Neuroendocrine and Adrenal Tumors, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology

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  • 1 The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute;
  • | 2 Fred & Pamela Buffett Cancer Center;
  • | 3 Robert H. Lurie Comprehensive Cancer Center of Northwestern University;
  • | 4 UCSF Helen Diller Family Comprehensive Cancer Center;
  • | 5 Massachusetts General Hospital Cancer Center;
  • | 6 Dana-Farber/Brigham and Women’s Cancer Center;
  • | 7 Vanderbilt-Ingram Cancer Center;
  • | 8 St. Jude Children's Research Hospital/The University of Tennessee Health Science Center;
  • | 9 UC San Diego Moores Cancer Center;
  • | 10 University of Michigan Rogel Cancer Center;
  • | 11 Mayo Clinic Cancer Center;
  • | 12 The University of Texas MD Anderson Cancer Center;
  • | 13 The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins;
  • | 14 UCLA Jonsson Comprehensive Cancer Center;
  • | 15 O'Neal Comprehensive Cancer Center at UAB;
  • | 16 City of Hope National Medical Center;
  • | 17 Case Comprehensive Cancer Center/University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute;
  • | 18 Yale Cancer Center/Smilow Cancer Hospital;
  • | 19 Roswell Park Comprehensive Cancer Center;
  • | 20 University of Colorado Cancer Center;
  • | 21 Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance;
  • | 22 Memorial Sloan Kettering Cancer Center;
  • | 23 UT Southwestern Simmons Comprehensive Cancer Center;
  • | 24 Stanford Cancer Institute;
  • | 25 Huntsman Cancer Institute at the University of Utah;
  • | 26 Abramson Cancer Center at the University of Pennsylvania;
  • | 27 Moffitt Cancer Center;
  • | 28 Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine;
  • | 29 University of Wisconsin Carbone Cancer Center;
  • | 30 Fox Chase Cancer Center;
  • | 31 Duke Cancer Institute; and
  • | 32 National Comprehensive Cancer Network;

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Neuroendocrine and Adrenal Gland Tumors focus on the diagnosis, treatment, and management of patients with neuroendocrine tumors (NETs), adrenal tumors, pheochromocytomas, paragangliomas, and multiple endocrine neoplasia. NETs are generally subclassified by site of origin, stage, and histologic characteristics. Appropriate diagnosis and treatment of NETs often involves collaboration between specialists in multiple disciplines, using specific biochemical, radiologic, and surgical methods. Specialists include pathologists, endocrinologists, radiologists (including nuclear medicine specialists), and medical, radiation, and surgical oncologists. These guidelines discuss the diagnosis and management of both sporadic and hereditary neuroendocrine and adrenal tumors and are intended to assist with clinical decision-making. This article is focused on the 2021 NCCN Guidelines principles of genetic risk assessment and counseling and recommendations for well-differentiated grade 3 NETs, poorly differentiated neuroendocrine carcinomas, adrenal tumors, pheochromocytomas, and paragangliomas.

Overview

Neuroendocrine tumors (NETs) are thought to arise from cells throughout the diffuse endocrine system. They comprise a broad family of tumors, the most common of which are in the gastrointestinal tract, lungs and bronchi (so-called bronchopulmonary), thymus, and pancreas. Sites of origin within the gastrointestinal tract include the stomach, small intestine, appendix, and rectum.1,2 Other NETs include those arising in the parathyroid, thyroid, adrenal, and pituitary glands.

An analysis of the SEER database estimated that the incidence of NETs in the United States was 6.98 cases per 100,000 people in the year 2012.2 This analysis suggested that the incidence of NETs is increasing, and that the prevalence of individuals with NETs in the United States may exceed 170,000.

Most NETs seem to be sporadic, and risk factors for sporadic NETs are poorly understood. NETs may also arise in the context of inherited genetic syndromes, including multiple endocrine neoplasia types 1 (MEN1), 2 (MEN2), and 4 (MEN4), and succinate dehydrogenase mutations. NETs have also been associated with other conditions, including von Hippel-Lindau disease, tuberous sclerosis complex, and neurofibromatosis.3,4

Patients with NETs can have symptoms attributable to hormonal hypersecretion. These symptoms include intermittent flushing and diarrhea in patients with gastrointestinal NETs,5 bronchospasm and wheezing in lung NETs,5 hypertension in patients with pheochromocytoma or paraganglioma,6 and symptoms attributable to secretion of insulin, glucagon, gastrin, and other peptides in patients with pancreatic NETs.7 Patients with hormonal symptoms are considered to have “functional” tumors, and those without symptoms are considered to have “nonfunctional” tumors.

Histologic Classification and Staging of Neuroendocrine and Adrenal Tumors

NETs are generally subclassified by site of origin, stage, and histologic characteristics.

Histologic Classification

Neuroendocrine neoplasms (NENs) are divided into NETs and neuroendocrine carcinomas (NECs). The 2019 WHO classification of NENs includes significant updates.8 Previously, the gastrointestinal NENs and the pancreatic NENs were classified separately; now they share a common classification scheme.8,9 NETs are well-differentiated while NECs are poorly differentiated neoplasms. Well differentiated NETs are further classified into 3 categories: low-grade (G1); intermediate-grade (G2); high-grade (G3). All poorly differentiated NECs are G3, but not all G3 NENs are poorly differentiated. Some tumors can have mixed, both well and poorly differentiated histology and are termed as mixed neuroendocrine-nonneuroendocrine neoplasms.

Tumor differentiation and tumor grade often correlate with mitotic count and Ki-67 proliferation index. In fact, most commonly used histologic classification schemes, including the European Neuroendocrine Tumor Society (ENETS), WHO systems, and the International Agency for Research on Cancer, incorporate mitotic rate and Ki-67 index.7,913 Numerous studies have confirmed that increased mitotic rate and high Ki-67 index are associated with a more aggressive clinical course and worse prognosis.1417 In gastrointestinal and pancreatic NETs, well-differentiated, low-grade tumors have a mitotic count of <2/10 high-power field (HPF) and/or a Ki-67 index of less than 3%. Well-differentiated, intermediate-grade tumors have a mitotic count of 2 to 20/10 HPF and/or a Ki-67 index of 3%–20%. In high-grade well-differentiated tumors, the mitotic count exceeds 20/10 HPF and/or the Ki-67 index exceeds 20%.

Grade is generally defined by mitotic count and/or Ki-67 index, whichever is higher. If both mitotic rate and Ki-67 index are used and these are discordant, it is currently recommended that the higher grade be used to assign classification.1820 Ki-67 immunohistochemistry should be analyzed and/or counted in the areas of highest activity referred to as hot spots. A key recommendation is that tumor differentiation, mitotic rate, and Ki-67 index should all be included in the pathology report. Doing so allows the treating physician to factor these data into the clinical picture to make appropriate treatment decisions in gastrointestinal and pancreatic NENs. The current grading of lung NENs does not rely on Ki-67.21

Staging

NETs are staged according to the AJCC tumor (T), node (N), metastasis (M) staging system. The AJCC introduced its first TNM staging system for the classification of NETs in its seventh edition of the AJCC Cancer Staging Manual.22 The T and N definitions and other staging definitions were revised in the 8th edition of the AJCC Cancer Staging Manual.23 The 8th edition also added the first staging system for thymic tumors and adrenal NETs (including staging for pheochromocytoma and paraganglioma).23 NETs of the stomach, duodenum/ampulla, jejunum/ileum, appendix, colon/rectum, and pancreas have separate staging systems. The association of tumor stage with prognosis has been confirmed in analyses of the SEER database and the National Cancer Database.2430 An analysis of 691 patients with jejunal-ileocecal NETs treated at the Moffitt Cancer Center between 2000 and 2010 revealed 5-year survival rates of 100%, 100%, 91%, and 72% for stages I through IV, respectively, further validating the TNM staging system.31 Of note, however, this analysis also suggested that, unlike other malignancies, primary tumor size and depth of invasion had little bearing on survival in early-stage disease.32 Similar results were reported in a separate analysis of 6,792 small intestine NETs in the SEER database, which found that outcomes were similar for patients with T1 and T2 tumors.33 These results have been supported in additional analyses, confirming that the presence of lymph node and distant metastases have the strongest effect on survival.34,35

The TNM staging system for the classification of pancreatic NETs in the eighth edition of the AJCC Cancer Staging Manual is separate from exocrine pancreatic carcinoma.22,23 The primary tumor (T) is differentiated based on size and involvement of major vessels or other organs (see “Staging” in the algorithm, available at NCCN.org). A retrospective analysis of 425 patients with pancreatic NETs treated at the Moffitt Cancer Center between 1999 and 2010 validated the AJCC 2017 classification system, with 5-year overall survival (OS) rates of 92%, 84%, 81%, and 57% for stages I through IV, respectively (P<.001).36 Although the trends of this analysis are consistent with population-based studies, the survival rates from this analysis were significantly higher than those seen in population-based studies.37,38 For example, in the SEER database analysis of pancreatic NETs, the 5-year survival rate for patients with metastatic disease was only 19.5%.38

Pathologic Reporting

In addition to information on histologic classification and stage, the margin status (positive or negative) and the presence of vascular or perineural invasion should be included in the pathology report; some studies have suggested that these factors may also have prognostic significance.39,40

Whether tumors are associated with symptoms of hormone hypersecretion (“functioning” or “non-functioning”) is a clinical rather than histologic diagnosis. The presence of hormone-staining granules without a clinical syndrome does not make a tumor “functioning.” Thus, functional status is usually not included in the pathology report.

Principles of Genetic Risk Assessment and Counseling

In the 2021 guidelines, the panel included a new principles of genetic risk assessment and counseling for hereditary endocrine neoplasias. This section outlines how to go about genetic counseling, provides an overview of clinical manifestations associated with these disorders, and advises the readers of resources that can be accessed for more information (eg, how to find a genetic counselor, see “Principles of Genetic Risk Assessment and Counseling,” in the algorithm [NE-E]). Recommendations are provided regarding pretest counseling, considerations when determining the most appropriate testing strategy, posttest counseling, and criteria for genetic risk evaluation for hereditary endocrine neoplasia syndromes.

Genetic risk evaluation is recommended in patients with any of the following: (1) adrenocortical carcinoma (ACC); (2) paraganglioma/pheochromocytoma; (3) gastrinoma (duodenal/pancreatic or type 2 gastric NET); (4) multifocal pancreatic NETs; (5) parathyroid adenoma or primary hyperparathyroidism before age 30, multiple parathyroid adenomas, multigland hyperplasia (without obvious secondary causes), or recurrent primary hyperparathyroidism; (6) clinical suspicion for MEN2 due to the presence of medullary thyroid cancer or other combination of MEN2-related features; (7) a mutation identified on tumor genomic testing that has clinical implications if also identified in the germline (eg, tumor analysis shows a mutation in BRCA1/2 or mismatch repair (MMR) gene); (8) a close blood relative with a known pathogenic variant/likely pathogenic variant in a cancer susceptibility gene; (9) a first-degree relative meeting one of the above criteria but not available for testing; and (10) clinical suspicion for MEN1 due to 2 or more of the following, or 1 of the following and a family history of 1 or more of the following: primary hyperparathyroidism, duodenal/pancreatic NET, pituitary adenoma, or foregut carcinoid (bronchial, thymic, or gastric). Genetic risk evaluation should be considered at any age in patients with duodenal/pancreatic NET.

Genetic syndromes covered in this section include hereditary paraganglioma/pheochromocytoma syndrome; MEN1, MEN2, and MEN4; neurofibromatosis type 1; tuberous sclerosis complex; and von Hippel Lindau syndrome. Some resources are also listed for hereditary cancer predisposition syndromes associated with ACCs such as Li-Fraumeni syndrome, Lynch syndrome, MEN1, and familial adenomatous polyposis (see “Principles of Genetic Risk Assessment and Counseling,” NE-E). Additional screening recommendations are also provided for patients with hereditary paraganglioma/pheochromocytoma, MEN2, and von Hippel Lindau syndrome.

Well-Differentiated Grade 3 Neuroendocrine Tumors

Well-differentiated G3 NETs were introduced as a new category in the 2017 WHO classification update of pancreatic NENs, and in the 2019 WHO classification for digestive system (gastroenteropancreatic) NENs (including unknown primary tumors). These encompass tumors that have a high proliferation rate, with a mitotic index greater than 20 or a Ki-67 index greater than 20%, and a well-differentiated morphology.41 These occur mostly in the pancreas, stomach, and colon, although they can occur at any primary site. Well-differentiated G3 tumors have a better prognosis than poorly differentiated NECs, but a worse prognosis when compared with G1–G2 well-differentiated NETs.19 The results from 2 studies showed that patients with well-differentiated G3 NETs had a significantly higher median OS (41–99 vs 17 months) compared with patients with poorly differentiated NECs.42,43

Evaluation of Well-Differentiated Grade 3 Neuroendocrine Tumors

Imaging with multiphasic abdominal/pelvic CT or MRI scans with contrast, with or without chest CT scans (if clinically indicated), and somatostatin-receptor (SSR)-based PET imaging (SSR-PET) is recommended. Unless otherwise indicated, the preferred SSR-based imaging in this discussion includes SSR-PET/CT or SSR-PET/MRI imaging using 68Ga-DOTATATE, 68Ga-DOTATOC, or 64Cu-DOTATATE. SSR scintigraphy using 111In-octreotide (with SPECT/CT) is appropriate only if SSR-PET is not available. SSR-PET imaging is more sensitive than SSR scintigraphy for determining SSR status.

SSR-based PET imaging should include PET/CT or PET/MRI of the skull base to midthigh with intravenous contrast (both arterial and portal venous phase), when possible. Data are limited on the optimal timing of SSR scans after administration of somatostatin analogs. FDG-PET/CT scans can be performed as appropriate if SSR PET imaging is negative. There are some instances where FDG PET is useful in patients with positive SSR PET. Biochemical evaluation should be performed if the patient has symptoms suggestive of a secretory tumor. Pathology review is recommended, and assessment of p53, Rb, and p16, by histopathologic analysis or molecular profiling, can be considered if there is uncertainty about the tumor’s degree of differentiation, because a mutation in these genes would suggest a poorly differentiated NEC.4446 SSR 2A staining may also be helpful.47 Genetic counseling and testing for inherited genetic syndromes is recommended only for duodenal or pancreatic NETs.

Primary Treatment of Well-Differentiated Grade 3 Neuroendocrine Tumors

Treatment recommendations are based on the biology of the tumor. A tumor with favorable biology typically possesses Ki-67 less than 55%, is slow-growing, and may yield a positive SSR-based PET result. A tumor with unfavorable biology typically has Ki-67% greater than or equal to 55%, is faster-growing, and may yield a negative SSR-based PET result. Importantly, the data informing the appropriate Ki-67 cutoff are limited and variability/heterogeneity of Ki-67 in a given tumor and over time in serial biopsies make decision-making less straightforward in this entity compared with other NENs. The combination of clinical course and histopathologic workup should dictate therapy, not solely Ki-67. For locoregional (resectable) disease, resection is recommended, along with regional lymphadenectomy, if feasible, regardless of tumor biology.48 Patient factors should be considered.

For resectable locoregional disease with unfavorable biology, a clinical trial is preferred. Neoadjuvant chemotherapy can also be given on a case-by-case basis, and options include temozolomide with or without capecitabine, oxaliplatin-based therapy (FOLFOX or CAPEOX), cisplatin/etoposide, or carboplatin/etoposide. Temozolomide may have more activity in tumors arising in the pancreas. Following the completion of neoadjuvant chemotherapy, the patient should undergo resection with regional lymphadenectomy if feasible.

For resectable locally advanced or metastatic disease with favorable biology, resection of the primary and metastatic sites may be performed, if feasible. The treatment of unresectable locally advanced or metastatic tumors depends on the degree of tumor burden. If the patient is asymptomatic with low tumor burden, observation with a short interval follow-up scan is an option for select patients; otherwise, octreotide or lanreotide is recommended if the patient is SSR-positive and/or has hormonal symptoms. There are multiple treatment modalities if the patient has a clinically significant tumor burden or evidence of disease progression. Octreotide or lanreotide is recommended if the patient is SSR-positive and/or has hormonal symptoms. Enrollment in a clinical trial is preferred. Other recommended treatment options include peptide receptor radionuclide therapy (PRRT) with 177Lu-dotatate, everolimus, sunitinib (pancreas only), chemotherapy, or liver-directed therapy (for liver-predominant disease). Chemotherapy options consist of temozolomide with or without capecitabine,49 oxaliplatin-based therapy (FOLFOX, CAPEOX), cisplatin/etoposide, or carboplatin/etoposide. Pembrolizumab (category 2B) is also an option for patients with advanced tumor mutational burden-high (TMB-H) tumors (≥10 mutations/Mb), as determined by an FDA-approved test, that have progressed after prior treatment and have no satisfactory alternative treatment options.50,51 There is some concern with the TMB cutoff. In some cancers, compared with a TMB-low status, a TMB-H status did not result in a higher objective response rate (ORR) in patients treated with an immune checkpoint inhibitor,52 especially after additional cohort stratification.53 See “Principles of Peptide Receptor Radionuclide Therapy (PRRT) with 177Lu-dotatate” in the algorithm (available online, in these guidelines, at NCCN.org) for practical guidance and information, including patient eligibility, patient preparation for treatment, dose and administration of 177Lu-dotatate, posttreatment instructions, and timing of somatostatin analogs.

In the event of locally advanced or metastatic disease with unfavorable biology, a clinical trial is a preferred option. Other recommended options include chemotherapy (as described previously) and the combination of nivolumab and ipilimumab (category 2B).54 Pembrolizumab is also an option for patients with advanced TMB-H tumors, as determined by an FDA-approved test, that have progressed after prior treatment and have no satisfactory alternative treatment options.50,51 Additional chemotherapy options in this setting include irinotecan-based therapies (eg, FOLFIRI, cisplatin/irinotecan, FOLFIRINOX). The addition of liver-directed therapies, including embolization, selective internal radiation therapy, ablation, and stereotactic body radiation therapy, can be considered in selected cases with residual liver-predominant disease after systemic therapy. Palliative RT is recommended for symptomatic bone metastases.

Evolving data suggest that well-differentiated tumors with intermediate Ki-67 levels (in the 20%–55% range) may not respond as well to platinum/etoposide as those with higher Ki-67 (>55%).55 A few studies reported that treatment with platinum-based chemotherapy yielded almost no response (0%–2% response rate).42,43,56

Surveillance of Well- Differentiated Grade 3 Neuroendocrine Tumors

Surveillance for resectable locoregional, locally advanced, or metastatic disease consists of a routine patient history and physical examination along with appropriate imaging studies (abdominal/pelvic MRI scans with contrast or abdominal/pelvic multiphasic CT, and chest CT scans as clinically indicated) every 12 to 24 weeks for the first 2 years and every 6 to 12 months thereafter, for up to 10 years. Surveillance for resectable locoregional disease depends on the tumor biology and Ki-67%. Patients with unresectable locally advanced or metastatic disease with favorable biology should be monitored every 12 to 24 weeks (depending on tumor biology), with a history and physical and a chest CT with or without contrast and an abdominal/pelvic MRI with contrast or a chest/abdominal/pelvic multiphasic CT scan. SSR-PET/CT or SSR-PET/MRI or FDG PET/CT scans and biochemical markers are also recommended as clinically indicated. Patients with unresectable locally advanced or metastatic disease with unfavorable biology should follow the same surveillance recommendations (except for SSR imaging) but should be followed every 8 to 12 weeks (depending on tumor biology).

Poorly Differentiated Neuroendocrine Carcinomas/Large or Small Cell Carcinomas or Unknown Primary

Although rare, extrapulmonary poorly differentiated NECs can occur in a wide variety of organs. They are characterized by a high mitotic index and high Ki-67 index. The most aggressive of these tumors histologically resemble classic small cell carcinoma of the lung. The most frequent organs involved are the cervix, esophagus, pharynx and larynx, colon, rectum, prostate, pancreas, and bladder.57 Most extrapulmonary poorly differentiated NECs are aggressive and require combined multimodality treatment, usually following a treatment paradigm that parallels the treatment of small cell lung cancer. These tumors are rarely associated with a hormonal syndrome. Gastrointestinal tumors with mixed histology of poorly differentiated adenocarcinoma can be treated according to the NCCN Guidelines for Colon Cancer and Pancreatic Adenocarcinoma (available at NCCN.org).

Results from a SEER database analysis of NECs found that 9% were extrapulmonary.57 The median survival for all NECs was 7.7 months. Compared with other primary NECs (26.0%), the survival was lower for lung NECs (5.6%) and gastrointestinal NECs (13.1%) at 5 years. The median survival of patients with gastrointestinal NECs was 7.5 months, with patients with small intestine tumors doing better (25.1 months) than patients with pancreatic tumors (5.7 months). The median survival for patients with unknown primary NECs was 2.5 months.

Evaluation of Poorly Differentiated/Large or Small Cell Carcinomas or Unknown Primary

CT scans of the chest, abdomen, and pelvis or CT scans of the chest and MRI of the abdomen and pelvis are recommended as baseline staging studies. Brain imaging with MRI or CT scan with contrast and FDG-PET should be performed as clinically indicated and should be considered routinely in poorly differentiated NECs of the thorax and neck. Biochemical markers are recommended if symptoms are suggestive of a secretory tumor. SSR imaging is not part of the routine evaluation of poorly differentiated NECs. Tumor biomarkers such as microsatellite instability (MSI), MMR, and TMB testing (by an FDA-approved test) should be considered as they can aid in assessing targeted therapy options.

Primary Treatment of Extrapulmonary Poorly Differentiated/Large or Small Cell Neuroendocrine Carcinomas or Unknown Primary

For resectable poorly differentiated/large or small cell NECs, poorly differentiated of unknown primary, treatment options depend on the disease site. Such options include surgical resection and adjuvant chemotherapy with or without radiotherapy, neoadjuvant chemotherapy with or without radiation and resection, chemotherapy alone, radiotherapy alone, and definitive chemoradiation (with cisplatin/etoposide or carboplatin/etoposide). For unresectable locoregional disease, concurrent or sequential radiotherapy in combination with chemotherapy, or chemotherapy alone are recommended. If metastatic disease is present, chemotherapy alone is recommended.

Cytotoxic chemotherapy regimens, such as cisplatin/etoposide58,59 or carboplatin/etoposide,60 FOLOFOX,61 FOLFIRI,62 and temozolomide with or without capecitabine,63 are generally used as primary treatment of resectable, locoregional unresectable, or metastatic disease. For locoregional unresectable or metastatic disease, additional chemotherapy options include cisplatin/irinotecan,59 carboplatin/irinotecan, and FOLFIRINOX.64,65 The efficacy of second-line or later lines of chemotherapy is very limited and survival is short.66 The combination of ipilimumab and nivolumab (category 2B) can be considered if the disease progresses following chemotherapy.54,67 The results of one phase II study (S1609 DART) revealed an ORR of 44% in patients with nonpancreatic high-grade NECs (including lung primaries) treated with combined ipilimumab and nivolumab.67 Subsequent data from an additional cohort of patients (n=19) with high-grade NENs (median Ki-67 80%) revealed an ORR of 26% and a 6-month progression-free survival (PFS) of 32%.68 The median PFS was 2.0 months and the median OS was 8.7 months. The subgroup analysis of the CA209-538 trial, centered on patients with advanced NENs that received the combined treatment, demonstrated an ORR of 24%.54 The median PFS was 4.8 months and the OS was 14.8 months. Immune-related toxicity occurred in 66% of cases. Importantly, preliminary data from the multicohort phase II study (n=123) of durvalumab plus tremelimumab for patients with NENs of gastroenteropancreatic or lung origin suggested only modest activity (irRECIST ORR 9.1%) in G3 gastroenteropancreatic NENs.69

Finally, pembrolizumab can also be considered for patients with MMR-deficient, MSI-high, or advanced TMB-high (as determined by an FDA-approved test) tumors that have progressed following prior treatment and have no satisfactory alternative treatment options.50,51,70

Surveillance of Poorly Differentiated/Large or Small Cell Carcinomas or Unknown Primary

For patients with resectable disease, surveillance after treatment completion consists of a routine history and physical along with appropriate imaging studies (chest CT with or without contrast and abdominal/pelvic MRI with contrast or chest/abdominal/pelvic multiphasic CT) every 12 weeks for the first year and every 6 months thereafter. However, patients with locoregional, unresectable disease and with metastatic disease should be monitored more closely every 6 to 16 weeks with an history and physical and appropriate imaging studies as described.

Adrenal Gland Tumors

Adrenocortical carcinomas are rare (incidence, 0.7–2 per million).71,72 ACC has a bimodal age distribution, with peak incidences in early childhood and the fourth to fifth decades of life. Women are more frequently affected (55%–60%).71,73 Most cases are sporadic; however, ACCs have been observed in association with several hereditary syndromes, including Li-Fraumeni syndrome, Lynch syndrome, Beckwith-Wiedemann syndrome, MEN1, and familial adenomatous polyposis.7480 The underlying mechanisms of carcinogenesis in sporadic ACCs have not been fully elucidated; however, inactivating somatic mutations of the p53 tumor suppressor gene (chromosome 17p1381,82) and alterations at the 11p15 locus (site of the IGF2 gene83,84) seem to occur frequently.

Approximately 60% of patients present with evidence of adrenal steroid hormone excess, with or without virilization.72 Signs and symptoms associated with hypersecretion of cortisol, called Cushing syndrome, include weight gain, weakness (primarily in proximal muscles), hypertension, psychiatric disturbances, hirsutism, centripetal obesity, purple striae, dorsocervical fat pad and supraclavicular fat pad enlargement, hyperglycemia, and hypokalemia. Aldosterone-secreting tumors may present with hypertension, weakness, and hypokalemia. Androgen-secreting tumors in women may induce hirsutism, virilization, deepening of the voice, and oligo/amenorrhea.72 In men, estrogen-secreting tumors may induce gynecomastia and testicular atrophy. Hormonally inactive ACCs typically produce symptoms related to tumor burden, including abdominal pain, back pain, early satiety, and weight loss.72

Evaluation and Treatment of Adrenal Gland Tumors

All patients with adrenal gland tumors need biochemical evaluation and appropriate imaging. Biochemical evaluation to evaluate for hyperaldosteronism, Cushing syndrome, pheochromocytoma, and suspected ACC should be done with every adrenal mass. Comprehensive guidelines for the workup of adrenal tumors, adrenal incidentalomas, hyperaldosteronism, Cushing syndrome, and pheochromocytoma and paraganglioma are published through the Endocrine Society8587 and the European Society of Endocrinology (ESE).88,89

NCCN recommends doing a morphologic evaluation of adrenal nodules with adrenal protocol CT, or MRI with or without contrast, to determine the size, heterogeneity, lipid content (with MRI), contrast washout (with CT), and margin characteristics. If the Hounsfield unit (HU) attenuation value is less than 10 on unenhanced CT, then the tumor is probably benign. If the HU attenuation value is greater than 10 on unenhanced CT, then enhanced CT and washout at 15 minutes is recommended. If the absolute washout value is greater than 60% at 15 minutes, the tumor is likely benign; if less than 60%, the tumor is possibly malignant.90,91 Functional evaluation should be done as noted previously. Most ACCs secrete multiple hormones; therefore, if imaging is suspicious for adrenal cortical carcinoma, evaluation for sex steroid in addition to the previously noted evaluation is indicated. If several hormones are over-secreted, ACCs are more likely.

History of a primary cancer outside of the adrenal gland raises the question of metastatic disease to the adrenals. However, it is very important that pheochromocytoma is ruled out prior to considering diagnostic biopsy of the adrenal mass. In these patients, an image-guided needle biopsy can be considered only if clinical suspicion for pheochromocytoma is low and plasma or urine fractionated metanephrines are normal. False-negative biopsies are possible; therefore, proceeding directly to surgery should be considered in some cases. If the tumor is determined to be a metastasis from another site, treatment should be according to the appropriate NCCN disease-specific treatment guideline (to see the NCCN Guidelines Table of Contents, go to www.NCCN.org). If biopsy reveals adrenal cortical tissue, then morphologic and functional evaluation should proceed as described here.

Evaluation and Treatment of Hyperaldosteronism

When hyperaldosteronism (also called primary aldosteronism) is suspected, plasma aldosterone and plasma renin activity should be assessed. Patients with primary aldosteronism have elevated plasma levels of aldosterone and low levels of renin activity. The plasma aldosterone-to-renin ratio in patients with primary hyperaldosteronism is usually greater than 30.87 Confirmatory testing is often recommended for equivocal results. Twenty-four-hour urine for aldosterone, following salt loading or a saline suppression test, as well as sodium and potassium levels should be considered for definitive diagnosis. Serum electrolytes should also be measured, because excessive aldosterone production causes both retention of sodium and excretion of potassium. The Endocrine Society has developed detailed guidelines for the detection, diagnosis, and treatment of primary aldosteronism,87 and these guidelines have been modified over time.92,93

Hyperaldosteronism is rarely associated with malignancy, but malignancy should be suspected if the tumor has an irregular or inhomogeneous morphology, is lipid-poor, does not wash out on contrast-enhanced CT, is larger than 4 cm, or is secreting more than one hormone. When malignant hyperaldosteronism is suspected, an open adrenalectomy is recommended, because these tumors are prone to rupture.89

Benign hyperaldosteronism is much more common and can be caused by a unilateral adrenal adenoma or bilateral adrenal hyperplasia. Adrenal vein sampling for aldosterone and cortisol can be considered for distinguishing these two causes of benign hyperaldosteronism and should be considered if the patient is a surgical candidate, because CT imaging cannot always differentiate between an adenoma and hyperplasia. It may be reasonable, however, to exclude adrenal vein sampling in patients younger than 40 years when imaging only shows one affected gland, because bilateral hyperplasia is rare in this population. Minimally invasive adrenalectomy is recommended for adenoma, whereas medical management with spironolactone or eplerenone for hypertension and hypokalemia is recommended for patients with bilateral adrenal hyperplasia and for nonsurgical candidates.

Evaluation and Treatment of Cushing Syndrome

Patients who present with symptoms of Cushing syndrome should be evaluated for evidence of hypercortisolemia with one of the following tests: (1) overnight 1-mg dexamethasone suppression test; (2) 2 to 3 midnight salivary cortisol measurements; or (3) free cortisol in a 24-hour urine sample.86,94 Elevated levels of cortisol are indicative of Cushing syndrome. Plasma ACTH should be checked to determine if it is ACTH dependent or ACTH independent (ACTH <5 pg/mL). Adrenal masses that secrete cortisol are not mediated by ACTH (ACTH independent), and ACTH dependent tumors can arise in the pituitary or ectopic NET sources. If a clear pituitary adenoma is not visible by MRI, inferior petrosal sinus vein sampling can be considered to differentiate between pituitary and ectopic causes in ACTH-dependent Cushing syndrome. Endocrinology referral should be considered for the biochemical workup, localization of hypercortisolemia, and medical therapy for hypercortisolism until more definitive therapy can be arranged.

Cushing syndrome can be associated with either benign adrenal tumors (adrenal adenoma) or malignant adrenal tumors. Malignancy should be suspected if the tumor is larger than 4 cm or is inhomogeneous with irregular margins and/or has local invasion and other malignant imaging characteristics. Some centers may use 6 cm as a cutoff instead of 4 cm. FDG PET/CT scans, chest CT scans with or without contrast, and CT or MRI scans with contrast of the abdomen and pelvis are recommended. Benign adrenal tumors (ie, <4 cm, contralateral gland normal, circumscribed tumor, other benign imaging characteristics) should be resected. It is important that patients who have cortisol-secreting adrenal tumor receive perioperative glucocorticoids since the contralateral adrenal secretion will be transiently suppressed. For more details, please see the Endocrine Society's Clinical Practice Guidelines for the Treatment of Cushing Syndrome.95

Treatment of Nonfunctioning, Benign Adrenal Tumors

Adrenal tumors that do not secrete hormones are often discovered incidentally during scans for unrelated reasons (incidentalomas). It is still important to evaluate for biochemical secretion of hormones for hyperaldosteronism, Cushing syndrome, and pheochromocytoma and paraganglioma as listed previously to confirm they are nonsecreting. Please refer to the American Association of Clinical Endocrinology and American Association of Endocrine Surgeons (AACE/AAES) guidelines96 and the ESE guidelines89 for the management of adrenal incidentalomas. Most nonfunctioning tumors are benign and can be left untreated. Masses showing radiographic features of myelolipoma are considered benign. In addition, tumors smaller than 4 cm that are homogenous, with smooth margins, and that appear lipid-rich according to CT or MRI criteria are also usually benign. A minimally invasive adrenalectomy is preferred for these tumors if resection is indicated due to tumor growth. If malignancy is suspected and the disease is localized, locally resectable, or regionally advanced, an open adrenalectomy is recommended.

Evaluation of Adrenocortical Carcinoma

ACC should be strongly suspected in tumors larger than 4 cm with irregular margins or that are internally heterogeneous and if they secrete multiple hormones.72 On CT scans with IV contrast, adjacent lymph nodes or liver metastases may be present. On unenhanced CTs, the HU number is typically higher in carcinomas than in adenomas, and a threshold value of 10 HU has been proposed as a means of distinguishing benign from malignant adrenal tumors.72 If the HU attenuation value is less than 10 on unenhanced CT, then the tumor is probably benign. If the HU attenuation value is greater than 10 on unenhanced CT, then enhanced CT and washout at 15 minutes is recommended. If the absolute washout value is greater than 60% at 15 minutes, the tumor is likely benign; if less than 60%, the tumor is possibly malignant.90,91 MRIs more clearly document local invasion and involvement of the inferior vena cava than CT scans.72 Whether CT or MRI scans are performed, they should be performed using an adrenal protocol to determine size, heterogeneity, lipid content (MRI), contrast washout (CT), and margin characteristics.

FDG PET/CT, chest CT scans with or without contrast, CT or MRI scans with contrast of the abdomen and pelvis, and a biochemical workup are also recommended for resectable, unresectable, or suspected metastatic disease.

One study found that 5.8% of adults with ACC tested positive for Li Fraumeni syndrome (TP53 gene) and genetic testing should be routinely offered to all patients with ACC.97 Another analysis found that approximately 3% of patients with ACC have Lynch syndrome, leading the authors to recommend that patients with ACC also undergo genetic testing for Lynch syndrome.79 Patients with ACC may also consider MSI, MMR, and TMB (by an FDA-approved test) testing. Genetic counseling and testing for inherited genetic syndromes is also recommended.

Treatment and Surveillance of Nonmetastatic Adrenocortical Carcinoma

Surgical resection of the tumor with removal of adjacent lymph nodes is recommended in patients with localized ACC, and may require removal of adjacent structures such as the liver, kidney, pancreas, spleen, and/or diaphragm for complete resection. Open adrenalectomy is recommended in tumors with a high risk of being malignant because of increased risk for local recurrence and peritoneal spread when performed laparoscopically.98 It is thus important to achieve negative margins and avoid breaching the tumor capsule.

Because of the rarity of ACCs, no randomized, prospective trials of adjuvant therapy have been published. Most retrospective reports have examined the use of adjuvant mitotane, an oral adrenocorticolytic agent.99 A recent systematic review and meta-analysis of the benefits of mitotane after resection of ACC in patients without distant metastasis included five retrospective studies reporting on 1249 patients.100 The meta-analysis found benefit of adjuvant mitotane, with significantly longer recurrence-free survival and OS, suggesting that adjuvant mitotane may be an effective postoperative strategy. The randomized phase III ADIUVO trial is currently underway to assess the efficacy of adjuvant mitotane in patients with ACCs considered to be at low to intermediate risk for progression (ClinicalTrials.gov identifier: NCT00777244). Disease-free survival is the primary endpoint.

Based on the available data, adjuvant therapy can be considered if the patient is at high risk for local recurrence based on positive margins, ruptured capsule, large size, and high grade. Adjuvant external beam RT to the tumor bed can be considered in these cases, particularly if concern exists regarding tumor spillage or close margins after surgery. Adjuvant mitotane therapy can also be considered after resection of ACC, although its use in this setting is controversial (category 3). Mitotane blood levels should be monitored. Some institutions recommend target levels of 14 to 20 mcg/mL if tolerated. Steady-state levels may be reached several months after initiation of mitotane. Because of the adrenolytic effects of mitotane, replacement doses of corticosteroids (hydrocortisone with or without fludrocortisone) should be prescribed to treat adrenal insufficiency if it is used; corticosteroids may be required for the rest of the patient’s life. Because of the potential risks and uncertain benefits of adjuvant mitotane, several NCCN Member Institutions do not advocate its use in the adjuvant treatment of patients with resected ACCs.

A follow-up should be performed every 12 weeks to 12 months for up to 5 years, and then as clinically indicated. Recurrences after 5 years are thought to be very rare. A chest CT scan, with or without contrast, and an abdominal CT or MRI scan with contrast and biomarkers (if the tumor is initially functional) should be considered.

Management of Locoregional Unresectable or Metastatic Adrenocortical Carcinoma

Resection may be considered if greater than 90% of the tumor and metastases can be removed. In the case of bulky disease or if less than 90% of the tumor is removable, surgery can be reconsidered following a response to systemic therapy. Observation with chest CT scans with or without contrast, abdominal/pelvic CT or MRI scans with contrast, and relevant biomarkers (if the tumor is initially functional) every 12 weeks can also be considered for clinically indolent disease, with systemic treatment initiated at tumor progression. For locoregional unresectable or metastatic disease, local therapy may be considered (ie, SBRT, thermal ablative therapies, liver-directed therapies).

Systemic therapy should be considered, preferably in a clinical trial. Choices of systemic therapy for advanced ACC are mitotane monotherapy or various combinations of cisplatin, carboplatin, etoposide, doxorubicin, streptozocin, and mitotane. Mitotane monotherapy has been studied in the setting of locally advanced or metastatic disease.101103 Partial response rates are thought to be 10%–30% at most.104 Pembrolizumab can also be considered as a single agent or in combination with mitotane. These regimens were preference stratified. Preferred regimens include cisplatin or carboplatin in combination with etoposide, with or without doxorubicin, and with or without mitotane. Pembrolizumab, with or without mitotane, and mitotane monotherapy are listed as “other recommended” regimens. Streptozocin, with or without mitotane, is listed as “useful in certain circumstances.”

A small phase II study investigating the use of pembrolizumab in patients with advanced ACCs found an ORR of 23% and a disease control rate of 52%.105 The median OS was 24.9 months. Another small study with 16 patients with advanced ACC demonstrated an ORR of 14% (95% CI, 2%–43%).106 One phase II study reported a 15% ORR and a 54% clinical benefit rate.107

Several studies have evaluated the combination of mitotane with other cytotoxic agents, including cisplatin and etoposide. One of the larger studies analyzed the combination of mitotane (4 g/day) with cisplatin, etoposide, and doxorubicin in 72 patients with unresectable adrenal carcinoma, yielding an ORR of 49% (according to WHO criteria) and a complete hormonal response in 16 of 42 patients with functioning tumors.108 Another study examined the combination of mitotane with streptozocin and reported an ORR of 36%.109 Of 12 patients in this study with advanced disease, 3 (25%) were converted to a resectable status with this therapy and remained disease-free or with stable disease 3 to 18 years after surgery; 1 (8%) had stable disease for 3 months, and the other 8 (67%) showed no response.

Analysis of results from the international randomized controlled phase III FIRM-ACT trial comparing treatment of metastatic ACC with etoposide, doxorubicin, cisplatin, and mitotane versus treatment with streptozotocin and mitotane with a crossover design found no difference between the regimens in the primary endpoint of OS (14.8 vs 12.0 months; hazard ratio [HR], 0.79; 95% CI, 0.61–1.02; P=.07).110 However, response rates and PFS were improved with the 4-drug regimen and an OS benefit was seen in those who did not cross over to the other combination (17.1 vs 4.7 months). Rates of serious adverse events were similar in the 2 arms.

However, the toxicity of concurrent chemotherapy plus mitotane should be considered when making treatment decisions, and mitotane monotherapy may still be appropriate in selected cases. The optimal doses and duration of mitotane treatment of metastatic disease have not yet been standardized, but some institutions recommend target levels of 14 to 20 mcg/mL, if tolerated. Higher doses may be difficult for patients to tolerate, whereas lower doses may be less effective.104 Steady-state levels may be reached several months after initiation of mitotane. As noted previously, because of the adrenolytic effects of mitotane, replacement doses of corticosteroids (hydrocortisone with or without fludrocortisone) should be prescribed to treat adrenal insufficiency. This replacement therapy may be required for the remainder of the patient’s lifetime. A follow-up with chest CT scans, with or without contrast, and abdominal/pelvic CT or MRI scans, with contrast, or FDG-PET/CT scans should be performed every 12 weeks to 12 months, up to 5 years, and then as clinically indicated.

Pheochromocytomas/Paragangliomas

Pheochromocytomas are neoplasms of the chromaffin cells of the adrenal medulla in 80%–90% of cases. Ectopic/extra-adrenal pheochromocytomas that arise from sympathetic and para-aortic sympathetic ganglia are called paragangliomas.85 Pheochromocytomas and paragangliomas occur in 0.05%–0.1% of hypertensive patients, and their combined annual incidence in the United States is estimated to be between 500 and 1,600 cases.111 Approximately 10%–15% of pheochromocytomas and paragangliomas are malignant, but it could be up to 40%.88,112 Pheochromocytomas release catecholamines (epinephrine and norepinephrine) and their metabolites metanephrine and normetanephrine, resulting in hypertension, arrhythmia, and/or hyperglycemia. About 40% of paragangliomas secrete catecholamines. Head and neck paragangliomas only secrete catecholamines about 5% of the time and often it is dopamine.

The peak incidence of occurrence for pheochromocytomas is between the third and fifth decades of life, but they generally occur at a younger age and are more likely to be bilateral in patients with familial disease. Paragangliomas are more likely to be malignant than pheochromocytomas in the adrenal medulla (about 40% vs 10%). Pheochromocytomas and paragangliomas associated with a familial syndrome tend to be more aggressive and more likely to metastasize than sporadic tumors.113 In fact, a study showed that 87.5% of patients presenting with these tumors prior to age 20 harbored a germline mutation in one of several genes tested if they also had metastatic disease.114 For those without metastases, the rate of identification of these mutations was still high, at 64.7%. The OS of patients with pheochromocytomas and paragangliomas can be heterogeneous, but a systematic review and meta-analysis of 7 studies of 738 patients reported survival to be 63% at 5 years.115 Predicting who will go on to develop metastasis is difficult, but some studies have reported that almost half of patients have not progressed a year after diagnosis.116 Delays at a median of 5.5 years with a range from 0.3 to 53.4 years between initial diagnosis and metastasis have been reported in a retrospective study spanning 55 years of patients with pheochromocytomas or paragangliomas, and many such patients survive long term after treatment of metastatic disease.117 Thus, patients presenting during childhood, adolescence, or young adulthood require careful, lifelong surveillance (see “Surveillance of Pheochromocytomas/Paragangliomas,” page 864).

Evaluation for Pheochromocytomas/Paragangliomas

A patient with possible pheochromocytoma should be evaluated with fractionated metanephrines and normetanephrines in 24-hour urine or free metanephrines in plasma. Elevated levels of metanephrines or normetanephrines are suggestive of pheochromocytoma or paraganglioma. In general, adrenal pheochromocytomas more commonly secrete metanephrines and paragangliomas secrete normetanephrines, with a few exceptions.85 Concurrent medications should be reviewed before testing for those that interfere with plasma or blood metanephrine/normetanephrine evaluation, including acetaminophen, certain beta- and alpha-adrenoreceptor blocking drugs, serotonin-reuptake inhibitors, and monoamine oxidase inhibitors.118 Elevations in metanephrine or normetanephrine levels that are 3 times above the upper limit of normal are diagnostic. Urine or plasma catecholamines are no longer routinely recommended for the evaluation of pheochromocytoma as 15%–20% of patients with pheochromocytoma have normal levels of urine catecholamines due to intermittent secretion in some tumors and insignificant secretion by others.119 Measurement of serum and/or 24-hour urine fractionated catecholamines can be considered since rare tumors preferentially secrete catecholamines, and cervical paragangliomas can secrete dopamine.

Adrenal protocol CT scans (abdomen/pelvis) are recommended. Other imaging studies, including abdominal/pelvic multiphasic CT or MRI scans, SSR-based imaging (PET/CT or PET/MRI), FDG-PET/CT scans (skull base to midthigh), chest CT scans with or without contrast, and metaiodobenzylguanidine (MIBG) scans should be performed as appropriate if metastatic or multifocal disease is suspected. CT scans are most helpful for adrenal masses and paragangliomas. However, there are some instances where extra-adrenal paragangliomas are seen better with MRI scans.

Genetic Counseling/Testing in Pheochromocytomas/Paragangliomas

Although many pheochromocytomas and paragangliomas are thought to be sporadic, increasing evidence shows that a number of pheochromocytomas and paragangliomas are in fact associated with inherited genetic syndromes.111,120 Pheochromocytomas occur in patients with MEN2A, MEN2B, and other familial diseases such as neurofibromatosis and von Hippel-Lindau syndrome (see “Principles of Genetic Risk Assessment and Counseling,” NE-E). Paragangliomas are also associated with polycythemia-paraganglioma-somatostatinoma syndrome due to somatic mutations in the HIF2A gene.121,122 In addition to germline mutations associated with these syndromes (ie, RET, NF1, VHL), germline mutations in SDHB, SDHA, SDHAF2, SDHD, SDHC, TMEM127, MAX, FH, and MDH2 have also been associated with an increased incidence of pheochromocytomas and paragangliomas.112,120126 SDHB gene mutations are associated with a 40%–60% risk of developing metastatic disease.112 Patients younger than 45 years of age or those with multifocal, bilateral, or recurrent lesions are more likely to have a heritable mutation, although many individuals with a hereditary syndrome present with solitary disease and no family history.126 Because a significant proportion of patients with a pheochromocytoma or paraganglioma have a heritable mutation,120 genetic counseling is recommended in patients with such a diagnosis and in those with a family history of these tumors, with genetic testing when appropriate. The Endocrine Society has published guidelines that include a genetic testing decision algorithm.85

Individuals with known germline mutations associated with pheochromocytomas and paragangliomas should undergo lifelong biochemical and clinical surveillance, beginning around ages 6 to 8 years.126 The type and timing of the surveillance should be based on which gene is affected and take into account known genotype-phenotype relationships. MRI may be the preferable imaging modality for tumor detection in these individuals to limit radiation exposure.

Primary Treatment of Pheochromocytomas/Paragangliomas

Surgical resection is the mainstay of treatment of both benign and malignant pheochromocytomas and paragangliomas. Surgery or stress can cause a sudden release of large amounts of catecholamines, causing very significant and sometimes life-threatening hypertension. Therefore, patients with pheochromocytomas or paragangliomas should receive preoperative alpha-adrenergic blockade with aggressive volume repletion and high-salt diet for 7 to 14 days or until stable. Alpha 1-selective receptor blockers include terazosin, doxazosin, and prazosin, and nonselective receptor blockers include phenoxybenzamine. If additional blood pressure control is needed after alpha blockade, the addition of dihydropyridine calcium channel blockers can be considered. Calcium channel blockers are not recommended as monotherapy unless the patient cannot tolerate alpha blockade. Metyrosine can be used in addition to alpha blockade to control blood pressure. Beta blockade (B1-selective blockers or nonselective beta-blockers) can also be added to alpha blockade to control tachycardia. Generally, alpha- and beta-blockers should be administered independently, and use of combination beta-/alpha-blockers is not recommended. Nonselective alpha blockade phentolamine (intravenous) can be used intraoperatively for additional blood pressure control.

Resection is the recommended treatment of patients with resectable tumors. A minimally invasive approach, when safe and feasible, is the preferred treatment of adrenal medullary tumors, including pheochromocytomas.127129

For locally unresectable tumors, observation is recommended, if asymptomatic. Radiation therapy is recommended with cytoreductive resection, when possible. Alternatively, if tumors are positive on MIBG scan,130,131 treatment with high-specific-activity (HSA) iobenguane I-131 or other iodine-131-MIBG therapy is recommended. If tumors are SSR-positive on imaging, PRRT with 177Lu-dotatate or treatment with octreotide or lanreotide (if symptomatic) may be considered. The panel advises diligence to ensure that the maximum cumulative radiation dose is not reached for these patients. In addition, medical therapy as described previously should be continued for unresectable secreting tumors.

The results of a phase 2, open-label, multicenter study investigating HSA iobenguane I-131 to treat patients with malignant, recurrent, and/or unresectable pheochromocytoma or paraganglioma132,133 revealed that the primary endpoint, which was a reduction in antihypertension medication by at least half, was met by 25% of all patients who received at least one therapeutic dose (n=68) and 32% of patients who received 2 therapeutic doses (n=50).134 The objective tumor response was evaluated as a secondary endpoint. Overall, 23% of patients had partial response, which went up to 30% in patients who received 2 therapeutic doses, and 68% of patients had stable disease. The median OS was 37 months. The most commonly reported side effects in patients who received any dose of HSA iobenguane I-131 were nausea, myelosuppression, and fatigue. In 2018, HSA iobenguane I-131 became an FDA-approved option for patients who have an MIBG positive scan; have unresectable, locally advanced, or metastatic pheochromocytoma or paraganglioma; and require systemic anticancer therapy.

A study of 20 patients with high SSR expressing pheochromocytoma or paraganglioma treated with 177Lu-dotatate measured the effectiveness of PRRT in controlling hypertension.135 Most patients receiving PRRT saw no increase or reduction in medication to treat hypertension. The median PFS was 39 months and median OS was not reached with a median follow-up time of 28 months. A systematic review and meta-analysis of 201 patients with inoperable or metastatic pheochromocytomas or paragangliomas determined that treatment with PRRT led to an ORR of 25% (95% CI, 19%–32%) and a disease control rate of 84% (95% CI, 77%–89%).136 Clinical responses were reported in 61% of patients.

An ENETS Centre study with 22 patients with progressive or metastatic pheochromocytomas or paragangliomas treated patients with PRRT with either 90Y-dotatate or 177Lu-dotatate, and 131I-MIBG.137 Patients treated with PRRT had increased PFS and treatment response compared with 131I-MIBG treatment, but no significant differences were seen in OS. Other case studies have been presented at conferences138140 or published141,142 that have also shown improvements in patients with high SSR-expressing pheochromocytoma or paraganglioma treated with 177Lu-dotatate.

When distant metastases are present, observation is recommended if asymptomatic. Medical therapy with octreotide or lanreotide should be continued for secreting tumors. For the latter, cytoreductive resection is recommended when possible. Other options for treating unresectable, metastatic disease include: (1) clinical trial; (2) systemic chemotherapy (eg, cyclophosphamide/vincristine/dacarbazine [CVD] or temozolomide)143147; (3) HSA iobenguane 131I or other iodine-131-MIBG therapy after positive MIBG scan130,131,134; (4) if SSR-positive PET imaging, consider PRRT with 177Lu-dotatate; or 5) palliative radiation therapy for symptomatic metastases.

A retrospective review of 52 evaluable patients treated with various systemic chemotherapy regimens for metastatic pheochromocytomas or paragangliomas showed that patients with a response to chemotherapy (reduction in symptoms, antihypertensive medications, or tumor size) had a median survival of 6.4 years and nonresponders had a median survival of 3.7 years.144 Approximately 33% of patients exhibited a tumor response.

A review of 48 patients with pheochromocytoma or paraganglioma treated with iodine-131-MIBG therapy at 4 centers showed that, although partial responses were rare, stable disease was achieved after 83.1% of treatments.148 A meta-analysis of 17 studies that included a total of 243 patients with malignant paraganglioma or pheochromocytoma found a stable disease rate of 52% (95% CI, 0.41–0.62) after iodine-131-MIBG therapy.149 Partial and complete responses were seen in 27% and 3% of patients, respectively.

Surveillance of Pheochromocytomas/Paragangliomas

Surveillance intervals for patients with pheochromocytomas or paragangliomas are similar to those for other NETs. Following complete resection, history and physical should be performed and blood pressure and tumor markers should be measured after 12 weeks to 12 months, then every 6 to 12 months for the first 3 years, and then annually for up to 10 years. After 10 years, surveillance should be considered as clinically indicated. In addition, chest CT scans with or without contrast, and abdominal/pelvic CT or MRI scans with contrast can be considered. Timing for these surveillance events and procedures can be earlier if symptoms dictate or less frequently if the disease is stable and there are no new symptoms. For locally unresectable disease or distant metastases, history and physical should be performed and blood pressure and relevant markers should be measured every 12 weeks to 12 months. Chest/abdominal/pelvic CT scans with contrast, chest CT scans (with or without contrast) and abdominal/pelvic MRI scans without contrast (if the patient is at risk for a hypertensive episode), FDG-PET/CT scans, or SSR-based imaging can be considered. In addition, individuals with hereditary paraganglioma/pheochromocytoma may require more frequent and longer follow-up (seePrinciples of Genetic Risk Assessment and Counseling,” NE-E in the algorithm).

Summary

In the 2021 update, a new section was created to provide recommendations for patients with well-differentiated G3 NETs. A principles of genetic risk assessment section was also added. Because NETs can be associated with inherited genetic syndromes, genetic counseling and testing should be recommended, as appropriate. Recent successes have shown that large randomized controlled trials studying treatments for NETs can provide practice-changing results. Rigorous studies will allow continued progress in the development of improved treatments for patients with NETs.

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NCCN CATEGORIES OF EVIDENCE AND CONSENSUS

Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.

Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.

All recommendations are category 2A unless otherwise noted.

Clinical trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

PLEASE NOTE

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult the NCCN Guidelines is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient's care or treatment. The National Comprehensive Cancer Network® (NCCN®) makes no representations or warranties of any kind regarding their content, use, or application and disclaims any responsibility for their application or use in any way.

The complete NCCN Guidelines for Neuroendocrine and Adrenal Tumors are not printed in this issue of JNCCN but can be accessed online at NCCN.org.

© National Comprehensive Cancer Network, Inc. 2021. All rights reserved. The NCCN Guidelines and the illustrations herein may not be reproduced in any form without the express written permission of NCCN.

Disclosures for the NCCN Neuroendocrine and Adrenal Tumors Panel

At the beginning of each NCCN Guidelines Panel meeting, panel members review all potential conflicts of interest. NCCN, in keeping with its commitment to public transparency, publishes these disclosures for panel members, staff, and NCCN itself.

Individual disclosures for the NCCN Neuroendocrine and Adrenal Tumors Panel members can be found on page 868. (The most recent version of these guidelines and accompanying disclosures are available at NCCN.org.)

The complete and most recent version of these guidelines is available free of charge at NCCN.org.

Individual Disclosures for the NCCN Neuroendocrine and Adrenal Tumors Panel

T1

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