
M0 = No distant metastasis.
Table 4. Definitions of TNM Stage IVa
Stage TNM Description
T = primary tumor; N = regional lymph node; M = metastasis.
aReprinted with permission from AJCC: Malignant Pleural Mesothelioma. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 457–68.
IV Any T, Any N, M1 TX = Primary tumor cannot be assessed.
T0 = No evidence of primary tumor.
T1 = Tumor limited to the ipsilateral parietal pleura with or without involvement of:
–visceral pleura.
–mediastinal pleura.
–diaphragmatic pleura.
T2 = Tumor involving each of the ipsilateral pleural surfaces (parietal, mediastinal, diaphragmatic, and visceral pleura) with at least one of the following features:
–involvement of diaphragmatic muscle.
–extension of tumor from visceral pleura into the underlying pulmonary parenchyma.
T3 = Describes locally advanced but potentially resectable tumor.
Tumor involving all of the ipsilateral pleural surfaces (parietal, mediastinal, diaphragmatic, and visceral pleura) with at least one of the following features:
–involvement of the endothoracic fascia.
–extension into the mediastinal fat.
–solitary, completely resectable focus of tumor extending into the soft tissues of the chest wall.
–nontransmural involvement of the pericardium.
T4 = Describes locally advanced technically unresectable tumor. Tumor involving all of the ipsilateral pleural surfaces (parietal, mediastinal, diaphragmatic, and visceral pleura) with at least one of the following features:
–diffuse extension or multifocal masses of the tumor in the chest wall, with or without associated rib destruction.
–direct transdiaphragmatic extension of the tumor to the peritoneum.
–direct extension of the tumor to the contralateral pleura.
–direct extension of the tumor to the mediastinal organs.
–direct extension of the tumor into the spine.
–tumor extending through to the internal surface of the pericardium with or without a pericardial effusion; or tumor involving the myocardium.
NX = Regional lymph nodes cannot be assessed.
N0 = No regional lymph node metastases.
N1 = Metastases in the ipsilateral bronchopulmonary, hilar, or mediastinal (including the internal mammary, peridiaphragmatic, pericardial fat pad, or intercostal) lymph nodes.
N2 = Metastases in the contralateral mediastinal, ipsilateral, or contralateral supraclavicular lymph nodes.
M1 = Distant metastasis present.
References
  1. Malignant Pleural Mesothelioma. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. Springer; 2017, pp. 457–68.
  2. Chahinian AP, Pass HI: Malignant mesothelioma. In: Holland JC, Frei E, eds.: Cancer Medicine e.5. 5th ed. B.C. Decker Inc, 2000, pp 1293-1312.

Treatment Option Overview for Malignant Mesothelioma

Standard treatment for all but localized mesothelioma is generally not curative. Some patients will experience long-term survival with aggressive treatment approaches, but it remains unclear if overall survival (OS) is significantly altered by different treatment modalities or combinations of modalities.

Extrapleural pneumonectomy may improve the recurrence-free survival of selected patients with early-stage disease, but the impact on OS is unknown.[1] Pleurectomy and decortication can provide palliative relief from symptomatic effusions, discomfort caused by tumor burden, and pain caused by invasive tumor. For more information, see Cancer Pain. Trimodality therapy refers to a combination of chemotherapy, definitive surgery, and radiation therapy. Because of the rarity of mesothelioma and the complexities of patient selection, surgical technique, and optimal sequencing of therapy, delivery of such therapy in centers with established experience and expertise in the management of mesothelioma has shown better results. Operative mortality from pleurectomy with decortication is less than 2%,[2] while mortality from extrapleural pneumonectomy ranges from 6% to 30%.[1,3]

Several single-arm phase II studies have demonstrated prolonged survival times (compared with historical controls) for selected patients who received adjuvant radiation therapy after definitive surgery.[2,4,5] Most patients with pleural mesothelioma who receive radiation therapy experience pain relief, but symptom control is short-lived.[6,7] Other single-arm phase II studies investigated neoadjuvant chemotherapy (mainly with platinum and pemetrexed or gemcitabine) followed by definitive surgery and adjuvant radiation therapy.[8–10] These studies have also shown prolonged survival compared with historical controls; however, this advantage has yet to be confirmed in a randomized study.

References
  1. Rusch VW, Piantadosi S, Holmes EC: The role of extrapleural pneumonectomy in malignant pleural mesothelioma. A Lung Cancer Study Group trial. J Thorac Cardiovasc Surg 102 (1): 1-9, 1991. [PUBMED Abstract]
  2. Rusch V, Saltz L, Venkatraman E, et al.: A phase II trial of pleurectomy/decortication followed by intrapleural and systemic chemotherapy for malignant pleural mesothelioma. J Clin Oncol 12 (6): 1156-63, 1994. [PUBMED Abstract]
  3. Sugarbaker DJ, Mentzer SJ, DeCamp M, et al.: Extrapleural pneumonectomy in the setting of a multimodality approach to malignant mesothelioma. Chest 103 (4 Suppl): 377S-381S, 1993. [PUBMED Abstract]
  4. Rusch VW, Rosenzweig K, Venkatraman E, et al.: A phase II trial of surgical resection and adjuvant high-dose hemithoracic radiation for malignant pleural mesothelioma. J Thorac Cardiovasc Surg 122 (4): 788-95, 2001. [PUBMED Abstract]
  5. Batirel HF, Metintas M, Caglar HB, et al.: Trimodality treatment of malignant pleural mesothelioma. J Thorac Oncol 3 (5): 499-504, 2008. [PUBMED Abstract]
  6. Bissett D, Macbeth FR, Cram I: The role of palliative radiotherapy in malignant mesothelioma. Clin Oncol (R Coll Radiol) 3 (6): 315-7, 1991. [PUBMED Abstract]
  7. Ball DL, Cruickshank DG: The treatment of malignant mesothelioma of the pleura: review of a 5-year experience, with special reference to radiotherapy. Am J Clin Oncol 13 (1): 4-9, 1990. [PUBMED Abstract]
  8. Krug LM, Pass HI, Rusch VW, et al.: Multicenter phase II trial of neoadjuvant pemetrexed plus cisplatin followed by extrapleural pneumonectomy and radiation for malignant pleural mesothelioma. J Clin Oncol 27 (18): 3007-13, 2009. [PUBMED Abstract]
  9. Flores RM, Krug LM, Rosenzweig KE, et al.: Induction chemotherapy, extrapleural pneumonectomy, and postoperative high-dose radiotherapy for locally advanced malignant pleural mesothelioma: a phase II trial. J Thorac Oncol 1 (4): 289-95, 2006. [PUBMED Abstract]
  10. Weder W, Kestenholz P, Taverna C, et al.: Neoadjuvant chemotherapy followed by extrapleural pneumonectomy in malignant pleural mesothelioma. J Clin Oncol 22 (17): 3451-7, 2004. [PUBMED Abstract]

Treatment of Localized Malignant Mesothelioma (Stage I)

Treatment Options for Localized Malignant Mesothelioma (Stage I)

Treatment options for localized malignant mesothelioma (stage I) include:[1]

  1. Surgery. Solitary mesotheliomas are treated with surgical resection en bloc including contiguous structures to ensure wide disease-free margins. Sessile polypoid lesions are treated with surgical resection to ensure maximal potential for cure.[2] Intracavitary mesotheliomas are treated with extrapleural pneumonectomy.
  2. Palliative surgery. Pleurectomy and decortication with or without postoperative radiation therapy may be used for intracavitary mesothelioma.
  3. Palliative radiation therapy (for intracavitary mesothelioma).
  4. Intracavitary chemotherapy after resection (under clinical evaluation).[3,4]
  5. Multimodality therapy (under clinical evaluation).[4–6]
  6. Clinical trials.

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. Antman KH, Li FP, Osteen R, et al.: Mesothelioma. Cancer: Principles and Practice of Oncology Updates 3(1): 1-16, 1989.
  2. Martini N, McCormack PM, Bains MS, et al.: Pleural mesothelioma. Ann Thorac Surg 43 (1): 113-20, 1987. [PUBMED Abstract]
  3. Markman M, Kelsen D: Efficacy of cisplatin-based intraperitoneal chemotherapy as treatment of malignant peritoneal mesothelioma. J Cancer Res Clin Oncol 118 (7): 547-50, 1992. [PUBMED Abstract]
  4. Rusch V, Saltz L, Venkatraman E, et al.: A phase II trial of pleurectomy/decortication followed by intrapleural and systemic chemotherapy for malignant pleural mesothelioma. J Clin Oncol 12 (6): 1156-63, 1994. [PUBMED Abstract]
  5. Sugarbaker DJ, Mentzer SJ, DeCamp M, et al.: Extrapleural pneumonectomy in the setting of a multimodality approach to malignant mesothelioma. Chest 103 (4 Suppl): 377S-381S, 1993. [PUBMED Abstract]
  6. Vogelzang NJ: Malignant mesothelioma: diagnostic and management strategies for 1992. Semin Oncol 19 (4 Suppl 11): 64-71, 1992. [PUBMED Abstract]

Treatment of Advanced Malignant Mesothelioma (Stages II, III, and IV)

Treatment Options for Advanced Malignant Mesothelioma (Stages II, III, and IV)

Treatment options for advanced malignant mesothelioma (stages II, III, and IV) include:

  1. First-line systemic therapy.
  2. Multimodality clinical trials.[7–10]
  3. Symptomatic treatment to include drainage of effusions, chest tube pleurodesis, or thoracoscopic pleurodesis.[11] For more information, see Cardiopulmonary Syndromes.
  4. Palliative surgical resection in selected patients.[12,13]
  5. Palliative radiation therapy for patients with pain related to their cancer.[14,15]
  6. Intracavitary therapy. Intrapleural or intraperitoneal administration of chemotherapeutic agents (e.g., cisplatin, mitomycin, and cytarabine) has been reported to produce transient reduction in the size of tumor masses and temporary control of effusions in small clinical studies.[16–18] Additional studies are needed to define the role of intracavitary therapy.

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

First-line systemic therapy

Nivolumab and ipilimumab

Evidence (nivolumab and ipilimumab):

  1. An open-label, randomized, phase III study (CheckMate743 [NCT02899299]) included 605 patients with advanced treatment-naive pleural mesothelioma. Patients were randomly assigned to receive either nivolumab and ipilimumab (n = 303) or chemotherapy (n = 302).[1]
    • At the prespecified interim analysis, patients who received nivolumab plus ipilimumab had significantly extended overall survival (OS) compared with patients who received chemotherapy (median OS, 18.1 months [95% confidence interval (CI), 16.8–21.4] vs. 14.1 months [12.4–16.2]; hazard ratio [HR], 0.74; 96.6% CI, 0.60–0.91; P = .002).[1][Level of evidence A1]
    • The median progression-free survival (PFS) and objective response rates were not significantly different.
    • Grade 3 to 4 treatment-related adverse events occurred in 91 of 300 patients (30%) who received nivolumab plus ipilimumab and 91 of 284 patients (32%) who received chemotherapy.
    • Three (1%) treatment-related deaths occurred among patients who received nivolumab plus ipilimumab (pneumonitis, encephalitis, and heart failure) and one (<1%) among patients who received chemotherapy (myelosuppression).
Cisplatin plus pemetrexed, with or without bevacizumab

Evidence (cisplatin plus pemetrexed, with or without bevacizumab):

  1. A randomized phase III trial demonstrated the safety and efficacy of pemetrexed, an antifolate, and cisplatin in chemotherapy-naive patients with malignant mesothelioma who were not eligible for curative surgery.[4][Level of evidence A1] This trial compared pemetrexed (500 mg/m2) and cisplatin (75 mg/m2 on day 1) with cisplatin alone (75 mg/m2 on day 1 intravenously [IV] every 21 days). With 456 patients enrolled in the trial, 226 patients received pemetrexed plus cisplatin, 222 patients received cisplatin alone, and 8 patients did not receive therapy.

    After 117 patients had enrolled, folic acid and vitamin B12 were added to reduce toxic effects.

    • Folic acid (350–1,000 µg PO) was given daily, beginning 1 to 3 weeks before the first chemotherapy dose and continuing daily until 1 to 3 weeks after treatment ended.
    • A vitamin B12 injection (1,000 µg intramuscularly) was given 1 to 3 weeks before the first chemotherapy dose and was repeated approximately every 9 weeks until treatment ended.

    Dexamethasone (4 mg) or an equivalent corticosteroid was given orally twice daily for skin rash prophylaxis to all patients 1 day before, on the day of, and 1 day after each pemetrexed dose.

    • In an analysis of all patients who were randomly assigned and treated, the combination of pemetrexed and cisplatin was associated with a statistically significant improvement in survival compared with cisplatin alone.
      • The median survival was 12.1 months in the pemetrexed-plus-cisplatin arm and 9.3 months in the cisplatin-alone arm (P = .020).
      • The HR for death of patients in the pemetrexed-plus-cisplatin arm, compared with those in the control arm, was 0.77.
      • Median time-to-progression was significantly longer in the pemetrexed-plus-cisplatin arm (5.7 months vs. 3.9 months; P = .001).
    • This superiority in the combination arm was also demonstrated in the vitamin-supplemented subgroup.
      • The median survival was 13.3 months in the combination arm and 10.0 months in the cisplatin-alone arm (P = .051).
      • The principal adverse effects of the pemetrexed-plus-cisplatin regimen were myelosuppression, fatigue, nausea, vomiting, and dyspnea.
      • Most grade 3 to 4 adverse effects were significantly reduced by vitamin supplementation, without any decrease in efficacy.
  2. A randomized controlled, open-label, phase III trial (IFCT-GFPC-0701 [NCT00651456]) evaluated the addition of bevacizumab to chemotherapy and showed an improved OS with the three-drug regimen.[3] The trial included 448 patients with unresectable malignant pleural mesothelioma who had not received previous chemotherapy. Patients had an Eastern Cooperative Oncology Group performance status of 0 to 2 and had no contraindications to bevacizumab, including the use of antiplatelet agents, anticoagulants, and nonsteroidal anti-inflammatory agents. Patients were randomly assigned to receive IV pemetrexed (500 mg/m2) plus cisplatin (75 mg/m2) (PC) with or without bevacizumab (15 mg/kg) (PCB) in 21-day cycles for up to six cycles, until disease progression or toxic effects were seen.
    • The primary outcome was OS in the intention-to-treat population.
    • OS was significantly longer with PCB (median, 18.8 months; 95% CI, 15.9–22.6) than with PC (median, 16.1 months; 95% CI, 14.0–17.9; HR, 0.77; 0.62–0.95; P = .0167).
    • Overall, 158 of 222 patients (71%) who received PCB and 139 of 224 patients (62%) who received PC had grade 3 to 4 adverse events.
      • Patients who received PCB had more grade 3 or higher hypertension (51 of 222 [23%] vs. 0) and thrombotic events (13 of 222 [6%] vs. 2 of 224 [1%]) than patients who received PC.[3][Level of evidence A1]

    Combination immune checkpoint inhibitor therapy may be considered as an alternative to combination chemotherapy.

Durvalumab with platinum plus pemetrexed

Evidence (durvalumab with platinum plus pemetrexed):

  1. A phase II, single-arm, multicenter trial (PrE0505 [NCT02899195]) included 55 patients with unresectable, treatment-naive, pleural mesothelioma. Patients received up to six cycles of durvalumab (an anti–programmed death-ligand 1 [PD-L1] antibody) with a platinum plus pemetrexed. The primary end point was OS compared with historical controls (cisplatin and pemetrexed).[5]
    • After a median follow-up of 24.2 months, the median OS was 20.4 months (95% CI, 13.0–28.5) for patients in the durvalumab arm compared with the historical control of 12.1 months (HR, 0.034; one-sided P = .0014).[5][Level of evidence C1]
    • The median PFS was 6.7 months (95% CI, 6.1–8.4), and the objective response rate was 56.4% (95% CI, 42.3%–69.7%).
    • In a non-predefined subgroup analysis, patients with epithelioid malignant pleural mesothelioma had a higher objective response rate (65.9% vs. 28.6%; P = .03), and longer median OS (24.3 months vs. 9.2 months; HR, 0.27; 95% CI, 0.13–0.57; P < .001) than patients with nonepithelioid malignant pleural mesothelioma.
    • Responding tumors with epithelioid histology were characterized by a higher degree of genomic instability. Favorable clinical outcomes were also observed in patients with a higher immunogenic mutational burden and a more diverse T-cell repertoire, and in individuals with germline alterations in cancer-predisposing genes.
    • Grade 3 or higher treatment-related adverse events occurred in 65.5% of patients and included anemia (20%), hyponatremia (9%), fatigue (7%), leukopenia (5%), thrombocytopenia (5%), and hypertension (5%). There were no treatment-related deaths.
Platinum plus pemetrexed, followed by best supportive care, with or without maintenance gemcitabine

Evidence (platinum plus pemetrexed, followed by best supportive care, with or without maintenance gemcitabine):

  1. A randomized, open-label, phase II clinical trial (NVALT19 [Netherlands Trial Registry ID NTR4132/NL3847]) included 130 patients with unresectable malignant mesothelioma and no evidence of disease progression after at least four cycles of first-line chemotherapy with platinum plus pemetrexed. Patients were randomly assigned (1:1) to receive either maintenance IV gemcitabine (1,250 mg/m2 on days 1 and 8 of 21-day cycles) plus supportive care (n = 65), or to receive best supportive care alone (n = 65). Patients received treatment until disease progression, unacceptable toxicity, serious intercurrent illness, need for other anticancer therapy (except for palliative radiotherapy), or patient request for discontinuation. The primary end point was PFS in the intention-to-treat population.[6]
    • After a median follow-up of 36.5 months, the median PFS was 6.2 months in the gemcitabine group (95% CI, 4.6–8.7) and 3.2 months (95% CI, 2.8–4.1) in the supportive-care group (HR, 0.48; 95% CI, 0.33–0.71; P = .0002). The PFS benefit was confirmed by masked independent central review (HR, 0.49; 95% CI, 0.33–0.72; P = .0002).[6][Level of evidence B1]
    • Among patients with measurable disease at baseline, the objective radiological response rate was 17% in the gemcitabine group and 4% in the supportive-care group (P = .048).
    • The median OS was 16.4 months (95% CI, 11.6–20.2) in the gemcitabine group and 13.4 months (95% CI, 12.4–17.8) in the supportive care group (HR, 0.90; 95% CI, 0.60–1.34; P = .60).
    • Grade 3 or higher treatment-related adverse events occurred in 52% of patients in the gemcitabine group and 16% of patients in the supportive-care group. One patient in the gemcitabine group died of a treatment-related serious adverse event (grade 5 infection).

    The study demonstrated delayed disease progression in patients receiving maintenance gemcitabine, but the effect on OS is unclear.

Treatment of Malignant Peritoneal Mesothelioma

Malignant peritoneal mesothelioma arises from the mesothelial cells of the peritoneum and spreads within the confines of the abdominal cavity. There have been few prospective clinical trials conducted in this patient population. Most clinical evidence arises from single-center retrospective studies. Male sex and sarcomatoid or biphasic subtype disease are correlated with poor prognosis.[19,20]

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) are offered to patients with diffuse malignant peritoneal mesothelioma, no extraperitoneal disease spread, a good performance status, and an expectation to achieve complete surgical cytoreduction. Among centers with expertise in this form of therapy, reported median survival for appropriately selected patients approaches 3 to 4 years.[19,20]

  1. A large multi-institutional registry study evaluated cytoreductive surgery combined with HIPEC in patients with diffuse, malignant, peritoneal mesothelioma.[19] Among 401 patients, 187 (46%) had complete or near-complete cytoreduction, and 372 (92%) received HIPEC. Of the patients who received HIPEC, 311 (83%) received cisplatin and doxorubicin. The median follow-up period was 33 months (range, 1–235 months).
    • Grade 3 to 4 complications occurred in 127 of 401 patients (31%), and 9 patients (2%) died perioperatively.
    • The median actuarial OS was 53 months, with survival rates of 81% at 1 year, 60% at 3 years, and 47% at 5 years.
    • Prognostic factors associated with improved survival on multivariate analysis included epithelioid histological subtype, absence of lymph node metastases, complete or near complete resection, and the use of HIPEC.
  2. A second multi-institutional report included 211 patients treated at three centers in the United States (who were not part of the previous study).[20] All patients underwent cytoreductive surgery and HIPEC using either cisplatin or mitomycin.
    • The actuarial OS was 38 months. The survival rates were 41% at 5 years and 26% at 10 years.
    • Prognostic factors associated with improved survival were age younger than 60 years, complete or near-complete gross resection, low versus high histological grade, and the use of cisplatin versus mitomycin.

    In patients with malignant peritoneal mesothelioma, the efficacy of pemetrexed plus cisplatin appeared comparable with that seen in patients with pleural mesothelioma, and the regimen was well tolerated. Prospective phase II or III clinical trials of this regimen have not been conducted in patients with peritoneal mesothelioma.

  3. In the U.S. Pemetrexed Expanded Access Program, 98 patients (9.3%) had peritoneal mesothelioma, 57 patients were previously treated, and 38 patients were chemotherapy-naive.[21] Of the 73 patients with malignant peritoneal mesothelioma and measurable disease, 28 patients were chemotherapy-naive and 43 patients were previously treated. Twenty-six patients received single-agent pemetrexed, and 47 patients received pemetrexed and cisplatin.
    • The overall response rate was 26%. Similar objective response rates were achieved in previously treated and chemotherapy-naive patients.
    • The median OS for previously treated patients was 13.1 months; it had not been reached at the time of the analysis for chemotherapy-naive patients.
    • As expected, both response rate (29% vs. 19%) and median survival (13.1 vs. 8.7 months) were higher for patients who received the pemetrexed doublet than for those who received pemetrexed alone in this nonrandomized study.
    • These results were comparable with those seen in pleural mesothelioma.

    Carboplatin may be substituted for cisplatin.

  4. In the International Pemetrexed Expanded Access Program, 29 evaluable patients with peritoneal mesothelioma received pemetrexed 500 mg/m2 and carboplatin, dosed at an area under the curve of 5.[22]
    • Seven patients (24%) had objective responses (one complete), and 52% had stable disease.
    • These results were comparable with those achieved with pemetrexed and cisplatin.

The pemetrexed/cisplatin/bevacizumab and nivolumab/ipilimumab regimens that improved OS were conducted exclusively in patients with malignant pleural mesothelioma. Data to support the efficacy and safety of these regimens in patients with malignant peritoneal mesothelioma are required.

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. Baas P, Scherpereel A, Nowak AK, et al.: First-line nivolumab plus ipilimumab in unresectable malignant pleural mesothelioma (CheckMate 743): a multicentre, randomised, open-label, phase 3 trial. Lancet 397 (10272): 375-386, 2021. [PUBMED Abstract]
  2. Chahinian AP, Antman K, Goutsou M, et al.: Randomized phase II trial of cisplatin with mitomycin or doxorubicin for malignant mesothelioma by the Cancer and Leukemia Group B. J Clin Oncol 11 (8): 1559-65, 1993. [PUBMED Abstract]
  3. Zalcman G, Mazieres J, Margery J, et al.: Bevacizumab for newly diagnosed pleural mesothelioma in the Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS): a randomised, controlled, open-label, phase 3 trial. Lancet 387 (10026): 1405-14, 2016. [PUBMED Abstract]
  4. Vogelzang NJ, Rusthoven JJ, Symanowski J, et al.: Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol 21 (14): 2636-44, 2003. [PUBMED Abstract]
  5. Forde PM, Anagnostou V, Sun Z, et al.: Durvalumab with platinum-pemetrexed for unresectable pleural mesothelioma: survival, genomic and immunologic analyses from the phase 2 PrE0505 trial. Nat Med 27 (11): 1910-1920, 2021. [PUBMED Abstract]
  6. de Gooijer CJ, van der Noort V, Stigt JA, et al.: Switch-maintenance gemcitabine after first-line chemotherapy in patients with malignant mesothelioma (NVALT19): an investigator-initiated, randomised, open-label, phase 2 trial. Lancet Respir Med 9 (6): 585-592, 2021. [PUBMED Abstract]
  7. Mattson K, Holsti LR, Tammilehto L, et al.: Multimodality treatment programs for malignant pleural mesothelioma using high-dose hemithorax irradiation. Int J Radiat Oncol Biol Phys 24 (4): 643-50, 1992. [PUBMED Abstract]
  8. Weissmann LB, Antman KH: Incidence, presentation and promising new treatments for malignant mesothelioma. Oncology (Huntingt) 3 (1): 67-72; discussion 73-4, 77, 1989. [PUBMED Abstract]
  9. de Perrot M, Feld R, Cho BC, et al.: Trimodality therapy with induction chemotherapy followed by extrapleural pneumonectomy and adjuvant high-dose hemithoracic radiation for malignant pleural mesothelioma. J Clin Oncol 27 (9): 1413-8, 2009. [PUBMED Abstract]
  10. Sugarbaker DJ, Mentzer SJ, DeCamp M, et al.: Extrapleural pneumonectomy in the setting of a multimodality approach to malignant mesothelioma. Chest 103 (4 Suppl): 377S-381S, 1993. [PUBMED Abstract]
  11. Boutin C, Viallat JR, Rey R: Thoracoscopy in Diagnosis, Prognosis and Treatment of Mesothelioma. In: Antman K, Aisner J, eds.: Asbestos-Related Malignancy. Grune & Stratton, 1987, pp 301-21.
  12. Butchart EG, Ashcroft T, Barnsley WC, et al.: The role of surgery in diffuse malignant mesothelioma of the pleura. Semin Oncol 8 (3): 321-8, 1981. [PUBMED Abstract]
  13. Martini N, McCormack PM, Bains MS, et al.: Pleural mesothelioma. Ann Thorac Surg 43 (1): 113-20, 1987. [PUBMED Abstract]
  14. Bissett D, Macbeth FR, Cram I: The role of palliative radiotherapy in malignant mesothelioma. Clin Oncol (R Coll Radiol) 3 (6): 315-7, 1991. [PUBMED Abstract]
  15. Ball DL, Cruickshank DG: The treatment of malignant mesothelioma of the pleura: review of a 5-year experience, with special reference to radiotherapy. Am J Clin Oncol 13 (1): 4-9, 1990. [PUBMED Abstract]
  16. Markman M, Kelsen D: Efficacy of cisplatin-based intraperitoneal chemotherapy as treatment of malignant peritoneal mesothelioma. J Cancer Res Clin Oncol 118 (7): 547-50, 1992. [PUBMED Abstract]
  17. Markman M, Cleary S, Pfeifle C, et al.: Cisplatin administered by the intracavitary route as treatment for malignant mesothelioma. Cancer 58 (1): 18-21, 1986. [PUBMED Abstract]
  18. Rusch VW, Figlin R, Godwin D, et al.: Intrapleural cisplatin and cytarabine in the management of malignant pleural effusions: a Lung Cancer Study Group trial. J Clin Oncol 9 (2): 313-9, 1991. [PUBMED Abstract]
  19. Yan TD, Deraco M, Baratti D, et al.: Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for malignant peritoneal mesothelioma: multi-institutional experience. J Clin Oncol 27 (36): 6237-42, 2009. [PUBMED Abstract]
  20. Alexander HR, Bartlett DL, Pingpank JF, et al.: Treatment factors associated with long-term survival after cytoreductive surgery and regional chemotherapy for patients with malignant peritoneal mesothelioma. Surgery 153 (6): 779-86, 2013. [PUBMED Abstract]
  21. Jänne PA, Wozniak AJ, Belani CP, et al.: Open-label study of pemetrexed alone or in combination with cisplatin for the treatment of patients with peritoneal mesothelioma: outcomes of an expanded access program. Clin Lung Cancer 7 (1): 40-6, 2005. [PUBMED Abstract]
  22. Carteni G, Manegold C, Garcia GM, et al.: Malignant peritoneal mesothelioma-Results from the International Expanded Access Program using pemetrexed alone or in combination with a platinum agent. Lung Cancer 64 (2): 211-8, 2009. [PUBMED Abstract]

Treatment of Recurrent Malignant Mesothelioma

Treatment of patients with recurrent malignant mesothelioma usually involves procedures and agents not previously used in the initial treatment attempt. No standard treatment approaches have improved survival or controlled symptoms for a prolonged period. Selected patients with localized disease recurrence may be candidates for additional chest wall resection.

Treatment Options for Recurrent Malignant Mesothelioma

Treatment options for recurrent malignant mesothelioma include:

  1. Patients who have not received previous systemic therapy are candidates for first-line chemotherapy, chemoimmunotherapy, or dual immune checkpoint inhibition. For more information, see the Treatment of Advanced Malignant Mesothelioma (Stages II, III, and IV) section.
  2. Systemic therapy for recurrent malignant mesothelioma previously treated with first-line chemotherapy or immunotherapy.
  3. Patients with disease recurrence are candidates for phase I and II clinical trials that evaluate new targeted therapies, biological therapies, chemotherapeutic agents, or physical approaches.[1–8]
  4. Selected patients with localized disease recurrence may be candidates for additional chest-wall resection. One trial of 47 carefully selected patients at a single institution indicated that chest-wall resection could be safely performed. Time-to-recurrence from initial resection appeared to predict the expected survival benefit and was factored into decision making.[9][Level of evidence C1]

Systemic therapy

Gemcitabine in combination with ramucirumab

Evidence (gemcitabine in combination with ramucirumab):

  1. A multicenter, randomized, double-blind, placebo-controlled, phase II trial (RAMES [NCT03560973]) included 161 patients with malignant pleural mesothelioma that progressed during or after first-line treatment with pemetrexed plus platinum. Patients were randomly assigned (1:1) to receive either gemcitabine plus ramucirumab, an anti-VEGFR-2 antibody (n = 80), or gemcitabine plus placebo (n = 81). The primary end point was overall survival (OS).[10] Of note, patients enrolled in the RAMES trial had no previous exposure to bevacizumab or immune checkpoint inhibitors.
    • The median OS was 13.8 months (70% confidence interval [CI], 12.7–14.4) in the gemcitabine-plus-ramucirumab group and 7.5 months (70% CI, 6.9–8.9) in the gemcitabine-plus-placebo group (hazard ratio [HR], 0.71; 70% CI, 0.59–0.85; P = .028).[10][Level of evidence A1]
    • The median progression-free survival (PFS), although longer in the gemcitabine-plus-ramucirumab group, was not significantly different (HR, 0.79; 70% CI, 0.66–0.94; P = .082).
    • More patients who received gemcitabine plus ramucirumab had controlled disease than patients who received gemcitabine plus placebo (73% [70% CI, 66%–78%] vs. 52% [70% CI, 46%–58%]).
    • Grade 3 to 4 treatment-related adverse events were reported in 35 of 80 patients (44%) who received gemcitabine plus ramucirumab and 24 of 81 patients (30%) who received gemcitabine plus placebo.
    • There were no treatment-related deaths in either study group.
Pemetrexed

Evidence (pemetrexed):

  1. A large randomized study compared pemetrexed with best supportive care in 243 patients who received one previous regimen of chemotherapy that did not include pemetrexed.[11][Level of evidence A1]
    • No survival benefit was shown in patients who received pemetrexed, although the PFS rate, time-to-progression, and the response rates favored the pemetrexed arm.
Nivolumab

Evidence (nivolumab):

  1. A multicenter, placebo-controlled, double-blind, randomized, phase III trial (CONFIRM [NCT03063450]) included 332 patients with malignant pleural or peritoneal mesothelioma and disease progression after previous first-line platinum-based chemotherapy. Patients were randomly assigned (2:1) to receive either nivolumab, an anti–programmed death 1 (PD-1) antibody, at a flat dose of 240 mg intravenously every 2 weeks (n = 221), or placebo (n = 111) until disease progression or a maximum of 12 months. Co-primary end points were investigator-assessed PFS and OS.[12]
    • The median OS was 10.2 months (95% CI, 8.5–12.1) in the nivolumab group and 6.9 months (95% CI, 5.0–8.0) in the placebo group (HR, 0.69; 95% CI, 0.52–0.91; P = .0090). Programmed death-ligand 1 (PD-L1) expression was not predictive of response to treatment for either OS or PFS based on a positivity threshold of 1%.
    • At a median follow-up of 11.6 months, the median PFS was 3.0 months (95% CI, 2.8–4.1) in the nivolumab group and 1.8 months (95% CI, 1.4–2.6) in the placebo group (HR, 0.67; 95% CI, 0.55–0.85; P = .0012).[12][Level of evidence A1]
    • The overall response rate was 11% in the nivolumab group and 1% in the placebo group (odds ratio, 14.0; 95% CI, 2.4–not estimable; P = .00086).
    • Serious adverse events occurred in 41% of patients in the nivolumab group and 44% of patients in the placebo group. There were no treatment-related deaths in either group.
Vinorelbine

Evidence (vinorelbine):

  1. A multicenter, open-label, randomized, phase II trial (VIM [NCT02139904]) included 154 patients with malignant pleural mesothelioma and disease progression after previous platinum-based chemotherapy. Patients were randomly assigned (2:1) to receive either active symptom control (ASC) with oral vinorelbine (n = 98) or ASC alone (n = 56) every 3 weeks until disease progression, unacceptable toxicity, or withdrawal. The primary end point was PFS.[13]
    • The median PFS was 4.2 months in the ASC-plus-vinorelbine group and 2.8 months in the ASC-alone group (adjusted HR, 0.60; 80% CI [upper limit, 0.70]; one-sided adjusted log-rank P < .001).[13][Level of evidence B1]
    • The median OS did not differ significantly between the two groups (9.3 months in ASC-plus-vinorelbine group vs. 9.1 months in the ASC-alone group).
    • The objective response rate was 3% in the ASC-plus-vinorelbine group and 2% in the ASC-alone group.
    • Although BRCA1 expression is required for vinorelbine-induced apoptosis in preclinical models, and loss of expression may correlate with vinorelbine resistance, low BRCA1 expression did not correlate with clinical activity in this study.
    • Vinorelbine was generally well tolerated and most treatment-related adverse events in both groups were mild to moderate in severity. The most common serious adverse events in the ASC-plus-vinorelbine group versus the ASC-alone group were dyspnea (5% vs. 0%), lower respiratory tract infection (5% vs. 6%), unspecified infection (3% vs. 0%), and febrile neutropenia (3% vs. 0%). Treatment-related deaths were reported in two patients in the ASC-plus-vinorelbine group (caused by pneumonia and lower respiratory tract infection) and in one patient in the ASC-alone group (caused by lower respiratory tract infection).

    The clinical impact of vinorelbine monotherapy for treatment of relapsed malignant pleural mesothelioma is limited, with a modest improvement in PFS and no difference in OS. This clinical impact should be weighed against the potential impact on quality of life caused by treatment-related adverse events.

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. Rusch V, Saltz L, Venkatraman E, et al.: A phase II trial of pleurectomy/decortication followed by intrapleural and systemic chemotherapy for malignant pleural mesothelioma. J Clin Oncol 12 (6): 1156-63, 1994. [PUBMED Abstract]
  2. Markman M, Kelsen D: Efficacy of cisplatin-based intraperitoneal chemotherapy as treatment of malignant peritoneal mesothelioma. J Cancer Res Clin Oncol 118 (7): 547-50, 1992. [PUBMED Abstract]
  3. Zucali PA, Ceresoli GL, Garassino I, et al.: Gemcitabine and vinorelbine in pemetrexed-pretreated patients with malignant pleural mesothelioma. Cancer 112 (7): 1555-61, 2008. [PUBMED Abstract]
  4. Boutin C, Viallat JR, Van Zandwijk N, et al.: Activity of intrapleural recombinant gamma-interferon in malignant mesothelioma. Cancer 67 (8): 2033-7, 1991. [PUBMED Abstract]
  5. Ong ST, Vogelzang NJ: Chemotherapy in malignant pleural mesothelioma. A review. J Clin Oncol 14 (3): 1007-17, 1996. [PUBMED Abstract]
  6. Gregorc V, Zucali PA, Santoro A, et al.: Phase II study of asparagine-glycine-arginine-human tumor necrosis factor alpha, a selective vascular targeting agent, in previously treated patients with malignant pleural mesothelioma. J Clin Oncol 28 (15): 2604-11, 2010. [PUBMED Abstract]
  7. Papa S, Popat S, Shah R, et al.: Phase 2 study of sorafenib in malignant mesothelioma previously treated with platinum-containing chemotherapy. J Thorac Oncol 8 (6): 783-7, 2013. [PUBMED Abstract]
  8. Calabrò L, Morra A, Fonsatti E, et al.: Tremelimumab for patients with chemotherapy-resistant advanced malignant mesothelioma: an open-label, single-arm, phase 2 trial. Lancet Oncol 14 (11): 1104-11, 2013. [PUBMED Abstract]
  9. Burt BM, Ali SO, DaSilva MC, et al.: Clinical indications and results after chest wall resection for recurrent mesothelioma. J Thorac Cardiovasc Surg 146 (6): 1373-9; discussion 1379-80, 2013. [PUBMED Abstract]
  10. Pinto C, Zucali PA, Pagano M, et al.: Gemcitabine with or without ramucirumab as second-line treatment for malignant pleural mesothelioma (RAMES): a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol 22 (10): 1438-1447, 2021. [PUBMED Abstract]
  11. Jassem J, Ramlau R, Santoro A, et al.: Phase III trial of pemetrexed plus best supportive care compared with best supportive care in previously treated patients with advanced malignant pleural mesothelioma. J Clin Oncol 26 (10): 1698-704, 2008. [PUBMED Abstract]
  12. Fennell DA, Ewings S, Ottensmeier C, et al.: Nivolumab versus placebo in patients with relapsed malignant mesothelioma (CONFIRM): a multicentre, double-blind, randomised, phase 3 trial. Lancet Oncol 22 (11): 1530-1540, 2021. [PUBMED Abstract]
  13. Fennell DA, Porter C, Lester J, et al.: Active symptom control with or without oral vinorelbine in patients with relapsed malignant pleural mesothelioma (VIM): A randomised, phase 2 trial. EClinicalMedicine 48: 101432, 2022. [PUBMED Abstract]

Latest Updates to This Summary (05/12/2025)

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 adult malignant mesothelioma. 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 Malignant Mesothelioma Treatment are:

  • Janet Dancey, MD, FRCPC (Ontario Institute for Cancer Research & NCIC Clinical Trials Group)
  • 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.

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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® Adult Treatment Editorial Board. PDQ Malignant Mesothelioma Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/mesothelioma/hp/mesothelioma-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389420]

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Malignant Mesothelioma Treatment (PDQ®)–Patient Version

Malignant Mesothelioma Treatment (PDQ®)–Patient Version

General Information About Malignant Mesothelioma

Go to Health Professional Version

Key Points

  • Malignant mesothelioma is a type of cancer that forms in the thin layer of tissue that covers organs in the chest or abdomen.
  • Being exposed to asbestos can increase the risk of malignant mesothelioma.
  • Signs and symptoms of malignant mesothelioma include shortness of breath and pain under the rib cage.
  • Tests that examine the inside of the chest and abdomen are used to diagnose malignant mesothelioma.
  • After malignant mesothelioma has been diagnosed, tests are done to find out if cancer cells have spread to other parts of the body.
  • Some people decide to get a second opinion.
  • Certain factors affect prognosis (chance of recovery) and treatment options.

Malignant mesothelioma is a type of cancer that forms in the thin layer of tissue that covers organs in the chest or abdomen.

Malignant mesothelioma may be found in one or more of the following:

  • the pleura, a thin layer of tissue that lines the chest cavity and covers the lungs
  • the peritoneum, a thin layer of tissue that lines the abdomen and covers most of the organs in the abdomen
  • the pericardium, a thin layer of tissue that surrounds the heart

Malignant mesothelioma may also form in the heart or testicles, but this is rare.

EnlargeDrawing shows parts of the body where malignant mesothelioma may form, including the pleura (the tissue that lines the chest cavity and covers the lungs), the pericardium (the tissue that surrounds the heart), the peritoneum (the tissue that lines the abdomen and covers most of the organs in the abdomen), and the testicles. The heart and lungs are also shown.
Malignant mesothelioma forms in the tissue that lines the chest or abdomen, including the pleura (the tissue that lines the chest cavity and covers the lungs) and the peritoneum (the tissue that lines the abdomen and covers most of the organs in the abdomen). Malignant mesothelioma may also form in the pericardium (the tissue that surrounds the heart) or the testicles, but this is rare.

Being exposed to asbestos can increase the risk of malignant mesothelioma.

Malignant mesothelioma is caused by certain changes to the way the cells that line the organs function, especially how they grow and divide into new cells. Often, the exact cause of the cell change is unknown. Learn more about how cancer develops at What Is Cancer?

A risk factor is anything that increases the chance of getting a disease. Most people with malignant mesothelioma have worked or lived in places where they inhaled or swallowed asbestos, which has been used in the building and textile industries. After being exposed to asbestos, it usually takes a long time for malignant mesothelioma to form. Living with a person who works near asbestos is also a risk factor for malignant mesothelioma. Not every person with one or more of these risk factors will develop malignant mesothelioma. And it can develop in some people who don’t have any known risk factors.

Talk to your doctor if you think you may be at risk.

Signs and symptoms of malignant mesothelioma include shortness of breath and pain under the rib cage.

Sometimes the cancer causes fluid to collect in the chest or in the abdomen. Signs and symptoms may be caused by the fluid, malignant mesothelioma, or other conditions. Check with your doctor if you have any of the following:

  • trouble breathing
  • cough
  • pain under the rib cage
  • pain or swelling in the abdomen
  • lumps in the abdomen
  • constipation
  • problems with blood clots (clots form when they shouldn’t)
  • weight loss for no known reason
  • fatigue (feeling very tired)

Tests that examine the inside of the chest and abdomen are used to diagnose malignant mesothelioma.

Sometimes it is hard to tell the difference between malignant mesothelioma in the chest and lung cancer. If you have symptoms that suggest mesothelioma, the doctor will need to find out if these are due to cancer or to another problem. The doctor will ask when the symptoms started and how often you have been having them. They will also ask about your personal and family health history and do a physical exam. Depending on these results, they may recommend other tests. If you are diagnosed with mesothelioma, the results of these tests will help you and your doctor plan treatment.

The tests and procedures used to diagnose mesothelioma may include:

  • 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) 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. Learn more about Computed Tomography (CT) Scans and Cancer.
  • Biopsy is the removal of cells or tissues from the pleura or peritoneum so that a pathologist can view it under a microscope to check for signs of cancer.

    Procedures used to collect the cells or tissues include:

    • Fine-needle (FNA) aspiration biopsy of the lung uses a thin needle to remove tissue or fluid. An 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, and a sample is removed.
      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.
    • Thoracoscopy is surgery to look at the organs inside the chest to check for abnormal areas. An incision (cut) is made between two ribs, and a thoracoscope (a thin, tube-like instrument with a light and a lens for viewing) is inserted into the chest.
    • Thoracotomy is surgery to look inside the chest. An incision (cut) is made between two ribs to check inside the chest for signs of disease.
    • Peritoneoscopy is surgery to look inside the abdomen. An incision (cut) is made in the abdominal wall, and a peritoneoscope (a thin, tube-like instrument with a light and a lens for viewing) is inserted into the abdomen to check for signs of disease.
    • Open biopsy is surgery to remove abnormal tissues so a pathologist can check it under a microscope for signs of disease. An incision (cut) is made through the skin to expose and remove the tissues.

    The following tests may be done on the cells and tissue samples that are taken:

    • A cytologic exam is a laboratory test to view cells under a microscope to check for anything abnormal. For mesothelioma, fluid is taken from the chest or the abdomen. A pathologist checks the fluid for signs of cancer.
    • Immunohistochemistry is a laboratory test that 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.
    • Electron microscopy is a laboratory test in which cells in a sample of tissue are viewed under a high-powered microscope to look for certain changes in the cells. An electron microscope shows tiny details better than other types of microscopes.

After malignant mesothelioma has been diagnosed, tests are done to find out if cancer cells have spread to other parts of the body.

The process used to find out if cancer has spread outside the pleura or peritoneum is called staging. The information gathered from the staging process determines the stage of the disease. It is important to know whether the cancer has spread in order to plan treatment.

The following tests and procedures may be used in the staging process:

  • 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 and abdomen. 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 at Computed Tomography (CT) Scans and Cancer.
  • PET scan (positron emission tomography scan) uses a small amount of radioactive sugar that is injected into a vein. The PET 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.
  • MRI (magnetic resonance imaging) uses a magnet, radio waves, and a computer to make a series of detailed pictures of areas inside the body. This procedure is also called nuclear magnetic resonance imaging (NMRI).
  • Endoscopic ultrasound (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. This procedure is also called endosonography. EUS may be used to guide fine-needle aspiration (FNA) biopsy of the lung, lymph nodes, or other areas.
    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.
  • Laparoscopy is surgery to look at the organs inside the abdomen to check for signs of disease. Small incisions (cuts) are made in the wall of the abdomen, and a laparoscope (a thin, lighted tube) is inserted into one of the incisions. Other instruments may be inserted through the same or other incisions to perform procedures such as taking tissue samples to be checked under a microscope for signs of disease.
  • 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.
  • Mediastinoscopy is surgery 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.

Some people decide to get a second opinion.

You may want to get a second opinion to confirm your 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 prognosis (chance of recovery) and treatment options.

The prognosis and treatment options depend on:

  • the stage of the cancer
  • the size of the tumor
  • whether the tumor can be removed completely by surgery
  • the amount of fluid in the chest or abdomen
  • the patient’s age
  • the patient’s activity level
  • the patient’s general health, including lung and heart health
  • the type of mesothelioma cells and how they look under a microscope
  • the number of white blood cells and how much hemoglobin is in the blood
  • whether the patient is male or female
  • whether the cancer has just been diagnosed or has recurred (come back)

Stages of Malignant Mesothelioma

Key Points

  • Cancer stage describes the extent of cancer in the body.
  • The following stages are used for malignant mesothelioma of the lung:
    • Stage I (also called stage 1) malignant mesothelioma
    • Stage II (also called stage 2) malignant mesothelioma
    • Stage III (also called stage 3) malignant mesothelioma
    • Stage IV (also called stage 4) malignant mesothelioma
  • Malignant mesothelioma can recur (come back) after it has been treated.

Cancer stage describes the extent of cancer in the body.

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 mesothelioma to plan the best treatment.

There are several staging systems for cancer that describe the extent of the cancer. Malignant mesothelioma 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 mesothelioma. Learn more about Cancer Staging.

The following stages are used for malignant mesothelioma of the lung:

Stage I (also called stage 1) malignant mesothelioma

Stage I is divided into stages IA and IB:

  • In stage IA, cancer is found in the inside lining of the chest wall on one side of the chest. On the same side of the chest, cancer may also be found in one or more of the following:
    • the thin layer of tissue that covers the lung
    • the thin layer of tissue that covers the organs between the lungs
    • the thin layer of tissue that covers the top of the diaphragm
  • In stage IB, cancer is found in the inside lining of the chest wall, and in each of the thin layers of tissue that cover the lung, the organs between the lungs, and the top of the diaphragm on one side of the chest. On the same side of the chest, cancer has also spread into one or more of the following:
    • diaphragm
    • lung tissue
    • tissue between the ribs and the inside lining of the chest wall
    • fat in the area between the lungs
    • soft tissues of the chest wall
    • sac around the heart

Stage II (also called stage 2) malignant mesothelioma

In stage II, cancer is found in the inside lining of the chest wall on one side of the chest. On the same side of the chest, cancer may also be found in one or more of the following:

  • the thin layer of tissue that covers the lung
  • the thin layer of tissue that covers the organs between the lungs
  • the thin layer of tissue that covers the top of the diaphragm

Cancer has spread to lymph nodes along the center of the chest on the same side of the chest as the tumor.

or

Cancer is found in the inside lining of the chest wall, and in each of the thin layers of tissue that cover the lung, the organs between the lungs, and the top of the diaphragm on one side of the chest. On the same side of the chest, cancer has also spread into one or both of the following:

  • diaphragm
  • lung tissue

Cancer has spread to lymph nodes along the center of the chest on the same side of the chest as the tumor.

Stage III (also called stage 3) malignant mesothelioma

Stage III is divided into stages IIIA and IIIB.

  • In stage IIIA, cancer is found in the inside lining of the chest wall, and in each of the thin layers of tissue that cover the lung, the organs between the lungs, and the top of the diaphragm on one side of the chest. On the same side of the chest, cancer has also spread into one or more of the following:
    • tissue between the ribs and the inside lining of the chest wall
    • fat in the area between the lungs
    • soft tissues of the chest wall
    • sac around the heart

    Cancer has spread to lymph nodes along the center of the chest on the same side of the chest as the tumor.

  • In stage IIIB, cancer is found in the inside lining of the chest wall, and may also be found in the thin layers of tissue that cover the lung, the organs between the lungs, and/or the top of the diaphragm on one side of the chest. On the same side of the chest, cancer may have also spread into one or more of the following:
    • diaphragm
    • lung tissue
    • tissue between the ribs and the inside lining of the chest wall
    • fat in the area between the lungs
    • soft tissues of the chest wall
    • sac around the heart

    Cancer has spread to lymph nodes above the collarbone on either side of the chest or cancer has spread to lymph nodes along the center of the chest on the opposite side of the chest as the tumor.

    or

    Cancer is found in the inside lining of the chest wall, and in each of the thin layers of tissue that cover the lung, the organs between the lungs, and the top of the diaphragm on one side of the chest. Cancer has also spread to one or more of the following:

    • the chest wall and may be found in the rib
    • through the diaphragm into the peritoneum
    • the tissue lining the chest on the opposite side of the body as the tumor
    • the organs in the area between the lungs (esophagus, trachea, thymus, blood vessels)
    • the spine
    • through the sac around the heart or into the heart muscle

    Cancer may have spread to lymph nodes.

Stage IV (also called stage 4) malignant mesothelioma

In stage IV, cancer has spread to the tissue covering the lung or the lung on the opposite side of the chest, peritoneum, bones, liver, lymph nodes outside the chest, or to other parts of the body.

Stage IV malignant mesothelioma is also called metastatic mesothelioma. Metastatic cancer happens when cancer cells travel through the lymphatic system or blood and form tumors in other parts of the body. The metastatic tumor is the same type of cancer as the primary tumor. For example, if malignant mesothelioma spreads to the liver, the cancer cells in the liver are actually malignant mesothelioma cells. The disease is called metastatic mesothelioma, not liver cancer. Learn more in Metastatic Cancer: When Cancer Spreads.

Malignant mesothelioma can recur (come back) after it has been treated.

Recurrent malignant mesothelioma is cancer that has come back after it has been treated. If mesothelioma comes back, it may come back in the chest or in other parts of the body, such as the liver, lungs, or both. Tests will be done to help determine where the cancer has returned. The type of treatment for recurrent mesothelioma 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 patients with malignant mesothelioma.
  • The following types of treatment are used:
    • Surgery
    • Radiation therapy
    • Chemotherapy
    • Immunotherapy
    • Targeted therapy
  • New types of treatment are being tested in clinical trials.
  • Treatment for malignant mesothelioma may cause side effects.
  • Follow-up care may be needed.

There are different types of treatment for patients with malignant mesothelioma.

Different types of treatments are available for malignant mesothelioma. 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

The following surgical treatments may be used for malignant mesothelioma in the chest:

  • Wide local excision is surgery to remove the cancer and some of the healthy tissue around it. The amount of healthy tissue removed depends on how deep or how large the tumor being removed is.
  • Pleurectomy and decortication is surgery to remove part of the covering of the lungs and lining of the chest and part of the outside surface of the lungs.
  • Extrapleural pneumonectomy is surgery to remove one whole lung and part of the lining of the chest, the diaphragm, and the lining of the sac around the heart.
  • Pleurodesis is surgery that uses chemicals or drugs to make a scar in the space between the layers of the pleura. Fluid is first drained from the space using a catheter or chest tube and the chemical or drug is put into the space. The scarring stops the build-up of fluid in the pleural cavity.

After the doctor removes all the cancer that can be seen at the time of the surgery, some people may receive chemotherapy or radiation therapy 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 uses high-energy x-rays or other types of radiation to kill cancer cells or keep them from growing. External radiation therapy uses a machine outside the body to send radiation toward the area of the body with cancer. It may also be used as palliative care to relieve symptoms and improve quality of life.

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. Combination chemotherapy is the use of more than one anticancer drug.

Systemic chemotherapy is when chemotherapy is taken by mouth or injected into a vein or muscle. When given this way, the drugs enter the bloodstream and can reach cancer cells throughout the body.

Regional chemotherapy is when chemotherapy is placed directly into an organ or a body cavity, such as the chest or peritoneum. When given this way, the drugs mainly affect cancer cells in those areas. Hyperthermic intraperitoneal chemotherapy (HIPEC) is a type of regional chemotherapy used to treat malignant mesothelioma:

  • HIPEC may be used to treat mesothelioma that has spread to the peritoneum (tissue that lines the abdomen and covers most of the organs in the abdomen). After the surgeon removes all the cancer that can be seen, a solution containing anticancer drugs is heated and pumped into and out of the abdomen to kill cancer cells that remain. Heating the anticancer drugs may kill more cancer cells.

The way the chemotherapy is given depends on the type and stage of the cancer being treated.

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.

Visit Drugs Approved for Malignant Mesothelioma for more information.

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 advanced mesothelioma include:

Other immunotherapy drugs, such as durvalumab, are being studied in malignant mesothelioma.

Learn more about Immunotherapy to Treat Cancer.

Targeted therapy

Targeted therapy uses drugs or other substances to identify and attack specific cancer cells. Bevacizumab is a targeted therapy drug used to treat malignant mesothelioma.

Other targeted therapies, such as ramucirumab, are being studied in malignant mesothelioma.

Learn more about Targeted Therapy to Treat Cancer.

New types of treatment are being tested in clinical trials.

Joining a clinical trial may be an option. There are different types of clinical trials for people with mesothelioma. For example, a treatment trial tests new treatments or new ways of using existing 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 that are accepting participants. This 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 at Clinical Trials Information for Patients and Caregivers.

Treatment for malignant mesothelioma 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 Localized Malignant Mesothelioma (Stage I)

If stage I malignant mesothelioma is in one part of the chest lining, treatment may include surgery to remove the cancer and the tissue around it.

Treatment of stage I intracavitary mesothelioma may include:

  • a surgery called extrapleural pneumonectomy
  • palliative surgery with pleurectomy and decortication, which may be followed by radiation therapy, to relieve symptoms and improve quality of life
  • palliative radiation therapy to relieve symptoms and improve quality of life

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 Advanced Malignant Mesothelioma (Stages II, III, and IV)

If stage II, stage III, or stage IV malignant mesothelioma is found in the chest, treatment may include:

  • immunotherapy (nivolumab and ipilimumab)
  • combination chemotherapy with or without targeted therapy (bevacizumab)
  • combination chemotherapy and palliative care, which may be followed by maintenance chemotherapy
  • palliative care, which may include draining fluid from the chest, a procedure to prevent fluid from collecting in the chest (pleurodesis), surgery, or radiation therapy, to relieve symptoms and improve quality of life
  • chemotherapy placed directly into the chest or abdominal cavity to shrink the tumors and keep fluid from building up

If stage II, stage III, or stage IV malignant mesothelioma is found in the peritoneum, treatment 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 Recurrent Malignant Mesothelioma

When malignant mesothelioma recurs (comes back), the treatment strategy often involves options that weren’t used in the initial treatment. If you haven’t received systemic therapy before, treatment may include:

If you have received systemic therapy, treatment might include the following, given alone or in combination:

  • chemotherapy
  • immunotherapy

For certain people with locally recurrent cancer, surgery to remove the affected part of the chest wall may be an option.

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.

To Learn More About Malignant Mesothelioma

For more from the National Cancer Institute about malignant mesothelioma, see the following:

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 adult malignant mesothelioma. 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 Malignant Mesothelioma Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/mesothelioma/patient/mesothelioma-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389166]

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.

Malignant Mesothelioma—Health Professional Version

Malignant Mesothelioma—Health Professional Version

Treatment

PDQ Treatment Information for Health Professionals

More information

Causes & Prevention

NCI does not have PDQ evidence-based information about prevention of malignant mesothelioma.

More information

Screening

NCI does not have PDQ evidence-based information about screening for malignant mesothelioma.

More information

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.

Cancer Pain Nausea and Vomiting Nutrition in Cancer Care Transition to End-of-Life Care Last Days of Life View all Supportive and Palliative Care Summaries

Gastric Cancer Treatment (PDQ®)–Health Professional Version

Gastric Cancer Treatment (PDQ®)–Health Professional Version

General Information About Gastric Cancer

Incidence and Mortality

Estimated new cases and deaths from gastric cancer in the United States in 2025:[1]

  • New cases: 30,300.
  • Deaths: 10,780.

Epidemiology

This summary discusses the management of gastric adenocarcinoma, which accounts for 90% to 95% of all gastric malignancies. Changing epidemiological patterns in the United States regarding the anatomical location of esophagogastric cancers show a trend of decreased occurrence of distal or noncardia gastric cancers.[2] However, in people aged 25 to 39 years, there has been an increase in the incidence of noncardia gastric cancers, from 0.27 cases per 100,000 individuals (1977–1981) to 0.45 cases per 100,000 individuals (2002–2006).[2] Additional studies are needed to confirm the observed increases in noncardia gastric cancers in this specific age group.

In contrast to the overall stable trend for noncardia gastric cancers, earlier studies demonstrated an increased incidence of adenocarcinomas of the gastric cardia of 4% to 10% per year from the mid-1970s to the late 1980s.[3] Similarly, the incidence of gastroesophageal junction adenocarcinomas increased sharply, from 1.22 cases per 100,000 individuals (1973–1978) to 2.00 cases per 100,000 individuals (1985–1990).[4] Since that time, the incidence has remained steady at 1.94 cases per 100,000 individuals (2003–2008).[4] More recent data demonstrate that the incidence of gastric cardia cancers has been relatively stable, although an increase has been observed, from 2.4 cases per 100,000 individuals (1977–1981) to 2.9 cases per 100,000 individuals (2001–2006) in the White population.[2] The reasons for these temporal changes in incidence are unclear.

Risk Factors

In the United States, gastric cancer ranks 15th in incidence among the major types of cancer. While the precise etiology is unknown, acknowledged risk factors for gastric cancer include:[5–8]

  • Helicobacter pylori gastric infection.
  • Advanced age.
  • Male sex.
  • Diet low in fruits and vegetables.
  • Diet high in salted, smoked, or preserved foods.
  • Chronic atrophic gastritis.
  • Intestinal metaplasia.
  • Pernicious anemia.
  • Gastric adenomatous polyps.
  • Family history of gastric cancer.
  • Cigarette smoking.
  • Ménétrier disease (giant hypertrophic gastritis).
  • Epstein-Barr virus infection.
  • Familial syndromes (including familial adenomatous polyposis).

Prognosis and Survival

The prognosis of patients with gastric cancer is related to tumor extent and includes both nodal involvement and direct tumor extension beyond the gastric wall.[9,10] Tumor grade may also provide some prognostic information.[11]

In localized distal gastric cancer, more than 50% of patients can be cured. However, early-stage disease accounts for only 10% to 20% of all cases diagnosed in the United States. The remaining patients present with metastatic disease in either regional or distant sites. The 5-year overall survival rate in these patients ranges from almost no survival for patients with disseminated disease to almost 50% survival for patients with localized distal gastric cancers confined to resectable regional disease. Even with apparent localized disease, the 5-year survival rate of patients with proximal gastric cancer is only 10% to 15%. Although the treatment of patients with disseminated gastric cancer may result in palliation of symptoms and some prolongation of survival, long remissions are uncommon.

Gastrointestinal stromal tumors occur most commonly in the stomach. For more information, see Gastrointestinal Stromal Tumors Treatment.

References
  1. American Cancer Society: Cancer Facts and Figures 2025. American Cancer Society, 2025. Available online. Last accessed January 16, 2025.
  2. Anderson WF, Camargo MC, Fraumeni JF, et al.: Age-specific trends in incidence of noncardia gastric cancer in US adults. JAMA 303 (17): 1723-8, 2010. [PUBMED Abstract]
  3. Blot WJ, Devesa SS, Kneller RW, et al.: Rising incidence of adenocarcinoma of the esophagus and gastric cardia. JAMA 265 (10): 1287-9, 1991. [PUBMED Abstract]
  4. Buas MF, Vaughan TL: Epidemiology and risk factors for gastroesophageal junction tumors: understanding the rising incidence of this disease. Semin Radiat Oncol 23 (1): 3-9, 2013. [PUBMED Abstract]
  5. Kurtz RC, Sherlock P: The diagnosis of gastric cancer. Semin Oncol 12 (1): 11-8, 1985. [PUBMED Abstract]
  6. Scheiman JM, Cutler AF: Helicobacter pylori and gastric cancer. Am J Med 106 (2): 222-6, 1999. [PUBMED Abstract]
  7. Fenoglio-Preiser CM, Noffsinger AE, Belli J, et al.: Pathologic and phenotypic features of gastric cancer. Semin Oncol 23 (3): 292-306, 1996. [PUBMED Abstract]
  8. National Cancer Institute: SEER Cancer Stat Facts: Stomach Cancer. Bethesda, Md: National Cancer Institute. Available online. Last accessed February 21, 2025.
  9. Siewert JR, Böttcher K, Stein HJ, et al.: Relevant prognostic factors in gastric cancer: ten-year results of the German Gastric Cancer Study. Ann Surg 228 (4): 449-61, 1998. [PUBMED Abstract]
  10. Nakamura K, Ueyama T, Yao T, et al.: Pathology and prognosis of gastric carcinoma. Findings in 10,000 patients who underwent primary gastrectomy. Cancer 70 (5): 1030-7, 1992. [PUBMED Abstract]
  11. Adachi Y, Yasuda K, Inomata M, et al.: Pathology and prognosis of gastric carcinoma: well versus poorly differentiated type. Cancer 89 (7): 1418-24, 2000. [PUBMED Abstract]

Cellular Classification of Gastric Cancer

There are two major types of gastric adenocarcinoma:

  • Intestinal.
  • Diffuse.

Intestinal adenocarcinomas are well differentiated, and the cells tend to arrange themselves in tubular or glandular structures. The terms tubular, papillary, and mucinous are assigned to the various types of intestinal adenocarcinomas. Rarely, adenosquamous cancers can occur.

Diffuse adenocarcinomas are undifferentiated or poorly differentiated, and they lack a gland formation. Clinically, diffuse adenocarcinomas can give rise to infiltration of the gastric wall (i.e., linitis plastica).

Some tumors can have mixed features of intestinal and diffuse types.

Stage Information for Gastric Cancer

AJCC Prognostic Stage Groups and TNM Definitions

The American Joint Committee on Cancer (AJCC) has designated staging by TNM (tumor, node, metastasis) classification to define gastric cancer.[1]

Pathological (pTNM)

Table 1. Definitions of pTNM Stage 0a
Stage TNM Description
T = primary tumor; N = regional lymph node; M = distant metastasis; p = pathological.
aReprinted with permission from AJCC: Stomach. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 203–20.
0 Tis, N0, M0 Tis = Carcinoma in situ: intraepithelial tumor without invasion of the lamina propria, high-grade dysplasia.
N0 = No regional lymph node metastasis.
M0 = No distant metastasis.
Table 2. Definitions of pTNM Stages IA and IBa
Stage TNM Description
T = primary tumor; N = regional lymph node; M = distant metastasis; p = pathological.
aReprinted with permission from AJCC: Stomach. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 203–20.
bA tumor may penetrate the muscularis propria with extension into the gastrocolic or gastrohepatic ligaments, or into the greater or lesser omentum, without perforation of the visceral peritoneum covering these structures. In this case, the tumor is classified T3. If there is perforation of the visceral peritoneum covering the gastric ligaments or the omentum, the tumor should be classified T4.
IA T1, N0, M0 T1 = Tumor invades lamina propria, muscularis mucosae, or submucosa.
–T1a = Tumor invades lamina propria or muscularis mucosae.
–T1b = Tumor invades submucosa.
N0 = No regional lymph node metastasis.
M0 = No distant metastasis.
IB T1, N1, M0 T1 = Tumor invades lamina propria, muscularis mucosae, or submucosa.
–T1a = Tumor invades lamina propria or muscularis mucosae.
–T1b = Tumor invades submucosa.
N1 = Metastases in 1 or 2 regional lymph nodes.
M0 = No distant metastasis.
T2, N0, M0 T2 = Tumor invades muscularis propria.b
N0 = No regional lymph node metastasis.
M0 = No distant metastasis.
Table 3. Definitions of pTNM Stages IIA and IIBa
Stage TNM Description
T = primary tumor; N = regional lymph node; M = distant metastasis; p = pathological.
aReprinted with permission from AJCC: Stomach. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 203–20.
bA tumor may penetrate the muscularis propria with extension into the gastrocolic or gastrohepatic ligaments, or into the greater or lesser omentum, without perforation of the visceral peritoneum covering these structures. In this case, the tumor is classified T3. If there is perforation of the visceral peritoneum covering the gastric ligaments or the omentum, the tumor should be classified T4.
cThe adjacent structures of the stomach include the spleen, transverse colon, liver, diaphragm, pancreas, abdominal wall, adrenal gland, kidney, small intestine, and retroperitoneum.
dIntramural extension to the duodenum or esophagus is not considered invasion of an adjacent structure, but is classified using the depth of the greatest invasion in any of these sites.
IIA T1, N2, M0 T1 = Tumor invades lamina propria, muscularis mucosae, or submucosa.
–T1a = Tumor invades lamina propria or muscularis mucosae.
–T1b = Tumor invades submucosa.
N2 = Metastases in 3 to 6 regional lymph nodes.
M0 = No distant metastasis.
T2, N1, M0 T2 = Tumor invades muscularis propria.b
N1 = Metastases in 1 or 2 regional lymph nodes.
M0 = No distant metastasis.
T3, N0, M0 T3 = Tumor penetrates the subserosal connective tissue without invasion of the visceral peritoneum or adjacent structures.c,d
N0 = No regional lymph node metastasis.
M0 = No distant metastasis.
IIB T1, N3a, M0 T1 = Tumor invades lamina propria, muscularis mucosae, or submucosa.
–T1a = Tumor invades lamina propria or muscularis mucosae.
–T1b = Tumor invades submucosa.
N3a = Metastasis in 7 to 15 regional lymph nodes.
M0 = No distant metastasis.
T2, N2, M0 T2 = Tumor invades muscularis propria.b
N2 = Metastases in 3 to 6 regional lymph nodes.
M0 = No distant metastasis.
T3, N1, M0 T3 = Tumor penetrates the subserosal connective tissue without invasion of the visceral peritoneum or adjacent structures.c,d
N1 = Metastasis in 1or 2 regional lymph nodes.
M0 = No distant metastasis.
T4a, N0, M0 T4a = Tumor invades serosa (visceral peritoneum).
N0 = No regional lymph node metastasis.
M0 = No distant metastasis.
Table 4. Definitions of pTNM Stages IIIA, IIIB, and IIICa
Stage TNM Description
T = primary tumor; N = regional lymph node; M = distant metastasis; p = pathological.
aReprinted with permission from AJCC: Stomach. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 203–20.
bA tumor may penetrate the muscularis propria with extension into the gastrocolic or gastrohepatic ligaments, or into the greater or lesser omentum, without perforation of the visceral peritoneum covering these structures. In this case, the tumor is classified T3. If there is perforation of the visceral peritoneum covering the gastric ligaments or the omentum, the tumor should be classified T4.
cThe adjacent structures of the stomach include the spleen, transverse colon, liver, diaphragm, pancreas, abdominal wall, adrenal gland, kidney, small intestine, and retroperitoneum.
dIntramural extension to the duodenum or esophagus is not considered invasion of an adjacent structure, but is classified using the depth of the greatest invasion in any of these sites.
IIIA T2, N3a, M0 T2 = Tumor invades muscularis propria.b
N3a = Metastasis in 7 to 15 regional lymph nodes.
M0 = No distant metastasis.
T3, N2, M0 T3 = Tumor penetrates the subserosal connective tissue without invasion of the visceral peritoneum or adjacent structures.c,d
N2 = Metastasis in 3 to 6 regional lymph nodes.
M0 = No distant metastasis.
T4a, N1, M0 T4a = Tumor invades serosa (visceral peritoneum).
N1 = Metastasis in 1or 2 regional lymph nodes.
M0 = No distant metastasis.
T4a, N2, M0 T4a = Tumor invades serosa (visceral peritoneum).
N2 = Metastasis in 3 to 6 regional lymph nodes.
M0 = No distant metastasis.
T4b, N0, M0 T4b = Tumor invades adjacent structures/organs.c,d
N0 = No regional lymph node metastasis.
M0 = No distant metastasis.
IIIB T1, N3b, M0 T1 = Tumor invades lamina propria, muscularis mucosae, or submucosa.
N3b = Metastases in 16 or more regional lymph nodes.
M0 = No distant metastasis.
T2, N3b, M0 T2 = Tumor invades muscularis propria.b
N3b = Metastases in 16 or more regional lymph nodes.
M0 = No distant metastasis.
T3, N3a, M0 T3 = Tumor penetrates the subserosal connective tissue without invasion of the visceral peritoneum or adjacent structures.c,d
N3a = Metastasis in 7 to 15 regional lymph nodes.
M0 = No distant metastasis.
T4a, N3a, M0 T4a = Tumor invades serosa (visceral peritoneum).
N3a = Metastasis in 7 to 15 regional lymph nodes.
M0 = No distant metastasis.
T4b, N1, M0 T4b = Tumor invades adjacent structures/organs.c,d
N1 = Metastasis in 1or 2 regional lymph nodes.
M0 = No distant metastasis.
T4b, N2, M0 T4b = Tumor invades adjacent structures/organs.c,d
N2 = Metastasis in 3 to 6 regional lymph nodes.
M0 = No distant metastasis.
IIIC T3, N3b, M0 T3 = Tumor penetrates the subserosal connective tissue without invasion of the visceral peritoneum or adjacent structures.cd
N3b = Metastasis in 16 or more regional lymph nodes.
M0 = No distant metastasis.
T4a, N3b, M0 T4a = Tumor invades serosa (visceral peritoneum).
N3b = Metastasis in 16 or more regional lymph nodes.
M0 = No distant metastasis.
T4b, N3a, M0 T4b = Tumor invades adjacent structures/organs.c,d
N3a = Metastasis in 7 to 15 regional lymph nodes.
M0 = No distant metastasis.
T4b, N3b, M0 T4b = Tumor invades adjacent structures/organs.c,d
N3b = Metastasis in 16 or more regional lymph nodes.
M0 = No distant metastasis.
Table 5. Definitions of pTNM Stage IVa
Stage TNM Description
T = primary tumor; N = regional lymph node; M = distant metastasis; p = pathological.
aReprinted with permission from AJCC: Stomach. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 203–20.
bA tumor may penetrate the muscularis propria with extension into the gastrocolic or gastrohepatic ligaments, or into the greater or lesser omentum, without perforation of the visceral peritoneum covering these structures. In this case, the tumor is classified T3. If there is perforation of the visceral peritoneum covering the gastric ligaments or the omentum, the tumor should be classified T4.
cThe adjacent structures of the stomach include the spleen, transverse colon, liver, diaphragm, pancreas, abdominal wall, adrenal gland, kidney, small intestine, and retroperitoneum.
dIntramural extension to the duodenum or esophagus is not considered invasion of an adjacent structure, but is classified using the depth of the greatest invasion in any of these sites.
IV Any T, Any N, M1 TX = Primary tumor cannot be assessed.
T0 = No evidence of primary tumor.
Tis = Carcinoma in situ: intraepithelial tumor without invasion of the lamina propria, high-grade dysplasia.
T1 = Tumor invades lamina propria, muscularis mucosae, or submucosa.
–T1a = Tumor invades lamina propria or muscularis mucosae.
–T1b = Tumor invades submucosa.
T2 = Tumor invades muscularis propria.b
T3 = Tumor penetrates the subserosal connective tissue without invasion of the visceral peritoneum or adjacent structures.c,d
T4 = Tumor invades the serosa (visceral peritoneum) or adjacent structures.c,d
–T4a = Tumor invades serosa (visceral peritoneum).
–T4b = Tumor invades adjacent structures/organs.
NX = Regional lymph node(s) cannot be assessed.
N0 = No regional lymph node metastasis.
N1 = Metastases in 1 or 2 regional lymph nodes.
N2 = Metastases in 3 to 6 regional lymph nodes.
N3 = Metastases in ≥7 regional lymph nodes.
–N3a = Metastases in 7 to 15 regional lymph nodes.
–N3b = Metastases in 16 or more regional lymph nodes.
M1 = Distant metastasis.
References
  1. Stomach. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. Springer; 2017, pp. 203–20.

Treatment Option Overview for Gastric Cancer

The standard form of curative therapy for gastric cancer is radical surgery. However, the incidences of local failure in the tumor bed and regional lymph nodes, and distant failures via hematogenous or peritoneal routes, remain high.[1] As such, comprehensive staging and evaluation with a multidisciplinary team to determine roles of neoadjuvant, perioperative, and adjuvant combination chemotherapy, surgery, and external-beam radiation therapies should be considered.

Investigators in Europe evaluated the role of perioperative chemotherapy without radiation therapy.[2] Initially, in a randomized phase III trial (MRC-ST02 [NCT00002615]), patients with stage II or higher adenocarcinoma of the stomach or of the lower third of the esophagus were assigned to receive three cycles of epirubicin, cisplatin, and continuous infusion fluorouracil (5-FU) (ECF) before and after surgery or to receive surgery alone. Compared with the surgery group, the perioperative chemotherapy group had a significantly higher overall survival (OS) (hazard ratio [HR]death, 0.75; 95% confidence interval [CI], 0.60–0.93; P = .009).[2][Level of evidence A1]

In addition, in the randomized phase III AIO-FLOT4 trial (NCT01216644), patients with resectable disease that was stage T2 or higher and/or node positive received either perioperative epirubicin, cisplatin, and 5-FU or capecitabine (ECF/ECX) (three cycles before and after surgery) or perioperative docetaxel, oxaliplatin, and 5-FU/leucovorin (FLOT) (four 2-week cycles before and after surgery). OS was significantly prolonged from 35 months with ECF/ECX to 50 months with FLOT (HR, 0.77; 95% CI, 0.63–0.94; P = .012).[3]

In a phase III Intergroup trial (SWOG-9008 [NCT01197118]), 559 patients with completely resected stage IB to stage IV (M0) adenocarcinoma of the stomach and gastroesophageal junction were randomly assigned to receive either surgery alone or surgery plus postoperative chemotherapy (5-FU and leucovorin) and concurrent radiation therapy (45 Gy). With a median follow-up of more than 10 years, a significant survival benefit was reported for patients who received adjuvant combined modality therapy.[4][Level of evidence A1] Median OS was 35 months for the adjuvant chemoradiation therapy group and 27 months for the surgery-alone arm (P = .0046). Median relapse-free survival was 27 months in the chemoradiation arm compared with 19 months in the surgery-alone arm (P < .001).

Gastroesophageal junction cancers may be treated like esophageal cancers and are best managed under the care of a multidisciplinary team. For more information, see Esophageal Cancer Treatment.

Capecitabine and Fluorouracil Dosing

The DPYD gene encodes an enzyme that catabolizes pyrimidines and fluoropyrimidines, like capecitabine and fluorouracil. An estimated 1% to 2% of the population has germline pathogenic variants in DPYD, which lead to reduced DPD protein function and an accumulation of pyrimidines and fluoropyrimidines in the body.[5,6] Patients with the DPYD*2A variant who receive fluoropyrimidines may experience severe, life-threatening toxicities that are sometimes fatal. Many other DPYD variants have been identified, with a range of clinical effects.[5–7] Fluoropyrimidine avoidance or a dose reduction of 50% may be recommended based on the patient’s DPYD genotype and number of functioning DPYD alleles.[8–10] DPYD genetic testing costs less than $200, but insurance coverage varies due to a lack of national guidelines.[11] In addition, testing may delay therapy by 2 weeks, which would not be advisable in urgent situations. This controversial issue requires further evaluation.[12]

References
  1. Gunderson LL, Sosin H: Adenocarcinoma of the stomach: areas of failure in a re-operation series (second or symptomatic look) clinicopathologic correlation and implications for adjuvant therapy. Int J Radiat Oncol Biol Phys 8 (1): 1-11, 1982. [PUBMED Abstract]
  2. Cunningham D, Allum WH, Stenning SP, et al.: Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med 355 (1): 11-20, 2006. [PUBMED Abstract]
  3. Al-Batran SE, Homann N, Pauligk C, et al.: Perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus cisplatin and epirubicin for locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4): a randomised, phase 2/3 trial. Lancet 393 (10184): 1948-1957, 2019. [PUBMED Abstract]
  4. Smalley SR, Benedetti JK, Haller DG, et al.: Updated analysis of SWOG-directed intergroup study 0116: a phase III trial of adjuvant radiochemotherapy versus observation after curative gastric cancer resection. J Clin Oncol 30 (19): 2327-33, 2012. [PUBMED Abstract]
  5. Sharma BB, Rai K, Blunt H, et al.: Pathogenic DPYD Variants and Treatment-Related Mortality in Patients Receiving Fluoropyrimidine Chemotherapy: A Systematic Review and Meta-Analysis. Oncologist 26 (12): 1008-1016, 2021. [PUBMED Abstract]
  6. Lam SW, Guchelaar HJ, Boven E: The role of pharmacogenetics in capecitabine efficacy and toxicity. Cancer Treat Rev 50: 9-22, 2016. [PUBMED Abstract]
  7. Shakeel F, Fang F, Kwon JW, et al.: Patients carrying DPYD variant alleles have increased risk of severe toxicity and related treatment modifications during fluoropyrimidine chemotherapy. Pharmacogenomics 22 (3): 145-155, 2021. [PUBMED Abstract]
  8. Amstutz U, Henricks LM, Offer SM, et al.: Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Dihydropyrimidine Dehydrogenase Genotype and Fluoropyrimidine Dosing: 2017 Update. Clin Pharmacol Ther 103 (2): 210-216, 2018. [PUBMED Abstract]
  9. Henricks LM, Lunenburg CATC, de Man FM, et al.: DPYD genotype-guided dose individualisation of fluoropyrimidine therapy in patients with cancer: a prospective safety analysis. Lancet Oncol 19 (11): 1459-1467, 2018. [PUBMED Abstract]
  10. Lau-Min KS, Varughese LA, Nelson MN, et al.: Preemptive pharmacogenetic testing to guide chemotherapy dosing in patients with gastrointestinal malignancies: a qualitative study of barriers to implementation. BMC Cancer 22 (1): 47, 2022. [PUBMED Abstract]
  11. Brooks GA, Tapp S, Daly AT, et al.: Cost-effectiveness of DPYD Genotyping Prior to Fluoropyrimidine-based Adjuvant Chemotherapy for Colon Cancer. Clin Colorectal Cancer 21 (3): e189-e195, 2022. [PUBMED Abstract]
  12. Baker SD, Bates SE, Brooks GA, et al.: DPYD Testing: Time to Put Patient Safety First. J Clin Oncol 41 (15): 2701-2705, 2023. [PUBMED Abstract]

Treatment of Stage 0 Gastric Cancer

Treatment Options for Stage 0 Gastric Cancer

Treatment options for stage 0 gastric cancer include:

  1. Surgery.
  2. Endoscopic mucosal resection (EMR).

Surgery

Stage 0 is gastric cancer confined to mucosa. Experience in Japan, where stage 0 is diagnosed frequently, indicates that more than 90% of patients treated by gastrectomy with lymphadenectomy survive beyond 5 years. An American series confirmed these results.[1]

Endoscopic mucosal resection (EMR)

EMR has been studied in Japan and throughout Asia in patients with early-stage tumors with good-risk features (Tis or T1a, diameter ≤2 cm, predominantly differentiated type, without ulcerative findings) that have a lower risk of nodal metastasis. Intramucosal tumors have a lower risk of nodal metastasis than submucosal tumors.[2] Careful patient selection according to risk criteria, treatment with an experienced endoscopist, and close surveillance should be considered.

Evidence (EMR):

  1. A prospective trial of EMR included 445 patients with intramucosal carcinoma (a total of 479 tumors) treated in Tokyo between 1987 and 1998. Complete resection was recommended for patients with evidence of submucosal invasion, blood vessel involvement, and/or positive margins.[3][Level of evidence C2]
    • Of the 405 patients with intramucosal disease, 278 underwent complete resection, with 2% local recurrence treated with curative intent and 100% disease-free survival at a median follow-up of 38 months.
    • In those with resections that were incomplete or not evaluable, 18 of 127 patients had a local recurrence and underwent curative 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.

References
  1. Green PH, O’Toole KM, Slonim D, et al.: Increasing incidence and excellent survival of patients with early gastric cancer: experience in a United States medical center. Am J Med 85 (5): 658-61, 1988. [PUBMED Abstract]
  2. Japanese Gastric Cancer Association: Japanese gastric cancer treatment guidelines 2014 (ver. 4). Gastric Cancer 20 (1): 1-19, 2017. [PUBMED Abstract]
  3. Ono H, Kondo H, Gotoda T, et al.: Endoscopic mucosal resection for treatment of early gastric cancer. Gut 48 (2): 225-9, 2001. [PUBMED Abstract]

Treatment of Stage I Gastric Cancer

Treatment Options for Stage I Gastric Cancer

Treatment options for stage I gastric cancer include:

  1. Surgical resection with one of the following procedures:
    • Distal subtotal gastrectomy (if the lesion is not in the fundus or at the cardioesophageal junction).
    • Proximal subtotal gastrectomy or total gastrectomy, both with distal esophagectomy (if the lesion involves the cardia). These tumors often involve the submucosal lymphatics of the esophagus.
    • Total gastrectomy (if the tumor involves the stomach diffusely or arises in the body of the stomach and extends to within 6 cm of the cardia or distal antrum).

    Regional lymphadenectomy is recommended with all of the above procedures. Splenectomy is not routinely performed.[1]

  2. Endoscopic mucosal resection (EMR) for select patients with stage IA gastric cancer.
  3. Postoperative chemoradiation therapy or perioperative chemotherapy for patients with node-positive (T1 N1) and muscle-invasive (T2 N0) disease.[2,3]
  4. Neoadjuvant chemoradiation (under clinical evaluation).[4]

Surgical resection

Surgical resection including regional lymphadenectomy is the treatment of choice for patients with stage I gastric cancer.[1] If the lesion is not in the cardioesophageal junction and does not diffusely involve the stomach, subtotal gastrectomy is the procedure of choice, because it has demonstrated equivalent survival when compared with total gastrectomy and is associated with decreased morbidity.[5][Level of evidence A1] When the lesion involves the cardia, proximal subtotal gastrectomy or total gastrectomy (including a sufficient length of esophagus) may be performed with curative intent. If the lesion diffusely involves the stomach, total gastrectomy is required. At a minimum, surgical resection includes greater and lesser curvature perigastric regional lymph nodes. In patients with stage I gastric cancer, perigastric lymph nodes may contain cancer.

Endoscopic mucosal resection (EMR)

EMR has been studied in Japan and throughout Asia in patients with early-stage tumors with good-risk features (Tis or T1a, diameter ≤2 cm, predominantly differentiated type, without ulcerative findings) that have a lower risk of nodal metastasis. Intramucosal tumors have a lower risk of nodal metastasis than submucosal tumors.[6] Careful patient selection according to risk criteria, treatment with an experienced endoscopist, and close surveillance should be considered.

Evidence (EMR):

  1. A prospective trial of EMR included 445 patients with intramucosal carcinoma (a total of 479 tumors) treated in Tokyo between 1987 and 1998. Complete resection was recommended for patients with evidence of submucosal invasion, blood vessel involvement, and/or positive margins.[7][Level of evidence C2]
    • Of the 405 patients with intramucosal disease, 278 underwent complete resection, with 2% local recurrence treated with curative intent and 100% disease-free survival at a median follow-up of 38 months.
    • In those with resections that were incomplete or not evaluable, 18 of 127 patients had a local recurrence and underwent curative surgery.

Postoperative chemoradiation therapy

Patients with node-positive (T1 N1) and muscle-invasive (T2 N0) disease may consider postoperative chemoradiation therapy.

Evidence (postoperative chemoradiation therapy):

  1. A prospective, multi-institution, phase III trial (SWOG-9008 [NCT01197118]) evaluated postoperative combined chemoradiation therapy versus surgery alone in 559 patients with completely resected stage IB to stage IV (M0) adenocarcinoma of the stomach and gastroesophageal junction. There was a significant survival benefit with adjuvant combined modality therapy.[2][Level of evidence A1]
    • With more than 10 years of follow-up, median survival was 35 months for the adjuvant chemoradiation therapy group and 27 months for the surgery-alone arm (P = .0046).
    • Median relapse-free survival was 27 months in the chemoradiation arm compared with 19 months in the surgery-alone arm (P < .001). Improvement was primarily seen for locoregional recurrence risk (improvement from 47% for surgery vs. 29% for chemoradiation).[2] However, only 36 patients in the trial had stage IB tumors (18 patients in each arm).[8]

    Because the prognosis is relatively favorable for patients with completely resected stage IB disease, the effectiveness of adjuvant chemoradiation therapy for this group is less clear.

Perioperative chemotherapy

Investigators in Europe evaluated the role of perioperative chemotherapy without radiation therapy.[9]

Evidence (perioperative chemotherapy):

  1. In the randomized phase III AIO-FLOT4 trial (NCT01216644), 716 patients with stage IB to stage III resectable gastric or gastroesophageal adenocarcinoma were randomly assigned to receive either perioperative chemotherapy with docetaxel, oxaliplatin, and fluorouracil (5-FU)/leucovorin (FLOT); or epirubicin, cisplatin, and 5-FU or capecitabine (ECF/ECX).[3][Level of evidence A1]
    • Median overall survival was 50 months with FLOT and 35 months with ECF/ECX (hazard ratio, 0.77; 95% confidence interval, 0.63–0.94; P = .012).
    • Margin-free resection in the FLOT group was 85% versus 78% in the ECF/ECX group (P = .0162).
    • Toxicity rates were similar between groups (26% required hospitalizations in the ECF/ECX group and 25% in the FLOT group). However, types of side effects differed, with increased nausea, thromboembolic events, and anemia in the ECF/ECX group versus higher rates of grade 3/4 infections, neutropenia, diarrhea, and neuropathy in the FLOT group.

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. Brennan MF, Karpeh MS: Surgery for gastric cancer: the American view. Semin Oncol 23 (3): 352-9, 1996. [PUBMED Abstract]
  2. Smalley SR, Benedetti JK, Haller DG, et al.: Updated analysis of SWOG-directed intergroup study 0116: a phase III trial of adjuvant radiochemotherapy versus observation after curative gastric cancer resection. J Clin Oncol 30 (19): 2327-33, 2012. [PUBMED Abstract]
  3. Al-Batran SE, Homann N, Pauligk C, et al.: Perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus cisplatin and epirubicin for locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4): a randomised, phase 2/3 trial. Lancet 393 (10184): 1948-1957, 2019. [PUBMED Abstract]
  4. Ajani JA, Winter K, Okawara GS, et al.: Phase II trial of preoperative chemoradiation in patients with localized gastric adenocarcinoma (RTOG 9904): quality of combined modality therapy and pathologic response. J Clin Oncol 24 (24): 3953-8, 2006. [PUBMED Abstract]
  5. Bozzetti F, Marubini E, Bonfanti G, et al.: Subtotal versus total gastrectomy for gastric cancer: five-year survival rates in a multicenter randomized Italian trial. Italian Gastrointestinal Tumor Study Group. Ann Surg 230 (2): 170-8, 1999. [PUBMED Abstract]
  6. Japanese Gastric Cancer Association: Japanese gastric cancer treatment guidelines 2014 (ver. 4). Gastric Cancer 20 (1): 1-19, 2017. [PUBMED Abstract]
  7. Ono H, Kondo H, Gotoda T, et al.: Endoscopic mucosal resection for treatment of early gastric cancer. Gut 48 (2): 225-9, 2001. [PUBMED Abstract]
  8. Kelsen DP: Postoperative adjuvant chemoradiation therapy for patients with resected gastric cancer: intergroup 116. J Clin Oncol 18 (21 Suppl): 32S-4S, 2000. [PUBMED Abstract]
  9. Cunningham D, Allum WH, Stenning SP, et al.: Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med 355 (1): 11-20, 2006. [PUBMED Abstract]

Treatment of Stages II and III Gastric Cancer

Treatment Options for Stages II and III Gastric Cancer

Treatment options for stage II gastric cancer and stage III gastric cancer include:

  1. Surgical resection (after discussion with a multidisciplinary team regarding the role of perioperative and adjuvant therapy) may include one of the following procedures:
    • Distal subtotal gastrectomy (if the lesion is not in the fundus or at the cardioesophageal junction).
    • Proximal subtotal gastrectomy or total gastrectomy (if the lesion involves the cardia).
    • Total gastrectomy (if the tumor involves the stomach diffusely or arises in the body of the stomach and extends to within 6 cm of the cardia).

    Regional lymphadenectomy is recommended with all of the above procedures. Splenectomy is not routinely performed.[1]

  2. Perioperative chemotherapy.[2]
  3. Postoperative (adjuvant) chemoradiation therapy.[3]
  4. Postoperative (adjuvant) chemotherapy.
  5. Neoadjuvant chemoradiation therapy (under clinical evaluation).[4]
  6. Perioperative chemotherapy and immunotherapy regimens (under clinical evaluation).

No randomized trials of adjuvant chemoradiation versus perioperative chemotherapy have been undertaken.

All newly diagnosed patients with stages II and III gastric cancer should consider clinical trials.

Surgical resection

Because of the high risk of locoregional and distant recurrence, perioperative and postoperative therapy should be considered in addition to surgery.

Surgical resection with regional lymphadenectomy is the treatment of choice for patients with stages II and III gastric cancer; all eligible patients undergo surgery.[1] If the lesion is not in the cardioesophageal junction and does not diffusely involve the stomach, subtotal gastrectomy is the procedure of choice. When the lesion involves the cardia, proximal subtotal gastrectomy or total gastrectomy may be performed with curative intent. If the lesion diffusely involves the stomach, total gastrectomy and appropriate lymph node resection may be required. The role of extended lymph node (D2) dissection is uncertain [5] and in some series is associated with increased morbidity.[6,7] As many as 15% of selected stage III patients can be cured by surgery alone, particularly if lymph node involvement is minimal (<7 lymph nodes).

Perioperative chemotherapy

Investigators in Europe evaluated the role of perioperative chemotherapy without radiation therapy.[2]

Evidence (perioperative chemotherapy):

  1. In the randomized phase III AIO-FLOT4 trial (NCT01216644), 716 patients with stage IB to stage III resectable gastric or gastroesophageal adenocarcinoma were randomly assigned to receive either perioperative chemotherapy with docetaxel, oxaliplatin, and fluorouracil (5-FU)/leucovorin (FLOT) or epirubicin, cisplatin, and 5-FU or capecitabine (ECF/ECX).[8][Level of evidence A1]
    • Median overall survival (OS) was 50 months with FLOT and 35 months with ECF/ECX (hazard ratio [HR], 0.77; 95% confidence interval [CI], 0.63–0.94; P = .012).
    • Margin-free resection in the FLOT group was 85% versus 78% in the ECF/ECX group (P = .0162).
    • Toxicity rates were similar between groups (26% required hospitalizations in the ECF/ECX group and 25% in the FLOT group). However, types of side effects differed, with increased nausea, thromboembolic events, and anemia in the ECF/ECX group versus higher rates of grade 3/4 infections, neutropenia, diarrhea, and neuropathy in the FLOT group.
  2. In the randomized phase III MAGIC trial (NCT00002615), patients with stage II or higher adenocarcinoma of the stomach or of the lower third of the esophagus were assigned to receive three cycles of epirubicin, cisplatin, and continuous infusion 5-FU (ECF) before and after surgery or to receive surgery alone.[2]
    • Compared with the surgery group, the perioperative chemotherapy group had a significantly higher likelihood of progression-free survival (HRprogression, 0.66; 95% CI, 0.53–0.81; P < .001) and of OS (HRdeath, 0.75; 95% CI, 0.60–0.93; P = .009).
    • The 5-year OS rate was 36.3% (95% CI, 29.5%‒43.0%) for the perioperative chemotherapy group and 23% (95% CI, 16.6%‒29.4%) for the surgery group.[2][Level of evidence A1]

Postoperative (adjuvant) chemoradiation therapy

Patients with stages II and III gastric cancer who have not received neoadjuvant therapy may consider postoperative chemoradiation therapy.

Evidence (postoperative [adjuvant] chemoradiation therapy):

  1. A prospective, multi-institution, phase III trial (SWOG-9008 [NCT01197118]) evaluated postoperative combined chemoradiation therapy compared with surgery alone in 559 patients with completely resected stage IB to stage IV (M0) adenocarcinoma of the stomach and gastroesophageal junction. Investigators reported a significant survival benefit for patients who received adjuvant combined-modality therapy.[3][Level of evidence A1]
    • With more than 10 years of follow-up, median survival was 35 months for the adjuvant chemoradiation therapy arm and 27 months for the surgery-alone arm (P = .0046).
    • Median relapse-free survival was 27 months in the chemoradiation arm compared with 19 months in the surgery-alone arm (P < .001). Improvement was primarily seen for locoregional recurrence risk (improvement from 47% for surgery vs. 29% for chemoradiation).[3] However, only 36 patients in the trial had stage IB tumors (18 patients in each arm).[9]
  2. Attempts to evaluate the role of more intensive chemotherapy regimens in combination with radiation in the Cancer and Leukemia Group B study (CALGB-80101 [NCT00052910]) demonstrated no survival benefit. The 546 patients who had undergone curative resection of stage IB to stage IV (M0) gastric or gastroesophageal junction adenocarcinoma received postoperative 5-FU with leucovorin before and after radiation or postoperative ECF before and after combined radiation therapy.[10]
    • The 5-year OS rate was 44% in both arms.
  3. In a phase III Dutch trial (CRITICS [NCT00407186]), 788 patients with stage IB to stage IVA gastric/gastroesophageal junction adenocarcinoma received preoperative chemotherapy and surgery, and then were randomly assigned to receive postoperative chemotherapy or chemoradiotherapy.[11] Adjuvant chemoradiation did not improve survival in those who received neoadjuvant chemotherapy.
    • Median OS was 43 months in the chemotherapy arm and 37 months in the chemoradiotherapy group (95% CI, 0.84–1.22; P = .90).

Postoperative (adjuvant) chemotherapy

Investigators in Europe evaluated the role of postoperative chemotherapy without radiation therapy.[2]

Evidence (postoperative [adjuvant] chemotherapy):

  1. Japanese investigators randomly assigned 1,059 patients with stage II or III gastric cancer who had undergone a D2 gastrectomy to receive either 1 year of S-1, an oral fluoropyrimidine not available in the United States, or follow-up after surgery alone.[12] Patients were randomly assigned in a 1:1 fashion.
    • The 3-year OS rate was 80.1% in the S-1 group and 70.1% in the surgery-only group. The HRdeath in the S-1 group, as compared with the surgery-only group, was 0.68 (95% CI, 0.52–0.87; P = .003).[12][Level of evidence A1]
  2. Investigators in Asia evaluated the role of capecitabine/oxaliplatin as adjuvant therapy after gastric cancer resection. In the CLASSIC trial (NCT00411229), 37 centers in South Korea, China, and Taiwan randomly assigned 1,035 patients with stages IIA, IIB, IIIA, or IIIB gastric cancer who had undergone a curative D2 gastrectomy to receive either adjuvant chemotherapy (eight 3-week cycles of capecitabine plus oxaliplatin) or follow-up alone after surgery.[13]
    • The 3-year disease-free survival rate was 74% in the chemotherapy group and 59% in the surgery-alone group (HR, 0.56; 95% CI, 0.44–0.72; P < .0001).
    • The 3-year OS rate was 83% in the chemotherapy group and 78% in the surgery-alone group (HR, 0.72; 95% CI, 0.52–1.00; P = .0493).[13][Level of evidence A1]
    • Further follow-up is anticipated.

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. Brennan MF, Karpeh MS: Surgery for gastric cancer: the American view. Semin Oncol 23 (3): 352-9, 1996. [PUBMED Abstract]
  2. Cunningham D, Allum WH, Stenning SP, et al.: Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med 355 (1): 11-20, 2006. [PUBMED Abstract]
  3. Smalley SR, Benedetti JK, Haller DG, et al.: Updated analysis of SWOG-directed intergroup study 0116: a phase III trial of adjuvant radiochemotherapy versus observation after curative gastric cancer resection. J Clin Oncol 30 (19): 2327-33, 2012. [PUBMED Abstract]
  4. Ajani JA, Winter K, Okawara GS, et al.: Phase II trial of preoperative chemoradiation in patients with localized gastric adenocarcinoma (RTOG 9904): quality of combined modality therapy and pathologic response. J Clin Oncol 24 (24): 3953-8, 2006. [PUBMED Abstract]
  5. Kitamura K, Yamaguchi T, Sawai K, et al.: Chronologic changes in the clinicopathologic findings and survival of gastric cancer patients. J Clin Oncol 15 (12): 3471-80, 1997. [PUBMED Abstract]
  6. Bonenkamp JJ, Songun I, Hermans J, et al.: Randomised comparison of morbidity after D1 and D2 dissection for gastric cancer in 996 Dutch patients. Lancet 345 (8952): 745-8, 1995. [PUBMED Abstract]
  7. Cuschieri A, Fayers P, Fielding J, et al.: Postoperative morbidity and mortality after D1 and D2 resections for gastric cancer: preliminary results of the MRC randomised controlled surgical trial.The Surgical Cooperative Group. Lancet 347 (9007): 995-9, 1996. [PUBMED Abstract]
  8. Al-Batran SE, Homann N, Pauligk C, et al.: Perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus cisplatin and epirubicin for locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4): a randomised, phase 2/3 trial. Lancet 393 (10184): 1948-1957, 2019. [PUBMED Abstract]
  9. Kelsen DP: Postoperative adjuvant chemoradiation therapy for patients with resected gastric cancer: intergroup 116. J Clin Oncol 18 (21 Suppl): 32S-4S, 2000. [PUBMED Abstract]
  10. Fuchs CS, Niedzwiecki D, Mamon HJ, et al.: Adjuvant Chemoradiotherapy With Epirubicin, Cisplatin, and Fluorouracil Compared With Adjuvant Chemoradiotherapy With Fluorouracil and Leucovorin After Curative Resection of Gastric Cancer: Results From CALGB 80101 (Alliance). J Clin Oncol 35 (32): 3671-3677, 2017. [PUBMED Abstract]
  11. Cats A, Jansen EPM, van Grieken NCT, et al.: Chemotherapy versus chemoradiotherapy after surgery and preoperative chemotherapy for resectable gastric cancer (CRITICS): an international, open-label, randomised phase 3 trial. Lancet Oncol 19 (5): 616-628, 2018. [PUBMED Abstract]
  12. Sakuramoto S, Sasako M, Yamaguchi T, et al.: Adjuvant chemotherapy for gastric cancer with S-1, an oral fluoropyrimidine. N Engl J Med 357 (18): 1810-20, 2007. [PUBMED Abstract]
  13. Bang YJ, Kim YW, Yang HK, et al.: Adjuvant capecitabine and oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): a phase 3 open-label, randomised controlled trial. Lancet 379 (9813): 315-21, 2012. [PUBMED Abstract]

Treatment of Stage IV, Inoperable, and Recurrent Gastric Cancer

Treatment Options for Stage IV, Inoperable, and Recurrent Gastric Cancer

Treatment options for stage IV, inoperable, and recurrent gastric cancer, including patients with medically or surgically unresectable disease, include a combination of cytotoxic therapies, targeted therapies, immunotherapies, and palliative locoregional therapies.

Patients with metastatic gastric adenocarcinoma should consider undergoing testing for HER2 amplification, defective mismatch repair (dMMR) (immunohistochemistry [IHC] staining), or microsatellite instability (MSI) (polymerase chain reaction), along with programmed death ligand 1 (PD-L1) combined positive score (CPS score in the United States).

  1. First-line palliative systemic therapy for patients with HER2-negative tumors.
    1. Palliative chemotherapy with or without immunotherapy.
      • Chemotherapy with immunotherapy: fluorouracil (5-FU) or capecitabine combined with oxaliplatin and nivolumab.
    2. Monoclonal antibody therapy with chemotherapy for patients with CLDN18.2-positive tumors.
    3. Triplet regimens.
      • 5-FU combined with either epirubicin and cisplatin, etoposide and leucovorin, doxorubicin and methotrexate, leucovorin and irinotecan, or docetaxel and cisplatin or oxaliplatin.[3–9]
    4. Doublet regimens.
      • A taxane (docetaxel or paclitaxel) and either cisplatin or carboplatin.
      • 5-FU and cisplatin.
      • CAPOX.[10]
    5. Single agents.
      • 5-FU or capecitabine.[11,12]
      • A taxane (either docetaxel or paclitaxel).
  2. First-line palliative systemic therapy for patients with HER2-positive tumors (3+ on IHC or 2+ on IHC with a positive fluorescence in situ hybridization [FISH]).
    1. Immunotherapy with chemotherapy.
  3. Second-line palliative systemic therapy.
    1. Palliative chemotherapy.
    2. Ramucirumab with or without chemotherapy.
    3. Pembrolizumab for patients with dMMR or MSI-high (MSI-H) tumors.
    4. Trastuzumab deruxtecan for patients with HER2-positive tumors (3+ on IHC or 2+ on IHC with a positive FISH).
  4. Third-line palliative systemic therapy.
    1. Trifluridine and tipiracil.
  5. Endoluminal laser therapy, endoluminal stent placement, or gastrojejunostomy may be helpful to patients with gastric obstruction.[13]
  6. Palliative radiation therapy may alleviate bleeding, pain, and obstruction.
  7. Palliative resection is reserved for patients with continued bleeding or obstruction.
  8. Regorafenib with nivolumab (under clinical evaluation).
  9. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (under clinical evaluation).

Treatment with poly (ADP-ribose) polymerase (PARP) inhibitors and hepatocyte growth factor inhibitors have not shown efficacy at this time, but combination studies are under way.

First-line palliative systemic therapy for patients with HER2-negative tumors

Palliative chemotherapy with or without immunotherapy

Standard chemotherapy versus best supportive care for patients with metastatic gastric cancer has been tested in several clinical trials, and there is general agreement that patients who receive chemotherapy live for several months longer on average than patients who receive supportive care.[14–16][Level of evidence A1] During the last 20 years, multiple randomized studies evaluating different treatment regimens (monotherapy vs. combination [doublet and triplet] chemotherapy) have been performed in patients with metastatic gastric cancer with no clear consensus as to the best management approach. A meta-analysis of these studies demonstrated a hazard ratio (HR) of 0.83 for overall survival (OS) (95% confidence interval [CI], 0.74–0.93) in favor of combination chemotherapy.[17] The addition of immune checkpoint inhibitors to oxaliplatin-based chemotherapy has shown further OS benefit.

Evidence (palliative chemotherapy):

  1. Of all the combination regimens, epirubicin, cisplatin, and 5-FU (ECF) is often considered the reference standard in the United States and Europe. In one European trial, 274 patients with metastatic esophagogastric cancer were randomly assigned to receive either ECF or 5-FU, doxorubicin, and methotrexate (FAMTX).[18]
    • The group who received ECF had a significantly longer median survival (8.9 vs. 5.7 months, P = .0009) than the FAMTX group.[18][Level of evidence A1]
  2. In a second trial that compared ECF with mitomycin, cisplatin, and 5-FU (MCF), there was no statistically significant difference in median survival (9.4 vs. 8.7 months, P = .315).[4][Level of evidence A1]
  3. Oxaliplatin or capecitabine are often substituted for cisplatin and 5-FU within the ECF regimen on the basis of results from the REAL-2 trial (ISRCTN51678883).[10] This randomized trial of 1,002 patients with advanced esophageal, gastroesophageal junction, or gastric cancer utilized a 2 × 2 design.
    • The trial demonstrated noninferior median OS in patients treated with capecitabine rather than 5-FU (HRdeath, 0.86; 95% CI, 0.82–0.99) and in patients treated with oxaliplatin in place of cisplatin (HRdeath, 0.92; 95% CI, 0.80–1.10)
  4. An international collaboration of investigators randomly assigned 445 patients with metastatic gastric cancer to receive docetaxel, cisplatin, and 5-FU (DCF) or cisplatin and 5-FU.[19] Time-to-treatment progression (TTP) was the primary end point.
    • Patients who received DCF experienced a significantly longer TTP (5.6 months; 95% CI, 4.9–5.9; vs. 3.7 months; 95% CI, 3.4–4.5; HR, 1.47; 95% CI, 1.19–1.82; log-rank P < .001; risk reduction, 32%).
    • The median OS was significantly longer for patients who received DCF compared with patients who received cisplatin and 5-FU (9.2 months; 95% CI, 8.4–10.6; vs. 8.6 months; 95% CI, 7.2–9.5; HR, 1.29; 95% CI, 1.0–1.6; log-rank P = .02; risk reduction, 23%).[19][Level of evidence A1]
    • The toxicity rates were high in both arms.[20]
    • Febrile neutropenia was more common in patients who received DCF (29% vs. 12%). The death rate was 10.4% in patients who received DCF and 9.4% in patients who received cisplatin and 5-FU.
  5. It is unclear if cisplatin and 5-FU should be considered as an index regimen for the treatment of patients with metastatic gastric cancer.[20] The results of a study that randomly assigned 245 patients with metastatic gastric cancer to receive cisplatin and 5-FU, FAMTX, or etoposide, leucovorin, and 5-FU (ELF) demonstrated no significant difference in response rate, progression-free survival (PFS), or OS between the arms.[5]
    • Grades 3 and 4 neutropenia occurred in 35% to 43% of patients on all arms, but severe nausea and vomiting was more common in patients in the cisplatin-and-5-FU arm and occurred in 26% of those patients.[5][Level of evidence B3]

Phase II studies that evaluated irinotecan-based or oxaliplatin-based regimens demonstrated similar response rates and TTP to those reported in trials using ECF or cisplatin and 5-FU, but the former regimen may be less toxic.[21–26] There are conflicting data regarding relative efficacy of any one regimen.

Monoclonal antibody therapy with chemotherapy for patients with CLDN18.2-positive tumors
Zolbetuximab plus CAPOX or mFOLFOX6

Two randomized trials tested the addition of zolbetuximab to either CAPOX or mFOLFOX6 in patients with CLDN18.2-positive, HER2-negative metastatic gastroesophageal or gastric adenocarcinoma.[1,2]

Evidence (zolbetuximab with chemotherapy):

  1. In the phase III GLOW trial (NCT03653507), 507 patients were randomly assigned to receive CAPOX and either zolbetuximab or placebo.[1]
    • The median PFS was 8.21 months in the zolbetuximab arm and 6.80 months in the placebo arm (HR, 0.687; 95% CI, 0.544–0.866; P = .0007). The median OS was 14.39 months in the zolbetuximab arm and 12.16 months in the placebo arm (HR, 0.771; 95% CI, 0.615–0.965; P = .0118).[1][Level of evidence B1]
  2. The phase III SPOTLIGHT trial (NCT03504397) included 565 patients with CLDN18.2-positive, HER2-negative metastatic gastroesophageal or gastric adenocarcinoma. Patients were randomly assigned to receive mFOLFOX6 and either zolbetuximab or placebo.[2]
    • The median PFS was 10.61 months (95% CI, 8.90–12.48) in the zolbetuximab arm and 8.67 months (95% CI, 8.21–10.28) in the placebo arm (HR, 0.75; 95% CI, 0.60–0.94; P = .0066). Patients who received zolbetuximab had a reduced risk of death (HR, 0.75; 95% CI, 0.60–0.94; P = .0053).[2][Level of evidence A1]

A subsequent combined analysis of the SPOTLIGHT and GLOW trials showed that the addition of zolbetuximab did not negatively affect health-related quality of life.[27]

First-line palliative systemic therapy for patients with HER2-positive tumors (3+ on IHC or 2+ on IHC with a positive FISH)

Immunotherapy with chemotherapy
Nivolumab with chemotherapy

Nivolumab may be considered in combination with chemotherapy for patients with advanced or metastatic gastric cancer regardless of PD-L1 CPS status.[28]

Evidence (nivolumab with chemotherapy):

  1. In a randomized, open-label, international, phase III study (CheckMate-649 [NCT02872116]), patients with HER2-negative gastric or gastroesophageal junction adenocarcinomas were randomly assigned 1:1:1 to receive either nivolumab with chemotherapy (nivolumab 360 mg with CAPOX every 3 weeks or nivolumab 240 mg with leucovorin, 5-FU, and oxaliplatin [FOLFOX] every 2 weeks), chemotherapy alone (CAPOX every 3 weeks or FOLFOX every 2 weeks), or nivolumab 1 mg/kg and ipilimumab 3 mg/kg every 3 weeks × 4 (followed by maintenance nivolumab). The trial randomly assigned 1,581 patients (including 955 with PD-L1 CPS ≥5) to the chemotherapy-plus-nivolumab arm (n = 789; n = 473 with PD-L1 CPS ≥5) or the chemotherapy-alone arm (n = 792; n = 482 with PD-L1 CPS ≥5).[28]
    • For all patients (regardless of PD-L1 status), the median OS was 14.0 months (95% CI, 12.6–15.0) in the nivolumab-plus-chemotherapy arm compared with 11.3 months (95 % CI, 10.6–12.3) in the chemotherapy-alone arm (HR, 0.77; 99.3% CI, 0.64–0.92; P < .0001).
    • Patients with tumors with PD-L1 CPS greater than 5 had a median OS of 14.4 months (95% CI, 13.1–16.2) in the nivolumab-plus-chemotherapy arm compared with 11.1 months (95% CI, 10.0−12.1) in the chemotherapy-alone arm (HR, 0.71; 98.4% CI, 0.59–0.86; P = .0001).
    • Grades 3 and 4 adverse events occurred in 462 patients in the combination arm and in 341 patients in the chemotherapy-alone arm.[28][Level of evidence A1]
Trastuzumab with chemotherapy

Trastuzumab may be combined with pembrolizumab and chemotherapy (either 5-FU and cisplatin or CAPOX) as treatment for patients with HER2-positive metastatic gastric adenocarcinoma. For patients who do not tolerate pembrolizumab, trastuzumab may be combined with cisplatin and 5-FU or capecitabine. HER2 testing is recommended for patients with metastatic disease.[29]

Evidence (trastuzumab and pembrolizumab with chemotherapy):

  1. The double-blind, placebo-controlled, phase III, international KEYNOTE-811 trial (NCT03615326) studied dual pembrolizumab, trastuzumab, and chemotherapy (either 5-FU with cisplatin or CAPOX). A total of 434 patients with metastatic HER2-positive gastric adenocarcinoma were randomly assigned in a 1:1 ratio to receive either chemotherapy and trastuzumab (6 mg/kg every 3 weeks) with or without pembrolizumab (200 mg intravenously [IV] every 3 weeks).
    • The objective response rate at the first interim analysis was 74.4% (95% CI, 66.2%–81.6%) for patients in the pembrolizumab arm and 51.9% (95% CI, 43.0%–60.7%) for patients in the placebo arm.[29][Level of evidence B3]
    • Adverse events grade 3 or higher were observed in 57.1% of patients in the pembrolizumab arm (including 33.6% of patients with immune-related reactions) and 57.4% of patients in the placebo arm.

Evidence (trastuzumab):

  1. In the open-label, international, phase III Trastuzumab for Gastric Cancer trial (ToGA [NCT01041404]), patients with HER2-positive metastatic, inoperable locally advanced, or recurrent gastric or gastroesophageal junction cancer were randomly assigned to receive chemotherapy with or without the anti-HER2 monoclonal antibody trastuzumab.[30] HER2 positivity was defined as either 3+ by IHC or a HER2 to CEP17 ratio of 2 or more using FISH. Tumors from 3,665 patients were tested for HER2; of the patients, 810 were positive (22%) and 594 met eligibility criteria for randomization. Chemotherapy consisted of cisplatin plus 5-FU or capecitabine chosen at the investigator’s discretion. The study treatment was administered every 3 weeks for six cycles, and trastuzumab was continued every 3 weeks until disease progression, unacceptable toxicity, or withdrawal of consent. Crossover to trastuzumab at disease progression was not permitted.
    • The median OS was 13.8 months (95% CI, 12–16) in patients assigned to trastuzumab and 11.1 months (95% CI, 10–13) in patients assigned to chemotherapy alone (HR, 0.74; 95% CI, 0.60–0.91; P = .0046).[30][Level of evidence A1]
    • There was no significant difference in rates of any adverse event, and cardiotoxic effects were equally rare in both arms.
Pembrolizumab with chemotherapy

The combination of pembrolizumab and chemotherapy has not shown superiority over chemotherapy alone.

Evidence (pembrolizumab with chemotherapy):

  1. A phase III, partially blinded, randomized, international study (KEYNOTE-062 [NCT02494583]) of 763 patients with previously untreated advanced gastric cancer with a PD-L1 CPS of one or greater randomly assigned patients 1:1:1 to receive either pembrolizumab 200 mg IV every 3 weeks, pembrolizumab with chemotherapy (cisplatin with 5-FU or capecitabine), or chemotherapy alone.[31]
    • The final results did not show superiority of pembrolizumab or pembrolizumab with chemotherapy over chemotherapy alone.
    • However, when selected for a PD-L1 CPS of ten or greater, median OS was 17.4 months (95% CI, 9.1−23.1) in the pembrolizumab-alone arm compared with 10.8 months (95% CI, 8.5−13.8) in the chemotherapy-alone arm (HR, 0.69; 95% CI, 0.49−0.97). The prespecified statistical analysis plan did not test this difference further.

Second-line palliative systemic therapy

There is no standard treatment option for patients who develop disease progression after first-line palliative chemotherapy. Accepted regimens include paclitaxel with or without ramucirumab, docetaxel, and irinotecan with or without 5-FU/leucovorin. Pembrolizumab is approved for the treatment of patients with dMMR or MSI-H tumors, and trastuzumab deruxtecan is approved for patients with HER2-positive gastric cancer.

Palliative chemotherapy

Evidence (palliative chemotherapy):

  1. Investigators in Korea randomly assigned patients with advanced gastric cancer who had previously received one or two chemotherapy regimens that involved both a fluoropyrimidine and a platinum agent to receive either salvage chemotherapy or best supportive care in a 2:1 fashion.[32] Salvage chemotherapy consisted of either docetaxel (60 mg/m2 every 3 weeks) or irinotecan (150 mg/m2 every 2 weeks) and was left to the discretion of the treating physicians. Of the 202 patients enrolled, 133 received salvage chemotherapy and 69 received best supportive care.
    • The median OS was 5.3 months in the group that received salvage chemotherapy and 3.8 months in the group that received best supportive care (HR, 0.657; P = .007).
    • There was no difference in median OS between docetaxel and irinotecan (5.2 months vs. 6.5 months, P = .116).[32][Level of evidence A1]
Ramucirumab with or without chemotherapy

Ramucirumab is a fully humanized monoclonal antibody directed against the vascular endothelial growth factor receptor-2.

Evidence (ramucirumab):

  1. The international, phase III, placebo-controlled, REGARD trial (NCT00917384) included 355 patients with stage IV gastric or gastroesophageal junction cancer who had progressed on a first-line 5-FU‒ or platinum-containing regimen. Patients were randomly assigned in a 2:1 fashion to receive either ramucirumab or placebo.[33]
    • Patients who were assigned to ramucirumab had a significantly improved median OS of 5.2 months compared with a median OS of 3.8 months in patients who were assigned to the placebo (HR, 0.776; P = .047).
    • Rates of hypertension were higher in the ramucirumab group than in the placebo group.[33][Level of evidence A1]

    Ramucirumab is an acceptable treatment in patients with cisplatin- or 5-FU‒refractory, stage IV, gastric cancer.

  2. In the international, double-blinded, phase III RAINBOW trial (NCT01170663), 665 patients were randomly assigned to receive paclitaxel (80 mg/m2) on days 1, 8, and 15 every 28 days with either ramucirumab (8 mg/kg) added on days 1 and 15 or a placebo added on days 1 and 15.[34]
    • Patients who were assigned to ramucirumab had a significant improvement in median OS of 9.6 months compared with a median OS of 7.4 months in patients who were assigned to a placebo (HR, 0.807; P = .017).
    • Grade 3 or higher neutropenia, fatigue, hypertension, and abdominal pain were more common in the ramucirumab group.[34][Level of evidence A1]

    The combination of paclitaxel and ramucirumab is an acceptable second-line chemotherapy regimen in patients with stage IV gastric or gastroesophageal junction cancer.

Pembrolizumab for patients with dMMR or MSI-H tumors

Evidence (pembrolizumab for patients with dMMR or MSI-H tumors):

  1. In a phase II study of pembrolizumab 200 mg IV every 3 weeks in patients with colon cancer with or without dMMR, and noncolorectal cancer with dMMR, the immune-related objective response rate was 71% (5 of 7 patients). Based on these data, pembrolizumab was approved for patients with dMMR solid tumors that have progressed after previous treatment and who have no satisfactory alternative treatment options.[35]
Trastuzumab deruxtecan for patients with HER2-positive tumors (3+ on IHC or 2+ on IHC with a positive FISH)

Trastuzumab deruxtecan is an antibody-drug conjugate combining an anti-HER2 antibody with a topoisomerase I inhibitor via a cleavable tetrapeptide-based linker. The U.S. Food and Drug Administration (FDA) approved trastuzumab deruxtecan for patients with locally advanced or metastatic gastric or gastroesophageal junction cancer that is HER2-positive who have previously received a trastuzumab-based regimen.

Evidence (trastuzumab deruxtecan for patients with HER2-positive tumors):

  1. The international, open-label, randomized, phase II DESTINY-Gastric01 trial (NCT03329690) included 187 patients from Japan and South Korea with HER2-positive advanced gastric cancer that had progressed after at least two previous therapies (including trastuzumab). Patients were randomly assigned in a 2:1 ratio to receive either trastuzumab deruxtecan (6.4 mg/kg every 3 weeks) or the physician’s choice of chemotherapy. The primary study end point was objective response.[36]
    • The objective response rate was 51% for patients who received trastuzumab deruxtecan and 14% for patients who received chemotherapy (P < .001).
    • The OS was 12.5 months for patients who received trastuzumab deruxtecan and 8.4 months for patients who received chemotherapy (HR, 0.59; 95% CI, 0.39–0.88, P = .02).[36][Level of evidence A1]
    • Common side effects of trastuzumab deruxtecan included neutropenia (grade 3–4 in 51% of patients, with six patients developing neutropenic fever) and anemia (grade 3–4 in 38% of patients). Twelve patients (10%) developed drug-related interstitial lung disease.

Third-line palliative systemic therapy

Trifluridine and tipiracil

Trifluridine and tipiracil is an oral cytotoxic therapy approved by the FDA for third-line treatment of patients with metastatic gastric or gastroesophageal junction cancer.

Evidence (trifluridine and tipiracil):

  1. A randomized, double-blinded, placebo-controlled, international, phase III trial (TAGS [NCT02500043]) included 507 patients with metastatic gastric or gastroesophageal junction adenocarcinoma who had progressive disease after receiving two previous regimens, including a fluoropyrimidine, a platinum agent, and a taxane and/or irinotecan. Patients were randomly assigned in a 2:1 ratio to receive either trifluridine and tipiracil (35 mg/m2 twice a day on days 1−5 and 8−12 every 28 days) or placebo.[37]
    • The median OS was 5.7 months (95% CI, 4.8−6.2) in patients who received trifluridine and tipiracil, compared with 3.6 months (95% CI, 3.1−4.1) in patients who received placebo (HR, 0.69; 95% CI, 0.57−0.85; P = .00058).
    • The objective response rate was 4% (disease control rate, 44%) in the trifluridine and tipiracil arm, compared with 2% (disease control rate, 14%) in the placebo arm.
    • Grade 3 or higher adverse events occurred in 80% of patients treated with trifluridine and tipiracil, compared with 58% of patients who received placebo.
Immunotherapy
Pembrolizumab

While pembrolizumab was previously evaluated as third-line treatment for patients with gastric and gastroesophageal junction cancers and a PD-L1 CPS of one or greater, this approval was withdrawn after updates to first-line therapy using combination chemotherapy and programmed death 1 (PD-1) inhibitors.

Nivolumab

Nivolumab has been approved by the Japanese Ministry of Health, Labor, and Welfare for treatment of advanced gastric cancer, regardless of PD-L1 CPS status.

Evidence (nivolumab):

  1. A randomized, double-blinded, placebo-controlled, phase III trial (ONO-4538-12 [ATTRACTION-2] [NCT02267343]) enrolled 493 patients with refractory gastroesophageal/gastric cancer from Japan, South Korea, and Taiwan.[38] Patients were randomly assigned 2:1 to receive either nivolumab (3 mg/kg every 2 weeks) or placebo.
    • The median OS was 5.26 months (95% CI, 4.60–6.37) in the nivolumab group compared with 4.14 months (95% CI, 3.42–4.86) in the placebo group.
    • Serious treatment-related adverse events occurred in 10% of the patients.[38][Level of evidence A1]

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. Shah MA, Shitara K, Ajani JA, et al.: Zolbetuximab plus CAPOX in CLDN18.2-positive gastric or gastroesophageal junction adenocarcinoma: the randomized, phase 3 GLOW trial. Nat Med 29 (8): 2133-2141, 2023. [PUBMED Abstract]
  2. Shitara K, Lordick F, Bang YJ, et al.: Zolbetuximab plus mFOLFOX6 in patients with CLDN18.2-positive, HER2-negative, untreated, locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma (SPOTLIGHT): a multicentre, randomised, double-blind, phase 3 trial. Lancet 401 (10389): 1655-1668, 2023. [PUBMED Abstract]
  3. Waters JS, Norman A, Cunningham D, et al.: Long-term survival after epirubicin, cisplatin and fluorouracil for gastric cancer: results of a randomized trial. Br J Cancer 80 (1-2): 269-72, 1999. [PUBMED Abstract]
  4. Ross P, Nicolson M, Cunningham D, et al.: Prospective randomized trial comparing mitomycin, cisplatin, and protracted venous-infusion fluorouracil (PVI 5-FU) With epirubicin, cisplatin, and PVI 5-FU in advanced esophagogastric cancer. J Clin Oncol 20 (8): 1996-2004, 2002. [PUBMED Abstract]
  5. Vanhoefer U, Rougier P, Wilke H, et al.: Final results of a randomized phase III trial of sequential high-dose methotrexate, fluorouracil, and doxorubicin versus etoposide, leucovorin, and fluorouracil versus infusional fluorouracil and cisplatin in advanced gastric cancer: A trial of the European Organization for Research and Treatment of Cancer Gastrointestinal Tract Cancer Cooperative Group. J Clin Oncol 18 (14): 2648-57, 2000. [PUBMED Abstract]
  6. Van Cutsem E, Moiseyenko VM, Tjulandin S, et al.: Phase III study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and fluorouracil as first-line therapy for advanced gastric cancer: a report of the V325 Study Group. J Clin Oncol 24 (31): 4991-7, 2006. [PUBMED Abstract]
  7. Al-Batran SE, Homann N, Pauligk C, et al.: Perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus cisplatin and epirubicin for locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4): a randomised, phase 2/3 trial. Lancet 393 (10184): 1948-1957, 2019. [PUBMED Abstract]
  8. Ajani JA, Ota DM, Jackson DE: Current strategies in the management of locoregional and metastatic gastric carcinoma. Cancer 67 (1 Suppl): 260-5, 1991. [PUBMED Abstract]
  9. Guimbaud R, Louvet C, Ries P, et al.: Prospective, randomized, multicenter, phase III study of fluorouracil, leucovorin, and irinotecan versus epirubicin, cisplatin, and capecitabine in advanced gastric adenocarcinoma: a French intergroup (Fédération Francophone de Cancérologie Digestive, Fédération Nationale des Centres de Lutte Contre le Cancer, and Groupe Coopérateur Multidisciplinaire en Oncologie) study. J Clin Oncol 32 (31): 3520-6, 2014. [PUBMED Abstract]
  10. Cunningham D, Starling N, Rao S, et al.: Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med 358 (1): 36-46, 2008. [PUBMED Abstract]
  11. Cullinan SA, Moertel CG, Fleming TR, et al.: A comparison of three chemotherapeutic regimens in the treatment of advanced pancreatic and gastric carcinoma. Fluorouracil vs fluorouracil and doxorubicin vs fluorouracil, doxorubicin, and mitomycin. JAMA 253 (14): 2061-7, 1985. [PUBMED Abstract]
  12. Ohtsu A, Shimada Y, Shirao K, et al.: Randomized phase III trial of fluorouracil alone versus fluorouracil plus cisplatin versus uracil and tegafur plus mitomycin in patients with unresectable, advanced gastric cancer: The Japan Clinical Oncology Group Study (JCOG9205). J Clin Oncol 21 (1): 54-9, 2003. [PUBMED Abstract]
  13. Ell C, Hochberger J, May A, et al.: Coated and uncoated self-expanding metal stents for malignant stenosis in the upper GI tract: preliminary clinical experiences with Wallstents. Am J Gastroenterol 89 (9): 1496-500, 1994. [PUBMED Abstract]
  14. Murad AM, Santiago FF, Petroianu A, et al.: Modified therapy with 5-fluorouracil, doxorubicin, and methotrexate in advanced gastric cancer. Cancer 72 (1): 37-41, 1993. [PUBMED Abstract]
  15. Pyrhönen S, Kuitunen T, Nyandoto P, et al.: Randomised comparison of fluorouracil, epidoxorubicin and methotrexate (FEMTX) plus supportive care with supportive care alone in patients with non-resectable gastric cancer. Br J Cancer 71 (3): 587-91, 1995. [PUBMED Abstract]
  16. Glimelius B, Ekström K, Hoffman K, et al.: Randomized comparison between chemotherapy plus best supportive care with best supportive care in advanced gastric cancer. Ann Oncol 8 (2): 163-8, 1997. [PUBMED Abstract]
  17. Wagner AD, Grothe W, Haerting J, et al.: Chemotherapy in advanced gastric cancer: a systematic review and meta-analysis based on aggregate data. J Clin Oncol 24 (18): 2903-9, 2006. [PUBMED Abstract]
  18. Webb A, Cunningham D, Scarffe JH, et al.: Randomized trial comparing epirubicin, cisplatin, and fluorouracil versus fluorouracil, doxorubicin, and methotrexate in advanced esophagogastric cancer. J Clin Oncol 15 (1): 261-7, 1997. [PUBMED Abstract]
  19. Ajani JA, Moiseyenko VM, Tjulandin S, et al.: Clinical benefit with docetaxel plus fluorouracil and cisplatin compared with cisplatin and fluorouracil in a phase III trial of advanced gastric or gastroesophageal cancer adenocarcinoma: the V-325 Study Group. J Clin Oncol 25 (22): 3205-9, 2007. [PUBMED Abstract]
  20. Ilson DH: Docetaxel, cisplatin, and fluorouracil in gastric cancer: does the punishment fit the crime? J Clin Oncol 25 (22): 3188-90, 2007. [PUBMED Abstract]
  21. Ilson DH, Saltz L, Enzinger P, et al.: Phase II trial of weekly irinotecan plus cisplatin in advanced esophageal cancer. J Clin Oncol 17 (10): 3270-5, 1999. [PUBMED Abstract]
  22. Beretta E, Di Bartolomeo M, Buzzoni R, et al.: Irinotecan, fluorouracil and folinic acid (FOLFIRI) as effective treatment combination for patients with advanced gastric cancer in poor clinical condition. Tumori 92 (5): 379-83, 2006 Sep-Oct. [PUBMED Abstract]
  23. Pozzo C, Barone C, Szanto J, et al.: Irinotecan in combination with 5-fluorouracil and folinic acid or with cisplatin in patients with advanced gastric or esophageal-gastric junction adenocarcinoma: results of a randomized phase II study. Ann Oncol 15 (12): 1773-81, 2004. [PUBMED Abstract]
  24. Bouché O, Raoul JL, Bonnetain F, et al.: Randomized multicenter phase II trial of a biweekly regimen of fluorouracil and leucovorin (LV5FU2), LV5FU2 plus cisplatin, or LV5FU2 plus irinotecan in patients with previously untreated metastatic gastric cancer: a Federation Francophone de Cancerologie Digestive Group Study–FFCD 9803. J Clin Oncol 22 (21): 4319-28, 2004. [PUBMED Abstract]
  25. Ajani JA, Baker J, Pisters PW, et al.: CPT-11 plus cisplatin in patients with advanced, untreated gastric or gastroesophageal junction carcinoma: results of a phase II study. Cancer 94 (3): 641-6, 2002. [PUBMED Abstract]
  26. Cavanna L, Artioli F, Codignola C, et al.: Oxaliplatin in combination with 5-fluorouracil (5-FU) and leucovorin (LV) in patients with metastatic gastric cancer (MGC). Am J Clin Oncol 29 (4): 371-5, 2006. [PUBMED Abstract]
  27. Lordick F, Van Cutsem E, Shitara K, et al.: Health-related quality of life in patients with CLDN18.2-positive, locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma: results from the SPOTLIGHT and GLOW clinical trials. ESMO Open 9 (8): 103663, 2024. [PUBMED Abstract]
  28. Janjigian YY, Shitara K, Moehler M, et al.: First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial. Lancet 398 (10294): 27-40, 2021. [PUBMED Abstract]
  29. Janjigian YY, Kawazoe A, Yañez P, et al.: The KEYNOTE-811 trial of dual PD-1 and HER2 blockade in HER2-positive gastric cancer. Nature 600 (7890): 727-730, 2021. [PUBMED Abstract]
  30. Bang YJ, Van Cutsem E, Feyereislova A, et al.: Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet 376 (9742): 687-97, 2010. [PUBMED Abstract]
  31. Shitara K, Van Cutsem E, Bang YJ, et al.: Efficacy and Safety of Pembrolizumab or Pembrolizumab Plus Chemotherapy vs Chemotherapy Alone for Patients With First-line, Advanced Gastric Cancer: The KEYNOTE-062 Phase 3 Randomized Clinical Trial. JAMA Oncol 6 (10): 1571-1580, 2020. [PUBMED Abstract]
  32. Kang JH, Lee SI, Lim do H, et al.: Salvage chemotherapy for pretreated gastric cancer: a randomized phase III trial comparing chemotherapy plus best supportive care with best supportive care alone. J Clin Oncol 30 (13): 1513-8, 2012. [PUBMED Abstract]
  33. Fuchs CS, Tomasek J, Yong CJ, et al.: Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet 383 (9911): 31-9, 2014. [PUBMED Abstract]
  34. Wilke H, Muro K, Van Cutsem E, et al.: Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol 15 (11): 1224-35, 2014. [PUBMED Abstract]
  35. Le DT, Uram JN, Wang H, et al.: PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N Engl J Med 372 (26): 2509-20, 2015. [PUBMED Abstract]
  36. Shitara K, Bang YJ, Iwasa S, et al.: Trastuzumab Deruxtecan in Previously Treated HER2-Positive Gastric Cancer. N Engl J Med 382 (25): 2419-2430, 2020. [PUBMED Abstract]
  37. Shitara K, Doi T, Dvorkin M, et al.: Trifluridine/tipiracil versus placebo in patients with heavily pretreated metastatic gastric cancer (TAGS): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 19 (11): 1437-1448, 2018. [PUBMED Abstract]
  38. Kang YK, Boku N, Satoh T, et al.: Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 390 (10111): 2461-2471, 2017. [PUBMED Abstract]

Latest Updates to This Summary (02/21/2025)

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.

General Information About Gastric Cancer

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

Revised text to state that, in the United States, gastric cancer ranks 15th in incidence among the major types of cancer (cited National Cancer Institute as reference 8).

Treatment of Stage IV, Inoperable, and Recurrent Gastric Cancer

Revised the list of treatment options for stage IV, inoperable, and recurrent gastric cancer to include monoclonal antibody therapy with chemotherapy for patients with CLDN18.2-positive tumors.

Added Monoclonal antibody therapy with chemotherapy for patients with CLDN18.2-positive tumors as a new subsection.

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 gastric 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 Gastric Cancer Treatment are:

  • Amit Chowdhry, MD, PhD (University of Rochester Medical Center)
  • Leon Pappas, MD, PhD (Massachusetts General Hospital)

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 Gastric Cancer Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/stomach/hp/stomach-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389209]

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Thymoma and Thymic Carcinoma Treatment (PDQ®)–Health Professional Version

Thymoma and Thymic Carcinoma Treatment (PDQ®)–Health Professional Version

General Information About Thymoma and Thymic Carcinoma Treatment

Go to Patient Version

Thymoma and thymic carcinoma, collectively termed thymic epithelial tumors (TETs), are relatively rare tumors arising from the thymus. Although infrequent, TETs are the most common tumors of the anterior mediastinum in adults. TETs, particularly thymomas, have unique biological properties and are associated with autoimmune paraneoplastic diseases. TETs have the lowest tumor mutational burden of all solid tumors in adults. All TETs have malignant potential and the ability to metastasize. The clinical behavior of TETs can vary from relatively indolent to aggressive, resulting in a range of clinical outcomes.

Surgery is the main treatment, especially for early-stage disease. Multimodality therapy, including chemotherapy and radiation therapy, is used to treat locally advanced disease, and systemic therapy alone is indicated for metastatic TETs.[1]

Incidence and Mortality

TETs are relatively rare tumors, representing about 0.2% to 1.5% of all malignancies.[2] The overall incidence of thymoma is 0.13 cases per 100,000 person-years, based on data from the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) Program.[3] Thymic carcinomas account for approximately 20% of all TETs.[4] The 5-year survival rate is 36% for patients with inoperable, locally advanced carcinoma and 24% for patients with metastatic thymoma and thymic carcinoma.[5]

Autoimmune Paraneoplastic Diseases Associated With Thymoma and Thymic Carcinomas

Autoimmune paraneoplastic diseases are associated with thymoma but rarely with thymic carcinomas.[6–9]

The occurrence of autoimmune paraneoplastic diseases in patients with thymoma is related to defective negative selection of autoreactive T cells. Decreased expression of AIRE, the autoimmune regulator gene, contributes to this process.[10] Thymoma-associated autoimmune paraneoplastic disease also involves an alteration in circulating T-cell subsets.[11,12] The primary T-cell abnormality may be related to the acquisition of the CD45RA+ phenotype on naive CD4+ T cells during terminal intratumorous thymopoiesis, followed by the export of these activated CD4+ T cells into the circulation.[13]

In addition to T-cell defects, B-cell lymphopenia and the presence of anticytokine antibodies have been observed in patients with thymoma-related immunodeficiency, resulting in an increased risk of developing opportunistic infection.[6,14,15]

The most common autoimmune paraneoplastic diseases associated with thymoma are myasthenia gravis, hypogammaglobulinemia, and autoimmune pure red cell aplasia.

  • Myasthenia gravis is the most common autoimmune paraneoplastic disease associated with thymoma. In reported series, approximately 30% to 65% of patients with thymoma have been diagnosed with myasthenia gravis.[7,16,17] Patients with thymoma-associated myasthenia gravis can produce autoantibodies to a variety of neuromuscular antigens, particularly the acetylcholine receptor and titin, a striated muscle antigen.[18,19]
  • Thymoma-associated hypogammaglobulinemia (Good syndrome) has a frequency of 5% to 20%, and thymoma-associated autoimmune pure red cell aplasia has a frequency of approximately 4%.[7,14]

A variety of other autoimmune paraneoplastic diseases can be associated with TETs and include virtually any organ system.[7,9]

Thymoma patients with myasthenia gravis or other autoimmune paraneoplastic diseases are typically diagnosed with early-stage disease and are more likely to undergo complete surgical resection than those who do not have autoimmune paraneoplastic diseases.[9,20] Thymectomy may not significantly improve the course of thymoma-associated autoimmune paraneoplastic disease in all cases.[21,22] The presence of autoimmune paraneoplastic disease also does not appear to be an independent prognostic factor in patients with TETs.[9]

Clinical Features

Most patients with thymoma or thymic carcinoma are asymptomatic at diagnosis.[23] About one-third of patients present with symptoms that arise either from the underlying tumor or from the presence of associated autoimmune paraneoplastic diseases. Typical clinical signs and symptoms include cough, dyspnea, chest pain, hoarseness of voice, phrenic nerve palsy, or signs suggestive of superior vena cava syndrome.[24]

Diagnostic and Staging Evaluation

TETs are differentiated from a number of nonthymic neoplasms that can present with mediastinal masses, including:[25,26]

  • Germ cell tumors.
  • Lymphomas.
  • Stromal tumors.
  • Metastatic tumors.
  • Lung cancer.

Nonneoplastic thymic conditions that can present with mediastinal masses include thymic hyperplasia and thymic cysts.

The following tests and procedures may be used to diagnose and stage thymoma and thymic carcinoma:

  • Physical examination and history.
  • Chest x-ray. Approximately 50% of thymomas are diagnosed when they are localized within the thymic capsule and do not infiltrate surrounding tissues.[23]
  • Computed tomography (CT) scan. CT with intravenous contrast is useful in the diagnosis and clinical staging of thymoma. CT is usually accurate in predicting tumor size, location, and invasion into vessels, the pericardium, and the lungs.[27,28]

    The appearance of the tumor on CT may indicate the histological tumor type.[25] In a retrospective study involving 53 patients who underwent thymectomy for TETs, CT indicated that smooth contours with a round shape were most suggestive of type A thymomas, and irregular contours were most suggestive of thymic carcinomas. Calcification was suggestive of type B thymomas. In this study, however, CT was found to be of limited value in differentiating type AB, B1, B2, and B3 thymomas.[29]

  • Positron emission tomography (PET) scan. Fluorine F 18-fludeoxyglucose (18F-FDG) PET and thallium single-photon emission CT have been reported in small series for diagnosis and evaluation of therapeutic outcomes in thymic carcinoma.[30–33] Two small series reported that 18F-FDG uptake was related to the invasiveness of thymic carcinoma.[32,33] This raises the possibility of 18F-FDG PET use for diagnosis, treatment planning, and monitoring for recurrence. The impact of sensitivity and specificity on clinical therapeutic decisions is yet to be defined.
  • Magnetic resonance imaging (MRI). MRI can distinguish TETs from other malignant and benign mediastinal lesions. Chemical-shift MRI can help differentiate TETs from thymic hyperplasia and a normal thymus. Cardiac MRI is the preferred modality to evaluate for the presence of myocardial involvement. An MRI can help identify phrenic nerve involvement and is considered superior to CT for assessing chest wall invasion.[34]

Thymic carcinoma can metastasize to regional lymph nodes, bone, liver, or lungs. An evaluation for sites of metastases may be warranted.

Prognostic Factors and Prognosis

The World Health Organization (WHO) pathological classification of tumors of the thymus and stage correlate with prognosis.[25] The degree of invasion or tumor stage is generally thought to be a more important indicator of overall survival (OS).[27,35,36]

Thymoma

Histological classification of thymoma is not sufficient to distinguish biologically indolent thymomas from thymomas that exhibit aggressive clinical behavior. Although some thymoma histological types are more likely to be clinically aggressive, treatment outcome and the likelihood of recurrence appear to correlate more closely with the invasive/metastasizing properties of the tumor cells.[25,35] Therefore, some thymomas that appear to be relatively benign by histological criteria may behave very aggressively. Independent evaluations of both tumor invasiveness (using staging criteria) and tumor histology may be combined to predict the clinical behavior of a thymoma.

Both histological classification of thymomas and stage may have independent prognostic significance.[35,36] A few series have reported the prognostic value of the WHO classifications. Two large retrospective analyses, one with 100 thymoma cases and the other with 178 thymoma cases, showed that disease-free survival at 10 years varied (see Table 1).[37,38] In these series, stage and complete resection were significant independent prognostic factors. Another analysis reported on 273 thymoma patients who were treated over a 44-year period. See Table 1 for the 20-year survival rates.[35]

Table 1. Disease-Free Survival (DFS) of Patients With Thymoma by Histological Subtype
Study Histological Subtype
  A AB B1 B2 B3 C
a10-year DFS.
b20-year DFS.
[37] (N = 100)a 100% 100% 83% 83% 36% 28%
[38] (N = 178)a 95% 90% 85% 71% 40%  
[35] (N = 273)b 100% 87% 91% 59% 36%  

Thymic carcinoma

Thymic carcinomas are usually advanced when diagnosed.[39,40] Thymic carcinomas have a greater propensity for capsular invasion, metastases, and recurrence than thymomas. Patients with thymic carcinoma have worse survival than patients with thymoma (5-year survival rate, 30%–50%).[41] In a retrospective study of 40 patients with thymic carcinoma, the OS rates were 38% for 5 years and 28% for 10 years.[39] In another retrospective study evaluating 43 cases of thymic carcinoma, prognosis was found to depend solely on tumor invasion of the brachiocephalic artery.[40]

Follow-Up After Treatment of Thymoma

Thymoma has been associated with an increased risk of second malignancies. Because of this risk and because thymoma can recur after a long interval, lifelong surveillance should be considered.[22] The measurement of interferon-alpha and interleukin-2 antibodies is helpful in identifying patients with a thymoma recurrence.[42]

In a study of 849 cases between 1973 and 1998, there was an excess risk of subsequent non-Hodgkin lymphoma and soft tissue sarcomas following thymoma.[43] Risk of second malignancy does not appear to be related to thymectomy, radiation therapy, or a clinical history of myasthenia gravis.[22,43,44]

References
  1. Kelly RJ, Petrini I, Rajan A, et al.: Thymic malignancies: from clinical management to targeted therapies. J Clin Oncol 29 (36): 4820-7, 2011. [PUBMED Abstract]
  2. Fornasiero A, Daniele O, Ghiotto C, et al.: Chemotherapy of invasive thymoma. J Clin Oncol 8 (8): 1419-23, 1990. [PUBMED Abstract]
  3. Engels EA: Epidemiology of thymoma and associated malignancies. J Thorac Oncol 5 (10 Suppl 4): S260-5, 2010. [PUBMED Abstract]
  4. Carter BW, Benveniste MF, Madan R, et al.: IASLC/ITMIG Staging System and Lymph Node Map for Thymic Epithelial Neoplasms. Radiographics 37 (3): 758-776, 2017 May-Jun. [PUBMED Abstract]
  5. Kondo K, Monden Y: Therapy for thymic epithelial tumors: a clinical study of 1,320 patients from Japan. Ann Thorac Surg 76 (3): 878-84; discussion 884-5, 2003. [PUBMED Abstract]
  6. Levy Y, Afek A, Sherer Y, et al.: Malignant thymoma associated with autoimmune diseases: a retrospective study and review of the literature. Semin Arthritis Rheum 28 (2): 73-9, 1998. [PUBMED Abstract]
  7. Marx A, Willcox N, Leite MI, et al.: Thymoma and paraneoplastic myasthenia gravis. Autoimmunity 43 (5-6): 413-27, 2010. [PUBMED Abstract]
  8. Bernard C, Frih H, Pasquet F, et al.: Thymoma associated with autoimmune diseases: 85 cases and literature review. Autoimmun Rev 15 (1): 82-92, 2016. [PUBMED Abstract]
  9. Padda SK, Yao X, Antonicelli A, et al.: Paraneoplastic Syndromes and Thymic Malignancies: An Examination of the International Thymic Malignancy Interest Group Retrospective Database. J Thorac Oncol 13 (3): 436-446, 2018. [PUBMED Abstract]
  10. Kisand K, Lilic D, Casanova JL, et al.: Mucocutaneous candidiasis and autoimmunity against cytokines in APECED and thymoma patients: clinical and pathogenetic implications. Eur J Immunol 41 (6): 1517-27, 2011. [PUBMED Abstract]
  11. Hoffacker V, Schultz A, Tiesinga JJ, et al.: Thymomas alter the T-cell subset composition in the blood: a potential mechanism for thymoma-associated autoimmune disease. Blood 96 (12): 3872-9, 2000. [PUBMED Abstract]
  12. Buckley C, Douek D, Newsom-Davis J, et al.: Mature, long-lived CD4+ and CD8+ T cells are generated by the thymoma in myasthenia gravis. Ann Neurol 50 (1): 64-72, 2001. [PUBMED Abstract]
  13. Ströbel P, Helmreich M, Menioudakis G, et al.: Paraneoplastic myasthenia gravis correlates with generation of mature naive CD4(+) T cells in thymomas. Blood 100 (1): 159-66, 2002. [PUBMED Abstract]
  14. Martinez B, Browne SK: Good syndrome, bad problem. Front Oncol 4: 307, 2014. [PUBMED Abstract]
  15. Burbelo PD, Browne SK, Sampaio EP, et al.: Anti-cytokine autoantibodies are associated with opportunistic infection in patients with thymic neoplasia. Blood 116 (23): 4848-58, 2010. [PUBMED Abstract]
  16. Morgenthaler TI, Brown LR, Colby TV, et al.: Thymoma. Mayo Clin Proc 68 (11): 1110-23, 1993. [PUBMED Abstract]
  17. Souadjian JV, Enriquez P, Silverstein MN, et al.: The spectrum of diseases associated with thymoma. Coincidence or syndrome? Arch Intern Med 134 (2): 374-9, 1974. [PUBMED Abstract]
  18. Voltz RD, Albrich WC, Nägele A, et al.: Paraneoplastic myasthenia gravis: detection of anti-MGT30 (titin) antibodies predicts thymic epithelial tumor. Neurology 49 (5): 1454-7, 1997. [PUBMED Abstract]
  19. Gautel M, Lakey A, Barlow DP, et al.: Titin antibodies in myasthenia gravis: identification of a major immunogenic region of titin. Neurology 43 (8): 1581-5, 1993. [PUBMED Abstract]
  20. Kondo K, Monden Y: Thymoma and myasthenia gravis: a clinical study of 1,089 patients from Japan. Ann Thorac Surg 79 (1): 219-24, 2005. [PUBMED Abstract]
  21. Budde JM, Morris CD, Gal AA, et al.: Predictors of outcome in thymectomy for myasthenia gravis. Ann Thorac Surg 72 (1): 197-202, 2001. [PUBMED Abstract]
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  23. Schmidt-Wolf IG, Rockstroh JK, Schüller H, et al.: Malignant thymoma: current status of classification and multimodality treatment. Ann Hematol 82 (2): 69-76, 2003. [PUBMED Abstract]
  24. Rajan A, Giaccone G: Treatment of advanced thymoma and thymic carcinoma. Curr Treat Options Oncol 9 (4-6): 277-87, 2008. [PUBMED Abstract]
  25. Rosai J: Histological Typing of Tumours of the Thymus. Springer-Verlag, 2nd ed., 1999.
  26. Strollo DC, Rosado-de-Christenson ML: Tumors of the thymus. J Thorac Imaging 14 (3): 152-71, 1999. [PUBMED Abstract]
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  29. Tomiyama N, Johkoh T, Mihara N, et al.: Using the World Health Organization Classification of thymic epithelial neoplasms to describe CT findings. AJR Am J Roentgenol 179 (4): 881-6, 2002. [PUBMED Abstract]
  30. Sasaki M, Kuwabara Y, Ichiya Y, et al.: Differential diagnosis of thymic tumors using a combination of 11C-methionine PET and FDG PET. J Nucl Med 40 (10): 1595-601, 1999. [PUBMED Abstract]
  31. Kageyama M, Seto H, Shimizu M, et al.: Thallium-201 single photon emission computed tomography in the evaluation of thymic carcinoma. Radiat Med 12 (5): 237-9, 1994 Sep-Oct. [PUBMED Abstract]
  32. Adams S, Baum RP, Hertel A, et al.: Metabolic (PET) and receptor (SPET) imaging of well- and less well-differentiated tumours: comparison with the expression of the Ki-67 antigen. Nucl Med Commun 19 (7): 641-7, 1998. [PUBMED Abstract]
  33. Kubota K, Yamada S, Kondo T, et al.: PET imaging of primary mediastinal tumours. Br J Cancer 73 (7): 882-6, 1996. [PUBMED Abstract]
  34. Carter BW, Lichtenberger JP, Benveniste MF: MR Imaging of Thymic Epithelial Neoplasms. Top Magn Reson Imaging 27 (2): 65-71, 2018. [PUBMED Abstract]
  35. Okumura M, Ohta M, Tateyama H, et al.: The World Health Organization histologic classification system reflects the oncologic behavior of thymoma: a clinical study of 273 patients. Cancer 94 (3): 624-32, 2002. [PUBMED Abstract]
  36. Chen G, Marx A, Wen-Hu C, et al.: New WHO histologic classification predicts prognosis of thymic epithelial tumors: a clinicopathologic study of 200 thymoma cases from China. Cancer 95 (2): 420-9, 2002. [PUBMED Abstract]
  37. Kondo K, Yoshizawa K, Tsuyuguchi M, et al.: WHO histologic classification is a prognostic indicator in thymoma. Ann Thorac Surg 77 (4): 1183-8, 2004. [PUBMED Abstract]
  38. Rena O, Papalia E, Maggi G, et al.: World Health Organization histologic classification: an independent prognostic factor in resected thymomas. Lung Cancer 50 (1): 59-66, 2005. [PUBMED Abstract]
  39. Ogawa K, Toita T, Uno T, et al.: Treatment and prognosis of thymic carcinoma: a retrospective analysis of 40 cases. Cancer 94 (12): 3115-9, 2002. [PUBMED Abstract]
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  42. Buckley C, Newsom-Davis J, Willcox N, et al.: Do titin and cytokine antibodies in MG patients predict thymoma or thymoma recurrence? Neurology 57 (9): 1579-82, 2001. [PUBMED Abstract]
  43. Engels EA, Pfeiffer RM: Malignant thymoma in the United States: demographic patterns in incidence and associations with subsequent malignancies. Int J Cancer 105 (4): 546-51, 2003. [PUBMED Abstract]
  44. Pan CC, Chen PC, Wang LS, et al.: Thymoma is associated with an increased risk of second malignancy. Cancer 92 (9): 2406-11, 2001. [PUBMED Abstract]

Cellular Classification and Molecular Characteristics of Thymoma and Thymic Carcinomas

The histological classification of thymic epithelial tumors (TETs) is largely based on the third edition of the World Health Organization (WHO) classification of tumors of the lung, pleura, thymus, and heart, published in 2004. The fourth edition of the WHO classification, published in 2015, contains refined histological and immunohistochemical diagnostic criteria and is the most widely accepted cellular classification of TETs.[1,2] Thymomas arise from the thymic epithelium and consist of epithelial cells mixed with varying proportions of immature T cells. Thymic carcinomas are epithelial tumors with overt cytological atypia and without organotypic (i.e., thymus-like) features.

Thymoma

The epithelial component of thymomas exhibit no or minimal overt atypia and retain histological features specific to the normal thymus.[1] Immature nonneoplastic lymphocytes are present in variable numbers depending on the histological type of thymoma.

Table 2, Table 3, Table 4, Table 5, and Table 6 describe morphologic, molecular, and clinical characteristics of various subtypes of thymoma.

Table 2. Characteristics of Subtype A Thymoma
OS = overall survival.
Histological subtype percentage of all thymomas in study cited.[3,4] Approximately 4%–7%.
Myasthenia gravis association.[3] Approximately 17%.
Morphologic characteristics.[2] Composed of bland, spindle-shaped epithelial cells (at least focally) with a paucity or absence of immature (TdT+) T cells throughout the tumor.
Molecular characteristics.[5,6] Chromosome abnormalities, when present, may correlate with an aggressive clinical course and may include: chromosome 6q25 loss, chromosome 6p23 loss (FOXC1), C19MC overexpression, GTF2I variants, HRAS (G13V) variants, and miR-515 upregulation.
Prognosis and survival.[3,4] Excellent, with a ≥15-year OS rate of 100%.
Table 3. Characteristics of Subtype AB Thymoma
OS = overall survival.
Histological subtype percentage of all thymomas in study cited.[3,4] Approximately 28%–34%.
Myasthenia gravis association.[3] Approximately 16%.
Morphologic characteristics.[2] Composed of bland, spindle-shaped epithelial cells (at least focally), with an abundance of immature (TdT+) T cells focally or throughout the tumor.
Molecular characteristics.[5,6] Includes chromosome 6q25 loss, chromosome 6p23 loss (FOXC1), chromosome 7p15 loss, C19MC overexpression, and GTF2I variants.
Prognosis and survival.[3,4] Good, with a ≥15-year OS rate of approximately 90%.
Table 4. Characteristics of Subtype B1 Thymoma
OS = overall survival.
Histological subtype percentage of all thymomas in study cited.[3,4] Approximately 9%–20%.
Myasthenia gravis association.[3] Approximately 57%.
Morphologic characteristics.[2] Tumors exhibit thymus-like architecture and cytology including the abundance of immature T cells, areas of medullary differentiation (medullary islands), and a paucity of polygonal or dendritic epithelia cells without clustering (i.e., <3 contiguous epithelial cells).
Molecular characteristics.[5] Includes chromosome 1p, 2q, 3q, 6q losses.
Prognosis and survival.[3,4] Good, with a ≥20-year OS rate of approximately 90%.
Table 5. Characteristics of Subtype B2 Thymoma
OS = overall survival.
Histological subtype percentage of all thymomas in study cited.[3,4] Approximately 20%–36%.
Myasthenia gravis association.[3] Approximately 71%.
Morphologic characteristics.[2] Tumors consist of increased numbers of single or clustered polygonal or dendritic epithelial cells intermingled with abundant immature T cells.
Molecular characteristics.[5] Includes chromosome 6q25 loss, chromosome 6p23 loss (FOXC1), chromosome 1q gain, and KRAS (G12A) variants.
Prognosis and survival.[3] Worse than for thymoma types A, AB, and B1, with a 20-year OS rate (as defined by freedom from tumor death) of approximately 60%.
Table 6. Characteristics of Subtype B3 Thymoma
OS = overall survival.
Histological subtype percentage of all thymomas in study cited.[3,4] Approximately 10%–14%.
Myasthenia gravis association.[3] Approximately 46%.
Morphologic characteristics.[2] Predominantly composed of sheets of polygonal, slightly-to-moderately atypical epithelial cells, absent or rare intercellular bridges, and paucity or absence of intermingled TdT+ T cells.
Molecular characteristics.[5] Includes chromosome 6q25 loss, chromosome 6p23 loss (FOXC1), chromosome 11q4 loss, chromosome 1q gain, chromosomal translocation t(11;X), BCL2 copy number gains (18q21.33), MCL1 copy number gain, CDKN2A/B copy number losses (9p21.3), BCOR variants, and PHF15 variants.
Prognosis and survival.[3] A 20-year OS rate (as defined by freedom from tumor death) of approximately 40%.

Thymic Carcinoma

Thymic carcinoma is a TET that exhibits a definite cytological atypia and a set of histological features no longer specific to the thymus but similar to histological features observed in carcinomas of other organs. Unlike type A and B thymomas, thymic carcinomas lack immature lymphocytes. Any lymphocytes that are present are mature and usually admixed with plasma cells.[1]

The characteristics of thymic carcinoma subtypes are described in Table 7.

Table 7. Characteristics of Thymic Carcinoma Subtypesa
Subtype Characteristics
CEA = carcinoembryonic antigen; CK = cytokeratin; EMA = epithelial membrane antigen; PAS = periodic acid-Schiff; PLAP = placental alkaline phosphatase.
aAdapted from [7,8].
Squamous cell carcinoma (SCC) The most common subtype of thymic carcinoma, SCC exhibits clear-cut cytological atypia and resembles SCC arising in other organs. Not all cases have clear evidence of keratinization. SCC lacks immature T lymphocytes. CD5, CD70, CD117, FoxN1, and CD205 are expressed by most thymic SCCs.
Basaloid carcinoma Composed of compact lobules of tumor cells that exhibit peripheral palisading and an overall basophilic staining pattern caused by the high nucleocytoplasmic ratio. Basaloid carcinoma tends to originate from multilocular thymic cysts, expresses keratin and EMA, can express CD5 but does not express S-100 and neuroendocrine markers.
Lymphoepithelioma-like carcinoma Syncytial growth of undifferentiated carcinoma cells accompanied by a lymphoplasmacytic infiltration is like undifferentiated carcinoma of the respiratory tract. Lymphoepithelioma-like carcinoma may or may not be Epstein-Barr virus positive. Tumor cells are strongly positive for AE1-defined acidic CKs and negative for AE3-defined basic CKs. CK7 and CK20 are also negative. BCL-2 expression is common. CD5 is focally expressed or absent. Lymphoid cells are CD3+, CD5+, CD1a-, CD99-, and TdT-mature T cells. CD20+ B cells are present in small numbers in the stroma.
Sarcomatoid thymic carcinoma Part or all of the tumor resembles one of the types of soft tissue sarcoma. Sarcomatoid carcinoma includes spindle cell carcinoma (i.e., malignant transformation of type A thymoma), sarcomatoid transformation of preexisting thymic carcinoma, and true carcinosarcoma with heterologous component(s).
Clear cell thymic carcinoma Composed predominantly or exclusively of cells with optically clear cytoplasm. Tumor cells usually show strong cytoplasmic diastase-labile PAS positivity. Clear cell carcinomas are keratin positive. EMA is expressed in 20% of cases. CD5 expression is present in some cases. PLAP, vimentin, CEA, and S-100 are negative.
Mucoepidermoid thymic carcinoma Consists of squamous cells, mucus-producing cells, and cells of intermediate type and resembles mucoepidermoid carcinoma of other organs. Translocation of the MAML2 gene is present and can help distinguish this tumor from adenosquamous carcinomas and adenocarcinomas.
Papillary thymic adenocarcinoma Grows in a papillary fashion. Histology may be accompanied by psammoma body formation, which may result in a marked similarity with papillary carcinoma of the thyroid gland. Variable expression of Leu M1 and BerEP4 is observed. CEA and CD5 may also be positive. CD20, thyroglobulin, pulmonary surfactant apoprotein, and calretinin are absent.
Undifferentiated thymic carcinoma A rare type of thymic carcinoma that grows in a solid undifferentiated fashion but without exhibiting sarcomatoid (spindle cell or pleomorphic) features.
Carcinoma with t(15;19) translocation (NUT carcinoma) A rare, aggressive carcinoma of unknown histogenesis. The presence of undifferentiated, intermediate-sized, vigorously mitotic cells is characteristic. Pan-cytokeratin markers are expressed. Focal positivity of vimentin, EMA, and CEA is observed. CD30, CD45, PLAP, HMB45, S100, and neuroendocrine markers are negative. t(15;19)-translocation is observed with the generation of a BRD4::NUT fusion oncogene. Immunohistochemistry for NUT is highly sensitive and should be considered in any undifferentiated cancer, especially if focal squamous differentiation is seen.

Molecular Characteristics of Thymoma and Thymic Carcinomas

TETs have the lowest tumor mutational burden of all adult cancers. Multiplatform analyses have revealed four molecular subtypes that are associated with survival and WHO histological subtypes. Pathogenic variants in HRAS, NRAS, TP53, and GTF2I have been observed. Targetable variants are uncommon. Tumor overexpression of muscle autoantigens and increased aneuploidy have also been identified and provide a molecular link between thymoma and myasthenia gravis.[6]

References
  1. Travis WD, Brambilla E, Burke E, et al.: WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart. 4th ed. International Agency for Research on Cancer, 2015.
  2. Marx A, Chan JK, Coindre JM, et al.: The 2015 World Health Organization Classification of Tumors of the Thymus: Continuity and Changes. J Thorac Oncol 10 (10): 1383-95, 2015. [PUBMED Abstract]
  3. Hirabayashi H, Fujii Y, Sakaguchi M, et al.: p16INK4, pRB, p53 and cyclin D1 expression and hypermethylation of CDKN2 gene in thymoma and thymic carcinoma. Int J Cancer 73 (5): 639-44, 1997. [PUBMED Abstract]
  4. Sasaki H, Kobayashi Y, Tanahashi M, et al.: Ets-1 gene expression in patients with thymoma. Jpn J Thorac Cardiovasc Surg 50 (12): 503-7, 2002. [PUBMED Abstract]
  5. Rajan A, Girard N, Marx A: State of the art of genetic alterations in thymic epithelial tumors. J Thorac Oncol 9 (9 Suppl 2): S131-6, 2014. [PUBMED Abstract]
  6. Radovich M, Pickering CR, Felau I, et al.: The Integrated Genomic Landscape of Thymic Epithelial Tumors. Cancer Cell 33 (2): 244-258.e10, 2018. [PUBMED Abstract]
  7. Travis W, Brambilla E, Müller-Hermelink H, et al., eds.: Pathology and Genetics of Tumours of the Lung, Pleura, and Thymus. IARC Press, 2004. World Health Organization Classification of Tumours.
  8. Marx A, Chan J, Coindre J-M, et al.: The 2015 WHO classification of tumors of the thymus: continuity and changes. J Thorac Oncol 10 (10): 1383–95, 2015.

Stage Information for Thymoma and Thymic Carcinoma

Evaluating the invasiveness of a thymoma involves the use of staging criteria that indicate the presence and degree of contiguous invasion, the presence of tumor implants, and lymph node or distant metastases regardless of histological type. The staging system, proposed by Masaoka in 1981 and modified by Koga in 1994, is most commonly used, with the modified system being recommended by the International Thymic Malignancies Interest Group (ITMIG) (see Table 8).[1,2] To establish consistency in the staging of thymic epithelial tumors (TETs), the American Joint Committee on Cancer (AJCC) and the Union for International Cancer Control (UICC) adopted a new TNM (tumor, node, metastasis) classification system developed by the International Association for the Study of Lung Cancer (IASLC) and ITMIG.[3–5]

Table 8. Masaoka-Koga Staging System for Thymoma, 1994a
Stage Description
a[2]
I Macroscopically, completely encapsulated; microscopically, no capsular invasion.
II Macroscopic invasion into surrounding fatty tissue or mediastinal pleura; microscopic invasion into capsule.
III Macroscopic invasion into neighboring organs (pericardium, lung, and great vessels).
IVa Pleural or pericardial dissemination.
IVb Lymphogenous or hematogenous metastases.

AJCC Stage Groupings and TNM Definitions

Table 9. Definition of TNM Stage Ia
Stage Tb,cNbM Description
T = primary tumor; N = regional lymph node; M = distant metastasis.
aAdapted from AJCC: Thymus. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 423–9.
The explanations for superscripts b and c are at the end of Table 12.
 
I T1a,b, N0, M0 T1 = Tumor encapsulated or extending into the mediastinal fat; may involve the mediastinal pleura.
–T1a = Tumor with no mediastinal pleura involvement.
–T1b = Tumor with direct invasion of mediastinal pleura.
N0 = No regional lymph node metastasis.
M0 = No pleural, pericardial, or distant metastasis.
Table 10. Definition of TNM Stage IIa
Stage Tb,cNbM Description
T = primary tumor; N = regional lymph node; M = distant metastasis.
aAdapted from AJCC: Thymus. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 423–9.
The explanations for superscripts b and c are at the end of Table 12.
 
II T2, N0, M0 T2 = Tumor with direct invasion of the pericardium (either partial or full thickness).
N0 = No regional lymph node metastasis.
M0 = No pleural, pericardial, or distant metastasis.
Table 11. Definition of TNM Stages IIIA and IIIBa
Stage Tb,cNbM Description
T = primary tumor; N = regional lymph node; M = distant metastasis.
aAdapted from AJCC: Thymus. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 423–9.
The explanations for superscripts b and c are at the end of Table 12.
 
IIIA T3, N0, M0 T3 = Tumor with direct invasion into any of the following: lung, brachiocephalic vein, superior vena cava, phrenic nerve, chest wall, or extrapericardial pulmonary artery or veins.
N0 = No regional lymph node metastasis.
M0 = No pleural, pericardial, or distant metastasis.
IIIB T4, N0, M0 T4 = Tumor with invasion into any of the following: aorta (ascending, arch, or descending), arch vessels, intrapericardial pulmonary artery, myocardium, trachea, esophagus.
N0 = No regional lymph node metastasis.
M0 = No pleural, pericardial, or distant metastasis.
Table 12. Definition of TNM Stages IVA and IVBa
Stage Tb,cNbM Description
T = primary tumor; N = regional lymph node; M = distant metastasis.
aAdapted from AJCC: Thymus. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 423–9.
bInvolvement must be microscopically confirmed in pathological staging, if possible.
cT categories are defined by levels of invasion; they reflect the highest degree of invasion regardless of how many other (lower-level) structures are invaded. T1, level 1 structures: thymus, anterior mediastinal fat, mediastinal pleura; T2, level 2 structures: pericardium; T3, level 3 structures: lung, brachiocephalic vein, superior vena cava, phrenic nerve, chest wall, hilar pulmonary vessels; T4, level 4 structures: aorta (ascending, arch, or descending), arch vessels, intrapericardial pulmonary artery, myocardium, trachea, esophagus.
IVA Any T, N1, M0 TX = Primary tumor cannot be assessed.
T0 = No evidence of primary tumor.
T1 = Tumor encapsulated or extending into the mediastinal fat; may involve the mediastinal pleura.
–T1a = Tumor with no mediastinal pleura involvement.
–T1b = Tumor with direct invasion of mediastinal pleura.
T2 = Tumor with direct invasion of the pericardium (either partial or full thickness).
T3 = Tumor with direct invasion into any of the following: lung, brachiocephalic vein, superior vena cava, phrenic nerve, chest wall, or extrapericardial pulmonary artery or veins.
T4 = Tumor with invasion into any of the following: aorta (ascending, arch, or descending), arch vessels, intrapericardial pulmonary artery, myocardium, trachea, esophagus.
N1 = Metastasis in anterior (perithymic) lymph nodes.
M0 = No pleural, pericardial, or distant metastasis.
Any T, N0,1, M1a Any T = See descriptions (stage IVA) in this table.
N0 = No regional lymph node metastasis.
N1 = Metastasis in anterior (perithymic) lymph nodes.
M1a = Separate pleural or pericardial nodule(s).
IVB Any T, N2, M0, M1a Any T = See descriptions (stage IVA) in this table.
N2 = Metastasis in deep intrathoracic or cervical lymph nodes.
M0 = No pleural, pericardial, or distant metastasis.
M1a = Separate pleural or pericardial nodule(s).
Any T, Any N, M1b Any T = See descriptions (stage IVA) in this table.
NX = Regional lymph nodes cannot be assessed.
N0 = No regional lymph node metastasis.
N1 = Metastasis in anterior (perithymic) lymph nodes.
N2 = Metastasis in deep intrathoracic or cervical lymph nodes.
M1b = Pulmonary intraparenchymal nodule or distant organ metastasis.

When the Masaoka staging system was applied to a series of 85 surgically treated patients with thymoma, its value in determining prognosis was confirmed, with 5-year survival rates of 96% for stage I disease, 86% for stage II disease, 69% for stage III disease, and 50% for stage IV disease.[1] In a large, retrospective study involving 273 patients with thymoma, 20-year survival rates (as defined by freedom from tumor death) according to the Masaoka staging system were reported to be 89% for stage I disease, 91% for stage II disease, 49% for stage III disease, and 0% for stage IV disease.[6]

The TNM staging system, applicable to thymoma and thymic carcinoma, is based on a large, global database of more than 10,000 subjects, as opposed to smaller series of fewer than 100 patients that were used to develop older staging systems. The TNM system also benefits from rigorous statistical analysis of a large pool of data and input from a multidisciplinary panel of experts. The rate of disease recurrence was 5% in patients with stage I disease, 18% for stage II disease, 32% for stage III disease, 59% for stage IVA disease, and 49% for stage IVB disease. The death rate was 7% in patients with stage I disease, 16% for stage II disease, 18% for stage III disease, 30% for stage IVA disease, and 33% for stage IVB disease.[5]

References
  1. Masaoka A, Monden Y, Nakahara K, et al.: Follow-up study of thymomas with special reference to their clinical stages. Cancer 48 (11): 2485-92, 1981. [PUBMED Abstract]
  2. Koga K, Matsuno Y, Noguchi M, et al.: A review of 79 thymomas: modification of staging system and reappraisal of conventional division into invasive and non-invasive thymoma. Pathol Int 44 (5): 359-67, 1994. [PUBMED Abstract]
  3. Thymus. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. Springer; 2017, pp. 423–9.
  4. Carter BW, Benveniste MF, Madan R, et al.: IASLC/ITMIG Staging System and Lymph Node Map for Thymic Epithelial Neoplasms. Radiographics 37 (3): 758-776, 2017 May-Jun. [PUBMED Abstract]
  5. Detterbeck FC, Stratton K, Giroux D, et al.: The IASLC/ITMIG Thymic Epithelial Tumors Staging Project: proposal for an evidence-based stage classification system for the forthcoming (8th) edition of the TNM classification of malignant tumors. J Thorac Oncol 9 (9 Suppl 2): S65-72, 2014. [PUBMED Abstract]
  6. Okumura M, Ohta M, Tateyama H, et al.: The World Health Organization histologic classification system reflects the oncologic behavior of thymoma: a clinical study of 273 patients. Cancer 94 (3): 624-32, 2002. [PUBMED Abstract]

Treatment Option Overview for Thymoma and Thymic Carcinoma

The primary treatment for patients with thymoma or thymic carcinoma is surgical resection with en bloc resection for invasive tumors, if possible.[1–3] Depending on tumor stage, multimodality treatment options—including the use of radiation therapy and chemotherapy with or without surgery—may be used.[4,5] The optimal strategy for induction therapy, which minimizes operative morbidity and mortality and optimizes resectability rates and ultimately survival, remains unknown. A review of the management of thymic epithelial tumors has been published.[1]

Table 13. Treatment Options for Thymoma and Thymic Carcinoma
Stage Treatment Options
Stage I and II thymoma Surgery
Surgery with or without postoperative radiation therapy
Stage III and IV thymoma (operable) Surgery followed by radiation therapy
Induction chemotherapy followed by surgery and radiation therapy
Stage III and IV thymoma (inoperable) Chemotherapy
Chemotherapy followed by radiation therapy
Chemotherapy followed by surgery (if operable) and radiation therapy
Thymic carcinoma (operable) Surgery (en bloc surgical resection) followed by postoperative radiation therapy with or without postoperative chemotherapy.
Thymic carcinoma (inoperable) Chemotherapy
Chemoradiation therapy
Chemotherapy followed by surgery (if operable) and radiation therapy
Recurrent thymoma and thymic carcinoma Chemotherapy
Biological therapies
Surgery or radiation therapy in carefully selected cases
Pembrolizumab (under clinical evaluation)

Capecitabine and Fluorouracil Dosing

The DPYD gene encodes an enzyme that catabolizes pyrimidines and fluoropyrimidines, like capecitabine and fluorouracil. An estimated 1% to 2% of the population has germline pathogenic variants in DPYD, which lead to reduced DPD protein function and an accumulation of pyrimidines and fluoropyrimidines in the body.[6,7] Patients with the DPYD*2A variant who receive fluoropyrimidines may experience severe, life-threatening toxicities that are sometimes fatal. Many other DPYD variants have been identified, with a range of clinical effects.[6–8] Fluoropyrimidine avoidance or a dose reduction of 50% may be recommended based on the patient’s DPYD genotype and number of functioning DPYD alleles.[9–11] DPYD genetic testing costs less than $200, but insurance coverage varies due to a lack of national guidelines.[12] In addition, testing may delay therapy by 2 weeks, which would not be advisable in urgent situations. This controversial issue requires further evaluation.[13]

References
  1. Girard N, Ruffini E, Marx A, et al.: Thymic epithelial tumours: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 26 (Suppl 5): v40-55, 2015. [PUBMED Abstract]
  2. Ruffini E, Filosso PL, Guerrera F, et al.: Optimal surgical approach to thymic malignancies: New trends challenging old dogmas. Lung Cancer 118: 161-170, 2018. [PUBMED Abstract]
  3. Cameron RB, Loehrer Sr, Marx A: Neoplasms of the mediastinum. In: DeVita VT Jr, Lawrence TS, Rosenberg SA, et al., eds.: DeVita, Hellman, and Rosenberg’s Cancer: Principles & Practice of Oncology. 11th ed. Wolters Kluwer, 2019, pp 700-12.
  4. Rimner A, Yao X, Huang J, et al.: Postoperative Radiation Therapy Is Associated with Longer Overall Survival in Completely Resected Stage II and III Thymoma-An Analysis of the International Thymic Malignancies Interest Group Retrospective Database. J Thorac Oncol 11 (10): 1785-92, 2016. [PUBMED Abstract]
  5. Rajan A, Giaccone G: Chemotherapy for thymic tumors: induction, consolidation, palliation. Thorac Surg Clin 21 (1): 107-14, viii, 2011. [PUBMED Abstract]
  6. Sharma BB, Rai K, Blunt H, et al.: Pathogenic DPYD Variants and Treatment-Related Mortality in Patients Receiving Fluoropyrimidine Chemotherapy: A Systematic Review and Meta-Analysis. Oncologist 26 (12): 1008-1016, 2021. [PUBMED Abstract]
  7. Lam SW, Guchelaar HJ, Boven E: The role of pharmacogenetics in capecitabine efficacy and toxicity. Cancer Treat Rev 50: 9-22, 2016. [PUBMED Abstract]
  8. Shakeel F, Fang F, Kwon JW, et al.: Patients carrying DPYD variant alleles have increased risk of severe toxicity and related treatment modifications during fluoropyrimidine chemotherapy. Pharmacogenomics 22 (3): 145-155, 2021. [PUBMED Abstract]
  9. Amstutz U, Henricks LM, Offer SM, et al.: Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Dihydropyrimidine Dehydrogenase Genotype and Fluoropyrimidine Dosing: 2017 Update. Clin Pharmacol Ther 103 (2): 210-216, 2018. [PUBMED Abstract]
  10. Henricks LM, Lunenburg CATC, de Man FM, et al.: DPYD genotype-guided dose individualisation of fluoropyrimidine therapy in patients with cancer: a prospective safety analysis. Lancet Oncol 19 (11): 1459-1467, 2018. [PUBMED Abstract]
  11. Lau-Min KS, Varughese LA, Nelson MN, et al.: Preemptive pharmacogenetic testing to guide chemotherapy dosing in patients with gastrointestinal malignancies: a qualitative study of barriers to implementation. BMC Cancer 22 (1): 47, 2022. [PUBMED Abstract]
  12. Brooks GA, Tapp S, Daly AT, et al.: Cost-effectiveness of DPYD Genotyping Prior to Fluoropyrimidine-based Adjuvant Chemotherapy for Colon Cancer. Clin Colorectal Cancer 21 (3): e189-e195, 2022. [PUBMED Abstract]
  13. Baker SD, Bates SE, Brooks GA, et al.: DPYD Testing: Time to Put Patient Safety First. J Clin Oncol 41 (15): 2701-2705, 2023. [PUBMED Abstract]

Treatment of Thymoma

For patients presenting with a mediastinal mass that is highly suspicious for an early-stage thymic epithelial tumor (TET) and is potentially completely resectable, surgical resection is the preferred initial treatment.[1] Under these circumstances, surgical resection serves as a diagnostic and therapeutic procedure. Complete resection of the tumor can be achieved in nearly all patients with stage I and stage II TETs.

Postoperative radiation therapy (PORT) is associated with survival benefit and is generally recommended for patients with stage II or stage III disease.[2] Patients with stage IVA disease are usually offered multimodality therapy consisting of induction chemotherapy followed by surgery (if the disease is considered resectable) and PORT.[3–6] Patients with stage IVB disease are treated with definitive chemotherapy.[7–9,9,10] Surgery and radiation therapy usually do not have a role as primary treatment modalities for advanced disease.

Stage I and Stage II Thymoma

Treatment options for stages I and II thymoma

Treatment options for stage I and stage II thymoma (operable disease) include:

  1. Surgery (stage I).
  2. Surgery with or without PORT (stage II).
Surgery (stage I)

Excellent long-term survival can be obtained after complete surgical excision for patients with a pathological stage I thymoma. There appears to be no benefit to adjuvant radiation therapy after complete resection of encapsulated noninvasive tumors.[1,11]

Surgery with or without PORT (stage II)

For patients with stage II thymomas with pathologically demonstrated capsular invasion, adjuvant radiation therapy after complete surgical excision has been considered a standard of care, despite the lack of prospective clinical trials.[12,13] Most studies use 40 Gy to 70 Gy with a standard fractionation scheme (1.8–2.0 Gy per fraction).

The role and risks of adjuvant radiation therapy for patients with completely resected stage II thymomas need further study. To avoid the potential morbidity and costs associated with thoracic radiation, PORT may be reserved for stage II patients when adjacent organs are within a few millimeters or involve the surgical margin (close or positive surgical margins), as determined by both pathological and intraoperative findings.

Evidence (surgery followed by PORT):

  1. Data were obtained from a clinical study of 1,320 Japanese patients.[14] Patients with stage I thymoma were treated with surgery only, and patients with stage II thymoma underwent surgery and additional radiation therapy.
    • Prophylactic mediastinal radiation therapy did not appear to prevent local recurrences effectively in patients with totally resected stage II thymoma.
  2. Some, but not all, retrospective clinical studies show improved local control and survival with the addition of PORT.[2,14–17][Level of evidence C3]
  3. Other retrospective studies have found no outcome difference in patients treated with or without PORT after complete resection of the thymic tumor.[18–21]

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.

Stage III and Stage IV Thymoma

Treatment options for operable or potentially operable stages III and IV thymoma

Advances in imaging techniques have resulted in more accurate staging of TETs. However, on occasion, stage III thymoma may be difficult to identify before surgery, and invasion of adjacent mediastinal structures may be identified only at the time of surgery.

Surgical resection with curative intent should be considered for all patients deemed to have resectable stage III thymoma after the initial work-up. PORT is offered to all patients, regardless of surgical margin status, because it is associated with longer overall survival (OS).[2]

Combined-modality treatment consisting of induction chemotherapy followed by surgery and radiation therapy should be considered for all patients with unresectable stage III thymoma. The optimal strategy for induction therapy, which optimizes resectability rates and ultimately survival, is not defined. However, commonly used induction chemotherapy regimens include combinations of cisplatin, doxorubicin, and cyclophosphamide, or cisplatin and etoposide. Rates of response to induction chemotherapy ranged from 79% to 100%, with subsequent resectability rates of 36% to 69%.[3–7,22–25]

Treatment options for operable or potentially operable stage III and stage IV thymoma include:

  1. Surgery followed by PORT.
  2. Induction chemotherapy followed by surgery and radiation therapy.

Evidence (treatment of stage III and IV operable or potentially operable thymoma):

  1. Data were obtained from a large clinical study of 1,320 Japanese patients.[14] Patients with stage III and stage IV thymoma underwent surgery and multimodality therapy with surgical resection followed by adjuvant therapy consisting of radiation therapy and/or chemotherapy.
    • The Masaoka clinical stage was found to correlate well with prognosis of thymoma and thymic carcinoma.
    • For patients with stage III or stage IV thymoma, the 5-year survival rates were 93% for patients treated with total resection, 64% for patients treated with subtotal resection, and 36% for patients whose disease was inoperable. These data highlight the prognostic significance of achieving complete surgical resection of the tumor.
    • Prophylactic mediastinal radiation therapy did not appear to prevent local recurrences effectively in patients with totally resected stage III thymoma.
    • Adjuvant therapy, including radiation and/or chemotherapy did not appear to improve the prognosis in patients with totally resected stage III or stage IV thymoma.
  2. In a large retrospective study, 1,334 patients diagnosed with malignant thymoma and treated between 1973 and 2005 were identified in a Surveillance, Epidemiology, and End Results (SEER) Program database.[25]
    • At a relatively short median follow-up of 65 months, radiation therapy did not appear to increase the risk of cardiac mortality or secondary malignancy.
    • In patients with stage III and stage IV disease (after excluding patients surviving less than 4 months to account for surgical mortality), the routine use of PORT did not appear to improve long-term survival.
  3. In a retrospective study, 476 patients with stage III thymoma who underwent surgical resection were identified using the SEER database. PORT was administered to 322 patients (67.6%).[26]
    • Patients who received PORT had a median OS of 127 months (95% confidence interval [CI], 100.9–153.1) compared with 105 months (95% CI, 76.9–133.1) in patients treated with surgery alone (P = .038).
    • Disease-specific survival was significantly improved in patients receiving PORT compared with patients undergoing surgery alone (P = .049).
  4. Different published series have reported long-term survival rates following induction chemotherapy and surgery, with or without radiation therapy and consolidation chemotherapy. The rates have ranged from 50% at 4 years to 77% at 7 years, with 10-year rates of 86% for stage III patients and 76% for stage IV patients.[5,22,23,27]
  5. Similar survival rates have been reported with preoperative radiation therapy without chemotherapy, particularly if great vessels are involved. Results showed a 5-year OS rate of 77% and a 10-year OS rate of 59%.[28,29]

Treatment options for inoperable stages III and IV thymoma

Treatment options for patients with inoperable stage III and stage IV thymoma include:

  1. Chemotherapy.
  2. Chemotherapy followed by radiation therapy.
  3. Chemotherapy followed by surgery (if operable) and radiation therapy.

The role of surgical debulking for patients with either stage III or stage IVA disease is controversial. Phase II data suggest that prolonged survival can be accomplished with chemotherapy and radiation therapy alone in many patients who present with locally advanced or even metastatic thymoma.[24] The value of surgery may be questioned if complete or, at the very least, near-complete extirpation cannot be accomplished.

Evidence (treatment of stage III and IV inoperable thymoma):

  1. An intergroup trial conducted in the United States reported a predicted 5-year OS rate of 52% in 26 patients who received the PAC chemotherapy regimen (cisplatin, doxorubicin, cyclophosphamide) followed by radiation therapy without surgery.[24]
  2. In a series of 30 patients with stage IV or locally progressive recurrent tumor after radiation therapy, the PAC regimen was given.[7][Level of evidence C3]
    • A 50% response rate was achieved, including three complete responses.
    • The median duration of response was 12 months.
    • The 5-year survival rate was 32%.
  3. The ADOC regimen (doxorubicin, cisplatin, vincristine, cyclophosphamide) was given to 37 patients.[8][Level of evidence C3]
    • A 92% response rate (34 of 37 patients) was achieved, including complete responses in 43% of patients.
  4. A study of combined chemotherapy with cisplatin and etoposide reported:[30][Level of evidence C3]
    • A 56% response rate (9 of 16 patients) was achieved.
    • There was a median response duration of 3.4 years and a median survival of 4.3 years.
  5. Patients with invasive thymoma or thymic carcinoma were treated with four cycles of etoposide, ifosfamide, and cisplatin (VIP) at 3-week intervals.[9][Level of evidence C3]
    • Nine of 28 evaluable patients had partial responses (32%; 95% CI, 16%–52%).
    • The median follow-up was 43 months (range, 12.8–52.3).
    • The median duration of response was 11.9 months (range, <1–26).
    • The median OS was 31.6 months.
    • The 1-year survival rate was 89% and the 2-year survival rate was 70%, based on Kaplan-Meier estimates.
    • These results appear to be inferior to other combinations.
  6. A phase II study evaluated the activity of a combination of carboplatin and paclitaxel in 46 patients with unresectable TETs, including 21 patients with unresectable thymoma.[10][Level of evidence C3]
    • Nine of 21 patients with thymoma had objective responses (42.9%; 90% CI, 24.5%–62.8%).
    • The median duration of response in patients with thymoma was 16.9 months (95% CI, 3.1–22.0).
    • The median progression-free survival for the thymoma cohort was 16.7 months (95% CI, 7.2–19.8); median OS was not reached after median follow-up of 59.4 months.
References
  1. Maggi G, Casadio C, Cavallo A, et al.: Thymoma: results of 241 operated cases. Ann Thorac Surg 51 (1): 152-6, 1991. [PUBMED Abstract]
  2. Rimner A, Yao X, Huang J, et al.: Postoperative Radiation Therapy Is Associated with Longer Overall Survival in Completely Resected Stage II and III Thymoma-An Analysis of the International Thymic Malignancies Interest Group Retrospective Database. J Thorac Oncol 11 (10): 1785-92, 2016. [PUBMED Abstract]
  3. Macchiarini P, Chella A, Ducci F, et al.: Neoadjuvant chemotherapy, surgery, and postoperative radiation therapy for invasive thymoma. Cancer 68 (4): 706-13, 1991. [PUBMED Abstract]
  4. Rea F, Sartori F, Loy M, et al.: Chemotherapy and operation for invasive thymoma. J Thorac Cardiovasc Surg 106 (3): 543-9, 1993. [PUBMED Abstract]
  5. Kim ES, Putnam JB, Komaki R, et al.: Phase II study of a multidisciplinary approach with induction chemotherapy, followed by surgical resection, radiation therapy, and consolidation chemotherapy for unresectable malignant thymomas: final report. Lung Cancer 44 (3): 369-79, 2004. [PUBMED Abstract]
  6. Yokoi K, Matsuguma H, Nakahara R, et al.: Multidisciplinary treatment for advanced invasive thymoma with cisplatin, doxorubicin, and methylprednisolone. J Thorac Oncol 2 (1): 73-8, 2007. [PUBMED Abstract]
  7. Loehrer PJ, Kim K, Aisner SC, et al.: Cisplatin plus doxorubicin plus cyclophosphamide in metastatic or recurrent thymoma: final results of an intergroup trial. The Eastern Cooperative Oncology Group, Southwest Oncology Group, and Southeastern Cancer Study Group. J Clin Oncol 12 (6): 1164-8, 1994. [PUBMED Abstract]
  8. Fornasiero A, Daniele O, Ghiotto C, et al.: Chemotherapy for invasive thymoma. A 13-year experience. Cancer 68 (1): 30-3, 1991. [PUBMED Abstract]
  9. Loehrer PJ, Jiroutek M, Aisner S, et al.: Combined etoposide, ifosfamide, and cisplatin in the treatment of patients with advanced thymoma and thymic carcinoma: an intergroup trial. Cancer 91 (11): 2010-5, 2001. [PUBMED Abstract]
  10. Lemma GL, Lee JW, Aisner SC, et al.: Phase II study of carboplatin and paclitaxel in advanced thymoma and thymic carcinoma. J Clin Oncol 29 (15): 2060-5, 2011. [PUBMED Abstract]
  11. Masaoka A, Monden Y, Nakahara K, et al.: Follow-up study of thymomas with special reference to their clinical stages. Cancer 48 (11): 2485-92, 1981. [PUBMED Abstract]
  12. Pollack A, Komaki R, Cox JD, et al.: Thymoma: treatment and prognosis. Int J Radiat Oncol Biol Phys 23 (5): 1037-43, 1992. [PUBMED Abstract]
  13. Ogawa K, Uno T, Toita T, et al.: Postoperative radiotherapy for patients with completely resected thymoma: a multi-institutional, retrospective review of 103 patients. Cancer 94 (5): 1405-13, 2002. [PUBMED Abstract]
  14. Kondo K, Monden Y: Therapy for thymic epithelial tumors: a clinical study of 1,320 patients from Japan. Ann Thorac Surg 76 (3): 878-84; discussion 884-5, 2003. [PUBMED Abstract]
  15. Ariaratnam LS, Kalnicki S, Mincer F, et al.: The management of malignant thymoma with radiation therapy. Int J Radiat Oncol Biol Phys 5 (1): 77-80, 1979. [PUBMED Abstract]
  16. Penn CR, Hope-Stone HF: The role of radiotherapy in the management of malignant thymoma. Br J Surg 59 (7): 533-9, 1972. [PUBMED Abstract]
  17. Curran WJ, Kornstein MJ, Brooks JJ, et al.: Invasive thymoma: the role of mediastinal irradiation following complete or incomplete surgical resection. J Clin Oncol 6 (11): 1722-7, 1988. [PUBMED Abstract]
  18. Mangi AA, Wright CD, Allan JS, et al.: Adjuvant radiation therapy for stage II thymoma. Ann Thorac Surg 74 (4): 1033-7, 2002. [PUBMED Abstract]
  19. Singhal S, Shrager JB, Rosenthal DI, et al.: Comparison of stages I-II thymoma treated by complete resection with or without adjuvant radiation. Ann Thorac Surg 76 (5): 1635-41; discussion 1641-2, 2003. [PUBMED Abstract]
  20. Thomas CR, Wright CD, Loehrer PJ: Thymoma: state of the art. J Clin Oncol 17 (7): 2280-9, 1999. [PUBMED Abstract]
  21. Berman AT, Litzky L, Livolsi V, et al.: Adjuvant radiotherapy for completely resected stage 2 thymoma. Cancer 117 (15): 3502-8, 2011. [PUBMED Abstract]
  22. Berruti A, Borasio P, Gerbino A, et al.: Primary chemotherapy with adriamycin, cisplatin, vincristine and cyclophosphamide in locally advanced thymomas: a single institution experience. Br J Cancer 81 (5): 841-5, 1999. [PUBMED Abstract]
  23. Shin DM, Walsh GL, Komaki R, et al.: A multidisciplinary approach to therapy for unresectable malignant thymoma. Ann Intern Med 129 (2): 100-4, 1998. [PUBMED Abstract]
  24. Loehrer PJ, Chen M, Kim K, et al.: Cisplatin, doxorubicin, and cyclophosphamide plus thoracic radiation therapy for limited-stage unresectable thymoma: an intergroup trial. J Clin Oncol 15 (9): 3093-9, 1997. [PUBMED Abstract]
  25. Fernandes AT, Shinohara ET, Guo M, et al.: The role of radiation therapy in malignant thymoma: a Surveillance, Epidemiology, and End Results database analysis. J Thorac Oncol 5 (9): 1454-60, 2010. [PUBMED Abstract]
  26. Weksler B, Shende M, Nason KS, et al.: The role of adjuvant radiation therapy for resected stage III thymoma: a population-based study. Ann Thorac Surg 93 (6): 1822-8; discussion 1828-9, 2012. [PUBMED Abstract]
  27. Lucchi M, Melfi F, Dini P, et al.: Neoadjuvant chemotherapy for stage III and IVA thymomas: a single-institution experience with a long follow-up. J Thorac Oncol 1 (4): 308-13, 2006. [PUBMED Abstract]
  28. Yagi K, Hirata T, Fukuse T, et al.: Surgical treatment for invasive thymoma, especially when the superior vena cava is invaded. Ann Thorac Surg 61 (2): 521-4, 1996. [PUBMED Abstract]
  29. Akaogi E, Ohara K, Mitsui K, et al.: Preoperative radiotherapy and surgery for advanced thymoma with invasion to the great vessels. J Surg Oncol 63 (1): 17-22, 1996. [PUBMED Abstract]
  30. Giaccone G, Ardizzoni A, Kirkpatrick A, et al.: Cisplatin and etoposide combination chemotherapy for locally advanced or metastatic thymoma. A phase II study of the European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group. J Clin Oncol 14 (3): 814-20, 1996. [PUBMED Abstract]

Treatment of Thymic Carcinoma

Thymic carcinoma is rare, and the optimal treatment is undefined. For patients with clearly resectable well-defined disease, surgical resection is often the initial therapeutic intervention. For patients with clinically borderline or frankly unresectable lesions, neoadjuvant (preoperative) chemotherapy, thoracic radiation therapy, or both have been given.[1] Patients presenting with locally advanced disease are carefully evaluated and undergo multimodality therapy. Patients with poor performance status and high associated operative risks are generally not candidates for these aggressive treatments. Patients with metastatic disease may respond to combination chemotherapy.

Treatment Options for Thymic Carcinoma

Treatment options for patients with operable thymic carcinoma include:[2]

  1. Surgery (en bloc surgical resection) followed by postoperative radiation therapy (PORT) with or without postoperative chemotherapy.

Treatment options for patients with inoperable thymic carcinoma (stage III and stage IV with vena caval obstruction, pleural involvement, pericardial implants, etc.) include:

  1. Chemotherapy.
  2. Chemoradiation therapy.
  3. Chemotherapy followed by surgery (if operable) and radiation therapy.

In most published studies, surgery has been followed by adjuvant radiation therapy.[3,4] A prescriptive dose range has yet to be identified. Most studies use 40 Gy to 70 Gy with a standard fractionation scheme (1.8–2.0 Gy per fraction).

Evidence (surgery followed by PORT with or without postoperative chemotherapy):

  1. In the largest series reported, data were obtained from a clinical study of 1,320 Japanese patients.[5] Patients with thymic carcinoma were treated with PORT or chemotherapy.
    • The 5-year survival rates were 67% for patients treated with total resection, 30% for patients treated with subtotal resection, and 24% for patients whose disease was inoperable.
    • Adjuvant therapy, including radiation or chemotherapy, did not appear to improve the prognosis in patients with thymic carcinoma.
  2. A multi-institutional retrospective outcome analysis of 186 patients with thymic carcinoma has been reported.[5]
    • The 5-year survival rates for patients with totally resected thymic carcinoma were 81.5% for patients treated with chemotherapy, 46.6% for patients treated with radiation therapy and chemotherapy, 73.6% for patients treated with radiation therapy alone, and 72.2% for patients who received no adjuvant therapy.
    • This study failed to detect a long-term survival benefit in patients treated with subtotal resection or any statistically significant survival augmentation from the addition of adjuvant radiation to surgical resection.
    • The authors stipulated that no definitive conclusions could be made regarding the role of adjuvant radiation therapy in thymic carcinoma because of sample size limitations.

The results of these studies call into question conventional thinking regarding the efficacy of an aggressive multimodality approach that includes debulking, radiation therapy, and cisplatin-based chemotherapy.[6–8] While other studies support the addition of adjuvant radiation therapy and chemotherapy, optimum treatment regimens are undetermined.

Chemotherapy is the primary treatment modality for patients with inoperable thymic carcinoma. Most regimens used are similar to those used to treat thymoma and include a platinum compound with or without an anthracycline (PAC [cisplatin, doxorubicin, cyclophosphamide], VIP [etoposide, ifosfamide, and cisplatin], ADOC [doxorubicin, cisplatin, vincristine, cyclophosphamide], cisplatin/etoposide, carboplatin/paclitaxel).[1,9–14]

Evidence (chemotherapy):

  1. A phase II study evaluated the combination of carboplatin and paclitaxel in 46 patients with unresectable thymic epithelial tumors, including 23 patients with unresectable thymic carcinoma.[14][Level of evidence C3]
    • Five of 23 patients with thymic carcinoma had objective responses (21.7%; 90% confidence interval [CI], 9.0%–40.4%).
    • The median duration of response in patients with thymic carcinoma was 4.5 months (95% CI, 3.4–9.9).
    • The median progression-free survival for the thymic carcinoma cohort was 5 months (95% CI, 3.0–8.3) and the median overall survival was 20 months (95% CI, 5.0–43.6) after a median follow-up of 59.4 months.
  2. VIP was used in a prospective North American Intergroup trial.[11]
    • Two of 8 patients with thymic carcinoma (25%) had a partial response.
    • The 1-year survival rate for patients with thymic carcinoma was 75% and the 2-year rate was 50%.

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. Koizumi T, Takabayashi Y, Yamagishi S, et al.: Chemotherapy for advanced thymic carcinoma: clinical response to cisplatin, doxorubicin, vincristine, and cyclophosphamide (ADOC chemotherapy). Am J Clin Oncol 25 (3): 266-8, 2002. [PUBMED Abstract]
  2. Hsu HC, Huang EY, Wang CJ, et al.: Postoperative radiotherapy in thymic carcinoma: treatment results and prognostic factors. Int J Radiat Oncol Biol Phys 52 (3): 801-5, 2002. [PUBMED Abstract]
  3. Omasa M, Date H, Sozu T, et al.: Postoperative radiotherapy is effective for thymic carcinoma but not for thymoma in stage II and III thymic epithelial tumors: the Japanese Association for Research on the Thymus Database Study. Cancer 121 (7): 1008-16, 2015. [PUBMED Abstract]
  4. Ahmad U, Yao X, Detterbeck F, et al.: Thymic carcinoma outcomes and prognosis: results of an international analysis. J Thorac Cardiovasc Surg 149 (1): 95-100, 101.e1-2, 2015. [PUBMED Abstract]
  5. Kondo K, Monden Y: Therapy for thymic epithelial tumors: a clinical study of 1,320 patients from Japan. Ann Thorac Surg 76 (3): 878-84; discussion 884-5, 2003. [PUBMED Abstract]
  6. Ogawa K, Toita T, Uno T, et al.: Treatment and prognosis of thymic carcinoma: a retrospective analysis of 40 cases. Cancer 94 (12): 3115-9, 2002. [PUBMED Abstract]
  7. Greene MA, Malias MA: Aggressive multimodality treatment of invasive thymic carcinoma. J Thorac Cardiovasc Surg 125 (2): 434-6, 2003. [PUBMED Abstract]
  8. Lucchi M, Mussi A, Ambrogi M, et al.: Thymic carcinoma: a report of 13 cases. Eur J Surg Oncol 27 (7): 636-40, 2001. [PUBMED Abstract]
  9. Weide LG, Ulbright TM, Loehrer PJ, et al.: Thymic carcinoma. A distinct clinical entity responsive to chemotherapy. Cancer 71 (4): 1219-23, 1993. [PUBMED Abstract]
  10. Loehrer PJ, Kim K, Aisner SC, et al.: Cisplatin plus doxorubicin plus cyclophosphamide in metastatic or recurrent thymoma: final results of an intergroup trial. The Eastern Cooperative Oncology Group, Southwest Oncology Group, and Southeastern Cancer Study Group. J Clin Oncol 12 (6): 1164-8, 1994. [PUBMED Abstract]
  11. Loehrer PJ, Jiroutek M, Aisner S, et al.: Combined etoposide, ifosfamide, and cisplatin in the treatment of patients with advanced thymoma and thymic carcinoma: an intergroup trial. Cancer 91 (11): 2010-5, 2001. [PUBMED Abstract]
  12. Fornasiero A, Daniele O, Ghiotto C, et al.: Chemotherapy for invasive thymoma. A 13-year experience. Cancer 68 (1): 30-3, 1991. [PUBMED Abstract]
  13. Giaccone G, Ardizzoni A, Kirkpatrick A, et al.: Cisplatin and etoposide combination chemotherapy for locally advanced or metastatic thymoma. A phase II study of the European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group. J Clin Oncol 14 (3): 814-20, 1996. [PUBMED Abstract]
  14. Lemma GL, Lee JW, Aisner SC, et al.: Phase II study of carboplatin and paclitaxel in advanced thymoma and thymic carcinoma. J Clin Oncol 29 (15): 2060-5, 2011. [PUBMED Abstract]

Treatment of Recurrent Thymoma and Thymic Carcinoma

Treatment Options for Recurrent Thymoma and Thymic Carcinoma

Treatment options for recurrent thymoma and thymic carcinoma include:

  1. Chemotherapy.
  2. Biological therapies.
  3. Surgery or radiation therapy in carefully selected cases.
  4. Pembrolizumab (under clinical evaluation).

Chemotherapy

A number of studies have demonstrated that certain chemotherapy drugs can induce tumor responses as single-agent or combination therapy. These drugs include pemetrexed, gemcitabine, taxanes, capecitabine, or fluorouracil and etoposide. In general, higher response rates have been reported with combinations, however, no randomized trials have been conducted. In most cases of inoperable disease recurrence, single-agent systemic therapy is preferred. Combination chemotherapy can be considered for selected patients who have demonstrated a good response previously, have had a long recurrence-free interval and good performance status, and, in the case of anthracycline-containing regimen, have not received high cumulative doses previously, which can jeopardize safety, especially in relation to cardiac toxicity.[1]

Evidence (single-agent chemotherapy):

  1. A phase II trial of pemetrexed (500 mg/m2) was conducted in 27 patients with recurrent thymic epithelial tumors (TETs) (16 patients) and recurrent thymic carcinoma (11 patients).[2]
    • The objective response rate was 19.2% (95% confidence interval [CI], 6.3%–38.1%) (26.7% [95% CI, 7.8%–55.1%] in patients with thymoma and 9.1% [95% CI, 0.2%–41.3%] in patients with thymic carcinoma).
    • The median progression-free survival (PFS) was 10.6 months (12.1 months for patients with thymoma vs. 2.9 months for patients with thymic carcinoma).
    • The median overall survival (OS) was 28.7 months (46.4 months for patients with thymoma vs. 9.8 months for patients with thymic carcinoma).
    • The median duration of response was 4 months in patients with thymoma (range, 3.26–6.28 months) and 3.8 months in the one patient with thymic carcinoma who had a partial response.
  2. Six of 16 patients achieved objective responses to octreotide (1.5 mg every day subcutaneously) associated with prednisone (0.6 mg/kg every day orally for 3 months, 0.2 mg/kg every day orally during follow-up).[3]

Evidence (combination chemotherapy):

  1. Thirty patients (22 patients with recurrent thymoma and 8 patients with thymic carcinoma) were enrolled in a phase II trial and treated with capecitabine (650 mg/m2 twice daily on days 1–14) and gemcitabine (1,000 mg/m2 on days 1 and 8 every 3 weeks).[4]
    • Objective responses were observed in 9 of 22 patients (41%) with thymoma and 3 of 8 patients (38%) with thymic carcinoma.
    • After a median follow-up of 18 months (range, 15–22), the median PFS was 11 months (range, 6.5–16.5). The median PFS was 11 months for patients with thymoma and 6 months for patients with thymic carcinoma. The overall median PFS was also 11 months.
    • One-year and 2-year survival rates for the study population were 90% and 66%, respectively.

Biological therapies

Octreotide with or without prednisone may induce responses in patients with octreotide scan–positive thymoma. Objective responses have also been observed with sunitinib and everolimus in patients with recurrent TETs.

Octreotide with or without prednisone

Evidence (octreotide with or without prednisone):

  1. In one study, six of 16 patients achieved objective responses to octreotide (1.5 mg every day subcutaneously) associated with prednisone (0.6 mg/kg every day orally for 3 months, 0.2 mg/kg every day orally during follow-up).[3]
  2. In a study of octreotide with or without prednisone, two complete responses (5.3%) and ten partial responses (25%) were observed among 42 patients.[5]
Sunitinib

Evidence (sunitinib):

  1. Forty-one patients with recurrent TETs (25 thymic carcinoma, 16 thymoma) were enrolled in a phase II trial and treated with sunitinib at a dose of 50 mg per day administered in 6-week cycles (4 weeks on treatment followed by a 2-week break).[6][Level of evidence C3]
    • After a median follow-up of 17 months, 6 of 23 assessable patients with thymic carcinoma (26%; 90% CI, 12.1%–45.3%; 95% CI, 10.2%–48.4%) had an objective response, and 15 patients (65%; 95% CI, 42.7%–83.6%) achieved disease stabilization. Of 16 patients with thymoma, 1 patient (6%; 95% CI, 0.2%–30.2%) had a partial response, and 12 patients (75%; 47.6%–92.7%) had stable disease.
    • The median time to response in the thymic carcinoma cohort was 5.6 months (range, 2.7–13.8), and the median duration of response was 16.4 months (range, 1.4–16.4).
    • The median PFS was 7.2 months (95% CI, 3.4–15.2) for patients with thymic carcinoma and 8.5 months (2.8–11.3) for patients with thymoma.
    • The median OS was not reached for patients with thymic carcinoma and was 15.5 months (95% CI, 12.6–undefined) in patients with thymoma.
    • The estimated OS at 1 year was 78% (95% CI, 58.0%–90.4%) for patients with thymic carcinoma and 86% (60.9%–96.1%) for patients with thymoma.
Everolimus

Evidence (everolimus):

  1. A phase II study included 51 patients with recurrent TETs (32 with thymoma and 19 with thymic carcinoma). Patients received oral everolimus at a dose of 10 mg per day.[7][Level of evidence C3]
    • Objective responses were observed in 3 of 32 patients (9.4%) with thymoma and in 3 of 19 patients (15.8%) with thymic carcinoma.
    • The disease-control rate was 88% (thymoma: 93.8%; thymic carcinoma: 77.8%).
    • After a median follow-up of 25.7 months, the median PFS was 10.1 months (thymoma: 16.6 months; thymic carcinoma: 5.6 months).
    • The median OS was 25.7 months (thymoma: not reached; thymic carcinoma: 14.7 months).
Lenvatinib

Lenvatinib is an orally administered multikinase inhibitor that targets vascular endothelial growth factor receptors, platelet-derived growth factor receptor-alpha, fibroblast growth factor receptors, c-kit, and the RET proto-oncogene.

Evidence (lenvatinib):

  1. Forty-two patients with recurrent thymic carcinoma were enrolled in a phase II trial and treated with oral lenvatinib at a dose of 24 mg per day in 4-week cycles until disease progression or development of unacceptable adverse events. The primary end point was objective response rate, assessed by independent central review.[8][Level of evidence C3]
    • Objective responses were observed in 16 of 42 patients (38%; 90% CI, 25.6%–52.0%).
    • The disease-control rate was 95% (95% CI, 83.8%–99.4%).
    • After a median follow-up of 15.5 months, the median time to response was 2.0 months, the median duration of response was 11.6 months (95% CI, 5.8–18.0), the median PFS was 9.3 months (95% CI, 7.7–13.9), and the median OS was not reached (NR) (95% CI, 16.1–NR).
    • The most common treatment-related adverse events were hypertension (88%), palmar-plantar erythrodysesthesia (69%), thrombocytopenia (52%), and diarrhea (50%).
    • All patients required at least one dose reduction due to adverse events. Five dose reductions were permitted in this study (20 mg, 14 mg, 10 mg, 8 mg, 4 mg). There were no treatment-related deaths.
    • Predictive biomarker analysis was not performed as part of this clinical trial.

Surgery

Surgical resection may be repeated, particularly for local recurrences and, in some cases, pleural and pericardial implants. Patients with recurrent thymomas who undergo repeat resection of recurrent disease may have prolonged survival when complete resection is attained.[9] However, only a minority of patients may be candidates for resection.

Evidence (surgery):

  1. In a review of 395 patients who underwent resections for TETs, 67 had tumor recurrence and 22 underwent a repeat resection procedure.[10]
    • The 10-year survival rate was 70%.
  2. In another study, 30 of 266 patients initially treated by total resection of the tumor had a recurrence; in all 30 patients, surgical resection was attempted.[11] Complete resection of the recurrent tumor was obtained in ten cases.
    • The 5-year survival rate was 48%.
    • The 10-year survival rate was 24%.

Of note, patients in these series may have received chemotherapy and/or radiation therapy in addition to surgery.

Radiation therapy

Postoperative radiation therapy has been used for patients with incomplete resections and for selected patients after complete resections of recurrent thymomas.[9] Radiation therapy is also indicated for palliation of symptoms such as pain due to chest wall invasion, and superior vena cava syndrome.

Pembrolizumab

Pembrolizumab (an anti-programmed death ligand 1 antibody) has been evaluated in patients with recurrent TETs. Immune checkpoint inhibitor therapy is under clinical evaluation and should be used in the context of a clinical trial.

  1. Thirty-three patients with refractory or relapsed TETs (26 with thymic carcinoma, 7 with thymoma) were enrolled in a phase II trial of pembrolizumab.[12]
    • Objective responses were observed in 2 of 7 patients with thymoma (28.6%; 95% CI, 8.2%–64.1%) and in 5 of 26 patients with thymic carcinoma (19.2%; 95% CI, 8.5%–37.9%).
    • The median PFS was 6.1 months for both groups.
    • Grade 3 or greater immune-related adverse events were observed in 5 of 7 patients (71.4%) with thymoma and in 4 of 26 patients (15.4%) with thymic carcinoma, including hepatitis (12.1%), myocarditis (9.1%), and myasthenia gravis (6.1%).
  2. Forty-one patients with recurrent thymic carcinoma were enrolled in a single-arm phase II study of pembrolizumab.[13]
    • After a median follow-up of 20 months, the objective response rate was 22.5% (95% CI, 10.8%–38.5%).
    • The median duration of response was 22.4 months (95% CI, 12.3–34.7).
    • The median PFS was 4.2 months (95% CI, 2.9–10.3), and the median OS was 24.9 months (15.5–NR).
    • Severe immune-related adverse events were observed in six patients (15%), including two patients (5%) with myocarditis.

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. Girard N, Ruffini E, Marx A, et al.: Thymic epithelial tumours: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 26 (Suppl 5): v40-55, 2015. [PUBMED Abstract]
  2. Gbolahan OB, Porter RF, Salter JT, et al.: A Phase II Study of Pemetrexed in Patients with Recurrent Thymoma and Thymic Carcinoma. J Thorac Oncol 13 (12): 1940-1948, 2018. [PUBMED Abstract]
  3. Palmieri G, Montella L, Martignetti A, et al.: Somatostatin analogs and prednisone in advanced refractory thymic tumors. Cancer 94 (5): 1414-20, 2002. [PUBMED Abstract]
  4. Palmieri G, Buonerba C, Ottaviano M, et al.: Capecitabine plus gemcitabine in thymic epithelial tumors: final analysis of a Phase II trial. Future Oncol 10 (14): 2141-7, 2014. [PUBMED Abstract]
  5. Loehrer PJ, Wang W, Johnson DH, et al.: Octreotide alone or with prednisone in patients with advanced thymoma and thymic carcinoma: an Eastern Cooperative Oncology Group phase II trial. J Clin Oncol 22 (2): 293-9, 2004. [PUBMED Abstract]
  6. Thomas A, Rajan A, Berman A, et al.: Sunitinib in patients with chemotherapy-refractory thymoma and thymic carcinoma: an open-label phase 2 trial. Lancet Oncol 16 (2): 177-86, 2015. [PUBMED Abstract]
  7. Zucali PA, De Pas T, Palmieri G, et al.: Phase II Study of Everolimus in Patients With Thymoma and Thymic Carcinoma Previously Treated With Cisplatin-Based Chemotherapy. J Clin Oncol 36 (4): 342-349, 2018. [PUBMED Abstract]
  8. Sato J, Satouchi M, Itoh S, et al.: Lenvatinib in patients with advanced or metastatic thymic carcinoma (REMORA): a multicentre, phase 2 trial. Lancet Oncol 21 (6): 843-850, 2020. [PUBMED Abstract]
  9. Urgesi A, Monetti U, Rossi G, et al.: Aggressive treatment of intrathoracic recurrences of thymoma. Radiother Oncol 24 (4): 221-5, 1992. [PUBMED Abstract]
  10. Okumura M, Shiono H, Inoue M, et al.: Outcome of surgical treatment for recurrent thymic epithelial tumors with reference to world health organization histologic classification system. J Surg Oncol 95 (1): 40-4, 2007. [PUBMED Abstract]
  11. Ruffini E, Mancuso M, Oliaro A, et al.: Recurrence of thymoma: analysis of clinicopathologic features, treatment, and outcome. J Thorac Cardiovasc Surg 113 (1): 55-63, 1997. [PUBMED Abstract]
  12. Cho J, Kim HS, Ku BM, et al.: Pembrolizumab for Patients With Refractory or Relapsed Thymic Epithelial Tumor: An Open-Label Phase II Trial. J Clin Oncol 37 (24): 2162-2170, 2019. [PUBMED Abstract]
  13. Giaccone G, Kim C, Thompson J, et al.: Pembrolizumab in patients with thymic carcinoma: a single-arm, single-centre, phase 2 study. Lancet Oncol 19 (3): 347-355, 2018. [PUBMED Abstract]

Latest Updates to This Summary (10/25/2024)

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 adult thymoma and thymic carcinoma. 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:

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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 Thymoma and Thymic Carcinoma Treatment are:

  • Janet Dancey, MD, FRCPC (Ontario Institute for Cancer Research & NCIC Clinical Trials Group)
  • Meredith McAdams, MD (National Cancer Institute)
  • 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.

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The preferred citation for this PDQ summary is:

PDQ® Adult Treatment Editorial Board. PDQ Thymoma and Thymic Carcinoma Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/thymoma/hp/thymoma-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389476]

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General Information About Thymoma and Thymic Carcinoma

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Key Points

  • Thymoma and thymic carcinoma are diseases in which malignant (cancer) cells form in the thymus.
  • Thymoma is linked with myasthenia gravis and other autoimmune paraneoplastic diseases.
  • Signs and symptoms of thymoma and thymic carcinoma include a cough and chest pain.
  • Tests that examine the thymus are used to help diagnose and stage thymoma and thymic carcinoma.
  • Certain factors affect prognosis (chance of recovery) and treatment options.

Thymoma and thymic carcinoma are diseases in which malignant (cancer) cells form in the thymus.

Thymoma and thymic carcinoma, also called thymic epithelial tumors (TETs), are two types of rare cancers that can form in the cells that cover the outside surface of the thymus. The thymus is a small organ that lies in the upper chest above the heart and under the breastbone. It is part of the lymph system and makes white blood cells, called lymphocytes, that help fight infection. These cancers usually form between the lungs in the front part of the chest and are sometimes found during a chest x-ray that is done for another reason.

EnlargeAnatomy of the thymus gland; drawing shows the thymus gland in the upper chest under the breastbone. Also shown are the ribs, lungs, and heart.
Anatomy of the thymus gland. The thymus gland is a small organ that lies in the upper chest under the breastbone. It makes white blood cells, called lymphocytes, which protect the body against infections.

Even though thymoma and thymic carcinoma form in the same type of cell, they act differently:

  • Thymoma. The cancer cells look a lot like the normal cells of the thymus, grow slowly, and rarely spread beyond the thymus.
  • Thymic carcinoma. The cancer cells do not look like the normal cells of the thymus, grow more quickly, and are more likely to spread to other parts of the body. About one in every five TETs is a thymic carcinoma. Thymic carcinoma is more difficult to treat than thymoma.

Other types of tumors, such as lymphoma or germ cell tumors, may form in the thymus, but they are not considered to be thymoma or thymic carcinoma.

Thymoma is linked with myasthenia gravis and other autoimmune paraneoplastic diseases.

Autoimmune paraneoplastic diseases are often linked with thymoma. Autoimmune paraneoplastic diseases may occur in patients with cancer but are not caused directly by cancer. Autoimmune paraneoplastic diseases are marked by signs and symptoms that develop when the body’s immune system attacks not only cancer cells but also normal cells. Autoimmune paraneoplastic diseases linked with thymoma include:

Other autoimmune paraneoplastic diseases may be linked with TETs and can involve any organ.

Signs and symptoms of thymoma and thymic carcinoma include a cough and chest pain.

Most patients do not have signs or symptoms when first diagnosed with thymoma or thymic carcinoma. Check with your doctor if you have any of the following:

  • A cough that doesn’t go away.
  • Shortness of breath.
  • Chest pain.
  • A hoarse voice.
  • Swelling in the face, neck, upper body, or arms.

Tests that examine the thymus are used to help diagnose and stage thymoma and thymic carcinoma.

The following tests and procedures may be used:

  • Physical exam and health history: An exam of the body to check general signs of health, including checking for signs of disease, such as lumps or anything else that seems unusual. A history of the patient’s health habits and past illnesses and treatments will also be taken.
  • 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.
  • CT scan (CAT scan): A procedure that makes a series of detailed pictures of areas inside the body, such as the chest, taken from different angles. The pictures are made by a computer linked to an x-ray machine. 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.
  • PET scan (positron emission tomography scan): A procedure to find malignant tumor cells in the body. A small amount of radioactive glucose (sugar) is injected into a vein. The PET scanner rotates around the body and makes a picture of where glucose is being used in the body. Malignant tumor cells show up brighter in the picture because they are more active and take up more glucose than normal cells do.
  • MRI (magnetic resonance imaging): A procedure that uses a magnet, radio waves, and a computer to make a series of detailed pictures of areas inside the body, such as the chest. This procedure is also called nuclear magnetic resonance imaging (NMRI).
  • Biopsy: The removal of cells or tissues using a needle so they can be viewed under a microscope by a pathologist to check for signs of cancer.

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

The prognosis and treatment options depend on the following:

  • Whether the cancer is thymoma or thymic carcinoma.
  • Whether the cancer has spread to nearby areas or other parts of the body.
  • Whether the tumor can be removed completely by surgery.
  • Whether the cancer has just been diagnosed or has recurred (come back).

Stages of Thymoma and Thymic Carcinoma

Key Points

  • After thymoma or thymic carcinoma has been diagnosed, tests are done to find out if cancer cells have spread to nearby areas or to other parts of the body.
  • There are three ways that cancer spreads in the body.
  • Cancer may spread from where it began to other parts of the body.
  • The following stages are used for thymoma:
    • Stage I
    • Stage II
    • Stage III
    • Stage IV
  • Thymic carcinomas have usually spread to other parts of the body when diagnosed.
  • Thymic carcinoma is more likely to recur than thymoma.

After thymoma or thymic carcinoma has been diagnosed, tests are done to find out if cancer cells have spread to nearby areas or to other parts of the body.

The process used to find out if thymoma or thymic carcinoma has spread from the thymus to nearby areas or other parts of the body is called staging. Thymoma and thymic carcinoma may spread to the lungs, chest wall, major vessels, esophagus, or the lining around the lungs and heart. The results of tests and procedures done to diagnose thymoma or thymic carcinoma are used to help make decisions about treatment.

There are three ways that cancer spreads in the body.

Cancer can spread through tissue, the lymph system, and the blood:

  • Tissue. The cancer spreads from where it began by growing into nearby areas.
  • Lymph system. The cancer spreads from where it began by getting into the lymph system. The cancer travels through the lymph vessels to other parts of the body.
  • Blood. The cancer spreads from where it began by getting into the blood. The cancer travels through the blood vessels to other parts of the body.

Cancer may spread from where it began to other parts of the body.

When cancer spreads to another part of the body, it is called metastasis. Cancer cells break away from where they began (the primary tumor) and travel through the lymph system or blood.

  • Lymph system. The cancer gets into the lymph system, travels through the lymph vessels, and forms a tumor (metastatic tumor) in another part of the body.
  • Blood. The cancer gets into the blood, travels through the blood vessels, and forms a tumor (metastatic tumor) in another part of the body.

The metastatic tumor is the same type of cancer as the primary tumor. For example, if thymic carcinoma spreads to the bone, the cancer cells in the bone are actually thymic carcinoma cells. The disease is metastatic thymic carcinoma, not bone cancer.

Many cancer deaths are caused when cancer moves from the original tumor and spreads to other tissues and organs. This is called metastatic cancer. This animation shows how cancer cells travel from the place in the body where they first formed to other parts of the body.

The following stages are used for thymoma:

Stage I

In stage I, cancer is found only within the thymus. All cancer cells are inside the capsule (sac) that surrounds the thymus.

Stage II

In stage II, cancer has spread through the capsule and into the fat around the thymus or into the lining of the chest cavity.

Stage III

In stage III, cancer has spread to nearby organs in the chest, including the lung, the sac around the heart, or large blood vessels that carry blood to the heart.

Stage IV

Stage IV is divided into stage IVA and stage IVB, depending on where the cancer has spread.

Thymic carcinomas have usually spread to other parts of the body when diagnosed.

The staging system used for thymomas is sometimes used for thymic carcinomas.

Thymic carcinoma is more likely to recur than thymoma.

Recurrent thymoma and thymic carcinoma are cancers that have recurred (come back) after treatment. The cancer may come back in the thymus or in other parts of the body. Thymic carcinoma is more likely to recur than thymoma.

  • Thymomas may recur a long time after treatment is completed. There is also an increased risk of having another type of cancer after having a thymoma. For these reasons, lifelong follow-up is needed.
  • Thymic carcinomas often recur.

Treatment Option Overview

Key Points

  • There are different types of treatment for patients with thymoma and thymic carcinoma.
  • The following types of treatment are used:
    • Surgery
    • Radiation therapy
    • Chemotherapy
    • Hormone therapy
    • Targeted therapy
  • New types of treatment are being tested in clinical trials.
    • Immunotherapy
  • Treatment for thymoma and thymic carcinoma may cause side effects.
  • Patients may want to think about taking part in a clinical trial.
  • Patients can enter clinical trials before, during, or after starting their cancer treatment.
  • Follow-up tests may be needed.

There are different types of treatment for patients with thymoma and thymic carcinoma.

Different types of treatments are available for patients with thymoma and thymic carcinoma. Some treatments are standard (the currently used treatment), and some are being tested in clinical trials. A treatment clinical trial is a research study meant to help improve current treatments or obtain information on new treatments for patients with cancer. When clinical trials show that a new treatment is better than the standard treatment, the new treatment may become the standard treatment. 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.

The following types of treatment are used:

Surgery

Surgery to remove the tumor is the most common treatment of thymoma.

After the doctor removes all the cancer that can be seen at the time of the surgery, some patients may be given 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. External radiation therapy uses a machine outside the body to send radiation toward the area of the body with cancer.

Chemotherapy

Chemotherapy is a cancer treatment that uses drugs to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. When chemotherapy is taken by mouth or injected into a vein or muscle, the drugs enter the bloodstream and can reach cancer cells throughout the body (systemic chemotherapy).

Chemotherapy may be used to shrink the tumor before surgery or radiation therapy. This is called neoadjuvant chemotherapy.

Hormone therapy

Hormone therapy is a cancer treatment that removes hormones or blocks their action and stops cancer cells from growing. Hormones are substances made by glands in the body and flow through the bloodstream. Some hormones can cause certain cancers to grow. If tests show that the cancer cells have places where hormones can attach (receptors), drugs, surgery, or radiation therapy is used to reduce the production of hormones or block them from working. Hormone therapy using octreotide with or without prednisone may be used to treat thymoma or thymic carcinoma.

Targeted therapy

Targeted therapy is a type of treatment that uses drugs or other substances to identify and attack specific cancer cells. Tyrosine kinase inhibitors (TKIs) and mammalian target of rapamycin (mTOR) inhibitors are types of targeted therapies used in the treatment of thymoma and thymic carcinoma.

  • TKIs: This treatment blocks signals needed for tumors to grow. Sunitinib and lenvatinib are TKIs that may be used to treat recurrent thymoma or recurrent thymic carcinoma.
  • mTOR inhibitors: This treatment blocks a protein called mTOR, which may keep cancer cells from growing and prevent the growth of new blood vessels that tumors need to grow. Everolimus is an mTOR inhibitor that may be used to treat recurrent thymoma or recurrent thymic carcinoma.

New types of treatment are being tested in clinical trials.

This summary section describes treatments that are being studied in clinical trials. It may not mention every new treatment being studied. Information about clinical trials is available from the NCI website.

Immunotherapy

Immunotherapy is a treatment that uses the patient’s immune system to fight cancer. Substances made by the body or made in a laboratory are used to boost, direct, or restore the body’s natural defenses against cancer. This cancer treatment is a type of biologic therapy.

  • Immune checkpoint inhibitor therapy: PD-1 is a protein on the surface of T cells that helps keep the body’s immune responses in check. PD-L1 is a protein found on some types of cancer cells. When PD-1 attaches to PD-L1, it stops the T cell from killing the cancer cell. PD-1 and PD-L1 inhibitors keep PD-1 and PD-L1 proteins from attaching to each other. This allows the T cells to kill cancer cells. Pembrolizumab is a type of PD-1 inhibitor that is being studied in the treatment of recurrent thymoma and thymic carcinoma.
EnlargeImmune checkpoint inhibitor; the panel on the left shows the binding of proteins PD-L1 (on the tumor cell) to PD-1 (on the T cell), which keeps T cells from killing tumor cells in the body. Also shown are a tumor cell antigen and T cell receptor. The panel on the right shows immune checkpoint inhibitors (anti-PD-L1 and anti-PD-1) blocking the binding of PD-L1 to PD-1, which allows the T cells to kill tumor cells.
Immune checkpoint inhibitor. Checkpoint proteins, such as PD-L1 on tumor cells and PD-1 on T cells, help keep immune responses in check. The binding of PD-L1 to PD-1 keeps T cells from killing tumor cells in the body (left panel). Blocking the binding of PD-L1 to PD-1 with an immune checkpoint inhibitor (anti-PD-L1 or anti-PD-1) allows the T cells to kill tumor cells (right panel).
Immunotherapy uses the body’s immune system to fight cancer. This animation explains one type of immunotherapy that uses immune checkpoint inhibitors to treat cancer.

Treatment for thymoma and thymic carcinoma may cause side effects.

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

Patients may want to think about taking part in a clinical trial.

For some patients, taking part in a clinical trial may be the best treatment choice. Clinical trials are part of the cancer research process. Clinical trials are done to find out if new cancer treatments are safe and effective or better than the standard treatment.

Many of today’s standard treatments for cancer are based on earlier clinical trials. Patients who take part in a clinical trial may receive the standard treatment or be among the first to receive a new treatment.

Patients who take part in clinical trials also help improve the way cancer will be treated in the future. Even when clinical trials do not lead to effective new treatments, they often answer important questions and help move research forward.

Patients can enter clinical trials before, during, or after starting their cancer treatment.

Some clinical trials only include patients who have not yet received treatment. Other trials test treatments for patients whose cancer has not gotten better. There are also clinical trials that test new ways to stop cancer from recurring (coming back) or reduce the side effects of cancer treatment.

Clinical trials are taking place in many parts of the country. 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.

Follow-up tests 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 Stage I and Stage II Thymoma

For information about the treatments listed below, see the Treatment Option Overview section.

Treatment of stage I and stage II thymoma is surgery, which may be followed by radiation therapy.

Treatment of Stage III and Stage IV Thymoma

For information about the treatments listed below, see the Treatment Option Overview section.

Treatment of stage III and stage IV thymoma that may be completely removed by surgery includes the following:

Treatment of stage III and stage IV thymoma that cannot be completely removed by surgery includes the following:

  • Chemotherapy.
  • Chemotherapy followed by radiation therapy.
  • Neoadjuvant chemotherapy followed by surgery (if operable) and radiation therapy.

Treatment of Thymic Carcinoma

For information about the treatments listed below, see the Treatment Option Overview section.

Treatment of thymic carcinoma that may be completely removed by surgery includes the following:

Treatment of thymic carcinoma that cannot be completely removed by surgery includes the following:

  • Chemotherapy.
  • Chemotherapy with radiation therapy.
  • Chemotherapy followed surgery, if the tumor may be completely removed, and radiation therapy.

Treatment of Recurrent Thymoma and Thymic Carcinoma

For information about the treatments listed below, see the Treatment Option Overview section.

Treatment of recurrent thymoma and thymic carcinoma may include the following:

To Learn More About Thymoma and Thymic Carcinoma

For more information from the National Cancer Institute about thymoma and thymic carcinoma, see the following:

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 adult thymoma and thymic carcinoma. 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 Thymoma and Thymic Carcinoma Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/thymoma/patient/thymoma-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389395]

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.

Testicular Cancer Screening (PDQ®)–Health Professional Version

Testicular 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 on Testicular Cancer Treatment and Levels of Evidence for Cancer Screening and Prevention Studies are also available.

Benefits

Based on fair evidence, screening for testicular cancer would not result in an appreciable decrease in mortality, in part because therapy at each stage is so effective.

Magnitude of Effect: Fair evidence of no reduction in mortality.

  • Study Design: Opinions of respected authorities based on clinical experience, descriptive studies, or reports of expert committees.
  • Internal Validity: Not applicable (N/A).
  • Consistency: N/A.
  • External Validity: N/A.

Harms

Based on fair evidence, screening for testicular cancer would result in unnecessary diagnostic procedures with attendant morbidity.

Magnitude of Effect: Fair evidence for rare but serious harms.

  • Study Design: Opinions of respected authorities based on clinical experience, descriptive studies, or reports of expert committees.
  • Internal Validity: N/A.
  • Consistency: N/A.
  • External Validity: N/A.

Incidence and Mortality

It is estimated that 9,720 new cases of testicular cancer will be diagnosed in men, and 600 men will die of this disease in the United States in 2025.[1] Testicular cancer is the most common malignancy in men aged 15 to 34 years.[2,3] It accounts for approximately 1% of all cancers in men. Worldwide, testicular cancer has more than doubled in the last 40 years. Incidence varies considerably in different geographical areas, being highest in Scandinavia and Switzerland; intermediate in the United States, Australia, and the United Kingdom; and lowest in Asia and Africa. It also varies according to ethnic groups, with a much higher rate among White men than Black men in the American population.[4] An annual increase of 3% is reported for White populations.[5] Despite the increase in observed incidence, there has been a dramatic decrease in mortality as a result of effective treatments.

Unlike most other cancers, testicular cancer is generally found in young men and has the highest incidence rate among men aged 25 to 34 years at approximately 15 cases per 100,000 men. Men in the surrounding age groups (20–24 years and 35–39 years) have a slightly lower incidence at approximately 12 cases per 100,000 men. The racial and ethnic groups with the highest incidence rates include non-Hispanic White men and non-Hispanic American Indian or Alaskan Native men, both at approximately 7 cases per 100,000 men. Testicular cancer is the most commonly diagnosed cancer among men aged 20 to 39 years.[6]

Approximately 66% of testicular cancers are localized, 19% are regional, and 12% are distant stage at diagnosis.[6] Although there has been no appreciable change in the stage distribution at diagnosis, advances in treatment have been associated with a 60% decrease in mortality. Most testicular cancers are curable even at advanced stages, and it would be impractical to document a further decrease in mortality associated with screening.

Germ cell tumors (GCTs) of the testis constitute 94% of testicular tumors and include five basic cell types:[7]

  • Seminoma.
  • Embryonal carcinoma.
  • Yolk sac tumor.
  • Teratoma.
  • Choriocarcinoma.

Sixty percent of GCTs are seminomas; the remainder are nonseminomatous GCTs. Almost half of all GCTs contain more than one of the five cell types.[7]

Three subtypes of pure seminomas have been described: classic, anaplastic, and spermatocytic. Classic seminoma accounts for 80% to 85% of all seminomas and occurs most commonly in men aged 30 to 50 years. Anaplastic seminoma accounts for 5% to 10% of all seminomas and has an age distribution similar to that of the typical subtype. A number of features suggest that anaplastic seminoma is a more aggressive and potentially more lethal variant of typical seminoma. These characteristics include greater mitotic activity, higher rate of local invasion, increased rate of metastatic spread, and higher rate of tumor marker (human chorionic gonadotropin [hCG] beta, or beta hCG) production. Spermatocytic seminoma accounts for 2% to 12% of all seminomas, and nearly half occur in men older than 50 years. The cells closely resemble different phases of maturing spermatogonia. The metastatic potential of this tumor is extremely low, and the prognosis is favorable.[8]

References
  1. American Cancer Society: Cancer Facts and Figures 2025. American Cancer Society, 2025. Available online. Last accessed January 16, 2025.
  2. McGlynn KA, Devesa SS, Sigurdson AJ, et al.: Trends in the incidence of testicular germ cell tumors in the United States. Cancer 97 (1): 63-70, 2003. [PUBMED Abstract]
  3. Garner MJ, Turner MC, Ghadirian P, et al.: Epidemiology of testicular cancer: an overview. Int J Cancer 116 (3): 331-9, 2005. [PUBMED Abstract]
  4. Huyghe E, Matsuda T, Thonneau P: Increasing incidence of testicular cancer worldwide: a review. J Urol 170 (1): 5-11, 2003. [PUBMED Abstract]
  5. Horwich A, Shipley J, Huddart R: Testicular germ-cell cancer. Lancet 367 (9512): 754-65, 2006. [PUBMED Abstract]
  6. 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.
  7. Dieckmann KP, Pichlmeier U: Clinical epidemiology of testicular germ cell tumors. World J Urol 22 (1): 2-14, 2004. [PUBMED Abstract]
  8. Richie JP, Steele GS: Neoplasms of the testis. In: Campbell MF, Wein AJ, Kavoussi LR: Campbell-Walsh Urology. 9th ed. Saunders Elsevier, 2007, pp 893-935.

Risk Factors

Testicular cancer is more than four times more common among White men than Black men,[1,2] with intermediate incidence rates for Hispanic, American Indian, and Asian men. High-risk groups exist. Males with cryptorchidism have 3 to 17 times the average risk. Approximately 7% to 10% of patients with testicular tumors have a history of cryptorchidism.[2,3] Although the association is established, the biological mechanism underlying the association remains uncertain; testicular cancer and cryptorchidism may share environmental and/or genetic risk factors; or, it is the ectopic position per se that is a postnatal risk factor for testicular cancer, or it is a combination of the two.[3] Orchiopexy may not prevent cancer in these children but allows clinical surveillance of patients with a previously impalpable gonad.

There is also an increased risk in males with gonadal dysgenesis and Klinefelter syndrome.[4] Men with a family history of testicular cancer may be at a higher risk of this disease.[5] A history of testicular cancer is associated with a higher risk of a contralateral tumor.[3,2] Although not consistently found, infertility, testicular atrophy, twinship, or abnormal semen parameters have been associated with a higher risk of testicular cancer, but the evidence is weak.[3,6–8]

There is a low cumulative risk of metachronous contralateral testicular cancer and a favorable overall survival of patients diagnosed with metachronous contralateral testicular cancer.[9] Future research is necessary to delineate the genetic and environmental risk factors for testicular cancer.[10]

Carcinoma In Situ

An additional risk factor for the development of testicular cancer is the presence of carcinoma in situ (CIS), also called intratubular germ cell neoplasia. Testicular CIS appears to develop from fetal gonocytes and is characterized histologically by seminiferous tubules containing only Sertoli cells and malignant-appearing germ cells.[11]

Early reports suggest that CIS is associated with the development of contralateral testicular cancer in 50% of patients at 5 years of follow-up.[12] CIS will be found in approximately 5% of contralateral testes (approximately the same rate as cryptorchid testes).[13]

There is controversy regarding the clinical significance and management of CIS of the testis.[2] Treatment options for CIS include observation, radiation therapy, chemotherapy, and orchiectomy. Although low-dose radiation therapy can preserve Leydig cell function and prevent germ cell tumors development, a conservative approach of observation may also be warranted. Individuals at high risk (e.g., cryptorchidism, atrophic testis, and intersex conditions) require close observation.

References
  1. Moul JW, Schanne FJ, Thompson IM, et al.: Testicular cancer in blacks. A multicenter experience. Cancer 73 (2): 388-93, 1994. [PUBMED Abstract]
  2. Richie JP, Steele GS: Neoplasms of the testis. In: Campbell MF, Wein AJ, Kavoussi LR: Campbell-Walsh Urology. 9th ed. Saunders Elsevier, 2007, pp 893-935.
  3. Dieckmann KP, Pichlmeier U: Clinical epidemiology of testicular germ cell tumors. World J Urol 22 (1): 2-14, 2004. [PUBMED Abstract]
  4. Henderson BE, Benton B, Jing J, et al.: Risk factors for cancer of the testis in young men. Int J Cancer 23 (5): 598-602, 1979. [PUBMED Abstract]
  5. Dieckmann KP, Pichlmeier U: The prevalence of familial testicular cancer: an analysis of two patient populations and a review of the literature. Cancer 80 (10): 1954-60, 1997. [PUBMED Abstract]
  6. Jacobsen R, Bostofte E, Engholm G, et al.: Risk of testicular cancer in men with abnormal semen characteristics: cohort study. BMJ 321 (7264): 789-92, 2000. [PUBMED Abstract]
  7. Walsh TJ, Croughan MS, Schembri M, et al.: Increased risk of testicular germ cell cancer among infertile men. Arch Intern Med 169 (4): 351-6, 2009. [PUBMED Abstract]
  8. Hotaling JM, Walsh TJ: Male infertility: a risk factor for testicular cancer. Nat Rev Urol 6 (10): 550-6, 2009. [PUBMED Abstract]
  9. Fosså SD, Chen J, Schonfeld SJ, et al.: Risk of contralateral testicular cancer: a population-based study of 29,515 U.S. men. J Natl Cancer Inst 97 (14): 1056-66, 2005. [PUBMED Abstract]
  10. Richiardi L, Pettersson A, Akre O: Genetic and environmental risk factors for testicular cancer. Int J Androl 30 (4): 230-40; discussion 240-1, 2007. [PUBMED Abstract]
  11. Olesen IA, Hoei-Hansen CE, Skakkebaek NE, et al.: Testicular carcinoma in situ in subfertile Danish men. Int J Androl 30 (4): 406-11; discussion 412, 2007. [PUBMED Abstract]
  12. Jørgensen N, Müller J, Giwercman A, et al.: Clinical and biological significance of carcinoma in situ of the testis. Cancer Surv 9 (2): 287-302, 1990. [PUBMED Abstract]
  13. Dieckmann KP, Loy V: Prevalence of contralateral testicular intraepithelial neoplasia in patients with testicular germ cell neoplasms. J Clin Oncol 14 (12): 3126-32, 1996. [PUBMED Abstract]

Evidence of Benefit Associated With Screening

The sensitivity, specificity, and positive predictive value of routine screening of asymptomatic men for testicular cancer are not known.[1,2] In a report of a single-center case series of men being evaluated for infertility, testicular symptoms, or erectile dysfunction, 1,320 men underwent testicular ultrasonography.[3] Focal lesions were found in 27 (2%) men, 17 of the lesions were palpable, and 10 were nonpalpable. Eighty percent of the lesions were ultimately shown to have benign histologies, for a positive predictive value of about 0.2. It is not clear if early discovery of the cancers resulted in clinical benefit, and the positive predictive value is likely to be lower in the target population of asymptomatic men in the screening setting.

Most testicular cancers are first detected by the patient, either unintentionally or by self-examination. Some are discovered by routine physical examination. However, no studies have been done to determine the effectiveness of testicular self-examination or clinical testicular examination in reducing mortality from testicular cancer. An updated systematic review performed on behalf of the U.S. Preventive Services Task Force, published in 2010, found no randomized trials, cohort studies, or case-control studies that examined benefits of testicular cancer screening (whether by physical examination, self-examination, or other screening tests) in an asymptomatic population.[2] Likewise, a systematic Cochrane Collaboration review found no randomized or quasi-randomized controlled trials that evaluated the effectiveness of screening by a health professional or patient self-examination.[4]

Screening would be very unlikely to decrease mortality substantially because therapy is so effective at virtually all stages of disease.[5] For more information, see Testicular Cancer Treatment. However, early detection may affect therapy. There is an increase in both the number of courses of chemotherapy and the extent of surgery required for treatment of advanced disease that results in higher morbidity. Patients diagnosed with localized disease require less treatment and have lower morbidity.[6]

References
  1. U.S. Preventive Services Task Force: Screening for testicular cancer: U.S. Preventive Services Task Force reaffirmation recommendation statement. Ann Intern Med 154 (7): 483-6, 2011. [PUBMED Abstract]
  2. Lin K, Sharangpani R: Screening for testicular cancer: an evidence review for the U.S. Preventive Services Task Force. Ann Intern Med 153 (6): 396-9, 2010. [PUBMED Abstract]
  3. Carmignani L, Gadda F, Gazzano G, et al.: High incidence of benign testicular neoplasms diagnosed by ultrasound. J Urol 170 (5): 1783-6, 2003. [PUBMED Abstract]
  4. Ilic D, Misso ML: Screening for testicular cancer. Cochrane Database Syst Rev (2): CD007853, 2011. [PUBMED Abstract]
  5. Feldman DR, Bosl GJ, Sheinfeld J, et al.: Medical treatment of advanced testicular cancer. JAMA 299 (6): 672-84, 2008. [PUBMED Abstract]
  6. Sagalowsky AI: Expectant management of stage A nonseminomatous testicular tumors. In: Ratiff TL, Catalona WJ, eds.: Genitourinary Cancer. Martinus Nijhoff, 1987, pp 225-237.

Evidence of Harm Associated With Screening

Harms of screening for testicular cancer are poorly quantified. They may include false positive tests [1] and resulting anxiety as well as subsequent unwarranted invasive diagnostic procedures. Two systematic reviews found no studies that provided a quantitative assessment of the harms of screening.[2,3]

References
  1. Carmignani L, Gadda F, Gazzano G, et al.: High incidence of benign testicular neoplasms diagnosed by ultrasound. J Urol 170 (5): 1783-6, 2003. [PUBMED Abstract]
  2. Lin K, Sharangpani R: Screening for testicular cancer: an evidence review for the U.S. Preventive Services Task Force. Ann Intern Med 153 (6): 396-9, 2010. [PUBMED Abstract]
  3. Ilic D, Misso ML: Screening for testicular cancer. Cochrane Database Syst Rev (2): CD007853, 2011. [PUBMED Abstract]

Latest Updates to This Summary (04/07/2025)

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 testicular 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 Testicular Cancer Screening. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/testicular/hp/testicular-screening-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389404]

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.

Testicular Cancer Screening (PDQ®)–Patient Version

Testicular 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 Testicular Cancer

Key Points

  • Testicular cancer is a disease in which malignant (cancer) cells form in the tissues of one or both testicles.
  • Testicular cancer is the most commonly diagnosed cancer in men aged 20 to 39 years.
  • Testicular cancer can usually be cured.
  • A condition called cryptorchidism (an undescended testicle) is a risk factor for testicular cancer.

Testicular cancer is a disease in which malignant (cancer) cells form in the tissues of one or both testicles.

The testicles are 2 egg-shaped glands inside the scrotum (a sac of loose skin that lies directly below the penis). The testicles are held within the scrotum by the spermatic cord. The spermatic cord also contains the vas deferens and vessels and nerves of the testicles.

EnlargeAnatomy of the male reproductive and urinary systems; drawing shows front and side views of ureters, lymph nodes, rectum, bladder, prostate gland, vas deferens, urethra, penis, testicles, seminal vesicle, and ejaculatory duct.
Anatomy of the male reproductive and urinary systems, showing the testicles, prostate, bladder, and other organs.

The testicles are the male sex glands and make testosterone and sperm. Germ cells in the testicles make immature sperm. These sperm travel through a network of tubules (tiny tubes) and larger tubes into the epididymis (a long coiled tube next to the testicles). This is where the sperm cells mature and are stored.

Almost all testicular cancers start in the germ cells. The two main types of testicular germ cell tumors are seminomas and nonseminomas.

Learn more about testicular cancer at Testicular Cancer Treatment.

Testicular cancer is the most commonly diagnosed cancer in men aged 20 to 39 years.

Testicular cancer is the most common cancer in men between the ages of 20 to 39 years, with the highest rates between ages 25 to 34 years. The racial and ethnic groups with the highest rates of testicular cancer include non-Hispanic White men, non-Hispanic American Indian men, and Alaska Native men.

Testicular cancer can usually be cured.

Although the number of new cases of testicular cancer has doubled in the last 40 years, the number of deaths caused by testicular cancer has decreased greatly because of better treatments. Testicular cancer can usually be cured, even in late stages of the disease. Learn more about testicular cancer at Testicular Cancer Treatment.

A condition called cryptorchidism (an undescended testicle) is a risk factor for testicular cancer.

Anything that increases a person’s chance of getting a disease is called a risk factor. Not every person with one or more of these risk factors will develop testicular cancer, and it will also develop in some people who don’t have any known risk factors. Talk with your doctor if you think you may be at risk.

Risk factors for testicular cancer include:

Men who have cryptorchidism, a testicle that is not normal, or testicular carcinoma in situ have an increased risk of testicular cancer in one or both testicles and need to be followed closely.

Testicular Cancer Screening

Key Points

  • Tests are used to screen for different types of cancer when a person does not have symptoms.
  • There is no standard or routine screening test for testicular cancer.
  • Screening tests for testicular 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.

There is no standard or routine screening test for testicular cancer.

There is no standard or routine screening test used for early detection of testicular cancer. Most often, testicular cancer is first found by men themselves, either by chance or during self-exam. Sometimes the cancer is found by a doctor during a routine physical exam.

No studies have been done to find out if testicular self-exams, regular exams by a doctor, or other screening tests in men with no symptoms would decrease the risk of dying from this disease. However, routine screening probably would not decrease the risk of dying from testicular cancer. This is partly because testicular cancer can usually be cured at any stage. Finding testicular cancer early may make it easier to treat. Patients who are diagnosed with testicular cancer that has not spread to other parts of the body may need less chemotherapy and surgery, resulting in fewer side effects.

If a lump is found in the testicle by the patient or during a routine physical exam, tests may be done to check for cancer. Some tests have risks and may cause anxiety.

Screening tests for testicular 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 testicular 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 Testicular Cancer Screening. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/testicular/patient/testicular-screening-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389226]

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.

Ovarian Borderline Tumors Treatment (PDQ®)–Patient Version

Ovarian Borderline Tumors Treatment (PDQ®)–Patient Version

General Information About Ovarian Borderline Tumors

Go to Health Professional Version

Key Points

  • Ovarian borderline tumor is a disease in which abnormal cells form in the tissue covering the ovary.
  • Signs and symptoms of ovarian borderline tumor include pain or swelling in the abdomen.
  • Tests that examine the ovaries are used to diagnose and stage ovarian borderline tumor.
  • Some people decide to get a second opinion.
  • Certain factors affect prognosis (chance of recovery) and treatment options.

Ovarian borderline tumor is a disease in which abnormal cells form in the tissue covering the ovary.

Ovarian borderline tumors have abnormal cells that may become cancer, but usually do not. This disease usually remains in the ovary. When disease is found in one ovary, the other ovary should also be checked carefully for signs of disease.

The ovaries are a pair of organs in the female reproductive system. They are in the pelvis, one on each side of the uterus (the hollow, pear-shaped organ where a fetus grows). Each ovary is about the size and shape of an almond. The ovaries make eggs and female hormones.

EnlargeAnatomy of the female reproductive system; drawing shows the uterus, myometrium (muscular outer layer of the uterus), endometrium (inner lining of the uterus), ovaries, fallopian tubes, cervix, and vagina.
Anatomy of the female reproductive system. The organs in the female reproductive system include the uterus, ovaries, fallopian tubes, cervix, and vagina. The uterus has a muscular outer layer called the myometrium and an inner lining called the endometrium.

Signs and symptoms of ovarian borderline tumor include pain or swelling in the abdomen.

Ovarian borderline tumor may not cause early signs or symptoms. If you do have signs or symptoms, they may include:

These signs and symptoms may be caused by other conditions. If they get worse or do not go away on their own, check with your doctor.

Tests that examine the ovaries are used to diagnose and stage ovarian borderline tumor.

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:

  • Pelvic exam is an exam of the vagina, cervix, uterus, fallopian tubes, ovaries, and rectum. A speculum is inserted into the vagina and the doctor or nurse looks at the vagina and cervix for signs of disease. A Pap test of the cervix is usually done. The doctor or nurse also inserts one or two lubricated, gloved fingers of one hand into the vagina and places the other hand over the lower abdomen to feel the size, shape, and position of the uterus and ovaries. The doctor or nurse also inserts a lubricated, gloved finger into the rectum to feel for lumps or abnormal areas.
    EnlargePelvic exam; drawing shows a side view of the female reproductive anatomy during a pelvic exam. The uterus, left fallopian tube, left ovary, cervix, vagina, bladder, and rectum are shown. Two gloved fingers of one hand of the doctor or nurse are shown inserted into the vagina, while the other hand is shown pressing on the lower abdomen. The inset shows a woman covered by a drape on an exam table with her legs apart and her feet in stirrups.
    Pelvic exam. A doctor or nurse inserts one or two lubricated, gloved fingers of one hand into the vagina and presses on the lower abdomen with the other hand. This is done to feel the size, shape, and position of the uterus and ovaries. The vagina, cervix, fallopian tubes, and rectum are also checked.
  • Ultrasound exam is a procedure in which high-energy sound waves (ultrasound) are bounced off internal tissues or organs and make echoes. The echoes form a picture of body tissues called a sonogram. The picture can be printed to be looked at later.
    EnlargeAbdominal ultrasound; drawing shows a woman on an exam table during an abdominal ultrasound procedure. A diagnostic sonographer (a person trained to perform ultrasound procedures) is shown passing a transducer (a device that makes sound waves that bounce off tissues inside the body) over the surface of the patient’s abdomen. A computer screen shows a sonogram (computer picture).
    Abdominal ultrasound. An ultrasound transducer connected to a computer is passed over the surface of the abdomen. The ultrasound transducer bounces sound waves off internal organs and tissues to make echoes that form a sonogram (computer picture).

    Other patients may have a transvaginal ultrasound.

    EnlargeTransvaginal ultrasound; drawing shows a side view of the female reproductive anatomy during a transvaginal ultrasound procedure. An ultrasound probe (a device that makes sound waves that bounce off tissues inside the body) is shown inserted into the vagina. The bladder, uterus, right fallopian tube, and right ovary are also shown. The inset shows the diagnostic sonographer (a person trained to perform ultrasound procedures) examining a woman on a table, and a computer screen shows an image of the patient’s internal tissues.
    Transvaginal ultrasound. An ultrasound probe connected to a computer is inserted into the vagina and is gently moved to show different organs. The probe 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. 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.
  • CA 125 assay is a laboratory test that measures the level of CA 125 in the blood. CA 125 is a substance released by cells into the bloodstream. An increased CA 125 level is sometimes a sign of cancer or other condition.
  • 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.
  • Biopsy is the removal of cells or tissues so they can be viewed under a microscope by a pathologist to check for signs of cancer. The tissue is usually removed during surgery to remove the tumor.
  • Staging laparotomy is surgery to determine the extent of cancer within the abdomen. An incision (cut) is made in the wall of the abdomen to remove tissue so a pathologist can check it for signs of cancer.

Some people decide to get a second opinion.

You may want to get a second opinion to confirm your 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 tumor.

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 prognosis (chance of recovery) and treatment options.

The prognosis and treatment options depend on:

  • the stage of the disease (whether it affects part of the ovary, involves the whole ovary, or has spread to other places in the body)
  • what type of cells make up the tumor
  • the size of the tumor
  • the patient’s general health

Patients with ovarian borderline tumors have a good prognosis, especially when the tumor is found early.

Stages of Ovarian Borderline Tumors

Key Points

  • After ovarian borderline tumor has been diagnosed, tests are done to find out if abnormal cells have spread within the ovary or to other parts of the body.
  • The following stages are used for ovarian borderline tumor:
    • Stage I (also called stage 1) ovarian borderline tumor
    • Stage II (also called stage 2) ovarian borderline tumor
    • Stage III (also called stage 3) ovarian borderline tumor
    • Stage IV (also called stage 4) ovarian borderline tumor
  • Ovarian borderline tumors can recur (come back) after they have been treated.

After ovarian borderline tumor has been diagnosed, tests are done to find out if abnormal cells have spread within the ovary or to other parts of the body.

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 the ovarian borderline tumors to plan the best treatment. Most people are diagnosed with stage I disease.

Borderline ovarian tumor staging usually uses the FIGO staging system. The tumor may be described by this staging system in your pathology report. Based on the FIGO results, a stage (I, II, III, or IV, also written as 1, 2, 3, or 4) is assigned to your tumor. When talking to you about your diagnosis, your doctor may describe the tumor as one of these stages. 

The following stages are used for ovarian borderline tumor:

Stage I (also called stage 1) ovarian borderline tumor

EnlargeThree-panel drawing of stage IA, stage IB, and stage IC; each panel shows the ovaries, fallopian tubes, uterus, cervix, and vagina. The first panel (stage IA) shows cancer inside one ovary. The second panel (stage IB) shows cancer inside both ovaries. The third panel (stage IC) shows cancer inside both ovaries and (a) the tumor in the ovary on the left has ruptured (broken open), (b) there is cancer on the surface of the ovary on the right, and (c) there are cancer cells in the pelvic peritoneal fluid (inset).
In stage IA, cancer is found inside a single ovary or fallopian tube. In stage IB, cancer is found inside both ovaries or fallopian tubes. In stage IC, cancer is found inside one or both ovaries or fallopian tubes and one of the following is true: (a) either the tumor or the capsule (outer covering) of the ovary has ruptured (broken open), or (b) cancer is also found on the surface of the ovary or fallopian tube, or (c) cancer cells are found in the pelvic peritoneal fluid.

In stage I, the tumor is found in one or both ovaries or fallopian tubes. Stage I is divided into stage IA, stage IB, and stage IC.

  • Stage IA: The tumor is found inside a single ovary or fallopian tube.
  • Stage IB: The tumor is found inside both ovaries or fallopian tubes.
  • Stage IC: The tumor is found inside one or both ovaries or fallopian tubes and one of the following is true:
    • tumor cells are found on the outside surface of one or both ovaries or fallopian tubes; or
    • the capsule (outer covering) of the ovary ruptured (broke open) before or during surgery; or
    • tumor cells are found in the fluid of the peritoneal cavity (the body cavity that contains most of the organs in the abdomen) or in washings of the peritoneum (tissue lining the peritoneal cavity).

Stage II (also called stage 2) ovarian borderline tumor

EnlargeThree-panel drawing of stage IIA, stage IIB, and stage II primary peritoneal cancer; the first panel (stage IIA) shows cancer inside both ovaries that has spread to the fallopian tube and uterus. Also shown are the cervix and vagina. The second panel (stage IIB) shows cancer inside both ovaries that has spread to the colon. The third panel (primary peritoneal cancer) shows cancer in the pelvic peritoneum.
In stage IIA, cancer is found in one or both ovaries or fallopian tubes and has spread to the uterus and/or the fallopian tubes and/or the ovaries. In stage IIB, cancer is found in one or both ovaries or fallopian tubes and has spread to organs in the peritoneal cavity, such as the colon. In primary peritoneal cancer, cancer is found in the pelvic peritoneum and has not spread there from another part of the body.

In stage II, the tumor is found in one or both ovaries or fallopian tubes and has spread into other areas of the pelvis, or primary peritoneal cancer is found within the pelvis. Stage II is divided into stage IIA and stage IIB.

  • Stage IIA: The tumor has spread from where it first formed to the uterus and/or the fallopian tubes and/or the ovaries.
  • Stage IIB: The tumor has spread from the ovary or fallopian tube to organs in the peritoneal cavity (the space that contains the abdominal organs).

Stage III (also called stage 3) ovarian borderline tumor

EnlargeDrawing shows different sizes of a tumor in centimeters (cm) compared to the size of a pea (1 cm), a peanut (2 cm), a grape (3 cm), a walnut (4 cm), a lime (5 cm), an egg (6 cm), a peach (7 cm), and a grapefruit (10 cm). Also shown is a 10-cm ruler and a 4-inch ruler.
Tumor sizes are often measured in centimeters (cm) or inches. Common food items that can be used to show tumor size in cm include: a pea (1 cm), a peanut (2 cm), a grape (3 cm), a walnut (4 cm), a lime (5 cm or 2 inches), an egg (6 cm), a peach (7 cm), and a grapefruit (10 cm or 4 inches).

In stage III, the tumor is found in one or both ovaries or fallopian tubes, or is primary peritoneal cancer, and has spread outside the pelvis to other parts of the abdomen and/or to nearby lymph nodes. Stage III is divided into stage IIIA, stage IIIB, and stage IIIC.

  • In stage IIIA, one of the following is true:
    • The tumor has spread to lymph nodes in the area outside or behind the peritoneum only; or
    • Tumor cells that can be seen only with a microscope have spread to the surface of the peritoneum outside the pelvis, such as the omentum (a fold of the peritoneum that surrounds the stomach and other organs in the abdomen). The tumor may have spread to nearby lymph nodes.
    EnlargeDrawing of stage IIIA shows cancer inside both ovaries that has spread to (a) lymph nodes behind the peritoneum and (b) the omentum. The small intestine, colon, fallopian tubes, uterus, and bladder are also shown.
    In stage IIIA, cancer is found in one or both ovaries or fallopian tubes and (a) cancer has spread to lymph nodes behind the peritoneum only, or (b) cancer cells that can be seen only with a microscope have spread to the surface of the peritoneum outside the pelvis, such as the omentum. Cancer may have also spread to nearby lymph nodes.
  • Stage IIIB: The tumor has spread to the peritoneum outside the pelvis, such as the omentum, and the tumor in the peritoneum is 2 centimeters or smaller. The tumor may have spread to lymph nodes behind the peritoneum.
    EnlargeDrawing of stage IIIB shows cancer inside both ovaries that has spread to the omentum. The cancer in the omentum is 2 centimeters or smaller. An inset shows 2 centimeters is about the size of a peanut. Also shown are the small intestine, colon, fallopian tubes, uterus, bladder, and lymph nodes behind the peritoneum.
    In stage IIIB, cancer is found in one or both ovaries or fallopian tubes and has spread to the peritoneum outside the pelvis, such as the omentum. The cancer in the omentum is 2 centimeters or smaller. Cancer may have also spread to lymph nodes behind the peritoneum.
  • Stage IIIC: The tumor has spread to the peritoneum outside the pelvis, such as the omentum, and the tumor in the peritoneum is larger than 2 centimeters. The tumor may have spread to lymph nodes behind the peritoneum or to the surface of the liver or spleen.
    EnlargeDrawing of stage IIIC shows cancer inside both ovaries that has spread to the omentum. The cancer in the omentum is larger than 2 centimeters. An inset shows 2 centimeters is about the size of a peanut. Also shown are the small intestine, colon, fallopian tubes, uterus, bladder, and lymph nodes behind the peritoneum.
    In stage IIIC, cancer is found in one or both ovaries or fallopian tubes and has spread to the peritoneum outside the pelvis, such as the omentum. The cancer in the omentum is larger than 2 centimeters. Cancer may have also spread to lymph nodes behind the peritoneum or to the surface of the liver or spleen (not shown).

Stage IV (also called stage 4) ovarian borderline tumor

In stage IV, tumor cells have spread beyond the abdomen to other parts of the body. Stage IV is divided into stage IVA and stage IVB.

EnlargeDrawing of stage IV shows other parts of the body where ovarian cancer may spread, including the lung, liver, and lymph nodes in the groin. An inset on the top shows extra fluid around the lung. An inset on the bottom shows cancer cells spreading through the blood and lymph system to another part of the body where metastatic cancer has formed.
In stage IV, cancer has spread beyond the abdomen to other parts of the body. In stage IVA, cancer cells are found in extra fluid that builds up around the lungs. In stage IVB, cancer has spread to organs and tissues outside the abdomen, including the lung, liver, and lymph nodes in the groin.

  • Stage IVA: Tumor cells are found in extra fluid that builds up around the lungs.
  • Stage IVB: The tumor has spread to organs and tissues outside the abdomen, including lymph nodes in the groin.

Ovarian borderline tumors can recur (come back) after they have been treated.

Recurrent ovarian borderline tumors are tumors that have come back after they have been treated. The tumors may come back in the other ovary or in other parts of the body. Tests will be done to help determine where the tumor has returned. The type of treatment for a recurrent ovarian borderline tumor will depend on where it has come back.

Treatment Option Overview

Key Points

  • There are different types of treatment for patients with ovarian borderline tumors.
  • The following types of treatment are used:
    • Surgery
    • Chemotherapy
  • New types of treatment are being tested in clinical trials.
  • Treatment for ovarian borderline tumors may cause side effects.
  • Follow-up care may be needed.

There are different types of treatment for patients with ovarian borderline tumors.

Different types of treatments are available for ovarian borderline tumors. You and your 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 tumor, your overall health, and your preferences. Your plan will include information about your tumor, the goals of treatment, your treatment options and the possible side effects, and the expected length of treatment. 

Talking with your 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

The type of surgery (removing the tumor in an operation) depends on the size and spread of the tumor and the patient’s plans for having children. Surgery may include:

  • Unilateral salpingo-oophorectomy is surgery to remove one ovary and one fallopian tube.
  • Bilateral salpingo-oophorectomy is surgery to remove both ovaries and both fallopian tubes.
  • Total hysterectomy and bilateral salpingo-oophorectomy is surgery to remove the uterus, cervix, and both ovaries and fallopian tubes. If the uterus and cervix are taken out through the vagina, the operation is called a vaginal hysterectomy. If the uterus and cervix are taken out through a large incision (cut) in the abdomen, the operation is called a total abdominal hysterectomy. If the uterus and cervix are taken out through a small incision (cut) in the abdomen using a laparoscope, the operation is called a total laparoscopic hysterectomy.
    EnlargeHysterectomy; drawing shows the female reproductive anatomy, including the ovaries, uterus, vagina, fallopian tubes, and cervix. Dotted lines show which organs and tissues are removed in a total hysterectomy, a total hysterectomy with salpingo-oophorectomy, and a radical hysterectomy. An inset shows the location of two possible incisions on the abdomen: a low transverse incision is just above the pubic area and a vertical incision is between the navel and the pubic area.
    Hysterectomy. The uterus is surgically removed with or without other organs or tissues. In a total hysterectomy, the uterus and cervix are removed. In a total hysterectomy with salpingo-oophorectomy, (a) the uterus plus one (unilateral) ovary and fallopian tube are removed; or (b) the uterus plus both (bilateral) ovaries and fallopian tubes are removed. In a radical hysterectomy, the uterus, cervix, both ovaries, both fallopian tubes, and nearby tissue are removed. These procedures are done using a low transverse incision or a vertical incision.
  • Partial oophorectomy is surgery to remove part of one ovary or part of both ovaries.
  • Omentectomy is surgery to remove the omentum (a tissue layer that lines the abdominal wall).

After the doctor removes all disease that can be seen at the time of the surgery, the patient may be given chemotherapy (also called chemo) after surgery to kill any tumor cells that are left. Treatment given after the surgery to lower the risk that the tumor will come back is called adjuvant therapy.

Chemotherapy

Chemotherapy uses drugs to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Chemotherapy for ovarian borderline tumors 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.  

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.

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 ovarian borderline tumors 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 Early Stage Ovarian Borderline Tumors (Stages I and II)

Surgery is the standard treatment for early stage ovarian borderline tumors. The type of surgery usually depends on whether a patient plans to have children.

For patients who plan to have children, surgery is either:

To prevent recurrence of disease, most doctors recommend surgery to remove the remaining ovarian tissue when a patient no longer plans to have children.

For patients who do not plan to have children, treatment may be hysterectomy and bilateral salpingo-oophorectomy.

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 Advanced Stage Ovarian Borderline Tumors (Stages III and IV)

Treatment for advanced stage ovarian borderline tumors may be hysterectomy, bilateral salpingo-oophorectomy, and omentectomy. A lymph node dissection may also be done. Patients with advanced disease should undergo a total hysterectomy, bilateral salpingo-oophorectomy, omentectomy, node sampling, and aggressive cytoreductive surgery.

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 Recurrent Ovarian Borderline Tumors

Treatment for recurrent ovarian borderline tumors may include:

  • surgery to remove cancer that has spread in the abdominal cavity
  • surgery followed by chemotherapy

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.

To Learn More About Ovarian Borderline Tumors

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

About This PDQ Summary

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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.

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PDQ® Adult Treatment Editorial Board. PDQ Ovarian Borderline Tumors Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/ovarian/patient/ovarian-low-malignant-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389247]

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