NCCN Flash Updates: NCCN Guidelines for Hepatobiliary Cancers

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

Link directly to the Updates section of the NCCN Guidelines: Hepatobiliary Cancers

• Hepatocellular Carcinoma Screening
  • Column 2, footnote a moved: From Alpha fetoprotein (AFP) to Ultrasound (US).
  • Footnote e added: Niazi SK, et al. J Natl Compr Canc Netw 2021;19:829-838.

HCC-2

• Diagnosis of HCC
  • Footnote p revised: The optimal diagnostic method is core needle biopsy. See Principles of Core Needle Biopsy (HCC-B). (Also for HCC-6)

HCC-3

• Column 3, pathway 4 revised: Metastatic disease or extensive liver tumor burden.

HCC-4

• Surgical Assessment
  • Column 3, bullet 2 revised, Consider bBridge therapy as indicated.

Surveillance

• Bullet 1 revised, "...every 3–6 mo for 2 y, then every 6–12 mo". (Also for HCC-5)
• Bullet 2 revised: "...every 3–6 mo for 2 y, then every 6–12 mo". (Also for HCC-5)
• Footnote x revised: In highly selected patients with Child-Pugh Class B liver function patients with limited resection.

• Footnote z added: Consider biopsy if imaging is not consistent or to confirm imaging diagnosis if it does not meet AASLD or LIRADS-5 criteria. See Principles of Imaging (HCC-A). The optimal diagnostic method is core needle biopsy. See Principles of Core Needle Biopsy (HCC-B). (Also for HCC-5)
• Footnote gg added: Surveillance imaging and AFP should continue for at least 5 years and thereafter screening dependent on HCC risk factors. See Principles of Imaging (See HCC-A). (Also for HCC-5)

HCC-5

• Unresectable
  • Column 2 revised: Evaluate whether patient is a candidate for transplant [See UNOS/extended criteria under Surgical Assessment.
  • Treatment, transplant candidate, bullet 2 revised: Consider Bridge therapy as indicated.
• Footnote kk added: See NCCN Guidelines for Palliative Care. (Also for HCC-6)

HCC-A 1 of 3

• Screening and surveillance, bullet 2 added: Patients with viral hepatitis who have had a complete or sustained viral response should continue with screening despite that response.

HCC-A 2 of 3

Footnote a added: The optimal diagnostic method is core needle biopsy. See Principles of Core Needle Biopsy (HCC-B).

HCC-A (3 of 3)

• Reference 5 added: Ioannou, GN. HCC surveillance after SVR in patients with F3/F4 fibrosis. J Hepatol 2021;74:458-465.
• Reference 11 updated: Claudon M, Dietrich CF, Choi BI, et al. Guidelines and good clinical practice recommendations for contrast enhanced ltrasound (CEUS) in the liver - update 2012: A WFUMB-EFSUMB initiative in cooperation with representatives of AFSUMB, AIUM, ASUM, FLAUS. Ultrasound Med Biol 2013;4639:187-210. Dietrich CF, Nolsøe CP, Barr RG, et al. Guidelines and good clinical practice recommendations for contrast-enhanced ultrasound (CEUS) in the liver - update 2020: WFUMB in cooperation with EFSUMB, AFSUMB, AIUM, and FLAUS. Ultrasound Med Biol 2020;46:2579-2604.

HCC-B

• Title changed: Principles of Core Needle Biopsy.
  • Added "Core needle" before each instance of biopsy.
  • First statement revised: The optimal diagnostic method is core needle biopsy. Indicators for consideration of core needle biopsymay include ...
  • Bullet 2 added: If core needle biopsy is considered, obtain prior to ablation.

HCC-D

• Principles of Surgery
  • Bullet 5 added: Select patients with unresectable disease with response can be considered for surgery. Consultation with a medical oncologist and a multidisciplinary team is recommended to determine the timing of surgery after systemic therapy.
  • Footnote 3 updated: Heimbach, JK. Evolution of Liver Transplant Selection Criteria and U.S. Allocation Policy for Patients with Hepatocellular Carcinoma, Semin Liver Dis (2020) [Epub ahead of print]. Heimbach JK. Evolution of liver transplant selection criteria and U.S. allocation policy for patients with hepatocellular carcinoma. Semin Liver Dis 2020;40:358-364.

HCC-F (1 of 2)

• Principles of Radiation Therapy
  • Treatment Modalities
    • Sub-bullet 8 revised: Palliative EBRT is appropriate for symptom control and/or prevention of complications from metastatic HCC lesions, such as bone or brain, and extensive liver tumor burden.
  • Bullet 2 revised, RT Dosing, depending on the ability to meet normal organ constraints and underlying liver function:
    • Sub-bullet 1 revised: EBRT: SBRT or Hypofractionation preferred.
    • Tertiary bullet 1 revised: SBRT: 30–50 Gy (typically in 3–5 fractions), depending on the ability to meet normal organ constraints and underlying liver function.
    • Tertiary sub-bullets added:
      • Hypofractionation
        • 37.5–72 Gy in 10–15 fractions.
      • Conventional fractionation:
        • 50–66 GY in 25–33 fractions.

HCC-F (2 of 2)

• Principles of Radiation Therapy, References
  • Reference removed: Tao R, Krishnan S, Bhosale PR, et al. Ablative radiotherapy doses lead to a substantial prolongation of survival in patients with inoperable intrahepatic cholangiocarcinoma: a retrospective dose response analysis. J Clin Oncol 2016;34:219-226.
  • Reference 1 added: Apisarnthanarax S, Barry A, Cao M, et al. External beam radiation therapy for primary liver cancers: An ASTRO Clinical Practice Guideline. Pract Radiat Oncol 2022;12:28-51.
  • Reference 11 added: Soliman H, Ringash J, Jiang H, et al. Phase II trial of palliative radiotherapy for hepatocellular carcinoma and liver metastases. J Clin Oncol 2013;31:3980-3986.
  • Reference 12 added: Ohri N, Tomé WA, Méndez Romero A, et al. Local control after stereotactic body radiation therapy for liver tumors. Int J Radiat Oncol Biol Phys 2021;110:188-195.
  • Reference 13 added: Seong J, Lee IJ, Shim SJ, et al. A multicenter retrospective cohort study of practice patterns and clinical outcome on radiotherapy for hepatocellular carcinoma in Korea. Liver Int 2009;29:147-152.
  • Reference 14 added: Ben-Josef E, Lawrence TS. Radiotherapy for unresectable hepatic malignancies. Semin Radiat Oncol 2005;15:273-278.

HCC-G (1 of 2)

• First-Line Systemic Therapy
  • Other Recommended Regimens: Durvalumab added as a Category 2A recommendation.
  • Other Recommended Regimens: Pembrolizumab added as a Category 2B recommendation.
  • Useful in Certain Circumstances: Removed FOLFOX (category 2B).
• Subsequent-Line Therapy If Disease Progression
  • Bullet 3 revised: Ramucirumab (AFP ≥400 ng/mL and Child-Pugh Class A only) (category 1).
• Footnotes
  • Footnote e revised: "Caution: There are limited safety data available for patients with Child-Pugh Class B or C liver function patients and dosing is uncertain..."
  • Footnote g revised: There are no comparative data to define optimal treatment after first-line systemic therapy. There are no data to define optimal treatment for those who progress after first-line systemic therapy, other than sorafenib or nivolumab.
  • Footnote i added: The data reflect use on or after sorafenib.
  • Footnote removed: There are limited data supporting the use of FOLFOX, and use of chemotherapy in the context of a clinical trial is preferred. (Qin S, et al. J Clin Oncol 2013;31:3501-3508).

HCC-G (2 of 2)

• Reference 5 revised: Alsina A, Kudo M, Vogel A, et al. Subsequent anticancer medication following first-line lenvatinib: a posthoc responder analysis from the phase 3 REFLECT study in unresectable hepatocellular carcinoma. J Clin Oncol 2019;37:371-371.Alsina A, Kudo M, Vogel A, et al. Effects of subsequent systemic anticancer medication following first-line lenvatinib: A post hoc responder analysis from the phase 3 REFLECT study in unresectable hepatocellular carcinoma. Liver Cancer 2020;9:93-104.
• Reference 6 added: Abou-Alfa GK, Chan SL, Kudo M, et al. Phase 3 randomized, open-label, multicenter study of tremelimumab (T) and durvalumab (D) as first-line therapy in patients (pts) with unresectable hepatocellular carcinoma (uHCC): HIMALAYA [abstract]. J Clin Oncol 2022;40:Abstract 379.
• Reference 7 added: van Laethem JL, Borbath I, Karwal M, et al. Updated results for pembrolizumab (pembro) monotherapy as first-line therapy for advanced hepatocellular carcinoma (HCC) in the phase II KEYNOTE-224 study [abstract]. Ann Oncol 2021;32:Abstract 933P.
• Reference 8 revised:Yau T, Park JW, Finn RS, et al. CheckMate 459: a randomized, multi-center phase III study of nivolumab (NIVO) vs sorafenib (SOR) as first-line (1L) treatment in patients (pts) with advanced hepatocellular carcinoma. Ann Oncol 2019 Oct;30 Suppl 5:v874-v87.Yau T, Park JW, Finn RS, et al. Nivolumab versus sorafenib in advanced hepatocellular carcinoma (CheckMate 459): A randomised, multicentre, open-label, phase 3 trial. Lancet Oncol 2022;23:77-90.
• Reference 11 revised:Zhu AX, Kang YK, Yen CJ, et al. REACH-2: A randomized, double-blind, placebo-controlled phase 3 study of ramucirumab versus placebo as second-line treatment in patients with advanced hepatocellular carcinoma (HCC) and elevated baseline alpha-fetoprotein (AFP) following first-line sorafenib. J Clin Oncol 2018;36:4003. Zhu AX, Kang YK, Yen CJ, et al. Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations (REACH-2): A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2019;20:282-296.
• Reference 14 added: Finn RS, Ryoo B-Y, Merle P, et al. Pembrolizumab as second-line therapy in patients with advanced hepatocellular carcinoma in KEYNOTE-240: A randomized, double-blind, phase III trial. J Clin Oncol 2020;38:193-202.
• Reference 15 added: Qin S, Chen Z, Fang W, et al. Pembrolizumab plus best supportive care versus placebo plus best supportive care as second-line therapy in patients in Asia with advanced hepatocellular carcinoma (HCC): KEYNOTE study [abstract]. J Clin Oncol 2022;40:Abstract 383.
• Reference 17 revised: Kudo M, Matilla A, Santoro A, et al. Checkmate-040 cohort 5: A phase I/II study of nivolumab in patients with advanced hepatocellular carcinoma and Child-Pugh B cirrhosis. J Hepatol 2021;75:600-609nivolumab (NIVO) in patients (pts) with advanced hepatocellular carcinoma (aHCC) and Child-Pugh B (CPB) status. J Clin Oncol 2019;37:327-327.
• Reference 18 added: Matilla A, Sangro B, El-Khoureiry A, et al. Checkmate 040 cohort 5: Long-term efficacy and safety of nivolumab in patients with Child-Pugh B advanced hepatocellular carcinoma: Associations between baseline biomarker analyses and outcomes [abstract]. J Hepatol 2021:75:Abstract OS-295.

GALL-1

• Biliary Tract Cancers: Gallbladder Cancer: This section has been significantly revised.

GALL-2

New algorithm: Hepatobiliary surgery expertise unavailable.

GALL-3

• Presentation
  • T1b or greater and/or T1a with positive margins.
• Primary Treatment
  • Unresectable
    • "TMB testing" sub-bullet moved above Additional molecular testing as a bullet. (Also for GALL-4, GALL-5, INTRA-1, EXTRA-1)
• Footnotes
  • Footnote k added: See NCCN Guidelines for Palliative Care. (Also for GALL-4, GALL-5)

GALL-4

• Footnote c added: The optimal diagnostic method is core needle biopsy. (Also for GALL-5)

GALL-5

• Presentation and Workup
  • Metastatic disease
    • "TMB testing" sub-bullet moved above Additional molecular testing as a bullet. (Also for INTRA-1, EXTRA-1)

GALL-6

• Treatment
  • "Options" added above the treatment options.
  • Resected, negative margin (R0), negative regional nodes, carcinoma in situ at margin pathway, bullet order has been revised.
  • Resected gross residual disease (R2) pathway, revised: See treatment for unresectable disease.
• Footnote h added: Order does not indicate preference. The choice of treatment modality may depend on extent/location of disease and institutional capabilities. 
•  GALL-A (1 of 2)
• Principles of Surgery and Pathology
  • Incidental Finding at Surgery
    • Bullet 2 revised: If expertise is available and there is convincing clinical evidence of cancer, a definitive resection can should be performed as written below. If the diagnosis is not clear, frozen section biopsies can be considered in selected cases before proceeding with definitive resection. If malignancy is suspected or confirmed after cholecystectomy has been initiated and expertise is available, then definitive resection should be undertaken.
    • Bullet 3 added: If malignancy is suspected before cholecystectomy has begun and there is a question of resectability (ie, locally advanced, possible metastatic disease, other), then definitive resection can be postponed, regardless of available expertise, until complete staging and evaluation has been performed. Document all findings and consider biopsy if chemotherapy is anticipated.
  • Footnote a added: The optimal diagnostic method is core needle biopsy.

Intrahepatic Cholangiocarcinoma

INTRA-1

• Unresectable
  • Recommendation added: Biopsy, if not previously performed. (Also for Metastatic disease)
• Primary Treatment
  • Metastatic disease pathway, bullet 1 revised: Systemic therapy (preferred).
  • Metastatic disease pathway, bullet 2 revised: Clinical trial (preferred).
• Footnote b revised: See Principles of Imaging (HCC-A) (BIL-A). (Also for INTRA-2)
• Footnote f added: The optimal diagnostic method is core needle biopsy.
• Footnote n revised: Intra-arterial chemotherapy (with or without systemic chemotherapy) may be used in a clinical trial or at experienced centers in carefully selected cases.
• Footnote p added: See NCCN Guidelines for Palliative Care.

INTRA-2

• Treatment
  • No residual local disease (R0 resection), bullet order has been revised.
    • Bullet 1, revised: Systemic therapy (preferred).
    • Bullet 2, revised: Clinical trial (preferred).
  • Microscopic margins (R1) or Positive regional nodes, bullet order has been revised.
    • Bullet 1, revised: Systemic therapy (preferred).
    • Bullet 2, revised: Clinical trial (preferred).
  • Residual local disease (R2 resection) pathway revised: See treatment for unresectable disease.

Extrahepatic Cholangiocarcinoma

EXTRA-1

• Footnote h revised: Consider biliary drainage for patients with jaundice prior to instituting systemic therapy chemotherapy. Consider baseline CA 19-9 after biliary decompression.
• Footnote i added: The optimal diagnostic method is core needle biopsy.
• Footnote p added: See NCCN Guidelines for Palliative Care.

EXTRA-2

• Treatment
  • Resected, negative margin (R0), Negative regional nodes or Carcinoma in situ at margin, bullet order has been revised.
    • "Options" added above the treatment options.
    • Bullet 1 revised: Systemic therapy (preferred).
    • Bullet 2 revised: Clinical trial (preferred).
  • Resected, positive margin (R1) or Positive regional nodes, bullet order has been revised.
    • "Options" added above the treatment options.
    • Bullet 1 revised: Systemic therapy (preferred).
    • Bullet 2 revised: Clinical trial (preferred).
  • Resected gross residual disease (R2) pathway revised: See treatment for unresectable disease
  • Footnote s added: Order does not indicate preference. The choice of treatment modality may depend on extent/location of disease and institutional capabilities.

BIL-A

• Reference 6 added: Sutton TL, Billingsley KG, Walker BS, et al. Detection of tumor multifocality in resectable intrahepatic cholangiocarcinoma: Defining the optimal pre-operative imaging modality. J Gastrointest Surg 2021;25:2250-2257.
• Reference 7 added: ACR-SAR-SPR practice parameter for the performance of magnetic resonance imaging (MRI) of the liver. American College of Radiology, 2020. Available at: https://www.acr.org/-/media/ACR/Files/Practice-Parameters/MR-Liver.pdf. Accessed 01/18/22.

BIL-B

• General Principles
  • Bullet 2, sub-bullet 1 revised: ...Target volumes should cover the draining regional lymph nodes: porta hepatis, celiac, superior mesenteric, gastrohepatic, and para-aortic to 45 Gy at 1.8 Gy/fraction and 50–60 Gy in 1.8–2 Gy/fraction to the tumor bed depending on margin positivity.
• Bullet 4, RT Dosing, depending on the ability to meet normal organ constraints and underlying liver function:
  • Sub-bullet 1 revised: EBRTConventional fractionation (postoperative or unresectable):
  • Sub-bullet 2 added: Hypofractionation (unresectable): 58–67.5 Gy in 15 fractions for a median biologic equivalent dose of 80.5 Gy
  • Sub-bullet 3 revised: SBRT (unresectable):
    • Tertiary bullet 1 revised: 30–50 Gy (typically in 3–5 fractions), depending on the ability to meet normal organ constraints and underlying liver function.
    • Tertiary bullet removed: Other hypofractionated schedules >5 fractions may also be used if clinically indicated.
    • Tertiary bullet removed: For intrahepatic tumors, SBRT (typically 3–5 fractions) is an acceptable option.
• Reference 7 added: Apisarnthanarax S, Barry A, Cao M, et al. External beam radiation therapy for primary liver cancers: An ASTRO Clinical Practice Guideline. Pract Radiat Oncol 2022;12:28-51.

BIL-C (1 of 4)

• Principles of Systemic Therapy
  • Footnote a 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 ..."
  • Footnote b revised: "Adjuvant therapy up to 6 months. Adjuvant chemotherapy ..."

BIL-C (2 of 4)

• Primary Treatment for Unresectable and Metastatic Disease
  • Other Recommended Regimens
    • Bullet 9 added: Durvalumab + gemcitabine + cisplatin added as a category 2B recommendation.
  • Useful in Certain Circumstances
    • Bullet 3 added: For RET fusion-positive tumors, Pralsetinib added as a category 2B recommendation.
• Subsequent-Line Therapy for Biliary Tract Cancers if Disease Progression
  • Other Recommended Regimens
    • Bullet 3 added: Liposomal irinotecan + fluorouracil + leucovorin added as a category 2B recommendation.
    • Bullet 4 added: Durvalumab + gemcitabine + cisplatin added as a category 2B recommendation.
  • Useful in Certain Circumstances
    • Bullet 7 added: For RET fusion-positive tumors, Pralsetinib added as a category 2B recommendation.
    • Bullet 8 added: For HER2-positive tumors, Trastuzumab + pertuzumab added as a category 2A recommendation.
• Footnote d added: Durvalumab + gemcitabine + cisplatin is also a recommended treatment option for patients who developed recurrent disease >6 months after surgery with curative intent and >6 months after completion of adjuvant therapy.

BIL-C (3 of 4) and BIL-C (4 of 4)

• Principles of Systemic Therapy
  • Reference 5 added: Oh DY, He AR, Qin S, et al. A phase 3 randomized, double-blind, placebo-controlled study of durvalumab in combination with gemcitabine plus cisplatin (GemCis) in patients (pts) with advanced biliary tract cancer (BTC): TOPAZ-1 [abstract]. J Clin Oncol 2022;40:Abstract 378.
  • Reference 12 added: Subbiah V, Hu MI, Gainor JF, et al. Clinical activity of the RET inhibitor pralsetinib (BLU-667) in patients with RET fusion-positive solid tumors [abstract]. J Clin Oncol 2021;39: Abstract 467.
  • Reference 13 revised: Lamarca A, Palmer DH, Wasan HS, et al. ABC-06 | A randomised phase III, multi-centre, open-label study of active symptom control (ASC) alone or ASC with oxaliplatin / 5-FU chemotherapy (ASC+mFOLFOX) for patients (pts) with locally advanced / metastatic biliary tract cancers (ABC) previously-treated with cisplatin/gemcitabine (CisGem) chemotherapy [abstract]. J Clin Oncol 2019; 37(Suppl 15):Abstract 4003. Lamarca A, Palmer DH, Wasan HS, et al. Second-line FOLFOX chemotherapy versus active symptom control for advanced biliary tract cancer (ABC-06): a phase 3, open-label, randomised, controlled trial. Lancet Oncol 2021;22:690-701.
  • Reference 16 added: Yoo C, Kim KP, Jeong JH, et al. Liposomal irinotecan plus fluorouracil and leucovorin versus fluorouracil and leucovorin for metastatic biliary tract cancer after progression on gemcitabine plus cisplatin (NIFTY): A multicentre, open-label, randomised, phase 2b study. Lancet Oncol 2021;22:1560–72.
  • Reference 23 revised: Javle M, Roychowdhury S, Kelley RK, et al. Final results from a phase II study of infigratinib (BGJ398), an FGFR-selective tyrosine kinase inhibitor, in patients with previously treated advanced cholangiocarcinoma harboring an FGFR2 gene fusion or rearrangement. J Clin Oncol 2021;39:265-265 Javle M, Roychowdhury S, Kelley RK, et al. Infigratinib (BGJ398) in previously treated patients with advanced or metastatic cholangiocarcinoma with FGFR2 fusions or rearrangements: mature results from a multicentre, open-label, single-arm, phase 2 study. Lancet Gastroenterol Hepatol 2021;6:803-815.
  • Reference 25 added: Zhu AX, Macarulla T, Javle MM, et al. Final overall survival efficacy results of ivosidenib for patients with advanced cholangiocarcinoma with IDH1 mutation: The phase 3 randomized clinical ClarIDHy trial. JAMA Oncol 2021:7:1669-1677.
  • Reference 26 added: Javle M, Borad MJ, Azad NS, et al. Pertuzumab and trastuzumab for HER2-positive metastatic biliary tract cancer (MyPathway): A multicentre, open-label, phase 2a, multiple basket study. Lancet Oncol 2021;22:1290-1300.

ST-6

• New section added: Barcelona Clinic Liver Cancer (BCLC) Staging System (2022).

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