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NCCN Flash Updates: NCCN Guidelines and NCCN Templates Updated for Hepatocellular Carcinoma and Biliary Tract Cancers

NCCN has published updates to the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) the NCCN Drugs & Biologics Compendium (NCCN Compendium®), the NCCN Radiation Therapy Compendium™, the NCCN Imaging Appropriate Use Criteria (NCCN Imaging AUC™), and NCCN Chemotherapy Order Templates (NCCN Templates®) for Hepatocellular Carcinoma. These NCCN Guidelines® are currently available as Version 1.2025.

Link directly to the Updates section of the NCCN Guidelines: Hepatocellular Carcinoma

General

  • Child-Pugh was changed to Child-Turcotte-Pugh throughout.
  • Nonalcoholic fatty liver disease was changed to metabolic dysfunction-associated steatotic liver disease (MASLD) throughout.

HCC-1

  • Column 1
    • Bullet 1, sub-bullet 3 revised: Nonalcoholic Metabolic dysfunction associated steatohepatitis.

HCC-2

  • Imaging
    • Column revised: Abdominal multiphasic CT (preferred) or MRI (preferred) or contrast-enhanced US.

HCC-3

  • Footnote t added: Multidisciplinary evaluation of HCC should include hepatologists, diagnostic and interventional radiologists, surgeons, medical oncologists, radiation oncologists, and pathologists with HCC expertise.
  • Footnote removed: See NCCN Guidelines for Older Adult Oncology.

HCC-4

  • Footnote revised: In patients being considered for surgery, patients with CTP Class A or highly selected patients with CTP Class B liver function, who fit UNOS criteria/extended criteria (www.unos.org) and are resectable could be considered for resection or transplant. There is controversy over which initial strategy is preferable to treat such patients. These patients should be evaluated by a multidisciplinary team for individualized decision-making.
  • Footnote removed: Adjuvant therapy with atezolizumab + bevacizumab may be considered in patients at high risk for recurrence (defined as size >5 cm, >3 tumors, macrovascular invasion or microvessel invasion on histology, or grade 3/4 histology based on the trial) on a case by case basis. Interim analysis of the phase III study of adjuvant therapy with atezolizumab + bevacizumab for 12 months in patients at high risk for recurrence after resection or ablation showed a higher rate of recurrence-free survival at 12 months compared to active surveillance, though overall survival benefit has not been established. Qin S, et al. Lancet 2023;402:1835-1847. Atezolizumab and hyaluronidase-tqjs subcutaneous injection may be substituted for IV atezolizumab. Atezolizumab and hyaluronidase-tqjs has different dosing and administration instructions compared to atezolizumab for intravenous infusion. An FDA-approved biosimilar is an appropriate substitute for bevacizumab.

HCC-6

  • Response assessment
    • Bullet 1 revised: Reconsider resection, transplant, locoregional therapy and multidisciplinary review.
  • Footnote removed: Principles of Pathology (HCC-D).

HCC-A (1 of 3)

  • Imaging Diagnosis of HCC
    • Bullet 1, 5th sentence revised: Major imaging features of HCC include nonrim arterial phase hyperenhancement, nonperipheral washout, enhancing capsule, and threshold growth.
    • Bullet 2, 1st sentence revised: Importantly, imaging criteria for parenchymal nodules apply only to patients at high risk for developing HCC: namely, those with cirrhosis (with exceptions of patients with cirrhosis due to congenital hepatic fibrosis, vascular causes, or less than 18 years of age), CHB, or current or prior HCC.

HCC-A (3 of 3)

HCC-B

  • Bullet 1, sub-bullet 1 revised: Lesion is highly suspicious for malignancy at multiphasic CT or MRI but does not meet imaging features criteria for HCC. Multidisciplinary review at a center of expertise is recommended.
  • Bullet 1, sub-bullet 2 revised: Lesion meets imaging features criteria for HCC but:

HCC-C (1 of 2)

HCC-F

  • Last bullet, last sentence revised: Minimally invasive approaches inby experienced surgeons hands have been proven to be safe and effective.
  • Bullet removed: For appropriate patients, adjuvant therapy with atezolizumab + bevacizumab may be considered in patients at high risk for recurrence (defined as size >5 cm, >3 tumors, macrovascular invasion or microvessel invasion on histology, or grade 3/4 histology) on a case by case basis. Interim analysis of the phase III study of adjuvant therapy with atezolizumab + bevacizumab for 12 months in patients at high risk for recurrence after resection or ablation showed a higher rate of recurrence-free survival at 12 months compared to active surveillance, though overall survival benefit has not been established.
  • Reference 2 added: Boubaddi M, Marichez A, Adam JP, et al. Comprehensive review of future liver remnant (FLR) assessment and hypertrophy techniques before major hepatectomy: how to assess and manage the FLR. Ann Surg Oncol 2024;31:9205-9220.
  • Reference 3 added: Entezari P, Gabr A, Kennedy K, et al. Radiation lobectomy: An overview of concept and applications, technical considerations, outcomes. Semin Intervent Radiol 2021;38:419-424.
  • Footnote removed: Atezolizumab and hyaluronidase-tqjs subcutaneous injection may be substituted for IV atezolizumab. Atezolizumab and hyaluronidase-tqjs has different dosing and administration instructions compared to atezolizumab for intravenous infusion.
  • Footnote removed: An FDA-approved biosimilar is an appropriate substitute for bevacizumab.
  • Reference removed: Brouquet A, Andreou A, Shindoh J, et al. Methods to improve resectability of hepatocellular carcinoma. Recent Results Cancer Res 2013;190:57-67.
  • Reference removed: Qin S, Chen M, Cheng AL, et al. Atezolizumab plus bevacizumab versus active surveillance in patients with resected or ablated high-risk hepatocellular carcinoma (IMbrave050): a randomised, open-label, multicentre, phase 3 trial. Lancet 2023;402:1835-1847.

HCC-H (2 of 2)

  • Reference 6 added: Dawson LA, Winter KA, Knox JJ, et al. NRG/RTOG 1112: Stereotactic body radiotherapy vs sorafenib alone in hepatocellular carcinoma: the NRG Oncology/RTOG 1112 phase 3 randomized clinical trial. JAMA Oncol 2025;11:136-144.

HCC-I (1 of 2)

  • First-Line Systemic Therapy
    • Other Recommended Regimens
      • Nivolumab + ipilimumab was added as a category 2A recommendation.
    • Useful in Certain Circumstances
      • "None" added.
      • Repotrectinib (category 2B) for NTRK gene-fusion positive tumors was removed.
  • Subsequent-Line Systemic Therapy if Disease Progression
    • Options
      • Lenvatinib was removed.
      • Sorafenib was removed.
    • Other Recommended Regimens
      • Added: Consider Preferred and Other Recommended Regimens for First-Line Systemic Therapy above.
      • Nivolumab + ipilimumab was removed.
      • Pembrolizumab was removed.
    • Useful in Certain Circumstances
      • For NTRK gene-fusion positive tumors:
        • Entrectinib was added as a category 2A recommendation.
        • Larotrectinib was added as a category 2A recommendation.
        • Repotrectinib was added as a category 2A recommendation.
  • Footnote a added: An FDA-approved biosimilar is an appropriate substitute for any recommended systemic biologic therapy in the NCCN Guidelines.
  • Footnote h revised: For patients who have not been previously treated with a checkpoint inhibitor when used as subsequent-line therapy because there is a lack of data for subsequent use of single agent immunotherapy in patients who have previously been treated with a checkpoint inhibitor.
  • Footnote i revised: For patients who have not been previously treated with anti-CTLA4-based combinations when used as subsequent-line therapy a checkpoint inhibitor unless following atezolizumab + bevacizumab.
  • Footnote k revised: Pembrolizumab is a recommended treatment option for patients with or without microsatellite instability-high (MSI-H) HCC. Pembrolizumab is FDA-approved for MSI-H tumors in the subsequent-line setting.
  • Footnote l revised: Regimens with first-line data are reasonable to consider for subsequent-line treatment, if not previously used. There are no comparative data to define optimal treatment after first-line systemic therapy.
  • Footnote p added: NTRK gene fusion-positive tumors are extremely rare in HCC.
  • Footnote removed: An FDA-approved biosimilar is an appropriate substitute for bevacizumab.
  • Footnote removed: For patients who have not been previously treated with a checkpoint inhibitor.
  • Footnote removed: Larotrectinib and entrectinib are treatment options for patients with NTRK gene-fusion positive HCC. Repotrectinib (category 2B) is a treatment option for patients with NTRK gene-fusion positive HCC that has progressed on a prior NTRK-targeted treatment.

HCC-I (2 of 2)

  • Reference 8 added: Galle PR, Decaens T, Kudo M, et al. Nivolumab (NIVO) plus ipilimumab (IPI) vs lenvatinib (LEN) or sorafenib (SOR) as first-line treatment for unresectable hepatocellular carcinoma (uHCC): First results from CheckMate 9DW [abstract]. J Clin Oncol 2024;24:Abstract LBA4008.

 

NCCN has published updates to the NCCN Guidelines the NCCN Drugs & Biologics Compendium (NCCN Compendium®), the NCCN Radiation Therapy Compendium™, the NCCN Imaging Appropriate Use Criteria (NCCN Imaging AUC™), and NCCN Chemotherapy Order Templates (NCCN Templates®) for Biliary Tract Cancers. These NCCN Guidelines are currently available as Version 1.2025.

Link directly to the Updates section of the NCCN Guidelines: Biliary Tract Cancers

General

  • Fatty liver disease was changed to metabolic dysfunction-associated steatotic liver disease (MASLD) throughout.

GALL-1

  • Primary Treatment
    • Bottom pathway, options: Best supportive care moved to separate node. (Also for GALL-2 through GALL-5 and EXTRA-1)
  • Bottom pathway, last column revised: Assess for response and Reconsider resection or locoregional therapy or Subsequent-line systemic therapy if progression on or after systemic therapy. (Also for GALL-2 through GALL-5 and EXTRA-1)

GALL-6

  • Bottom pathway, column 2 revised: Resected Gross residual disease (R2). (Also for INTRA-2 and EXTRA-2)

GALL-A (1 of 2)

  • Incidental Finding of Suspicious Mass During Surgery
    • Last bullet added: Minimally invasive approaches by experienced surgeons have been proven to be safe and effective for well-selected cases. (Also for General Principles on INTRA-A)

GALL-A (2 of 2)

  • Mass on Imaging: Patients Presenting with Gallbladder Mass/Disease Suspicious for Gallbladder Cancer
    • Bullet 1 revised: Staging should be carried out with multiphasic cross-sectional imaging of the liver with chest, abdomen, and pelvis CT.

Intrahepatic Cholangiocarcinoma

INTRA-1

  • Workup
    • Bullet 1 added: Multidisciplinary evaluation.
    • Bullet 3 revised: Multiphasic abdomen/pelvis CT/MRI with IV contrast (preferred) or contrast-enhanced US.
  • Primary Treatment
    • Middle pathway: Last bullet added: Consider referral to transplant center.
    • Middle and bottom pathways, added "Options" before 1st bullet.
  • Middle and bottom pathways, last column: Last bullet added: Consider evaluation for liver transplantation.
  • Footnote d revised: ASCO guidelines for management of viral hepatitis B virus in patients with cancer/receiving chemotherapy: https://www.asco.org/sites/new-www.asco.org/files/content-files/advocacy-and-policy/documents/2020-HBV-PCO-Algorithm.pdf Hwang JP, et al. J Clin Oncol 2020;38:3698-3715.
  • Footnote q revised: Hepatic intra-arterial infusion chemotherapy (with or without systemic chemotherapy) may be used in a clinical trial or at experienced centers in carefully selected cases.
  • Footnote s added: Patients who meet the following criteria will be eligible for transplant exception points: biopsy-proven iCCA or mixed HCC-iCCA, presence of cirrhosis, unresectable, received locoregional or systemic therapy, and 6 months from time of diagnosis or last treatment with no new lesions or extrahepatic disease.
  • Footnote removed: Consult with multidisciplinary team.

INTRA-B (1 of 2)

  • Paragraph 3 revised: Those identified as Patients with HCC-CCA that are is limited to Milan criteria in size based on center-specific criteria used should be considered for evaluation in a transplant center, but may need a research protocol or live donor approach to do so.

INTRA-D

  • Ablation, bullet 3 revised: Options for ablation include cryoablation, radiofrequency ablation, microwave ablation, and irreversible electroporation.
  • Arterially directed therapies, last bullet added: Hepatic arterial infusion chemotherapy (with or without systemic chemotherapy) may be used in a clinical trial or at experienced centers in carefully selected cases.

Extrahepatic Cholangiocarcinoma

EXTRA-1

  • Column 2
    • Bullet 1 added: Multidisciplinary evaluation.
    • Bullet 5 added: Biliary protocol imaging.
    • Last bullet revised: Consider serum IgG4 to rule out IgG4-related sclerosing cholangitis autoimmune cholangitis.
  • Column 4, resectable pathway, bullet removed: Multidisciplinary review.
  • Footnote b added: Imaging evaluation for suspected extrahepatic CCA is ideally performed prior to biliary decompression to facilitate accurate local staging for surgical candidacy.
  • Footnote g revised: Before biopsy, evaluate if patient is a resection or transplant candidate. If patient is a potential transplant candidate, consider referral to transplant center before biopsy. Importantly, transperitoneal and surgical biopsy may be contraindicated in transplant candidates. Unresectable perihilar or hilar CCAs that measure ≤3 cm in radial diameter, with the absence of intrahepatic or extrahepatic metastases and without nodal disease, as well as those with primary sclerosing cholangitis, may be considered for liver transplantation at a transplant center that has an UNOS-approved protocol for transplantation of CCA.

Biliary Tract Cancers

BIL-A

  • Gallbladder Cancer, bullet 2 revised: If gallbladder cancer is suspected preoperatively, multidetector multiphase CT of the abdomen (and pelvis) or contrast-enhanced MRI with magnetic resonance cholangiopancreatography (MRCP) of the abdomen (and pelvis) and chest CT with or without contrast should be performed. MRI is preferred for evaluating masses within the gallbladder and demonstrating bile duct involvement.
  • Biliary Drainage, bullets added:
    • Multidisciplinary discussion of drainage is recommended, especially in patients with potentially resectable disease.
    • Route (percutaneous vs. endoscopic) should be considered based on local expertise after multidisciplinary review.
    • All segments that are opacified should be drained, with the aim to drain >50% of the viable liver volume, including the future liver remnant. Atrophic liver segments, in general, should not be drained.

BIL-B (6 of 8)

  • HER2/ERBB2 Overexpression/Amplification/Activating Mutations
    • Bullet 1 revised: Testing Modalities and Considerations: HER2 overexpression/amplification...

BIL-C (1 of 5)

  • References were moved from footnotes to references pages. (Also for BIL-C 3)
  • Footnote b revised: The decision to use neoadjuvant therapy needs to be individualized and in close consultation with surgical oncologist and multidisciplinary team. A period of 2 to 6 months with reassessment every 2 to 3 months is reasonable. There are limited clinical trial data to define a standard regimen or definitive benefit. Clinical trial participation is encouraged. The listed regimens are extrapolated from the metastatic setting.
  • Footnote e added: If a patient is ineligible for cisplatin, carboplatin may be used. (Also for BIL-C 2)

BIL-C (3 of 5)

  • Subsequent-Line Therapy for Biliary Tract Cancers if Disease Progression
    • For CCA with FGFR2 fusions or rearrangements: Erdafitinib was added as a category 2A recommendation.
    • For HER-2-positive tumors
      • Sub-bullet 2 revised: Trastuzumab + pertuzumab (IHC3+/ISH+/NGS amplification).
      • Sub-bullet 3 revised: Tucatinib + trastuzumab (IHC3+/ISH+/NGS amplification).
  • Footnote k added: An FDA-approved biosimilar is an appropriate substitute for any recommended systemic biologic therapy in the NCCN Guidelines.
  • Footnote m added: Repotrectinib is an option if there was progression on a prior therapy, which may include prior NTRK inhibitors. Entrectinib and larotrectinib should not be used if there was progression on prior NTRK inhibitors.
  • Footnote p added: Futibatinib and pemigatinib are preferred over erdafitinib.
  • Footnote q added: The data available for this agent are from a smaller trial.
  • Footnote removed: An FDA-approved biosimilar is an appropriate substitute for trastuzumab.

BIL-C (4 of 5)

  • Reference 4 added: Williams KJ, Picus J, Trinkhaus K, et al. Gemcitabine with carboplatin for advanced biliary tract cancers: a phase II single institution study. HPB (Oxford) 2010;12:418-426.
  • Reference 21 revised: Schenker M, Burotto M, Richardet M, et al. CheckMate 848: A randomized, open-label, phase 2 study of nivolumab in combination with ipilimumab or nivolumab monotherapy in patients with advanced or metastatic solid tumors of high tumor mutational burden [abstract]. Cancer Res 2022;82:Abstract CT022. Schenker M, Burotto M, Richardet M, et al. Randomized, open-label, phase 2 study of nivolumab plus ipilimumab or nivolumab monotherapy in patients with advanced or metastatic solid tumors of high tumor mutational burden. J Immunother Cancer 2024;12:e008872.

BIL-C (5 of 5)

  • Reference 30 added: Pant S, Schuler M, Iyer G, et al. Erdafitinib in patients with advanced solid tumours with FGFR alterations (RAGNAR): an international, single-arm, phase 2 study. Lancet Oncol 2023;24:925-935.

 

NCCN has published updates to the NCCN Chemotherapy Order Templates (NCCN Templates®) for Hepatocellular Carcinoma to reflect the currently published NCCN Guidelines for Hepatocellular Carcinoma v1.2025.

  • Regimen names may have been updated in this library to reflect NCCN standard naming conventions
  • Changes to the Indication section have been made on the following NCCN Templates®:
    • HEP32: Atezolizumab + Bevacizumab
    • HEP33: CHECKMATE-040 Ipilimumab + Nivolumab
    • HEP43: Dostarlimab-gxly
    • HEP44: Durvalumab
    • HEP51: Durvalumab + Tremelimumab-actl
    • HEP52: Tislelizumab-jsgr
    • HEP53: Repotrectinib
  • Changes to the Chemotherapy Regimen section have been made on the following templates:
    • HEP27: Ramucirumab
    • HEP32: Atezolizumab + Bevacizumab
  • Drug information notes for the following agents have been updated in the Chemotherapy Regimen, Supportive Care, Monitoring and Hold Parameters, and/or Safety Parameters and Special Instructions sections:
    •  Dostarlimab-gxly
    • Durvalumab
    • Larotrectinib
    • Nivolumab
    • Pembrolizumab
    • Ramucirumab
    • Repotrectinib
    • Selpercatinib
    • Tremelimumab-actl

 

NCCN has published updates to the NCCN Templates for Biliary Tract Cancers to reflect the currently published NCCN Guidelines for Biliary Tract Cancers v1.2025.

  • Regimen names may have been updated in this library to reflect NCCN standard naming conventions
  • The following NEW templates have been published:
    • BIL40: Erdafitinib
    • BIL41: CARBOplatin/Gemcitabine
  • Changes to the Indication section have been made on the following NCCN Templates:
    • BIL38: Zanidatamab-hrii
  • Drug information notes for the following agents have been updated in the Chemotherapy Regimen, Supportive Care, Monitoring and Hold Parameters, and/or Safety Parameters and Special Instructions sections:
    •  Albumin-bound PACLitaxel
    • CISplatin
    • Dostarlimab-gxly
    • Durvalumab
    • Fam-trastuzumab deruxtecan-nxki
    • Gemcitabine
    • Larotrectinib
    • Leucovorin
    • Nivolumab
    • Oxaliplatin
    • Pembrolizumab
    • Repotrectinib
    • Selpercatinib
    • Trastuzumab

 

 

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.

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