NCCN Guidelines® Updates: Neuroendocrine and Adrenal Tumors

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Neuroendocrine and Adrenal Tumors, published in this issue (page 839), include the latest updates. To assist readers interested in noting how the guidelines were updated, highlights of major changes pertaining to the portion of the guidelines published in this issue are provided below. To view the most recent version of the guidelines, visit NCCN.org.

Updates in Version 2.2021 from Version 2.2020 include:

General

  1. Footnotes were added throughout:
    1. SSR PET tracers include: 68Ga-DOTATATE, 64Cu-DOTATATE, 68Ga-DOTATOC.
    2. See Principles of Genetic Risk Assessment and Counseling (NE-E).
  2. “Somatostatin receptor-based imaging or SSR scintigraphy” was modified to “SSR-PET/CT or SSR-PET/MRI.”
  3. “Well-Differentiated Grade 1/2” was added to page headings where applicable.
  4. Testing for inherited genetic syndromes was revised: Genetic counseling and testing for inherited genetic syndromes.

Neuroendocrine Tumors, Well-Differentiated Grade 3

WDG3-1 through WDG3-4

  1. New algorithm was added for Well-Differentiated, Grade 3 Neuroendocrine Tumors.

Poorly Differentiated Neuroendocrine Carcinoma/Large or Small Cell

PDNEC-1

  1. Treatment, Metastatic pathway, following chemotherapy, the following option was revised: “If progression, consider ipilimumab + nivolumab for non-pancreatic NET (category 2B).”
  2. Surveillance:
    1. Top pathway was revised: “Every 3 mo 12 weeks for 1 y, then every 6 mo.”
    2. Bottom pathway was revised: “Every 3 mo 6–16 weeks.”
  3. Footnote “a” was revised: “This page is for PDNEC and not high-grade NET. Not all high-grade (Ki-67 >20%) neuroendocrine cancers neoplasms are poorly differentiated. See WDG3-1. NETs with Ki-67 index >20% may be characterized by relatively well-differentiated histology, particularly tumors with Ki-67 index between 20%–50%. Tumors that fall into the “well-differentiated/ high-grade” category may respond relatively poorly to cisplatin/etoposide or carboplatin/etoposide, and respond more favorably to treatments described for well-differentiated NETs.
  4. Footnote “c” was revised: “Somatostatin scintigraphy with SPECT/CT is not part of the routine evaluation of poorly differentiated neuroendocrine carcinomas, but may be considered for morphologically well-differentiated tumors with higher proliferation index, as appropriate. See Principles of Imaging (NE-B). For options for well-differentiated tumors, see NET-10 or NET-11.
  5. Footnote “d” was revised: “Pembrolizumab can be considered for patients with mismatch repair-deficient (dMMR), microsatellite instability-high (MSI-H), or advanced tumor mutational burden-high (TMB-H) tumors (as determined by an FDA-approved test) that have progressed following prior treatment and have no satisfactory alternative treatment options.”
  6. Footnote “e” was revised: “Combination of pembrolizumab immune checkpoint inhibitors + chemotherapy is investigational for all patients with extrapulmonary poorly differentiated neuroendocrine carcinomas.”
  7. Footnotes with chemotherapy options were removed and replaced with a link to NE-F (4 of 4), where regimens are now listed.

Adrenal Gland Tumors

AGT-1

  1. Footnotes were added:
    1. For benign-appearing lesions, refer to the following guidelines for the management of adrenal incidentalomas: Zeiger MA, Thompson GB, Duh QY, et al. The American Association of Clinical Endocrinologists and American Association of Endocrine Surgeons medical guidelines for the management of adrenal incidentalomas. Endocrine practice: official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists 2009;15 Suppl 1:1-20; Fassnacht M, Arlt W, Bancos I, et al. Management of adrenal incidentalomas: European Society of Endocrinology Clinical Practice Guideline in collaboration with the European Network for the Study of Adrenal Tumors. Eur J Endocrinol 2016;175:G1-G34.
    2. For benign-appearing lesions, refer to the Endocrine Society's Clinical Practice Guidelines for the Treatment of Cushing's Syndrome (Nieman LK, et al. J Clin Endocrinol Metab 2015;100:2807-2831).

AGT-2

  1. Top pathway, second column was revised: “Rule out pheochromocytoma (See NE-C). Check plasma free or 23 hour urine fractionated metanephrines (See NE-C).
  2. Footnote “b” was added.

AGT-3

  1. Primary Treatment, top pathway, last column was revised: “Adrenalectomy (minimally invasive preferred).”
  2. Tumor >4 cm or inhomogeneous, irregular margins, local invasion, or other malignant imaging characteristics pathway:
    1. Additional evaluation:
      1. First bullet was added: FDG-PET/CT.
      2. Third bullet was revised: “Abdominal/pelvic CT or MRI with contrast to evaluate for metastases and local invasion.
    2. Primary treatment, middle pathway was revised: “Open Adrenalectomy for suspected carcinoma malignancy.”
  3. Footnote was removed: If size is resectable by laparoscopy, may explore using a minimally invasive approach with planned conversion for evidence of local invasion. The decision for open versus minimally invasive surgery is based on tumor size and degree of concern regarding potential malignancy, and local surgical expertise.
  4. Footnote “j” was added.

AGT-4

  1. Additional Evaluation:
    1. Bullet was added: FDG PET/CT.
    2. Third bullet was revised: “Abdominal/pelvic CT or MRI with contrast to evaluate for metastases and local invasion.”
    3. Last bullet was added: Biochemical workup.
  2. Following evaluation:
    1. Top pathway was revised: “Resectable disease (Intermediate-size tumor (4–6 cm) with aggressive features.
    2. Bottom pathway was revised: “Unresectable or suspected metastatic disease Large tumor (>6 cm) with aggressive features.
  3. Primary Treatment:
    1. Top pathway was revised: “Open adrenalectomy for suspected carcinoma.”
  4. The following footnotes were removed:
    1. For benign-appearing lesions, refer to the following guidelines for the management of adrenal incidentalomas...
    2. Aggressive features such as inhomogeneous, irregular margins, and local invasion.

AGT-5

  1. Workup:
    1. Second bullet was revised: “Consider tumor MSI, MMR and TMB testing.”
    2. Bullet was removed: Biochemical evaluation (See NE-C).
    3. Second option was revised: “Locoregional unresectable or metastatic disease.”
  2. Treatment, following Localized disease, the footnotes were removed from “Consider adjuvant mitotane therapy (category 3).”
  3. Treatment, following Locoregional unresectable or Metastatic disease, the following options were revised:
    1. First bullet was revised: “Consider observation with chest CT ± contrast and abdominal/pelvic CT or MRI with contrast for clinically indolent disease every 3 mo 12 weeks and biomarkers (if tumor initially functional).”
    2. Third bullet was revised: “Consider local therapy (ie, SBRT, thermal ablative therapies, liver-directed therapy).”
    3. Fourth bullet was revised: “Consider systemic therapy preferably in clinical trial (See Systemic Therapy for Metastatic Adrenocortical Tumors [AGT-A]).”
    4. Chemotherapy options were removed and replaced with a link to (AGT-A), where regimens are now listed.
  4. Follow-up, following Locoregional unresectable or Metastatic disease, the following was added: “Every 12 wk–12 mo up to 5 y (after 5 y as clinically indicated).”
    1. Second bullet was revised: “Abdominal/pelvic CT or MRI with contrast or FDG-PET/CT.”
    2. Footnote “n” was revised: “Chest CT with or without contrast and abdominal/pelvic CT or MRI with contrast to evaluate for metastases and local invasion to stage disease, if not previously done. Staging workup, see AGT-4.”
    3. Footnote “p” was revised: “FDA-approved test recommended for determination of TMB. Genetic counseling and testing for Lynch syndrome is recommended for any patient with mismatch repair-deficient adrenocortical carcinoma.
  5. Footnotes “o” and “s” were added.
  6. The following footnotes were removed:
    1. Monitor mitotane blood levels. Some institutions recommend target levels of 14–20 mcg/mL if tolerated. Steady-state levels may be reached several months after initiation of mitotane. Life-long hydrocortisone replacement may be required with mitotane.
    2. Mitotane may have more benefit for control of hormone symptoms than control of tumor.
    3. See Discussion for further information regarding the phase III FIRM-ACT trial. (Fassnacht et al. N Eng J Med 2012;366:2189-2197.)

AGT-A

  1. New page was added: Systemic Therapy for Locoregional Unresectable/Metastatic Adrenocortical Carcinoma.

Paraganglioma/Pheochromocytoma

PHEO-1

  1. Evaluation:
    1. Recommended:
      1. Bullet was added: Adrenal protocol CT (abdomen/pelvis).
      2. Bullet was removed: Abdominal/pelvic multiphasic CT or MRI.
    2. As appropriate:
      1. Bullet was added: Abdominal/pelvic multiphasic CT or MRI.
  2. Footnote was removed: A high incidence of inherited disease has been reported in patients with pheochromocytoma/paraganglioma. Certain genetic variants may require more frequent follow-up. (See Discussion) (Also page PHEO-3)
  3. Footnote “j” was revised: “PET/CT or PET/MRI of skull base to mid-thigh with IV contrast when possible. Data are limited on the optimal timing of scans following administration of SSAs.” (Also page PHEO-3)

PHEO-3

  1. Surveillance:
    1. For resectable disease, bullet was revised: “Consider chest CT ± contrast and abdominal/pelvic CT or MRI with contrast or FDG-PET/CT.
    2. For locally unresectable disease or distant metastases, bullet was revised: “SSR-PET/CT or SSR-PET/MRI or SSR scintigraphy (eg, 68Ga-dotatate imaging preferred [PET/CT or PET/MRI] or SSR scintigraphy).

NE-A 2 of 5

  1. 2019 WHO Classification and Grading Criteria for Neuroendocrine Neoplasms of the Gastrointestinal Tract and Hepatopancreatobiliary Organs table was added to the guideline.
  2. Footnotes “a,” “b,” and “c” were added.

NE-E

  1. New section was added: Principles of Genetic Risk Assessment and Counseling: Hereditary Endocrine Neoplasias.

NE-F

  1. “Well-Differentiated Grade 1/2” was added to table headings.

NE-F 4 of 5

  1. Table was added for Poorly Differentiated Neuroendocrine Carcinoma/Large or Small Cell (Extrapulmonary) (regimens formerly listed on PDNEC-1).
  2. Locoregional Unresectable/Metastatic Disease:
    1. The following options were added: FOLFIRINOX and Pembrolizumab.

The goal of the NCCN Guidelines® Updates is to provide readers with important changes that the NCCN Guidelines Panel has incorporated into the algorithm since it was last published. For a more complete detailing of the updated guideline‘s modifications, access the NCCN Guidelines in this issue or, for the complete and most up-to-date version, at NCCN.org.

Note: The addition of new language is indicated in italics. Wording that was removed from the previous update is indicated in strikeout.

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