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Childhood craniopharyngioma is a rare tumor usually found near the pituitary gland (a pea-sized organ at the bottom of the brain that controls other glands) and the hypothalamus (a small cone-shaped organ connected to the pituitary gland by nerves). Craniopharyngiomas can occur at any age but are most often diagnosed in children aged 5 to 14 years and older adults. They are rare in children younger than 2.
EnlargeCraniopharyngiomas are rare brain tumors that usually form near the pituitary gland and the hypothalamus. They are benign (not cancer) and do not spread to other parts of the brain or to other parts of the body. However, they may grow and press on nearby parts of the brain, including the pituitary gland, optic chiasm, and optic nerve. Craniopharyngiomas usually occur in children and young adults.
Craniopharyngiomas are usually part solid mass and part fluid-filled cyst. They are not cancer and do not spread to other parts of the brain or other parts of the body. However, they can grow and press on nearby parts of the brain, such as the pituitary gland. Or they may press on other areas, such as:
Craniopharyngiomas may affect many brain functions, including hormone production, growth, and vision. Treatments help stop the tumor from pushing on other areas of the brain.
Causes and risk factors for childhood craniopharyngioma
Craniopharyngioma is caused by certain changes to the way the brain cells function, especially how they grow and divide into new cells. Often, the exact cause of these changes is unknown.
There are no known risk factors for childhood craniopharyngioma.
Symptoms of childhood craniopharyngioma
The symptoms of childhood craniopharyngioma depend on where the tumor grows in the brain. It’s important to check with your child’s doctor if your child has:
headaches, including morning headache or headache that goes away after vomiting
These symptoms may be caused by problems other than craniopharyngioma. The only way to know is for your child to see a doctor.
Some symptoms caused by the tumor may continue for months or years after treatment. It is important to talk with your child’s doctors about problems that may continue after treatment.
Tests to diagnose childhood craniopharyngioma
If your child has symptoms that suggest a craniopharyngioma, the doctor will need to find out if they are due to a tumor or another problem. The doctor will ask when the symptoms started and how often your child has been having them. They will also ask about your child’s personal and family medical history and do a physical exam, including a neurologic exam. Depending on these results, they may recommend other tests. If your child is diagnosed with craniopharyngioma, the results of these tests will help you and your child’s doctor plan treatment.
The tests to diagnose craniopharyngioma may include:
Visual field exam
A visual field exam checks a person’s field of vision (the total area in which objects can be seen). This test measures both central vision (how much a person can see when looking straight ahead) and peripheral vision (how much a person can see in all other directions while staring straight ahead). Any loss of vision may be a sign of a tumor that has damaged or pressed on the parts of the brain that affect eyesight.
CT scan (CAT scan)
CT scan uses a computer linked to an x-ray machine to make a series of detailed pictures of areas inside the body. 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.
Magnetic resonance imaging (MRI) with gadolinium
MRI uses a magnet, radio waves, and a computer to make a series of detailed pictures of areas inside the body, such as the brain and the spine. A substance called gadolinium is injected into a vein. The gadolinium collects around the tumor cells so they show up brighter in the picture. This procedure is also called nuclear magnetic resonance imaging (NMRI).
Blood hormone studies
Blood hormone studies use a blood sample to measure the amounts of certain hormones released into the blood by organs and tissues in the body. If the amount of a hormone is higher or lower than normal, it can be a sign of disease in the organ or tissue that makes it. For craniopharyngioma, the blood may be checked for unusual levels of thyroid-stimulating hormone (TSH) or adrenocorticotropic hormone (ACTH). These hormones are made by the pituitary gland.
Biopsy
If the CT scan or MRI show there may be a brain tumor, your child will have a biopsy to remove a sample of the tumor.
Types of biopsy that may be used to take the sample of tissue include:
Open biopsy: A surgeon inserts a hollow needle through a hole in the skull into the brain.
Computer-guided needle biopsy: A surgeon inserts a hollow needle guided by a computer through a small hole in the skull into the brain.
Transsphenoidal biopsy: The surgeon inserts instruments through the nose and sphenoid bone (a butterfly-shaped bone at the base of the skull) and into the brain.
A pathologist views the tissue under a microscope to look for tumor cells. If they find tumor cells, the surgeon will remove as much tumor as safely possible during the same surgery.
Immunohistochemistry
Immunohistochemistry uses antibodies to check for certain antigens (markers) in a sample of a patient’s cells or 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.
Getting a second opinion
You may want to get a second opinion to confirm your child’s diagnosis and treatment plan. If you seek a second opinion, you will need to get medical test results and reports from the first doctor to share with the second doctor. The second doctor will review the pathology report, slides, and scans. This doctor may agree with the first doctor, suggest changes to the treatment plan, or provide more information about your child’s tumor.
To learn more about choosing a doctor and getting a second opinion, visit Finding Cancer Care. You can contact NCI’s Cancer Information Service via chat, email, or phone (both in English and Spanish) for help finding a doctor or hospital that can provide a second opinion. For questions you might want to ask at your child’s appointments, visit Questions to Ask Your Doctor about Cancer.
Types of treatment for childhood craniopharyngioma
Who treats children with craniopharyngioma?
A pediatric oncologist, a doctor who specializes in treating children with cancer, oversees treatment for childhood craniopharyngioma. The pediatric oncologist works with other health care providers who are experts in treating children with brain tumors and who specialize in certain areas of medicine. Other specialists may include:
There are different types of treatment for children and adolescents with craniopharyngioma. Although craniopharyngioma is not cancer, treatment is often similar to cancer treatment and may include surgery, radiation therapy, and other approaches. You and your child’s care team will work together to decide treatment. Many factors will be considered, such as your child’s age and overall health, where the tumor is located and whether it has spread into nearby tissue, and the possible side effects and late effects of treatment.
Your child’s treatment plan will include information about the tumor, the goals of treatment, treatment options, and the possible side effects. It will be helpful to talk with your child’s care team before treatment begins about what to expect. For help every step of the way, visit our booklet, Children with Cancer: A Guide for Parents.
Types of treatment your child might have include:
Surgery
The type of surgery your child will have depends on the size of the tumor, where it is in the brain, and whether it has grown into nearby tissue in a finger-like way. It also depends on expected late effects that may occur after surgery.
The types of surgery that may be used to remove the tumor that can be seen with the eye include:
Transsphenoidal surgery is a type of surgery in which a surgeon inserts instruments into the brain by going through a cut made under the upper lip or at the bottom of the nose between the nostrils. Then they go through the sphenoid bone (a butterfly-shaped bone at the base of the skull) to reach the tumor near the pituitary gland and hypothalamus. EnlargeTranssphenoidal surgery. An endoscope and a curette are inserted through the nose and sphenoid sinus to remove the tumor.
A craniotomy is surgery to remove the tumor through an opening made in the skull. EnlargeCraniotomy. An opening is made in the skull and a piece of the skull is removed to show part of the brain.
To help make a diagnosis, sometimes the surgeon will remove only part of the tumor. If a tumor is near the pituitary gland or hypothalamus, it will not be removed. Leaving the tumor helps reduce serious side effects from the surgery.
Sometimes, the surgeon will remove all of the tumor that they can see and no further treatment is needed. At other times, they may not be able to remove the tumor because it is growing into or pressing on nearby organs.
Surgery for cysts
If your child’s tumor is mostly a fluid-filled cyst, they may have surgery to drain it. Draining it lowers the pressure in the brain and relieves symptoms.
A surgery called a partial resection can be used to remove fluid from cystic craniopharyngiomas. Or a thin tube called a catheter can be inserted into the cyst, and a small container placed under the skin. The fluid drains into the container and is later removed.
Sometimes, after the cyst is drained, a drug is put through the catheter into the cyst. This causes the inside wall of the cyst to scar and stops the cyst from making fluid. Or it can slow down how long it takes for the fluid to build up again. Surgery to remove the tumor or radiation therapy may be done after the cyst is drained.
Radiation therapy
Radiation therapy uses high-energy x-rays or other types of radiation to kill tumor cells or keep them from growing. It is often given after surgery to kill any tumor that is left in the brain.
Both external radiation therapy and internal radiation therapy (also called brachytherapy) are used to treat craniopharyngiomas.
External radiation therapy uses a machine outside the body to send radiation toward the area of the body with the tumor.
Internal radiation therapy uses a radioactive substance sealed in needles, seeds, wires, or catheters that are placed directly into or near the tumor.
Radiation therapy to the brain can affect growth and development in young children, so ways of giving radiation therapy that have fewer side effects are often used. These include:
Stereotactic radiosurgery may be used for very small craniopharyngiomas at the base of the brain. For this treatment, a rigid head frame is attached to the skull to keep the head still during the treatment. Then, a machine aims a single large dose of radiation directly at the tumor. This procedure is a type of radiation therapy and does not involve surgery. It is also called stereotaxic radiosurgery, radiosurgery, and radiation surgery.
Intracavitary radiation therapy is a type of internal radiation therapy that may be used in tumors that are part solid mass and part fluid-filled cyst. For this treatment, radioactive material is placed inside the tumor. This type of radiation therapy causes less damage to the nearby hypothalamus and optic nerves.
Intensity-modulated photon therapy is a type of radiation therapy that uses x-rays or gamma rays that come from a special machine called a linear accelerator (linac) to kill tumor cells. A computer is used to target the exact shape and location of the tumor. Then thin beams of photons of different strengths are aimed at the tumor from many angles. This type of 3-dimensional radiation therapy may cause less damage to healthy tissue in the brain and other parts of the body.
Proton-beam radiation therapy is a type of radiation therapy that uses streams of protons (tiny particles with a positive charge) to kill tumor cells. This treatment can reduce the amount of radiation damage to healthy tissue near a tumor.
Chemotherapy (also called chemo) uses drugs to stop the growth of tumor cells. Chemotherapy either kills the tumor cells or stops them from dividing.
Chemotherapy can be placed directly into a cavity, such as a cyst. This way of giving chemotherapy is intracavitary chemotherapy. Bleomycin is a type of chemotherapy that can be placed directly into a cystic craniopharyngioma.
Observation means that your child’s condition is closely watched without receiving treatment until symptoms appear or change.
Clinical trials
For some children, joining a clinical trial may be an option. There are different types of clinical trials for childhood cancer. For example, a treatment trial tests new treatments or new ways of using current treatments. Supportive care and palliative care trials look at ways to improve quality of life, especially for those who have side effects from cancer and its treatment.
You can use the clinical trial search to find NCI-supported cancer clinical trials accepting participants. The search allows you to filter trials based on the type of cancer, your child’s age, and where the trials are being done. Clinical trials supported by other organizations can be found on the ClinicalTrials.gov website.
Treatment of newly diagnosed childhood craniopharyngioma
Treatment of newly diagnosed childhood craniopharyngioma may include:
complete removal of the tumor with surgery with or without radiation therapy
partial removal of the tumor with surgery followed by radiation therapy
cyst drainage, followed by observation, radiation therapy, or surgery
brachytherapy or chemotherapy placed directly in the cyst or tumor
Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.
Treatment of progressive or recurrent childhood craniopharyngioma
Treatment options for progressive or recurrent childhood craniopharyngioma depend on the type of treatment that your child received when the tumor was first diagnosed and your child’s needs.
Treatment may include:
surgery
external-beam radiation therapy
brachytherapy or intracavitary chemotherapy
observation
Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.
Prognostic factors for childhood craniopharyngioma
If your child has been diagnosed with craniopharyngioma, you likely have questions about how serious the tumor is and your child’s chances of survival. The likely outcome or course of a disease is called prognosis.
The prognosis depends on:
the size of the tumor
where the tumor is in the brain
whether there are tumor cells left after surgery
your child’s age
side effects that may occur months or years after treatment
whether the tumor has just been diagnosed or has recurred (come back)
No two people are alike, and responses to treatment can vary greatly. While the prognosis for childhood craniopharyngioma is generally good, the tumor often comes back after surgery. Your child’s treatment team is in the best position to talk with you about your child’s prognosis.
Side effects and late effects of treatment
Cancer treatments used for craniopharyngioma can cause side effects. Which side effects your child might have depends on the type of treatment they receive, the dose, and how their body reacts. Talk with your child’s treatment team about which side effects to look for and ways to manage them.
Problems from treatment that begin 6 months or later after treatment and continue for months or years are called late effects. Late effects of treatment may include:
changes in mood, feelings, thinking, learning, or memory
second cancers (new types of cancer)
Serious physical problems may occur if the pituitary gland, hypothalamus, optic nerves, or carotid artery are affected during surgery or radiation therapy. These problems include:
Some late effects may be treated or controlled. Your child may need life-long hormone replacement therapy with several medicines. It is important to talk with your child’s doctors about the effects treatment can have on your child. Learn more about Late Effects of Treatment for Childhood Cancer.
Follow-up care
Some of the tests that were done to diagnose the disease or decide how to treat it may be repeated. Some tests will be repeated in order 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 child’s condition has changed. These tests are sometimes called follow-up tests or check-ups.
After treatment, follow-up testing with MRI will be done for several years to check if the tumor has come back.
Coping with your child's diagnosis
When your child has a tumor, every member of the family needs support. Taking care of yourself during this difficult time is important. Reach out to your child’s treatment team and to people in your family and community for support. To learn more, visit Support for Families When a Child Has Cancer and the booklet Children with Cancer: A Guide for Parents.
Related resources
For more childhood cancer information and other general cancer resources, visit:
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 childhood craniopharyngioma. It is meant to inform and help patients, families, and caregivers. It does not give formal guidelines or recommendations for making decisions about health care.
Reviewers and Updates
Editorial Boards write the PDQ cancer information summaries and keep them up to date. These Boards are made up of experts in cancer treatment and other specialties related to cancer. The summaries are reviewed regularly and changes are made when there is new information. The date on each summary (“Updated”) is the date of the most recent change.
The information in this patient summary was taken from the health professional version, which is reviewed regularly and updated as needed, by the PDQ Pediatric Treatment Editorial Board.
Clinical Trial Information
A clinical trial is a study to answer a scientific question, such as whether one treatment is better than another. Trials are based on past studies and what has been learned in the laboratory. Each trial answers certain scientific questions in order to find new and better ways to help cancer patients. During treatment clinical trials, information is collected about the effects of a new treatment and how well it works. If a clinical trial shows that a new treatment is better than one currently being used, the new treatment may become “standard.” Patients may want to think about taking part in a clinical trial. Some clinical trials are open only to patients who have not started treatment.
Clinical trials can be found online at NCI’s website. For more information, call the Cancer Information Service (CIS), NCI’s contact center, at 1-800-4-CANCER (1-800-422-6237).
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PDQ® Pediatric Treatment Editorial Board. PDQ Childhood Craniopharyngioma. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/brain/patient/child-cranio-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389237]
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Brain tumors account for 85% to 90% of all primary central nervous system (CNS) tumors.[1] Estimated new cases and deaths from brain tumors and other nervous system tumors in the United States in 2025:[2]
New cases: 24,820.
Deaths: 18,330.
Data from the Surveillance, Epidemiology, and End Results (SEER) Program database for 2017 to 2021 indicated that the combined incidence of brain and other CNS tumors in the United States was 6.2 cases per 100,000 people per year. The mortality rate was 4.4 deaths per 100,000 people per year based on age-adjusted deaths from 2018 to 2022.[3] Worldwide, approximately 321,476 new cases of brain and other CNS tumors were diagnosed in the year 2022, with an estimated 248,305 deaths.[4]
In general, the incidence of primary CNS tumors is higher in White individuals than in Black individuals, and mortality is higher in men than in women.[3]
Primary brain tumors include the following in decreasing order of frequency:[1]
Anaplastic astrocytomas and glioblastomas (38% of primary brain tumors).
Meningiomas and other mesenchymal tumors (27% of primary brain tumors).
Pituitary tumors.
Schwannomas.
CNS lymphomas.
Oligodendrogliomas.
Ependymomas.
Low-grade astrocytomas.
Medulloblastomas.
Primary spinal tumors include the following in decreasing order of frequency:
Schwannomas, meningiomas, and ependymomas (79% of primary spinal tumors).
Sarcomas.
Astrocytomas.
Vascular tumors.
Chordomas.
Primary brain tumors rarely spread to other areas of the body, but they can spread to other parts of the brain and to the spinal axis.
Anatomy
EnlargeAnatomy of the inside of the brain. The supratentorium contains the cerebrum, ventricles (with cerebrospinal fluid shown in blue), choroid plexus, hypothalamus, pineal gland, pituitary gland, and optic nerve. The infratentorium contains the cerebellum and brain stem.
Risk Factors
Few definitive observations have been made about environmental or occupational causes of primary CNS tumors.[1]
The following potential risk factors have been considered:
Exposure to vinyl chloride may be a risk factor for glioma.
Epstein-Barr virus infection has been implicated in the etiology of primary CNS lymphoma.
The following familial tumor syndromes and related chromosomal abnormalities are associated with CNS neoplasms:[6,7]
Neurofibromatosis type 1 (17q11).
Neurofibromatosis type 2 (22q12).
von Hippel-Lindau disease (3p25-26).
Tuberous sclerosis (9q34, 16p13).
Li-Fraumeni syndrome (17p13).
Turcot syndrome type 1 (3p21, 7p22).
Turcot syndrome type 2 (5q21).
Nevoid basal cell carcinoma syndrome (9q22.3).
Clinical Features
The clinical presentation of various brain tumors is best appreciated by considering the relationship of signs and symptoms to anatomy.[1]
General signs and symptoms include:
Headaches.
Seizures.
Visual changes.
Gastrointestinal symptoms such as loss of appetite, nausea, and vomiting.
Changes in personality, mood, mental capacity, and concentration.
Seizures are a presenting symptom in approximately 20% of patients with supratentorial brain tumors and may antedate the clinical diagnosis by months to years in patients with slow-growing tumors. Among all patients with brain tumors, 70% with primary parenchymal tumors and 40% with metastatic brain tumors develop seizures at some time during the clinical course.[8]
Diagnostic Evaluation
All brain tumors, whether primary, metastatic, malignant, or benign, must be differentiated from other space-occupying lesions that can have similar clinical presentations, such as abscesses, arteriovenous malformations, and infarctions.[9]
Imaging tests
Contrast-enhanced computed tomography (CT) and magnetic resonance imaging (MRI) have complementary roles in the diagnosis of CNS neoplasms.[1,9,10]
The speed of CT is desirable for evaluating clinically unstable patients. CT is superior for detecting calcifications, skull lesions, and hyperacute hemorrhages (bleeding less than 24 hours old) and helps direct differential diagnosis and immediate management.
MRI has superior soft-tissue resolution. MRI can better detect isodense lesions, tumor enhancements, and associated findings such as edema, all phases of hemorrhagic states (except hyperacute), and infarctions. High-quality MRI is the diagnostic study of choice in the evaluation of intramedullary and extramedullary spinal cord lesions.[1]
In posttherapy imaging, single-photon emission computed tomography (SPECT) and positron emission tomography (PET) may be useful in differentiating tumor recurrence from radiation necrosis.[9]
Biopsy
Biopsy confirmation to corroborate the suspected diagnosis of a primary brain tumor is critical, whether before surgery by needle biopsy or at the time of surgical resection. The exception is cases in which the clinical and radiological evidence clearly points to a benign tumor, which could potentially be managed with active surveillance without biopsy or treatment. For other cases, radiological patterns may be misleading, and a definitive biopsy is needed to rule out other causes of space-occupying lesions, such as metastatic cancer or infection.
CT- or MRI-guided stereotactic techniques can be used to place a needle safely and accurately into almost all locations in the brain.
Prognostic Factors
Several genetic alterations have emerged as powerful prognostic factors in diffuse glioma (astrocytoma, oligodendroglioma, mixed glioma, and glioblastoma), and these alterations may guide patient management. Specific alterations include:
DNA methylation of the MGMT gene promoter.
IDH1 or IDH2 variants.
Codeletion of chromosomes 1p and 19q.
Other prognostic factors that confer poor prognosis include:[11,12]
Age older than 40 years.
Progressive disease.
Tumor size larger than 5 cm.
Tumor crossing the midline.
Contrast enhancement on MRI.
World Health Organization performance status (≥1).
Neurological symptoms.
Less than a gross total resection.
An exploratory analysis of 318 patients with low-grade glioma treated with either radiation therapy alone or temozolomide chemotherapy alone reported the following results for patients with a combination of these prognostic factors:[11]
Progression-free survival (PFS) was prolonged in patients with IDH variants without codeletion of 1p/19q when treated with radiation therapy (hazard ratio, 1.86; 95% confidence interval, 1.21–2.87; log-rank P = .0043).
There were no significant treatment-dependent differences in PFS for patients with IDH variants with codeletion of 1p/19q and IDH wild-type tumors.
Patients with wild-type IDH tumors had the worst prognosis independent of treatment type.
Patients with IDH variants with codeletion of 1p/19q had the best prognosis.
The O6-methylguanine-DNA methyltransferase (MGMT) promoter status in low-grade tumors was methylated in:
All IDH variants with codeletion of 1p/19q (45/45).
Most, but not all (86%, 62/72), of the IDH variants without codeletion of 1p/19q.
Fifty-six percent (5/9) of the IDH wild-type cases.
Mehta M, Vogelbaum MA, Chang S, et al.: Neoplasms of the central nervous system. In: DeVita VT Jr, Lawrence TS, Rosenberg SA: Cancer: Principles and Practice of Oncology. 9th ed. Lippincott Williams & Wilkins, 2011, pp 1700-49.
American Cancer Society: Cancer Facts and Figures 2025. American Cancer Society, 2025. Available online. Last accessed January 16, 2025.
National Cancer Institute: SEER Cancer Stat Facts: Brain and Other Nervous System Cancer. Bethesda, Md: National Cancer Institute. Available online. Last accessed January 24, 2025.
Bray F, Laversanne M, Sung H, et al.: Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 74 (3): 229-263, 2024. [PUBMED Abstract]
Hutter A, Schwetye KE, Bierhals AJ, et al.: Brain neoplasms: epidemiology, diagnosis, and prospects for cost-effective imaging. Neuroimaging Clin N Am 13 (2): 237-50, x-xi, 2003. [PUBMED Abstract]
Ricci PE: Imaging of adult brain tumors. Neuroimaging Clin N Am 9 (4): 651-69, 1999. [PUBMED Abstract]
Baumert BG, Hegi ME, van den Bent MJ, et al.: Temozolomide chemotherapy versus radiotherapy in high-risk low-grade glioma (EORTC 22033-26033): a randomised, open-label, phase 3 intergroup study. Lancet Oncol 17 (11): 1521-1532, 2016. [PUBMED Abstract]
Reijneveld JC, Taphoorn MJ, Coens C, et al.: Health-related quality of life in patients with high-risk low-grade glioma (EORTC 22033-26033): a randomised, open-label, phase 3 intergroup study. Lancet Oncol 17 (11): 1533-1542, 2016. [PUBMED Abstract]
World Health Organization (WHO) Classification of Primary CNS Tumors
This classification is based on the World Health Organization (WHO) classification of central nervous system (CNS) tumors.[1] The WHO approach incorporates and interrelates morphology, cytogenetics, molecular genetics, and immunological markers in an attempt to construct a cellular classification that is universally applicable and prognostically valid. Earlier attempts to develop a TNM (tumor, node, metastasis)-based classification were dropped for the following reasons:[2]
Tumor size (T) is less relevant than are tumor histology and location.
Nodal status (N) does not apply because the brain and spinal cord have no lymphatics.
Metastatic spread (M) rarely applies because most patients with CNS neoplasms do not live long enough to develop metastatic disease.
The WHO grading of CNS tumors establishes a malignancy scale based on histological features of the tumor.[3]
WHO grade I includes lesions with low proliferative potential, a frequently discrete nature, and the possibility of cure following surgical resection alone.
WHO grade II includes lesions that are generally infiltrating and low in mitotic activity but recur more frequently than do grade I malignant tumors after local therapy. Some tumor types tend to progress to higher grades of malignancy.
WHO grade III includes lesions with histological evidence of malignancy, including nuclear atypia and increased mitotic activity. These lesions have anaplastic histology and infiltrative capacity. They are usually treated with aggressive adjuvant therapy.
WHO grade IV includes lesions that are mitotically active, necrosis prone, and generally associated with a rapid preoperative and postoperative progression and fatal outcomes. The lesions are usually treated with aggressive adjuvant therapy.
Table 1 lists the tumor types and grades.[4] Tumors limited to the peripheral nervous system are not included. Histopathology, grading methods, incidence, and what is known about etiology specific to each tumor type have been described in detail elsewhere.[4,5]
Table 1. WHO Grades of CNS Tumorsa
I
II
III
IV
aReprinted with permission from Louis, DN, Ohgaki H, Wiestler, OD, Cavenee, WK. World Health Organization Classification of Tumours of the Central Nervous System. IARC, Lyon, 2007.
Astrocytic tumors
Subependymal giant cell astrocytoma
X
Pilocytic astrocytoma
X
Pilomyxoid astrocytoma
X
Diffuse astrocytoma
X
Pleomorphic xanthoastrocytoma
X
Anaplastic astrocytoma
X
Glioblastoma
X
Giant cell glioblastoma
X
Gliosarcoma
X
Oligodendroglial tumors
Oligodendroglioma
X
Anaplastic oligodendroglioma
X
Oligoastrocytic tumors
Oligoastrocytoma
X
Anaplastic oligoastrocytoma
X
Ependymal tumors
Subependymoma
X
Myxopapillary ependymoma
X
Ependymoma
X
Anaplastic ependymoma
X
Choroid plexus tumors
Choroid plexus papilloma
X
Atypical choroid plexus papilloma
X
Choroid plexus carcinoma
X
Other neuroepithelial tumors
Angiocentric glioma
X
Chordoid glioma of the third ventricle
X
Neuronal and mixed neuronal-glial tumors
Gangliocytoma
X
Ganglioglioma
X
Anaplastic ganglioma
X
Desmoplastic infantile astrocytoma and ganglioglioma
X
Dysembryoplastic neuroepithelial tumor
X
Central neurocytoma
X
Extraventricular neurocytoma
X
Cerebellar liponeurocytoma
X
Paraganglioma of the spinal cord
X
Papillary glioneuronal tumor
X
Rosette-forming glioneural tumor of the fourth ventricle
X
Pineal tumors
Pineocytoma
X
Pineal parenchymal tumor of intermediate differentiation
X
X
Pineoblastoma
X
Papillary tumor of the pineal region
X
X
Embryonal tumors
Medulloblastoma
X
CNS primitive neuroectodermal tumor
X
Atypical teratoid/rhabdoid tumor
X
Tumors of the cranial and paraspinal nerves
Schwannoma
X
Neurofibroma
X
Perineurioma
X
X
X
Malignant peripheral nerve sheath tumor
X
X
X
Meningeal tumors
Meningioma
X
Atypical meningioma
X
Anaplastic/malignant meningioma
X
Hemangiopericytoma
X
Anaplastic hemangiopericytoma
X
Hemangioblastoma
X
Tumors of the sellar region
Craniopharyngioma
X
Granular cell tumor of the neurohypophysis
X
Pituicytoma
X
Spindle cell oncocytoma of the adenohypophysis
X
Genomic Alterations
Alterations in the BRAF, IDH1, and IDH2 genes, and genomic 1p/19q codeletion, appear to be hallmark aberrations in particular glioma subtypes. Assessment for the presence of these variants aids diagnosis and prognosis and, with regard to 1p/19q codeletion, predicts for response to chemotherapy.
In pilocytic astrocytomas (WHO grade I), tandem duplication at 7q34 leading to a KIAA1549::BRAF gene fusion is found in approximately 70% of pilocytic astrocytomas.[6–8] Activating single nucleotide variants in BRAF (V600E) are found in an additional 5% to 9% of these tumors. Overall, RAF alterations occur in approximately 80% of pilocytic astrocytomas.
BRAF V600E variants are observed (in about 60%) of other benign gliomas, including pleomorphic xanthoastrocytoma and ganglioglioma, while BRAF tandem duplications are not found in these variant glioma tumors.[9–11]
Most WHO grade II and III diffuse gliomas (astrocytomas, oligodendrogliomas, and oligoastrocytomas) and 5% to 10% of glioblastomas (WHO grade IV) harbor single nucleotide variants in the R132 position of IDH1 or, rarely, the analogous codon in IDH2 (R172).[12–16] The presence of an IDH1 or IDH2 variant is a strong prognostic factor. Patients with these tumor variants have significantly longer survival independent of WHO grade or histological subtype.
Deletion of chromosomes 1p and 19q occurs through a translocation event [17] and is common in oligodendrogliomas. 1p/19q codeletion is a powerful prognostic factor and may predict for response to chemotherapy. For more information, see the Anaplastic oligodendrogliomas treatment section.
These genetic alterations have potential diagnostic utility. Presence of the IDH1 and IDH2 variants may distinguish diffuse gliomas from other gliomas, which often have BRAF genetic alterations, and nonneoplastic reactive astrocytosis.[18] Most (90%) IDH variants in gliomas result in an R132H substitution, which can be detected with a highly sensitive and specific monoclonal antibody. A rapid immunohistochemical analysis using the variant-specific IDH1 antibody can aid diagnostic analysis.[19]
Other CNS tumors are associated with characteristic patterns of altered oncogenes, altered tumor suppressor genes, and chromosomal abnormalities. Familial tumor syndromes with defined chromosomal abnormalities are associated with gliomas.
References
Kleihues P, Cavenee WK, eds.: Pathology and Genetics of Tumours of the Nervous System. International Agency for Research on Cancer, 2000.
Brain and Spinal Cord. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. Springer; 2017, pp. 857–69.
Kleihues P, Burger PC, Scheithauer BW: The new WHO classification of brain tumours. Brain Pathol 3 (3): 255-68, 1993. [PUBMED Abstract]
Louis DN, Ohgaki H, Wiestler OD, et al.: The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 114 (2): 97-109, 2007. [PUBMED Abstract]
Louis DN, Ohgaki H, Wiestler OD, et al., eds.: WHO Classification of Tumours of the Central Nervous System. 4th ed. IARC Press, 2007.
Sievert AJ, Jackson EM, Gai X, et al.: Duplication of 7q34 in pediatric low-grade astrocytomas detected by high-density single-nucleotide polymorphism-based genotype arrays results in a novel BRAF fusion gene. Brain Pathol 19 (3): 449-58, 2009. [PUBMED Abstract]
Pfister S, Janzarik WG, Remke M, et al.: BRAF gene duplication constitutes a mechanism of MAPK pathway activation in low-grade astrocytomas. J Clin Invest 118 (5): 1739-49, 2008. [PUBMED Abstract]
Jones DT, Kocialkowski S, Liu L, et al.: Tandem duplication producing a novel oncogenic BRAF fusion gene defines the majority of pilocytic astrocytomas. Cancer Res 68 (21): 8673-7, 2008. [PUBMED Abstract]
Dias-Santagata D, Lam Q, Vernovsky K, et al.: BRAF V600E mutations are common in pleomorphic xanthoastrocytoma: diagnostic and therapeutic implications. PLoS One 6 (3): e17948, 2011. [PUBMED Abstract]
MacConaill LE, Campbell CD, Kehoe SM, et al.: Profiling critical cancer gene mutations in clinical tumor samples. PLoS One 4 (11): e7887, 2009. [PUBMED Abstract]
Parsons DW, Jones S, Zhang X, et al.: An integrated genomic analysis of human glioblastoma multiforme. Science 321 (5897): 1807-12, 2008. [PUBMED Abstract]
Yan H, Parsons DW, Jin G, et al.: IDH1 and IDH2 mutations in gliomas. N Engl J Med 360 (8): 765-73, 2009. [PUBMED Abstract]
Dubbink HJ, Taal W, van Marion R, et al.: IDH1 mutations in low-grade astrocytomas predict survival but not response to temozolomide. Neurology 73 (21): 1792-5, 2009. [PUBMED Abstract]
Sanson M, Marie Y, Paris S, et al.: Isocitrate dehydrogenase 1 codon 132 mutation is an important prognostic biomarker in gliomas. J Clin Oncol 27 (25): 4150-4, 2009. [PUBMED Abstract]
Hartmann C, Hentschel B, Wick W, et al.: Patients with IDH1 wild type anaplastic astrocytomas exhibit worse prognosis than IDH1-mutated glioblastomas, and IDH1 mutation status accounts for the unfavorable prognostic effect of higher age: implications for classification of gliomas. Acta Neuropathol 120 (6): 707-18, 2010. [PUBMED Abstract]
Hartmann C, Meyer J, Balss J, et al.: Type and frequency of IDH1 and IDH2 mutations are related to astrocytic and oligodendroglial differentiation and age: a study of 1,010 diffuse gliomas. Acta Neuropathol 118 (4): 469-74, 2009. [PUBMED Abstract]
Jenkins RB, Blair H, Ballman KV, et al.: A t(1;19)(q10;p10) mediates the combined deletions of 1p and 19q and predicts a better prognosis of patients with oligodendroglioma. Cancer Res 66 (20): 9852-61, 2006. [PUBMED Abstract]
Camelo-Piragua S, Jansen M, Ganguly A, et al.: A sensitive and specific diagnostic panel to distinguish diffuse astrocytoma from astrocytosis: chromosome 7 gain with mutant isocitrate dehydrogenase 1 and p53. J Neuropathol Exp Neurol 70 (2): 110-5, 2011. [PUBMED Abstract]
Capper D, Weissert S, Balss J, et al.: Characterization of R132H mutation-specific IDH1 antibody binding in brain tumors. Brain Pathol 20 (1): 245-54, 2010. [PUBMED Abstract]
Treatment Option Overview for Primary CNS Tumors
Primary CNS Tumors
This section discusses general treatment modalities for primary central nervous system (CNS) tumors. For a description of specific treatment options for each tumor type, see the Treatment of Primary CNS Tumors by Tumor Type section.
Radiation therapy and chemotherapy options vary according to histology and anatomical site of the CNS tumor. For glioblastoma, combined-modality therapy with resection, radiation, and chemotherapy is standard. Anaplastic astrocytomas, anaplastic oligodendrogliomas, and anaplastic oligoastrocytomas represent only a small proportion of CNS gliomas. Therefore, phase III randomized trials restricted to these tumor types are not generally practical. The natural histories of these tumors are variable, depending on histological and molecular factors; therefore, treatment guidelines for these tumors are evolving. Therapy involving surgically implanted carmustine-impregnated polymer wafers combined with postoperative external-beam radiation therapy (EBRT) may play a role in the treatment of high-grade (grades III and IV) gliomas in some patients.[1]
For most types of CNS tumors in most locations, complete or near-complete surgical removal is generally attempted, within the constraints of preserving neurological function and the patient’s underlying health. This practice is based on observational evidence that survival is better in patients who undergo tumor resection than in those who have closed biopsy alone.[2,3] The benefit of resection has not been tested in randomized trials. Selection bias can enter into observational studies despite attempts to adjust for patient differences that guide the decision to resect the tumor. Therefore, the actual difference in outcome between radical surgery and biopsy alone may not be as large as noted in the retrospective studies.[3]
An exception to the use of resection is the case of deep-seated tumors such as pontine gliomas, which are diagnosed on clinical evidence and treated without initial surgery approximately 50% of the time. In most cases, however, diagnosis by biopsy is preferred. Stereotactic biopsy can be used for lesions that are difficult to reach and resect.
The primary goals of surgical resection include:[4]
To establish a histological diagnosis.
To reduce intracranial pressure by removing as much tumor as is safely possible to preserve neurological function.
Total elimination of primary malignant intraparenchymal tumors by surgery alone is rarely achievable. Therefore, intraoperative techniques have been developed to reach a balance between removing as much tumor as is practical and preserving functional status. For example, craniotomies with stereotactic resections of primary gliomas can be performed in cooperative patients while they are awake, with real-time assessment of neurological function.[5] Examples of intraoperative neurological assessment include:
Resection proceeds until either the magnetic resonance imaging (MRI) signal abnormality being used to monitor the extent of surgery is completely removed or subtle neurological dysfunction appears (e.g., a slight decrease in rapid alternating motor movement or anomia).
When the tumor is located in or near language centers in the cortex, intraoperative language mapping can be performed by electrode discharge-induced speech arrest while the patient is asked to count or read.[6]
As is the case with several other specialized operations [7,8] in which postoperative mortality has been associated with the number of procedures performed, postoperative mortality after surgery for primary brain tumors may be associated with hospital and/or surgeon volume.[9] The following results were reported after an analysis of the Nationwide Inpatient Sample hospital discharge database for the years 1988 to 2000, which represented 20% of inpatient admissions to nonfederal U.S. hospitals:[9]
Large-volume hospitals had lower in-hospital mortality rates after craniotomies for primary brain tumors (odds ratio [OR], 0.75 for a tenfold higher caseload; 95% confidence interval [CI], 0.62–0.90) and after needle biopsies (OR, 0.54; 95% CI, 0.35–0.83).
Although there was no specific sharp threshold in all-cause mortality outcomes between low-volume hospitals and high-volume hospitals, craniotomy-associated in-hospital mortality was 4.5% for hospitals with 5 or fewer procedures per year and 1.5% for hospitals with at least 42 procedures per year.
In-hospital mortality rates decreased over the study years (perhaps because the proportion of elective nonemergent operations increased from 45% to 57%), but the decrease was more rapid in high-volume hospitals than in low-volume hospitals.
High-volume surgeons had lower in-hospital patient mortality rates after craniotomy (OR, 0.60; 95% CI, 0.45–0.79).
As with any study of volume-outcome associations, these results may not be causal because of residual confounding factors such as referral patterns, private insurance, and patient selection, despite multivariable adjustment.
Radiation therapy
High-grade tumors
Radiation therapy has a major role in the treatment of patients with high-grade gliomas.
A systematic review and meta-analysis of five randomized trials (plus one trial with allocation by birth date) comparing PORT with no radiation therapy showed a statistically significant survival advantage with radiation (risk ratio, 0.81; 95% CI, 0.74–0.88).[10][Level of evidence A1]
A randomized trial comparing 60 Gy (in 30 fractions over 6 weeks) with 45 Gy (in 25 fractions over 4 weeks) showed superior survival in the first group (12 months vs. 9 months median survival; hazard ratio [HR], 0.81; 95% CI, 0.66–0.99). The accepted standard dose of EBRT for malignant gliomas is 60 Gy.[11][Level of evidence A1]
EBRT using either 3-dimensional conformal radiation therapy (3D-CRT) or intensity-modulated radiation therapy (IMRT) is considered an acceptable technique in radiation therapy delivery. Typically used are 2- to 3-cm margins on the MRI-based volumes (T1-weighted and fluid-attenuated inversion recovery [FLAIR]) to create the planning target volume.
Dose escalation using radiosurgery has not improved outcomes. A randomized trial tested radiosurgery as a boost added to standard EBRT, but the trial found no improvement in survival, quality of life, or patterns of relapse compared with EBRT without the boost.[12,13]
Brachytherapy has been used to deliver high doses of radiation locally to the tumor while sparing normal brain tissue. However, this approach is technically demanding and is less common since the advent of 3D-CRT and IMRT.
Low-grade tumors
Treatment options for patients with low-grade gliomas (i.e., low-grade astrocytomas, oligodendrogliomas, and mixed oligoastrocytomas) are not as clear as in the case of high-grade tumors and include observation, PORT, and chemotherapy with temozolomide.
Evidence (PORT vs. observation):
The European Organisation for Research and Treatment of Cancer (EORTC) randomly assigned 311 patients with low-grade gliomas to undergo either radiation or observation in the EORTC-22845 trial.[14,15] On review of central pathology, about 25% of patients in the trial were reported to have high-grade tumors. Most of the control patients received radiation therapy at the time of progression.
After a median follow-up of 93 months, the median progression-free survival (PFS) was 5.3 years in the radiation arm versus 3.4 years in the control arm (HR, 0.59; 95% CI, 0.45–0.77).[14,15][Level of evidence B1]
There was no difference in the overall survival (OS). The median survival was 7.4 years in the radiation arm and 7.2 years in the control arm (HR, 0.97; 95% CI, 0.71–1.34; P = .87).[14,15][Level of evidence A1] This was caused by a longer survival after progression in the control arm (3.4 years) than in the radiation arm (1.0 year) (P < .0001).
The investigators did not collect reliable quality-of-life measurements, so it is not clear whether the delay in initial relapse in the radiation therapy arm translated into improved function or quality of life.
Evidence (PORT versus temozolomide for patients with low-grade World Health Organization [WHO] grade II tumors with at least one high-risk feature):
The EORTC 22033-26033 trial (NCT00182819) included 707 patients with low-grade glioma (WHO grade II astrocytoma, oligoastrocytoma, or oligodendroglioma) and at least one high-risk feature (age >40 years, progressive disease, tumor size >5 cm, tumor crossing the midline, or neurological symptoms). Patients were randomly assigned to receive either radiation therapy (n = 240) or temozolomide chemotherapy (n = 237). Radiation therapy consisted of conformal treatment (up to 50.4 Gy; 28 doses of 1.8 Gy daily, 5 days a week, for up to 6.5 weeks). Chemotherapy was dose-dense oral temozolomide (75 mg/m2 daily for 21 days, repeated every 28 days [one cycle], for a maximum of 12 cycles).[16,17]
There was no significant difference in PFS (primary end point) or health-related quality of life (secondary end point).
At a median follow-up of 48 months (interquartile range, 31–56), median PFS was 39 months (95% CI, 35–44) in the temozolomide group and 46 months (95% CI, 40–56) in the radiation therapy group (unadjusted HR, 1.16; 95% CI, 0.9–1.5; P = .22).[16][Level of evidence B1]
An exploratory analysis of 318 molecularly defined patients found that patients with IDH gene variants without codeletion of 1p/19q displayed a significantly longer PFS when treated with radiation therapy (HR, 1.86; 95% CI, 1.21–2.87; log-rank P = .0043).
There were no significant treatment-dependent differences in PFS for patients with IDH variants with codeletion of 1p/19q and IDH wild-type tumors.
Patients with wild-type IDH tumors had the worst prognosis independent of treatment type.
Patients with IDH variants with codeletion of 1p/19q had the best prognosis.
The O6-methylguanine-DNA methyltransferase (MGMT) promoter status was methylated in the following cases:
All IDH variants with codeletion of 1p/19q (45/45).
Sixty-two of 72 (86%) of the IDH variants without codeletion of 1p/19q.
Five of nine (56%) of the IDH wild-type cases.
Disease progression, subsequent neoplasms, or recurrences
There are no randomized trials to delineate the role of repeat radiation after disease progression or the development of radiation-induced cancers. The literature is limited to small retrospective case series, which makes interpretation difficult.[18] The decision to repeat radiation must be made carefully because of the risk of neurocognitive deficits and radiation-induced necrosis. One advantage of radiosurgery is the ability to deliver therapeutic doses to recurrent tumors that may require the re-irradiation of previously irradiated brain tissue beyond tolerable dose limits.
Chemotherapy
Systemic chemotherapy
For many years, the nitrosourea carmustine ([bis-chloroethylnitrosourea] BCNU) was the standard chemotherapy agent added to surgery and radiation therapy for malignant gliomas, based on the Radiation Therapy Oncology Group’s (RTOG’s) randomized trial (RTOG-8302).[19][Level of evidence A1] A modest impact on survival with the use of nitrosourea-containing chemotherapy regimens for malignant gliomas was confirmed in a patient-level meta-analysis of 12 randomized trials (combined HRdeath, 0.85; 95% CI, 0.78–0.91).[20]
A large multicenter trial (NCT00006353) of patients with glioblastoma, conducted by the EORTC-National Cancer Institute of Canada, reported a survival advantage with the use of temozolomide in addition to radiation therapy.[21,22][Level of evidence A1] Based on these results, the oral agent temozolomide has replaced BCNU as the standard systemic chemotherapy for malignant gliomas. For more information, see the Glioblastomas treatment section.
Long-term results of randomized trials in high-risk, low-grade (WHO grade II) gliomas [23][Level of evidence A1] and anaplastic (WHO grade III) oligodendroglial tumors [24,25][Level of evidence A1] have demonstrated that the addition of procarbazine, lomustine, and vincristine (PCV) chemotherapy to radiation therapy after surgery extends survival. Radiation and PCV chemotherapy should be considered for patients deemed appropriate for therapy. For more information, see the Treatment of Primary CNS Tumors by Tumor Type section.
Localized chemotherapy (carmustine wafer)
The ability to give high doses of chemotherapy while avoiding systemic toxicity is desirable because malignant glioma–related deaths are usually due to uncontrolled intracranial disease rather than distant metastases. A biodegradable carmustine wafer has been developed for that purpose. The wafers contain 3.85% carmustine, and up to eight wafers are implanted into the tumor bed lining at the time of open resection, with an intended total dose of about 7.7 mg per wafer (61.6 mg maximum per patient) over a period of 2 to 3 weeks.
Two randomized placebo-controlled trials of this focal drug-delivery method have shown an OS advantage associated with the carmustine wafers versus radiation therapy alone. In both trials, the upper age limit for patients was 65 years.
Evidence (carmustine wafer):
A small trial was closed because of a lack of continued availability of the carmustine wafers after 32 patients with high-grade gliomas had been entered.[26]
Although OS was better in the carmustine-wafer group (median 58.1 vs. 39.9 weeks; P = .012), there was an imbalance in the study arms (only 11 of 16 patients in the carmustine-wafer group vs. 16 of the 16 patients in the placebo-wafer group had grade IV glioblastoma tumors).
A multicenter study of 240 patients with primary malignant gliomas, 207 of whom had glioblastoma, was more informative.[27,28] At initial surgery, patients received either carmustine wafers or placebo wafers, followed by radiation therapy (55–60 Gy). Systemic therapy was not allowed until recurrence, except in the case of anaplastic oligodendrogliomas (n = 9). Unlike the initial trial, patient characteristics were well balanced between the study arms.
Median survival in the two groups was 13.8 months in patients treated with carmustine wafers versus 11.6 months in placebo-treated patients (HR, 0.73; 95% CI, 0.56–0.96; P = .017).
A systematic review combining both studies [26–28] estimated an HR for overall mortality of 0.65; 95% CI, 0.48–0.86; P = .003.[29][Level of evidence A1]
Active surveillance
Active surveillance is appropriate in some circumstances. With the increasing use of sensitive neuroimaging tools, detection of asymptomatic low-grade meningiomas has increased; most appear to show minimal growth and can often be safely observed, with therapy deferred until the detection of tumor growth or the development of symptoms.[30,31]
Supportive therapy
Dexamethasone, mannitol, and furosemide are used to treat the peritumoral edema associated with brain tumors. The use of anticonvulsants is mandatory for patients with seizures.[4]
References
Lallana EC, Abrey LE: Update on the therapeutic approaches to brain tumors. Expert Rev Anticancer Ther 3 (5): 655-70, 2003. [PUBMED Abstract]
Laws ER, Parney IF, Huang W, et al.: Survival following surgery and prognostic factors for recently diagnosed malignant glioma: data from the Glioma Outcomes Project. J Neurosurg 99 (3): 467-73, 2003. [PUBMED Abstract]
Chang SM, Parney IF, Huang W, et al.: Patterns of care for adults with newly diagnosed malignant glioma. JAMA 293 (5): 557-64, 2005. [PUBMED Abstract]
Meyer FB, Bates LM, Goerss SJ, et al.: Awake craniotomy for aggressive resection of primary gliomas located in eloquent brain. Mayo Clin Proc 76 (7): 677-87, 2001. [PUBMED Abstract]
Sanai N, Mirzadeh Z, Berger MS: Functional outcome after language mapping for glioma resection. N Engl J Med 358 (1): 18-27, 2008. [PUBMED Abstract]
Begg CB, Cramer LD, Hoskins WJ, et al.: Impact of hospital volume on operative mortality for major cancer surgery. JAMA 280 (20): 1747-51, 1998. [PUBMED Abstract]
Birkmeyer JD, Finlayson EV, Birkmeyer CM: Volume standards for high-risk surgical procedures: potential benefits of the Leapfrog initiative. Surgery 130 (3): 415-22, 2001. [PUBMED Abstract]
Barker FG, Curry WT, Carter BS: Surgery for primary supratentorial brain tumors in the United States, 1988 to 2000: the effect of provider caseload and centralization of care. Neuro Oncol 7 (1): 49-63, 2005. [PUBMED Abstract]
Laperriere N, Zuraw L, Cairncross G, et al.: Radiotherapy for newly diagnosed malignant glioma in adults: a systematic review. Radiother Oncol 64 (3): 259-73, 2002. [PUBMED Abstract]
Bleehen NM, Stenning SP: A Medical Research Council trial of two radiotherapy doses in the treatment of grades 3 and 4 astrocytoma. The Medical Research Council Brain Tumour Working Party. Br J Cancer 64 (4): 769-74, 1991. [PUBMED Abstract]
Tsao MN, Mehta MP, Whelan TJ, et al.: The American Society for Therapeutic Radiology and Oncology (ASTRO) evidence-based review of the role of radiosurgery for malignant glioma. Int J Radiat Oncol Biol Phys 63 (1): 47-55, 2005. [PUBMED Abstract]
Souhami L, Seiferheld W, Brachman D, et al.: Randomized comparison of stereotactic radiosurgery followed by conventional radiotherapy with carmustine to conventional radiotherapy with carmustine for patients with glioblastoma multiforme: report of Radiation Therapy Oncology Group 93-05 protocol. Int J Radiat Oncol Biol Phys 60 (3): 853-60, 2004. [PUBMED Abstract]
Karim AB, Afra D, Cornu P, et al.: Randomized trial on the efficacy of radiotherapy for cerebral low-grade glioma in the adult: European Organization for Research and Treatment of Cancer Study 22845 with the Medical Research Council study BRO4: an interim analysis. Int J Radiat Oncol Biol Phys 52 (2): 316-24, 2002. [PUBMED Abstract]
van den Bent MJ, Afra D, de Witte O, et al.: Long-term efficacy of early versus delayed radiotherapy for low-grade astrocytoma and oligodendroglioma in adults: the EORTC 22845 randomised trial. Lancet 366 (9490): 985-90, 2005. [PUBMED Abstract]
Baumert BG, Hegi ME, van den Bent MJ, et al.: Temozolomide chemotherapy versus radiotherapy in high-risk low-grade glioma (EORTC 22033-26033): a randomised, open-label, phase 3 intergroup study. Lancet Oncol 17 (11): 1521-1532, 2016. [PUBMED Abstract]
Reijneveld JC, Taphoorn MJ, Coens C, et al.: Health-related quality of life in patients with high-risk low-grade glioma (EORTC 22033-26033): a randomised, open-label, phase 3 intergroup study. Lancet Oncol 17 (11): 1533-1542, 2016. [PUBMED Abstract]
Paulino AC, Mai WY, Chintagumpala M, et al.: Radiation-induced malignant gliomas: is there a role for reirradiation? Int J Radiat Oncol Biol Phys 71 (5): 1381-7, 2008. [PUBMED Abstract]
Walker MD, Green SB, Byar DP, et al.: Randomized comparisons of radiotherapy and nitrosoureas for the treatment of malignant glioma after surgery. N Engl J Med 303 (23): 1323-9, 1980. [PUBMED Abstract]
Stewart LA: Chemotherapy in adult high-grade glioma: a systematic review and meta-analysis of individual patient data from 12 randomised trials. Lancet 359 (9311): 1011-8, 2002. [PUBMED Abstract]
Stupp R, Mason WP, van den Bent MJ, et al.: Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352 (10): 987-96, 2005. [PUBMED Abstract]
Stupp R, Hegi ME, Mason WP, et al.: Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 10 (5): 459-66, 2009. [PUBMED Abstract]
Buckner JC, Pugh SL, Shaw EG, et al.: Phase III study of radiation therapy with or without procarbazine, CCNU, and vincristine (PCV) in low-grade glioma: RTOG 9802 with Alliance, ECOG, and SWOG. [Abstract] J Clin Oncol 32 (Suppl 5): A-2000, 2014.
van den Bent MJ, Brandes AA, Taphoorn MJ, et al.: Adjuvant procarbazine, lomustine, and vincristine chemotherapy in newly diagnosed anaplastic oligodendroglioma: long-term follow-up of EORTC brain tumor group study 26951. J Clin Oncol 31 (3): 344-50, 2013. [PUBMED Abstract]
Cairncross G, Wang M, Shaw E, et al.: Phase III trial of chemoradiotherapy for anaplastic oligodendroglioma: long-term results of RTOG 9402. J Clin Oncol 31 (3): 337-43, 2013. [PUBMED Abstract]
Valtonen S, Timonen U, Toivanen P, et al.: Interstitial chemotherapy with carmustine-loaded polymers for high-grade gliomas: a randomized double-blind study. Neurosurgery 41 (1): 44-8; discussion 48-9, 1997. [PUBMED Abstract]
Westphal M, Hilt DC, Bortey E, et al.: A phase 3 trial of local chemotherapy with biodegradable carmustine (BCNU) wafers (Gliadel wafers) in patients with primary malignant glioma. Neuro-oncol 5 (2): 79-88, 2003. [PUBMED Abstract]
Westphal M, Ram Z, Riddle V, et al.: Gliadel wafer in initial surgery for malignant glioma: long-term follow-up of a multicenter controlled trial. Acta Neurochir (Wien) 148 (3): 269-75; discussion 275, 2006. [PUBMED Abstract]
Hart MG, Grant R, Garside R, et al.: Chemotherapeutic wafers for high grade glioma. Cochrane Database Syst Rev (3): CD007294, 2008. [PUBMED Abstract]
Nakamura M, Roser F, Michel J, et al.: The natural history of incidental meningiomas. Neurosurgery 53 (1): 62-70; discussion 70-1, 2003. [PUBMED Abstract]
Yano S, Kuratsu J; Kumamoto Brain Tumor Research Group: Indications for surgery in patients with asymptomatic meningiomas based on an extensive experience. J Neurosurg 105 (4): 538-43, 2006. [PUBMED Abstract]
Treatment of Primary CNS Tumors by Tumor Type
Table 2. Treatment of Primary Central Nervous System Tumors by Tumor Type
Patients with brain stem gliomas have relatively poor prognoses that correlate with histology (when biopsies are performed), location, and extent of tumor. The overall median survival time of patients in studies has been 44 to 74 weeks.
Treatment options for brain stem gliomas include:
Radiation therapy.
Pineal astrocytic tumors treatment
Depending on the degree of anaplasia, patients with pineal astrocytomas have variable prognoses. Patients with higher-grade tumors have worse prognoses.
Treatment options for pineal astrocytic tumors include:
Surgery plus radiation therapy for pineal astrocytoma.
Surgery plus radiation therapy and chemotherapy for higher-grade tumors.
Pilocytic astrocytomas treatment
This astrocytic tumor is classified as a World Health Organization (WHO) grade I tumor and is often curable.
Treatment options for pilocytic astrocytomas include:
Surgery alone if the tumor is totally resectable.
Surgery followed by radiation therapy to known or suspected residual tumor.
Diffuse astrocytomas treatment
This WHO grade II astrocytic tumor is less often curable than is a pilocytic astrocytoma.
Treatment options for diffuse astrocytomas (WHO grade II) include:
Surgery with or without radiation therapy.
Surgery followed by radiation therapy and chemotherapy.
Controversy exists about the timing of radiation therapy after surgery. For more information, see the Low-grade tumors section.
Radiation therapy improved progression-free survival (PFS) in patients who received early radiation therapy in the European Organisation for Research and Treatment of Cancer (EORTC) EORTC-22845 trial. For more information, see the Oligodendrogliomas treatment section.[1][Level of evidence A1]
In the same trial, there was no difference in overall survival (OS) between patients who had radiation therapy after surgery and those who were treated with radiation therapy at the time of progression.[1][Level of evidence A1]
Some physicians use surgery alone if a patient has clinical factors that are considered low risk, such as age younger than 40 years and the lack of contrast enhancement on a computed tomography scan.[2]
Evidence (surgery followed by radiation therapy and chemotherapy):
For patients with low-grade (WHO grade II) tumors, which are considered high risk, radiation therapy followed by six cycles of vincristine (PCV) chemotherapy is a recommended option. This recommendation is based on the long-term follow-up results of the Radiation Therapy Oncology Group’s (RTOG’s) 1986-initiated randomized trial (RTOG 9802 [NCT00003375]).[3][Level of evidence A1] In this trial, patients with high-risk, low-grade glioma, defined as patients aged 18 to 39 years with biopsy or subtotal resection, or patients aged 40 years or older, were randomly assigned to either 54 Gy of radiation therapy or radiation therapy followed by six cycles of PCV chemotherapy.
The addition of PCV to radiation therapy increased median PFS from 4.0 years to 10.4 years (hazard ratio [HR], 0.50; P = .002) and median OS from 7.8 years to 13.3 years (HR, 0.59; P = .03).
Notably, the RTOG 9802 study enrolled patients with a variety of tumors, including astrocytomas, oligodendrogliomas, and mixed oligoastrocytomas.
In a risk-adjusted multivariate analysis, patients treated with PCV and patients with an oligodendroglial histology had better survival outcomes. A subset analysis of histological type suggested that the addition of PCV mainly benefited patients with oligodendroglial tumors, although this data is yet to be validated.[4]
Median OS for PCV versus the control arm was not reached versus 10.8 years for oligodendrogliomas (P = .008), 11.4 years versus 5.9 years for oligoastrocytomas (P = .05), and 7.7 years versus 4.4 years for astrocytomas (P = .31).
The discovery of the IDH1 and IDH2 variants in diffuse gliomas has greatly helped to identify patients with high-risk disease. Large retrospective studies have demonstrated that IDH1 and IDH2 variants are powerful independent prognostic factors for improved survival.[5–9] Most WHO grade II and III gliomas harbor IDH1 and IDH2 variants,[6,10,11] and, therefore, those variants should be included in the assessment of high risk. Molecular correlative data from the RTOG 98-02 trial, which would be informative about which patients benefited the most from the addition of PCV, have not been reported.
Anaplastic astrocytomas treatment
Patients with anaplastic astrocytomas (WHO grade III) have a low cure rate with standard local treatment.
Treatment options for anaplastic astrocytomas include:
Surgery plus radiation therapy with or without chemotherapy.
Surgery plus chemotherapy.
A subset of anaplastic astrocytomas is aggressive; these tumors are frequently managed in the same way as glioblastomas, with surgery and radiation, and often with chemotherapy. However, the optimal treatment for these tumors is not established. Two phase III randomized trials restricted to patients with anaplastic gliomas (NCT00626990 and NCT00887146) are active, but efficacy data are not available. It is not known whether the improved survival of patients with chemotherapy-treated glioblastoma can be extrapolated to patients with anaplastic astrocytomas.
IDH1 and IDH2 variants are present in 50% to 70% of anaplastic astrocytomas and are independently associated with significantly improved survival.[6,9] Assessment of IDH1 and IDH2 variant status may guide decisions about treatment options.
Evidence (surgery plus radiation therapy or chemotherapy):
Postoperative radiation alone has been compared with postoperative chemotherapy alone in patients with anaplastic gliomas (i.e., 144 astrocytomas, 91 oligoastrocytomas, and 39 oligodendrogliomas), with crossover to the other modality at the time of tumor progression. Of the 139 patients randomly assigned to undergo radiation therapy, 135 were randomly assigned to receive chemotherapy, with a 32-week course of either PCV or single-agent temozolomide (2:1:1 randomization).[12][Levels of evidence A1 and B1]
The order of the modalities did not affect time-to-treatment failure (TTF) or OS.
Neither TTF nor OS differed across the treatment arms.
Patients with anaplastic astrocytomas are appropriate candidates for clinical trials designed to improve local control by adding newer forms of treatment to standard treatment. Information about ongoing clinical trials is available from the NCI website.
Glioblastomas treatment
For patients with glioblastoma (WHO grade IV), the cure rate is very low with standard local treatment.
Methylation of the promoter of the MGMT DNA repair enzyme gene is an independent prognostic factor for improved survival in newly diagnosed glioblastoma.[13,14] MGMT promoter methylation and concomitant inactivation of the DNA repair enzyme activities may also predict for response to temozolomide chemotherapy.[13] However, the clinical data that MGMT promoter methylation is a predictive marker is less certain.
Treatment options for patients with newly diagnosed glioblastoma include:
Surgery plus radiation therapy and chemotherapy.
Surgery plus radiation therapy.
Carmustine-impregnated polymer implanted during initial surgery.
Radiation therapy and concurrent chemotherapy.
The standard treatment for patients with newly diagnosed glioblastoma is surgery followed by concurrent radiation therapy and daily temozolomide, and then followed by six cycles of temozolomide. The addition of bevacizumab to radiation therapy and temozolomide did not improve OS.
Evidence (surgery plus radiation therapy and chemotherapy):
Standard therapy is based on a large, multicenter, randomized trial (NCT00006353) conducted by the EORTC and National Cancer Institute of Canada (NCIC). This trial reported a survival benefit with concurrent radiation therapy and temozolomide, compared with radiation therapy alone.[15,16][Level of evidence A1] In this study, 573 patients with glioblastoma were randomly assigned to receive standard radiation to the tumor volume with a 2- to 3-cm margin (60 Gy, 2 Gy per fraction, over 6 weeks) alone or with temozolomide (75 mg/m2 orally per day during radiation therapy for up to 49 days, followed by a 4-week break and then up to six cycles of five daily doses every 28 days at a dose of 150 mg/m2, increasing to 200 mg/m2 after the first cycle).
OS was statistically significantly better in the combined radiation therapy–temozolomide group (HRdeath, 0.6; 95% confidence interval [CI], 0.5–0.7; OS rate at 3 years was 16.0% for the radiation therapy–temozolomide group vs. 4.4% in the radiation therapy–alone group).
A companion molecular correlation subset study to the EORTC-NCIC trial provided strong evidence that epigenetic silencing of the MGMT DNA-repair gene by promoter DNA methylation was associated with increased OS in patients with newly diagnosed glioblastoma.[13]
MGMT promoter methylation was an independent favorable prognostic factor (HR, 0.45; 95% CI, 0.32–0.61; log-rank P < .001).
The median OS for patients with MGMT methylation was 18.2 months (95% CI, 15.5–22.0), compared with 12.2 months (95% CI, 11.4–13.5) for patients without MGMT methylation.
To test whether protracted (dose-dense) temozolomide enhances treatment response in patients with newly diagnosed glioblastoma, a multicenter, randomized, phase III trial conducted by the RTOG, EORTC, and the North Central Cancer Therapy Group, RTOG 0525 (NCT00304031), compared standard adjuvant temozolomide treatment (days 1–5 of a 28-day cycle) with a dose-dense schedule (days 1–21 of a 28-day cycle). All patients were treated with surgery followed by radiation therapy and concurrent daily temozolomide. Patients were then randomly assigned to receive either standard adjuvant temozolomide or dose-dense temozolomide.[14][Level of evidence A1]
Among 833 randomly assigned patients, no statistically significant difference between standard and dose-dense temozolomide was observed for median OS (16.6 months for standard temozolomide vs. 14.9 months for dose-dense temozolomide; HR, 1.03; P = .63) or for median PFS (5.5 vs. 6.7 months; HR, 0.87; P = .06).
Protracted temozolomide, which depletes intracellular MGMT, was predicted to have greater efficacy in tumors with MGMT-promoter methylation. To test this retrospectively, MGMT status was determined in 86% of randomly assigned patients. No difference in efficacy was observed in either the MGMT-methylated or MGMT-unmethylated subsets. There was no survival advantage for the use of dose-dense temozolomide versus standard-dose temozolomide in newly diagnosed glioblastoma patients, regardless of MGMT status. However, this study confirmed the strong prognostic effect of MGMT methylation because the median OS was 21.2 months (95% CI, 17.9–24.8) for patients with methylation versus 14 months (HR, 1.74; 95% CI, 12.9–14.7; P < .001) for patients without methylation.
The efficacy of dose-dense temozolomide for patients who have recurrent glioblastoma, however, is yet to be determined.
Evidence (surgery and chemoradiation therapy with or without bevacizumab):
In 2013, final data from two multicenter, phase III, randomized, double-blind, placebo-controlled trials of bevacizumab in patients who had newly diagnosed glioblastoma were reported: RTOG 0825 (NCT00884741) and the Roche-sponsored AVAglio (NCT00943826).[17,18][Level of evidence A1] Bevacizumab did not improve OS in either trial.
There was significant crossover in both trials. Approximately 40% of RTOG 0825 patients and approximately 30% of AVAglio patients received bevacizumab at the first sign of disease progression.
RTOG 0825 (NCT00884741): Patients were randomly assigned to receive standard therapy (chemoradiation therapy with temozolomide) or standard therapy plus bevacizumab. OS and PFS were coprimary end points.[17][Level of evidence A1]
Bevacizumab did not improve OS (median OS was 16–17 months for each arm). However, it increased median PFS (10.7 months in the bevacizumab arm vs. 7.3 months in the placebo arm; HR, 0.79; P = .007).
The PFS result in the RTOG 0825 trial did not meet the prespecified significance level (P = .004).
AVAglio (NCT00943826): Patients were randomly assigned to receive standard therapy (chemoradiation therapy with temozolomide) or standard therapy plus bevacizumab. OS and PFS were coprimary end points.[18][Level of evidence A1]
Bevacizumab did not improve OS (median OS was 16–17 months for each arm). However, it increased median PFS (10.6 months in the bevacizumab arm vs. 6.2 months in the placebo arm; HR, 0.64; P < .0001).
The PFS result was statistically significant and associated with clinical benefit because patients who received bevacizumab remained functionally independent longer (9.0 months in the bevacizumab arm vs. 6.0 months in the standard therapy arm) and had a longer time until their Karnofsky Performance status deteriorated (HR, 0.65; P < .0001).
Patients who received bevacizumab also had delayed initiation of corticosteroids (12.3 months vs. 3.7 months; HR, 0.71; P = .002), and more patients were able to discontinue corticosteroids if they were already taking them (66% in the bevacizumab arm vs. 47% in the standard therapy arm).
The two trials had contradictory results in health-related quality of life (HRQOL) and neurocognitive outcomes studies. In the mandatory HRQOL studies in the AVAglio trial, bevacizumab-treated patients experienced improved HRQOL, but bevacizumab-treated patients in the elective RTOG 0825 studies showed more decline in patient-reported HRQOL and neurocognitive function. The reasons for these discrepancies are unclear.
Based on these results, there is no definite evidence that the addition of bevacizumab to standard therapy is beneficial for all newly diagnosed glioblastoma patients. Certain subgroups may benefit from the addition of bevacizumab, but this is not yet known.
Patients with glioblastoma are appropriate candidates for clinical trials designed to improve local control by adding newer forms of treatment to standard treatment. Information about ongoing clinical trials is available from the NCI website.
Oligodendroglial Tumors Treatment
Oligodendrogliomas treatment
Patients who have oligodendrogliomas (WHO grade II) generally have better prognoses than do patients who have diffuse astrocytomas. In particular, patients who have oligodendrogliomas with 1p/19q codeletion have a much longer survival.[3] Most of the oligodendrogliomas eventually progress.
Treatment options for oligodendrogliomas include:
Surgery with or without radiation therapy.
Surgery with radiation therapy and chemotherapy.
Controversy exists concerning the timing of radiation therapy after surgery. A study (EORTC-22845) of 300 patients with low-grade gliomas who had surgery and were randomly assigned to either radiation therapy or watchful waiting, did not show a difference in OS between the two groups.[1][Level of evidence A1] For more information, see the Low-grade tumors section.
For low-grade (WHO grade II) tumors that are considered high risk, radiation therapy followed by six cycles of PCV chemotherapy is a recommended option based on the long-term follow-up results of RTOG-9802, a randomized trial for high-risk, low-grade gliomas.[3][Level of evidence A1] Notably, RTOG-9802 enrolled patients with a variety of tumors, including astrocytomas, oligodendrogliomas, and mixed oligoastrocytomas. In a retrospective subset analysis, only the oligodendroglial tumors appeared to benefit from the addition of PCV.[4] For more information, see the Diffuse astrocytomas treatment section.
The discovery of the IDH1 and IDH2 variants, which are independent prognostic factors for significantly improved survival in diffuse gliomas, has greatly helped to identify patients with high-risk disease. For more information, see the Diffuse astrocytomas treatment section. In addition, a high proportion of WHO grade II oligodendrogliomas have 1p/19q codeletion, which is a powerful prognostic factor for improved survival.[19–21] Therefore, the presence of IDH1 and IDH2 variants and 1p/19q codeletion should be included in the assessment of high risk. Molecular correlative data from the RTOG-9802 trial, which would be informative about which patients benefited most from the addition of PCV, have not been reported.
Anaplastic oligodendrogliomas treatment
Patients with anaplastic oligodendrogliomas (WHO grade III) have a low cure rate with standard local treatment, but their prognoses are generally better than those of patients with anaplastic astrocytomas. Prognoses are particularly better for patients with 1p/19q codeletion, which occurs in most of these tumors. Two phase III randomized trials restricted to patients with anaplastic gliomas (NCT00626990 and NCT00887146) are active. However, efficacy data are not yet available. For more information, see the Anaplastic astrocytomas treatment section. These patients are appropriate candidates for clinical trials designed to improve local control by adding newer forms of treatment.
Information about ongoing clinical trials is available from the NCI website.
Treatment options for anaplastic oligodendrogliomas include:
Surgery plus radiation therapy with or without chemotherapy.[22]
Evidence (surgery followed by radiation therapy with or without chemotherapy):
Mature results from the EORTC Brain Tumor Group Study 26951 (NCT00002840), a phase III randomized study with 11.7 years of follow-up, demonstrated increased OS and PFS in patients with anaplastic oligodendroglial tumors with six cycles of adjuvant PCV chemotherapy after radiation therapy, compared with radiation therapy alone.[23][Level of evidence A1]
OS was significantly longer in the radiation therapy and PCV arm (42.3 months vs. 30.6 months; HR, 0.75; 95% CI, 0.60–0.95).
Patients with 1p/19q-codeleted tumors derived more benefit from adjuvant PCV chemotherapy than did those with non–1p/19q-deleted tumors.[23]
In contrast, the RTOG trial (RTOG-9402 [NCT00002569]) demonstrated no differences in median survival by treatment arm between an 8-week, intensive PCV chemotherapy regimen followed by immediate involved-field-plus-radiation therapy and radiation therapy alone.[24]
In an unplanned subgroup analysis, patients with 1p/19q-codeleted anaplastic oligodendrogliomas and mixed anaplastic astrocytomas demonstrated a median survival of 14.7 years versus 7.3 years (HR, 0.59; 95% CI, 0.37–0.95; P = .03).
For patients with non-codeleted tumors, there was no difference in median survival by treatment arm (2.6 vs. 2.7 years; HR, 0.85; 95% CI, 0.58–1.23; P = .39).[24][Level of evidence A1]
Postoperative radiation therapy alone has been compared with postoperative chemotherapy alone in patients with anaplastic gliomas (including 144 astrocytomas, 91 oligoastrocytomas, and 39 oligodendrogliomas) with crossover to the other modality at the time of tumor progression. Of the 139 patients randomly assigned to undergo radiation therapy, 135 were randomly assigned to receive chemotherapy, with a 32-week course of either PCV or single-agent temozolomide (2:1:1 randomization).[12][Levels of evidence A1 and B1]
TTF or OS did not differ across the treatment arms and were not affected by the order of the modalities.
Based on these data, CODEL (NCT00887146), a study that randomly assigned patients to receive radiation therapy alone (control arm), radiation therapy with temozolomide, and temozolomide alone (exploratory arm), was halted because radiation therapy alone was no longer considered adequate treatment in patients with anaplastic oligodendroglioma with 1p/19q-codeletions.[25] Temozolomide and PCV chemotherapy in anaplastic oligodendroglioma have not been compared, although in the setting of grade III anaplastic gliomas, no survival difference was seen between PCV chemotherapy and temozolomide.[12,26]
The combination of radiation and chemotherapy is not known to be superior in outcome to sequential modality therapy.
A high proportion of anaplastic oligodendrogliomas have IDH1 andIDH2 variants and 1p/19q codeletion, both powerful prognostic factors for improved survival. For more information, see the Diffuse astrocytomas treatment section.[23,24] In addition, PCV chemotherapy has been shown to be predictive in a retrospective analysis of the phase III trials described earlier. Therefore, assessment of these molecular markers may aid management decisions for anaplastic oligodendrogliomas.
Mixed Gliomas Treatment
Patients with mixed glial tumors, which include oligoastrocytoma (WHO grade II) and anaplastic oligoastrocytoma (WHO grade III), have highly variable prognoses based on their status of the IDH1 and IDH2 genes and 1p/19q chromosomes.[27–29] Therefore, the optimal treatment for these tumors as a group is uncertain. Often, they are treated similarly to astrocytic tumors because a subset of tumors may have outcomes similar to WHO grade III astrocytic or WHO grade IV glioblastoma tumors. Testing for these known, strong prognostic molecular markers should be performed, which may help to guide the assessment of risk and subsequent management.
Treatment options for mixed gliomas include:
Surgery plus radiation therapy with or without chemotherapy.
Ependymal tumors (WHO grade I) and ependymomas (WHO grade II)—i.e., subependymomas and myxopapillary ependymomas—are often curable.
Treatment options for grades I and II ependymal tumors include:
Surgery alone if the tumor is totally resectable.
Surgery followed by radiation therapy to known or suspected residual tumor.
Patients with anaplastic ependymomas (WHO grade III) have variable prognoses that depend on the location and extent of disease. Frequently, but not invariably, patients with anaplastic ependymomas have worse prognoses than do those patients with lower-grade ependymal tumors.
Treatment options for anaplastic ependymomas include:
Surgery plus craniospinal radiation therapy for patients with good-risk disease.[32]
Surgery plus craniospinal radiation therapy and various chemotherapy regimens for patients with poor-risk disease (under clinical evaluation).[32]
Pineal Parenchymal Tumors Treatment
Pineocytomas (WHO grade II), pineoblastomas (WHO grade IV), and pineal parenchymal tumors of intermediate differentiation are diverse tumors that require special consideration. Pineocytomas are slow-growing tumors and prognosis varies.
Pineoblastomas grow more rapidly and patients with these tumors have worse prognoses. Pineal parenchymal tumors of intermediate differentiation have unpredictable growth and clinical behavior.
Treatment options for pineal parenchymal tumors include:
Surgery plus radiation therapy for pineocytoma.
Surgery plus radiation therapy and chemotherapy for pineoblastoma.
Meningeal Tumors Treatment
WHO grade I meningiomas are usually curable when they are resectable. With the increasing use of sensitive neuroimaging tools, there has been more detection of asymptomatic low-grade meningiomas. Most appear to show minimal growth and can often be safely observed while therapy is deferred until growth or the development of symptoms.[33,34]
Treatment options for meningeal tumors include:
Active surveillance with deferred treatment, especially for incidentally discovered asymptomatic tumors.[33,34]
Surgery.
Stereotactic radiosurgery for tumors smaller than 3 cm.
Surgery plus radiation therapy in selected cases, such as for patients with known or suspected residual disease or with recurrence after previous surgery.
Fractionated radiation therapy for patients with unresectable tumors.[35]
The prognoses for patients with WHO grade II meningiomas (atypical, clear cell, and chordoid), WHO grade III meningiomas (anaplastic/malignant, rhabdoid, and papillary), and hemangiopericytomas are worse than the prognoses for patients with low-grade meningiomas because complete resections are less commonly feasible, and the proliferative capacity is greater.
Treatment options for grades II and III meningiomas and hemangiopericytomas include:
Surgery plus radiation therapy.
Germ Cell Tumors Treatment
The prognoses and treatment of patients with germ cell tumors—which include germinomas, embryonal carcinomas, choriocarcinomas, and teratomas—depend on tumor histology, tumor location, presence and levels of biological markers, and surgical resectability.
Treatment of Tumors of the Sellar Region
Craniopharyngiomas (WHO grade I) are often curable.
Treatment options for craniopharyngiomas include:
Surgery alone if the tumor is totally resectable.
Debulking surgery plus radiation therapy if the tumor is unresectable.
Treatment Options Under Clinical Evaluation for Primary CNS Tumors
Patients who have central nervous system (CNS) tumors that are either infrequently curable or unresectable should consider enrollment in clinical trials. Information about ongoing clinical trials is available from the NCI website.
Heavy-particle radiation, such as proton-beam therapy, carries the theoretical advantage of delivering high doses of ionizing radiation to the tumor bed while sparing surrounding brain tissue. The data are preliminary for this investigational technique and are not widely available.
Novel biological therapies under clinical evaluation for patients with CNS tumors include:[36]
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
References
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Parsons DW, Jones S, Zhang X, et al.: An integrated genomic analysis of human glioblastoma multiforme. Science 321 (5897): 1807-12, 2008. [PUBMED Abstract]
Yan H, Parsons DW, Jin G, et al.: IDH1 and IDH2 mutations in gliomas. N Engl J Med 360 (8): 765-73, 2009. [PUBMED Abstract]
Dubbink HJ, Taal W, van Marion R, et al.: IDH1 mutations in low-grade astrocytomas predict survival but not response to temozolomide. Neurology 73 (21): 1792-5, 2009. [PUBMED Abstract]
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Wick W, Hartmann C, Engel C, et al.: NOA-04 randomized phase III trial of sequential radiochemotherapy of anaplastic glioma with procarbazine, lomustine, and vincristine or temozolomide. J Clin Oncol 27 (35): 5874-80, 2009. [PUBMED Abstract]
Hegi ME, Diserens AC, Gorlia T, et al.: MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 352 (10): 997-1003, 2005. [PUBMED Abstract]
Gilbert MR, Wang M, Aldape KD, et al.: Dose-dense temozolomide for newly diagnosed glioblastoma: a randomized phase III clinical trial. J Clin Oncol 31 (32): 4085-91, 2013. [PUBMED Abstract]
Stupp R, Mason WP, van den Bent MJ, et al.: Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352 (10): 987-96, 2005. [PUBMED Abstract]
Stupp R, Hegi ME, Mason WP, et al.: Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 10 (5): 459-66, 2009. [PUBMED Abstract]
Gilbert MR, Dignam JJ, Armstrong TS, et al.: A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med 370 (8): 699-708, 2014. [PUBMED Abstract]
Chinot OL, Wick W, Mason W, et al.: Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N Engl J Med 370 (8): 709-22, 2014. [PUBMED Abstract]
Fallon KB, Palmer CA, Roth KA, et al.: Prognostic value of 1p, 19q, 9p, 10q, and EGFR-FISH analyses in recurrent oligodendrogliomas. J Neuropathol Exp Neurol 63 (4): 314-22, 2004. [PUBMED Abstract]
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van den Bent MJ, Chinot O, Boogerd W, et al.: Second-line chemotherapy with temozolomide in recurrent oligodendroglioma after PCV (procarbazine, lomustine and vincristine) chemotherapy: EORTC Brain Tumor Group phase II study 26972. Ann Oncol 14 (4): 599-602, 2003. [PUBMED Abstract]
van den Bent MJ, Brandes AA, Taphoorn MJ, et al.: Adjuvant procarbazine, lomustine, and vincristine chemotherapy in newly diagnosed anaplastic oligodendroglioma: long-term follow-up of EORTC brain tumor group study 26951. J Clin Oncol 31 (3): 344-50, 2013. [PUBMED Abstract]
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Killela PJ, Pirozzi CJ, Healy P, et al.: Mutations in IDH1, IDH2, and in the TERT promoter define clinically distinct subgroups of adult malignant gliomas. Oncotarget 5 (6): 1515-25, 2014. [PUBMED Abstract]
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Brandes AA, Ermani M, Amista P, et al.: The treatment of adults with medulloblastoma: a prospective study. Int J Radiat Oncol Biol Phys 57 (3): 755-61, 2003. [PUBMED Abstract]
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Treatment of Primary Tumors of the Spinal Axis
Surgery and radiation therapy are the primary modalities used to treat tumors of the spinal axis. Therapeutic options vary according to the histology of the tumor.[1] The experience with chemotherapy for primary spinal cord tumors is limited. No reports of controlled clinical trials are available for these types of tumors.[1,2] Chemotherapy is indicated for most patients with leptomeningeal involvement from a primary or metastatic tumor and positive cerebrospinal fluid cytology.[1] Most patients require treatment with corticosteroids, particularly if they are receiving radiation therapy.
Patients who have spinal axis tumors that are either infrequently curable or unresectable should consider enrollment in clinical trials. Information about ongoing clinical trials is available from the NCI website.
Mehta M, Vogelbaum MA, Chang S, et al.: Neoplasms of the central nervous system. In: DeVita VT Jr, Lawrence TS, Rosenberg SA: Cancer: Principles and Practice of Oncology. 9th ed. Lippincott Williams & Wilkins, 2011, pp 1700-49.
Metastatic Brain Tumors
General Information About Metastatic Brain Tumors
Brain metastases outnumber primary neoplasms by at least 10 to 1, and they occur in 20% to 40% of cancer patients, with subsequent median survival generally less than 6 months.[1] The exact incidence is unknown because no national cancer registry documents brain metastases, but it has been estimated that 98,000 to 170,000 new cases are diagnosed in the United States each year.[2,3] This number may be increasing because of the capacity of magnetic resonance imaging (MRI) to detect small metastases and because of prolonged survival resulting from improved systemic therapy.[1,2]
The most common primary tumors with brain metastases and the percentage of patients affected are as follows:[1,2]
Lung (18%–64%).
Breast (2%–21%).
Cancer of unknown primary (1%–18%).
Melanoma (4%–16%).
Colorectal (2%–12%).
Kidney (1%–8%).
Eighty percent of brain metastases occur in the cerebral hemispheres, 15% occur in the cerebellum, and 5% occur in the brain stem.[2] Metastases to the brain are multiple in more than 70% of cases, but solitary metastases also occur.[1]
Brain involvement can occur with cancers of the nasopharyngeal region by direct extension along the cranial nerves or through the foramina at the base of the skull. Dural metastases may constitute as much as 9% of total brain metastases.
Clinical Features
The diagnosis of brain metastases in cancer patients is based on:
Patient history.
Neurological examination.
Diagnostic procedures, including a contrast MRI of the brain.
Patients may describe any of the following symptoms:
Headaches.
Weakness.
Seizures.
Sensory defects.
Gait problems.
Often, family members or friends may notice the following changes:
Lethargy.
Emotional lability.
Personality change.
Diagnostic Evaluation
A physical examination may show objective neurological findings or only minor cognitive changes. The presence of multiple lesions and a high predilection of primary tumor metastasis may be sufficient to make the diagnosis of brain metastasis.
A lesion in the brain should not be assumed to be a metastasis just because a patient has had a previous cancer; such an assumption could result in overlooking appropriate treatment of a curable tumor.
Imaging tests
Computed tomography scans with contrast or MRIs with gadolinium are quite sensitive in diagnosing the presence of metastases. Positron emission tomography scanning and spectroscopic evaluation are new strategies to diagnose cerebral metastases and to differentiate the metastases from other intracranial lesions.[4]
Biopsy
In the case of a solitary lesion or a questionable relationship to the primary tumor, a brain biopsy (via resection or stereotactic biopsy) may be necessary.
Treatment of Metastatic Brain Tumors
The optimal therapy for patients with brain metastases continues to evolve.[1,2,5] The following treatments have been used in the management of metastatic brain tumors:
Radiation therapy.
Radiosurgery.
Surgical resection.
Corticosteroids.
Anticonvulsants.
Because most cases of brain metastases involve multiple metastases, a mainstay of therapy has historically been whole-brain radiation therapy (WBRT). However, stereotactic radiosurgery has become increasingly common. The role of radiosurgery continues to be defined. Stereotactic radiosurgery in combination with WBRT has been assessed.
Surgery is indicated to obtain tissue from a metastasis with an unknown primary tumor or to decompress a symptomatic dominant lesion that is causing significant mass effect.
Chemotherapy is usually not the primary therapy for most patients; however, it may have a role in the treatment of patients with brain metastases from chemosensitive tumors and can even be curative when combined with radiation for metastatic testicular germ cell tumors.[1,6] Intrathecal chemotherapy is also used for meningeal spread of metastatic tumors.
Treatment for patients with one to four metastases
Treatment options for patients with one to four metastases
About 10% to 15% of patients with cancer will have a single brain metastasis. Radiation therapy is the mainstay of palliation for these patients. The extent of extracranial disease can influence treatment of the brain lesions. In the presence of extensive active systemic disease, surgery provides little benefit for overall survival (OS). In patients with stable minimal extracranial disease, combined-modality treatment may be considered, using surgical resection followed by radiation therapy. However, the published literature does not provide clear guidance.
Treatment options for patients with one to four metastases include:
WBRT with or without surgical resection.
WBRT with or without stereotactic radiosurgery.
Focal therapy alone (surgical resection or stereotactic radiosurgery).
Evidence (treatment for one to four metastases):
Three randomized trials examined resection of solitary brain metastases followed by WBRT versus WBRT alone, totaling 195 randomly assigned patients.[7–9] The process that necessarily goes into selecting appropriate patients for surgical resection may account for the small numbers in each trial. In the first trial,[7][Level of evidence B1] performed at a single center, all patients were selected and operated upon by one surgeon.
The first two trials showed an improvement in survival in the surgery group,[7,8] but the third trial showed a trend in favor of the WBRT-only group.[9]
The three trials were combined in a trial-level meta-analysis.[10]
The combined analysis did not show a statistically significant difference in OS (hazard ratio [HR], 0.72; 95% confidence interval [CI], 0.34–1.53; P = .4); or in death from neurological causes (relative riskdeath, 0.68; 95% CI, 0.43–1.09; P = .11).[10]
One of the trials reported that combined therapy increased the duration of functionally independent survival.[7][Level of evidence B1]
None of the trials assessed or reported quality of life.
The need for WBRT after resection of solitary brain metastases has been studied.[11] Patients were randomly assigned to either undergo postoperative WBRT or receive no further treatment after resection.
Patients in the WBRT group were less likely to have tumor progression in the brain and were significantly less likely to die of neurological causes.
OS was the same in each group, and there was no difference in duration of functional independence.
One additional randomized study of observation versus WBRT after either surgery or stereotactic radiosurgery for solitary brain metastases was closed after 19 patients had been entered because of slow accrual; therefore, little can be deduced from the trial.[12]
A Radiation Therapy Oncology Group (RTOG) study (RTOG-9508) randomly assigned 333 patients with one to three metastases with a maximum diameter of 4 cm to WBRT (37.5 Gy over 3 weeks) with or without a stereotactic boost.[13] Patients with active systemic disease requiring therapy were excluded. The primary end point was OS with predefined hypotheses in both the full study population and the 186 patients with a solitary metastasis (and no statistical adjustment of P values for the two separate hypotheses).[13][Levels of evidence B1 for the full study population and A1 for patients with solitary metastases]
Mean OS in the combined-therapy group was 5.7 months, and mean OS in the WBRT-alone group was 6.5 months (P = .14).
In the subgroup with solitary metastases, OS was better in the combined-therapy group (6.5 months vs. 4.9 months; P = .039 in univariate analysis; P = .053 in a multivariable analysis adjusting for baseline prognostic factors).
In patients with multiple metastases, survival was 5.8 months in the combined-therapy group versus 6.7 months in the WBRT-only group (P = .98).
The combined-treatment group had a survival advantage of 2.5 months in patients with a single metastasis but not in patients with multiple lesions.
Local control was better in the full population with combined therapy.
At the 6-month follow-up, Karnofsky Performance status (considered a soft end point because of its imprecision and subjectivity) was better in the combined-therapy group, but there was no difference in mental status between the treatment groups. Acute and late toxicities were similar in both treatment arms. Quality of life was not assessed.
A phase III randomized trial compared adjuvant WBRT with observation after surgery or radiosurgery for a limited number of brain metastases in patients with stable solid tumors.[14][Level of evidence A3]
Health-related quality of life was improved in the observation-only arm, compared with WBRT.
Patients in the observation arm had better mean scores in physical, role, and cognitive functioning at 9 months.
In an exploratory analysis, statistically significant worse scores for bladder control, communication deficit, drowsiness, hair loss, motor dysfunction, leg weakness, appetite loss, constipation, nausea/vomiting, pain, and social functioning were observed in patients who underwent WBRT, compared with those who underwent observation only.
A meta-analysis of two trials with a total of 358 participants found no statistically significant difference in OS between the WBRT plus stereotactic radiosurgery group and the WBRT-alone group (HR, 0.82; 95% CI, 0.65–1.02).[15][Level of evidence B1]
Patients in the WBRT plus stereotactic radiosurgery group had decreased local failure, compared with patients who received WBRT alone (HR, 0.27; 95% CI, 0.14–0.52).
Unchanged or improved Karnofsky Performance status at 6 months was seen in 43% of patients in the combined-therapy group versus 28% in the WBRT-alone group (P = .03).
A study that had a primary end point of learning and neurocognition, using a standardized test for total recall, was stopped by the Data and Safety Monitoring Board because of worse outcomes in the WBRT group.[16][Level of evidence B1]
Given this body of information, focal therapy plus WBRT or focal therapy alone, with close follow-up with serial MRIs and initiation of salvage therapy when clinically indicated, appear to be reasonable treatment options. The pros and cons of each approach should be discussed with the patient.
Several randomized trials have been performed that were designed with varying primary end points to address whether WBRT is necessary after focal treatment. The results can be summarized as follows:[16–18]
Studies consistently show that the addition of WBRT to focal therapy decreases the risk of progression and new metastases in the brain.
The addition of WBRT does not improve OS.
The decrease in risk of intracranial disease progression does not translate into improved functional or neurological status, nor does it appear to decrease the risk of death from neurological deterioration.
About one-half or more of the patients who receive focal therapy alone ultimately require salvage therapy, such as WBRT or radiosurgery, compared with about one-quarter of the patients who are given up-front WBRT.
The impact of better local control associated with WBRT on quality of life has not been reported and remains an open question.
Leptomeningeal Carcinomatosis (LC)
LC occurs in about 5% of all cancer patients. The most common types of cancer to spread to the leptomeninges are:
Breast tumors (35%).
Lung tumors (24%).
Hematologic malignancies (16%).
Diagnosis includes a combination of neurospinal axis imaging and cerebrospinal fluid (CSF) cytology. Median OS is in the range of 10 to 12 weeks.
The management of LC includes:
Intrathecal chemotherapy.
Intrathecal chemotherapy and systemic chemotherapy.
Intrathecal chemotherapy and radiation therapy.
Supportive care.
In a series of 149 patients with metastatic non-small cell lung carcinoma, cytologically proven LC, poor performance status, high protein level in the CSF, and a high initial CSF white blood cell count were significant poor prognostic factors for survival.[19] Patients received active treatment, including intrathecal chemotherapy, WBRT, or epidermal growth factor receptor-tyrosine kinase inhibitors, or underwent a ventriculoperitoneal shunt procedure.
In a retrospective series of 38 patients with metastatic breast cancer and LC, the proportion of LC cases varied by breast cancer subtype:[20]
Luminal A (18.4%).
Luminal B (31.6%).
Human epidermal growth factor receptor 2 (HER2) positive (26.3%).
Triple-negative breast cancer subtype (23.7%).
Patients with triple-negative breast cancer had a shorter interval between metastatic breast cancer diagnosis and the development of LC. Median survival did not differ across breast cancer subtypes. Consideration of intrathecal administration of trastuzumab in patients with HER2-positive LC has also been described in case reports.[21]
References
Patchell RA: The management of brain metastases. Cancer Treat Rev 29 (6): 533-40, 2003. [PUBMED Abstract]
Mehta M, Vogelbaum MA, Chang S, et al.: Neoplasms of the central nervous system. In: DeVita VT Jr, Lawrence TS, Rosenberg SA: Cancer: Principles and Practice of Oncology. 9th ed. Lippincott Williams & Wilkins, 2011, pp 1700-49.
Hutter A, Schwetye KE, Bierhals AJ, et al.: Brain neoplasms: epidemiology, diagnosis, and prospects for cost-effective imaging. Neuroimaging Clin N Am 13 (2): 237-50, x-xi, 2003. [PUBMED Abstract]
Schaefer PW, Budzik RF, Gonzalez RG: Imaging of cerebral metastases. Neurosurg Clin N Am 7 (3): 393-423, 1996. [PUBMED Abstract]
Soffietti R, Cornu P, Delattre JY, et al.: EFNS Guidelines on diagnosis and treatment of brain metastases: report of an EFNS Task Force. Eur J Neurol 13 (7): 674-81, 2006. [PUBMED Abstract]
Ogawa K, Yoshii Y, Nishimaki T, et al.: Treatment and prognosis of brain metastases from breast cancer. J Neurooncol 86 (2): 231-8, 2008. [PUBMED Abstract]
Patchell RA, Tibbs PA, Walsh JW, et al.: A randomized trial of surgery in the treatment of single metastases to the brain. N Engl J Med 322 (8): 494-500, 1990. [PUBMED Abstract]
Vecht CJ, Haaxma-Reiche H, Noordijk EM, et al.: Treatment of single brain metastasis: radiotherapy alone or combined with neurosurgery? Ann Neurol 33 (6): 583-90, 1993. [PUBMED Abstract]
Mintz AH, Kestle J, Rathbone MP, et al.: A randomized trial to assess the efficacy of surgery in addition to radiotherapy in patients with a single cerebral metastasis. Cancer 78 (7): 1470-6, 1996. [PUBMED Abstract]
Hart MG, Grant R, Garside R, et al.: Chemotherapeutic wafers for high grade glioma. Cochrane Database Syst Rev (3): CD007294, 2008. [PUBMED Abstract]
Patchell RA, Tibbs PA, Regine WF, et al.: Postoperative radiotherapy in the treatment of single metastases to the brain: a randomized trial. JAMA 280 (17): 1485-9, 1998. [PUBMED Abstract]
Roos DE, Wirth A, Burmeister BH, et al.: Whole brain irradiation following surgery or radiosurgery for solitary brain metastases: mature results of a prematurely closed randomized Trans-Tasman Radiation Oncology Group trial (TROG 98.05). Radiother Oncol 80 (3): 318-22, 2006. [PUBMED Abstract]
Andrews DW, Scott CB, Sperduto PW, et al.: Whole brain radiation therapy with or without stereotactic radiosurgery boost for patients with one to three brain metastases: phase III results of the RTOG 9508 randomised trial. Lancet 363 (9422): 1665-72, 2004. [PUBMED Abstract]
Soffietti R, Kocher M, Abacioglu UM, et al.: A European Organisation for Research and Treatment of Cancer phase III trial of adjuvant whole-brain radiotherapy versus observation in patients with one to three brain metastases from solid tumors after surgical resection or radiosurgery: quality-of-life results. J Clin Oncol 31 (1): 65-72, 2013. [PUBMED Abstract]
Patil CG, Pricola K, Sarmiento JM, et al.: Whole brain radiation therapy (WBRT) alone versus WBRT and radiosurgery for the treatment of brain metastases. Cochrane Database Syst Rev 9: CD006121, 2012. [PUBMED Abstract]
Chang EL, Wefel JS, Hess KR, et al.: Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial. Lancet Oncol 10 (11): 1037-44, 2009. [PUBMED Abstract]
Aoyama H, Shirato H, Tago M, et al.: Stereotactic radiosurgery plus whole-brain radiation therapy vs stereotactic radiosurgery alone for treatment of brain metastases: a randomized controlled trial. JAMA 295 (21): 2483-91, 2006. [PUBMED Abstract]
Kocher M, Soffietti R, Abacioglu U, et al.: Adjuvant whole-brain radiotherapy versus observation after radiosurgery or surgical resection of one to three cerebral metastases: results of the EORTC 22952-26001 study. J Clin Oncol 29 (2): 134-41, 2011. [PUBMED Abstract]
Lee SJ, Lee JI, Nam DH, et al.: Leptomeningeal carcinomatosis in non-small-cell lung cancer patients: impact on survival and correlated prognostic factors. J Thorac Oncol 8 (2): 185-91, 2013. [PUBMED Abstract]
Torrejón D, Oliveira M, Cortes J, et al.: Implication of breast cancer phenotype for patients with leptomeningeal carcinomatosis. Breast 22 (1): 19-23, 2013. [PUBMED Abstract]
Bartsch R, Berghoff AS, Preusser M: Optimal management of brain metastases from breast cancer. Issues and considerations. CNS Drugs 27 (2): 121-34, 2013. [PUBMED Abstract]
Treatment of Recurrent CNS Tumors
Patients who have recurrent central nervous system (CNS) tumors are rarely curable and should consider enrollment in clinical trials. Information about ongoing clinical trials is available from the NCI website.
Treatment options for recurrent CNS tumors include:
Carmustine wafers have been investigated for the treatment of recurrent malignant gliomas, but the impact on survival is less clear than at the time of initial diagnosis and resection.
Evidence (localized chemotherapy):
In a multicenter, randomized, placebo-controlled trial, 222 patients with recurrent malignant primary brain tumors requiring reoperation were randomly assigned to receive implanted carmustine wafers or placebo biodegradable wafers.[1][Level of evidence A1] Approximately one-half of the patients had received previous systemic chemotherapy. The two treatment groups were well balanced at baseline.
Median survival was 31 weeks in the group receiving carmustine wafers versus 23 weeks in the group receiving placebo wafers. The statistical significance between the two overall survival curves depended on the method of analysis.
The hazard ratio (HR) for risk of dying in the direct intention-to-treat comparison between the two groups was 0.83 (95% confidence interval [CI], 0.63–1.10; P = .19). The baseline characteristics were similar in the two groups, but the investigators performed an additional analysis, adjusting for prognostic factors, because they felt that even small differences in baseline characteristics could have a powerful influence on outcomes. In the adjusted proportional hazards model, the HR for risk of death was 0.67 (95% CI, 0.51–0.90; P = .006). The investigators emphasized this latter analysis and reported this as a positive trial.[1][Level of evidence A1]
A Cochrane Collaboration systematic review of chemotherapeutic wafers for high-grade glioma focused on the unadjusted analysis and reported the same trial as negative.[2]
Systemic chemotherapy
Systemic therapy (e.g., temozolomide, lomustine, or the combination of procarbazine, a nitrosourea, and vincristine [PCV] in patients who have not previously received the drugs) has been used at the time of recurrence of primary malignant brain tumors. However, this approach has not been tested in controlled studies. Patient-selection factors likely play a strong role in determining outcomes, so the impact of therapy on survival is not clear.
Antiangiogenesis Therapy
In 2009, the U.S. Food and Drug Administration (FDA) granted accelerated approval of bevacizumab monotherapy for patients with progressive glioblastoma. The indication was granted under the FDA’s accelerated approval program that permits the use of certain surrogate end points or an effect on a clinical end point other than survival or irreversible morbidity as bases for approvals of products intended for serious or life-threatening illnesses or conditions.
The approval was based on the demonstration of improved objective response rates observed in two historically controlled, single-arm, or noncomparative phase II trials.[3,4][Level of evidence C3] Based on these data and the FDA approval, bevacizumab monotherapy has become standard therapy for recurrent glioblastoma.
Evidence (antiangiogenesis therapy):
The FDA independently reviewed an open-label, multicenter, noncomparative phase II study that randomly assigned 167 patients with recurrent glioblastoma multiforme (GBM) to receive bevacizumab alone or bevacizumab in combination with irinotecan.[3] However, only efficacy data from the bevacizumab monotherapy arm (n = 85) were used to support drug approval.
Tumor responses were observed in 26% of patients treated with bevacizumab alone, and the median duration of response in these patients was 4.2 months.
Based on this externally controlled trial, the incidence of adverse events associated with bevacizumab did not appear to be significantly increased in GBM patients.
The FDA independently assessed another single-arm, single-institution trial in which 56 patients with recurrent glioblastoma were treated with bevacizumab alone.[4]
Responses were observed in 20% of patients, and the median duration of response was 3.9 months.
No data are available from prospective randomized controlled trials demonstrating improvement in health outcomes, such as disease-related symptoms or increased survival with the use of bevacizumab to treat glioblastoma.
Radiation Therapy
Because there are no randomized trials, the role of repeat radiation after disease progression or the development of radiation-induced cancers is also ill defined. Interpretation is difficult because the literature is limited to small retrospective case series.[5] The decision must be made carefully because of the risk of neurocognitive deficits and radiation necrosis.
Surgery
Re-resection of recurrent CNS tumors is an option for some patients. However, most patients do not qualify because of a deteriorating condition or technically inoperable tumors. The evidence is limited to noncontrolled studies and case series of patients who are healthy enough and have tumors that are small enough to technically debulk. The impact on survival of reoperation versus patient selection is not known.
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
Brem H, Piantadosi S, Burger PC, et al.: Placebo-controlled trial of safety and efficacy of intraoperative controlled delivery by biodegradable polymers of chemotherapy for recurrent gliomas. The Polymer-brain Tumor Treatment Group. Lancet 345 (8956): 1008-12, 1995. [PUBMED Abstract]
Hart MG, Grant R, Garside R, et al.: Chemotherapeutic wafers for high grade glioma. Cochrane Database Syst Rev (3): CD007294, 2008. [PUBMED Abstract]
Friedman HS, Prados MD, Wen PY, et al.: Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol 27 (28): 4733-40, 2009. [PUBMED Abstract]
Kreisl TN, Kim L, Moore K, et al.: Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol 27 (5): 740-5, 2009. [PUBMED Abstract]
Paulino AC, Mai WY, Chintagumpala M, et al.: Radiation-induced malignant gliomas: is there a role for reirradiation? Int J Radiat Oncol Biol Phys 71 (5): 1381-7, 2008. [PUBMED Abstract]
Latest Updates to This Summary (03/28/2025)
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.
This summary was renamed from Adult Central Nervous System Tumors Treatment.
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 central nervous system tumors. 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 Central Nervous System Tumors Treatment are:
Solmaz Sahebjam, MD (Johns Hopkins at Sibley Memorial Hospital)
Minh Tam Truong, MD (Boston University Medical Center)
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 Central Nervous System Tumors Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/brain/hp/adult-brain-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389419]
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Childhood gastrointestinal neuroendocrine tumor (also called gastrointestinal carcinoid tumor) is a rare cancer that develops in neuroendocrine cells. These cells have features of both nerve cells and hormone-producing cells and are found throughout the body, most often in the chest and abdomen. In the digestive tract, these cells help control digestion and the movement of food through the stomach and intestines.
In children, these tumors most often form in the appendix, a small pouch connected to the beginning of the large intestine. They are usually found by accident during surgery to remove the appendix. Appendiceal neuroendocrine tumors in children tend to grow slowly and almost never spread to other parts of the body.
Rarely, neuroendocrine tumors can also form in other parts of the digestive system, such as the stomach, intestines, pancreas, or liver. Cancer that forms in these areas have a higher chance of spreading and may need more treatment.
EnlargeGastrointestinal neuroendocrine tumors form in the lining of the gastrointestinal tract and other organs in the abdomen. Most gastrointestinal neuroendocrine tumors in children form in the appendix, but they can also form in the stomach, intestines, pancreas, and liver.
Causes and risk factors for childhood gastrointestinal neuroendocrine tumors
Gastrointestinal neuroendocrine tumors in children are caused by certain changes to the way gastrointestinal neuroendocrine cells function, especially how they grow and divide into new cells. Often, the exact cause of these changes 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. Children with multiple endocrine neoplasia type 1 (MEN1) or von Hipple Lindau (VHL) syndrome may have a higher risk of gastrointestinal neuroendocrine tumors. Talk with your child’s doctor if you think your child may be at risk.
Genetic counseling for children with gastrointestinal neuroendocrine tumor that is not in the appendix
It may not be clear from the family medical history whether your child’s gastrointestinal neuroendocrine tumor is part of an inherited condition. Genetic counseling can assess the likelihood that your child’s cancer is inherited and whether genetic testing is needed. Genetic counselors and other specially trained health professionals can discuss your child’s diagnosis and your family’s medical history to help you understand:
the options for testing for changes in the MEN1 and VHL genes
the risk of other cancers for your child
the risk of gastrointestinal neuroendocrine tumor or other cancers for your child’s siblings
the risk and benefits of learning genetic information
Genetic counselors can also help you cope with your child’s genetic testing results, including how to discuss the results with family members. They can also advise you about whether other members of your family should receive genetic testing.
Symptoms of childhood gastrointestinal neuroendocrine tumor
The symptoms of a gastrointestinal neuroendocrine tumor depend on where the tumor forms in the abdomen. It’s important to check with your child’s doctor if your child has any symptoms below.
Neuroendocrine tumors in the appendix are often found during an appendectomy for appendicitis. Appendicitis is a medical emergency that can cause:
abdominal pain, especially on the lower right side of the abdomen
fever
nausea and vomiting
diarrhea
A gastrointestinal neuroendocrine tumor that is not in the appendix may release hormones and other substances. Carcinoid syndrome occurs when a neuroendocrine tumor in the digestive tract releases the hormone serotonin and other substances. It may cause:
redness and a warm feeling in the face, neck, and upper chest
a fast heartbeat
trouble breathing
sudden drop in blood pressure which can cause restlessness, confusion, weakness, dizziness, and pale, cool, and clammy skin
diarrhea
These symptoms may be caused by problems other than a gastrointestinal neuroendocrine tumor. The only way to know is for your child to see a doctor.
Tests to diagnose childhood gastrointestinal neuroendocrine tumor
If your child has symptoms that suggest a gastrointestinal tumor, the doctor will need to find out if they are due to cancer or another problem. The doctor will ask when the symptoms started and how often your child has been having them. The doctor will also ask about your child’s personal and family medical history and do a physical exam. Depending on these results, they may recommend other tests. If your child is diagnosed with gastrointestinal neuroendocrine tumor, the results of these tests will help plan treatment.
The tests used to diagnose gastrointestinal neuroendocrine tumor may include:
Blood chemistry study
Blood chemistry study uses a blood sample to measure the amounts of certain substances released into the blood by organs and tissues in the body. An unusual amount of a substance can be a sign of disease.
Magnetic resonance imaging (MRI)
MRI uses a magnet, radio waves, and a computer to make a series of detailed pictures of areas in the body. This procedure is also called nuclear magnetic resonance imaging (NMRI).
EnlargeMagnetic resonance imaging (MRI) scan. The child lies on a table that slides into the MRI machine, which takes a series of detailed pictures of areas inside the body. The positioning of the child on the table depends on the part of the body being imaged.
PET scan
PET scan (positron emission tomography scan) uses a small amount of radioactive sugar (also called radioactive glucose) that is injected into a vein. The PET scanner rotates around the body and makes pictures of where sugar is being used by the body. Cancer cells show up brighter in the pictures because they are more active and take up more sugar than normal cells do.
EnlargePositron emission tomography (PET) scan. The child lies on a table that slides through the PET scanner. The head rest and white strap help the child lie still. A small amount of radioactive glucose (sugar) is injected into the child’s vein, and a scanner makes a picture of where the glucose is being used in the body. Cancer cells show up brighter in the picture because they take up more glucose than normal cells do.
CT scan
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.
EnlargeComputed tomography (CT) scan. The child lies on a table that slides through the CT scanner, which takes a series of detailed x-ray pictures of areas inside the body.
Ultrasound
Ultrasound uses high-energy sound waves (ultrasound) that bounce off internal tissues or organs and make echoes. The echoes form a picture of body tissues called a sonogram.
EnlargeAbdominal ultrasound. An ultrasound transducer connected to a computer is pressed against the skin of the abdomen. The transducer bounces sound waves off internal organs and tissues to make echoes that form a sonogram (computer picture).
24-hour urine test
A 24-hour urine test collects urine for 24 hours to measure the amounts of certain substances, such as hormones. An unusual amount of a substance can be a sign of disease in the organ or tissue that makes it. The urine sample is checked to see if it contains 5-HIAA (a breakdown product of the hormone serotonin which may be made by neuroendocrine tumors). This test is used to help diagnose carcinoid syndrome.
Somatostatin receptor scintigraphy
Somatostatin receptor scintigraphy is a type of radionuclide scan that may be used to find tumors. A very small amount of radioactiveoctreotide (a hormone that attaches to tumors) is injected into a vein and travels through the blood. The radioactive octreotide attaches to the tumor and a special camera that detects radioactivity is used to show where the tumors are in the body. This procedure is also called octreotide scan and SRS.
Getting a second opinion
You may want to get a second opinion to confirm your child’s 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 genetic test report, pathology report, slides, and scans. This doctor may agree with the first doctor, suggest changes to the treatment plan, or provide more information about your child’s cancer.
To learn more about choosing a doctor and getting a second opinion, visit Finding Cancer Care. You can contact NCI’s Cancer Information Service via chat, email, or phone (both in English and Spanish) for help finding a doctor or hospital that can provide a second opinion. For questions you might want to ask at your appointments, visit Questions to Ask Your Doctor About Cancer.
Types of treatment for childhood gastrointestinal neuroendocrine tumor
Who treats children with gastrointestinal neuroendocrine tumor?
A pediatric oncologist, a doctor who specializes in treating children with cancer, oversees treatment of gastrointestinal neuroendocrine tumor. The pediatric oncologist works with other pediatric health care providers who are experts in treating children with cancer and who specialize in certain areas of medicine. Other specialists may include:
There are different types of treatment for children and adolescents with a gastrointestinal neuroendocrine tumor. You and your child’s cancer care team will work together to decide treatment. Many factors will be considered, such as your child’s overall health and whether the cancer is newly diagnosed or has come back.
Your child’s treatment plan will include information about the cancer, the goals of treatment, treatment options, and the possible side effects. It will be helpful to talk with your child’s cancer care team before treatment begins about what to expect. For help every step of the way, visit our booklet, Children with Cancer: A Guide for Parents.
Types of treatment your child might have include:
Surgery
Surgery to remove the tumor is the only treatment needed for neuroendocrine tumor in the appendix. Surgery is also used alone or with other therapies to treat neuroendocrine tumors outside the appendix.
Embolization
Embolization is a treatment in which contrast dye and particles are injected into the hepatic artery through a catheter (thin tube). The particles block the artery, cutting off blood flow to the tumor. Sometimes a small amount of a radioactive substance is attached to the particles. Most of the radiation is trapped near the tumor to kill the cancer cells. This is called radioembolization.
Radioactive drug
A radioactive drug contains a radioactive substance and is used to diagnose or treat disease, including cancer. Lutetium Lu 177-dotatate is a radioactive drug used to treat gastrointestinal neuroendocrine tumor.
Clinical trials
For some children, joining a clinical trial may be an option. There are different types of clinical trials for childhood cancer. For example, a treatment trial tests new treatments or new ways of using current treatments. Supportive care and palliative care trials look at ways to improve quality of life, especially for those who have side effects from cancer and its treatment.
You can use the clinical trial search to find NCI-supported cancer clinical trials accepting participants. The search allows you to filter trials based on the type of cancer, your child’s age, and where the trials are being done. Clinical trials supported by other organizations can be found on the ClinicalTrials.gov website.
Treatment of childhood gastrointestinal neuroendocrine tumor
Treatment of neuroendocrine tumor in the appendix in children is surgery to remove the appendix.
Treatment of neuroendocrine tumor in the large intestine, pancreas, or stomach is usually surgery.
Treatment of neuroendocrine tumor that cannot be removed by surgery, multiple tumors, or tumors that have spread may include:
embolization
radioactive drug (lutetium Lu 177-dotatate)
If the cancer comes back after treatment, your child’s doctor will talk with you about what to expect and possible next steps. There might be treatment options that may shrink the cancer or control its growth. If there are no treatments, your child can receive care to control symptoms from cancer so they can be as comfortable as possible.
Prognostic factors for childhood gastrointestinal neuroendocrine tumor
If your child has been diagnosed with a gastrointestinal neuroendocrine tumor, you likely have questions about how serious the cancer is and your child’s chances of survival. The likely outcome or course of a disease is called prognosis.
Prognosis depends on:
where the tumor first formed in the body
the size of the tumor
whether the tumor has spread to other parts of the body
whether the tumor is newly diagnosed or has recurred (come back)
The prognosis for neuroendocrine tumors in the appendix in children is usually excellent after surgery to remove the tumor. Gastrointestinal neuroendocrine tumors that are not in the appendix may be larger or have spread to other parts of the body at the time of diagnosis and usually do not respond well to chemotherapy. Larger tumors are more likely to recur (come back).
No two people are alike, and responses to treatment can vary greatly. Your child’s cancer care team is in the best position to talk with you about your child’s prognosis.
Side effects and late effects of treatment
Cancer treatments can cause side effects. Which side effects your child might have depends on the type of treatment they receive, the dose, and how their body reacts. Talk with your child’s treatment team about which side effects to look for and ways to manage them.
Problems from cancer treatment that begin 6 months or later after treatment and continue for months or years are called late effects. Late effects of cancer treatment may include:
physical problems
changes in mood, feelings, thinking, learning, or memory
second cancers (new types of cancer) or other problems
Some late effects may be treated or controlled. It is important to talk with your child’s doctors about the possible late effects caused by some treatments. Learn more about Late Effects of Treatment for Childhood Cancer.
Follow-up care
As your child goes through treatment, they will have follow-up tests or check-ups. Some of the tests that were done to diagnose 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 child’s condition has changed or if the cancer has recurred (come back).
When your child has cancer, every member of the family needs support. Taking care of yourself during this difficult time is important. Reach out to your child’s treatment team and to people in your family and community for support. To learn more, visit Support for Families: Childhood Cancer and the booklet Children with Cancer: A Guide for Parents.
Related resources
For more childhood cancer information and other general cancer resources, visit:
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 childhood gastrointestinal neuroendocrine tumors. It is meant to inform and help patients, families, and caregivers. It does not give formal guidelines or recommendations for making decisions about health care.
Reviewers and Updates
Editorial Boards write the PDQ cancer information summaries and keep them up to date. These Boards are made up of experts in cancer treatment and other specialties related to cancer. The summaries are reviewed regularly and changes are made when there is new information. The date on each summary (“Updated”) is the date of the most recent change.
The information in this patient summary was taken from the health professional version, which is reviewed regularly and updated as needed, by the PDQ Pediatric Treatment Editorial Board.
Clinical Trial Information
A clinical trial is a study to answer a scientific question, such as whether one treatment is better than another. Trials are based on past studies and what has been learned in the laboratory. Each trial answers certain scientific questions in order to find new and better ways to help cancer patients. During treatment clinical trials, information is collected about the effects of a new treatment and how well it works. If a clinical trial shows that a new treatment is better than one currently being used, the new treatment may become “standard.” Patients may want to think about taking part in a clinical trial. Some clinical trials are open only to patients who have not started treatment.
Clinical trials can be found online at NCI’s website. For more information, call the Cancer Information Service (CIS), NCI’s contact center, at 1-800-4-CANCER (1-800-422-6237).
Permission to Use This Summary
PDQ is a registered trademark. The content of PDQ documents can be used freely as text. It cannot be identified as an NCI PDQ cancer information summary unless the whole summary is shown and it is updated regularly. However, a user would be allowed to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks in the following way: [include excerpt from the summary].”
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.
Adrenocortical carcinoma is a rare disease in which malignant (cancer) cells form in the outer layer of the adrenal gland.
Having certain genetic conditions increases the risk of adrenocortical carcinoma.
Symptoms of adrenocortical carcinoma include pain in the abdomen.
Imaging studies and tests that examine the blood and urine are used to diagnose adrenocortical carcinoma.
Certain factors affect the prognosis (chance of recovery) and treatment options.
Adrenocortical carcinoma is a rare disease in which malignant (cancer) cells form in the outer layer of the adrenal gland.
There are two adrenal glands. The adrenal glands are small and shaped like a triangle. One adrenal gland sits on top of each kidney. Each adrenal gland has two parts. The outer layer of the adrenal gland is the adrenal cortex. The center of the adrenal gland is the adrenal medulla.
EnlargeAnatomy of the adrenal gland. There are two adrenal glands, one on top of each kidney. The outer part of each gland is the adrenal cortex and the inner part is the adrenal medulla.
Cause the body to have masculine or feminine characteristics.
Adrenocortical carcinoma is also called cancer of the adrenal cortex. A tumor of the adrenal cortex may be functioning (makes more hormones than normal) or nonfunctioning (does not make more hormones than normal). Most adrenocortical tumors are functioning. The hormones made by functioning tumors may cause certain signs or symptoms of disease.
The adrenal medulla makes hormones that help the body react to stress. Cancer that forms in the adrenal medulla is called pheochromocytoma and is not discussed in this summary. Learn more about Pheochromocytoma and Paraganglioma.
Having certain genetic conditions increases the risk of adrenocortical carcinoma.
Anything that increases a person’s risk of getting a disease is called a risk factor. Not every person with one or more of these risk factors will develop adrenocortical carcinoma, and it will 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 adrenocortical carcinoma include having the following hereditary diseases:
These and other signs and symptoms may be caused by adrenocortical carcinoma or by other conditions. Check with your doctor if you have any of these problems.
Imaging studies and tests that examine the blood and urine are used to diagnose adrenocortical carcinoma.
The tests and procedures used to diagnose adrenocortical carcinoma depend on the patient’s signs and symptoms. 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:
Twenty-four-hour urine test: A test in which urine is collected for 24 hours to measure the amounts of cortisol or 17-ketosteroids. A higher-than-normal amount of these in the urine may be a sign of disease in the adrenal cortex.
Low-dosedexamethasone suppression test: A test in which one or more small doses of dexamethasone are given. The level of cortisol is checked from a sample of blood or from urine that is collected for three days. This test is done to check if the adrenal gland is making too much cortisol.
High-dose dexamethasone suppression test: A test in which one or more high doses of dexamethasone are given. The level of cortisol is checked from a sample of blood or from urine that is collected for three days. This test is done to check if the adrenal gland is making too much cortisol or if the pituitary gland is telling the adrenal glands to make too much cortisol.
Blood chemistry study: A procedure in which a blood sample is checked to measure the amounts of certain substances, such as potassium or sodium, released into the blood by organs and tissues in the body. An unusual (higher or lower than normal) amount of a substance can be a sign of disease.
CT scan (CAT scan): A procedure that makes a series of detailed pictures of areas inside the body, 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.
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. This procedure is also called nuclear magnetic resonance imaging (NMRI). An MRI of the abdomen is done to diagnose adrenocortical carcinoma.
Adrenal angiography: A procedure to look at the arteries and the flow of blood near the adrenal glands. A contrast dye is injected into the adrenal arteries. As the dye moves through the arteries, a series of x-rays are taken to see if any arteries are blocked.
Adrenal venography: A procedure to look at the adrenal veins and the flow of blood near the adrenal glands. A contrast dye is injected into an adrenal vein. As the contrast dye moves through the veins, a series of x-rays are taken to see if any veins are blocked. A catheter (very thin tube) may be inserted into the vein to take a blood sample, which is checked for abnormal hormone levels.
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.
MIBG scan: A very small amount of radioactive material called MIBG is injected into a vein and travels through the bloodstream. Adrenal gland cells take up the radioactive material and are detected by a device that measures radiation. This scan is done to tell the difference between adrenocortical carcinoma and pheochromocytoma.
The stage of the cancer (the size of the tumor and whether it is in the adrenal gland only or has spread to other places in the body).
Whether the tumor can be completely removed in surgery.
Whether the cancer has been treated in the past.
The patient’s general health.
The grade of tumor cells (how different they look from normal cells under a microscope).
Adrenocortical carcinoma may be cured if treated at an early stage.
Stages of Adrenocortical Carcinoma
Key Points
After adrenocortical carcinoma has been diagnosed, tests are done to find out if cancer cells have spread within the adrenal gland 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 adrenocortical carcinoma:
Stage I
Stage II
Stage III
Stage IV
Adrenocortical carcinoma can recur (come back) after it has been treated.
After adrenocortical carcinoma has been diagnosed, tests are done to find out if cancer cells have spread within the adrenal gland or to other parts of the body.
The process used to find out if cancer has spread within the adrenal gland or to other parts of the body is called staging. The information gathered from the staging process determines the stage of the disease. It is important to know the stage in order to plan treatment. The following tests and procedures may be used in the staging process:
CT scan (CAT scan): A procedure that makes a series of detailed pictures of areas inside the body, such as the abdomen or 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.
MRI (magnetic resonance imaging) with gadolinium: 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 abdomen. A substance called gadolinium may be injected into a vein. The gadolinium collects around the cancer cells so they show up brighter in the picture. This procedure is also called nuclear magnetic resonance imaging (NMRI).
PET scan (positron emission tomography scan): A procedure to find malignanttumor 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.
Ultrasound exam: A procedure in which high-energy sound waves (ultrasound) are bounced off internal tissues or organs, such as the vena cava, and make echoes. The echoes form a picture of body tissues called a sonogram.
Adrenalectomy: A procedure to remove the affected adrenal gland. A tissue sample is viewed under a microscope by a pathologist to check for signs of cancer.
There are three ways that cancer spreads in the body.
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 adrenocortical carcinoma spreads to the lung, the cancer cells in the lung are actually adrenocortical carcinoma cells. The disease is metastatic adrenocortical carcinoma, not lung 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 adrenocortical carcinoma:
EnlargeTumor 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 IV, the tumor is any size, may have spread to nearby lymph nodes, and has spread to other parts of the body, such as the lung, bone, or peritoneum.
Adrenocortical carcinoma can recur (come back) after it has been treated.
The cancer may come back in the adrenal cortex or in other parts of the body.
Treatment Option Overview
Key Points
There are different types of treatment for patients with adrenocortical carcinoma.
The following types of treatment are used:
Surgery
Radiation therapy
Chemotherapy
New types of treatment are being tested in clinical trials.
Immunotherapy
Targeted therapy
Treatment for adrenocortical 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 care may be needed.
There are different types of treatment for patients with adrenocortical carcinoma.
Different types of treatments are available for patients with adrenocortical 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 adrenal gland (adrenalectomy) is often used to treat adrenocortical carcinoma. Sometimes surgery is done to remove the nearby lymph nodes and other tissue where the cancer has spread.
Radiation therapy
Radiation therapy is a cancer treatment that uses high-energy x-rays or other types of radiation to kill cancer cells or keep them from growing. There are two types of radiation therapy:
External radiation therapy uses a machine outside the body to send radiation toward the area of the body with cancer.
The way the radiation therapy is given depends on the type and stage of the cancer being treated.
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). When chemotherapy is placed directly into the cerebrospinal fluid, an organ, or a body cavity such as the abdomen, the drugs mainly affect cancer cells in those areas (regional chemotherapy). Combination chemotherapy is treatment using more than one anticancer drug. The way the chemotherapy is given depends on the type and stage of the cancer being treated.
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.
Targeted therapy
Targeted therapy is a type of treatment that uses drugs or other substances to identify and attack specific cancer cells.
Treatment for adrenocortical carcinoma may cause side effects.
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 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).
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.
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.
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.
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.
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.
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 adrenocortical 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 Adrenocortical Carcinoma Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/adrenocortical/patient/adrenocortical-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389225]
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.
Adrenocortical carcinoma (ACC) is a rare tumor with an annual incidence of 2 cases per 1 million people.[1] Although it mainly occurs in adults, children may be affected. The median age at diagnosis is 46 years. Historically, about 30% of these malignancies are confined to the adrenal gland at diagnosis.[2] However, more ACCs are being diagnosed at early stages, most likely because of the widespread use of high-quality imaging techniques.
Prognostic Factors
Retrospective studies have identified the following three important prognostic factors:[3]
Completeness of resection.
Stage of disease.
Pathological grade.
Patients who have low-grade tumors without evidence of invasion into local tissues or spread to lymph nodes have an improved prognosis. The role of other prognostic indicators is controversial.
Clinical Features
In approximately 60% of patients, symptoms related to excessive hormone secretion are the main reason for seeking medical attention. Biochemical hormone testing reveals that up to 80% of tumors are functioning. The second most common symptoms at time of initial presentation are unspecific abdominal symptoms, such as abdominal pain or fullness. A small percentage of ACCs are incidentally discovered when imaging studies are conducted for reasons other than potential adrenal disease.
Diagnosis
Initial evaluation should include careful endocrine studies to reveal any excessive hormone production by the tumor, which can serve as a tumor marker during therapy. Staging should include imaging of the primary site by computed tomography (CT) and/or magnetic resonance imaging of the abdomen. In addition, a CT of the chest is necessary to assess potential lung metastasis. Although the use of positron emission tomography may be effective in identifying unsuspected sites of metastases, its role as a staging tool is unclear. The detection of metastatic lesions may allow effective palliation of both functioning and nonfunctioning tumors.
Prognosis and Survival
The most common sites of metastases are the lung, liver, peritoneum, and, less commonly, the bones and major veins. Palliation of metastatic functioning tumors may be achieved by resection of both the primary tumor and metastatic lesions. Unresectable or widely disseminated tumors may be palliated by adrenolytic therapy with mitotane, antihormonal drugs (i.e., ketoconazole and metyrapone), systemic chemotherapy, and/or radiation therapy. However, 5-year survival rates for patients with stage IV tumors are usually less than 20%.[2]
Although several studies have shown partial or even complete remission, there is no convincing evidence that systemic therapy improves the survival duration of patients with adrenal cancer. Radical open surgical excision is the treatment of choice for patients with localized malignancies and remains the only method for achieving long-term disease-free survival.[4] Overall 5-year survival rates are approximately 38% to 46%.[1,2]
References
Bilimoria KY, Shen WT, Elaraj D, et al.: Adrenocortical carcinoma in the United States: treatment utilization and prognostic factors. Cancer 113 (11): 3130-6, 2008. [PUBMED Abstract]
Fassnacht M, Allolio B: Epidemiology of adrenocortical carcinoma. In: Hammer GD, Else T, eds.: Adrenocortical Carcinoma: Basic Science and Clinical Concepts. Springer, 2010, pp 23-9.
Miller BS, Gauger PG, Hammer GD, et al.: Proposal for modification of the ENSAT staging system for adrenocortical carcinoma using tumor grade. Langenbecks Arch Surg 395 (7): 955-61, 2010. [PUBMED Abstract]
Cellular Classification of Adrenocortical Carcinoma
Adrenocortical carcinoma (ACC) can be classified into functioning and nonfunctioning tumors by clinical and biochemical assessment. Approximately 60% of ACCs produce hormones.[1] The associated clinical syndromes include:
Hypercortisolism (Cushing syndrome).
Hirsutism/virilization.
Feminization.
Precocious puberty.
Hyperaldosteronism.
Biochemical assessment aims to detect increased levels of cortisol (24-hour urine, 1 mg dexamethasone suppression test, serum adrenocorticotropic hormone and cortisol), androgens (dehydroepiandrosterone sulfate, testosterone), estrogens (estradiol), and mineralocorticoids (renin, aldosterone).
Pathological assessment can differentiate high-grade and low-grade tumors according to the mitotic activity of the tumor. The Weiss score can differentiate benign and malignant adrenocortical tumors, based on several histopathological criteria, including:[2]
Weiss LM, Medeiros LJ, Vickery AL: Pathologic features of prognostic significance in adrenocortical carcinoma. Am J Surg Pathol 13 (3): 202-6, 1989. [PUBMED Abstract]
Stage Information for Adrenocortical Carcinoma
Several staging systems for adrenocortical carcinoma (ACC) are in use.
The American Joint Committee on Cancer (AJCC) defines ACC stage by the size of the primary tumor, the degree of local invasion, and whether it has spread to regional lymph nodes or distant sites.[1] Proper staging should include computed tomography (CT) of the abdomen and chest. Magnetic resonance imaging (MRI) may add specificity to CT evaluation of an adrenal mass.[2] In-phase and out-of-phase T1-weighted imaging may be the most effective noninvasive method to differentiate benign from malignant adrenal masses. MRI may suggest evidence of extracapsular tumor invasion, extension into the vena cava, or metastases. Patency of surrounding vessels can often be demonstrated with gadolinium-enhanced sequences or flip-angle techniques.[3]
In addition to AJCC staging, the European Network for the Study of Adrenal Tumors (ENSAT) staging system is widely used internationally.[4] The ENSAT staging system is essentially the same as the AJCC system, but reserves stage IV only for tumors with distant metastasis. Other staging systems include the classical Macfarlane system, modified by Sullivan, and the Union Internationale Contre le Cancer staging system, published by the World Health Organization.[5]
AJCC Stage Groupings and TNM Definitions
The AJCC has designated staging by TNM (tumor, node, metastasis) to define ACC.[1]
Table 1. Definitions of TNM Stage Ia
Stage
TNM
Description
T = primary tumor; N = regional lymph node; M = distant metastasis.
aReprinted with permission from AJCC: Adrenal Cortical Carcinoma. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 911–8.
I
T1, N0, M0
T1 = Tumor ≤5 cm in greatest dimension, no extra-adrenal invasion.
N0 = No regional lymph node metastasis.
M0 = No distant metastasis.
Table 2. Definitions of TNM Stage IIa
Stage
TNM
Description
T = primary tumor; N = regional lymph node; M = distant metastasis.
aReprinted with permission from AJCC: Adrenal Cortical Carcinoma. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 911–8.
II
T2, N0, M0
T2 = Tumor >5 cm, no extra-adrenal invasion.
N0 = No regional lymph node metastasis.
M0 = No distant metastasis.
Table 3. Definitions of TNM Stage IIIa
Stage
TNM
Description
T = primary tumor; N = regional lymph node; M = distant metastasis.
aReprinted with permission from AJCC: Adrenal Cortical Carcinoma. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 911–8.
III
T1, N1, M0
T1 = Tumor ≤5 cm in greatest dimension, no extra-adrenal invasion.
N1 = Metastasis in regional lymph node(s).
M0 = No distant metastasis.
T2, N1, M0
T2 = Tumor >5 cm, no extra-adrenal invasion.
N1 = Metastasis in regional lymph node(s).
M0 = No distant metastasis.
T3, Any N, M0
T3 = Tumor of any size with local invasion but not invading adjacent organs.
NX = Regional lymph nodes cannot be assessed.
N0 = No regional lymph node metastasis.
N1 = Metastasis in regional lymph node(s).
M0 = No distant metastasis.
T4, Any N, M0
T4 = Tumor of any size that invades adjacent organs (kidney, diaphragm, pancreas, spleen, or liver) or large blood vessels (renal vein or vena cava).
Any N = See descriptions in this table, T3, Any N, M0.
M0 = No distant metastasis.
Table 4. Definitions of TNM Stage IVa
Stage
TNM
Description
T = primary tumor; N = regional lymph node; M = distant metastasis.
aReprinted with permission from AJCC: Adrenal Cortical Carcinoma. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 911–8.
IV
Any T, Any N, M1
TX = Primary tumor cannot be assessed.
T0 = No evidence of primary tumor.
T1 = Tumor ≤5 cm in greatest dimension, no extra-adrenal invasion.
T2 = Tumor >5 cm, no extra-adrenal invasion.
T3 = Tumor of any size with local invasion but not invading adjacent organs.
T4 = Tumor of any size that invades adjacent organs (kidney, diaphragm, pancreas, spleen, or liver) or large blood vessels (renal vein or vena cava).
Adrenal Cortical Carcinoma. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. Springer; 2017, pp. 911–8.
Doppman JL, Reinig JW, Dwyer AJ, et al.: Differentiation of adrenal masses by magnetic resonance imaging. Surgery 102 (6): 1018-26, 1987. [PUBMED Abstract]
Brown ED, Semelka RC: Magnetic resonance imaging of the adrenal gland and kidney. Top Magn Reson Imaging 7 (2): 90-101, 1995 Spring. [PUBMED Abstract]
Fassnacht M, Johanssen S, Quinkler M, et al.: Limited prognostic value of the 2004 International Union Against Cancer staging classification for adrenocortical carcinoma: proposal for a Revised TNM Classification. Cancer 115 (2): 243-50, 2009. [PUBMED Abstract]
Complete surgical removal of the tumor is the treatment of choice for patients with stage I ACC. The long-term survival of patients with nonfunctioning tumors is comparable with that of patients with functioning tumors. The removal of regional lymph nodes that are not clinically enlarged is not indicated.
Adjuvant mitotane (under clinical evaluation).
Adjuvant mitotane has shown some progression-free or disease-free survival advantage, but no overall survival advantage.[1–3]
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
Terzolo M, Angeli A, Fassnacht M, et al.: Adjuvant mitotane treatment for adrenocortical carcinoma. N Engl J Med 356 (23): 2372-80, 2007. [PUBMED Abstract]
Polat B, Fassnacht M, Pfreundner L, et al.: Radiotherapy in adrenocortical carcinoma. Cancer 115 (13): 2816-23, 2009. [PUBMED Abstract]
Sabolch A, Feng M, Griffith K, et al.: Adjuvant and definitive radiotherapy for adrenocortical carcinoma. Int J Radiat Oncol Biol Phys 80 (5): 1477-84, 2011. [PUBMED Abstract]
Treatment of Stage II Adrenocortical Carcinoma
Treatment Options for Stage II Adrenocortical Carcinoma (ACC)
Complete surgical removal of the tumor is the treatment of choice for patients with stage II ACC. The long-term survival of patients with nonfunctioning tumors is comparable with that of patients with functioning tumors. The removal of regional lymph nodes that are not clinically enlarged is not indicated.
Adjuvant mitotane (under clinical evaluation).
Adjuvant mitotane has shown some progression-free or disease-free survival advantage, no overall survival advantage.[1–3]
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
Terzolo M, Angeli A, Fassnacht M, et al.: Adjuvant mitotane treatment for adrenocortical carcinoma. N Engl J Med 356 (23): 2372-80, 2007. [PUBMED Abstract]
Polat B, Fassnacht M, Pfreundner L, et al.: Radiotherapy in adrenocortical carcinoma. Cancer 115 (13): 2816-23, 2009. [PUBMED Abstract]
Sabolch A, Feng M, Griffith K, et al.: Adjuvant and definitive radiotherapy for adrenocortical carcinoma. Int J Radiat Oncol Biol Phys 80 (5): 1477-84, 2011. [PUBMED Abstract]
Treatment of Stage III Adrenocortical Carcinoma
Treatment Options for Stage III Adrenocortical Carcinoma (ACC)
Complete surgical removal of the tumor, with or without regional lymph node dissection, is the treatment of choice for patients with stage III ACC. The treatment of patients who have tumors with local invasion, but without clinically enlarged regional lymph nodes, is complete surgical removal, as for stage I and stage II tumors. For those with enlarged regional lymph nodes, a lymph node dissection should be included in the procedure. These patients are at high risk of disease recurrence and should consider enrolling in a clinical trial.
Radiation therapy (approximately 50–70 Gy over a period of 4 weeks) may be given to patients with localized but unresectable tumors (under clinical evaluation).[1]
Chemotherapy with mitotane in doses as high as 10 to 12 g/day to achieve a blood level of 14 to 20 mg/L should be considered for patients unable to undergo complete resection (under clinical evaluation). This adrenolytic drug produces useful clinical responses in about 20% to 30% of patients with measurable tumor burden.[2,3]
The role of mitotane as adjuvant therapy after complete tumor resection is still unclear but should be discussed with the patient. For patients who undergo a complete resection, the role of adjuvant mitotane and radiation therapy is the same as for patients with stage I and stage II ACC.
Chemotherapy with mitotane plus streptozotocin or mitotane plus etoposide, doxorubicin, and cisplatin may be effective and has been compared in a phase III clinical trial (NCT00924144) (under clinical evaluation).[2]
Many patients with functioning tumors who receive treatment experience reduced hormone production. In patients with increased hormone production, antisteroidogenic drugs, such as ketoconazole and metyrapone, and steroid receptor antagonists, such as spironolactone and mifepristone, should be considered.
Clinical trials are appropriate for newly diagnosed patients.
Current Clinical Trials
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
Chemotherapy with mitotane plus streptozotocin or mitotane plus etoposide, doxorubicin, and cisplatin, as evidenced by the NCT00924144 phase III clinical trial.[1]
Radiation therapy to bone metastases.
Surgical removal of localized metastases, particularly for tumors that are functioning.
Temporary palliation of disseminated ACC can sometimes be achieved with the chemotherapeutic agent mitotane. Although measurable partial remissions are unusual and are reported in only 20% to 30% of patients, palliation of hormone symptoms is commonly observed. Prolonged treatment with mitotane, however, is often limited by gastrointestinal and neurological toxicity. Local recurrences and selected sites of metastatic disease can sometimes be palliated surgically or with radiation therapy.[1,2]
Two other cytotoxic chemotherapy regimens may be effective and have been compared in a phase III clinical trial:[1]
Streptozotocin plus mitotane.
Etoposide, doxorubicin, and cisplatin plus mitotane.
Clinical trials of other chemotherapy regimens are ongoing.
Many patients with functioning tumors who receive treatment experience reduced hormone production. In patients with increased hormone production, antisteroidogenic drugs, such as ketoconazole and metyrapone, and steroid receptor antagonists, such as spironolactone and mifepristone, should be considered.
Clinical trials, including phase I and II trials of newer chemotherapeutic and biological agents, are appropriate and should be considered.
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.
Terzolo M, Ardito A, Zaggia B, et al.: Mitotane. In: Hammer GD, Else T, eds.: Adrenocortical Carcinoma: Basic Science and Clinical Concepts. Springer, 2010, pp 369-82.
Treatment of Recurrent Adrenocortical Carcinoma
Deciding to treat patients with recurrent adrenocortical carcinoma (ACC), and what treatment to use, depends on many factors, including previous treatment, site of recurrence, and individual patient considerations. Local recurrence and selected sites of metastatic disease can sometimes be palliated by surgery or radiation therapy. Although recurrent ACC is not considered curable, palliation of hormonal symptoms and occasional 5-year survivals can be achieved.[1] However, substantial morbidity is associated with resection of recurrent tumors.
Clinical trials, including phase I and II trials of newer chemotherapeutic and biological agents, are appropriate and should be considered.
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
Jensen JC, Pass HI, Sindelar WF, et al.: Recurrent or metastatic disease in select patients with adrenocortical carcinoma. Aggressive resection vs chemotherapy. Arch Surg 126 (4): 457-61, 1991. [PUBMED Abstract]
Latest Updates to This Summary (12/13/2024)
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.
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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 adrenocortical 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.
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PDQ® Adult Treatment Editorial Board. PDQ Adrenocortical Carcinoma Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/adrenocortical/hp/adrenocortical-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389393]
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Pancreatic neuroendocrine tumors form in hormone-making cells (islet cells) of the pancreas.
Pancreatic NETs may or may not cause signs or symptoms.
There are different kinds of functional pancreatic NETs.
Having certain syndromes can increase the risk of pancreatic NETs.
Different types of pancreatic NETs have different signs and symptoms.
Lab tests and imaging tests are used to diagnose pancreatic NETs.
Other kinds of lab tests are used to check for the specific type of pancreatic NETs.
Certain factors affect prognosis (chance of recovery) and treatment options.
Pancreatic neuroendocrine tumors form in hormone-making cells (islet cells) of the pancreas.
The pancreas is a gland about 6 inches long that is shaped like a thin pear lying on its side. The wider end of the pancreas is called the head, the middle section is called the body, and the narrow end is called the tail. The pancreas lies behind the stomach and in front of the spine.
EnlargeAnatomy of the pancreas. The pancreas has three areas: the head, body, and tail. It is found in the abdomen near the stomach, intestines, and other organs.
Endocrine pancreas cells make several kinds of hormones (chemicals that control the actions of certain cells or organs in the body), such as insulin to control blood sugar. They cluster together in many small groups (islets) throughout the pancreas. Endocrine pancreas cells are also called islet cells or islets of Langerhans. Tumors that form in islet cells are called islet cell tumors, pancreatic endocrine tumors, or pancreatic neuroendocrine tumors (pancreatic NETs).
Pancreatic neuroendocrine tumors (NETs) may be benign (not cancer) or malignant (cancer). When pancreatic NETs are malignant, they are called pancreatic endocrine cancer or islet cell carcinoma.
Pancreatic NETs are much less common than pancreatic exocrine tumors and have a better prognosis.
Pancreatic NETs may or may not cause signs or symptoms.
Functional tumors make extra amounts of hormones, such as gastrin, insulin, and glucagon, that cause signs and symptoms.
Nonfunctional tumors do not make extra amounts of hormones. Signs and symptoms are caused by the tumor as it spreads and grows. Most nonfunctional tumors are malignant (cancer).
Most pancreatic NETs are functional tumors.
There are different kinds of functional pancreatic NETs.
Pancreatic NETs make different kinds of hormones such as gastrin, insulin, and glucagon. Functional pancreatic NETs include the following:
Gastrinoma: A tumor that forms in cells that make gastrin. Gastrin is a hormone that causes the stomach to release an acid that helps digest food. Both gastrin and stomach acid are increased by gastrinomas. When increased stomach acid, stomach ulcers, and diarrhea are caused by a tumor that makes gastrin, it is called Zollinger-Ellison syndrome. A gastrinoma usually forms in the head of the pancreas and sometimes forms in the small intestine. Most gastrinomas are malignant (cancer).
Insulinoma: A tumor that forms in cells that make insulin. Insulin is a hormone that controls the amount of glucose (sugar) in the blood. It moves glucose into the cells, where it can be used by the body for energy. Insulinomas are usually slow-growing tumors that rarely spread. An insulinoma forms in the head, body, or tail of the pancreas. Insulinomas are usually benign (not cancer).
Glucagonoma: A tumor that forms in cells that make glucagon. Glucagon is a hormone that increases the amount of glucose in the blood. It causes the liver to break down glycogen. Too much glucagon causes hyperglycemia (high blood sugar). A glucagonoma usually forms in the tail of the pancreas. Most glucagonomas are malignant (cancer).
Other types of tumors: There are other rare types of functional pancreatic NETs that make hormones, including hormones that control the balance of sugar, salt, and water in the body. These tumors include:
These other types of tumors are grouped together because they are treated in much the same way.
Having certain syndromes can increase the risk of pancreatic NETs.
Anything that increases your risk of getting a disease is called a risk factor. Having a risk factor does not mean that you will get cancer; not having risk factors doesn’t mean that you will not get cancer. Talk with your doctor if you think you may be at risk.
Different types of pancreatic NETs have different signs and symptoms.
Signs or symptoms can be caused by the growth of the tumor and/or by hormones the tumor makes or by other conditions. Some tumors may not cause signs or symptoms. Check with your doctor if you have any of these problems.
Signs and symptoms of a non-functional pancreatic NET
A non-functional pancreatic NET may grow for a long time without causing signs or symptoms. It may grow large or spread to other parts of the body before it causes signs or symptoms, such as:
Low blood sugar. This can cause blurred vision, headache, and feeling lightheaded, tired, weak, shaky, nervous, irritable, sweaty, confused, or hungry.
Fast heartbeat.
Too much glucagon may cause:
Skin rash on the face, stomach, or legs.
High blood sugar. This can cause headaches, frequent urination, dry skin and mouth, or feeling hungry, thirsty, tired, or weak.
Blood clots. Blood clots in the lung can cause shortness of breath, cough, or pain in the chest. Blood clots in the arm or leg can cause pain, swelling, warmth, or redness of the arm or leg.
Diarrhea.
Weight loss for no known reason.
Sore tongue or sores at the corners of the mouth.
Too much vasoactive intestinal peptide (VIP) may cause:
Very large amounts of watery diarrhea.
Dehydration. This can cause feeling thirsty, making less urine, dry skin and mouth, headaches, dizziness, or feeling tired.
Low potassium level in the blood. This can cause muscle weakness, aching, or cramps, numbness and tingling, frequent urination, fast heartbeat, and feeling confused or thirsty.
Cramps or pain in the abdomen.
Weight loss for no known reason.
Too much somatostatin may cause:
High blood sugar. This can cause headaches, frequent urination, dry skin and mouth, or feeling hungry, thirsty, tired, or weak.
Diarrhea.
Steatorrhea (very foul-smelling stool that floats).
The treatment of pancreatic NETs that make too much ACTH and Cushing syndrome are not discussed in this summary.
Lab tests and imaging tests are used to diagnose pancreatic NETs.
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.
Blood chemistry studies: A procedure in which a blood sample is checked to measure the amounts of certain substances, such as glucose (sugar), released into the blood by organs and tissues in the body. An unusual (higher or lower than normal) amount of a substance can be a sign of disease.
Chromogranin A test: A test in which a blood sample is checked to measure the amount of chromogranin A in the blood. A higher than normal amount of chromogranin A and normal amounts of hormones such as gastrin, insulin, and glucagon can be a sign of a non-functional pancreatic NET.
AbdominalCT scan (CAT scan): A procedure that makes a series of detailed pictures of the abdomen, 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.
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. This procedure is also called nuclear magnetic resonance imaging (NMRI).
Somatostatin receptor scintigraphy: A type of radionuclide scan that may be used to find small pancreatic NETs. A small amount of radioactiveoctreotide (a hormone that attaches to tumors) is injected into a vein and travels through the blood. The radioactive octreotide attaches to the tumor and a special camera that detects radioactivity is used to show where the tumors are in the body. This procedure is also called octreotide scan and SRS.
Endoscopic ultrasound (EUS): A procedure in which an endoscope is inserted into the body, usually through the mouth or rectum. 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.
Endoscopic retrograde cholangiopancreatography (ERCP): A procedure used to x-ray the ducts (tubes) that carry bile from the liver to the gallbladder and from the gallbladder to the small intestine. Sometimes pancreatic cancer causes these ducts to narrow and block or slow the flow of bile, causing jaundice. An endoscope is passed through the mouth, esophagus, and stomach into the first part of the small intestine. An endoscope is a thin, tube-like instrument with a light and a lens for viewing. A catheter (a smaller tube) is then inserted through the endoscope into the pancreatic ducts. A dye is injected through the catheter into the ducts and an x-ray is taken. If the ducts are blocked by a tumor, a fine tube may be inserted into the duct to unblock it. This tube (or stent) may be left in place to keep the duct open. Tissue samples may also be taken and checked under a microscope for signs of cancer.
Angiogram: A procedure to look at blood vessels and the flow of blood. A contrast dye is injected into the blood vessel. As the contrast dye moves through the blood vessel, x-rays are taken to see if there are any blockages.
Laparotomy: A surgical procedure in which an incision (cut) is made in the wall of the abdomen to check the inside of the abdomen for signs of disease. The size of the incision depends on the reason the laparotomy is being done. Sometimes organs are removed or tissue samples are taken and checked under a microscope for signs of disease.
Intraoperative ultrasound: A procedure that uses high-energy sound waves (ultrasound) to create images of internal organs or tissues during surgery. A transducer placed directly on the organ or tissue is used to make the sound waves, which create echoes. The transducer receives the echoes and sends them to a computer, which uses the echoes to make pictures called sonograms.
Biopsy: The removal of cells or tissues so they can be viewed under a microscope by a pathologist to check for signs of cancer. There are several ways to do a biopsy for pancreatic NETs. Cells may be removed using a fine or wide needle inserted into the pancreas during an x-ray or ultrasound. Tissue may also be removed during a laparoscopy (a surgical incision made in the wall of the abdomen).
Bone scan: A procedure to check if there are rapidly dividing cells, such as cancer cells, in the bone. A very small amount of radioactive material is injected into a vein and travels through the bloodstream. The radioactive material collects in bones with cancer and is detected by a scanner.
Other kinds of lab tests are used to check for the specific type of pancreatic NETs.
The following tests and procedures may be used:
Gastrinoma
Fasting serum gastrin test: A test in which a blood sample is checked to measure the amount of gastrin in the blood. This test is done after the patient has had nothing to eat or drink for at least 8 hours. Conditions other than gastrinoma can cause an increase in the amount of gastrin in the blood.
Basal acid output test: A test to measure the amount of acid made by the stomach. The test is done after the patient has had nothing to eat or drink for at least 8 hours. A tube is inserted through the nose or throat, into the stomach. The stomach contents are removed and four samples of gastric acid are removed through the tube. These samples are used to find out the amount of gastric acid made during the test and the pH level of the gastricsecretions.
Secretin stimulation test: If the basal acid output test result is not normal, a secretin stimulation test may be done. The tube is moved into the small intestine and samples are taken from the small intestine after a drug called secretin is injected. Secretin causes the small intestine to make acid. When there is a gastrinoma, the secretin causes an increase in how much gastric acid is made and the level of gastrin in the blood.
Somatostatin receptor scintigraphy: A type of radionuclide scan that may be used to find small pancreatic NETs. A small amount of radioactive octreotide (a hormone that attaches to tumors) is injected into a vein and travels through the blood. The radioactive octreotide attaches to the tumor and a special camera that detects radioactivity is used to show where the tumors are in the body. This procedure is also called octreotide scan and SRS.
Insulinoma
Fasting serum glucose and insulin test: A test in which a blood sample is checked to measure the amounts of glucose (sugar) and insulin in the blood. The test is done after the patient has had nothing to eat or drink for at least 24 hours.
Glucagonoma
Fasting serum glucagon test: A test in which a blood sample is checked to measure the amount of glucagon in the blood. The test is done after the patient has had nothing to eat or drink for at least 8 hours.
Other tumor types
VIPoma
Serum VIP (vasoactive intestinal peptide) test: A test in which a blood sample is checked to measure the amount of VIP.
Blood chemistry studies: A procedure in which a blood sample is checked to measure the amounts of certain substances released into the blood by organs and tissues in the body. An unusual (higher or lower than normal) amount of a substance can be a sign of disease. In VIPoma, there is a lower than normal amount of potassium.
Stool analysis: A stool sample is checked for a higher than normal sodium (salt) and potassium levels.
Somatostatinoma
Fasting serum somatostatin test: A test in which a blood sample is checked to measure the amount of somatostatin in the blood. The test is done after the patient has had nothing to eat or drink for at least 8 hours.
Somatostatin receptor scintigraphy: A type of radionuclide scan that may be used to find small pancreatic NETs. A small amount of radioactive octreotide (a hormone that attaches to tumors) is injected into a vein and travels through the blood. The radioactive octreotide attaches to the tumor and a special camera that detects radioactivity is used to show where the tumors are in the body. This procedure is also called octreotide scan and SRS.
Certain factors affect prognosis (chance of recovery) and treatment options.
Pancreatic NETs can often be cured. The prognosis and treatment options depend on the following:
The type of cancer cell.
Where the tumor is found in the pancreas.
Whether the tumor has spread to more than one place in the pancreas or to other parts of the body.
Whether the patient has MEN1 syndrome.
The patient’s age and general health.
Whether the cancer has just been diagnosed or has recurred (come back).
Stages of Pancreatic Neuroendocrine Tumors
Key Points
The plan for cancer treatment depends on where the NET is found in the pancreas and whether it has spread.
There are three ways that cancer spreads in the body.
Cancer may spread from where it began to other parts of the body.
Pancreatic NETs can recur (come back) after they have been treated.
The plan for cancer treatment depends on where the NET is found in the pancreas and whether it has spread.
The process used to find out if cancer has spread within the pancreas or to other parts of the body is called staging. The results of the tests and procedures used to diagnosepancreatic neuroendocrine tumors (NETs) are also used to find out whether the cancer has spread. See the General Information section for a description of these tests and procedures.
Although there is a standard staging system for pancreatic NETs, it is not used to plan treatment. Treatment of pancreatic NETs is based on the following:
Whether the cancer is found in one place in the pancreas.
Whether the cancer is found in several places in the pancreas.
Whether the cancer has spread to lymph nodes near the pancreas or to other parts of the body such as the liver, lung, peritoneum, or bone.
There are three ways that cancer spreads in the body.
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 tumor as the primary tumor. For example, if a pancreatic neuroendocrine tumor spreads to the liver, the tumor cells in the liver are actually neuroendocrine tumor cells. The disease is metastatic pancreatic neuroendocrine tumor, not liver 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.
Pancreatic NETs can recur (come back) after they have been treated.
The tumors may come back in the pancreas or in other parts of the body.
Treatment Option Overview
Key Points
There are different types of treatment for patients with pancreatic NETs.
The following types of treatment are used:
Surgery
Chemotherapy
Hormone therapy
Hepatic arterial occlusion or chemoembolization
Targeted therapy
Supportive care
New types of treatment are being tested in clinical trials.
Treatment for pancreatic neuroendocrine tumors 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 pancreatic NETs.
Different types of treatments are available for patients with pancreatic neuroendocrine tumors (NETs). 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
An operation may be done to remove the tumor. One of the following types of surgery may be used:
Enucleation: Surgery to remove the tumor only. This may be done when cancer occurs in one place in the pancreas.
Liverresection: Surgery to remove part or all of the liver.
Radiofrequency ablation: The use of a special probe with tiny electrodes that kill cancer cells. Sometimes the probe is inserted directly through the skin and only local anesthesia is needed. In other cases, the probe is inserted through an incision in the abdomen. This is done in the hospital with general anesthesia.
Cryosurgicalablation: A procedure in which tissue is frozen to destroy abnormal cells. This is usually done with a special instrument that contains liquid nitrogen or liquid carbon dioxide. The instrument may be used during surgery or laparoscopy or inserted through the skin. This procedure is also called cryoablation.
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). When chemotherapy is placed directly into the cerebrospinal fluid, an organ, or a body cavity such as the abdomen, the drugs mainly affect cancer cells in those areas (regional chemotherapy). Combination chemotherapy is the use of more than one anticancer drug. The way the chemotherapy is given depends on the type of the cancer being treated.
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 circulated in 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.
Hepatic arterial occlusion or chemoembolization
Hepatic arterial occlusion uses drugs, small particles, or other agents to block or reduce the flow of blood to the liver through the hepatic artery (the major blood vessel that carries blood to the liver). This is done to kill cancer cells growing in the liver. The tumor is prevented from getting the oxygen and nutrients it needs to grow. The liver continues to receive blood from the hepatic portal vein, which carries blood from the stomach and intestine.
Chemotherapy delivered during hepatic arterial occlusion is called chemoembolization. The anticancer drug is injected into the hepatic artery through a catheter (thin tube). The drug is mixed with the substance that blocks the artery and cuts off blood flow to the tumor. Most of the anticancer drug is trapped near the tumor and only a small amount of the drug reaches other parts of the body.
The blockage may be temporary or permanent, depending on the substance used to block the artery.
Targeted therapy
Targeted therapy is a type of treatment that uses drugs or other substances to identify and attack specific cancer cells. Targeted therapies usually cause less harm to normal cells than chemotherapy or radiation therapy do. Certain types of targeted therapies are being studied in the treatment of pancreatic NETs.
Supportive care
Supportive care is given to lessen the problems caused by the disease or its treatment. Supportive care for pancreatic NETs may include treatment for the following:
Stomach ulcers may be treated with drug therapy such as:
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).
Surgery to cut the nerve that causes stomach cells to make acid and treatment with a drug that decreases stomach acid.
Surgery to remove the whole stomach (rare).
For a single tumor in the body or tail of the pancreas, treatment is usually surgery to remove the body or tail of the pancreas.
For several tumors in the pancreas, treatment is usually surgery to remove the body or tail of the pancreas. If tumor remains after surgery, treatment may include either:
Surgery to cut the nerve that causes stomach cells to make acid and treatment with a drug that decreases stomach acid; or
Chemoembolization, with or without systemic chemotherapy.
Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.
For one large tumor in the body or tail of the pancreas, treatment is usually a distal pancreatectomy (surgery to remove the body and tail of the pancreas).
For more than one tumor in the pancreas, treatment is usually surgery to remove any tumors in the head of the pancreas and the body and tail of the pancreas.
For tumors that cannot be removed by surgery, treatment may include the following:
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.
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 Other Pancreatic Neuroendocrine Tumors (Islet Cell Tumors)
Surgery to remove as much of the tumor as possible when the tumor cannot be completely removed or has spread to distant parts of the body. This is palliative therapy to relieve symptoms and improve the quality of life.
For tumors that have spread to lymph nodes or other parts of the body, treatment may include the following:
For somatostatinoma, treatment may include the following:
Surgery to remove the tumor.
For cancer that has spread to distant parts of the body, surgery to remove as much of the cancer as possible to relieve symptoms and improve quality of life.
For tumors that continue to grow during treatment or have spread to other parts of the body, treatment may include the following:
For cancer that has spread to distant parts of the body, surgery to remove as much of the cancer as possible or hormone therapy to relieve symptoms and improve quality of life.
For tumors that continue to grow during treatment or have spread to other parts of the body, treatment may include the following:
Chemotherapy.
Targeted therapy.
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 or Progressive Pancreatic Neuroendocrine Tumors (Islet Cell Tumors)
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.
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 pancreatic neuroendocrine tumors (islet cell tumors). It is meant to inform and help patients, families, and caregivers. It does not give formal guidelines or recommendations for making decisions about health care.
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 Pancreatic Neuroendocrine Tumors (Islet Cell Tumors) Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/pancreatic/patient/pnet-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389340]
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This summary provides information about the treatment of exocrine pancreatic cancer.
Incidence and Mortality
Estimated new cases and deaths from pancreatic cancer in the United States in 2025:[1]
New cases: 67,440.
Deaths: 51,980.
The incidence of pancreatic cancer has markedly increased over the past several decades. In the United States, it ranks as the fourth leading cause of cancer death in men and the third leading cause of cancer death in women.[1] Despite the high mortality rate associated with pancreatic cancer, its etiology is poorly understood.
Risk Factors
Risk factors for development of pancreatic cancer include:[2,3]
A family history of pancreatic cancer.
Cigarette smoking.
Obesity.
Chronic pancreatitis.
Certain genetic disorders (such as those associated with the BRCA1, BRCA2, PALB2, and ATM genes).
Cancers of the pancreas are commonly identified by the site of involvement within the pancreas. Surgical approaches differ for masses in the head, body, tail, or uncinate process of the pancreas.
Clinical Features
Pancreatic cancer symptoms depend on the site of the tumor within the pancreas and the degree of tumor involvement.
In the early stages of pancreatic cancer, there are not many noticeable symptoms. As the cancer grows, symptoms may include:
Jaundice.
Light-colored stools or dark urine.
Pain in the upper or middle abdomen and back.
Weight loss for no known reason.
Loss of appetite.
Fatigue.
Diagnostic and Staging Evaluation
Pancreatic cancer is difficult to detect and diagnose for the following reasons:
There are no noticeable signs or symptoms in the early stages of pancreatic cancer.
The signs of pancreatic cancer, when present, are like the signs of many other illnesses, such as pancreatitis or an ulcer.
The pancreas is obscured by other organs in the abdomen and is difficult to visualize clearly on imaging tests.
To appropriately treat pancreatic cancer, it is crucial to evaluate whether the cancer can be resected.
Imaging
Imaging tests may help diagnose pancreatic cancer and identify patients with disease that is not amenable to resection. Imaging tests may include:[4]
Helical computed tomographic scan.
Magnetic resonance imaging scan.
Endoscopic ultrasonography.
Minimally invasive techniques, such as laparoscopy and laparoscopic ultrasonography, which may be used to decrease the use of laparotomy.[5,6]
Peritoneal cytology
In a case series of 228 patients, positive peritoneal cytology had a positive predictive value of 94%, specificity of 98%, and sensitivity of 25% for determining unresectability.[7]
Tumor markers
No tumor-specific markers exist for pancreatic cancer. Markers such as serum cancer antigen (CA) 19-9 have low specificity. Most patients with pancreatic cancer have an elevated CA 19-9 level at diagnosis. Increased CA 19-9 levels during or after definitive therapy may identify patients with progressive tumor growth.[8][Level of evidence C2] However, the presence of a normal CA 19-9 level does not preclude recurrence.
Prognosis and Survival
The primary factors that influence prognosis are:
Whether the tumor is localized and can be completely resected.
Whether the tumor has spread to lymph nodes or elsewhere.
Exocrine pancreatic cancer is rarely curable and has an overall survival (OS) rate of less than 6%.[9] Pancreatic cancer is associated with significant morbidity and mortality, and treatment decisions are complex. Management with a comprehensive multidisciplinary team should be considered.
The highest cure rate occurs when the tumor is truly localized to the pancreas; however, this stage of disease accounts for less than 20% of cases. For patients with localized disease and small cancers (<2 cm) with no lymph node metastases and no extension beyond the capsule of the pancreas, complete surgical resection is associated with an actuarial 5-year survival rate of 18% to 24%.[10][Level of evidence C1]
Surgical resection is the mainstay of curative treatment and provides a survival benefit in patients with small, localized pancreatic tumors, but it should be considered only alongside systemic therapy. Patients with unresectable, metastatic, or recurrent disease are unlikely to benefit from surgical resection.
Patients with any stage of pancreatic cancer are candidates for clinical trials because of the poor response to chemotherapy, radiation therapy, and surgery as conventionally used.
Information about ongoing clinical trials for pancreatic cancer is available from the NCI website.
Palliative Therapy
Palliation of symptoms may be achieved with conventional treatment (systemic chemotherapy).
Palliative measures that may improve quality of life without affecting OS include:[11,12]
Surgical or radiological biliary decompression.
Relief of gastric outlet obstruction.
Pain control.
Psychological care to address the potentially disabling psychological events associated with the diagnosis and treatment of pancreatic cancer.[13]
References
American Cancer Society: Cancer Facts and Figures 2025. American Cancer Society, 2025. Available online. Last accessed January 16, 2025.
Tersmette AC, Petersen GM, Offerhaus GJ, et al.: Increased risk of incident pancreatic cancer among first-degree relatives of patients with familial pancreatic cancer. Clin Cancer Res 7 (3): 738-44, 2001. [PUBMED Abstract]
Nöthlings U, Wilkens LR, Murphy SP, et al.: Meat and fat intake as risk factors for pancreatic cancer: the multiethnic cohort study. J Natl Cancer Inst 97 (19): 1458-65, 2005. [PUBMED Abstract]
Riker A, Libutti SK, Bartlett DL: Advances in the early detection, diagnosis, and staging of pancreatic cancer. Surg Oncol 6 (3): 157-69, 1997. [PUBMED Abstract]
John TG, Greig JD, Carter DC, et al.: Carcinoma of the pancreatic head and periampullary region. Tumor staging with laparoscopy and laparoscopic ultrasonography. Ann Surg 221 (2): 156-64, 1995. [PUBMED Abstract]
Minnard EA, Conlon KC, Hoos A, et al.: Laparoscopic ultrasound enhances standard laparoscopy in the staging of pancreatic cancer. Ann Surg 228 (2): 182-7, 1998. [PUBMED Abstract]
Merchant NB, Conlon KC, Saigo P, et al.: Positive peritoneal cytology predicts unresectability of pancreatic adenocarcinoma. J Am Coll Surg 188 (4): 421-6, 1999. [PUBMED Abstract]
Willett CG, Daly WJ, Warshaw AL: CA 19-9 is an index of response to neoadjunctive chemoradiation therapy in pancreatic cancer. Am J Surg 172 (4): 350-2, 1996. [PUBMED Abstract]
Siegel R, Naishadham D, Jemal A: Cancer statistics, 2013. CA Cancer J Clin 63 (1): 11-30, 2013. [PUBMED Abstract]
Yeo CJ, Abrams RA, Grochow LB, et al.: Pancreaticoduodenectomy for pancreatic adenocarcinoma: postoperative adjuvant chemoradiation improves survival. A prospective, single-institution experience. Ann Surg 225 (5): 621-33; discussion 633-6, 1997. [PUBMED Abstract]
Sohn TA, Lillemoe KD, Cameron JL, et al.: Surgical palliation of unresectable periampullary adenocarcinoma in the 1990s. J Am Coll Surg 188 (6): 658-66; discussion 666-9, 1999. [PUBMED Abstract]
Baron TH: Expandable metal stents for the treatment of cancerous obstruction of the gastrointestinal tract. N Engl J Med 344 (22): 1681-7, 2001. [PUBMED Abstract]
Passik SD, Breitbart WS: Depression in patients with pancreatic carcinoma. Diagnostic and treatment issues. Cancer 78 (3 Suppl): 615-26, 1996. [PUBMED Abstract]
Cellular Classification of Pancreatic Cancer
Pancreatic cancer includes the following carcinomas:
Malignant
Duct cell carcinoma (90% of all cases).
Acinar cell carcinoma.
Adenosquamous carcinoma.
Cystadenocarcinoma (serous and mucinous types).
Giant cell carcinoma.
Invasive adenocarcinoma associated with cystic mucinous neoplasm or intraductal papillary mucinous neoplasm.
Mixed type (ductal-endocrine or acinar-endocrine).
Mucinous carcinoma.
Pancreatoblastoma.
Papillary-cystic neoplasm (Frantz tumor). This tumor has lower malignant potential and may be cured with surgery alone.[1,2]
Papillary mucinous carcinoma.
Signet ring carcinoma.
Small cell carcinoma.
Unclassified.
Undifferentiated carcinoma.
Borderline Malignancies
Intraductal papillary mucinous tumor with dysplasia.[3]
Mucinous cystic tumor with dysplasia.
Pseudopapillary solid tumor.
References
Sanchez JA, Newman KD, Eichelberger MR, et al.: The papillary-cystic neoplasm of the pancreas. An increasingly recognized clinicopathologic entity. Arch Surg 125 (11): 1502-5, 1990. [PUBMED Abstract]
Warshaw AL, Compton CC, Lewandrowski K, et al.: Cystic tumors of the pancreas. New clinical, radiologic, and pathologic observations in 67 patients. Ann Surg 212 (4): 432-43; discussion 444-5, 1990. [PUBMED Abstract]
Sohn TA, Yeo CJ, Cameron JL, et al.: Intraductal papillary mucinous neoplasms of the pancreas: an increasingly recognized clinicopathologic entity. Ann Surg 234 (3): 313-21; discussion 321-2, 2001. [PUBMED Abstract]
Stage Information for Pancreatic Cancer
The staging system for pancreatic exocrine cancer continues to evolve. Clinical staging is guided by resectability, which is strongly influenced by surgical judgment. Consensus guidelines for surgical resectability (e.g., National Comprehensive Cancer Network, MD Anderson Cancer Center, American Hepato-Pancreato-Biliary Association, and International Hepato-Pancreato-Biliary Association) continue to be refined, but are traditionally stratified by the following tumor characteristics:
Resectable: tumors without vascular involvement.
Borderline resectable: tumors with involvement of vasculature, involvement of local structures, or other evidence of a high risk of R1 resection.
Locally advanced: tumors with local invasion (primarily vascular involvement) that preclude surgical intervention.
Metastatic: cancer that has spread beyond the primary pancreatic tumor to other organs.
The American Joint Committee on Cancer (AJCC) has designated staging by TNM (tumor, node, metastasis) classification.[1]
AJCC Stage Groupings and TNM Definitions
Table 1. Definitions for Exocrine Pancreas TNM Stage 0a
Stage
TNM
Description
Illustration
T = primary tumor; N = regional lymph node; M = distant metastasis.
aReprinted with permission from AJCC: Exocrine Pancreas. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 337–47.
0
Tis, N0, M0
Tis = Carcinoma in situ. This includes high-grade pancreatic intraepithelial neoplasia (PanIn-3), intraductal papillary mucinous neoplasm with high-grade dysplasia, intraductal tubulopapillary neoplasm with high-grade dysplasia, and mucinous cystic neoplasm with high-grade dysplasia.
Table 2. Definitions for Exocrine Pancreas TNM Stages IA and IBa
Stage
TNM
Description
Illustration
T = primary tumor; N = regional lymph node; M = distant metastasis.
aReprinted with permission from AJCC: Exocrine Pancreas. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 337–47.
–T1b = Tumor >0.5 cm and <1 cm in greatest dimension.
–T1c = Tumor 1–2 cm in greatest dimension.
N0 = No regional lymph node metastases.
M0 = No distant metastasis.
IB
T2, N0, M0
T2 = Tumor >2 cm and ≤4 cm in greatest dimension.
N0 = No regional lymph node metastases.
M0 = No distant metastasis.
Table 3. Definitions for Exocrine Pancreas TNM Stages IIA and IIBa
Stage
TNM
Description
Illustration
T = primary tumor; N = regional lymph node; M = distant metastasis.
aReprinted with permission from AJCC: Exocrine Pancreas. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 337–47.
–T1b = Tumor >0.5 cm and <1 cm in greatest dimension.
–T1c = Tumor 1–2 cm in greatest dimension.
N1 = Metastasis in one to three regional lymph nodes.
M0 = No distant metastasis.
T2, N1, M0
T2 = Tumor >2 cm and ≤4 cm in greatest dimension.
N1 = Metastasis in one to three regional lymph nodes.
M0 = No distant metastasis.
T3, N1, M0
T3 = Tumor >4 cm in greatest dimension.
N1 = Metastasis in one to three regional lymph nodes.
M0 = No distant metastasis.
Table 4. Definitions for Exocrine Pancreas TNM Stage IIIa
Stage
TNM
Description
Illustration
T = primary tumor; N = regional lymph node; M = distant metastasis.
aReprinted with permission from AJCC: Exocrine Pancreas. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 337–47.
–T1b = Tumor >0.5 cm and <1 cm in greatest dimension.
–T1c = Tumor 1–2 cm in greatest dimension.
N2 = Metastasis in four or more regional lymph nodes.
M0 = No distant metastasis.
T2, N2, M0
T2 = Tumor >2 cm and ≤4 cm in greatest dimension.
N2 = Metastasis in four or more regional lymph nodes.
M0 = No distant metastasis.
T3, N2, M0
T3 = Tumor >4 cm in greatest dimension.
N2 = Metastasis in four or more regional lymph nodes.
M0 = No distant metastasis.
T4, Any N, M0
T4 = Tumor involves celiac axis, superior mesenteric artery, and/or common hepatic artery, regardless of size.
NX = Regional lymph nodes cannot be assessed.
N0 = No regional lymph node metastases.
N1 = Metastasis in one to three regional lymph nodes.
N2 = Metastasis in four or more regional lymph nodes.
M0 = No distant metastasis.
Table 5. Definitions for Exocrine Pancreas TNM Stage IVa
Stage
TNM
Description
Illustration
T = primary tumor; N = regional lymph node; M = distant metastasis.
aReprinted with permission from AJCC: Exocrine Pancreas. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 337–47.
Tis = Carcinoma in situ. This includes high-grade pancreatic intraepithelial neoplasia (PanIn-3), intraductal papillary mucinous neoplasm with high-grade dysplasia, intraductal tubulopapillary neoplasm with high-grade dysplasia, and mucinous cystic neoplasm with high-grade dysplasia.
T1 = Tumor ≤2 cm in greatest dimension.
–T1a = Tumor ≤0.5 cm in greatest dimension.
–T1b = Tumor >0.5 cm and <1 cm in greatest dimension.
–T1c = Tumor 1–2 cm in greatest dimension.
T2 = Tumor >2 cm and ≤4 cm in greatest dimension.
T3 = Tumor >4 cm in greatest dimension.
T4 = Tumor involves celiac axis, superior mesenteric artery, and/or common hepatic artery, regardless of size.
NX = Regional lymph nodes cannot be assessed.
N0 = No regional lymph node metastases.
N1 = Metastasis in one to three regional lymph nodes.
N2 = Metastasis in four or more regional lymph nodes.
M1 = Distant metastasis.
References
Kakar S, Pawlik TM, Allen PJ: Exocrine Pancreas. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. Springer; 2017, pp. 337–47.
Treatment Option Overview for Pancreatic Cancer
Surgical resection, when feasible, remains the primary treatment modality for patients with pancreatic cancer. On occasion, resection can lead to long-term survival, and it provides effective palliation.[1–3][Level of evidence C1] Treatment is often guided by resectability, but this may vary depending on surgical judgment and experience. Referral to a high-volume center should be considered.[4]
Postoperative chemotherapy improves overall survival, but the role of chemoradiation remains controversial.
Complications of pancreatic cancer include:
Malabsorption: Frequently, malabsorption caused by exocrine insufficiency contributes to malnutrition. Pancreatic enzyme replacement can help alleviate this problem.
Pain: Celiac axis and intrapleural nerve blocks can provide highly effective and long-lasting control of pain for some patients. For more information, see Cancer Pain.
The survival rate of patients with any stage of pancreatic exocrine cancer is poor. Clinical trials are appropriate for patients with any stage of disease and should be considered before palliative approaches are selected.
Information about ongoing clinical trials for pancreatic cancer is available from the NCI website.
Clinical trials evaluating new anticancer agents alone or in combination with chemotherapy
Palliative therapies can be considered in patients with any stage of disease. For more information, see the Palliative Therapy section.
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
Yeo CJ, Cameron JL, Lillemoe KD, et al.: Pancreaticoduodenectomy for cancer of the head of the pancreas. 201 patients. Ann Surg 221 (6): 721-31; discussion 731-3, 1995. [PUBMED Abstract]
Conlon KC, Klimstra DS, Brennan MF: Long-term survival after curative resection for pancreatic ductal adenocarcinoma. Clinicopathologic analysis of 5-year survivors. Ann Surg 223 (3): 273-9, 1996. [PUBMED Abstract]
Yeo CJ, Abrams RA, Grochow LB, et al.: Pancreaticoduodenectomy for pancreatic adenocarcinoma: postoperative adjuvant chemoradiation improves survival. A prospective, single-institution experience. Ann Surg 225 (5): 621-33; discussion 633-6, 1997. [PUBMED Abstract]
Lidsky ME, Sun Z, Nussbaum DP, et al.: Going the Extra Mile: Improved Survival for Pancreatic Cancer Patients Traveling to High-volume Centers. Ann Surg 266 (2): 333-338, 2017. [PUBMED Abstract]
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]
Lam SW, Guchelaar HJ, Boven E: The role of pharmacogenetics in capecitabine efficacy and toxicity. Cancer Treat Rev 50: 9-22, 2016. [PUBMED Abstract]
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]
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]
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]
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]
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]
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 Resectable or Borderline Resectable Pancreatic Cancer
Treatment Options for Resectable or Borderline Resectable Pancreatic Cancer
Treatment options for resectable or borderline resectable pancreatic cancer include:
Neoadjuvant therapy: Neoadjuvant chemotherapy with or without chemoradiation therapy.
Alternative radiation techniques (under clinical evaluation).
Palliative therapies can be considered in patients with any stage of disease. For more information, see the Palliative Therapy section.
Neoadjuvant therapy
Neoadjuvant therapy is chemotherapy with or without chemoradiation therapy given before surgery. The role of neoadjuvant therapy has been evaluated in retrospective studies (Surveillance, Epidemiology, and End Results [SEER] Program database and National Cancer Database) and is recommended by multiple consensus guidelines for the management of patients with borderline resectable pancreatic cancer. It is being evaluated in patients with resectable or borderline resectable pancreatic cancer in several ongoing trials.[9–11]
Evidence (neoadjuvant chemotherapy with or without chemoradiation therapy):
The phase II, multicenter, randomized A021501 trial (NCT02839343) enrolled 126 patients with borderline resectable pancreatic cancer from institutions in the National Clinical Trials Network cooperative groups between 2017 and 2019. Patients were assigned to receive either eight 2-week cycles of modified FOLFIRINOX (oxaliplatin, leucovorin, irinotecan, and 5-FU) (n = 65) or seven 2-week cycles of modified FOLFIRINOX followed by stereotactic body radiotherapy (33 Gy–40 Gy in 5 fractions) or hypofractionated image-guided radiotherapy (25 Gy in 5 fractions) (n = 55). Patients without disease progression then underwent surgery followed by four 2-week cycles of adjuvant FOLFOX6 (oxaliplatin, leucovorin, and 5-FU).[12]
In the neoadjuvant chemotherapy-alone arm, the median overall survival (OS) was 29.8 months (95% confidence interval [CI], 21.1–36.6) with a 43% microscopically margin-negative (R0) resection rate. This was compared with estimated historical controls of median OS at 18 months.[12][Level of evidence C3]
Grade 3 or greater treatment-related adverse events occurred in 57% of patients who received neoadjuvant chemotherapy alone.
The neoadjuvant chemotherapy with radiation arm was closed at interim futility analysis because of low R0 resection rates (33%) in the first 30 patients enrolled.
The multicenter phase III PREOPANC trial included 246 patients diagnosed with resectable or borderline resectable pancreatic cancer between 2013 and 2017. Patients at 16 Dutch centers were randomly assigned to receive either diagnostic laparoscopy, neoadjuvant chemoradiation therapy, surgical resection, and four cycles of adjuvant gemcitabine or up-front surgery and six cycles of adjuvant gemcitabine. Neoadjuvant chemoradiation therapy included the following: cycle 1 (21 days) with gemcitabine 1,000 mg/m2 on days 1 and 8; cycle 2 (28 days) with gemcitabine on days 1, 8, and 15 with 15 concurrent fractions of hypofractionated radiation (36 Gy) to the tumor and suspected associated lymph nodes; and cycle 3 (21 days) with gemcitabine on days 1 and 8.[13]
The 5-year OS rate was 20.5% (95% CI, 14.2%–29.8%) for patients who received neoadjuvant chemoradiation therapy and 6.5% (95% CI, 3.1%–13.7%) for patients who received up-front surgery (hazard ratio [HR], 0.73; 95% CI, 0.56–0.96; P = .025).[13][Level of evidence A1]
The median OS was 15.7 months in the neoadjuvant chemoradiation therapy group and 14.3 months in the up-front surgery group.
In the intention-to-treat arm, 61% of patients who received neoadjuvant chemoradiation therapy underwent resection, resulting in R0 resection for 41% of patients and node-negative disease for 65% of patients. The resection rate was 72% in the up-front surgery arm, resulting in R0 resection in 28% of patients and node-negative disease in 18% of patients.
The optimal neoadjuvant therapy regimen is unknown, and additional chemotherapy regimens are being evaluated in the following trials: ALLIANCE (NCT04340141), PREOPANC-3 (NCT04927780), PANACHE-01-PRODIGE (NCT02959879), and NorPACT-01 (NCT02919787).
Surgery
Complete resection can yield 5-year survival rates of 18% to 24%, but ultimate control remains poor because of the high incidence of both local and distant tumor recurrence. Thus, systemic therapy is also recommended.[14–16][Level of evidence C1]
Approximately 20% of patients present with pancreatic cancer amenable to local surgical resection, with operative mortality rates of approximately 1% to 16%.[17–21] Using information from the Medicare claims database, a national cohort study of more than 7,000 patients undergoing pancreaticoduodenectomy between 1992 and 1995 revealed higher in-hospital mortality rates at low-volume hospitals (<1 pancreaticoduodenectomy per year) versus high-volume hospitals (>5 per year) (16% vs. 4%, respectively; P < .01).[17]
Postoperative chemotherapy
Historically, multiple randomized trials have established that adjuvant gemcitabine monotherapy [22] or adjuvant 5-FU monotherapy [3] improve OS for 6 months after surgical resection compared with surgery alone. More recent studies have looked at newer combination regimens that might further improve outcomes after surgical resection.
For patients with good performance status, adjuvant FOLFIRINOX chemotherapy or the combination of gemcitabine and capecitabine should be considered. However, for older patients or patients with marginal performance status, adjuvant gemcitabine or 5-FU monotherapy can be considered. In Asia, S-1 (tegafur, gimeracil, and oteracil potassium) is an appropriate alternative to gemcitabine-based therapies.
Evidence (postoperative chemotherapy):
FOLFIRINOX: In the randomized, open-label, phase III PRODIGE-24 trial (NCT01526135), 493 patients with R0/R1 resections were randomly assigned 1:1 to receive six cycles of gemcitabine (1,000 mg/m2 on days 1, 8, and 15 of a 28-day cycle) or 12 cycles of FOLFIRINOX (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, irinotecan 150 mg/m2, and 5-FU 2,400 mg/m2 over 46 hours every 2 weeks).[23,24][Level of evidence A1]
With a median follow-up of 69.7 months, the median disease-free survival (DFS) was 21.4 months (95% CI, 17.5–26.7) in the FOLFIRINOX group and 12.8 months in the gemcitabine group (95% CI, 11.6–15.2) (HR, 0.66; 95% CI, 0.54–0.82; P < .001).
The median OS was 53.5 months (95% CI, 43.5–58.4) in the FOLFIRINOX group and 35.5 months (95% CI, 30.1–40.3) in the gemcitabine group (HR, 0.68; 95% CI, 0.54–0.85; P = .001). The 5-year OS rate was 43.2% in the FOLFIRINOX group and 31.4% in the gemcitabine group.
Toxicity was higher with combination therapy; 75.9% of patients who received FOLFIRINOX had grade 3 or 4 toxicities, compared with 52.9% of those who received gemcitabine, with similar rates of neutropenia (although 62.2% of patients on FOLFIRINOX received granulocyte colony-stimulating factor). Thirty-three percent of patients who received FOLFIRINOX stopped treatment prematurely, compared with 21% of patients who received gemcitabine alone.
Gemcitabine and capecitabine: The European Study for Pancreatic Cancer (ESPAC-4 [NCT00058201]) trial randomly assigned 732 patients with resected pancreatic cancer to receive either six cycles of gemcitabine alone (1,000 mg/m2 given weekly for 3 weeks of every 4 weeks) or oral capecitabine (1,660 mg/m2 given for 21 days followed by 7 days of rest [one cycle]).[25][Level of evidence A1]
With a median follow-up of 43.2 months, the median OS for patients in the gemcitabine/capecitabine group was 28.0 months (95% CI, 23.5–31.5) compared with 25.5 months for the gemcitabine-alone group (95% CI, 22.7–27.9; HR, 0.82; P = .032). Treatment with gemcitabine/capecitabine yielded an improvement in the estimated 5-year OS rate from 16.3% with gemcitabine alone to 28.8% with gemcitabine/capecitabine.
There was no significant difference in overall rates of grade 3/4 toxicities between treatment arms. Compared with gemcitabine alone, capecitabine was associated with higher rates of grade 3/4 diarrhea (5% vs. 2%), neutropenia (38% vs. 24%), and hand-foot syndrome (7% vs. 0%).
There was no significant effect on the quality of life in the treatment groups.
Based on these findings, the adjuvant combination of gemcitabine and capecitabine is the standard of care after a resection for pancreatic cancer.
S-1: The Japan Adjuvant Study Group of Pancreatic Cancer (JASPAC-01) study was a phase III, multicenter, noninferiority trial conducted in Japan that randomly assigned 385 patients to receive either gemcitabine (1,000 mg/m2 weekly for 3 weeks of every 4 weeks) for six cycles or S-1 (tegafur, gimeracil, and oteracil potassium) (given orally twice a day for 4 weeks followed by a 2-week break).[26][Level of evidence A1]
The prespecified criteria for early discontinuation was met at interim analysis for efficacy with all of the protocol treatments completed. On early interim analysis, the HRmortality was 0.57 (95% CI, 0.44–0.72; P for noninferiority < .001; P for superiority < .001). These results were associated with a 5-year OS rate of 24.4% in the gemcitabine group and 44.1% in the S-1 group.
Grade 3 or 4 leukopenia, neutropenia, and liver transaminitis were observed more frequently in the gemcitabine group, and stomatitis and diarrhea were experienced more frequently in the S-1 group.
Among Japanese patients, adjuvant chemotherapy with S-1 can be a new standard of care for resected pancreatic patients. Additional studies are needed to validate these results in patients of other races and ethnicities.
The pharmacokinetics and pharmacodynamics of S-1 may be different between Eastern and Western patient populations because grade 3/4 gastrointestinal toxicities, especially diarrhea, have been reported more commonly in the Western patient population. S-1 is not currently approved by the U.S. Food and Drug Administration for use in the United States.
Gemcitabine: Charité Onkologie (CONKO)-001 was a multicenter phase III trial of 368 patients with resected pancreatic cancer who were randomly assigned to receive six cycles of adjuvant gemcitabine versus observation.[22][Level of evidence B1] In contrast to the previous trials, the primary end point was DFS.
With a median follow-up of 136 months, long-term follow-up of the CONKO-001 study demonstrated a significant improvement in OS that favors gemcitabine (median survival, 22.8 months vs. 20.2 months; HR, 0.76; 95% CI, 0.61–0.95, P = .01). Gemcitabine compared with observation alone yielded improved survival rates at 5 years of 20.7% for the gemcitabine arm versus 10.4% for the observation-alone arm, and the survival rates at 10 years were 12.2% for the gemcitabine arm versus 7.7% for the observation-alone arm.[27][Level of evidence A1]
Gemcitabine or 5-FU: The ESPAC-3 trial (NCT00058201) randomly assigned 1,088 patients who had undergone complete macroscopic resection to either 6 months of 5-FU (425 mg/m2) and leucovorin (20 mg/m2) on days 1 to 5 every 28 days or 6 months of gemcitabine (1,000 mg/m2) on days 1, 8, and 15 every 28 days.[3][Level of evidence A1]
Median OS was 23.0 months (95% CI, 21.1–25.0) for patients treated with 5-FU plus leucovorin and 23.6 months (95% CI, 21.4–26.4) for those treated with gemcitabine (HR, 0.94; 95% CI, 0.81–1.08; P = .39).
Postoperative chemoradiation therapy
The role of postoperative therapy (chemotherapy with or without chemoradiation therapy) in the management of this disease remains controversial because much of the randomized clinical trial data available are statistically underpowered and provide conflicting results.[4–8]
Evidence (postoperative chemoradiation therapy):
Several phase III trials examined the potential OS benefit of postoperative adjuvant 5-FU–based chemoradiation therapy:
Gastrointestinal Study Group (GITSG): A small randomized trial conducted by the GITSG in 1985 compared surgery alone with surgery followed by chemoradiation.[4][Level of evidence A1];[5][Level of evidence B4]
The investigators reported a significant but modest improvement in median-term and long-term survival over resection alone with postoperative bolus 5-FU and regional split-course radiation given at a dose of 40 Gy.
European Organisation for the Research and Treatment of Cancer (EORTC): An attempt by the EORTC to reproduce the results of the GITSG trial failed to confirm a significant benefit for adjuvant chemoradiation therapy over resection alone;[6][Level of evidence A1] however, this trial treated patients with pancreatic and periampullary cancers (with a potentially better prognosis).
A subset analysis of the patients with primary pancreatic tumors indicated a trend toward improved median, 2-year, and 5-year OS with adjuvant therapy (17.1 months, 37%, and 20%, respectively) compared with surgery alone (12.6 months, 23%, and 10%, respectively); P = .09 for median survival).
An updated analysis of a subsequent ESPAC-1 trial examined only patients who underwent strict randomization after pancreatic resection. The patients were assigned to one of four groups (observation, bolus 5-FU chemotherapy, bolus 5-FU chemoradiation therapy, or chemoradiation therapy followed by additional chemotherapy).[7,8,28][Level of evidence A1]
With a 2 × 2 factorial design reported at a median follow-up of 47 months, a median survival benefit was observed for only the patients who received postoperative 5-FU chemotherapy. However, these results were difficult to interpret because of a high rate of protocol nonadherence and the lack of a separate analysis for each of the four groups in the 2 × 2 design.
U.S. Gastrointestinal Intergroup: The U.S. Gastrointestinal Intergroup has reported the results of a randomized phase III trial (Radiation Therapy Oncology Group [RTOG]-9704) that included 451 patients with resected pancreatic cancers who were assigned to receive either postoperative infusional 5-FU plus infusional 5-FU and concurrent radiation or adjuvant gemcitabine plus infusional 5-FU and concurrent radiation.[29][Level of evidence A1] The primary end points were OS for all patients and OS for patients with pancreatic head tumors.
A 5-year update of RTOG-9704 reported that patients with pancreatic head tumors (n = 388) had a median survival of 20.5 months and a 5-year OS rate of 22% with gemcitabine, versus a median survival of 17.1 months and a 5-year OS rate of 18% with 5-FU (HR, 0.84; 95% CI, 0.67–1.05; P = .12).[30]
Univariate analysis showed no difference in OS. However, on multivariate analysis, patients on the gemcitabine arm with pancreatic head tumors experienced a trend toward improved OS (P = .08). Distant relapse remained the predominant site of first failure (78%).
The EORTC/U.S. Gastrointestinal Intergroup RTOG-0848 phase III adjuvant trial evaluating the impact of chemoradiation therapy after completion of a full course of gemcitabine with or without erlotinib has closed and results are pending.
Additional trials are still warranted to determine more effective systemic therapy for this disease.
Current Clinical Trials
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
References
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Katz MHG, Shi Q, Meyers J, et al.: Efficacy of Preoperative mFOLFIRINOX vs mFOLFIRINOX Plus Hypofractionated Radiotherapy for Borderline Resectable Adenocarcinoma of the Pancreas: The A021501 Phase 2 Randomized Clinical Trial. JAMA Oncol 8 (9): 1263-1270, 2022. [PUBMED Abstract]
Versteijne E, van Dam JL, Suker M, et al.: Neoadjuvant Chemoradiotherapy Versus Upfront Surgery for Resectable and Borderline Resectable Pancreatic Cancer: Long-Term Results of the Dutch Randomized PREOPANC Trial. J Clin Oncol 40 (11): 1220-1230, 2022. [PUBMED Abstract]
Cameron JL, Crist DW, Sitzmann JV, et al.: Factors influencing survival after pancreaticoduodenectomy for pancreatic cancer. Am J Surg 161 (1): 120-4; discussion 124-5, 1991. [PUBMED Abstract]
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Yeo CJ, Abrams RA, Grochow LB, et al.: Pancreaticoduodenectomy for pancreatic adenocarcinoma: postoperative adjuvant chemoradiation improves survival. A prospective, single-institution experience. Ann Surg 225 (5): 621-33; discussion 633-6, 1997. [PUBMED Abstract]
Birkmeyer JD, Finlayson SR, Tosteson AN, et al.: Effect of hospital volume on in-hospital mortality with pancreaticoduodenectomy. Surgery 125 (3): 250-6, 1999. [PUBMED Abstract]
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Spanknebel K, Conlon KC: Advances in the surgical management of pancreatic cancer. Cancer J 7 (4): 312-23, 2001 Jul-Aug. [PUBMED Abstract]
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Conroy T, Hammel P, Hebbar M, et al.: FOLFIRINOX or Gemcitabine as Adjuvant Therapy for Pancreatic Cancer. N Engl J Med 379 (25): 2395-2406, 2018. [PUBMED Abstract]
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Neoptolemos JP, Palmer DH, Ghaneh P, et al.: Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial. Lancet 389 (10073): 1011-1024, 2017. [PUBMED Abstract]
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Treatment of Locally Advanced Pancreatic Cancer
Treatment Options for Locally Advanced Pancreatic Cancer
While locally advanced and metastatic pancreatic cancer are both incurable, their natural histories may be different. An autopsy series demonstrated that 30% of patients presenting with locally advanced disease died without evidence of distant metastases.[1][Level of evidence A1] Therefore, investigators have struggled to determine whether chemoradiation therapy for patients presenting with locally advanced disease is warranted.
Treatment options for locally advanced pancreatic cancer include:
Palliative therapies can be considered in patients with any stage of disease. For more information, see the Palliative Therapy section.
Chemotherapy with or without targeted therapy
Chemotherapy is the primary treatment modality for patients with locally advanced pancreatic cancers and uses the same regimens as those used to treat patients with metastatic disease.
Evidence (chemotherapy):
FOLFIRINOX versus gemcitabine: A multicenter phase II/III trial included 342 patients with metastatic pancreatic adenocarcinoma with an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1.[6][Level of evidence A1] The patients were randomly assigned to receive FOLFIRINOX (oxaliplatin [85 mg/m2], irinotecan [180 mg/m2], leucovorin [400 mg/m2], and fluorouracil [5-FU; 400 mg/m2] given as a bolus followed by 2,400 mg/m2 given as a 46-hour continuous infusion, every 2 weeks) or gemcitabine (1,000 mg/m2 weekly for 7 of 8 weeks and then weekly for 3 of 4 weeks).
The median overall survival (OS) was 11.1 months in the FOLFIRINOX group compared with 6.8 months in the gemcitabine group (hazard ratio [HR]death, 0.57; 95% confidence interval [CI], 0.45–0.73; P < .001).
Median progression-free survival (PFS) was 6.4 months in the FOLFIRINOX group and 3.3 months in the gemcitabine group (HRdisease progression, 0.47; 95% CI, 0.37–0.59; P < .001).
FOLFIRINOX was more toxic than gemcitabine; 5.4% of patients in this group had febrile neutropenia. At 6 months, 31% of the patients in the FOLFIRINOX group had a definitive degradation of quality of life, versus 66% in the gemcitabine group (HR, 0.47; 95% CI, 0.30–0.70; P < .001).
Based on this trial, FOLFIRINOX is considered a standard treatment option for patients with advanced pancreatic cancer.
Gemcitabine and nab-paclitaxel versus gemcitabine: A multicenter, international, phase III trial (NCT00844649) included 861 patients with metastatic pancreatic adenocarcinoma. Patients had a Karnofsky Performance Status of at least 70 and had not previously received chemotherapy for metastatic disease.[7][Level of evidence A1] Patients who received adjuvant gemcitabine or any other chemotherapy were excluded. The patients were randomly assigned to receive gemcitabine (1,000 mg/m2) and nab-paclitaxel (125 mg/m2 of body-surface area) weekly for 3 of 4 weeks or gemcitabine monotherapy (1,000 mg/m2 weekly for 7 of 8 weeks and then weekly for 3 of 4 weeks).
The median OS was 8.5 months in the nab-paclitaxel/gemcitabine group compared with 6.7 months in the gemcitabine group (HRdeath, 0.72; 95% CI, 0.62–0.83; P < .001).
Median PFS was 5.5 months in the nab-paclitaxel/gemcitabine group and 3.7 months in the gemcitabine group (HRdisease progression, 0.69; 95% CI, 0.58–0.82; P < .001).
Nab-paclitaxel/gemcitabine was more toxic than gemcitabine. The most common grade 3 toxicities in the nab-paclitaxel/gemcitabine group were neutropenia (38%), fatigue (17%), and neuropathy (17%); febrile neutropenia occurred in 3% of patients. In the gemcitabine-alone group, the most common grade 3 toxicities were neutropenia (27%), fatigue (1%), and neuropathy (1%); febrile neutropenia occurred in 1% of patients.
In the nab-paclitaxel/gemcitabine group, the median time from grade 3 neuropathy to grade 1 or resolution was 29 days. Of patients with grade 3 peripheral neuropathy, 44% were able to resume treatment at a reduced dose within a median of 23 days after onset of a grade 3 event.
Based on this trial, nab-paclitaxel/gemcitabine is a standard treatment option for patients with advanced pancreatic cancer.
Quality-of-life data were not measured for this regimen, and this study did not address the efficacy of nab-paclitaxel/gemcitabine versus FOLFIRINOX.
Gemcitabine versus 5-FU: Gemcitabine has demonstrated activity in patients with pancreatic cancer and is a useful palliative agent.[8–10] A phase III trial of gemcitabine versus 5-FU as first-line therapy in patients with advanced or metastatic adenocarcinoma of the pancreas reported a significant improvement in survival among patients treated with gemcitabine (the 1-year survival rate was 18% with gemcitabine compared with 2% with 5-FU; P = .003).[9][Level of evidence A1]
Gemcitabine alone versus gemcitabine and erlotinib: The National Cancer Institute of Canada performed a phase III trial (CAN-NCIC-PA3 [NCT00026338]) that compared gemcitabine alone with the combination of gemcitabine and erlotinib (100 mg/d) in patients with advanced or metastatic pancreatic carcinomas.[11][Level of evidence A1]
The addition of erlotinib modestly prolonged survival when combined with gemcitabine versus gemcitabine alone (HR, 0.81; 95% CI, 0.69–0.99; P = .038).
The median and 1-year survival rates for patients who received erlotinib were 6.2 months and 23%. The median and 1-year survival rates for patients who received placebo were 5.9 months and 17%.
Platinum analogue or fluoropyrimidine versus single-agent gemcitabine: Many phase III studies have evaluated a combination regimen with either a platinum analogue (cisplatin or oxaliplatin) or fluoropyrimidine versus single-agent gemcitabine.[12,13]
None of these phase III trials have demonstrated a statistically significant advantage favoring the use of combination chemotherapy in the first-line treatment of metastatic pancreatic cancer.
5-FU, leucovorin, and oxaliplatin (OFF regimen) versus best supportive care (BSC): Second-line chemotherapy after progression on a gemcitabine-based regimen may be beneficial. The Charité Onkologie (CONKO)-003 investigators randomly assigned patients requiring a second line of chemotherapy to either the OFF regimen or BSC.[14,15][Level of evidence C1] The OFF regimen consisted of leucovorin (200 mg/m2) followed by 5-FU (2,000 mg/m2 [24-hour continuous infusion] on days 1, 8, 15, and 22) and oxaliplatin (85 mg/m2 on days 8 and 22). After a rest of 3 weeks, the next cycle was started on day 43. The trial was terminated early because of poor accrual, and only 46 patients were randomly assigned to either the OFF regimen or BSC.
The median survival was 4.82 months (95% CI, 4.29–5.35) with the OFF treatment regimen and 2.30 months (95% CI, 1.76–2.83) with BSC alone (HR, 0.45; 95% CI, 0.24–0.83).
Median OS was 9.09 months for the sequence of gemcitabine/OFF and 7.90 months for gemcitabine/BSC.
The early closure of the study and the very small number of patients made the P values misleading. Therefore, second-line chemotherapy with the OFF regimen may be falsely associated with improved survival.
Chemoradiation therapy
The role of chemoradiation in locally advanced pancreatic cancer remains controversial. Table 7 summarizes phase III randomized studies of chemoradiation for locally advanced pancreatic cancer.
Table 7. Randomized Studies in Locally Advanced Pancreatic Cancer: Median Survival
Trial
Regimen
Chemoradiation
Radiation Alone
Chemotherapy Alone
P Value
5-FU = fluorouracil; ECOG = Eastern Cooperative Oncology Group; FFCD = Fédération Francophone de Cancérologie Digestive; GEM = gemcitabine; GITSG = Gastrointestinal Tumor Study Group; Gy = gray (unit of absorbed radiation of ionizing radiation); P value = probability value; XRT = radiation therapy.
Three trials evaluated combined modality therapy versus radiation therapy alone.[16–18] The trials had substantial deficiencies in design or analysis. Initially, the standard of practice was to give chemoradiation therapy based on data from the first two studies. However, with the publication of the third study, standard practice changed to chemotherapy followed by chemoradiation in the absence of metastases.
LAP07 (NCT00634725): The LAP07 study was an international, randomized, phase III study based on the results of the Groupe Coopérateur Multidisciplinaire en Oncologie (GERCOR) study. In total, 449 patients were enrolled between 2008 and 2011, with random assignment via a two-step randomization process. In the first step, patients were randomly assigned to induction gemcitabine (n = 223) or gemcitabine plus erlotinib (n = 219) for four cycles. For the second step, patients with controlled tumors were randomly assigned (n = 269) a second time to receive either chemotherapy (n = 136) or chemoradiation therapy (n = 133). A total dose of 54 Gy in 30 daily fractions was prescribed with concurrent capecitabine at a dose of 800 mg/m2 twice daily on days of radiation therapy.[20][Level of evidence A1]
The primary end point was OS. After interim analysis, the study was stopped early because of futility.
With a median follow-up of 36.7 months, the median OS from the date of the first randomization was not significantly different between chemotherapy at 16.5 months (95% CI, 14.5–18.5) and chemoradiation therapy at 15.2 months (95% CI, 13.9–17.3; P = .83).
Median OS after the first randomization was 13.6 months (95% CI, 12.3–15.3) for the patients who received gemcitabine and was 11.9 months (95% CI, 10.4–13.5; P = .09) for the patients who received gemcitabine plus erlotinib.
The LAP07 study represents the most robust, prospective, randomized phase III data regarding the role of chemoradiation therapy in the setting of gemcitabine-based induction chemotherapy that demonstrates no OS benefit. However, this study was initiated before the advent of FOLFIRINOX chemotherapy, which has been widely adopted into the locally advanced setting. The role of chemoradiation in the setting of more active chemotherapy regimens, including gemcitabine/paclitaxel and FOLFIRINOX, has yet to be evaluated.
Gastrointestinal Tumor Study Group (GITSG) GITSG-9273 trial: Before 2000, several phase III trials evaluated combined modality therapy versus radiation therapy alone. Before the use of gemcitabine for patients with locally advanced or metastatic pancreatic cancer, investigators from the GITSG randomly assigned 106 patients with locally advanced pancreatic adenocarcinoma to receive external-beam radiation therapy (EBRT) (60 Gy) alone or concurrent EBRT (either 40 Gy or 60 Gy) plus bolus 5-FU.[16][Level of evidence A1]
The study was stopped early when the chemoradiation therapy groups were found to have better efficacy. The 1-year survival rate was 11% for patients who received EBRT alone compared with 38% for patients who received chemoradiation therapy with 40 Gy and 36% for patients who received chemoradiation therapy with 60 Gy.
After an additional 88 patients were enrolled in the combined modality arms, there was a trend toward improved survival with 60 Gy EBRT plus 5-FU, but the difference in time-to-progression and OS was not statistically significant when compared with the 40 Gy arm.[21]
ECOG E-8282 trial: Investigators from the ECOG randomly assigned 114 patients to receive radiation therapy (59.4 Gy) alone or with concurrent infusional 5-FU (1,000 mg/m2/d on days 2–5 and 28–31) plus mitomycin (10 mg/m2 on day 2).[17]
The trial reported no difference in OS between the two groups.
Fédération Francophone de Cancérologie Digestive–Société Française de Radiothérapie Oncologie (FFCD-SFRO) trial: As it became clear that radiation therapy alone was an inadequate treatment, investigators evaluated combined modality approaches versus chemotherapy alone. Investigators from the FFCD-SFRO randomly assigned 119 patients to induction chemoradiation therapy (60 Gy in 2 Gy fractions with 300 mg/m2/d of continuous-infusion 5-FU on days 1–5 for 6 weeks and 20 mg/m2/d of cisplatin on days 1–5 during weeks 1 and 5) or induction gemcitabine (1,000 mg/m2 weekly for 7 weeks). Maintenance gemcitabine was administered to both groups until stopped by disease progression or treatment discontinuation as a result of toxicity.[22][Level of evidence A1]
Median survival was superior in the gemcitabine group (13 vs. 8.6 months; P = .03).
Nonhematological grade 3 to 4 toxicities (primarily gastrointestinal) were significantly more common in the chemoradiation therapy group (44% vs. 18%; P = .004), and fewer patients completed at least 75% of induction therapy (42% vs. 73%).
Nonetheless, the survival benefit persisted in a per-protocol analysis of patients receiving at least 75% of planned therapy. Notably, the dose intensity of maintenance gemcitabine was significantly less in the chemoradiation therapy group because of a greater incidence of grades 3 to 4 hematological toxicities (71% vs. 27%; P = .0001).
As a result of this study, giving induction chemoradiation therapy has lost support.
ECOG: The results of the FFCD-SFRO study counter the results of a study from ECOG in which investigators randomly assigned 74 patients to either gemcitabine alone or gemcitabine with radiation followed by gemcitabine.[19] Of note, the study was closed early as the result of poor accrual.
The primary end point was survival, which was 9.2 months (95% CI, 7.9–11.4) for chemotherapy and 11.1 months (95% CI, 7.6–15.5) for combined modality therapy (one-sided P = .017 by stratified log-rank test).
Grades 4 and 5 toxicity were greater in the chemoradiation therapy arm than in the chemotherapy arm (41% vs. 9%).
GERCOR: Given the increased toxicity of chemoradiation therapy and the early development of metastatic disease in a large percentage of patients with locally advanced pancreatic cancer, investigators are pursuing a strategy of selecting patients with localized disease for chemoradiation therapy. With this strategy, the selected patients have an absence of progressive disease locally or systemically after several months of chemotherapy.[23][Level of evidence C1]
A retrospective analysis of 181 patients enrolled in prospective phase II and III GERCOR studies revealed that 29% had metastatic disease after 3 months of gemcitabine-based chemotherapy.
For the remaining 71%, median OS was significantly longer among patients treated with chemoradiation therapy than among patients treated with additional chemotherapy (15.0 months vs. 11.7 months; P = .0009).
Surgery
Patients with locally advanced pancreatic cancer have tumors that are technically unresectable because of local vessel impingement or invasion by tumor. However, with the combination of chemotherapy and chemoradiation therapy, some patients may become candidates for radical pancreatic resection.
Palliative surgery
A significant proportion (approximately one-third) of patients with pancreatic cancer present with locally advanced disease. Patients may benefit from palliation of biliary obstruction by endoscopic, surgical, or radiological means.[24]
Current Clinical Trials
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
References
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van den Bosch RP, van der Schelling GP, Klinkenbijl JH, et al.: Guidelines for the application of surgery and endoprostheses in the palliation of obstructive jaundice in advanced cancer of the pancreas. Ann Surg 219 (1): 18-24, 1994. [PUBMED Abstract]
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Conroy T, Desseigne F, Ychou M, et al.: FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 364 (19): 1817-25, 2011. [PUBMED Abstract]
Von Hoff DD, Ervin T, Arena FP, et al.: Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med 369 (18): 1691-703, 2013. [PUBMED Abstract]
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Poplin E, Feng Y, Berlin J, et al.: Phase III, randomized study of gemcitabine and oxaliplatin versus gemcitabine (fixed-dose rate infusion) compared with gemcitabine (30-minute infusion) in patients with pancreatic carcinoma E6201: a trial of the Eastern Cooperative Oncology Group. J Clin Oncol 27 (23): 3778-85, 2009. [PUBMED Abstract]
Colucci G, Labianca R, Di Costanzo F, et al.: Randomized phase III trial of gemcitabine plus cisplatin compared with single-agent gemcitabine as first-line treatment of patients with advanced pancreatic cancer: the GIP-1 study. J Clin Oncol 28 (10): 1645-51, 2010. [PUBMED Abstract]
Pelzer U, Kubica K, Stieler J, et al.: A randomized trial in patients with gemcitabine refractory pancreatic cancer. Final results of the CONKO 003 study. [Abstract] J Clin Oncol 26 (Suppl 15): A-4508, 2008.
Pelzer U, Schwaner I, Stieler J, et al.: Best supportive care (BSC) versus oxaliplatin, folinic acid and 5-fluorouracil (OFF) plus BSC in patients for second-line advanced pancreatic cancer: a phase III-study from the German CONKO-study group. Eur J Cancer 47 (11): 1676-81, 2011. [PUBMED Abstract]
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Cohen SJ, Dobelbower R, Lipsitz S, et al.: A randomized phase III study of radiotherapy alone or with 5-fluorouracil and mitomycin-C in patients with locally advanced adenocarcinoma of the pancreas: Eastern Cooperative Oncology Group study E8282. Int J Radiat Oncol Biol Phys 62 (5): 1345-50, 2005. [PUBMED Abstract]
Chauffert B, Mornex F, Bonnetain F, et al.: Phase III trial comparing initial chemoradiotherapy (intermittent cisplatin and infusional 5-FU) followed by gemcitabine vs. gemcitabine alone in patients with locally advanced non metastatic pancreatic cancer: a FFCD-SFRO study. [Abstract] J Clin Oncol 24 (Suppl 18): A-4008, 180s, 2006.
Loehrer PJ, Feng Y, Cardenes H, et al.: Gemcitabine alone versus gemcitabine plus radiotherapy in patients with locally advanced pancreatic cancer: an Eastern Cooperative Oncology Group trial. J Clin Oncol 29 (31): 4105-12, 2011. [PUBMED Abstract]
Hammel P, Huguet F, van Laethem JL, et al.: Effect of Chemoradiotherapy vs Chemotherapy on Survival in Patients With Locally Advanced Pancreatic Cancer Controlled After 4 Months of Gemcitabine With or Without Erlotinib: The LAP07 Randomized Clinical Trial. JAMA 315 (17): 1844-53, 2016. [PUBMED Abstract]
Moertel CG, Frytak S, Hahn RG, et al.: Therapy of locally unresectable pancreatic carcinoma: a randomized comparison of high dose (6000 rads) radiation alone, moderate dose radiation (4000 rads + 5-fluorouracil), and high dose radiation + 5-fluorouracil: The Gastrointestinal Tumor Study Group. Cancer 48 (8): 1705-10, 1981. [PUBMED Abstract]
Chauffert B, Mornex F, Bonnetain F, et al.: Phase III trial comparing intensive induction chemoradiotherapy (60 Gy, infusional 5-FU and intermittent cisplatin) followed by maintenance gemcitabine with gemcitabine alone for locally advanced unresectable pancreatic cancer. Definitive results of the 2000-01 FFCD/SFRO study. Ann Oncol 19 (9): 1592-9, 2008. [PUBMED Abstract]
Huguet F, André T, Hammel P, et al.: Impact of chemoradiotherapy after disease control with chemotherapy in locally advanced pancreatic adenocarcinoma in GERCOR phase II and III studies. J Clin Oncol 25 (3): 326-31, 2007. [PUBMED Abstract]
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Treatment of Metastatic or Recurrent Pancreatic Cancer
Treatment Options for Metastatic or Recurrent Pancreatic Cancer
Treatment options for metastatic or recurrent pancreatic cancer include:
Clinical trials evaluating new anticancer agents alone or in combination with chemotherapy.
Palliative therapies can be considered in patients with any stage of disease. For more information, see the Palliative Therapy section.
Chemotherapy with or without targeted therapy
Because of the low objective response rate and limited efficacy of palliative chemotherapy regimens, all newly diagnosed patients should consider enrolling in clinical trials. Multiagent chemotherapy combinations have been shown to prolong outcomes compared with single-agent gemcitabine.[1–3]
Evidence (single-agent chemotherapy):
Gemcitabine versus fluorouracil (5-FU): A phase III trial of gemcitabine versus 5-FU as first-line therapy in patients with advanced or metastatic adenocarcinoma of the pancreas reported a significant improvement in survival among patients treated with gemcitabine (the 1-year survival rate was 18% with gemcitabine vs. 2% with 5-FU; P = .003).[1][Level of evidence A1]
Evidence (multiagent chemotherapy):
FOLFIRINOX (leucovorin, 5-FU, irinotecan, and oxaliplatin) versus gemcitabine: A multicenter phase II/III trial included 342 patients with metastatic pancreatic adenocarcinoma with an Eastern Cooperative Oncology Group performance status score of 0 or 1.[4][Level of evidence A1] The patients were randomly assigned to receive FOLFIRINOX (oxaliplatin [85 mg/m2], irinotecan [180 mg/m2], leucovorin [400 mg/m2], and 5-FU [400 mg/m2] given as a bolus followed by 2,400 mg/m2 given as a 46-hour continuous infusion, every 2 weeks) or gemcitabine (1,000 mg/m2 weekly for 7 of 8 weeks and then weekly for 3 of 4 weeks).
The median overall survival (OS) was 11.1 months in the FOLFIRINOX group compared with 6.8 months in the gemcitabine group (hazard ratio [HR]death, 0.57; 95% confidence interval [CI], 0.45–0.73; P < .001).
Median progression-free survival (PFS) was 6.4 months in the FOLFIRINOX group and 3.3 months in the gemcitabine group (HR for disease progression, 0.47; 95% CI, 0.37–0.59; P < .001).
FOLFIRINOX was more toxic than gemcitabine; 5.4% of patients in this group had febrile neutropenia. At 6 months, 31% of the patients in the FOLFIRINOX group had a definitive degradation of quality of life versus 66% in the gemcitabine group (HR, 0.47; 95% CI, 0.30–0.70; P < .001).
Based on this trial, FOLFIRINOX is considered a standard treatment option for patients with advanced pancreatic cancer.
NALIRIFOX (5-FU, irinotecan sucrosofate [also called nanoliposomal irinotecan], and oxaliplatin) versus gemcitabine and nab-paclitaxel: The multicenter, open-label, phase III NAPOLI 3 study (NCT04083235) included 770 patients with confirmed pancreatic ductal adenocarcinoma who had not been treated previously for metastatic disease. The patients were randomly assigned 1:1 to receive NALIRIFOX (irinotecan sucrosofate [50 mg/m2], oxaliplatin [60 mg/m2], leucovorin [400 mg/m2], and 5-FU [2,400 mg/m2] as an intravenous infusion over 46 hours on days 1 and 15 of cycles lasting 28 days) or nab-paclitaxel (125 mg/m2) and gemcitabine (1,000 mg/m2 given intravenously on days 1, 8, and 15 of cycles lasting 28 days). The primary end point was OS from randomization to death due to any cause, for NALIRIFOX versus gemcitabine/nab-paclitaxel. Secondary end points included PFS and overall response rate by RECIST version 1.1.[5]
The median OS was 11.1 months (95% CI, 10.0–12.1) in the NALIRIFOX group and 9.2 months (95% CI, 8.3–10.6) in the nab-paclitaxel/gemcitabine group (HR, 0.83; 95% CI, 0.7–0.99; P = .036). The median follow-up was 16.1 months.[5][Level of evidence A1]
The median PFS was 7.4 months in the NALIRIFOX group and 5.6 months in the nab-paclitaxel/gemcitabine group (HR, 0.69; 95% CI, 0.58–0.83; P < .0001).
The overall response rate was 42% in the NALIRIFOX group and 36% in the nab-paclitaxel/gemcitabine group (P = .11). The median duration of response was 7.3 months in the NALIRIFOX group and 5 months in the nab-paclitaxel/gemcitabine group (HR, 0.67; 95% CI, 0.48–0.93).
There were 369 patients (>99%) with any adverse event in the NALIRIFOX group and 376 patients (99%) with any adverse event in the nab-paclitaxel/gemcitabine group. The most common grade 3 to 4 toxicities in the NALIRIFOX group were diarrhea (20%), hypokalemia (15%), neutropenia (14%), and nausea (12%). The most common grade 3 to 4 toxicities in the nab-paclitaxel/gemcitabine group were neutropenia (25%) and anemia (17%). Of note, hematological toxicities (i.e., neutropenia, anemia, thrombocytopenia) were lower in the NALIRIFOX group than the nab-paclitaxel/gemcitabine group. Peripheral neuropathy was noted in 3% of patients in the NALIRIFOX group compared with 6% of patients in the gemcitabine/nab-paclitaxel group.
Based on this trial, NALIRIFOX is a standard first-line treatment option for patients with advanced pancreatic cancer.
Gemcitabine and nab-paclitaxel versus gemcitabine: A multicenter, international, phase III trial (NCT00844649) included 861 patients with metastatic pancreatic adenocarcinoma. Patients had a Karnofsky Performance Status of at least 70 and had not previously received chemotherapy for metastatic disease.[6][Level of evidence A1] Patients who received adjuvant gemcitabine or any other chemotherapy were excluded. The patients were randomly assigned to receive gemcitabine (1,000 mg/m2) and nab-paclitaxel (125 mg/m2 of body-surface area) weekly for 3 of 4 weeks or gemcitabine monotherapy (1,000 mg/m2 weekly for 7 of 8 weeks and then weekly for 3 of 4 weeks).
The median OS was 8.5 months in the nab-paclitaxel/gemcitabine group compared with 6.7 months in the gemcitabine group (HRdeath, 0.72; 95% CI, 0.62–0.83; P < .001).
Median PFS was 5.5 months in the nab-paclitaxel/gemcitabine group and 3.7 months in the gemcitabine group (HRdisease progression, 0.69; 95% CI, 0.58–0.82; P < .001).
Nab-paclitaxel/gemcitabine was more toxic than gemcitabine. The most common grade 3 toxicities in the nab-paclitaxel/gemcitabine group were neutropenia (38%), fatigue (17%), and neuropathy (17%); febrile neutropenia occurred in 3% of patients. In the gemcitabine-alone group, the most common grade 3 toxicities were neutropenia (27%), fatigue (1%), and neuropathy (1%); febrile neutropenia occurred in 1% of patients.
In the nab-paclitaxel/gemcitabine group, the median time from grade 3 neuropathy to grade 1 neuropathy or resolution was 29 days. Of patients with grade 3 peripheral neuropathy, 44% were able to resume treatment at a reduced dose within a median of 23 days after onset of a grade 3 event.
Based on this trial, nab-paclitaxel plus gemcitabine is a standard treatment option for patients with advanced pancreatic cancer.
Quality-of-life data were not measured for this regimen, and this study did not address the efficacy of nab-paclitaxel/gemcitabine versus FOLFIRINOX.
Gemcitabine alone versus gemcitabine and erlotinib: The National Cancer Institute of Canada performed a phase III trial (CAN-NCIC-PA3 [NCT00026338]) that compared gemcitabine alone with the combination of gemcitabine and erlotinib (100 mg/d) in patients with advanced or metastatic pancreatic carcinomas.[7][Level of evidence A1]
The addition of erlotinib modestly prolonged survival when combined with gemcitabine alone (HR, 0.81; 95% CI, 0.69–0.99; P = .038).
The corresponding median survival rate for patients receiving erlotinib was 6.2 months versus 5.9 months for patients receiving placebo. The 1-year survival rate for patients receiving erlotinib was 23% versus 17% for patients receiving placebo.
Evidence (second-line chemotherapy):
Irinotecan sucrosofate with or without 5-FU and leucovorin: The NAPOLI-1 trial (NCT01494506) evaluated the role of irinotecan sucrosofate in patients with metastatic pancreatic cancer who were previously treated with gemcitabine-based therapies.[8] Irinotecan sucrosofate is an encapsulated formulation of irinotecan designed to increase intratumoral levels of irinotecan and its active metabolite. In this study, a total of 417 patients were randomly assigned to receive either irinotecan sucrosofate monotherapy (120 mg/m2 every 3 weeks; n = 151), 5-FU and leucovorin (n = 149), or irinotecan sucrosofate (80 mg/m2 every 2 weeks plus 5-FU) and leucovorin (n = 117).[8][Level of evidence B1]
Median OS was 6.1 months (95% CI, 4.8–8.9) in patients who received irinotecan sucrosofate with 5-FU and 4.2 months (95% CI, 3.6–4.9) in patients who received 5-FU and leucovorin (P = .012). Median OS was 4.9 months (95% CI, 4.2–5.6) for patients who received irinotecan sucrosofate monotherapy, compared with 4.2 months (95% CI, 3.6–4.9) for those who received 5-FU and leucovorin (unstratified HR, 0.99; P = .94). On multivariate analysis, irinotecan sucrosofate plus 5-FU and leucovorin was associated with improved OS (HR, 0.58; 95% CI, 0.42–0.81).
Grade 3 or 4 adverse events occurred most frequently in the patients who received irinotecan sucrosofate plus 5-FU and leucovorin and included neutropenia (27%), diarrhea (13%), vomiting (11%), and fatigue (14%).
Despite differences in survival and toxicity between regimens, quality of life was not significantly different between treatment groups.
The benefit of using irinotecan sucrosofate rather than unencapsulated irinotecan has not been established because the regimen for the control arm of this study was 5-FU/leucovorin. Additionally, the value of using irinotecan sucrosofate after FOLFIRINOX in the first-line setting is not clear.
5-FU, leucovorin, and oxaliplatin (OFF regimen) versus best supportive care (BSC): Second-line chemotherapy after progression on a gemcitabine-based regimen may be beneficial. The Charité Onkologie (CONKO)-003 investigators randomly assigned patients requiring a second line of chemotherapy to either an OFF regimen or BSC.[2]; [3][Level of evidence C1] The OFF regimen consisted of leucovorin (200 mg/m2) followed by 5-FU (2,000 mg/m2 [24 hours continuous infusion] on days 1, 8, 15, and 22) and oxaliplatin (85 mg/m2 on days 8 and 22). After a rest of 3 weeks, the next cycle was started on day 43. The trial was terminated early because of poor accrual, and only 46 patients were randomly assigned to either the OFF regimen or BSC.
The median survival was 4.82 months (95% CI, 4.29–5.35) with the OFF treatment regimen and 2.30 months (95% CI, 1.76–2.83) with BSC alone (HR, 0.45; 95% CI, 0.24–0.83).
Median OS was 9.09 months for the sequence of gemcitabine/OFF and 7.90 months for gemcitabine/BSC.
The early closure of the study and the very small number of patients made the P values misleading. Therefore, second-line chemotherapy with the OFF regimen may be falsely associated with improved survival.
FOLFOX (leucovorin, 5-FU, and oxaliplatin) versus 5-FU/leucovorin after gemcitabine chemotherapy: The prospective, multicenter PANCREOX trial included 108 patients with advanced pancreatic cancer who had previously received first-line gemcitabine-based chemotherapy. Patients were randomly assigned to receive 5-FU/leucovorin without oxaliplatin (n = 54) or with oxaliplatin (n = 54), administered as modified FOLFOX-6 (mFOLFOX-6).[9][Level of evidence C1] With a target accrual of 128 patients, the study closed prematurely because of slow accrual.
After a median follow-up of 8.8 months, the median PFS was 3.1 months in the mFOLFOX-6 arm and 2.9 months in the infusional 5-FU arm (HR, 1.00; 95% CI, 0.66–1.53, P = .989).
Overall response rate and quality of life was not significantly different in the two arms.
The overall incidence of grade 3 or 4 adverse events was 63% in the mFOLFOX-6 arm and 11% in the 5-FU/leucovorin arm. However, more patients in the mFOLFOX-6 arm withdrew from the study because of adverse events than did patients in the 5-FU/leucovorin arm (20% vs. 2%).
Based on this study, no benefit was seen with the addition of oxaliplatin, administered in the mFOLFOX-6 regimen, versus infusional 5-FU/leucovorin among patients with advanced pancreatic cancer after first-line gemcitabine-based chemotherapy. These results may suggest that oxaliplatin-based regimens for metastatic pancreatic cancer may yield the greatest benefit in the first-line setting.
Gemcitabine/paclitaxel versus gemcitabine after FOLFIRINOX failure or intolerance: The prospective, open-label, phase III GEMPAX study (NCT03943667) included 211 patients with metastatic pancreatic cancer that progressed during or within 3 months of completing first-line FOLFIRINOX (including FOLFIRINOX treatment as adjuvant therapy) or were intolerant of this therapy. Patients were randomly assigned to one of the following treatment arms:[10]
Gemcitabine/paclitaxel: Gemcitabine (1,000 mg/m2) and solvent-based paclitaxel (80 mg/m2) on days 1, 8, and 15 of a 28-day cycle.
Gemcitabine alone: Gemcitabine (1,000 mg/m2) on days 1, 8, and 15 of a 29-day cycle.
The following results were observed:
There was no significant difference in OS among patients who received gemcitabine/paclitaxel (6.4 months after a median follow-up of 13.4 months) or gemcitabine alone (5.9 months after 13.8 months of follow-up) (HR, 0.87; 95% CI, 0.63–1.20; P = .4095). However, OS was improved in the following subgroups of patients who received gemcitabine/paclitaxel: (1) patients aged 65 years or younger (HR, 0.66; 95% CI, 0.44–0.99), and (2) patients with CA 19-9 levels of 59 times the upper limit of normal or higher at baseline (HR, 0.64; 95% CI, 0.42–0.97).[10][Level of evidence B1]
PFS was 3.1 months in the gemcitabine/paclitaxel group and 2.0 months in the gemcitabine-alone group (HR, 0.64; 95% CI, 0.47–0.89, P = .0067). The objective response rate was 17.1% in the gemcitabine/paclitaxel group and 4.2% in the gemcitabine-alone group (P = .008).
Third-line therapies were given to 32.1% of patients in the gemcitabine/paclitaxel group and 46.5% of patients in the gemcitabine-alone group.
The overall incidence of grade 3 or greater treatment-related adverse events was 58% in the gemcitabine/paclitaxel group and 27.1% in the gemcitabine-alone group. In the gemcitabine/paclitaxel group, 13% of patients experienced serious treatment-related adverse events, versus 7.1% of patients in the gemcitabine-alone group. The most common grade 3 or greater treatment-related adverse events among patients in the gemcitabine/paclitaxel group versus those in the gemcitabine-alone group were anemia (15.2% vs. 4.3%), thrombocytopenia (19.6% vs. 4.3%), neutropenia (15.9% vs. 15.7%), peripheral neuropathy (12.3% vs. 0%), and asthenia (10.1% vs. 2.9%). There was one grade 5 adverse event associated with gemcitabine/paclitaxel therapy, which was attributed as acute respiratory distress.
Based on this study, no OS benefit was seen with second-line gemcitabine/paclitaxel over gemcitabine alone. However, there was an OS benefit in certain subgroups (patients aged 65 years or younger and patients with high CA 19-9 levels at baseline). PFS and objective response rate were significantly higher in the gemcitabine/paclitaxel group. Thus, combination therapy with gemcitabine/paclitaxel can be considered for the appropriate patient, recognizing the higher rate of treatment-related adverse events.
Special considerations for patients with germline BRCA1/BRCA2 variants
Germline variants in BRCA1 or BRCA2 are present in 4% to 8% of patients with pancreatic adenocarcinoma.[11,12] BRCA1/BRCA2 encode for proteins in the homologous repair pathway and DNA double-stranded break repair, and thus may be more sensitive to further DNA damage. Pancreatic tumors with BRCA1/BRCA2 variants demonstrate improved responses to platinum-based therapies.[13] Poly (ADP-ribose) polymerase (PARP) inhibition has been posited to act synergistically with BRCA1/BRCA2 variants by inhibiting single-stranded break repair. Several PARP inhibitors have been approved for treatment of patients with BRCA1/BRCA2-mutated advanced ovarian and breast cancers and are actively being studied for the management of patients with BRCA1/BRCA2-mutated pancreatic adenocarcinoma.
Olaparib
Olaparib (a PARP inhibitor) maintenance therapy can be considered for patients with germline BRCA1/BRCA2 variants and metastatic pancreatic adenocarcinoma who have responded to first-line platinum-based therapy for more than 4 months.
Evidence (olaparib):
POLO trial (NCT02184195): A multicenter, phase III, randomized, double-blind, placebo-controlled trial that included 154 patients with metastatic pancreatic adenocarcinoma with germline BRCA1 or BRCA2 variants whose disease had not progressed after 16 weeks of first-line platinum-based chemotherapy.[14][Level of evidence B1] The patients were assigned 3:2 to receive olaparib (300 mg twice daily) or placebo and were assessed for PFS.
Of 3,315 patients screened, 247 patients were identified with germline BRCA variants.
The median PFS was 7.4 months in the olaparib arm and 3.8 months in the placebo arm (HR, 0.53; 95% CI, 0.35‒0.82; P = .004)
Median OS was 18.9 months in the olaparib group and 18.1 months in the placebo arm (HR, 0.91; 95% CI, 0.56‒1.46; P = .68).
There were more grade 3 or 4 treatment-related adverse events with olaparib (40%) compared with placebo (23%).
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
Burris HA, Moore MJ, Andersen J, et al.: Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol 15 (6): 2403-13, 1997. [PUBMED Abstract]
Pelzer U, Kubica K, Stieler J, et al.: A randomized trial in patients with gemcitabine refractory pancreatic cancer. Final results of the CONKO 003 study. [Abstract] J Clin Oncol 26 (Suppl 15): A-4508, 2008.
Pelzer U, Schwaner I, Stieler J, et al.: Best supportive care (BSC) versus oxaliplatin, folinic acid and 5-fluorouracil (OFF) plus BSC in patients for second-line advanced pancreatic cancer: a phase III-study from the German CONKO-study group. Eur J Cancer 47 (11): 1676-81, 2011. [PUBMED Abstract]
Conroy T, Desseigne F, Ychou M, et al.: FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 364 (19): 1817-25, 2011. [PUBMED Abstract]
Wainberg ZA, Melisi D, Macarulla T, et al.: NALIRIFOX versus nab-paclitaxel and gemcitabine in treatment-naive patients with metastatic pancreatic ductal adenocarcinoma (NAPOLI 3): a randomised, open-label, phase 3 trial. Lancet 402 (10409): 1272-1281, 2023. [PUBMED Abstract]
Von Hoff DD, Ervin T, Arena FP, et al.: Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med 369 (18): 1691-703, 2013. [PUBMED Abstract]
Moore MJ, Goldstein D, Hamm J, et al.: Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 25 (15): 1960-6, 2007. [PUBMED Abstract]
Wang-Gillam A, Li CP, Bodoky G, et al.: Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial. Lancet 387 (10018): 545-57, 2016. [PUBMED Abstract]
Gill S, Ko YJ, Cripps C, et al.: PANCREOX: A Randomized Phase III Study of Fluorouracil/Leucovorin With or Without Oxaliplatin for Second-Line Advanced Pancreatic Cancer in Patients Who Have Received Gemcitabine-Based Chemotherapy. J Clin Oncol 34 (32): 3914-3920, 2016. [PUBMED Abstract]
De La Fouchardière C, Malka D, Cropet C, et al.: Gemcitabine and Paclitaxel Versus Gemcitabine Alone After 5-Fluorouracil, Oxaliplatin, and Irinotecan in Metastatic Pancreatic Adenocarcinoma: A Randomized Phase III PRODIGE 65-UCGI 36-GEMPAX UNICANCER Study. J Clin Oncol 42 (9): 1055-1066, 2024. [PUBMED Abstract]
Holter S, Borgida A, Dodd A, et al.: Germline BRCA Mutations in a Large Clinic-Based Cohort of Patients With Pancreatic Adenocarcinoma. J Clin Oncol 33 (28): 3124-9, 2015. [PUBMED Abstract]
Cancer Genome Atlas Research Network. Electronic address: andrew_aguirre@dfci.harvard.edu, Cancer Genome Atlas Research Network: Integrated Genomic Characterization of Pancreatic Ductal Adenocarcinoma. Cancer Cell 32 (2): 185-203.e13, 2017. [PUBMED Abstract]
Golan T, Kanji ZS, Epelbaum R, et al.: Overall survival and clinical characteristics of pancreatic cancer in BRCA mutation carriers. Br J Cancer 111 (6): 1132-8, 2014. [PUBMED Abstract]
Golan T, Hammel P, Reni M, et al.: Maintenance Olaparib for Germline BRCA-Mutated Metastatic Pancreatic Cancer. N Engl J Med 381 (4): 317-327, 2019. [PUBMED Abstract]
Palliative Therapy
Palliative therapy options for patients with pancreatic cancer include:
Palliative surgical bypass procedures such as endoscopic or radiologically placed stents.[1,2]
Palliative radiation procedures.
Pain relief by celiac axis nerve or intrapleural block (percutaneous).[3]
Other palliative medical care alone.
References
Sohn TA, Lillemoe KD, Cameron JL, et al.: Surgical palliation of unresectable periampullary adenocarcinoma in the 1990s. J Am Coll Surg 188 (6): 658-66; discussion 666-9, 1999. [PUBMED Abstract]
Baron TH: Expandable metal stents for the treatment of cancerous obstruction of the gastrointestinal tract. N Engl J Med 344 (22): 1681-7, 2001. [PUBMED Abstract]
Polati E, Finco G, Gottin L, et al.: Prospective randomized double-blind trial of neurolytic coeliac plexus block in patients with pancreatic cancer. Br J Surg 85 (2): 199-201, 1998. [PUBMED Abstract]
Latest Updates to This Summary (02/12/2025)
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.
Revised text about the results of the randomized, open-label, phase III PRODIGE-24 trial, which randomly assigned 493 patients with R0/R1 resections to receive six cycles of gemcitabine or 12 cycles of FOLFIRINOX (oxaliplatin, leucovorin, irinotecan, and fluorouracil) (cited Conroy et al. as reference 24).
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 pancreatic 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 Pancreatic 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.
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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 Pancreatic Cancer Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/pancreatic/hp/pancreatic-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389394]
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Based on the strength of the available evidence, treatment options may be described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.
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