NCCN Flash Updates: NCCN Guidelines Updated

NCCN has published updates to the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines^®), the NCCN Drugs and Biologics Compendium (NCCN Compendium^®), and the NCCN Imaging Appropriate Use Criteria (NCCN Imaging AUC™) for Gastrointestinal Stromal Tumors (GISTs).  These NCCN Guidelines^® are currently available as Version 1.2022.

Link directly to the Updates section of the NCCN Guidelines:
Gastrointestinal Stromal Tumors (GISTs)

• Workup at Primary Presentation (GIST-1)
  • Bullet 2 modified: Consider endoscopic ultrasound-guided fine-needle aspiration biopsy (EUS-FNAB) or Endoscopic ultrasound-guided core needle biopsy (EUS-CNB)
  • Management based on the result of initial diagnostic evaluation
    • Resectable with significant morbidity
      • Recommendation modified: If considering neoadjuvant therapy is planned, consider biopsy. Based on molecular testing, imatinib or avapritinib….
• Primary Presentation (GIST-2)
  • Primary Treatment header changed to Neoadjuvant Therapy
  • Baseline imaging changed to Mutational testing
  • Category 1 designation was removed for imatinib
• Postoperative Outcomes (GIST-3)
  • Completely resected after preoperative imatinib: Adjuvant imatinib recommendation clarified as follows, for patients with significant risk of recurrence (intermediate or high risk) (See GIST-A).
  • Modified: Persistent microscopic residual disease (R1 resection) or Gross residual disease (R2 resection)
  • Follow up
    • Modified H&P and imaging every 3-6 mo for high risk, every 3-6 mo for 5 y (every 3 mo if high risk), then annually
• Primary Treatment header changed to First-Line Therapy (GIST-4)
• Treatment for Progressive Disease (GIST-5)
  • Bullet 1 modified for limited progression: imatinib or “avapritinib”
  • Bullet 2 modified: If previously treated with standard dose imatinib: Switch to sunitinib (category 1) or escalate dose of imatinib as tolerated
  • Lower pathway, generalized progression modified: For performance status (PS) 0-2 and progression on imatinib or “avapritinib”
  • Bullet 3: List of treatment options were replaced with a link to GIST-D which outlines systemic therapy options for progressive or metastatic disease.
  • Bullet 4 modified: Dose escalation of imatinib as tolerated (if previously treated with standard dose imatinib)
• Principles of Biopsy and Risk Stratification for GISTs (GIST-A, 1 of 3)
  • Bullet 1, first sentence modified: An endoscopic transmural biopsy would be favored over a percutaneous transperitoneal biopsy, if as the risk for peritoneal seeding by the tumor is low is lower for this technique.
  • Risk stratification:
    • Pathologic grading by mitotic rate may not be accurate in small biopsies. Neoadjuvant therapy that has evidence of pathologic treatment effect will no yield accurate mitotic information. In this situation, risk stratification may need to be based on clinical parameters, size and anatomic location in the absence of mitotic rate.
• Table 1: Gastric GISTs: Proposed Guidelines for Assessing the Malignant Potential (GIST-A, 2 of 3)
  • New statement: This prognostic assessment applies best to KIT or PDGFRA-positive GISTs whereas succinate dehydrogenase (SDH)-deficient GISTs are more unpredictable.
  • New bullet: Risk stratification is determined without any prior exposure to tyrosine kinase inhibitor (TKI) therapy. Also for Table 2.
  • Risk Per CAP is a new column in the table:
    • ≤2 cm / ≤5 is None and >5 is None
    • >2 cm to ≤5 cm / ≤5 is Very low (1.9%) and >5 is Moderate (16%)
    • >5 cm to ≤10 cm / ≤5 is Low (3.6%) and >5 is High (55%)
    • >10 cm / ≤5 is Moderate (10%) and >5 is High (86%)
      • Reference 2 modified: Data from Laurini JA. Protocol for the Examination of Resection Specimens from Patients with Gastrointestinal Stromal Tumors (GIST). Version 4.2.0.0, June 2021. Available at: https://documents.cap.org/protocols/Stomach.GIST_4.2.0.0.REL_CAPCP.pdf.
• Table 2: Non-Gastric GISTs (includes small bowel and colorectal GISTs): Proposed Guidelines for Assessing the Malignant Potential (GIST-A, 3 of 3)
  • New statement: This prognostic assessment applies best to KIT or PDGFRA-positive GISTs whereas succinate dehydrogenase (SDH)-deficient GISTs are more unpredictable. For anatomic sites not listed in this table, such as esophagus, mesentery, and peritoneum, or in the case of “insufficient data,” it is best to use risk criteria for jejunum/ileum.
  • Risk Per CAP is a new column in the table:
    • ≤2 cm / ≤5 is None and >5 is Insufficient data – High (54%)
    • >2 cm to ≤5 cm / ≤5 is Low (4.3%-8.5%) and >5 is High (50%-73%)
    • >5 cm to ≤10 cm / ≤5 is Insufficient data - Moderate (24%) and >5 is Insufficient data - High (85%)
    • >10 cm / ≤5 is High (34%-57%) and >5 is High (71%-90%)
• Principles of Mutation Testing (GIST-B)
  • Bullet 4, first sentence modified: GISTs have different response rates to imatinib based upon the tumor mutation status: KIT exon 9 mutations have a lower response rate and progression-free survival (PFS) than exon 11 tumors at 400 mg, but dosing at 400 mg BID has been associated with better PFS.
  • Bullet 5 modified: Ripretinib is indicated for patients with disease progression on imatinib, sunitinib, and regorafenib. Ripretinib is indicated for patients who have received prior treatment with 3 or more kinase inhibitors, including imatinib. An additional clinical benefit may be obtained with the use of ripretinib 150 mg BID upon progression on ripretinib 150 mg daily
  • Bullet 6, last sentence modified: A small minority of GISTs that retain with loss of SDH expression have alternative driver mutations.
  • Bullet 7 deleted: Testing for alternative drive mutations is indicated for tumors that are negative for KIT or PDGFRA mutations.
    • First sentence is new: All GISTs lacking a KIT or PDGFRA mutation should be tested for SDH deficiency and alternative driver mutations using next-generation sequencing (NGS).
    • First sub-bullet deleted: Testing includes assessment for SDHB deficiency by IHC for gastric tumors and SDH mutation testing for SDHB-deficient tumors by IHC.
    • Second sub-bullet modified: In addition, alternative driver mutations using NGS next generation sequencing (NGS) testing (eg, BRAF, NF1, and FGFR fusions) should be performed for potential identification of a targeted therapy.
  • Bullet 8 modified: GISTs with SDH mutations typically arise in the stomach in younger individuals, frequently metastasize, may involve lymph nodes, and usually grow slowly. They are usually resistant to imatinib. In the absence of KIT and PDGFRA mutations, only a subset of patients with advanced GISTs benefit from imatinib, although tumors known to be SDH deficient or having alternative drivers (eg, NF1, BRAF) are unlikely to benefit from imatinib. SDH-deficient tumors may benefit from therapy with sunitinib or regorafenib. Referral to a genetic counselor for germline testing assessment is recommended for all patients with SDH-deficient GISTs and those with GISTs that have NF1 or SDH mutations. Patients with SDH mutations are at risk of paraganglioma; 24-hour urine testing is recommended prior to surgery (See GIST-C).
• Considerations Prior to Surgery (GIST-C)
  • Bullet 2 modified: Patients with SDH deficiency or known SDH mutations are at risk of paraganglioma and therefore serum/urine catecholamine/metanephrine testing should be considered before an operation prior to surgery.
• Systemic Therapy Agents and Regimens for GISTs (GIST-D, 1 of 2)
  • This page was reorganized for clarity and to include treatment options for progression of disease on avapritinib.
  • Title modified: Systemic Therapy Agents and Regimens for Resectable GISTs with Significant Morbidity
    • Neoadjuvant Therapy title modified to include, for Resectable Disease with Significant Morbidity
    • Adjuvant Therapy title modified to include, for Resectable Disease
    • Adjuvant imatinib for patients with significant risk of recurrence, intermediate or high risk (category 1 “following complete resection with no preoperative imatinib; category 2A following complete resection after preoperative imatinib) See GIST-3”
  • Title of the second table was modified to include, “unresectable, progressive, or metastatic disease”
  • Additional options after progression on approved therapies
    • Useful in Certain Circumstances
      • Ripretinib dose escalation to 150 mg BID (if previously treated with ripretinib 150 mg daily)
        • Zalcberg JR, Heinrich MC, George S, et al. Clinical benefit of ripretinib dose escalation after disease progression in advanced gastrointestinal stromal tumor: an analysis of the INVICTUS study. Oncologist 2021;25:1-8.

NCCN has published updates to the NCCN Guidelines NCCN Radiation Therapy Compendium™, the NCCN Radiation Therapy Compendium™, NCCN Imaging Appropriate Use Criteria (NCCN Imaging AUC™), and the NCCN Compendium^® for Primary Cutaneous Lymphomas. These NCCN Guidelines are currently available as Version 1.2022. 

Link directly to the Updates section of the NCCN Guidelines: 
Primary Cutaneous Lymphomas

• Primary Cutaneous B-Cell Lymphomas
  • CUTB/INTRO-1
    • Added new page: Principles of Primary Cutaneous B-Cell Lymphomas
  •  CUTB-1
    • Diagnosis, Useful, 1st bullet, 2nd sub-bullet revised: Assessment of IgM, IgD, IgA, IgG, IgE,...
    • Footnote c added: A multidisciplinary team approach involving hematology/oncology, dermatology, pathology (with expertise in cutaneous lymphoma), and radiation oncology is often optimal for the management of patients with CBCL.
  • CUTB-2
    • Solitary/Regional, Initial therapy, "Excision" was moved to in selected cases.
    • Footnote g revised: ...or C/A/P CT with contrast at the end of treatment are may be needed to assess response. (also for CUTB-3)
    • Footnote l added: Small lesions may be excised with minimal non-disfiguring surgery. (also for PCTLD-3)
• Mycosis Fungoides/Sezary Syndrome (MF/SS)
  • MFSS-6 through MFSS-12
    • Algorithms revised
      • Headers primary treatment, response to therapy, and additional therapy changed to "treatment and response assessment"
      • Specific treatment recommendations and associated footnotes removed and directed to the appropriate tables on MFSS-A.
    • Footnote u revised by adding: General Considerations for the Treatment of Patients with MF and SS (MFSS-A 1 of 12).
  • Suggested Treatment Regimens
    • Global changes for Suggested Regimen pages (MFSS-A)
      • Regimens were extensively reorganized and clarified by
        • Removing previous SYST-CAT A and SYST-CAT B categories
        • Separating the regimens by Stage and providing Treatment Considerations for each stage
        • Combination therapies are now listed with each of the stage specific recommendations
        • Removed ATRA as a systemic therapy option for all stages
• MFSS-A 1 of 12
  • Added new page: General Considerations for the Treatment of Patients with MF and SS
• MFSS-A 3 of 12
  • Removed the following systemic therapy options for Stage IA MF
    • Brentuximab vedotin
    • Mogamulizumab
    • Romidepsin
    • Vorinostat
  • Removed the following systemic therapy options for Stage IA MF with blood involvement
    • Gemcitabine
    • Liposomal doxorubicin 
    • Pralatrexate
    • Alemtuzumab 
    • Pembrolizumab
• MFSS-A 4 of 12
  • For Stage IB/IIA MF with blood involvement, the following regimens changed from a category 2A to a category 2B recommendation.
    • Gemcitabine
    • Liposomal doxorubicin 
    • Pralatrexate
    • Alemtuzumab 
    • Pembrolizumab
• MFSS-A 6 of 12
  • Stage III MF (erythrodermic disease)
    • Added the following as skin-directed therapy options
      • Phototherapy as a category 2A recommendation 
      • TSEBT as a category 2B recommendation
• MFSS-A 8 of 12
  • Non-Sézary (stage IVA2) or Visceral/solid organ (stage IVB) disease
    • Added mogamulizumab as a category 2A, Other Recommended Regimen
  • Relapsed or refractory disease to multiple prior therapies
    • 7th bullet revised: Temozolomide for CNS involvement at some NCCN Member Institutions
  • Supportive Care for MFSS (MFSS-B)
    • Pruritis, treatment, systemic agents
      • First-line added: pregabalin
      • Third-line added: systemic steroids
    • Infections
      • Ulcerated and necrotic tumors, sub-bullet revised by adding: Ulcer will not heal unless disease is treated. Consider RT beam if feasible.
• Primary Cutaneous CD30+ T-Cell Lymphoproliferative Disorders.
  • PCTLD-1
    • Diagnosis, Useful 1st bullet revised: ...perforin, GM1, IRF4/MUM1, EMA, TCRꞵ, TCRδ
  • PCTLD-3
    • Footnote s added: Small lesions may be excised with minimal non-disfiguring surgery
  • PCTLD-4
    • Footnote z added: NB-UVB is generally preferred over PUVA.
• Principles of Radiation Therapy
  • PCLYM-A 1 of 3
    • Link added: See NCCN Guidelines for Hodgkin Lymphoma - Radiation Dose Constraints.
  • Supportive Care
    • PCLYM-C
      • Adverse events associated with mogamulizumab, added: Drug Eruption: Mogamulizumab has been associated with a drug eruption that can clinically mimic CTCL. Skin biopsy is recommended to distinguish progression of disease versus drug eruption (Chen L, et al JAMA Dermatology 2019;155:968-971; Hirotsu K, et al JAMA Dermatol 2021;157:700-707).

NCCN has published updates to the following NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines^®) with NCCN Evidence Blocks™:

• Neuroendocrine and Adrenal Tumors, Version 4.2021
• Esophageal and Esophagogastric Junction Cancers, Version 1.2022
• Squamous Cell Skin Cancer, Version 1.2022

For the complete updated versions of the NCCN Guidelines, NCCN Guidelines with NCCN Evidence Blocks™, the NCCN Drugs & Biologics Compendium (NCCN Compendium^®), the NCCN Biomarkers Compendium^®, the NCCN Chemotherapy Order Templates (NCCN Templates^®), the NCCN Radiation Therapy Compendium™, and the NCCN Imaging Appropriate Use Criteria (NCCN Imaging AUC™), please visit NCCN.org.

To view the NCCN Guidelines for Patients^®, please visit NCCN.org/patientguidelines.

Free NCCN Guidelines apps for iPhone, iPad, and Android devices are now available! Visit NCCN.org/apps.

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