NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®)

Hepatobiliary Cancers
Version 1.2022 — March 29, 2022
NCCN.org
NCCN Guidelines for Patients® available at www.nccn.org/patients

Continue

Version 1.2022, 03/29/22 © 2022 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers*Al B. Benson, III, MD/Chair †Robert H. Lurie Comprehensive Cancer
Center of Northwestern University*Michael I. D’Angelica, MD/Vice-Chair ¶Memorial Sloan Kettering Cancer Center
Daniel E. Abbott, MD ¶University of Wisconsin
Carbone Cancer Center
Daniel A. Anaya, MD ¶Moffitt Cancer Center
Robert Anders, MD, PhD ¤ ≠The Sidney Kimmel Comprehensive
Cancer Center at Johns Hopkins
Chandrakanth Are, MD, MBA ¶Fred & Pamela Buffett Cancer Center
Melinda Bachini ¥The Cholangiocarcinoma Foundation
Mitesh Borad, MD †Mayo Clinic Cancer Center
Daniel Brown, MD † фVanderbilt-Ingram Cancer Center
Adam Burgoyne, MD, PhD †US San Diego Moores Cancer Center
Prabhleen Chahal, MD ¤Case Comprehensive Cancer Center/
University Hospitals Seidman Cancer Centerand Cleveland Clinic Taussig Cancer InstituteDaniel T. Chang, MD §Stanford Cancer InstituteJordan Cloyd, MD ¶The Ohio State University Comprehensive
Cancer Center - James Cancer Hospitaland Solove Research Institute
NCCN
Cindy Hochstetler, PhD
Nicole McMillian, MS
Ryan Schonfeld, BA

Anne M. Covey, MD ф
Memorial Sloan Kettering Cancer Center
Sepideh Gholami, MD ¶UC Davis Comprehensive Cancer Center
Evan S. Glazer, MD, PhD ¶St. Jude Children's Research Hospital/The
University of Tennessee Health Science
Center
Lipika Goyal, MD †Dana-Farber/Brigham and Women's
Cancer Center | Massachusetts General
Hospital Cancer Center
William G. Hawkins, MD ¶Siteman Cancer Center at BarnesJewish Hospital and Washington
University School of Medicine
Renuka Iyer, MD Þ †Roswell Park Comprehensive
Cancer Center
Rojymon Jacob, MD §O'Neal Comprehensive
Cancer Center at UAB
Lawrence Jennings, MD, PhD ≠Robert H. Lurie Comprehensive Cancer
Center of Northwestern University
R. Kate Kelley, MD † ‡UCSF Helen Diller Family
Comprehensive Cancer Center
Robin Kim, MD ξ ¶Huntsman Cancer Instituteat the University of Utah

Continue
NCCN Guidelines Panel Disclosures

NCCN Guidelines Index
Table of Contents
Discussion
Matthew Levine, MD, PhD ξ
Abramson Cancer Centerat the University of Pennsylvania
Manisha Palta, MD §Duke Cancer InstituteJames O. Park, MD ¶Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance
Steven Raman, MD ф
UCLA Jonsson Comprehensive Cancer Center
Sanjay Reddy, MD, FACS ¶Fox Chase Cancer Center
Vaibhav Sahai, MD, MS †University of Michigan
Rogel Cancer Center
Tracey Schefter, MD §University of Colorado Cancer Center
Gagandeep Singh, MD ¶City of Hope National Medical Center
Stacey Stein, MD †Yale Cancer Center/Smilow Cancer Hospital
Jean-Nicolas Vauthey, MD ¶The University of Texas MD Anderson Cancer Center
Alan P. Venook, MD † ‡ Þ
UCSF Helen Diller Family
Comprehensive Cancer Center
Adam Yopp, MD ¶UT Southwestern Simmons
Comprehensive Cancer Center¤ Gastroenterology≠ Pathology‡ Hematology/Hematology § Radiotherapy/Radiation
oncology
oncology
Þ Internal medicine¶ Surgery/Surgical oncology
ф Interventional radiology ξ Transplantation† Medical oncology* Discussion section writing¥ Patient advocacy
committee

Version 1.2022, 03/29/22 © 2022 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
NCCN Hepatobiliary Cancers Panel Members
Summary of the Guidelines Updates
Hepatocellular Carcinoma (HCC)• HCC Screening (HCC-1)• Diagnosis of HCC (HCC-2)• Clinical Presentation and Workup: HCC Confirmed (HCC-3)• Potentially Resectable or Transplantable, Operable by Performance Status or Comorbidity (HCC-4)• Unresectable Hepatocellular Carcinoma (HCC-5)• Liver-Confined Disease, Inoperable by Performance Status, Comorbidity, or With Minimal or Uncertain
Extrahepatic Disease (HCC-6)• Principles of Imaging (HCC-A)• Principles of Core Needle Biopsy (HCC-B)• Child-Pugh Score (HCC-C)• Principles of Surgery (HCC-D)• Principles of Locoregional Therapy (HCC-E)• Principles of Radiation (HCC-F)• Principles of Systemic Therapy (HCC-G)
Biliary Tract Cancers: Gallbladder Cancer• Incidental Finding at Surgery (GALL-1)• Incidental Finding on Pathologic Review (GALL-2)• Mass on Imaging (GALL-3)• Jaundice and Metastatic Disease (GALL-4)• Post-Resection (GALL-5)• Principles of Surgery and Pathology (GALL-A)
Biliary Tract Cancers: Intrahepatic Cholangiocarcinoma• Presentation, Workup, Primary Treatment (INTRA-1)• Adjuvant Treatment, Surveillance (INTRA-2)• Principles of Surgery (INTRA-A)

Biliary Tract Cancers: Extrahepatic
Cholangiocarcinoma• Presentation, Workup, Primary
Treatment (EXTRA-1)• Adjuvant Treatment, Surveillance(EXTRA-2)• Principles of Surgery (EXTRA-A)

NCCN Guidelines Index
Table of Contents
Discussion

Clinical Trials: NCCN believes thatthe best management for any patientwith cancer is in a clinical trial.
Participation in clinical trials is
especially encouraged.
Find an NCCN Member Institution:
https://www.nccn.org/home/memberinstitutions.
NCCN Categories of Evidence andConsensus: All recommendations
are category 2A unless otherwise
indicated.
See NCCN Categories of Evidence
and Consensus.
NCCN Categories of Preference:
All recommendations are consideredappropriate. See NCCN Categories
of Preference.

Biliary Tract Cancers• Principles of Imaging (BIL-A)• Principles of Radiation Therapy (BIL-B)• Principles of Systemic Therapy (BIL-C)
Hepatobiliary Cancers• AJCC Staging (ST-1)• BCLC Staging (ST-6)

The NCCN Guidelines® are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches totreatment. 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 NCCN
Guidelines are copyrighted by National Comprehensive Cancer Network®. All rights reserved. The NCCN Guidelines and the illustrations herein may not
be reproduced in any form without the express written permission of NCCN. ©2022.
Version 1.2022, 03/29/22 © 2022 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers

NCCN Guidelines Index
Table of Contents
Discussion

Updates in Version 1.2022 of the NCCN Guidelines for Hepatobiliary Cancers from Version 5.2021 include:
HCC-1• 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 despitethat 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 theliver - 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.

Continued
Version 1.2022, 03/29/22 © 2022 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

UPDATESPrinted by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers

NCCN Guidelines Index
Table of Contents
Discussion

Updates in Version 1.2022 of the NCCN Guidelines for Hepatobiliary Cancers from Version 5.2021 include:
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 biopsy may 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 forhepatocellular 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.

Version 1.2022, 03/29/22 © 2022 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

Continued
UPDATESPrinted by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers

NCCN Guidelines Index
Table of Contents
Discussion

Updates in Version 1.2022 of the NCCN Guidelines for Hepatobiliary Cancers from Version 5.2021 include:
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 inpatients 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;75:600-609 nivolumab (NIVO) in patients (pts) with advanced hepatocellular carcinoma (aHCC) and ChildPugh 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.

Version 1.2022, 03/29/22 © 2022 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

Continued
UPDATESPrinted by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers

NCCN Guidelines Index
Table of Contents
Discussion

Updates in Version 1.2022 of the NCCN Guidelines for Hepatobiliary Cancers from Version 5.2021 include:
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 orconfirmed 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.

Version 1.2022, 03/29/22 © 2022 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

Continued
UPDATESPrinted by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers

NCCN Guidelines Index
Table of Contents
Discussion

Updates in Version 1.2022 of the NCCN Guidelines for Hepatobiliary Cancers from Version 5.2021 include:
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.

Version 1.2022, 03/29/22 © 2022 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

Continued
UPDATESPrinted by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers

NCCN Guidelines Index
Table of Contents
Discussion

Updates in Version 1.2022 of the NCCN Guidelines for Hepatobiliary Cancers from Version 5.2021 include:
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, andpara-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: EBRT Conventional 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.

Version 1.2022, 03/29/22 © 2022 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

Continued
UPDATESPrinted by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers

NCCN Guidelines Index
Table of Contents
Discussion

Updates in Version 1.2022 of the NCCN Guidelines for Hepatobiliary Cancers from Version 5.2021 include:
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) previouslytreated 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).

Version 1.2022, 03/29/22 © 2022 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

UPDATESPrinted by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatocellular Carcinoma

NCCN Guidelines Index
Table of Contents
Discussion

HEPATOCELLULAR CARCINOMA (HCC) SCREENINGa

Patients at risk for HCCb:• Cirrhosisc
Hepatitis B, Cd
AlcoholeGenetic hemochromatosis
Non-alcoholic fatty liver disease (NAFLD)d,f
Stage 4 primary biliary cholangitisg
Alpha-1-antitrypsin deficiency
Other causes of cirrhosish• Without cirrhosis
Hepatitis Bc,iUltrasound (US)a,j+
Alpha fetoprotein (AFP)

AFP positivekor
US nodule(s) ≥10 mm

Additional
workup(See HCC-2)

US nodule(s) <10 mm

Repeat US + AFP in 3–6 mo

US negativel

Repeat US + AFP in 6 moa See Principles of Imaging (HCC-A).
b Adapted with permission from Marrero JA, et al. Hepatology 2018;68:723-750.
c Patients with cirrhosis or chronic hepatitis B viral infection should be enrolled in an HCC screening program (See Discussion).
d There is evidence suggesting improved outcomes for patients with HCC in the setting of NAFLD/HBV/HCV cirrhosis when the NAFLD/HBV/HCV is successfully

treated. Referral to a hepatologist should be considered for the management of these patients.

e Niazi SK, et al. J Natl Compr Canc Netw 2021;19:829-838.
f White DL, Clin Gastroenterol Hepatol 2012;10:1342-1359.
g Beuers U, et al. Am J Gastroenterol 2015;110:1536-1538.
h Schiff ER, Sorrell MF, and Maddrey WC. Schiff's Diseases of the Liver. Philadelphia: Lippincott Williams & Wilkins (LWW); 2007.
i Additional risk factors include HBV carrier with family history of HCC, Asian males ≥40 y, Asian females ≥50 y, and African/North American Blacks with hepatitis B.
j Most clinical practice guidelines recommend US for HCC screening. US exams should be done by qualified sonographers or physicians. Liver dynamic CT or dynamic

MRI may be performed as an alternative to US if US fails to detect nodules or if visualization is poor. Korean Liver Cancer Association; National Cancer Center. Gut
Liver 2019;13:227-299. (See Principles of Imaging, HCC-A).
k Positive or rising AFP should prompt CT or MRI regardless of US results.
l US negative means no observation or only definitely benign observation(s).
Note: All recommendations are category 2A unless otherwise indicated.
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.
Version 1.2022, 03/29/22 © 2022 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

HCC-1

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatocellular Carcinoma

NCCN Guidelines Index
Table of Contents
Discussion

DIAGNOSIS OF HCCb
IMAGINGa

FINDINGS

Observation(s)mdetected• Positive imaging result• Suspicious abnormality
detected on imaging
examination done forother reasons• Positive AFP

Abdominal
multiphasic CT
or
MRI

ADDITIONAL WORKUP
Definitely HCCn

HCC confirmed(See HCC-3)

Not definitely HCC,
not definitely benign

Individualized workup,
which may include
additional imaginga orbiopsy,o,p as informed bymultidisciplinary discussion

Definitely benign

Return to screeningq in
6 mo (See HCC-1)

No observationm
detected

Return to screening in
6 mo (See HCC-1)

a See Principles of Imaging (HCC-A).
b Adapted with permission from Marrero JA, et al. Hepatology 2018;68:723-750.
m An observation is an area identified at imaging that is distinctive from background liver. It may be a mass or a pseudo lesion.
n Criteria for observations that are definitely HCC have been proposed by LI-RADS and adopted by AASLD. These criteria apply only to patients at high risk for HCC.

OPTN has proposed imaging criteria for HCC applicable in candidates for liver transplant. See Principles of Imaging (HCC-A).

o 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.
p The optimal diagnostic method is core needle biopsy. See Principles of Core Needle Biopsy (HCC-B).
q If no observations are detected at diagnostic imaging despite positive surveillance tests, then return to surveillance in 6 months if the most reasonable explanationis that surveillance tests were false positive. Consider imaging with an alternative method ± AFP if there is reasonable suspicion that the diagnostic imaging test wasfalse negative.

Note: All recommendations are category 2A unless otherwise indicated.
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.
Version 1.2022, 03/29/22 © 2022 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

HCC-2

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatocellular Carcinoma
CLINICAL PRESENTATIONWORKUP

HCC confirmed

Multidisciplinary evaluationr(assess liver reserves and comorbidity) and staging:• History and physical examination (H&P)• Hepatitis panelt• Bilirubin, transaminases, alkaline phosphatase• PT or INR, albumin, BUN, creatinine• CBC, platelets• AFP• Chest CTa• Bone scan if clinically indicateda• Abdominal/pelvic CT or MRI with contrast, if notpreviously done or needs updatinga• Consider referral to a hepatologist

NCCN Guidelines Index
Table of Contents
Discussion

Potentially resectable or transplantable,
operable by performance status orcomorbidity (See HCC-4)
Unresectable (See HCC-5)
Liver-confined disease, inoperable byperformance status, comorbidity, or withminimal or uncertain extrahepatic disease(See HCC-6)
Metastatic disease or extensive
liver tumor burden (See HCC-6)

a See Principles of Imaging (HCC-A).
r See NCCN Guidelines for Older Adult Oncology.
s See Child-Pugh Score (HCC-C) and assessment of portal hypertension (eg, varices, splenomegaly, thrombocytopenia).
t An appropriate hepatitis panel should preferably include:• Hepatitis B surface antigen (HBsAg). If the HBsAg is positive, check HBeAg, HBeAb, and quantitative HBV DNA and refer to hepatologist.
• Hepatitis B surface antibody (for vaccine evaluation only).
• Hepatitis B core antibody (HBcAb) IgG. The HBcAb IgM should only be checked in cases of acute viral hepatitis. An isolated HBcAb IgG may still be chronic HBV andshould prompt testing for a quantitative HBV DNA.
• Hepatitis C antibody. If positive, check quantitative HCV RNA and HCV genotype and refer to hepatologist.
Note: All recommendations are category 2A unless otherwise indicated.
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.
Version 1.2022, 03/29/22 © 2022 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

HCC-3

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatocellular Carcinoma
CLINICAL PRESENTATIONSURGICAL ASSESSMENTu,v,w

TREATMENT• Child-Pugh Class A, Bx• No portal hypertension• Suitable tumor location• Adequate liver reserve• Suitable liver remnant
Potentially resectable
or transplantable,
operable byperformance status
or comorbidity• UNOS criteriaw,yAFP level ≤1000 ng/mL
and patient has a tumor
2–5 cm in diameter or
2–3 tumors 1–3 cm indiameterNo macrovascular
involvement
No extrahepatic disease• Extended criteriay

NCCN Guidelines Index
Table of Contents
Discussion

If ineligible
for transplantz• Refer to livertransplant centerv,aa• Bridge therapy as
indicatedbb

Resection, if
feasible (preferred)wor
Locoregional
therapycc• Ablationdd• Arterially directed
therapies• External beam
radiation therapy(EBRT)ee

SURVEILLANCE• Imagingff,gg every 3–6 mo
for 2 y, then every 6 mo
• AFPgg every 3–6 mo for 2y, then every 6 mo
• See relevant pathway(HCC-2 through HCC-6) if
disease recurs• Refer to a hepatologist fora discussion of antiviraltherapy for carriers ofhepatitis if not previously
doneTransplantu Discussion of surgical treatment with patient and determination of whether patient is amenable to surgery.
v Patients with Child-Pugh Class A liver function, who fit UNOS criteria (www.unos.org) and are resectable could be considered for resection or transplant. There iscontroversy over which initial strategy is preferable to treat such patients. These patients should be evaluated by a multidisciplinary team.

w See Principles of Surgery (HCC-D).
x In highly selected patients with Child-Pugh Class B liver function with limited resection.
y Extended criteria/downstaging protocols are available through UNOS. See https://optn.transplant.hrsa.gov/media/1200/optn_policies.pdf#nameddest=Policy_09.
z 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).

aa Mazzaferro V, et al. N Engl J Med 1996;334:693-700.
bb Many transplant centers consider bridge therapy for transplant candidates (See Discussion).
cc See Principles of Locoregional Therapy (HCC-E).
dd In well-selected patients with small, properly located tumors, ablation should be considered as definitive treatment in the context of a multidisciplinary review.
ee See Principles of Radiation Therapy (HCC-F).
ff Multiphasic abdominal MRI or multiphase CT scans for liver assessment, CT chest, and CT/MRI pelvis. See Principles of Imaging (HCC-A).
gg Surveillance imaging and AFP should continue for at least 5 years and thereafter screening dependent on HCC risk factors. See Principles of Imaging (HCC-A).
Note: All recommendations are category 2A unless otherwise indicated.
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.
Version 1.2022, 03/29/22 © 2022 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

For relapse, see Initial
Workup (HCC-3)
HCC-4

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatocellular Carcinoma
CLINICALPRESENTATIONTREATMENT

Transplantcandidate
Unresectable• Inadequate
hepatic
reserves• Tumorlocationw• Extent ofdiseasew

NCCN Guidelines Index
Table of Contents
Discussion

Evaluate whether
patient is a candidate fortransplant [See UNOS/
extended criteria under
Surgical Assessment(HCC-4)]w,aa
Not a transplantcandidatez• Refer to livertransplant center• Bridge therapy as
indicatedbb

SURVEILLANCE

Transplant

Options:hh• Locoregional
therapy preferredcc
Ablation
Arterially directed
therapiesii
EBRTee
Options:hh• Clinical trial• Systemic therapyjj• Best supportive
carekk• Imagingff,gg
every 3–6 mo for 2 y,then every 6 mo
• AFPgg every 3–6 mo for
2 y, then every 6 mo
• See relevant pathway(HCC-2 through HCC-6) if
disease recurs• Consider early imaging
per local protocol

Progression
on or after
systemictherapyjj

s See Child-Pugh Score (HCC-C) and assessment of portal hypertension (eg, varices, splenomegaly, thrombocytopenia).
w See Principles of Surgery (HCC-D).
z 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).

aa Mazzaferro V, et al. N Engl J Med 1996;334:693-700.
bb Many transplant centers consider bridge therapy for transplant candidates (See Discussion).
cc See Principles of Locoregional Therapy (HCC-E).
ee See Principles of Radiation Therapy (HCC-F).
ff Multiphasic abdominal MRI or multiphase CT scans for liver assessment, CT chest, and CT/MRI pelvis. See Principles of Imaging (HCC-A).
gg Surveillance imaging and AFP should continue for at least 5 years and thereafter screening dependent on HCC risk factors. See Principles of Imaging (HCC-A).
hh Order does not indicate preference. The choice of treatment modality may depend on extent/location of disease, hepatic reserve, and institutional capabilities.
ii Use of chemoembolization has also been supported by randomized controlled trials in selected populations over best supportive care.
jj See Principles of Systemic Therapy (HCC-G).
kk See NCCN Guidelines for Palliative Care.
Note: All recommendations are category 2A unless otherwise indicated.
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.
Version 1.2022, 03/29/22 © 2022 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

HCC-5

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatocellular Carcinoma

NCCN Guidelines Index
Table of Contents
Discussion

CLINICAL PRESENTATIONTREATMENT

Liver-confined disease, inoperable by performancestatus, comorbidity, or with minimal or uncertain
extrahepatic disease

Options:hh• Locoregional therapy preferredcc
Ablation
Arterially directed therapies
EBRTee• Clinical trial• Systemic therapyjj• Best supportive carekk

Progression on orafter systemic therapyjj

Options:hh• Clinical trial• Systemic therapyjj• Best supportive carekk

Progression on orafter systemic therapyjj

Metastatic diseaseorExtensive liver
tumor burden

Biopsyp for
histologic
confirmation if notpreviously done

p The optimal diagnostic method is core needle biopsy. See Principles of Core Needle Biopsy (HCC-B).
cc See Principles of Locoregional Therapy (HCC-E).
ee See Principles of Radiation Therapy (HCC-F).
hh Order does not indicate preference. The choice of treatment modality may depend on extent/location of disease, hepatic reserve, and institutional capabilities.
jj See Principles of Systemic Therapy (HCC-G).
kk See NCCN Guidelines for Palliative Care.
Note: All recommendations are category 2A unless otherwise indicated.
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.
Version 1.2022, 03/29/22 © 2022 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

HCC-6

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatocellular Carcinoma

NCCN Guidelines Index
Table of Contents
Discussion

PRINCIPLES OF IMAGING
Screening and Surveillance• Screening and surveillance for HCC is considered cost effective in patients with cirrhosis of any cause and patients with chronic hepatitis
B (CHB) even in the absence of cirrhosis.1,2 The recommended screening and surveillance imaging method is US, and the recommended
interval is every 6 months.1,2 Liver dynamic CT or dynamic MRI are more sensitive than US for HCC detection,3 but they are more costly.
They may be performed as an alternative to US if US fails to detect nodules or if visualization is poor (see below).4 Serum biomarkers suchas AFP may incrementally improve the performance of imaging-based screening and surveillance.
• Patients with viral hepatitis who have had a complete or sustained viral response should continue with screening despite that response.5
Imaging Diagnosis of HCC• After a positive screening or surveillance test or after lesions are detected incidentally on routine imaging studies done for other reasons,multiphasic abdominal CT or MRI studies with contrast are recommended to establish the diagnosis and stage the tumor burden in the liver.
Optimal imaging technique depends on the modality and contrast agent, as summarized by LI-RADS.6 To standardize interpretation, the
AASLD,1 EASL,2 OPTN,7 and LI-RADS6,8 have adopted imaging criteria to diagnose HCC nodules greater than or equal to 10 mm. Criteria
have not been proposed for nodules less than 10 mm as these are difficult to definitively characterize at imaging. Major imaging featuresof HCC include arterial phase hyperenhancement, nonperipheral venous or delayed phase washout appearance, enhancement of capsuleappearance, and threshold growth.6,8 LI-RADS also provides imaging criteria to diagnose major vascular invasion.6 Having criteria for
vascular invasion is necessary because the tumor in the vein may not have the same imaging features as parenchymal tumors.
• Importantly, imaging criteria for parenchymal nodules apply only to patients at high risk for developing HCC: namely, those with cirrhosis,
CHB, or current or prior HCC. In these patients, the prevalence of HCC is sufficiently high that lesions meeting imaging criteria for HCC haveclose to a 100% probability of being HCC. The criteria do not apply to the general population or, except for CHB, to patients with chronic
liver disease that has not progressed to cirrhosis. The criteria are designed to have high specificity for HCC; thus, lesions meeting thesecriteria can be assumed to represent HCC and may be treated as such without confirmatory biopsy. As a corollary, the criteria have modest
sensitivity; thus, many HCCs do not satisfy the required criteria and failure to meet the criteria does not exclude HCC.6• Lesions that do not meet the imaging criteria described above for HCC require individualized workup, which may include additional imaging
or biopsy as informed by multidisciplinary discussion and are outlined in the treatment algorithms.
• Quality of MRI is dependent on patient compliance.
Extrahepatic Staging• Frequent sites of extrahepatic metastases from HCC include lungs, bone, and lymph nodes. Adrenal and peritoneal metastases also may
occur. For this reason, chest CT, complete imaging of abdomen and pelvis with contrast-enhanced CT or MRI, and selective use of bone
scan9 when skeletal symptoms are present are recommended at initial diagnosis of HCC and for monitoring disease while on the transplant
wait list or during or after treatment for response assessment. Chest CT may be performed with contrast if concurrently acquired with
contrast-enhanced abdominal/pelvic CT. If MRI is performed, chest CT may be acquired without contrast.
References
Note: All recommendations are category 2A unless otherwise indicated.
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.
Version 1.2022, 03/29/22 © 2022 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

Continued
HCC-A
1 OF 3

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatocellular Carcinoma

NCCN Guidelines Index
Table of Contents
Discussion

PRINCIPLES OF IMAGING
Imaging Diagnosis of iCCA and cHCC-CCA
Patients at risk for HCC due to cirrhosis, CHB, or other conditions are also at elevated risk for developing non-HCC primary hepatic
malignancies such as intrahepatic cholangiocarcinoma (iCCA) and combined HCC-cholangiocarcinoma (cHCC-CCA). Although iCCAs andcHCC-CCAs tend to have malignant imaging features, the features are not sufficiently specific to permit noninvasive diagnosis.8,10 Biopsya or
definitive resection usually is necessary to make a diagnosis.
Imaging Protocol for Response Assessment After Treatment
CT of the chest and multiphasic CT or MRI of the abdomen and pelvis are the preferred modalities as they reliably assess intranodular arterial
vascularity, a key feature of residual or recurrent tumor. Overall nodule size does not reliably indicate treatment response since a variety offactors may cause a successfully treated lesion to appear stable in size or even larger after treatment.
Role of CEUS
Contrast-enhanced US (CEUS) is considered a problem-solving tool for use at select centers with the relevant expertise for characterization ofindeterminate nodules. It is not suitable for whole-liver assessment, surveillance, or cancer staging.11
Role of PET
PET/CT has limited sensitivity but high specificity, and may be considered when there is an equivocal finding.12 When an HCC is detectedby CT or MRI and has increased metabolic activity on PET/CT, higher intralesional standardized uptake value (SUV) is a marker of biologic
aggressiveness and might predict less optimal response to locoregional therapies.13

a The optimal diagnostic method is core needle biopsy. See Principles of Core Needle Biopsy (HCC-B).
Note: All recommendations are category 2A unless otherwise indicated.
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.
Version 1.2022, 03/29/22 © 2022 National Comprehensive Cancer Network (NCCN ), All rights reserved. NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
®

®

®

References
HCC-A
2 OF 3

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatocellular Carcinoma

NCCN Guidelines Index
Table of Contents
Discussion

PRINCIPLES OF IMAGINGREFERENCES
1 Marrero JA, Kulik LM, Sirlin C, et al. Diagnosis, staging, and management of hepatocellular carcinoma: 2018 Practice Guidance by the American Association for the

Study of Liver Diseases. Hepatology 2018;68:723-750.

2 European Association for the Study of the Liver, European Organisation for Research and Treatment of Cancer. EASL-EORTC clinical practice guidelines:

management of hepatocellular carcinoma. J Hepatol 2012;56:908-943.

3 Colli A, Fraquelli M, Casazza G, et al. Accuracy of ultrasonography, spiral CT, magnetic resonance, and alpha-fetoprotein in diagnosing hepatocellular carcinoma: asystematic review. Am J Gastroenterol 2006;101:513-523.

4 Korean Liver Cancer Association; National Cancer Center. 2018 Korean Liver Cancer Association-National Cancer Center Korea Practice Guidelines for theManagement of Hepatocellular Carcinoma. Gut Liver 2019;13:227-299.

5 Ioannou, GN. HCC surveillance after SVR in patients with F3/F4 fibrosis. J Hepatol 2021;74:458-465.
6 ACR. American College of Radiology (ACR) Liver Imaging Reporting And Data System (LI-RADS) v2017 2018 [cited 2018 May 28].

Available from: http://www.acr.org/Quality-Safety/Resources/LIRADS.

7 Pomfret EA, Washburn K, Wald C, et al. Report of a national conference on liver allocation in patients with hepatocellular carcinoma in the United States. Liver Transpl

2010;16:262-278.

8 Fowler KJ, Potretzke TA, Hope TA, et al. LI-RADS M (LR-M): definite or probable malignancy, not specific for hepatocellular carcinoma. Abdom Radiol (NY) 2018;

43:149-157.

9 Harding JJ, Abu-Zeinah G, Chour JF, et al. Frequency, morbidity, and mortality of bone metastases in advanced hepatocellular carcinoma. J Natl Compr Canc Netw

2018;16:50-58.

10 Choi JY, Lee JM, Sirlin CB. CT and MR imaging diagnosis and staging of hepatocellular carcinoma: part II. Extracellular agents, hepatobiliary agents, and ancillary

imaging features. Radiology 2014;273:30-50.

11 Dietrich CF, Nolsøe CP, Barr RG, et al. Guidelines and good clinical practice recommendations for contrast enhanced ltrasound (CEUS) in the liver - update 2020:

WFUMB in cooperation with EFSUMB, AFSUMB, AIUM, and FLAUS. Ultrasound Med Biol 2020;46:2579-2604.

12 Lamarca A, Barriuso J, Chander A, et al. 18F-fluorodeoxyglucose positron emission tomography (18FDG-PET) for patients with biliary tract cancer: Systematic review

and meta-analysis. J Hepatol 2019;71:115-129.

13 Sun DW, An L, Wei F, et al. Prognostic significance of parameters from pretreatment (18)F-FDG PET in hepatocellular carcinoma: a meta-analysis. Abdom Radiol(NY) 2016;41:33-41.

Note: All recommendations are category 2A unless otherwise indicated.
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.
Version 1.2022, 03/29/22 © 2022 National Comprehensive Cancer Network (NCCN ), All rights reserved. NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
®

®

®

HCC-A
3 OF 3

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatocellular Carcinoma

NCCN Guidelines Index
Table of Contents
Discussion

PRINCIPLES OF CORE NEEDLE BIOPSY
The optimal diagnostic method is core needle biopsy. Indicators for consideration of core needle biopsy may include:• Initial core needle biopsy
Lesion is highly suspicious for malignancy at multiphasic CT or MRI but does not meet imaging criteriaa for HCC.
Lesion meets imaging criteria1 for HCC but:
◊ Patient is not considered at high risk for HCC development (ie, does not have cirrhosis, CHB, or current or prior HCC).
◊ Patient has cardiac cirrhosis, congenital hepatic fibrosis, or cirrhosis due to a vascular disorder such as Budd-Chiari syndrome,
hereditary hemorrhagic telangiectasia, or nodular regenerative hyperplasia.b◊ Patient has elevated CA 19-9 or carcinoembryonic antigen (CEA) with suspicion of iCCA or cHCC-CCA.
Confirmation of metastatic disease could change clinical decision-making including enrollment in clinical trials.
Surgical resection without core needle biopsy should be considered with multidisciplinary review.
• If core needle biopsy is considered, obtain prior to ablation.
• Repeat core needle biopsy
Non-diagnostic core needle biopsy
Prior core needle biopsy discordant with imaging, biomarkers, or other factors

a Imaging criteria for HCC have been proposed by LI-RADS and adopted by AASLD. These criteria apply only to patients at high risk for HCC. OPTN has proposed

imaging criteria for HCC applicable in liver transplant candidates. See Principles of Imaging (HCC-A).

b These conditions are associated with formation of nonmalignant nodules that may resemble HCC at imaging.
Note: All recommendations are category 2A unless otherwise indicated.
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.
Version 1.2022, 03/29/22 © 2022 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

HCC-B

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatocellular Carcinoma

NCCN Guidelines Index
Table of Contents
Discussion

CHILD-PUGH SCORE
Chemical and Biochemical Parameters

Scores (Points) for Increasing Abnormality
1
2
3

Encephalopathy (grade)1

None

1–2

3–4

Ascites

AbsentSlightModerate>3.5

2.8–3.5<2.8

Seconds over control
INR

<4
<1.7

4–6
1.7–2.3>6>2.3

Bilirubin (mg/dL)• For primary biliary cirrhosis

<2
<4

2–3
4–10

>3
>10

Albumin (g/dL)
Prothrombin time2

Class A = 5–6 points; Class B = 7–9 points; Class C = 10–15 points.
Class A: Good operative risk
Class B: Moderate operative risk
Class C: Poor operative risk

1 Trey C, Burns DG, Saunders SJ. Treatment of hepatic coma by exchange blood transfusion. N Engl J Med 1966;274:473-481.
2 Van Rijn JL, Schmidt NA, Rutten WP. Correction of instrument- and reagent-based differences in determination of the International Normalized Ratio (INR) for

monitoring anticoagulant therapy. Clin Chem 1989;35:840-843.

Source: Pugh R, Murray-Lyon I, Dawson J, et al: Transection of the oesophagus for bleeding oesophageal varices. Br J of Surg 1973;60:646-649. ©British Journal ofSurgery Society Ltd. Adapted with permission. Permission is granted by John Wiley & Sons Ltd on behalf of the BJSS Ltd.
Note: All recommendations are category 2A unless otherwise indicated.
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.
Version 1.2022, 03/29/22 © 2022 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

HCC-C

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatocellular Carcinoma

NCCN Guidelines Index
Table of Contents
Discussion

PRINCIPLES OF SURGERY• Patients must be medically fit for a major operation.
• Hepatic resection is indicated as a potentially curative option in the following circumstances:Adequate liver function (generally Child-Pugh Class A without portal hypertension, but small series show feasibility of limited resections in patients withmild portal hypertension)1
Solitary mass without major vascular invasion
Adequate future liver remnant (FLR) (at least 20% without cirrhosis and at least 30%–40% with Child-Pugh Class A cirrhosis, adequate vascular andbiliary inflow/outflow)• Hepatic resection is controversial in the following circumstances, but can be considered:
Limited and resectable multifocal diseaseMajor vascular invasion• For patients with chronic liver disease being considered for major resection, preoperative portal vein embolization should be considered.2• 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.
• Patients meeting the United Network for Organ Sharing (UNOS) criteria ([AFP level ≤1000 ng/mL and single lesion ≥2 cm and ≤5 cm, or 2 or 3 lesions ≥1 cm
and ≤3 cm] www.unos.org) should be considered for transplantation (cadaveric or living donation).
• The Model for End-Stage Liver Disease (MELD) score is used by UNOS to assess the severity of liver disease and prioritize the allocation of the livertransplants.3,5 MELD score can be determined using the MELD calculator: https://optn.transplant.hrsa.gov/resources/allocation-calculators/meldcalculator/. There are patients whose tumor characteristics are marginally outside of the UNOS guidelines who should be considered for transplant.3
Furthermore, there are patients who are downstaged to within criteria that can also be considered for transplantation.4 Candidates are eligible for astandardized MELD exception if, before completing locoregional therapy, they have lesions that meet one of the following criteria:
One lesion >5 cm and ≤8 cm
2 or 3 lesions that meet all of the following:◊ Each lesion ≤5 cm, with at least one lesion >3 cm◊ A total diameter of all lesions ≤8 cm
4 or 5 lesions each <3 cm, and a total diameter of all lesions ≤8 cm.
For more information, see: https://optn.transplant.hrsa.gov/media/1200/optn_policies.pdf#nameddest=Policy_09• Patients with Child-Pugh Class A liver function, who fit UNOS criteria and are resectable, could be considered for resection or transplant. There iscontroversy over which initial strategy is preferable to treat such patients. These patients should be evaluated by a multidisciplinary team.
• Based on retrospective analyses, older patients may benefit from liver resection or transplantation for HCC, but they need to be carefully selected, as
overall survival is lower than for younger patients.6
1 Santambrogio R, Kluger MD, Costa M, et al. Hepatic resection for hepatocellular carcinoma in patients with Child-Pugh's A cirrhosis: Is clinical evidence of portal

hypertension a contraindication? HPB (Oxford) 2013;15:78-84.

2 Brouquet A, Andreou A, Shindoh J, et al. Methods to improve resectability of hepatocellular carcinoma. Recent Results Cancer Res. 2013;190:57-67.
3 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.
4 Rudnick SR, Russo MW. Liver transplantation beyond or downstaging within the Milan criteria for hepatocellular carcinoma. Expert Rev Gastroenterol Hepatol

201812:265-275.

5 Kamath PS, Wiesner RH, Malinchoc M, et al. A model to predict survival in patients with end-stage liver disease. Hepatology 2001:33:464-470.
6 Faber W, Stockmann M, Schirmer C, et al. Significant impact of patient age on outcome after liver resection for HCC cirrhosis. Eur J Surg Oncol 2014;40:208-213.
Note: All recommendations are category 2A unless otherwise indicated.
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.
Version 1.2022, 03/29/22 © 2022 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

HCC-D

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatocellular Carcinoma

NCCN Guidelines Index
Table of Contents
Discussion

PRINCIPLES OF LOCOREGIONAL THERAPY

I. General Principles• All patients with HCC should be evaluated for potential curative therapies (resection, transplantation, and for small lesions, ablative strategies).
Locoregional therapy should be considered in patients who are not candidates for surgical curative treatments, or as a part of a strategy to bridge patientsfor other curative therapies. These are broadly categorized into ablation, arterially directed therapies, and radiotherapy.
II. Treatment Information
A. Ablation (radiofrequency, cryoablation, percutaneous alcohol injection, microwave):• All tumors should be amenable to ablation such that the tumor and, in the case of thermal ablation, a margin of normal tissue is treated.
A margin is not expected following percutaneous ethanol injection.
• Tumors should be in a location accessible for percutaneous/laparoscopic/open approaches for ablation.
• Caution should be exercised when ablating lesions near major vessels, major bile ducts, diaphragm, and other intra-abdominal organs.
• Ablation alone may be curative in treating tumors less than or equal to 3 cm. In well-selected patients with small properly located tumors, ablation should
be considered as definitive treatment in the context of a multidisciplinary review. Lesions 3 to 5 cm may be treated to prolong survival using arteriallydirected therapies, or with combination of an arterially directed therapy and ablation as long as tumor location is accessible for ablation.1-3• Unresectable/inoperable lesions greater than 5 cm should be considered for treatment using arterially directed therapy, systemic therapy, or EBRT.4-6• Sorafenib should not be used as adjuvant therapy post-ablation.7
B. Arterially Directed Therapies:• All tumors irrespective of location may be amenable to arterially directed therapies provided that the arterial blood supply to the tumor may be isolated
without excessive non-target treatment.
• Arterially directed therapies include bland transarterial embolization (TAE),4,5,8,9 chemoembolization (transarterial chemoembolization [TACE]10 and TACE
with drug-eluting beads [DEB-TACE])4,11, and radioembolization (RE) with yttrium-90 (Y-90) microspheres.12,13• All arterially directed therapies are relatively contraindicated in patients with bilirubin greater than 3 mg/dL unless segmental treatment can be performed.14
RE with Y-90 microspheres has an increased risk of radiation-induced liver disease in patients with bilirubin greater than 2 mg/dL.13
With RE, delivery of 205 Gy or more to the tumor may be associated with increased overall survival.18• Arterially directed therapies in highly selected patients have been shown to be safe in the presence of limited tumor invasion of the portal vein.
Randomized controlled trials have shown that Y-90 is not superior to sorafenib for treating advanced HCC. RE may be appropriate in some patients withadvanced HCC,19,20 specifically patients with segmental or lobar portal vein, rather than main portal vein thrombosis.21• Sorafenib may be appropriate following arterially directed therapies in patients with adequate liver function once bilirubin returns to baseline if thereis evidence of residual/recurrent tumor not amenable to additional local therapies. The safety and efficacy of the use of sorafenib concomitantly witharterially directed therapies has not been associated with significant benefit in three randomized trials; other randomized phase lll trials are ongoing toinvestigate other systemic therapies including immunotherapy in combination with arterial therapies.15-17,21

Note: All recommendations are category 2A unless otherwise indicated.
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.
Version 1.2022, 03/29/22 © 2022 National Comprehensive Cancer Network (NCCN ), All rights reserved. NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
®

®

®

References
HCC-E
1 OF 2

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatocellular Carcinoma

NCCN Guidelines Index
Table of Contents
Discussion

PRINCIPLES OF LOCOREGIONAL THERAPYREFERENCES
1 Chen MS, Li JQ, Zheng Y, et al. A prospective randomized trial comparing

percutaneous local ablative therapy and partial hepatectomy for small
hepatocellular carcinoma. Ann Surg 2006;243:321-328.
2 Feng K, Yan J, Li X, et al. A randomized controlled trial of radiofrequency ablationand surgical resection in the treatment of small hepatocellular carcinoma. J
Hepatol 2012;57:794-802.
3 Peng ZW, Zhang YJ, Liang HH, et al. Recurrent hepatocellular carcinoma treatedwith sequential transcatheter arterial chemoembolization and RF ablation versus
RF ablation alone: a prospective randomized trial. Radiology 2012;262:689-700.
4 Malagari K, Pomoni M, Kelekis A, et al. Prospective randomized comparisonof chemoembolization with doxorubicin-eluting beads and bland embolization
with BeadBlock for hepatocellular carcinoma. Cardiovasc Intervent Radiol
2010;33:541-551.
5 Maluccio M, Covey AM, Gandhi R, et al. Comparison of survival rates after blandarterial embolization and ablation versus surgical resection for treating solitary
hepatocellular carcinoma up to 7 cm. J Vasc Interv Radiol 2005;16:955-961.
6 Yamakado K, Nakatsuka A, Takaki H, et al. Early-stage hepatocellular carcinoma:
radiofrequency ablation combined with chemoembolization versus hepatectomy.
Radiology 2008;247:260-266.
7 Bruix J, Takayama T, Mazzaferro V, et al. Adjuvant sorafenib for hepatocellular
carcinoma after resection or ablation (STORM): a phase 3, randomised, doubleblind, placebo-controlled trial. Lancet Oncol 2015;16:1344-1354.
8 Brown KT, Do RT, Gonen M, et al. Randomized trial of hepatic artery embolization
for hepatocellular carcinoma using doxorubicin-eluting microspheres comparedwith embolization with microspheres alone. J Clin Oncol 2016;34:2046-2053.
9 Maluccio MA, Covey AM, Porat LB, et al. Transcatheter arterial embolization with
only particles for the treatment of unresectable hepatocellular carcinoma. J Vasc
Interv Radiol 2008;19:862-869.
10 Llovet JM, Real MI, Montana X, et al. Arterial embolisation or chemoembolisation
versus symptomatic treatment in patients with unresectable hepatocellular
carcinoma: a randomised controlled trial. Lancet 2002;359:1734-1739.
11 Lammer J, Malagari K, Vogl T, et al. Prospective randomized study of
doxorubicin‑eluting‑bead embolization in the treatment of hepatocellular
carcinoma: results of the PRECISION V study. Cardiovasc Intervent Radiol
2010;33:41‑52.
12 Kulik LM, Carr BI, Mulcahy MF, et al. Safety and efficacy of 90Y radiotherapy
for hepatocellular carcinoma with and without portal vein thrombosis. Hepatology
2008;47:71-81.

13 Salem R, Lewandowski RJ, Mulcahy MF, et al. Radioembolization forhepatocellular carcinoma using Yttrium-90 microspheres: a comprehensive reportof long-term outcomes. Gastroenterology 2010;138:52-64.
14 Ramsey DE, Kernagis LY, Soulen MC, Geschwind J-FH. Chemoembolization ofhepatocellular carcinoma. J Vasc Interv Radiol 2002;13:211-221.
15 Kudo M, Imanaka K, Chida N, et al. Phase lll study of sorafenib after transarterial
chemoembolization in Japanese and Korean patients with unresectable
hepatocellular carcinoma. Eur J Cancer. 2011;47:2117-2127.
16 Lencioni R, Llovet JM, Han G, et al. Sorafenib or placebo plus TACE withdoxorubicin-eluting beads for intermediate stage HCC: the SPACE trial. J Hepatol
2016;64:1090-1098.
17 Pawlik TM, Reyes DK, Cosgrove D, et al. Phase II trial of sorafenib combinedwith concurrent transarterial chemoembolization with drug-eluting beads forhepatocellular carcinoma. J Clin Oncol 2011;29:3960-3967.
18 Garin E, Tselikas L, Guiu B, et al and the DOSISPHERE-01 Study Group.
Personalised versus standard dosimetry approach of selective internalradiation therapy in patients with locally advanced hepatocellular carcinoma(DOSISPHERE-01): a randomised, multicentre, open-label phase 2 trial. Lancet
Gastroenterol Hepatol 2021;6:17-29.
19 Vilgrain V, Pereira H, Assenat E, et al. Efficacy and safety of selective internal
radiotherapy with yttrium-90 resin microspheres compared with sorafenib in locallyadvanced and inoperable hepatocellular carcinoma (SARAH): an open-label
randomised controlled phase 3 trial. Lancet Oncol 2017;18:1624-1636.
20 Chow PKH, Gandhi M, Tan SB, et al. SIRveNIB: Selective Internal Radiation
Therapy Versus Sorafenib in Asia-Pacific Patients With Hepatocellular Carcinoma.
J Clin Oncol 2018;36:1913-1921.
21 Ricke J, Klümpen HJ, Amthauer H, et al. Impact of combined selective internalradiation therapy and sorafenib on survival in advanced hepatocellular carcinoma.
J Hepatol 2019;71:1164-1174.

Note: All recommendations are category 2A unless otherwise indicated.
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.
Version 1.2022, 03/29/22 © 2022 National Comprehensive Cancer Network (NCCN ), All rights reserved. NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
®

®

®

HCC-E
2 OF 2

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatocellular Carcinoma

NCCN Guidelines Index
Table of Contents
Discussion

PRINCIPLES OF RADIATION THERAPY
External Beam Radiation Therapy:• Treatment Modalities:1
EBRT is a treatment option for patients with unresectable disease, or for those who are medically inoperable due to comorbidity.
All tumors irrespective of the location may be amenable to radiation therapy (RT) (3D conformal RT (3D-CRT), intensity-modulated RT[IMRT], or stereotactic body RT [SBRT]). Image-guided RT (IGRT) is strongly recommended when using EBRT, IMRT, and SBRT to improvetreatment accuracy and reduce treatment-related toxicity.
Hypofractionation with photons2 or protons2,3 is an acceptable option for intrahepatic tumors, although treatment at centers withexperience is recommended.
SBRT is an advanced technique of hypofractionated EBRT with photons that delivers large ablative doses of radiation.
There is growing evidence for the usefulness of SBRT in the management of patients with HCC.4,5 SBRT can be considered as analternative to ablation/embolization techniques or when these therapies have failed or are contraindicated.
SBRT (typically 3–5 fractions) is often used for patients with 1 to 3 tumors. SBRT could be considered for larger lesions or more extensive
disease, if there is sufficient uninvolved liver and liver radiation tolerance can be respected. There should be no extrahepatic disease or it
should be minimal and addressed in a comprehensive management plan. The majority of data on radiation for HCC liver tumors arises frompatients with Child-Pugh A liver disease; safety data are limited for patients with Child-Pugh B or poorer liver function. Those with ChildPugh B cirrhosis can be safely treated, but they may require dose modifications and strict dose constraint adherence.6 The safety of liverradiation for HCC in patients with Child-Pugh C cirrhosis has not been established, as there are not likely to be clinical trials available forthese patients.7,8
Proton beam therapy (PBT) may be appropriate in specific situations.9,10
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.11• RT dosing,1 depending on the ability to meet normal organ constraints and underlying liver function:
EBRT: SBRT or hypofractionation preferred◊ SBRT: 30–50 Gy (typically in 3–5 fractions)12◊ Hypofractionation2– 37.5–72 Gy in 10–15 fractions◊ Conventional fractionation:13,14– 50–66 Gy in 25–33 fractions

Note: All recommendations are category 2A unless otherwise indicated.
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.
Version 1.2022, 03/29/22 © 2022 National Comprehensive Cancer Network (NCCN ), All rights reserved. NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
®

®

®

See next page for
References
HCC-F
1 OF 2

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatocellular Carcinoma

NCCN Guidelines Index
Table of Contents
Discussion

PRINCIPLES OF RADIATION THERAPYREFERENCES
1 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.

2 Hong TS, Wo JY, Yeap BY, et al. Multi-institutional phase II study of high-dose hypofractionated proton beam therapy in patients with localized, unresectable

hepatocellular carcinoma and intrahepatic cholangiocarcinoma. J Clin Oncol 2016;34:460-468.

3 Bush DA, Smith JC, Slater JD, et al. Randomized clinical trial comparing proton beam radiation therapy with transarterial chemoembolization for hepatocellular

carcinoma: results of an interim analysis. Int J Radiat Oncol Biol Phys 2016;95:477-482.

4 Hoffe SE, Finkelstein SE, Russell MS, Shridhar R. Nonsurgical options for hepatocellular carcinoma: evolving role of external beam radiotherapy. Cancer Control

2010;17:100-110.

5 Wahl DR, Stenmark MH, Tao Y, et al. Outcomes after stereotactic body radiotherapy or radiofrequency ablation for hepatocellular carcinoma. J Clin Oncol

2016;34:452-459.

6 Cardenes HR, Price TR, Perkins SM, et al. Phase I feasibility trial of stereotactic body radiation therapy for primary hepatocellular carcinoma. Clin Transl Oncol

2010;12:218-225.

7 Andolino DL, Johnson CS, Maluccio M, et al. Stereotactic body radiotherapy for primary hepatocellular carcinoma. Int J Radiat Oncol Biol Phys 2011;81:e447-453.
8 Bujold A, Massey CA, Kim JJ, et al. Sequential phase I and II trials of stereotactic body radiotherapy for locally advanced hepatocellular carcinoma. J Clin Oncol

2013;31:1631-1639.

9 Proton Beam Therapy. American Society for Radiation Oncology, 2014. Available at: http://www.astro.org/uploadedFiles/Main_Site/Practice_Management/

Reimbursement/ASTRO%20PBT%20Model%20Policy%20FINAL.pdf. Accessed 11/26/18.

10 Qi W, Fu S, Zhang Q, et al. Charged particle therapy versus photon therapy for patients with hepatocellular carcinoma: A systematic review and meta-analysis.

Radiother Oncol 2015;114:289-295.

11 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.
12 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.
13 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.

14 Ben-Josef E, Lawrence TS. Radiotherapy for unresectable hepatic malignancies. Semin Radiat Oncol 2005;15:273-278.

Note: All recommendations are category 2A unless otherwise indicated.
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.
Version 1.2022, 03/29/22 © 2022 National Comprehensive Cancer Network (NCCN ), All rights reserved. NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
®

®

®

HCC-F
2 OF 2

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatocellular Carcinoma

NCCN Guidelines Index
Table of Contents
Discussion

PRINCIPLES OF SYSTEMIC THERAPYFirst-Line Systemic Therapy
Preferred Regimens

Other Recommended Regimens Useful in Certain Circumstances• Atezolizumab + bevacizumab (Child-Pugh Class A only)(category 1)a,b,c,1

Subsequent-Line Therapyf if Disease Progressiong• Sorafenib• Nivolumabb,8 (if ineligible for tyrosine kinase inhibitors(Child-Pugh Class A)[TKIs] or other anti-angiogenic agents)([category 1] or B7)d,e,2,3(Child-Pugh Class A or B) (category 2B)• Lenvatinib(Child-Pugh Class A only)4,5(category 1)• Durvalumab6• Pembrolizumab7 (category 2B)

Options

Other Recommended Regimens

Useful in Certain Circumstances• Regorafenib (Child-Pugh Class A only) (category 1)h,9• Cabozantinib (Child-Pugh Class A only) (category 1)i,10• Ramucirumab (AFP ≥400 ng/mL and Child-PughClass A only) (category 1)i,11• Lenvatinib (Child-Pugh Class A only)• Sorafenib (Child-Pugh Class A or B7)d,e• Nivolumab + ipilimumab(Child-Pugh Class A only)b,i,12• Pembrolizumab(Child-Pugh Class A only)(category 2B)b,j,k,13-15• Nivolumab(Child-Pugh Class B only)b,j,16-19 (category 2B)• Dostarlimab-gxlyb,j,l,20,21 for MSI-H/dMMR tumors(category 2B)

f Larotrectinib and entrectinib are treatment options for patients with hepatocellular

carcinoma that is NTRK gene fusion positive. (Drilon A, et al. N Engl J Med
2018;378:731-739; Doebele RC, et al. Lancet Oncol 2020;21:271-282.)
a An FDA-approved biosimilar is an appropriate substitute for bevacizumab.
g There are no comparative data to define optimal treatment after first-line systemicb See NCCN Guidelines for Management of Immunotherapy-Related Toxicities.
therapy.
c Patients on atezolizumab + bevacizumab should have adequate endoscopich The data reflect use on or after sorafenib in patients who previously tolerated
evaluation and management for esophageal varices within approximately 6
sorafenib at a dose of at least 400 mg per day.
i The data reflect use on or after sorafenib.
months prior to treatment or according to institutional practice and based on the
j For patients who have not been previously treated with a checkpoint inhibitor
assessment of bleeding risk.
d See Child-Pugh Score (HCC-C) and assessment of portal hypertension (eg,because there is a lack of data for subsequent use of immunotherapy in patientsvarices, splenomegaly, thrombocytopenia).
who have previously been treated with a checkpoint inhibitor.
e Caution: There are limited safety data available for patients with Child-Pughk Pembrolizumab is a recommended treatment option for patients with or without
Class B or C liver function and dosing is uncertain. Use with extreme caution in
MSI-H HCC.
patients with elevated bilirubin levels. (Miller AA, et al. J Clin Oncol 2009;27:1800- l Dostarlimab-gxly is a recommended treatment option for patients with MSI-H/
1805). The impact of sorafenib on patients potentially eligible for transplant isdMMR recurrent or advanced tumors that have progressed on or following priorunknown.
treatment and who have no satisfactory alternative treatment options.
Note: All recommendations are category 2A unless otherwise indicated.
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.
Version 1.2022, 03/29/22 © 2022 National Comprehensive Cancer Network (NCCN ), All rights reserved. NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
®

®

®

HCC-G
1 OF 2

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatocellular Carcinoma

NCCN Guidelines Index
Table of Contents
Discussion

PRINCIPLES OF SYSTEMIC THERAPYREFERENCES

1 Finn RS, Qin S, Ikeda M, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med 2020;382:1894-1905.
2 Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008;359:378-390.
3 Cheng AL, Kang YK, Chen Z, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind,placebo-controlled trial. Lancet Oncol 2009;10:25-34.
4 Kudo M, Finn RS, Qin S, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet
2018;391:1163-1173.
5 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 inunresectable hepatocellular carcinoma. Liver Cancer 2020;9:93-104.
6 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) withunresectable hepatocellular carcinoma (uHCC): HIMALAYA [abstract]. J Clin Oncol 2022;40:Abstract 379.
7 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.
8 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.
9 Bruix J, Qin S, Merle P, et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomized, double-blind, placebocontrolled, phase 3 trial. Lancet 2017;389:56-66.
10 Abou-Alfa GK, Meyer T, Cheng AL, et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N Engl J Med 2018;379:54-63.
11 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.
12 Yau T, Kang YK, Kim TY, et al. Efficacy and safety of nivolumab plus ipilimumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib: The CheckMate
040 randomized clinical trial. JAMA Oncol 2020;6:e204564.
13 Zhu AX, Finn RS, Edeline J, et al. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-labelphase 2 trial. Lancet Oncol 2018;19:940-952.
14 Finn RS, Ryoo BY, 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.
15 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): Phase 3 KEYNOTE-394 study [abstract]. J Clin Oncol 2022;40:Abstract 383.
16 El-Khoueiry AB, Sangro B, Yau T, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalationand expansion trial. Lancet 2017;389:2492-2502.
17 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;75:600-609.
18 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.
19 Kambhampati S, Bauer KE, Bracci PM, et al. Nivolumab in patients with advanced hepatocellular carcinoma and Child-Pugh class B cirrhosis: safety and clinical outcomes in a
retrospective case series. Cancer 2019;125:3234-3241.
20 Andre T, Berton D, Curigliano G, et al. Safety and efficacy of anti–PD-1 antibody dostarlimab in patients (pts) with mismatch repair-deficient (dMMR) solid cancers: Results fromGARNET study [abstract]. J Clin Oncol 2021;39:Abstract 9.
21 Berton D, Banerjee SN, Curigliano G, et al. Antitumor activity of dostarlimab in patients with mismatch repair-deficient/microsatellite instability-high tumors: A combined analysis of twocohorts in the GARNET study [abstract]. J Clin Oncol 2021;39:Abstract 2564.

Note: All recommendations are category 2A unless otherwise indicated.
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.
Version 1.2022, 03/29/22 © 2022 National Comprehensive Cancer Network (NCCN ), All rights reserved. NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
®

®

®

HCC-G
2 OF 2

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Biliary Tract Cancers: Gallbladder Cancer
PRIMARY TREATMENTPRESENTATION

Resectabled,eHepatobiliary
surgery
expertiseavailableb• Intraoperative
staging ±biopsyc,dIncidental
finding of
suspicious
mass during
surgery
Hepatobiliary
surgery
expertise
unavailableb

See
GALL-2Cholecystectomyd + en
bloc hepatic resection+ lymphadenectomy± bile duct excision for
malignant involvement

Unresectable
Biopsy,c if notpreviously performed• Microsatellite
instability (MSI)/
mismatch repair(MMR) testingf• Tumor mutationalburden (TMB) testing• Additional molecular
testingg

NCCN Guidelines Index
Table of Contents
Discussion
POSTOPERATIVEWORKUPa• Multiphasic
abdominal/pelvic
CT/MRI with IVcontrast• Chest CT ±contrast• Consider CEA
and CA 19-9

Options:h• Systemic therapyi(preferred)• Clinical trial(preferred)• Palliative RTj• Best supportive
carek

See Adjuvant
Treatment
andSurveillance(GALL-6)

Progression
on or after
systemictherapyia See Principles of Imaging (BIL-A).
b If expertise unavailable or resectability unclear, visually inspect the abdomen, document all findings, and refer to surgeon with hepatobiliary expertise and/or proceedwith staging.

c The optimal diagnostic method is core needle biopsy.
d See Principles of Surgery and Pathology (GALL-A).
e For locoregionally advanced disease, consider neoadjuvant chemotherapy to rule out rapid progression and avoid futile surgery. There are limited clinical trial data todefine a standard regimen or definitive benefit. See Principles of Systemic Therapy (BIL-C).

f For patients with MMR deficient (dMMR)/MSI-high (MSI-H) tumors or a family history suggestive of BRCA1/2 mutations, consider germline testing and/or referral to a

genetic counselor.

g Testing may include NTRK gene fusion testingh Order does not indicate preference. The choice of treatment modality may depend on extent/location of disease and institutional capabilities.
i See Principles of Systemic Therapy (BIL-C).
j See Principles of Radiation Therapy (BIL-B).
k See NCCN Guidelines for Palliative Care.
Note: All recommendations are category 2A unless otherwise indicated.
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.
Version 1.2022, 03/29/22 © 2022 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

Other Clinical
Presentations
See GALL-3
and GALL-4
GALL-1

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Biliary Tract Cancers: Gallbladder Cancer

NCCN Guidelines Index
Table of Contents
Discussion

PRESENTATIONPOSTOPERATIVEWORKUPaPRIMARY TREATMENT

Cholecystectomyd + en
bloc hepatic resection+ lymphadenectomy± bile duct excision for
malignant involvement

See Adjuvant
Treatment
andSurveillance(GALL-6)

Hepatobiliary
surgery
expertise
unavailableb• H&P• Multiphasic
abdominal/pelvic
CT/MRI with IVcontrasta• Chest CT ±contrast• Liver function
tests (LFTs)• Surgicalconsultation• Assessment of
hepatic reserve• Consider CEA
and CA 19-9

Options:h• Systemic therapyi(preferred)• Clinical trial(preferred)• Palliative RTj• Best supportive
carek

Progression
on or after
systemictherapyi

Intraoperative
staging ±biopsycandEnd surgery
and refer tospecialistd

Resectabled,eUnresectable
Biopsy,c if notpreviously performed• MSI/MMR testingf• TMB testing• Additional
molecular testingga See Principles of Imaging (BIL-A).
b If expertise unavailable or resectability unclear, visually inspect the abdomen, document all findings, and refer to surgeon with hepatobiliary expertise and/or proceedwith staging.

c The optimal diagnostic method is core needle biopsy.
d See Principles of Surgery and Pathology (GALL-A).
e For locoregionally advanced disease, consider neoadjuvant chemotherapy to rule out rapid progression and avoid futile surgery. There are limited clinical trial data todefine a standard regimen or definitive benefit. See Principles of Systemic Therapy (BIL-C).

f For patients with dMMR/MSI-H tumors or a family history suggestive of BRCA1/2 mutations, consider germline testing and/or referral to a genetic counselor.
g Testing may include NTRK gene fusion testing.
h Order does not indicate preference. The choice of treatment modality may depend on extent/location of disease and institutional capabilities.
i See Principles of Systemic Therapy (BIL-C).
j See Principles of Radiation Therapy (BIL-B).
k See NCCN Guidelines for Palliative Care.
Note: All recommendations are category 2A unless otherwise indicated.
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.
Version 1.2022, 03/29/22 © 2022 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

GALL-2

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Biliary Tract Cancers: Gallbladder Cancer
PRESENTATIONPOSTOPERATIVEWORKUPlT1a (withnegative
margins)
Incidental
finding on
pathologic
reviewi

Cysticduct
node
positiveT1b orgreater
and/or
T1a with
positive
margins

NCCN Guidelines Index
Table of Contents
Discussion

PRIMARY TREATMENT

Observe

Multiphasic abdominal/pelvic
CT/MRI with IV contrast, chest
CT ± contrasta• Consider staging
laparoscopym• MSI/MMR testingMultiphasic abdominal/pelvic
CT/MRI with IV contrast, chest
CT ± contrasta• Consider staging
laparoscopym

Consider neoadjuvant
chemotherapye,iorClinical trial

Hepatic resectiond+ lymphadenectomy± bile duct excision for
malignant involvement

See Adjuvant
Treatment andSurveillance(GALL-6)

Resectabled,eUnresectable• MSI/MMR testingf• TMB testing• Additional
molecular testingg

Options:h• Systemic therapyi (preferred)• Clinical trial (preferred)• Palliative RTj• Best supportive carek

Progression
on or after
systemictherapyia See Principles of Imaging (BIL-A).
d See Principles of Surgery and Pathology (GALL-A).
e For locoregionally advanced disease, consider neoadjuvant chemotherapy to rule out rapid progression and avoid futile surgery. There are limited clinical trial data todefine a standard regimen or definitive benefit. See Principles of Systemic Therapy (BIL-C).

f For patients with dMMR/MSI-H tumors or a family history suggestive of BRCA1/2 mutations, consider germline testing and/or referral to a genetic counselor.
g Testing may include NTRK gene fusion testing.
h Order does not indicate preference. The choice of treatment modality may depend on extent/location of disease and institutional capabilities.
i See Principles of Systemic Therapy (BIL-C).
j See Principles of Radiation Therapy (BIL-B).
k See NCCN Guidelines for Palliative Care.
l Consider multidisciplinary review.
Other Clinicalm Butte JM, et al. HPB (Oxford) 2011;13:463-472.
Note: All recommendations are category 2A unless otherwise indicated.
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.
Version 1.2022, 03/29/22 © 2022 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

Presentations
See GALL-4
and GALL-5
GALL-3

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Biliary Tract Cancers: Gallbladder Cancer
PRESENTATION AND WORKUP

Mass onimaging• H&P• Multiphasic
abdominal/pelvic
CT/MRI with IV contrasta• Chest CT + contrasta• LFTs• Surgical consultation• Assessment of hepatic
reserve• Consider CEAn
• Consider CA 19-9n• Consider staging
laparoscopy

NCCN Guidelines Index
Table of Contents
Discussion

PRIMARY TREATMENT

Resectabled,eUnresectable

Biopsyc• MSI/MMR testingf• TMB testing• Additional
molecular testingg

Cholecystectomyd+ en bloc hepatic resection+ lymphadenectomy± bile duct excision for
malignant involvement

See Adjuvant
Treatment andSurveillance(GALL-6)

Options:h• Systemic therapyi (preferred)• Clinical trial (preferred)• Palliative RTj• Best supportive carek

Progression onor after systemic
therapyia See Principles of Imaging (BIL-A).
c The optimal diagnostic method is core needle biopsy.
d See Principles of Surgery and Pathology (GALL-A).
e For locoregionally advanced disease, consider neoadjuvant chemotherapy to rule out rapid progression and avoid futile surgery. There are limited clinical trial data todefine a standard regimen or definitive benefit. See Principles of Systemic Therapy (BIL-C).

f For patients with dMMR/MSI-H tumors or a family history suggestive of BRCA1/2 mutations, consider germline testing and/or referral to a genetic counselor.
g Testing may include NTRK gene fusion testing.
h Order does not indicate preference. The choice of treatment modality may depend on extent/location of disease and institutional capabilities.
i See Principles of Systemic Therapy (BIL-C).
j See Principles of Radiation Therapy (BIL-B).
k See NCCN Guidelines for Palliative Care.
n CEA and CA 19-9 are baseline tests and should not be done to confirm diagnosis.

Other Clinical Presentations
See GALL-1, GALL-3,
Note: All recommendations are category 2A unless otherwise indicated.
and GALL-5
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.

Version 1.2022, 03/29/22 © 2022 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

GALL-4

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Biliary Tract Cancers: Gallbladder Cancer
PRIMARY TREATMENTPRESENTATION AND WORKUP

Jaundice• H&P• LFTs• Chest CT ± contrasta
Resectabled• Multiphasic abdominal/
pelvic CT/MRI with IVcontrasta• Cholangiographyo• Surgical consultationp• Consider CEAn
• Consider CA 19-9n
Unresectable• Consider staging
laparoscopy• Biliary drainageq

Metastatic disease

NCCN Guidelines Index
Table of Contents
Discussion• Consider neoadjuvant
chemotherapy (category 2B)e,i• Clinical trial

Cholecystectomyd+ en bloc hepatic
resection+ lymphadenectomy+ bile duct excision

See Adjuvant
Treatment andSurveillance(GALL-6)

Biopsyc• MSI/MMR testingf• TMB testing• Additional
molecular testingg

Options:h• Systemic therapyi (preferred)• Clinical trial (preferred)• Palliative RTj• Best supportive carek

Progression onor after systemic
therapyi

Biopsyc• MSI/MMR testingf• TMB testing• Additional
molecular testingg

Options:h• Systemic therapyi (preferred)• Clinical trial (preferred)• Best supportive carek

Progression onor after systemic
therapyia See Principles of Imaging (BIL-A).
c The optimal diagnostic method is core needle biopsy.
d See Principles of Surgery and Pathology (GALL-A).
e For locoregionally advanced disease, consider neoadjuvant chemotherapy to rule out rapid progression and avoid futile surgery. There are limited clinical trial data todefine a standard regimen or definitive benefit. See Principles of Systemic Therapy (BIL-C).

f For patients with dMMR/MSI-H tumors or a family history suggestive of BRCA1/2 mutations, consider germline testing and/or referral to a genetic counselor.
g Testing may include NTRK gene fusion testing.
h Order does not indicate preference. The choice of treatment modality may depend on extent/location of disease and institutional capabilities.
i See Principles of Systemic Therapy (BIL-C).
j See Principles of Radiation Therapy (BIL-B).
k See NCCN Guidelines for Palliative Care.
n CEA and CA 19-9 are baseline tests and should not be done to confirm diagnosis.
o Magnetic resonance cholangiopancreatography (MRCP) is preferred. Endoscopic retrograde cholangiopancreatography/percutaneous transhepatic cholangiography(ERCP/PTC) are used more for therapeutic intervention.

p Consult with a multidisciplinary team.
q Consider biliary drainage for patients with jaundice prior to resection and systemic therapy. Consider baseline CA 19-9 after biliary decompression.
Note: All recommendations are category 2A unless otherwise indicated.
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.
Version 1.2022, 03/29/22 © 2022 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

Other Clinical
Presentations
See GALL-3
and GALL-4
GALL-5

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Biliary Tract Cancers: Gallbladder Cancer
TREATMENTs
Resected, negative margin(R0),
Negative regional nodes
orCarcinoma in situ at margin

Postresection
statusResected, positive margin (R1)ror
Positive regional nodes

Resected gross residual
disease (R2)r

Options:h• Systemic therapyi (preferred)• Clinical trial (preferred)• Observe• Fluoropyrimidine-based chemoradiationj,tOptions:h• Systemic therapyi (preferred)• Clinical trial (preferred)• Fluoropyrimidine-based chemoradiationj,t• Fluoropyrimidine- or gemcitabinebased chemotherapyu followed byfluoropyrimidine-based chemoradiationj• Fluoropyrimidine-based chemoradiationj,tfollowed by fluoropyrimidine- or
gemcitabine-based chemotherapyu

NCCN Guidelines Index
Table of Contents
Discussion
SURVEILLANCEv• Consider
imaging every
3–6 mo for 2 y,then every 6–12
mo for up to 5 y,aor as clinicallyindicatedw• Consider CEA
and CA 19-9
as clinicallyindicated

For relapse, seeWorkup of thefollowing initialclinicalpresentations:• Mass on imaging(See GALL-4)• Jaundice(See GALL-5)• Metastases(See GALL-5)

See unresectable disease (GALL-1)

a See Principles of Imaging (BIL-A).
h Order does not indicate preference. The choice of treatment modality may depend on extent/location of disease and institutional capabilities.
i See Principles of Systemic Therapy (BIL-C).
j See Principles of Radiation Therapy (BIL-B).
r Management of patients with R1 or R2 resections should be evaluated by a multidisciplinary team.
s Adjuvant chemotherapy or chemoradiation has been associated with survival benefit in patients with biliary tract cancer (BTC), especially in patients with lymph node-

positive disease (Horgan AM, et al. J Clin Oncol 2012;30:1934-1940).

t There are limited clinical trial data to define a standard regimen or definitive benefit. Clinical trial participation is encouraged. (Macdonald OK, et al. Surg Oncol Clin N

Am 2002;11:941-954).

u For a list of gemcitabine-based regimens and fluoropyrimidine-based regimens to be used before or after chemoradiation, see Adjuvant Chemotherapy (BIL-C, 1 of 3).
v There are no data to support a specific surveillance schedule or tests for monitoring. Physicians should discuss appropriate follow-up schedules/imaging with patients.
w Based on surveillance schedule used in the phase III BILCAP trial. Primrose JN, et al. Lancet Oncol 2019;20:663-673.
Note: All recommendations are category 2A unless otherwise indicated.
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.
Version 1.2022, 03/29/22 © 2022 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

GALL-6

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Biliary Tract Cancers: Gallbladder Cancer

NCCN Guidelines Index
Table of Contents
Discussion

PRINCIPLES OF SURGERY AND PATHOLOGY

Incidental Finding at Surgery:• If expertise is unavailable, document all relevant findings and refer the patient to a center with available expertise. If there is a suspicious
mass, a biopsy is not necessary as this can result in peritoneal dissemination.
• If expertise is available and there is convincing clinical evidence of cancer, a definitive resection can 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.
• 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 andevaluation has been performed. Document all findings and consider biopsya if chemotherapy is anticipated.
• The principles of resection are the same as below consisting of radical cholecystectomy including segments IV B and V andlymphadenectomy and extended hepatic or biliary resection as necessary to obtain a negative margin.
Incidental Finding on Pathologic Review:• Consider pathologic re-review by a hepatobiliary pathology expert and/or speak to surgeon to check for completeness of cholecystectomy,
signs of disseminated disease, location of tumor, and any other pertinent information. Review the pathology report for T stage, cystic duct
margin status, and other margins.
• Diagnostic laparoscopy can be performed but is of relatively low yield. Higher yields may be seen in patients with T3 or higher tumors,poorly differentiated tumors, or with a margin-positive cholecystectomy. Diagnostic laparoscopy should also be considered in patients withany suspicion of metastatic disease on imaging that is not amenable to percutaneous biopsy.1• Repeat cross-sectional imaging of the chest, abdomen, and pelvis should be performed prior to definitive resection.
• Initial exploration should rule out distant lymph node metastases in the celiac axis or aorto-caval groove as these contraindicate further
resection.
• Hepatic resection should be performed to obtain clear margins, which usually consists of segments IV B and V. Extended resections beyond
segments IV B and V may be needed in some patients to obtain negative margins.
• Lymphadenectomy should be performed to clear all lymph nodes in the porta hepatis.
• Resection of the bile duct may be needed to obtain negative margins. Routine resection of the bile duct for lymphadenectomy has beenshown to increase morbidity without convincing evidence for improved survival.2,3• Port site resection has not been shown to be effective, as the presence of a port site implant is a surrogate marker of underlying
disseminated disease and has not been shown to improve outcomes.4
Footnote
a The optimal diagnostic method is core needle biopsy.
References
1 Butte JM, Gonen M, Allen PJ, et al. The role of laparoscopic staging in patients with incidental gallbladder cancer. HPB (Oxford) 2011;13:463-472.
2 Fuks D, Regimbeau JM, Le Treut YP, et al. Incidental gallbladder cancer by the AFC-GBC-2009 Study Group. World J Surg 2011;35:1887-1897.
3 D'Angelica M, Dalal KM, Dematteo RP, et al. Analysis of extent of resection for adenocarcinoma of gallbladder. Ann Surg Oncol 2009;16:806-816.
4 Maker AV, Butte JM, Oxenberg J, et al. Is port site resection necessary in the surgical management of gallbladder cancer. Ann Surg Oncol 2012;19:409-417.
Note: All recommendations are category 2A unless otherwise indicated.
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.
Version 1.2022, 03/29/22 © 2022 National Comprehensive Cancer Network (NCCN ), All rights reserved. NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
®

®

®

GALL-A
1 OF 2

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Biliary Tract Cancers: Gallbladder Cancer

NCCN Guidelines Index
Table of Contents
Discussion

PRINCIPLES OF SURGERY AND PATHOLOGY
Mass on Imaging: Patients Presenting with Gallbladder Mass/Disease Suspicious for Gallbladder Cancer• Staging should be carried out with multiphasic cross-sectional imaging of the chest, abdomen, and pelvis.
• If there is a suspicious mass, a biopsy is not necessary and a definitive resection should be carried out.
• Diagnostic laparoscopy is recommended prior to definitive resection.
• In selected cases where the diagnosis is not clear it may be reasonable to perform a cholecystectomy (including intraoperative frozen
section) followed by the definitive resection during the same setting if pathology confirms cancer.
• The resection is carried out as per the principles described above.
Gallbladder Cancer and Jaundice• The presence of jaundice in gallbladder cancer usually portends a poor prognosis.5-7 These patients need careful surgical evaluation.
• Although a relative contraindication, in select patients curative intent resection can be attempted for resectable disease in centers withavailable expertise.

5 Hawkins WG, DeMatteo RP, Jarnagin WR, et al. Jaundice predicts advanced disease and early mortality in patients with gallbladder cancer. Ann Surg Oncol

2004;11:310-315.

6 Regimbeau JM, Fuks D, Bachellier P, et al. Prognostic value of jaundice in patients with gallbladder cancer by the AFC -GBC-2009 study group. Eur J Surg Oncol

2011;37:505-512.

7 Nishio H, Ebata T, Yokoyama Y, et al. Gallbladder cancer involving the extrahepatic bile duct is worthy of resection. Ann Surg 2011;253:953-960.
Note: All recommendations are category 2A unless otherwise indicated.
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.
Version 1.2022, 03/29/22 © 2022 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

GALL-A
2 OF 2

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Index
NCCN Guidelines Version 1.2022
Table of Contents
Discussion
Biliary Tract Cancers: Intrahepatic Cholangiocarcinoma
PRESENTATION

Isolated intrahepatic
massa (imaging
characteristics
consistent withmalignancy but
not consistent
with hepatocellular
carcinoma)(See NCCN
Guidelines for
Occult Primary)

WORKUP• H&P• Multiphasic abdominal/pelvic
CT/MRI with IV contrastb• Chest CT ± contrastb• Consider CEAc
• Consider CA 19-9c• LFTs• Surgical consultationd• Esophagogastroduodenoscopy(EGD) and colonoscopy• Consider viral hepatitis
serologiese• Consider biopsya,f• Consider AFP• Consider referral to ahepatologist

PRIMARY TREATMENT

Resectablea• Consider staging laparoscopyi• Resectiona and regional
lymphadenectomya

See Additional
Therapy and
Surveillance(INTRA-2)

Unresectable
Biopsy,f if notpreviously
performed• MSI/MMR testingg• TMB testing• Additional
molecular testingh

Options:j• Systemic therapyk• Clinical trial• EBRT with concurrent
fluoropyrimidinel,m• Consider locoregional therapyn,oEBRTmArterially directed therapiesn• Best supportive carep

Progression
on or after
systemictherapyk

Metastatic disease
Biopsy,f if notpreviously
performed• MSI/MMR testingg• TMB testing• Additional
molecular testingh

Options:j• Systemic therapyk (preferred)• Clinical trial (preferred)• Consider locoregional therapyn,oEBRTmArterially directed therapieso• Best supportive carep

Progression
on or after
systemictherapyk

a See Principles of Surgery (INTRA-A).
b See Principles of Imaging (BIL-A).
c CEA and CA 19-9 are baseline tests and should not be done to confirm diagnosis.
d Consult with multidisciplinary team.
e ASCO guidelines for management of viral HBV in cancer/chemo patients: https://www.asco.org/sites/new-www.asco.org/files/content-files/advocacy-and-policy/
documents/2020-HBV-PCO-Algorithm.pdf
f The optimal diagnostic method is core needle biopsy.
g For patients with dMMR/MSI-H tumors or a family history suggestive of BRCA1/2
mutations, consider germline testing and/or referral to a genetic counselor.
h Testing may include NTRK gene fusion testing.
i Laparoscopy may be done in conjunction with surgery if no distant metastases arefound.

j Order does not indicate preference. The choice of treatment modality may dependon extent/location of disease and institutional capabilities.

k See Principles of Systemic Therapy (BIL-C).
l There are limited clinical trial data to define a standard regimen or definitive

benefit. Participation in clinical trials is encouraged (Macdonald OK, et al. Surg
Oncol Clin N Am 2002;11:941-954).
m See Principles of Radiation Therapy (BIL-B).
n Intra-arterial chemotherapy (with or without systemic chemotherapy) may be used
in a clinical trial or at experienced centers in carefully selected cases.
o See Principles of Locoregional Therapy (HCC-E).
p See NCCN Guidelines for Palliative Care.

Note: All recommendations are category 2A unless otherwise indicated.
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.
Version 1.2022, 03/29/22 © 2022 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

INTRA-1

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Index
NCCN Guidelines Version 1.2022
Table of Contents
Discussion
Biliary Tract Cancers: Intrahepatic Cholangiocarcinoma
TREATMENTq

Post
resection
statusNo residual
local disease(R0 resection)

Options:j• Systemic therapyk (preferred)• Clinical trial (preferred)• Observe

Microscopic
margins (R1)orPositive
regional nodes

Options:j• Systemic therapyk (preferred)• Clinical trial (preferred)• Fluoropyrimidine-based chemoradiationl,m• Fluoropyrimidine-based or gemcitabine-based chemotherapyr
followed by fluoropyrimidine-based chemoradiationm• Fluoropyrimidine-based chemoradiationl,m followed byfluoropyrimidine-based or gemcitabine-based chemotherapyr

Residual
local diseased(R2 resection)

See unresectable disease (INTRA-1)

SURVEILLANCEs

Consider multiphasic
abdominal/pelvic CT/MRI
with IV contrastb and chest
CT + contrastb every 3–6 mo
for 2 y, then every 6–12 mofor up to 5 y, or as clinicallyindicatedtb See Principles of Imaging (BIL-A).
d Consult with multidisciplinary team.
j Order does not indicate preference. The choice of treatment modality may depend on extent/location of disease and institutional capabilities.
k See Principles of Systemic Therapy (BIL-C).
l There are limited clinical trial data to define a standard regimen or definitive benefit. Clinical trial participation is encouraged (Macdonald OK, et al. Surg Oncol Clin N

Am 2002;11:941-954).

m See Principles of Radiation Therapy (BIL-B).
q Adjuvant chemotherapy or chemoradiation has been associated with survival benefit in patients with BTC, especially in patients with lymph node-positive disease(Horgan AM, et al. J Clin Oncol 2012;30:1934-1940).

r For a list of gemcitabine-based regimens and fluoropyrimidine-based regimens to be used before or after chemoradiation, see Adjuvant Chemotherapy (BIL-C, 1 of 3).
s There are no data to support a specific surveillance schedule or tests for monitoring. Physicians should discuss appropriate follow-up schedules/imaging with patients.
t Based on surveillance schedule used in the phase III BILCAP trial. Primrose JN, et al. Lancet Oncol 2019;20:663-673.
Note: All recommendations are category 2A unless otherwise indicated.
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.
Version 1.2022, 03/29/22 © 2022 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

INTRA-2

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Index
NCCN Guidelines Version 1.2022
Table of Contents
Discussion
Biliary Tract Cancers: Intrahepatic Cholangiocarcinoma
PRINCIPLES OF SURGERY1,2
General Principles• A preoperative biopsy is not always necessary before proceeding with a definitive, potentially curative resection. A suspicious mass on
imaging in the proper clinical setting should be treated as malignant.
• Diagnostic laparoscopy to rule out unresectable disseminated disease should be considered.
• Initial exploration should assess for multifocal hepatic disease, lymph node metastases, and distant metastases. Lymph node metastases
beyond the porta hepatis and distant metastatic disease contraindicate resection.
• Hepatic resection with negative margins is the goal of surgical therapy. While major resections are often necessary, wedge resections andsegmental resections are all appropriate given that a negative margin can be achieved.
• A regional lymphadenectomy of the porta hepatis is carried out.
• Multifocal liver disease is generally representative of metastatic disease and is a contraindication to resection. In highly selected cases withlimited multifocal disease resection can be considered.
• Gross lymph node metastases to the porta hepatis portend a poor prognosis and resection should only be considered in highly selectedcases.

1 Endo I, Gonen M, Yopp A. Intrahepatic cholangiocarcinoma: Rising frequency, improved survival and determinants of outcome after resection. Ann Surg 2008;248:84-96.
2 de Jong MC, Nathan H, Sotiropoulos GC. Intrahepatic cholangiocarcinoma: an international multi-institutional analysis of prognostic factors and lymph node assessment.

J Clin Oncol 2011;29:3140-3145.

Note: All recommendations are category 2A unless otherwise indicated.
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.
Version 1.2022, 03/29/22 © 2022 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

INTRA-APrinted by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Index
NCCN Guidelines Version 1.2022
Table of Contents
Discussion
Biliary Tract Cancers: Extrahepatic Cholangiocarcinoma
PRIMARY TREATMENTPRESENTATION AND WORKUP• Surgical explorationg• Pain• Jaundice• Abnormal
LFTs• Obstruction
or
abnormality
on imaging• H&P• Multiphasic abdominal/
pelvic CT/MRI (assess
for vascular invasion)
with IV contrasta• Chest CT ± contrasta• Cholangiographyb• Consider CEAc
• Consider CA 19-9c• LFTs• Consider endoscopic
ultrasound (EUS) after
surgical consultation• Consider serum IgG4
to rule out autoimmune
cholangitisd

Resectablee• Consider laparoscopic staging• Consider preoperative biliary
drainage• Multidisciplinary review

Resectablee

Resectione

Unresectable, see below

See Adjuvant
Treatment
andSurveillance(EXTRA-2)

Unresectablef• Biliary drainage,h if indicated• Biopsyf,i (only after
determining transplant status)
MSI/MMR testingj
TMB testingAdditional molecular testingk• Consider referral to transplant
centerOptions:l• Systemic therapym• Clinical trial• EBRT with concurrent
fluoropyrimidinen,o• Palliative EBRTo• Best supportive carep

Progression
on or after
systemictherapym

Metastatic
disease• Biliary drainage,h if indicated• Biopsyi
MSI/MMR testingj
TMB testingAdditional molecular testingk

Options:l• Systemic therapym• Clinical trial• Best supportive carep

Progression
on or after
systemictherapyma See Principles of Imaging (BIL-A).
b MRCP is preferred. ERCP/PTC are used more for therapeutic intervention.
c CEA and CA 19-9 are baseline tests and should not be done to confirm diagnosis.
d Patients with IgG-4–related cholangiopathy should be referred to an expert

center.

e See Principles of Surgery (EXTRA-A).
f Before biopsy, evaluate if patient is a resection or transplant candidate. If patientis a potential transplant candidate, consider referral to transplant center before
biopsy. Unresectable perihilar or hilar CCAs that measure ≤3 cm in radial
diameter, with the absence of intrahepatic or extrahepatic metastases andwithout nodal disease, as well as those with primary sclerosing cholangitis, may
be considered for liver transplantation at a transplant center that has an UNOSapproved protocol for transplantation of CCA.
g Surgery may be performed when index of suspicion is high; biopsy is not
required.

h Consider biliary drainage for patients with jaundice prior to instituting systemic

therapy. Consider baseline CA 19-9 after biliary decompression.

i The optimal diagnostic method is core needle biopsy.
j For patients with dMMR/MSI-H tumors or a family history suggestive of BRCA1/2

mutations, consider germline testing and/or referral to a genetic counselor.

k Testing may include NTRK gene fusion testing.
l Order does not indicate preference. The choice of treatment modality may dependon extent/location of disease and institutional capabilities.

m See Principles of Systemic Therapy (BIL-C).
n There are limited clinical trial data to define a standard regimen or definitive

benefit. Clinical trial participation is encouraged (Macdonald OK, et al. Surg Oncol
Clin N Am 2002;11:941-954).
o See Principles of Radiation Therapy (BIL-B).
p See NCCN Guidelines for Palliative Care.

Note: All recommendations are category 2A unless otherwise indicated.
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.
Version 1.2022, 03/29/22 © 2022 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

EXTRA-1

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Index
NCCN Guidelines Version 1.2022
Table of Contents
Discussion
Biliary Tract Cancers: Extrahepatic Cholangiocarcinoma

Resected, negative margin (R0),
Negative regional nodes
orCarcinoma in situ at margin

Post
resection
statusResected, positive margin (R1)qor
Positive regional nodes

Resected gross residual disease (R2)q

TREATMENTr

SURVEILLANCEt

Options:l• Systemic therapym (preferred)• Clinical trial (preferred)• Fluoropyrimidine chemoradiationn,o• Observe
Options:l• Systemic therapym (preferred)• Clinical trial (preferred)• Fluoropyrimidine-based chemoradiationn,o• Fluoropyrimidine-based or gemcitabinebased chemotherapys followed byfluoropyrimidine-based chemoradiationo• Fluoropyrimidine-based chemoradiationn,ofollowed by fluoropyrimidine-based or
gemcitabine-based chemotherapys

Consider imaging every
3–6 mo for 2 y, then every
6–12 mo for up to 5 y,a or
as clinically indicatedu

See unresectable disease (EXTRA-1)

a See Principles of Imaging (BIL-A).
l Order does not indicate preference. The choice of treatment modality may depend on extent/location of disease and institutional capabilities.
m See Principles of Systemic Therapy (BIL-C).
n There are limited clinical trial data to define a standard regimen or definitive benefit. Clinical trial participation is encouraged (Macdonald OK, et al. Surg Oncol Clin N

Am 2002;11:941-954).

o See Principles of Radiation Therapy (BIL-B).
q Management of patients with R1 or R2 resections should be evaluated by a multidisciplinary team.
r Adjuvant chemotherapy or chemoradiation has been associated with survival benefit in patients with BTC, especially in patients with lymph node-positive disease(Horgan AM, et al. J Clin Oncol 2012;30:1934-1940).

s For a list of gemcitabine-based regimens and fluoropyrimidine-based regimens to be used before or after chemoradiation, see Adjuvant Chemotherapy (BIL-C, 1 of 3).
t There are no data to support a specific surveillance schedule or tests for monitoring. Physicians should discuss appropriate follow-up schedules/imaging with patients.
u Based on surveillance schedule used in the phase III BILCAP trial. Primrose JN, et al. Lancet Oncol 2019;20:663-673.
Note: All recommendations are category 2A unless otherwise indicated.
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.
Version 1.2022, 03/29/22 © 2022 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

EXTRA-2

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Index
NCCN Guidelines Version 1.2022
Table of Contents
Discussion
Biliary Tract Cancers: Extrahepatic Cholangiocarcinoma
PRINCIPLES OF SURGERY
General Principles• The basic principle is a complete resection with negative margins and regional lymphadenectomy. This generally requires apancreaticoduodenectomy for distal bile duct tumors and a major hepatic resection for hilar tumors. Rarely, a mid bile duct tumor can be resectedwith a bile duct resection and regional lymphadenectomy.
• A preoperative biopsy is not always necessary before proceeding with a definitive, potentially curative resection. A suspicious mass on imaging in
the proper clinical setting should be treated as malignant.
• Diagnostic laparoscopy should be considered.
• Occasionally a bile duct tumor will involve the biliary tree over a long distance such that a hepatic resection and pancreaticoduodenectomy will
be necessary. These are relatively morbid procedures and should only be carried out in very healthy patients without significant comorbidity.
Nonetheless, these can be potentially curative procedures and should be considered in the proper clinical setting. Combined liver and pancreaticresections performed to clear distant nodal disease are not recommended.
Hilar Cholangiocarcinoma• Detailed descriptions of imaging assessment of resectability are beyond the scope of this outline. The basic principle is that the tumor will need
to be resected along with the involved biliary tree and the involved hemi-liver with a reasonable chance of a margin-negative resection. The
contralateral liver requires intact arterial and portal inflow as well as biliary drainage.1-3• Detailed descriptions of preoperative surgical planning are beyond the scope of this outline but require an assessment of the FLR. This requires anassessment of biliary drainage and volumetrics of the FLR. While not necessary in all cases, the use of preoperative biliary drainage of the FLR andcontralateral portal vein embolization should be considered in cases of a small FLR.4,5• Initial exploration rules out distant metastatic disease to the liver, peritoneum, or distant lymph nodes beyond the porta hepatis as these findings
contraindicate resection. Further exploration must confirm local resectability.
• Since hilar tumors, by definition, abut or invade the central portion of the liver they require major hepatic resections on the involved side toencompass the biliary confluence and generally require a caudate resection.
• Resection and reconstruction of the portal vein and/or hepatic artery may be necessary for complete resection and require expertise in theseprocedures.
• Biliary reconstruction is generally through a Roux-en-Y hepaticojejunostomy.
• A regional lymphadenectomy of the porta hepatis is carried out.
• Frozen section assessment of proximal and distal bile duct margins is recommended if further resection can be carried out.
Distal Cholangiocarcinoma• Initial assessment is needed to rule out distant metastatic disease and local resectability.
• The operation generally requires a pancreaticoduodenectomy with typical reconstruction.
1 Nishio H, Nagino M, Nimura Y. Surgical management of hilar cholangiocarcinoma: the Nagoya experience. HPB (Oxford) 2005;7:259-262.
2 Matsuo K, Rocha FG, Ito K, et al. The Blumgart preoperative staging system for hilar cholangiocarcinoma: analysis of resectability and outcomes in 380 patients. J Am
Coll Surg 2012;215:343-355.
3 Jarnagin WR, Fong Y, DeMatteo RP, et al. Staging, resectability, and outcome in 225 patients with hilar cholangiocarcinoma. Ann Surg 2001;234:507-517.
4 Nimura Y. Preoperative biliary drainage before resection for cholangiocarcinoma. HPB (Oxford) 2008;10:130-133.
5 Kennedy TJ, Yopp A, Qin Y, et al. Role of preoperative biliary drainage of live remnant prior to extended liver resection for hilar cholangiocarcinoma. HPB (Oxford)
2009;11:445-451.
Note: All recommendations are category 2A unless otherwise indicated.
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.
Version 1.2022, 03/29/22 © 2022 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

EXTRA-APrinted by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Biliary Tract Cancers

NCCN Guidelines Index
Table of Contents
Discussion

PRINCIPLES OF IMAGING1-4
General Principles• CT of the chest with or without contrast and multiphasic contrast-enhanced CT or MRI of the abdomen and pelvis are recommended forfollow-up imaging.
• PET/CT has limited sensitivity but high specificity and may be considered when there is an equivocal finding.5 The routine use of PET/CT in
the preoperative setting has not been established in prospective trials.
Gallbladder Cancer• Detection of early-stage gallbladder cancer remains difficult, and is commonly discovered incidentally at surgery or pathologic examinationof the gallbladder.
• If gallbladder cancer is suspected preoperatively, multidetector multiphase CT of the abdomen (and pelvis) or contrast-enhanced MRI withmagnetic 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.
• Because lymphatic spread is common, careful attention should be made to evaluate nodal disease, specifically the porta hepatis and left
gastric and aorto-caval basins.
Intrahepatic6 and Extrahepatic Cholangiocarcinoma• Surgical management is based on the location and extent of the tumor.
• Preoperative imaging for accurate staging of extrahepatic CCA should be done with multidetector multiphasic abdominal/pelvic CT or MRI.
Contrast-enhanced MRI with MRCP is preferred for evaluating the extent of biliary tract involvement. Imaging with multiphasic CT or MRI withthin cuts, or multiphase CT or MRI of the liver and biliary tree should specifically address the anatomy of the biliary tree, hepatic arteries, andportal veins and their relationship to the tumor.7• Chest CT with or without contrast is recommended for staging.
• Imaging for staging ideally should be performed prior to biopsy or biliary drainage.
• EUS or endoscopic retrograde cholangiopancreatography (ERCP) may be helpful in the setting of bile duct dilation if no mass is seen on CT
or MRI. EUS or ERCP can also be used to establish tissue diagnosis and provide access to relieve biliary obstruction.
• CT of the chest with or without contrast and CT or MRI of the abdomen and pelvis with contrast may be used for follow-up.
• Delayed phase imaging is preferred when the diagnosis of iCCA is suspected or confirmed.
1 Srinivasa S, McEntee B, Koea JB. The role of PET scans in the management ofcholangiocarcinoma and gallbladder cancer: a systematic review for surgeons. Int J
Diagnostic Imaging 2015;2.
2 Corvera CU, Blumgart LH, Akhurst T, et al. 18F-fluorodeoxyglucose positron emission
tomography influences management decisions in patients with biliary cancer. J Am Coll
Surg 2008;206:57-65.
3 Brandi G, Venturi M, Pantaleo MA, Ercolani G, GICO. Cholangiocarcinoma: Current
opinion on clinical practice diagnostic and therapeutic algorithms: A review of the literature
and a long-standing experience of a referral center. Dig Liver Dis 2016;48:231-241.
4 Navaneethan U, Njei B, Venkatesh PG, et al. Endoscopic ultrasound in the diagnosis ofcholangiocarcinoma as the etiology of biliary strictures: a systematic review and metaanalysis. Gastroenterol Rep (Oxf) 2015;3:209-215.

5 Lamarca A, Barriuso J, Chander A, et al. 18F-fluorodeoxyglucose positron emission

tomography (18FDG-PET) for patients with biliary tract cancer: Systematic review andmeta-analysis. J Hepatol 2019;71:115-129.
6 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.
7 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.

Note: All recommendations are category 2A unless otherwise indicated.
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.
Version 1.2022, 03/29/22 © 2022 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

BIL-A

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Biliary Tract Cancers

NCCN Guidelines Index
Table of Contents
Discussion

PRINCIPLES OF RADIATION THERAPY
General Principles• IGRT is strongly recommended when using EBRT, IMRT, and SBRT to improve treatment accuracy and reduce treatment-related toxicity.
• Adjuvant EBRT1,2
Postoperative EBRT using conventional 3D-CRT or IMRT is an option for resected extrahepatic CCA and gallbladder cancer.3,4 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.
• Unresectable
All tumors irrespective of the location may be amenable to EBRT (3D-CRT, IMRT, or SBRT).
Conventionally fractionated radiotherapy with concurrent fluoropyrimidine-based chemotherapya to standard or high dose is acceptablefor intrahepatic and extrahepatic tumors.
Hypofractionation with photons5 or protons6 is an acceptable option for intrahepatic tumors, although treatment at centers with experience
is recommended.
Palliative EBRT is appropriate for symptom control and/or prevention of complications from metastatic lesions, such as bone or brain.
• RT dosing7, depending on the ability to meet normal organ constraints and underlying liver function:
Conventional fractionation (postoperative or unresectable):3◊ Initial volumes to 45 Gy in 1.8 Gy per fraction◊ Boost to 50 to 60 Gy in 1.8–2 Gy per fractionHypofractionation (unresectable): 58–67.5 Gy in 15 fractions for a median biologic equivalent dose of 80.5 Gy.5,6
SBRT (unresectable):◊ 30–50 Gy (typically in 3–5 fractions)
Footnotea See Principles of Systemic Therapy (BIL-C).
References
1 Mallick S, Benson R, Haresh KP, et al. Adjuvant radiotherapy in the treatment of gallbladder carcinoma: What is the current evidence? J Egypt Natl Canc Inst 2016;28:1-6.
2 Kim Y, Amini N, Wilson A, et al. Impact of chemotherapy and external-beam radiation therapy on outcomes among patients with resected gallbladder cancer: A multiinstitutional analysis. Ann Surg Oncol 2016;23:2998-3008.
3 Ben-Josef E, Guthrie KA, El-Khoueiry AB, et al. SWOG S0809: A phase II intergroup trial of adjuvant capecitabine and gemcitabine followed by radiotherapy andconcurrent capecitabine in extrahepatic cholangiocarcinoma and gallbladder carcinoma. J Clin Oncol 2015;33:2617-2622.
4 Wang SJ, Lemieux A, Kalpathy-Cramer J, et al. Nomogram for predicting the benefit of adjuvant chemoradiotherapy for resected gallbladder cancer. J Clin Oncol
2011;29:4627-4632.
5 Tao R, Krishnan S, Bhosale PR, et al. Ablative radiotherapy doses lead to a substantial prolongation of survival in patients with inoperable intrahepaticcholangiocarcinoma: a retrospective dose response analysis. J Clin Oncol 2016;34:219-226.
6 Hong TS, Wo JY, Yeap BY, et al. Multi-institutional phase II study of high-dose hypofractionated proton beam therapy in patients with localized, unresectable
hepatocellular carcinoma and intrahepatic cholangiocarcinoma. J Clin Oncol 2016;34:460-468.
7 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.
Note: All recommendations are category 2A unless otherwise indicated.
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.
Version 1.2022, 03/29/22 © 2022 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

BIL-B

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Biliary Tract Cancers

NCCN Guidelines Index
Table of Contents
Discussion

PRINCIPLES OF SYSTEMIC THERAPY
Neoadjuvant Therapya
Preferred Regimens

Other Recommended Regimens

Useful in Certain Circumstances• None• 5-fluorouracil + oxaliplatin• Capecitabine + oxaliplatin• Gemcitabine + capecitabine• Gemcitabine + cisplatin• Gemcitabine + cisplatin + albumin-bound paclitaxel1 (category 2B)• Gemcitabine + oxaliplatin (category 2B)• Single agents:
5-fluorouracil
CapecitabineGemcitabine• NonePreferred Regimens

Other Recommended Regimens

Useful in Certain Circumstances• Capecitabine• 5-fluorouracil + oxaliplatin• Capecitabine + oxaliplatin• Gemcitabine + capecitabine• Gemcitabine + cisplatin• Capecitabine + cisplatin (category 3)• Single agents:
5-fluorouracil
Gemcitabine• NoneAdjuvant Therapyb,2c,3 (category 1)

Agents Used with Concurrent Radiation• 5-fluorouracil• Capecitabine
a 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.
b Adjuvant therapy up to 6 months. Adjuvant chemotherapy or chemoradiation has
been associated with survival benefit in patients with BTC, especially in patientswith lymph node-positive disease.

c The phase III BILCAP study shows improved overall survival for adjuvant

capecitabine in the per-protocol analysis, and the overall survival did not reachstatistical significance in the intent-to-treat analysis. Primrose JN, Fox RP, Palmer
DH, et al. Capecitabine compared with observation in resected biliary tract cancer(BILCAP): a randomised, controlled, multicentre, phase 3 study. Lancet Oncol
2019;20:663-673. Ben-Josef E, Guthrie KA, El-Khoueiry AB, et al. SWOG S0809:
A phase II intergroup trial of adjuvant capecitabine and gemcitabine followed byradiotherapy and concurrent capecitabine in extrahepatic cholangiocarcinoma
and gallbladder carcinoma. J Clin Oncol 2015;33:2617-2622.

Note: All recommendations are category 2A unless otherwise indicated.
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.
Version 1.2022, 03/29/22 © 2022 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

References
Continued
BIL-C
1 OF 4

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Biliary Tract Cancers

NCCN Guidelines Index
Table of Contents
Discussion

PRINCIPLES OF SYSTEMIC THERAPY
Primary Treatment for Unresectable and Metastatic Disease
Preferred Regimens

4 (category 1)• Gemcitabine + cisplatin

Other Recommended Regimens

Useful in Certain Circumstances• 5-fluorouracil + oxaliplatin• 5-fluorouracil + cisplatin (category 2B)• Capecitabine + cisplatin (category 2B)• Capecitabine + oxaliplatin• Gemcitabine + albumin-bound paclitaxel• Gemcitabine + capecitabine• Gemcitabine + oxaliplatin• Gemcitabine + cisplatin + albumin-bound paclitaxel1 (category 2B)• Durvalumab + gemcitabine + cisplatin (category 2B)d,5• Single agents:
5-fluorouracil
CapecitabineGemcitabine• For NTRK gene fusion-positive tumors:Entrectinib6-8
Larotrectinib9• For MSI-H/dMMR tumors:Pembrolizumabe,f,10,11• For RET fusion-positive tumors:Pralsetinib (category 2B)12Subsequent-Line Therapy for Biliary Tract Cancers if Disease Progressiong
Preferred Regimens• FOLFOX13

Other Recommended Regimens• FOLFIRI14 (category 2B)• Regorafenib15 (category 2B)• Liposomal irinotecan + fluorouracil + leucovorin(category 2B)16• Durvalumab + gemcitabine + cisplatin (category 2B)h,5• See also: Preferred and Other Recommended Regimens forUnresectable and Metastatic Disease above

d 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.

e There are limited clinical trial data to support pembrolizumab in this setting. Sicklick JK, Kato S, Okamura R, et al.

Molecular profiling of cancer patients enables personalized combination therapy: the I-PREDICT study. Nat Med
2019;25:744-750.
f See NCCN Guidelines for Management of Immunotherapy-Related Toxicities.
g Treatment selection depends on clinical factors including previous treatment regimen/agent and extent of liver
dysfunction.
h For patients who have not been previously treated with a checkpoint inhibitor because there is a lack of data forsubsequent use of immunotherapy in patients who have previously been treated with a checkpoint inhibitor.
i Dostarlimab-gxly is a recommended treatment option for patients with MSI-H/dMMR recurrent or advanced tumorsthat have progressed on or following prior treatment and who have no satisfactory alternative treatment options.

Useful in Certain Circumstances• For NTRK gene fusion-positive tumors:Entrectinib6-8
Larotrectinib9• For MSI-H/dMMR tumors:Pembrolizumabe,f,h,10,11
Dostarlimab-gxlyf,h,i,17,18 (category 2B)• For TMB-H tumors:Pembrolizumabe,f,h,19• For BRAF-V600E mutated tumorsDabrafenib + trametinib20,21• For CCA with FGFR2 fusions or rearrangements:
Pemigatinib22
Infigratinib23• For CCA with IDH1 mutations
Ivosidenib24,25• For RET fusion-positive tumors:Pralsetinib (category 2B)12• For HER2-positive tumors:
Trastuzumab + pertuzumab26• Nivolumabf,h,27 (category 2B)• Lenvatinib + pembrolizumabf,h,28 (category 2B)

Note: All recommendations are category 2A unless otherwise indicated.
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.
Version 1.2022, 03/29/22 © 2022 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

References
Continued
BIL-C
2 OF 4

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Biliary Tract Cancers

NCCN Guidelines Index
Table of Contents
Discussion

PRINCIPLES OF SYSTEMIC THERAPYREFERENCES

1 Shroff RT, Javle MM, Xiao L, et al. Gemcitabine, cisplatin, and nab-paclitaxel for the treatment of advanced biliary tract cancers: a phase 2 clinical trial. JAMA Oncol

2019;5:824-830.

2 Horgan AM, Amir E, Walter T, Knox JJ. Adjuvant therapy in the treatment of biliary tract cancer: a systemic review and meta-analysis. J Clin Oncol 2012;30:1934-1940.
3 Primrose JN, Fox RP, Palmer DH, et al. Capecitabine compared with observation in resected biliary tract cancer (BILCAP): a randomised, controlled, multicentre,

phase 3 study. Lancet Oncol 2019;20:663-673.

4 Valle JW, Wasan HS, Palmer DH, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Eng J Med 2010;362:1273-1281.
5 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) inpatients (pts) with advanced biliary tract cancer (BTC): TOPAZ-1 [abstract]. J Clin Oncol 2022;40:Abstract 378.

6 Demetri GD, Paz-Ares LG, Farago AF, et al. Efficacy and safety of entrectinib in patients with NTRK fusion-positive (NTRK-fp) tumors: pooled analysis of STARTRK-2,

STARTRK-1 and ALKA-372-001. ESMO Congress 2018.

7 Drilon A, Siena S, Ou SI, et al. Safety and antitumor activity of the multitargeted pan-TRK, ROS1, and ALK inhibitor entrectinib: Combined results from two phase I

trials (ALKA-372-001 and STARTRK-1). Cancer Discov 2017;7:400-409.

8 Doebele RC, Drilon A, Paz-Ares L, et al. Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: integrated analysis of three phase 1-2

trials. Lancet Oncol 2020;21:271-282.

9 Drilon A, Laetsch TW, Kummar S, et al. Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children. N Engl J Med 2018;378:731-739.
10 Le DT, Durham JN, Smith KN, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 2017;357:409-413.
11 Marabelle A, Le DT, Ascierto PA, et al. Efficacy of pembrolizumab in patients with noncolorectal high microsatellite instability/mismatch repair-deficient cancer: Resultsfrom the phase II KEYNOTE-158 study. J Clin Oncol 2020;38:1-10.

12 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.

13 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.

14 Caparica R, Lengele A, Bekolo W, Hendlisz A. FOLFIRI as second-line treatment of metastatic biliary tract cancer patients. Autops Case Rep 2019;9:e2019087.
15 Sun W, Patel A, Normolle D, et al. A phase 2 trial of regorafenib as a single agent in patients with chemotherapy-refractory, advanced, and metastatic biliary tract

adenocarcinoma. Cancer 2019;125:902-909.

16 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.

17 Andre T, Berton D, Curigliano G, et al. Safety and efficacy of anti–PD-1 antibody dostarlimab in patients (pts) with mismatch repair-deficient (dMMR) solid cancers:

Results from GARNET study [abstract]. J Clin Oncol 2021;39:Abstract 9.

18 Berton D, Banerjee SN, Curigliano G, et al. Antitumor activity of dostarlimab in patients with mismatch repair-deficient/microsatellite instability-high tumors: A

combined analysis of two cohorts in the GARNET study [abstract]. J Clin Oncol 2021;39:Abstract 2564.

19 Merino DM, McShane LM, Fabrizio D, et al. Establishing guidelines to harmonize tumor mutational burden (TMB): in silico assessment of variation in TMB

quantification across diagnostic platforms: phase I of the Friends of Cancer Research TMB Harmonization Project. J Immunother Cancer 2020;8:e000147.

20 Subbiah V, Lassen U, Élez E, et al. Dabrafenib plus trametinib in patients with BRAFV600E-mutated biliary tract cancer (ROAR): a phase 2, open-label, single-arm,

multicentre basket trial. Lancet Oncol 2020;21:1234-1243.

Note: All recommendations are category 2A unless otherwise indicated.
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.
Version 1.2022, 03/29/22 © 2022 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

Continued
BIL-C
3 OF 4

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Biliary Tract Cancers

NCCN Guidelines Index
Table of Contents
Discussion

PRINCIPLES OF SYSTEMIC THERAPYREFERENCES

21 Salama AKS, Li S, Macrae ER, et al. Dabrafenib and trametinib in patients with tumors with BRAF-V600E mutations: Results of the NCI-MATCH trial subprotocol H. J

Clin Oncol 2020;38:3895-3904.

22 Abou-Alfa GK, Sahai V, Hollebecque A, et al. Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: a multicentre, open-label, phase2 study. Lancet Oncol 2020;21:671-684.

23 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.

24 Abou-Alfa GK, Macarulla T, Javle MM, et al. Ivosidenib in IDH1-mutant, chemotherapy-refractory cholangiocarcinoma (ClarIDHy): a multicentre, randomised, double-

blind, placebo-controlled, phase 3 study. Lancet Oncol 2020;21:796-807.

25 Zhu AX, Macarulla T, Javle MM, et al. Final overall survival efficacy results of ivosidenib for patients with advanced cholangiocarcinoma with IDH1 mutation: Thephase 3 randomized clinical ClarIDHy trial. JAMA Oncol 2021:7:1669-1677.

26 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.

27 Kim RD, Chung V, Alese OB, et al. A Phase 2 Multi-institutional study of nivolumab for patients with advanced refractory biliary tract cancer. JAMA Oncol 2020;6:888-894.

28 Lwin, Z, Gomez-Roca, C, Saada-Bouzid E, et al. LEAP-005: Phase II study of lenvatinib (len) plus pembrolizumab (pembro) in patients (pts) with previously treatedadvanced solid tumors. Ann. Oncol. 2020;31:S1142-S1215.

Note: All recommendations are category 2A unless otherwise indicated.
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.
Version 1.2022, 03/29/22 © 2022 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

BIL-C
4 OF 4

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers

NCCN Guidelines Index
Table of Contents
Discussion

American Joint Committee on Cancer (AJCC)
TNM Staging for Hepatocellular Cancer (8th ed., 2017)
Table 1. Definitions for T, N, M
T
TX
T0
T1
T1a
T1b
T2
T3
T4

N
NX
N0
N1
M
M0

M1

Primary Tumor
Primary tumor cannot be assessed
No evidence of primary tumor
Solitary tumor ≤2 cm, or >2 cm without vascular invasion
Solitary tumor ≤2 cm
Solitary tumor >2 cm without vascular invasion
Solitary tumor >2 cm with vascular invasion, or multiple
tumors, none >5 cm
Multiple tumors, at least one of which is >5 cm
Single tumor or multiple tumors of any size involving a major
branch of the portal vein or hepatic vein, or tumor(s) withdirect invasion of adjacent organs other than the gallbladderor with perforation of visceral peritoneum
Regional Lymph Nodes
Regional lymph nodes cannot be assessed
No regional lymph node metastasis
Regional lymph node metastasis
Distant Metastasis
No distant metastasis
Distant metastasis

Table 2. AJCC Prognostic Groups
T
Stage IAStage IB
Stage II
Stage IIIA
Stage IIIB
Stage IVA
Stage IVB

T1a
T1b
T2
T3
T4
Any T
Any T

N

M
N0
M0
N0
M0
N0
M0
N0
M0
N0
M0
N1
M0
Any N M1

Histologic Grade (G)
GX
G1
G2
G3
G4

Grade cannot be accessed
Well differentiatedModerately differentiatedPoorly differentiatedUndifferentiatedFibrosis Score (F)The fibrosis score as defined by Ishak is recommended because of its
prognostic value in overall survival. This scoring system uses a 0-6 scale.
F0
F1

Fibrosis score 0-4 (none to moderate fibrosis)
Fibrosis score 5-6 (severe fibrosis or cirrhosis)

Used with permission of the American College of Surgeons, Chicago, Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth Edition(2017) published by Springer International Publishing.

Continued

Version 1.2022, 03/29/22 © 2022 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

ST-1

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers

NCCN Guidelines Index
Table of Contents
Discussion

American Joint Committee on Cancer (AJCC)
TNM Staging for Gallbladder Carcinoma (8th ed., 2017)
Table 3. Definitions for T, N, M
T
TX
T0
Tis
T1
T1a
T1b
T2

T2a
T2b
T3

T4

Primary Tumor
Primary tumor cannot be assessed
No evidence of primary tumor
Carcinoma in situ
Tumor invades lamina propria or muscular layer
Tumor invades lamina propria
Tumor invades muscle layer
Tumor invades the perimuscular connective tissue on theperitoneal side, without involvement of the serosa (visceralperitoneum) Or tumor invades the perimuscular connective
tissue on the hepatic side, with no extension into the liver
Tumor invades the perimuscular connective tissue on theperitoneal side, without involvement of the serosa (visceralperitoneum)
Tumor invades the perimuscular connective tissue on thehepatic side, with no extension into the liver
Tumor perforates the serosa (visceral peritoneum) and/or directly invades the liver and/or one other adjacentorgan or structure, such as the stomach, duodenum, colon,
pancreas, omentum, or extrahepatic bile ducts
Tumor invades main portal vein or hepatic artery or invades
two or more extrahepatic organs or structures

N
NX
N0
N1
N2

Regional Lymph Nodes
Regional lymph nodes cannot be assessed
No regional lymph node metastasis
Metastases to one to three regional lymph nodes
Metastases to four or more regional lymph nodes

M
M0
M1

Distant Metastasis
No distant metastasis
Distant metastasis

Table 4. AJCC Prognostic Groups
T
Stage 0Stage I
Stage IIA
Stage IIB
Stage IIIA
Stage IIIB
Stage IVA
Stage IVB

Tis
T1
T2a
T2b
T3
T1-3
T4
Any T
Any T

N

M
N0
M0
N0
M0
N0
M0
N0
M0
N0
M0
N1
M0
N0-1
M0
N2
M0
Any N M1

Histologic Grade (G)
GX
G1
G2
G3

Grade cannot be assessed
Well differentiatedModerately differentiatedPoorly differentiated

Used with permission of the American College of Surgeons, Chicago, Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth Edition(2017) published by Springer International Publishing.

Continued

Version 1.2022, 03/29/22 © 2022 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

ST-2

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers

NCCN Guidelines Index
Table of Contents
Discussion

American Joint Committee on Cancer (AJCC)
TNM Staging for Intrahepatic Bile Duct Tumors (8th ed., 2017)
Table 5. Definitions for T, N, M
T
TX
T0
Tis
T1

T3
T4

Primary Tumor
Primary tumor cannot be assessed
No evidence of primary tumor
Carcinoma in situ (intraductal tumor)
Solitary tumor without vascular invasion, ≤5 cm or >5 cm
Solitary tumor ≤5 cm without vascular invasion
Solitary tumor >5 cm without vascular invasion
Solitary tumor with intrahepatic vascular invasion or multiple
tumors, with or without vascular invasion
Tumor perforating the visceral peritoneum
Tumor involving local extrahepatic structures by direct invasion

N
NX
N0
N1

Regional Lymph Nodes
Regional lymph nodes cannot be assessed
No regional lymph node metastasis
Regional lymph node metastasis present

M
M0
M1

Distant Metastasis
No distant metastasis
Distant metastasis present

T1a
T1b
T2

Table 6. AJCC Prognostic Groups
T
Stage 0Stage IAStage IB
Stage II
Stage IIIA
Stage IIIB
Stage IV

N

Tis
T1a
T1b
T2
T3
T4
Any T
Any T

M
N0
M0
N0
M0
N0
M0
N0
M0
N0
M0
N0
M0
N1
M0
Any N M1

Histologic Grade (G)
GX
G1
G2
G3

Grade cannot be assessed
Well differentiatedModerately differentiatedPoorly differentiated

Used with permission of the American College of Surgeons, Chicago, Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth Edition(2017) published by Springer International Publishing.

Continued

Version 1.2022, 03/29/22 © 2022 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

ST-3

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers

NCCN Guidelines Index
Table of Contents
Discussion

American Joint Committee on Cancer (AJCC)
TNM Staging for Perihilar Bile Duct Tumors (8th ed., 2017)
Table 7. Definitions for T, N, M
T
TX
T0
Tis
T1
T2
T2a
T2b
T3
T4

N
NX
N0
N1
N2

Primary Tumor
Primary tumor cannot be assessed
No evidence of primary tumor
Carcinoma in situ/high-grade dysplasia
Tumor confined to the bile duct, with extension up to the muscle
layer or fibrous tissue
Tumor invades beyond the wall of the bile duct to surrounding
adipose tissue, or tumor invades adjacent hepatic parenchyma
Tumor invades beyond the wall of the bile duct to surrounding
adipose tissue
Tumor invades adjacent hepatic parenchyma
Tumor invades unilateral branches of the portal vein or hepatic artery
Tumor invades main portal vein or its branches bilaterally, or thecommon hepatic artery; or unilateral second-order biliary radicals
bilaterally with contralateral portal vein or hepatic artery involvement
Regional Lymph Nodes
Regional lymph nodes cannot be assessed
No regional lymph node metastasis
One to three positive lymph nodes typically involving thehilar, cystic duct, common bile duct, hepatic artery, posterior
pancreatoduodenal, and portal vein lymph nodes
Four or more positive lymph nodes from the sites described for N1

M
M0
M1

Distant Metastasis
No distant metastasis
Distant metastasis

Table 8. AJCC Prognostic Groups
T
Stage 0Stage I
Stage II
Stage IIIA
Stage IIIB
Stage IIIC
Stage IVA
Stage IVB

Tis
T1
T2a-b
T3
T4
Any T
Any T
Any T

N

M
N0
M0
N0
M0
N0
M0
N0
M0
N0
M0
N1
M0
N2
M0
Any N M1

Histologic Grade (G)
GX
G1
G2
G3

Grade cannot be assessed
Well differentiatedModerately differentiatedPoorly differentiated

Used with permission of the American College of Surgeons, Chicago, Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth Edition(2017) published by Springer International Publishing.

Continued

Version 1.2022, 03/29/22 © 2022 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

ST-4

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers

NCCN Guidelines Index
Table of Contents
Discussion

American Joint Committee on Cancer (AJCC)
TNM Staging for Distal Bile Ducts Tumors (8th ed., 2017)
Table 9. Definitions for T, N, M
T
TX
Tis
T1
T2
T3
T4

Primary Tumor
Primary tumor cannot be assessed
Carcinoma in situ/high-grade dysplasia
Tumor invades the bile duct wall with a depth less than 5 mm
Tumor invades the bile duct wall with a depth of 5–12 mm
Tumor invades the bile duct wall with a depth greater than 12 mm
Tumor involves the celiac axis, superior mesenteric artery, and/or
common hepatic artery

Table 10. AJCC Prognostic Groups
T
Stage 0Stage I
Stage IIA
Stage IIB

Stage IIIA
N
NX
N0
N1
N2

Regional Lymph Nodes
Regional lymph nodes cannot be assessed
No regional lymph node metastasis
Metastasis in one to three regional lymph nodes
Metastasis in four or more regional lymph nodes

M
M0
M1

Distant Metastasis
No distant metastasis
Distant metastasis

Stage IIIB

Stage IV

N

Tis
T1
T1
T2
T2
T3
T3
T1
T2
T3
T4
T4
T4
Any T

M
N0
M0
N0
M0
N1
M0
N0
M0
N1
M0
N0
M0
N1
M0
N2
M0
N2
M0
N2
M0
N0
M0
N1
M0
N2
M0
Any N M1

Histologic Grade (G)
GX
G1
G2
G3

Grade cannot be assessed
Well differentiatedModerately differentiatedPoorly differentiated

Used with permission of the American College of Surgeons, Chicago, Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth Edition(2017) published by Springer International Publishing.

Version 1.2022, 03/29/22 © 2022 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

ST-5

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers

NCCN Guidelines Index
Table of Contents
Discussion

Barcelona Clinic Liver Cancer (BCLC) Staging System (2022)1
Table 1. Definitions for Prognostic Groups
Stage

Definition

Very early stage (0)• Single ≤2 cm• Preserved liver function,a PS 0

Early stage (A)• Single, or ≤3 nodules each ≤3 cm• Preserved liver function,a PS 0

Intermediate stage (B)• Multinodular• Preserved liver function,a PS 0

Advanced stage (C)• Portal invasion and/or extrahepatic spread• Preserved liver function, PS 1-2

Terminal stage (D)• Any tumor burden• End stage liver function, PS 3-4

a Except for those with tumor burden acceptable for transplant.

1 Adapted with permission from Reig M, Forner A, Rimola J, et al. BCLC strategy for prognosis prediction and treatment recommendation: The 2022 update. J Hepatol

2022;76:681-693.

Version 1.2022, 03/29/22 © 2022 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

ST-6

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers

NCCN Guidelines Index
Table of Contents
Discussion

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 indicated.

NCCN Categories of Preference
Preferred intervention

Interventions that are based on superior efficacy, safety, and evidence; and, when appropriate,affordability.

Other recommended
Other interventions that may be somewhat less efficacious, more toxic, or based on less mature data;or significantly less affordable for similar outcomes.
intervention
Useful in certain
Other interventions that may be used for selected patient populations (defined with recommendation).
circumstances
All recommendations are considered appropriate.

Version 1.2022, 03/29/22 © 2022 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

CAT-1

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
Discussion

This discussion corresponds to the NCCN Guidelines for Hepatobiliary Cancers. Last updated: September 21st, 2021.

Table of Contents
Overview ............................................................................................................................................................................................................. MS-2
Literature Search Criteria and Guidelines Update Methodology ...................................................................................................................... MS-2
Hepatocellular Carcinoma .................................................................................................................................................................................. MS-2
Risk Factors and Epidemiology ......................................................................................................................................................................... MS-2
Screening for HCC ............................................................................................................................................................................................ MS-5
Diagnosis .......................................................................................................................................................................................................... MS-6
Initial Workup .................................................................................................................................................................................................... MS-9
Pathology and Staging .................................................................................................................................................................................... MS-11
Treatment Options .......................................................................................................................................................................................... MS-13
Biliary Tract Cancers ........................................................................................................................................................................................ MS-36
Gallbladder Cancer ......................................................................................................................................................................................... MS-36
Cholangiocarcinomas ...................................................................................................................................................................................... MS-42
Adjuvant Chemotherapy and Chemoradiation for Biliary Tract Cancers ........................................................................................................... MS-50
Treatment for Advanced Biliary Tract Cancers................................................................................................................................................. MS-52
Summary........................................................................................................................................................................................................... MS-57
Figure 1: Classification of Cholangiocarcinoma ............................................................................................................................................. MS-59
References ........................................................................................................................................................................................................ MS-60

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-1

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
Overview
Hepatobiliary cancers are highly lethal cancers including a spectrum ofinvasive carcinomas arising in the liver (hepatocellular carcinoma; HCC),
gall bladder, and bile ducts (intrahepatic and extrahepaticcholangiocarcinoma). Gallbladder cancer and cholangiocarcinomas arecollectively known as biliary tract cancers. In 2020, it was estimated that
42,810 people in the United States would be diagnosed with liver cancer
and intrahepatic bile duct cancer and an additional 11,980 people would
be diagnosed with gallbladder cancer or other biliary tract cancer.
Approximately 30,160 deaths from liver or intrahepatic bile duct cancer,
and 4,090 deaths due to gallbladder cancer or other biliary tract cancer
were anticipated.1
The NCCN Guidelines for Hepatobiliary Cancers are the work of themembers of the NCCN Hepatobiliary Cancers Guidelines Panel. The typesof hepatobiliary cancers covered in these guidelines include: HCC,
gallbladder cancer, and intrahepatic and extrahepatic cholangiocarcinoma.
Guidelines for HCC are consistent with those offered by the European
Association for the Study of the Liver/European Organisation for Research
and Treatment of Cancer and the consensus statement from the 2009
Asian Oncology Summit.2 However, some discrepancies exist regarding
treatment and surveillance, largely due to geographical differences suchas available resources. By definition, the NCCN Guidelines cannot
incorporate all possible clinical variations and are not intended to replace
good clinical judgment or individualization of treatments. Although not
explicitly stated at every decision point of the guidelines, participation inprospective clinical trials is the preferred option for treatment of patientswith hepatobiliary cancers.

Literature Search Criteria and Guidelines Update
Methodology
Prior to the update of this version of the NCCN Guidelines for
Hepatobiliary Cancers, an electronic search of the PubMed database was
performed to obtain key literature in the field of hepatobiliary cancers,
using the following search terms: (hepatocellular carcinoma) OR (livercancer) OR (biliary tract cancer) OR (gallbladder cancer) OR(cholangiocarcinoma). The PubMed database was chosen because it
remains the most widely used resource for medical literature and indexes
only peer-reviewed biomedical literature.3
The search results were narrowed by selecting studies in humans
published in English. Results were confined to the following article types:
Clinical Trial, Phase II; Clinical Trial, Phase III; Clinical Trial, Phase IV;
Practice Guideline; Guidelines; Randomized Controlled Trial; MetaAnalysis; Systematic Reviews; and Validation Studies.
The data from key PubMed articles and articles from additional sources
deemed as relevant to these Guidelines and discussed by the panel havebeen included in this version of the Discussion section. Recommendations
for which high-level evidence is lacking are based on the panel’s review oflower-level evidence and expert opinion.
The complete details of the development and update of the NCCN
Guidelines are available on the NCCN website (www.NCCN.org).

Hepatocellular Carcinoma
Risk Factors and Epidemiology
Incidence and mortality rates for most cancers are declining; however, theincidence and mortality rates for liver cancer are increasing.4-6 7,8 Five-year
survival rates (based on SEER data from 2006–2012) are lowest for
blacks and American Indian/Alaska Natives who were diagnosed with liver

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-2

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
and intrahepatic bile duct cancer.7 Forecast analyses predict that rates will
be highest in blacks and Hispanics over the next 15 years.9 These
analyses also predict increasing incidence rates in those born between
1950 and 1959, due to high rates of hepatitis C viral infection in this age
group.
The major risk factors for the development of HCC are cirrhosis andchronic liver disease, regardless of etiology.10,11 Specific risk factors
include viral infections caused by hepatitis B virus (HBV) and/or hepatitis
C virus (HCV), chronic alcohol consumption, particular comorbidities orother conditions such as non-alcoholic fatty liver disease (NAFLD),
nonalcoholic steatohepatitis (NASH), genetic hemochromatosis (GH),coinfection with HBV/HVC, and human immunodeficiency virus (HIV).4,12-18
A retrospective analysis of patients at liver transplantation centers in the
United States found that nearly 50% and about 15% of patients were
infected with HBV or HCV, respectively, with approximately 5% of patients
having markers of both hepatitis B and hepatitis C infection.19
Seropositivity for hepatitis B e antigen (HBeAg) and hepatitis B surface
antigen (HBsAg) are associated with an increased risk for HCC in patientswith chronic hepatitis B viral infection.20,21 Data from large
population-based studies have also identified high serum HBV DNA andHCV RNA viral load as independent risk factors for developing HCC inpatients with chronic infection.22-25
The incidence of HCC is increasing in the United States, particularly in the
population infected with HCV. The annual incidence rate of HCC among
patients with HCV-related cirrhosis has been estimated to be between 2%
and 8%.6 However, HCV often goes undetected, making thesecalculations difficult to interpret. Although it has been reported that the
number of cases of hepatitis C infection diagnosed per year in the UnitedStates is declining, it is likely that the observed increase in the number ofcases of HCV-related HCC is associated with the often prolonged period

between viral infection and the manifestation of HCC.26,27 There is strong
evidence that direct-acting antivirals (DAAs) improve sustained virologic
response in patients with HCV,28,29 which in turn may eventually decrease
incidence of HCC.30,31
Globally, HBV is the leading cause of HCC incidence and mortality.5
Approximately 1.5 million people in the United States are chronicallyinfected with HBV.32,33 Results from a prospective controlled study showed
the annual incidence of HCC to be 0.5% in carriers of the virus without
liver cirrhosis and 2.5% in those with known cirrhosis,34 although studies
have shown wide variation in the annual incidence rate of HCC amongindividuals with chronic hepatitis B infection.35 A meta-analysis including
68 studies with 27,854 patients with untreated HBV showed an annual
HCC incidence of 0.88 per 100 person-years (95% CI, 0.76–0.99), withhigher incidence per 100 person-years for patients with cirrhosis (3.16;
95% CI, 2.58–3.74).36 An analysis of 634 patients with HBV showed that
long-term antiviral therapy was associated with reduced risk of HCC inpatients without cirrhosis (standardized incidence ratio [SIR], 0.40; 95%
CI, 0.20–0.80).37 Analyses from universal HBV vaccination programs in
Alaska and Taiwan showed that vaccination is associated with decreased
HCC incidence in children and young adults.38-40 Since universal HBVvaccination programs were implemented relatively recently, the potential
efficacy of these programs in adults will likely not be seen for at least 10 to
20 years.
Non-viral causes associated with an increased risk for HCC include
cirrhosis from any cause (eg, alcoholic cirrhosis); inherited errors of
metabolism (relatively rare), such as hereditary hemochromatosis,
porphyria cutanea tarda, and alpha-1 antitrypsin deficiency; Wilson’s
disease; and stage IV primary biliary cirrhosis.6,12,41
Alcoholic cirrhosis is a well-known risk factor for HCC,6 although many of
the studies evaluating the incidence rate of HCC in individuals with

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-3

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
alcohol-induced cirrhosis have been confounded by the presence of otherrisk factors such as viral hepatitis infection, which can interact
synergistically in the pathogenesis of HCC.42,43 It has been estimated that
60% to 80% of persons with HCC have underlying cirrhosis, possibly
approaching 90% in the United States.44 Importantly, certain populations
chronically infected with HBV have been identified as being at increased
risk for HCC in the absence of cirrhosis, especially when other risk factors
are present,35 and it has been estimated that 30% to 50% of patients withchronic hepatitis B viral infection who develop HCC do not have underlying
cirrhosis.45 Some risk factors for the development of HCC in HBV carriers
without evidence of liver cirrhosis include active viral replication, high HBVDNA levels, and a family history of HCC.35,46 Asian males ≥40 years, Asianfemales ≥50 years, and Black/African American men and women with
hepatitis B are also at increased risk for HCC.6 The presence of livercirrhosis is usually considered to be a prerequisite for development of
HCC in individuals with inherited metabolic diseases of the liver or liverdisease with an autoimmune etiology.47-49 Although the mechanism of
HCC development differs according to the underlying disease, HCC
typically occurs in the setting of a histologically abnormal liver. Hence, thepresence of chronic liver disease represents a risk for development of
HCC.12 However, HCC may also develop in patients with normal livers andno known risk factors.50,51
GH is a condition characterized by excess iron absorption due to thepresence of mutations in the HFE gene. A study from the National Centerfor Health Statistics found that patients with a known diagnosis ofhemochromatosis at death were 23 times more likely to have primary liver
neoplasms than those without GH. The annual incidence rates of HCC
associated with cirrhosis due to GH have been sufficiently high (about
3%–4%), and the American Association for the Study of Liver Diseases(AASLD) guidelines recommend surveillance for this group of patients
when cirrhosis is present.35

Metabolic disorders (ie, obesity, diabetes, impaired glucose metabolism,
metabolic syndrome, NAFLD) are associated with increased risk of
HCC.16,52-54 It is anticipated that sequelae of NAFLD, such as non-alcoholicsteatohepatitis (NASH, a spectrum of conditions characterized byhistologic findings of hepatic steatosis with inflammation in individuals who
consume little or no alcohol) will replace hepatitis as the most common
underlying cause of HCC.55-57 Estimations of the prevalence of NASH in
the United States are in the range of 3% to 5%, indicating that this sizable
subpopulation is at risk for cirrhosis and development of HCC.58 In one
study, 12.8% of 195 patients with cirrhosis secondary to NASH developed
HCC at a median follow-up of 3.2 years, with an annual incidence rate of
HCC of 2.6%.17 Available epidemiologic evidence supports an association
between NAFLD or NASH and an increased HCC risk predominantly inindividuals with cirrhosis.16,59 However, several studies suggest that HCC
may be somewhat less likely to develop in the setting of NASH-associatedcirrhosis compared with cirrhosis due to hepatitis C infection.60,61 The
American Gastroenterological Association clinical practice update
recommends that screening for HCC in patients with cirrhosis due to
NAFLD be considered.62 HCC screening should also be considered inpatients with NAFLD with noninvasive markers that provide evidence ofadvanced liver fibrosis or cirrhosis.
Fibrolamellar hepatocellular carcinoma (FLHC) is a variant of HCC thatmakes up a very small fraction of all HCCs. Patients with FLHC tend to be
younger and have a generally better prognosis than those with HCC,63-65
though recurrences following resection are common.64 FLHC also is rarely,
if ever, associated with hepatitis, cirrhosis, or elevated alpha-fetoprotein(AFP) levels.64,66 Though cross-sectional imaging results may be strongly
suggestive of FLHC, histologic confirmation is needed.67 A moleculartarget to identify FLHC, the DNAJB1-PRKACA chimera, has been found,68
which accurately identifies FLHC in 79% to 100% of cases.68-71 Complete
resection is the only potentially curative option.67 One clinical trial is

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-4

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
currently investigating systemic therapy for treatment of FLHC
(NCT01642186), but no effective regimen has been identified. An
unplanned analysis from a phase II study investigating the efficacy of
everolimus, combined leuprolide and letrozole, or the combination of all 3
drugs revealed that the primary endpoint of a 6–month progression-freesurvival (PFS) was not met.72 Given its rarity, the panel does not provide
treatment recommendations for FLHC in these guidelines.
Screening for HCC
The purpose of a cancer screening test is to identify the presence of a
specific cancer in an asymptomatic individual in a situation where early
detection has the potential to favorably impact patient outcome. The panel
supports the recommendation by the AASLD that HCC screening inpatients with risk factors for HCC should consist of a program including
standardized screening tests, recall procedures, and quality control
procedures in place.73 The AASLD and EASL-EORTC recommend thatultrasound (US) screening in at-risk patients be done every 6 months.6,73,74
Support for enrolling individuals at high risk for HCC in a screening
program comes from a large randomized controlled trial (RCT) in China of
18,816 men and women with hepatitis B infection or a history of chronic
hepatitis, defined as patients with abnormalities on serum liver tests
lasting for 6 months or more. In this study, screening with serum AFP
testing and liver US every 6 months was shown to result in a 37%
reduction in HCC mortality, despite the fact that less than 60% of
individuals in the screening arm completed the screening program.75
HCC screening should be carried out in at-risk populations regardless ofage. In a prospective observational study of 638 patients with HCC in
Singapore carried out over a 9-year period, patients 40 years or younger
were more likely than older patients to harbor hepatitis B infection and tohave more advanced disease at diagnosis.76 Although survival did not

differ in the two groups overall, a significant survival benefit was observed
for younger patients when the subgroup of patients with early-stage
disease was considered.
AFP and liver US are the most widely used methods of screening for
HCC.77 A review of serum protein biomarkers for early detection of HCC
showed that an AFP cut-off value of 100 ng/mL was associated with highspecificity (99%) but low sensitivity (31%).78 In a screening study involving
a large population of patients in China infected with HBV or those withchronic hepatitis, and using an AFP cut-off of >20 ng/mL, the detection
rate, false-positive rate, and positive predictive value with AFP alone were69%, 5.0%, and 3.3%; with US alone were 84%, 2.9%, and 6.6%; and withthe combination of AFP and US were 92%, 7.5%, and 3.0%.79 These
results demonstrate that US combined with AFP is a better modality for
HCC screening than AFP testing alone. A study of 333 patients with HCC
and HBV/HCV determined that patients with HCC diagnosed aftersurveillance with US and AFP had significantly longer overall survival (OS)and disease-free survival (DFS), compared to patients who had nosurveillance prior to diagnosis.80 Nevertheless, since US is highly operator
dependent, the addition of AFP may increase the likelihood of detecting
HCC in a screening setting. However, AFP is frequently normal in patientswith early-stage disease and its utility as a screening biomarker islimited.81-83 A recent meta-analysis including 32 studies with 13,367
patients with cirrhosis who were screened for HCC showed that US with
AFP improves sensitivity for detection of HCC, compared to US alone(97% vs. 78%, respectively; relative risk [RR], 0.88; 95% CI, 0.83–0.93).84
Due to the low cost and ease of use, AFP may have utility for enhancing
detection of HCC when used in combination with US for screening at-risk
individuals. A progressive elevation rate of ≥7 ng/mL per month may be
more useful as a diagnostic tool for HCC, relative to use of a fixed cut
point such as 200 ng/mL.85

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-5

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
In these guidelines, the populations considered to be “at risk” for HCC andlikely to benefit from participation in an HCC screening program include
patients with liver cirrhosis induced by viral (hepatitis B and C) as well as
non-viral causes of cirrhosis (ie, alcoholic cirrhosis, GH, NAFLD or NASH,
stage IV primary biliary cholangitis, alpha-1 antitrypsin deficiency) andhepatitis B carriers without cirrhosis, regardless of cause. Other lesscommon causes of cirrhosis include secondary biliary cirrhosis, Wilson’s
disease, sclerosing cholangitis, granulomatous disease, type IV glycogenstorage disease, drug-induced liver disease, venous outflow obstruction,
chronic right-sided heart failure, and tricuspid regurgitation.86
The panel recommends screening with US and AFP testing (every 6months) for patients with established risk factors for HCC. Additional
imaging (abdominal multiphasic CT or MRI) is recommended in the settingof a rising serum AFP or following identification of a liver mass nodule ≥10mm on US, based on AASLD and LI-RADS (Liver Imaging Reporting andData System) guidelines.6,87 It is also reasonable to screen patients withcross-sectional imaging (CT or MRI), and this may be commonly
employed, though not well-studied in the United States. Cost andavailability limit the widespread use of screening using cross-sectional
imaging. Liver masses <10 mm are difficult to definitively characterizethrough imaging. If nodules of this size are found, then US and AFP
testing should be repeated in 3 to 6 months.
Diagnosis
Localized HCC is asymptomatic for much of its natural history. Nonspecificsymptoms associated with more advanced HCC can include jaundice,anorexia, weight loss, malaise, and upper abdominal pain. Physical signsof HCC can include hepatomegaly and ascites.56 Paraneoplastic
syndromes, although rare, also can occur and include
hypercholesterolemia, erythrocytosis, hypercalcemia, and hypoglycemia.88

Combined hepatocellular-cholangiocarcinoma (cHCC-CC) is a rare
hepatobiliary tumor type. Resection for those with early stage disease is
the only potentially curative option.89-91 Diagnosis of cHCC-CC throughimaging is difficult since imaging characteristics consist of varying featuresof both HCC and cholangiocarcinoma.89,90,92 Therefore, misdiagnosis may
occur.90,93 Further, though AFP levels may be elevated in patients with
cHCC-CC, levels tend to not differ significantly from that of patients with
HCC.94 cHCC-CC may also be characterized by elevated serum CA 19-9,
similar to intrahepatic cholangiocarcinoma.92,95 If cHCC-CC is suspected,
thorough pathology review is recommended. It should be noted thatneedle biopsies will not necessarily show both elements of themalignancy.
Imaging

HCC lesions are characterized by arterial hypervascularity and “wash out”
on portal venous phases, since they derive most of their blood supply fromthe hepatic artery. This is unlike the surrounding liver, which receives its
blood supply from both the portal vein and hepatic artery.96 Diagnostic
HCC imaging involves the use of multiphasic liver protocol CT withmultiphasic (eg, precontrast, arterial phase, portal venous phase, delayed)
intravenous contrast-enhanced MRI.6,73 The classic imaging profile
associated with an HCC lesion is characterized by intense arterial uptake
or enhancement followed by contrast washout or hypointensity in the
delayed nonperipheral venous phase.6,87,97-101 LI-RADS also considers
enhancing capsule appearance and threshold growth compared toprevious imaging as part of diagnosis using CT or MRI imaging.87 The LIRADS criteria are applicable only to those with cirrhosis and a biopsy may
be necessary in patients without any history of liver disease.
Though contrast-enhanced ultrasound (CEUS) may be used at centers ofexpertise as a problem-solving tool for characterization of indeterminate
nodules, it is not recommended by the panel for whole-liver assessment,

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-6

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
surveillance, or staging.102 A meta-analysis including 241 studies showedthat CT and MRI are more sensitive than US without contrast for detectionof HCC.103 Another meta-analysis that included only studies of patientswith cirrhosis or chronic hepatitis (N = 30) also showed that US is lesssensitive than CT and MRI (60%, 68%, and 81%, respectively) for
diagnosis of HCC, though it is the most specific (97%, 93%, and 85%,
respectively).104 A meta-analysis including 22 studies with 1721 patientswith HCC showed that PET/CT may be useful for predicting prognosis (ie,OS and DFS, P < .001),105 but it is associated with low sensitivity for HCC
detection.106,107
Multiple meta-analyses have shown that MRI is more sensitive for HCC
diagnosis than CT.103,108,109 However, one meta-analysis including 19
comprehensive comparisons did not find a statistically significant
difference in specificity or in the positive likelihood ratio.109 When
comparing imaging modalities, it is important to keep in mind the quality of
the images being compared, which likely differ between studies.
Contrast-enhanced MRI for detection of lesions up to 2 cm has acceptablesensitivity (78%) and excellent specificity (92%) when criteria are appliedin appropriate clinical context in patients with known liver disease.110 The
results of a prospective study evaluating the accuracy of CEUS anddynamic contrast-enhanced MRI for the diagnosis of liver nodules 2 cm orsmaller observed on screening US demonstrated that the diagnosis of
HCC can be established without biopsy confirmation if both imaging
studies are conclusive.99 Comparing MRI to CEUS, the sensitivity was
61.7% versus 51.7%, the specificity was 96.6% versus 93.1%, the positive
predictive value was 97.4% versus 93.9%, and the negative predictive
value was 54.9% versus 50.9%.99 However, as noted earlier, CEUS is notcommonly utilized in the United States. Other investigators havesuggested that a finding of classical arterial enhancement using a single
imaging technique is sufficient to diagnose HCC in patients with cirrhosis

and liver nodules between 1 and 2 cm detected during surveillance,
thereby reducing the need for a biopsy.111 In the updated AASLD
guidelines, the algorithms for liver nodules between 1 and 2 cm have beenchanged to reflect these considerations. LI-RADS also offers some
guidance regarding the use of CEUS for the diagnosis of HCC.112
The NCCN Guidelines’ recommendations for diagnostic imaging in thesetting of high clinical suspicion for HCC (eg, following identification of aliver nodule on US or in the setting of a rising serum AFP level) apply only
to patients with known risk factors for HCC and are adapted from the
AASLD guidelines.6 For these patients, as well as patients with anincidental liver mass or nodule found on US or on another imaging exam,
the guidelines recommend evaluation using multiphasic abdominal
contrast-enhanced CT or MRI to determine the enhancement
characteristics, extent and number of lesions, vascular anatomy, andextrahepatic disease. Gadolinium contrast is preferred for MRI as
hepatobiliary agents such as gadolinium ethoxybenzyl diethylenetriamine
pentaacetic acid that require more subspecialized experience to interpret
hepatobiliary phase imaging are not currently included in AASLD or LIRADS interpretation. The quality of MRI is dependent on patientcompliance, since some patients may be unable to hold their breath. If nomass is detected using multiphasic contrast-enhanced imaging, or if theobserved lesion is definitely benign, then the patients should return to ascreening program (ie, US and AFP in 6 months). If there is suspicion thatthe diagnostic imaging test yielded a false negative, then a different
imaging method with or without AFP may be considered. If the observation
is inconclusive (ie, not definitely HCC but not definitely benign), thenmultidisciplinary discussion and individualized workup may be pursued,
including additional imaging or biopsy. Multidisciplinary team management
has been associated with improved outcomes in HCC, including higher
rates of treatment, higher rates of curative treatments in early stages, andprolonged survival in advanced disease.113-116

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-7

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
Serum Biomarkers

Although serum AFP has long been used as a marker for HCC, it is not asensitive or specific diagnostic test for HCC. Serum AFP levels >400ng/mL are observed only in a small percentage of patients with HCC. In aseries of 1158 patients with HCC, only 18% of patients had values >400ng/mL and 46% of patients had normal serum AFP levels <20 ng/mL.117 In
patients with chronic liver disease, an elevated AFP could be moreindicative of HCC than in non-infected patients.118 Furthermore, AFP canalso be elevated in pregnancy, and other cancers such as intrahepaticcholangiocarcinoma, some metastases from colon cancer, lymphoma, andgerm cell tumors.35,119 AFP testing can be useful in conjunction with othertest results to guide the management of patients for whom a diagnosis of
HCC is suspected. An elevated AFP level in conjunction with imaging
results showing the presence of a growing liver mass has been shown tohave a high positive predictive value for HCC in two retrospective
analyses involving small numbers of patients.120,121 However, thediagnostic accuracy of an absolute AFP cutoff value has not beenvalidated in this setting, and such values may vary by institution andpatient population.
Since the level of serum AFP may be elevated in those with certain
nonmalignant conditions such as chronic HBV122 or HCV or be within
normal limits in up to 30% of patients with HCC,123 the panel considers animaging finding of classic enhancement to be more definitive in the
diagnostic setting compared to AFP alone. Additional imaging studies (CTor MRI) are recommended for patients with a rising serum AFP level in theabsence of a liver mass. If no liver mass is detected following
measurement of an elevated AFP level, the patient should be followedwith AFP testing and liver imaging. Further, assessment of AFP levels
may be helpful in monitoring treatment response as appropriate (seeSurveillance below).

Other serum biomarkers being studied in this setting include
des-gamma-carboxy prothrombin (DCP), also known as protein inducedby vitamin K absence or antagonist-II (PIVKA-II), and lens culinaris
agglutinin-reactive AFP (AFP-L3), an isoform of AFP.44,124,125 Although
AFP was found to be more sensitive than DCP or AFP-L3 in detecting
early-stage and very-early-stage HCC in a retrospective case-control
study, none of these biomarkers was considered optimal in this setting.126
A case-control study involving patients with hepatitis C enrolled in thelarge, randomized HALT-C trial who developed HCC showed that a
combination of AFP and DCP is superior to either biomarker alone as acomplementary assay to screening.82
The GALAD model, which accounts for gender, age, AFP-L3, AFP, anddes-carboxy-prothrombin, is a serum biomarker model used to assess therisk of HCC in patients with chronic liver disease.127 In validation studies,
the GALAD model identified HCC cases in patients with chronic liverdisease or nonalcoholic steatohepatitis with a high degree of accuracy.128130
The GALADUS score, which combines the GALAD score and US, wasfound to improve the performance of the GALAD score.129
BiopsyA diagnosis of HCC can often be made noninvasively by imaging inpatients with established risk factors for HCC with diagnostic imaging
findings on multiphase imaging as described above. However, there are a
few clinical scenarios in which biopsy of a suspected HCC may beconsidered. First, biopsy may be considered when a lesion is suspicious
for malignancy, but multiphasic CT or MRI results do not meet imaging
criteria for HCC.6,74,81,100,131 AASLD describes the limitations of biopsy inthis scenario, specifically the cost, emotional distress for the patient, risk ofcomplications, and potential sampling error for small lesions.73 Second,
biopsy may be done in patients who are not considered high risk fordeveloping HCC (ie, patients who do not have cirrhosis, chronic HBV, or a

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-8

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
previous history of HCC). Third, biopsy may be indicated in patients withconditions associated with formation of nonmalignant nodules that may be
confused with HCC during imaging. These conditions include cardiac
cirrhosis, congenital hepatic fibrosis, or cirrhosis due to a vascular disordersuch as Budd-Chiari syndrome, hereditary hemorrhagic telangiectasia, or
nodular regenerative hyperplasia.132 Finally, biopsy may be considered inpatients with elevated CA 19-9 or carcinoembryonic antigen (CEA), in
order to rule out intrahepatic cholangiocarcinoma or mixed HCCcholangiocarcinoma133,134 or in patients with history of another primarymalignancy at risk for metastatic disease. If transplant or resection is aconsideration, patients should be referred to a transplant center and/or
hepatic surgeon before biopsy since biopsy may not be necessary incertain patients with resectable malignant-appearing masses.
Both core needle biopsy and fine-needle aspiration biopsy (FNAB) haveadvantages and disadvantages in this setting. For example, FNAB may be
associated with a lower complication rate when sampling deeply situatedlesions or those located near major blood vessels. In addition, the ability to
rapidly stain and examine cytologic samples can provide for immediate
determinations of whether a sufficient sample has been obtained, as wellas the possibility of an upfront tentative diagnosis.135 However, FNAB ishighly dependent on the skill of the cytopathologist,136 and there arereports of high false-negative rates99,137 as well as the possibility offalse-positive findings with this procedure.138 Although a core needle
biopsy is a more invasive procedure, it has the advantage of providing
pathologic information on both cytology and tissue architecture.
Furthermore, additional histologic and immunohistochemical tests can be
performed on the paraffin wax-embedded sample.81,135,137 However, someevidence indicates that a core needle biopsy does not provide an accurate
determination of tumor grade.139

Nevertheless, the use of biopsy to diagnose HCC is limited by sampling
error, particularly when lesions are <1 cm.35,44 Patients with anondiagnostic biopsy result should be followed closely, and subsequent
additional imaging and/or biopsy is recommended if a change in nodule
size is observed. The guidelines emphasize that a growing mass with anegative biopsy does not rule out HCC. Continual monitoring with amultidisciplinary review including surgeons is recommended since
definitive resection may be considered.
Initial Workup
The foundation of initial workup for patients with suspected HCC is amultidisciplinary evaluation including investigations of the etiologic origin ofliver disease, a hepatitis panel for detection of hepatitis B and/or C viral
infection (ie, HBsAg, hepatitis B surface antibody, hepatitis B core
antibody [HBcAb], HBcAb IgM [recommended only in patients with acuteviral hepatitis], and HCV antibodies), an assessment of the presence ofcomorbidity; imaging studies to detect the presence of metastatic disease,and an evaluation of hepatic function, including a determination of whether
portal hypertension is present. The guidelines recommend confirmation ofviral load in patients who test positive for HBsAg, HBcAb IgG (since anisolated HBcAb IgG may still indicate chronic HBV infection), and HCV
antibodies. If viral load is positive, patients should be evaluated by ahepatologist for consideration of antiviral therapy.45,140
Common sites of HCC metastasis include the lung, adrenal glands,
peritoneum, and bone.141,142 Hence, routine chest CT is recommended
since lung metastases are typically asymptomatic. Bone scan and/or
additional bone imaging may be considered as clinically indicated if
suspicious bone pain is present or cross-sectional imaging raises thepossibility of bone metastases.143 Multiphasic contrast-enhanced CT or
MRI of the abdomen, CT of the chest, and CT/MRI of the pelvis is also
used in the evaluation of the HCC tumor burden to detect the presence ofVersion 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-9

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
metastatic disease, nodal disease, and vascular invasion; to assess
whether evidence of portal hypertension is present; to provide an estimateof the size and location of HCC and the extent of chronic liver disease;
and, in the case of patients being considered for resection, to provide anestimate of the future liver remnant (FLR).98 Enlarged lymph nodes arecommonly seen in patients with viral hepatitis, primary biliary cirrhosis, andother underlying liver disorders that predispose patients to HCC.144
Detection of nodal disease by cross-sectional imaging is non-specific andcan be challenging in patients with hepatitis.
Assessment of Liver Function

An initial assessment of hepatic function involves liver function testing
including measurement of serum levels of bilirubin, aspartate
aminotransferase (AST), alanine transaminase (ALT), alkaline
phosphatase (ALP), measurement of prothrombin time (PT) expressed asinternational normalized ratio (INR), albumin, and platelet count (surrogate
for portal hypertension). Other recommended tests include complete bloodcount (CBC), blood urea nitrogen (BUN), and creatinine to assess kidney
function; creatinine is also an established prognostic marker in patientswith liver disease.145 Further assessment of hepatic functional reserveprior to hepatic resection in patients with cirrhosis may be performed withdifferent tools such as US and MRI elastography (which may provide andquantify the degree of cirrhosis-related fibrosis), non-focal liver biopsy, andtransjugular liver biopsy with pressure measurements.
The Child-Pugh classification has been traditionally used for theassessment of hepatic functional reserve in patients with cirrhosis.146,147
The Child-Pugh score incorporates laboratory measurements (ie, serum
albumin, bilirubin, PT) as well as more subjective clinical assessments ofencephalopathy and ascites. It provides a general estimate of the liverfunction by classifying patients as having compensated (class A) or
decompensated (classes B and C) cirrhosis. Advantages of the Child-Pughscore include ease of performance (ie, can be done at the bedside) andthe inclusion of clinical parameters.
An important additional assessment of liver function not included in theChild-Pugh score is an evaluation of signs of clinically significant portal
hypertension (ie, esophagogastric varices, splenomegaly, splenorenal
shunts and recanalization of the umbilical vein, thrombocytopenia).
Evidence of portal hypertension may be evident on CT/MRI.98 146-149
Esophageal varices may be evaluated usingesophagogastroduodenoscopy (EGD) or contrast-enhanced crosssectional imaging.
Model for End-Stage Liver Disease (MELD) is another system for theevaluation of hepatic reserve. MELD is a numerical scale ranging from 6(less ill) to 40 (gravely ill) for individuals 12 years or older. It is derived
using three laboratory values (serum bilirubin, creatinine, and INR) andwas originally devised to provide an assessment of mortality for patients
undergoing transjugular intrahepatic portosystemic shunts.150,151 The
MELD score has since been adopted by the United Network for Organ
Sharing (UNOS; www.unos.org) to stratify patients on the livertransplantation waiting list according to their risk of death within 3months.152 The MELD score has sometimes been used in place of theChild-Pugh score to assess prognosis in patients with cirrhosis.
Advantages of the MELD score include the inclusion of a measurement ofrenal function and an objective scoring system based on widely available
laboratory tests, although clinical assessments of ascites andencephalopathy are not included. It is currently unclear whether the MELD
score is superior to the Child-Pugh score as a predictor of survival inpatients with liver cirrhosis. The MELD score has not been validated as apredictor of survival in patients with cirrhosis who are not on a livertransplantation waiting list.153 While the MELD model is used to stratify
organ access for transplantation, it also favors patients with renal

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-10

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
dysfunction. Serum creatinine, an important component of the MELD
score, can be an unreliable marker of renal dysfunction, especially inpatients with cirrhosis.154

type is characterized by diffuse hepatic involvement with many small
indistinct tumor nodules throughout the liver.

Albumin and bilirubin are objectively measured, while ascites andencephalopathy, other scoring parameters used to calculate the ChildPugh score, are subjective. Therefore, another alternative to the ChildPugh score is the Albumin-Bilirubin (ALBI) grade, a model proposed by
Johnson et al that takes into account only serum bilirubin and albumin
levels.155 It has been shown to be especially helpful in predicting thesurvival outcome of patients with stable decompensated cirrhosis.156,157 An
analysis of almost 6000 patients from Europe, the United States, Japan,
and China showed that the ALBI grade, which stratifies patients into threerisk categories, performs as well as the Child-Pugh score.155 Further,patients scored as Child-Pugh grade A were categorized into either ALBI
grade 1 or 2.

Clinical staging systems for the patient with cancer can provide a moreaccurate prognostic assessment before and after a particular treatment
intervention, and they may be used to guide treatment decision-making
including enrollment in clinical trials. Therefore, staging can have a critical
impact on treatment outcome by facilitating appropriate patient selection
for specific therapeutic interventions, and by providing risk stratification
information following treatment. The key factors affecting prognosis inpatients with HCC are the clinical stage, growth rate of the tumor, thegeneral health of the patient, the liver function of the patient, and thetreatments administered.161 Many staging systems for patients with HCC
have been devised.162,163 Each of the staging systems includes variables
that evaluate one or more of the factors listed above. For example, theChild-Pugh164 and MELD scores150 can be considered to be staging
systems that evaluate aspects of liver function.

The indocyanine green (ICG) clearance test is extensively used in Asia forthe assessment of liver function prior to hepatic resection in patients withcirrhosis.158 159The Japanese evidence-based clinical guidelines for HCC
recommend the ICG retention rate at 15 minutes (ICGR-15) after
intravenous injection for the assessment of liver function prior tosurgery.160 However, this test is not widely used in Western countries.
Pathology and Staging
Pathology

Three gross morphologic types of HCC have been identified: nodular,
massive, and diffuse. Nodular HCC is often associated with cirrhosis andis characterized by well-circumscribed nodules. The massive type of HCC,
usually associated with a non-cirrhotic liver, occupies a large area with orwithout satellite nodules in the surrounding liver. The less common diffuse

Staging

The AJCC staging system provides information on the pathologic
characteristics of resected specimens only,165 whereas the Okuda system
incorporates aspects of liver function and tumor characteristics.166 The
French classification (GRETCH) system incorporates the Karnofsky
performance score as well as measurements of liver function and serum
AFP.167 Several staging systems include all parameters from other staging
systems as well as additional parameters. For example, the Chinese
University Prognostic Index (CUPI) system168 and the Japanese Integrated
Staging (JIS)169 scores incorporate the TNM staging system, and theCancer of the Liver Italian Program (CLIP),170 Barcelona Clinic Liver
Cancer (BCLC),171 SLiDe (stage, liver damage, DCP),172 and JIS systems
include the Child-Pugh score (with modified versions of CLIP and JIS
substituting the MELD score for the Child-Pugh score).173-175 In addition,

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-11

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
the BCLC system also incorporates the Okuda system, as well as othertumor characteristics, measurements of liver function, and patient
performance status.176
Although some of these systems have been found to be applicable for all
stages of HCC (eg, BCLC),44,176,177 limitations of all of these systems havebeen identified. For example, the AJCC staging system has limited
usefulness since most patients with HCC do not undergo surgery. An
analysis from the SEER database (1998–2013) questioned the AJCC
definition of T2 disease (solitary tumor >2 cm with vascular invasion;
multiple tumors <5 cm).178 Specifically, survival was significantly different
for patients with solitary tumors >2 cm than multifocal tumors <5 cm (P <.001), and, for patients with multifocal tumors <5 cm, survival was
significantly associated with vascular invasion (P < .001). A number ofstudies have shown that particular staging systems perform well for
specific patient populations likely related to differing etiologies.
Furthermore, staging systems may be used to direct treatment and/or to
predict survival outcomes following a particular type of therapeuticintervention. For example, the AJCC staging system has been shown toaccurately predict survival for patients who underwent orthotopic livertransplantation.179 The CLIP, CUPI, and GRETCH staging systems havebeen shown to perform well in predicting survival in patients withadvanced disease.180
The CLIP system has been specifically identified as being useful forstaging patients who underwent transarterial chemoembolization (TACE)
and those treated in a palliative setting.181,182 The utility of the BCLC
staging system with respect to stratifying patients with HCC according to
the natural history of the disease has been demonstrated in ameta-analysis of untreated patients with HCC enrolled in RCTs.183 In
addition, an advantage of the BCLC system is that it attempts to stratify
patients into treatment groups, although the type of treatment is notincluded as a staging variable.163 Furthermore, the BCLC staging system
was shown to be very useful for predicting outcome in patients following
liver transplantation or radiofrequency ablation (RFA).184,185 In a
multicenter cohort study of 1328 patients with HCC eligible for livertransplantation, survival benefit for liver transplantation was seen inpatients with advanced liver cirrhosis and in those with intermediatetumors (BCLC stage D and stages B–C, respectively), regardless of thenumber and size of the lesions, provided there was no macroscopic
vascular invasion and extrahepatic disease. However, treatment
recommendations may vary.
A novel staging system based on a nomogram of particularclinicopathologic variables, including patient age, tumor size and margin
status, postoperative blood loss, the presence of satellite lesions andvascular invasion, and serum AFP level, that was developed has beenshown to perform well in predicting postoperative outcome for patients
undergoing liver resection for HCC.186 In addition, another study showedtumor size >2 cm, multifocal tumors, and vascular invasion to be
independent predictors of poor survival in patients with early HCC
following liver resection or liver transplantation.187 This staging system has
been retrospectively validated in a population of patients with early
HCC.188
Due to the unique characteristics of HCC that vary with geographic region,
many of the existing staging systems are specific to the region in which
they are developed and there is no universally accepted staging systemthat could be used across all institutions in different countries. The BCLC
and the Hong Kong Liver Cancer staging systems are amongst the mostwidely used. Although no particular staging system (with the exception of
the Child-Pugh score and TNM staging system) is currently used in theseguidelines, following an initial workup, patients are stratified into one of thefollowing four categories:

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-12

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers•

Potentially resectable or transplantable, operable by performancestatus or comorbidity•

Unresectable disease•

Liver-confined disease, inoperable by performance status, comorbidity,
or with minimal or uncertain extrahepatic disease•

Metastatic disease

Treatment Options
All patients with HCC should be carefully evaluated by an experienced
multidisciplinary team for the many available treatment options. It is
important to reiterate that the management of patients with HCC iscomplicated by the presence of underlying liver disease. Furthermore,different etiologies of HCC and their effects on the host liver may impact
treatment response and outcome. These complexities make treatment
decisions in patients with HCC challenging and are the reason for
multidisciplinary care with the involvement of hepatologists, diagnostic
radiologists, interventional radiologists, surgeons, medical oncologists andpathologists with hepatobiliary cancer expertise, thereby requiring careful
coordination of care.44 Given the comorbidities associated with thisdisease, patients need careful consideration of treatment choice given therisk of potential toxicities from treatment and potential benefits.
Surgery

Partial hepatectomy is a potentially curative therapy for patients with asolitary tumor of any size with no evidence of gross vascular invasion.189
Partial hepatectomy for well-selected patients with HCC can now be
performed with low operative morbidity and mortality (≤5%).190,191 Resultsof large retrospective studies have shown 5-year survival rates of >50%
for patients undergoing liver resection for HCC,191-193 and some studies
suggest that for selected patients with preserved liver function andearly-stage HCC, liver resection is associated with a 5-year survival rate of

approximately 70%.193-195 However, recurrence rates at 5 years following
liver resection have been reported to exceed 70%.176,192
Since liver resection for patients with HCC includes removal of functionalliver parenchyma in the setting of underlying liver disease, careful patient
selection, based on patient characteristics as well as characteristics of theliver and the tumor(s), is essential. Assessments of patient performancestatus must be considered; the presence of comorbidity has been shown
to be an independent predictor of perioperative mortality.196 Likewise,
estimates of overall liver function and the size and function of the putative
FLR, as well as technical considerations related to tumor and liver
anatomy, must be taken into account before a patient is determined tohave potentially resectable disease. Univariate analyses from a databasestudy including 141 patients with HCC and liver cirrhosis who underwent
resection at a German hospital showed that patient age greater than 70
years (P < .05), Clavien grade of complications (P < .001), positive lymph
vessels (P < .001), mechanical ventilation (P < .001), and body massindex (BMI) (P < .05) were significantly associated with survival.197
Resection is recommended only in the setting of preserved liver function.
The Child-Pugh score provides an estimate of liver function, although it
has been suggested that it is more useful as a tool to rule out patients forliver resection (ie, serving as a means to identify patients with substantiallydecompensated liver disease).198 An evaluation of the presence ofsignificant portal hypertension is also an important part of the surgicalassessment. A meta-analysis including 11 studies showed that clinicallysignificant portal hypertension is associated with increased 3- and 5-year
mortality (pooled odds ratio [OR], 2.09; 95% CI, 1.52–2.88 for 3-year
mortality; pooled OR, 2.07; 95% CI, 1.51–2.84 for 5-year mortality), as wellas postoperative clinical decompensation (pooled OR, 3.04; 95% CI, 2.02–
4.59).199 In general, evidence of optimal liver function in the setting of liverresection is characterized by a Child-Pugh class A score and absence ofVersion 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-13

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
portal hypertension. However, in highly selected cases, patients with aChild-Pugh class B score may be considered for limited liver resection,
particularly if liver function tests are normal and clinical signs of portal
hypertension are absent. Further, limited resection may be feasible incases where portal hypertension is mild. A prospective observational studyof 223 cirrhotic patients with HCC showed that, though portal hypertension
was significantly associated with liver-related morbidity following resection,
it was only associated with worse survival when there was biochemical
evidence of liver decompensation. A multivariate analysis showed thatalbumin, but not portal hypertension, was significantly associated withsurvival following resection.200
With respect to tumor characteristics and estimates of the FLR following
resection, preoperative imaging is essential for surgical planning.98
CT/MRI can be used to facilitate characterization of the number and sizeof the HCC lesions in order to detect the presence of satellite nodules,
extrahepatic metastasis, and tumor invasion of the portal vein or thehepatic veins/inferior vena cava, and to help establish the location of thetumors with respect to vascular and biliary structures.
Optimal tumor characteristics for liver resection are solitary tumors withoutmajor vascular invasion. Although no limitation on the size of the tumor is
specified for liver resection, the risk of vascular invasion and dissemination
increases with size.190,201 However, in one study no evidence of vascularinvasion was seen in approximately one-third of patients with single HCC
tumors ≥10 cm.190 Nevertheless, the presence of macro- or microscopic
vascular invasion is a strong predictor of HCC recurrence.190,202,203 The roleof liver resection for patients with limited and resectable multifocal disease
and/or signs of major vascular invasion is controversial, as the recurrence
rates are extremely high.189,202,204 A systematic review including 23 studies
with 2412 patients showed that predicted 5-year OS and DFS rates forpatients with multinodular disease who underwent resection were 35%

and 22%, respectively.205 The authors also examined survival rates ofpatients with macrovascular invasion who underwent resection (29 studies
with 3659 patients). The 5-year predicted OS and DFS rates were 20%
and 16%, respectively. Results of a retrospective analysis showed a
5-year OS rate of 81% for selected patients with a single tumor ≤5 cm, or
3 or fewer tumors ≤3 cm undergoing liver resection.206
Another critical preoperative assessment includes evaluation of the
postoperative FLR volume, which serves as an indicator of postoperative
liver function. Cross-sectional imaging is used to measure the FLR andtotal liver volume. The ratio of future remnant/total liver volume(subtracting tumor volume) is then determined.207 The panel recommends
that this ratio be at least 20% in patients without cirrhosis and at least 30%
to 40% in patients with chronic liver disease and a Child-Pugh A
score.208,209 For patients with an estimated FLR/total liver volume ratio
below recommended values who are otherwise suitable candidates forliver resection, preoperative portal vein embolization (PVE) should beconsidered. PVE is a safe and effective procedure for redirecting bloodflow toward the portion of the liver that will remain following surgery.210
Hypertrophy is induced in these segments of the liver while the embolized
portion of the liver undergoes atrophy.211 There are some investigational
methods focused on improving FLR growth, such as PVE combined with
hepatic vein embolization or with arterial embolization The estimatedfuture liver remnant function (eFLRF), which accounts for individual
differences in body surface area, can also be calculated.212 A comparisonof the two methods showed that the eFLRF deviated from the FLR by ≥5%
in 32% of 116 patients enrolled.213
In one analysis, Roayaie et al categorized 8656 patients with HCC from
Asia, Europe, and North America into one of four groups: 1) met standard
criteria for resection and underwent resection (n = 718); 2) met standard
criteria for resection but did not undergo resection (n = 144); 3) did not

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-14

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
meet standard criteria for resection but underwent resection (n = 1624);
and 4) did not meet standard criteria for resection and did not undergo
resection (n = 6170).214 For patients who met criteria for resection(including those who did not actually undergo resection), receiving atreatment other than resection was associated with an increased risk ofmortality (hazard ratio [HR], 2.07; 95% CI, 1.35–3.17; P < .001). For
patients who did not meet criteria for resection (including those who
underwent resection), resection was associated with greater survival,
relative to embolization (HR, 1.43; 95% CI, 1.27–1.61; P < .001) and othertreatments (eg, yttrium-90 (Y-90) radioembolization, external beam
radiation therapy [EBRT], systemic therapy) (HR, 1.78; 95% CI, 1.36–2.34,
P < .001). However, survival rates for resection in these patients were
worse than those for ablation (HR, 0.85; 95% CI, 0.74–0.98, P = .022) andtransplantation (HR, 0.20; 95% CI, 0.14–0.27, P < .001). Despite the factthat these study results are powerfully influenced by selection bias, thestudy investigators suggest that criteria for resection could potentially be
expanded, since patients who are not considered candidates for resection
based on current criteria may still benefit.
Postoperative Adjuvant Therapy
The phase III STORM trial examined sorafenib, an antiangiogenic agent
approved for treating unresectable HCC, for use in the adjuvant setting forpatients who underwent hepatic resection or ablation with curative intent.
This international trial accrued 1114 patients, 62% of whom were Asian.215
Patients were randomized to receive sorafenib (800 mg daily) or placebo
until progression or for a maximum duration of 4 years. Treatmentemergent adverse events were high in both study groups, and sorafenib
was not well tolerated at the intended study dose (median dose achieved
was 578 mg daily [72.3% of the intended dose]). No significant betweengroup differences were observed in OS, recurrence-free survival (RFS),
and time to recurrence (TTR). The panel does not recommend sorafenib
as adjuvant therapy.

A study of 200 patients with microvascular invasion-HCC (MVI-HCC)
found that adjuvant TACE after resection led to significantly higher OS (P= 0.03), especially in patients with tumor diameter >5 cm or multinodular
tumors.216 DFS was also improved in these patients. A meta-analysis of 12
studies and 2,190 patients found similar results. However, more studies
are needed to validate these findings.217
Historically, postoperative prognosis for patients with HBV-related HCC
has been poor. In a two-stage longitudinal study that enrolled 780 patientswith HBV infection and HCC, viral load above 10,000 copies per milliliter
was correlated with poor outcomes.218 Adjuvant antiviral therapy in a
postoperative setting may improve outcomes. In a randomized trial
including 163 patients, antiviral therapy with lamivudine, adefovir, dipivoxil,or entecavir significantly decreased HCC recurrence (HR, 0.48; 95% CI,
0.32–0.70) and HCC-related death (HR, 0.26; 95% CI, 0.14–0.50), andimproved liver function at 6 months after surgery (P = .001).218 In another
RCT including 200 patients who received R0 resection for HBV-related
HCC, adefovir improved RFS (P = .026) and OS (P = .001), relative tothose who did not receive adefovir.219 The RR of mortality with adefovir
after resection was 0.42 (95% CI, 0.27–0.65; P < .001), and results
indicated that antiviral therapy may protect against late tumor recurrence(HR, 0.35; 95% CI, 0.18–0.69; P = .002).
With the recent availability of newer potent antiviral therapies for chronic
hepatitis C viral infection, similar trials are anticipated. Two meta-analyses
showed that antiviral therapy for HBV or HCV after curative HCC
treatment may improve outcomes including survival.220,221 A recent metaanalysis including 10 studies with 1794 patients with HCV showed thatsustained viral response is associated with improved OS (HR, 0.18; 95%
CI, 0.11–0.29) and better RFS (HR, 0.50; 95% CI, 0.40–0.63) following
resection or locoregional therapy for HCC.222 There is some concern thatthe rising use of DAAs might increase HCC recurrence or progression

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-15

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
following treatment.223-225 This is an area of controversy, and well-designed
trials are needed to determine the mechanism through which HCC
incidence increases.223,224 The panel recommends that providers discuss
the potential use of antiviral therapy with a hepatologist to individualize
postoperative therapy.
A meta-analysis including five studies (two RCTs and three case-control
studies) with 334 patients showed that I131 lipiodol injected into the hepatic
artery following resection may improve DFS (Peto OR, 0.47; 95% CI,
0.37–0.59) and OS (Peto OR, 0.50; 95% CI, 0.39–0.64).226 However, more
randomized studies with long follow-up are needed to determine thebenefit of this treatment in patients with resected HCC.
Immunotherapy, or using the immune system to treat cancer, is beginningto be investigated as adjuvant HCC treatment. A systematic review of
adjuvant treatment options for HCC including 14 studies (twoimmunotherapy studies with 277 patients) showed that immunotherapy
may prevent recurrence in resected HCC.227 In a Korean phase III
randomized trial, the efficacy and safety of activated cytokine-induced
killer cells was examined as adjuvant immunotherapy for HCC.228 Patients(N = 230) who received the adjuvant immunotherapy had greater RFS
relative to patients in the control group (HR, 0.63; 95% CI, 0.43–0.94; P =.01). Data are currently too preliminary for the panel to provide specificrecommendations regarding immunotherapy treatment in an adjuvant
setting.
Liver Transplantation

Liver transplantation is a potentially curative therapeutic option for patientswith early HCC. It is especially appealing since it removes both detectableand undetectable tumor lesions, treats underlying liver cirrhosis, andavoids surgical complications associated with a small FLR. However, there
is also a risk of potential complications such as early mortality and issues
related to chronic immunosuppression.229 In a landmark study published in

1996, Mazzaferro et al proposed the Milan criteria (single tumors ≤5 cm indiameter or no more than three nodules ≤3 cm in diameter in patients withmultiple tumors and no macrovascular invasion) for patients withunresectable HCC and cirrhosis.230 The 4-year OS and RFS rates were85% and 92%, respectively, when liver transplantation was restricted to a
subgroup of patients meeting the Milan selection criteria. These results
have been supported by studies in which patient selection for livertransplantation was based on these criteria.231 These selection criteria
were adopted by UNOS, because they identify a subgroup of patients with
HCC whose liver transplantation results are similar to those who
underwent liver transplantation for end-stage cirrhosis without HCC.
The UNOS criteria (radiologic evidence of a single lesion ≥2 cm and ≤5
cm in diameter, or 2–3 lesions ≥1 cm and ≤3 cm in diameter, and noevidence of macrovascular involvement or extrahepatic disease) specify
that patients eligible for liver transplantation should not be candidates forliver resection.232 Therefore, liver transplantation has been generally
considered to be the initial treatment of choice for well selected patientswith early-stage HCC and moderate-to-severe cirrhosis (ie, patients withChild-Pugh class B and C scores), with partial hepatectomy generally
accepted as the best option for the first-line treatment of patients withearly-stage HCC and Child-Pugh class A scores when tumor location isamenable to resection. Retrospective studies have reported similar
survival rates for hepatic resection and liver transplantation in patients withearly-stage HCC when accounting for the fallout while on waiting lists fortransplantation.193,233-236 However, there are no prospective randomized
studies that have compared the effectiveness of liver resection and livertransplantation for this group of patients.
The MELD score as a measure of liver function is also used as a measureof pre-transplant mortality.150 The MELD score was adopted by UNOS in
2002 to provide an estimate of risk of death within 3 months for patients on

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-16

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
the waiting list for cadaveric liver transplant. MELD score is also used by
UNOS to assess the severity of liver disease and prioritize the allocation of
the liver transplants. According to the current Organ Procurement andTransplantation Network (OPTN) policy, patients with AFP levels ≤1000
ng/mL and with T2 tumors are eligible for a standardized MELD
exception.237 In a retrospective analysis of data provided by UNOS of
15,906 patients undergoing first-time liver transplantation during 1997 to
2002 and 19,404 patients undergoing the procedure during 2002 to 2007,
4.6% of liver transplant recipients had HCC compared with 26% in 2002 to
2007, with most patients in the latter group receiving an “HCC MELD
exception.”238 From 2002 to 2007, patients with an “HCC MELD-exception”
had similar survival to patients without HCC. Important predictors of poor
post-transplantation survival for patients with HCC were a MELD score of≥20 and serum AFP level of ≥455 ng/mL,238 although the reliability of the
MELD score as a measure of post-transplantation mortality iscontroversial. Survival was also significantly lower for the subgroup ofpatients with HCC tumors between 3 and 5 cm.
Expansion of the Milan/UNOS criteria to provide patients who havemarginally larger HCC tumors with liver transplant eligibility is an active
area of debate, with exceptional cases frequently prompting analysis andrevisions.176,231,239,240 An expanded set of criteria including patients with asingle HCC tumor ≤6.5 cm, with a maximum of 3 total tumors with notumor larger than 4.5 cm (and cumulative tumor size <8 cm) as livertransplant candidates has been proposed by Yao et al at the University ofCalifornia at San Francisco (UCSF).241,242 Studies evaluating the posttransplantation survival of patients who exceed the Milan criteria but meet
the UCSF criteria show wide variation in 5-year survival rates (range of
38%–93%).239-241,243-245 An argument in favor of expanding theMilan/UNOS criteria includes the general recognition that many patientswith HCC tumors exceeding the Milan criteria can be cured by livertransplant. Opponents of an expansion of the Milan/UNOS criteria cite theincreased risk of vascular invasion and tumor recurrence associated withlarger tumors and higher HCC stage, the shortage of donor organs, andtaking organs away from patients with liver failure who do not have
HCC.231,239,243 Some support for the former objection comes from a large
retrospective analysis of the UNOS database showing significantly lower
survival for the subgroup of patients with tumors between 3 and 5 cmcompared with those who had smaller tumors.238
There is a risk of tumor recurrence following liver transplantation. A groupfrom France argued that the Milan criteria may be overly restrictive andthus developed a predictive model of HCC recurrence that combines AFP
value with tumor size and number.246 Analyses from samples of patientsfrom France and Italy who underwent liver transplantation showed that this
AFP model predicted an increase in 5-year risk of recurrence anddecreased survival.246,247 The panel does not provide specificrecommendations regarding whether or not AFP should be considered atransplant criterion, and this may depend on local practice. Anotheranalysis of patients who underwent liver transplantation (N = 1061)
showed that MVI, AFP at time of transplant, and sum of the largest
diameter of viable tumor plus number of viable tumors on explant wereassociated with HCC recurrence.248
Resection or liver transplantation can be considered for patients withChild-Pugh Class A liver function who meet UNOS criteria(www.unos.org/) and are resectable. Controversy exists over which initialstrategy is preferable to treat such patients. The guidelines recommendthat these patients be evaluated by a multidisciplinary team when deciding
an optimal treatment approach. The OPTN has proposed imaging criteria
for patients with HCC who may be candidates for transplant.131
Specifically, they propose a classification system for nodules identified bywell-defined imaging from contrast-enhanced CT or MRI. OPTN also
provides guidance on equipment specifications and use of a standardized

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-17

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
protocol. While the panel does not have a recommendation regarding livertransplantation in older adults with HCC, some centers report transplant inhighly selected patients older than 70 years.249,250 A systematic review of
50 studies with 4,169 elderly patients and 13,158 young patients with HCC
found that while old age increased the risk of mortality after resection(3.0% vs. 1.2%), the 5-year OS was only marginally lower (51% vs.
56%).251
Bridge Therapy
Bridge therapy is used to decrease tumor progression and the dropout
rate from the liver transplantation waiting list.252 It is considered forpatients who meet the transplant criteria. An analysis including 205
patients from a transplant center registry who had HCC showed thatbridging locoregional therapy was associated with survival following
transplant (P = .005).253 A number of studies have investigated the role oflocoregional therapies as a bridge to liver transplantation in patients on a
waiting list.254,255 These studies included RFA/microwave ablation(MWA);256-259 transarterial embolization (TAE);260,261 TACE,258,262 including
conventional TACE258,263,264 and TACE with drug-eluting beads(DEB-TACE);265 selective internal radiotherapy (SIRT) or
radioembolization (TARE) with Y-90 microspheres;266 EBRT;267 and TACE
followed by EBRT,268 as “bridge” therapies.
A recent meta-analysis showed that bridge therapy did not significantly
impact post-transplantation mortality, survival, and recurrence rates,
compared to transplant alone.269 The small size and retrospective
methodology of studies in this area, as well as the heterogeneous natureof the study populations, and the absence of RCTs evaluating the utility ofbridge therapy for reducing the liver transplantation waiting list drop-out
rate, limit the conclusions that can be drawn.269-271 Nevertheless, the useof bridge therapy in this setting is increasing, and it is administered at most

NCCN Member Institutions, especially in areas where there are long wait
times for a transplant.
Downstaging Therapy
Downstaging therapy is used to reduce the tumor burden in selectedpatients with more advanced HCC (without distant metastasis) who arebeyond the accepted transplant criteria with the goal of futuretransplant.252,272,273 A meta-analysis including three studies showed that
downstaging therapy was associated with increased 1- (RR, 1.11; 95% CI,
1.01–1.23) and 5-year survival (RR, 1.17; 95% CI, 1.03–1.32) posttransplant, compared to transplant alone.269 Downstaging therapy did not
significantly increase RFS. However, the three studies included in theseanalyses were heterogeneous and biased by the fact that outcomes were
measured in patients who responded well to therapy. A systematic review
including 13 studies with 950 patients showed that downstaging
decreased tumor burden to within Milan criteria (pooled success rate of
0.48; 95% CI, 0.39–0.58), with recurrence rates after transplantation at
16% (95% CI, 0.11–0.23).274 Candidates are eligible for a standardized
MELD exception if, before completing locoregional therapy, they havelesions that meet one of the following: 1) one lesion >5 cm and ≤8 cm, 2)
two or three lesions that meet all of the following: each lesion ≤5 cm, withat least one lesion >3 cm and a total diameter of all lesions ≤8 cm, and 3)
four or five lesions each <3 cm, and a total diameter of all lesions ≤8cm.237 The UCSF criteria can be used as the current limit for considerationof downstaging and potential candidates for this therapy should beassessed by a transplant center.
Prospective studies have demonstrated that downstaging (prior totransplant) with percutaneous ethanol injection (PEI),275 RFA,275,276
TACE,275-279 TARE with Y-90 microspheres,278 and transarterial
chemoinfusion280 is associated with improved outcomes such as DFS andrecurrence following transplant. However, such studies have used different

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-18

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
selection criteria for the downstaging therapy and different transplantcriteria after successful downstaging. In some studies, response tolocoregional therapy has been associated with good outcomes after
transplantation.281-283 In a phase IIb/III randomized trial, patients underwent
downstaging with locoregional, surgical, or systemic therapies. Livertransplantation was then performed in one group.284 The results showedthat transplantation improved the 5-year tumor–free survival (77% vs.
18%) and the 5-year OS (78% vs. 31%) compared to non-transplantation.
Further validation is needed to define the endpoints for successful
downstaging prior to transplant.273
The NCCN Guidelines recommend that patients meeting the UNOS
criteria be considered for transplantation using either cadaveric or living
donation. Patients with tumor characteristics that are marginally outside of
the UNOS guidelines may be considered for transplantation at selectinstitutions. For patients with initial tumor characteristics beyond the Milancriteria who have undergone successful downstaging therapy (ie, tumor
currently meeting Milan criteria), transplantation can also be considered.
Locoregional Therapies

Locoregional therapies are directed toward inducing selective tumor
necrosis, and are broadly classified into ablation, arterially directed
therapies, and radiation therapy (RT). Tumor necrosis induced bylocoregional therapy is typically estimated by the extent to which contrast
uptake on dynamic CT/MRI is diminished at a specified time following thetreatment when compared with pretreatment imaging findings. The
absence of contrast uptake within the treated tumor is believed to be anindication of tumor necrosis. A number of factors are involved inmeasuring the effectiveness of locoregional therapies, and the criteria forevaluating tumor response are evolving.161,285-288 A few studies haveshown that the use of modified RECIST (mRECIST) is more suitable than
RECIST.289,290 AFP response after locoregional therapy has also beenreported to be a reliable predictor of tumor response, time to progression(TTP), PFS, and OS.291
Ablation
In an ablative procedure, tumor necrosis can be induced either by thermal
ablation (RFA or MWA), or cryoablation. Ablative procedures can be
performed by percutaneous, laparoscopic, or open approaches. RFA and
MWA have largerly replaced PEI, although PEI is used in select patients.
The safety and efficacy of RFA and PEI in the treatment of Child-Pughclass A patients with early-stage HCC tumors (either a single tumor ≤5 cm
or multiple tumors [up to 3 tumors] each ≤3 cm) has been compared in a
number of RCTs.292-299 Both RFA and PEI were associated with relatively
low complication rates. RFA was shown to be superior to PEI with respect
to complete response (CR) rate (65.7% vs. 36.2%, respectively; P =.0005)297 and local recurrence rate (3-year local recurrence rates were
14% and 34%, respectively; P = .012).295 Local tumor progression rates
were also significantly lower for RFA than for PEI (4-year local tumor
progression rates were 1.7% and 11%, respectively; P = .003).296
In addition, in two studies, patients in the RFA arm were shown to require
fewer treatment sessions.293,296 However, an OS benefit for RFA over PEI
was demonstrated in three randomized studies performed in Asia,294-296
whereas three European randomized studies failed to show a significant
difference in the OS between the two treatment arms.293,297,298 In an Italianrandomized trial of 143 patients with HCC, the 5-year survival rates were
68% and 70%, respectively, for PEI and RFA groups; the corresponding
RFS rates were 12.8% and 11.7%, respectively.298 Nevertheless,independent meta-analyses of randomized trials that have compared RFA
and PEI have concluded that RFA is superior to PEI with respect to OS
and tumor response in patients with early-stage HCC, particularly fortumors larger than 2 cm.300-302 Results of some long-term studies show

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-19

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
survival rates of greater than 50% at 5 years for patients with early HCC
treated with RFA.303-306

studies support ablation as an alternative to resection in patients withsmall (<3 cm), properly located tumors.

The reported OS and recurrence rates vary widely across the studies forpatients treated with RFA, which is most likely due to differences in thesize and number of tumors and, perhaps more importantly, tumor biology
and the extent of underlying liver function in the patient populations
studied. In a multivariate analysis, Child-Pugh class, tumor size, and tumor
number were independent predictors of survival.304-306

RFA has been compared to resection in some meta-analyses, which haveshown that resection is generally associated with better survival outcomesthan RFA313-315 but is associated with more complications and morbidityfrom complications.313,315 Subgroup analyses from one meta-analysis
showed no significant differences in 1-year mortality and disease
recurrence when including only studies with patients who had solitary or
small tumors (>3 cm).314 One meta-analysis comparing RFA to resection
in recurrent HCC (including 6 retrospective comparative studies) showedthat 3- and 5-year DFS rates were greater for resection, relative to RFA(OR, 2.25; 95% CI, 1.37–3.68; P = .001; OR, 3.70; 95% CI, 1.98–6.93; P <.001, respectively).316

RFA and PEI have also been compared with resection in randomized
studies. In the only randomized study that compared PEI with resection in
76 patients without cirrhosis, with one or two tumors 3 cm or smaller, PEI
was equally as effective as resection.307 On the other hand, studies thathave compared RFA and resection have failed to provide conclusive
evidence (reviewed by Weis et al299). RFA and liver resection in thetreatment of patients with HCC have been compared in randomized
prospective studies.308-312 The results of one randomized trial showed asignificant survival benefit for resection over RFA in 235 patients withsmall HCC conforming to the Milan criteria.309 The 5-year OS rates were
54.8% and 75.6%, respectively, for the RFA group and resection. The
corresponding RFS rates for the two groups were 28.7% and 51.3%,
respectively. However, more patients in the resection group were lost tofollow-up than the RFA group. Conversely, other randomized studies
demonstrated that percutaneous local ablative therapy with RFA is aseffective as resection for patients with early-stage disease (eg, small
tumors).308,310-312 These studies failed to show statistically significant
differences in OS and DFS between the two treatment groups. In addition,in one of the studies, tumor location was an independent risk factor
associated with survival.310 These studies, however, were limited by thesmall number of patients (180 patients and 168 patients, respectively) andthe lack of a non-inferiority design. Nevertheless, results from these

Subgroup analyses from some retrospective studies suggest that tumor
size is a critical factor in determining the effectiveness of RFA or
resection.256,257,317-319 Mazzaferro et al reported findings from a prospective
study of 50 consecutive patients with liver cirrhosis undergoing RFA while
awaiting liver transplantation (the rate of overall complete tumor necrosis
was 55% [63% for tumors ≤3 cm and 29% for tumors ≥3 cm]).257 In a
retrospective analysis, Vivarelli et al reported that OS and DFS weresignificantly higher with surgery compared to percutaneous RFA. The
advantage of surgery was more evident for Child-Pugh class A patientswith single tumors >3 cm in diameter, and the results were similar in 2
groups for Child-Pugh class B patients.318 In another retrospective analysisof 40 Child-Pugh class A or B patients with HCC treated withpercutaneous ablative procedures, the overall rate of complete necrosis
was 53%, which increased to 62% when considering only the subset oftumors <3 cm treated with RFA.256 In a propensity case-matched study
that compared liver resection and percutaneous ablative therapies in 478
patients with Child-Pugh A cirrhosis, survival was not different between

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-20

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
resection and ablation for tumors that met the Milan criteria; however,resection was associated with significantly improved long-term survival forpatients with single HCC tumors larger than 5 cm or multiple tumors (up to
3 tumors) larger than 3 cm.319 Median survival for the resection group was
80 months and 83 months, respectively, compared to 21.5 months and 19
months, respectively, for patients treated with ablative procedures.
Some investigators consider RFA as the first-line treatment in highly
selected patients with HCC tumors that are ≤2 cm in diameter in anaccessible location and away from major vascular and biliary structures
and adjacent organs.320,321 In one study, RFA as the initial treatment in 218
patients with a single HCC lesion ≤2.0 cm induced complete necrosis in
98% of patients (214 of 218 patients).320 After a median follow-up of 31
months, the sustained CR rate was 97% (212 of 218 patients). In a
retrospective comparative study, Peng et al reported that percutaneous
RFA was better than resection in terms of OS and RFS, especially forpatients with central HCC tumors <2 cm.321 The 5-year OS rates inpatients with central HCC tumors were 80% for RFA compared to 62% forresection (P = .02). The corresponding RFS rates were 67% and 40%,
respectively (P = .033).
MWA is an alternative to RFA for the treatment of patients with small orunresectable HCC.322-326 So far, only two randomized trials have compared
MWA with resection and RFA.322,326 In the RCT that compared RFA withpercutaneous microwave coagulation, no significant differences wereobserved between these two procedures in terms of therapeutic effects,
complication rates, and the rates of residual foci of untreated disease.322 In
a randomized study that evaluated the efficacy of MWA and resection in
the treatment of HCC conforming to Milan criteria, MWA was associatedwith lower DFS rates than resection with no differences in OS rates.326
Irreversible electroporation (IRE) is an emerging modality for tumor
ablation.327 It targets tumor tissue by delivering non-thermal high-voltage

electric pulses. By doing so, it increases permeability of the cell
membrane, disrupting cellular homeostasis and triggering apoptosis. IRE
has some advantages over RFA, notably the lack of “heat sink” effect andthe ability to treat near vessels, bile ducts, and other criticalstructures.328,329 However, IRE can cause cardiac arrhythmias anduncontrolled muscle contractions.330 Some small studies have shown thatIRE treatment for unresectable HCC is safe and feasible.331-333 In a small
nonrandomized trial including 30 patients with malignant liver tumors,none of the eight patients with HCC experienced a recurrence through 6month follow-up.333 Recurrences have been reported following IRE forlarger tumors.330,332 Larger studies are needed to determine theeffectiveness of IRE for local HCC treatment.
Although inconclusive, available evidence suggests that the choice of
ablative therapy for patients with early-stage HCC should be based ontumor size and location, underlying liver function, as well as available local
radiologist expertise and experience. Ablative therapies are most effective
for tumors <3 cm that are in an appropriate location away from otherorgans and major vessels/bile ducts, with the best outcomes in tumors <2cm.
Arterially Directed Therapies
Arterially directed therapy involves the selective catheter-based infusion ofparticles targeted to the arterial branch of the hepatic artery feeding the
portion of the liver in which the tumor is located.334 Arterially directed
therapy is made possible by the dual blood supply to the liver; whereas the
majority of the blood supply to normal liver tissue comes from the portal
vein, blood flow to liver tumors is mainly from the hepatic artery.96
Furthermore, HCC tumors are hypervascular resulting from increased
blood flow to tumor relative to normal liver tissue. Arterially directed
therapies that are currently in use include TAE, conventional TACE,DEB-TACE, and SIRT/TARE with Y-90 microspheres.

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-21

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
The principle of TAE is to reduce or eliminate blood flow to the tumor,
resulting in tumor ischemia followed by tumor necrosis. Gelatin sponge
particles, polyvinyl alcohol particles, and polyacrylamide microspheres
have been used to block arterial flow. TAE has been shown to be aneffective treatment option for patients with unresectable HCC.335-338 In a
multicenter retrospective study of 476 patients with unresectable HCC,
TAE was associated with prolonged survival compared to supportive care
(P = .0002). The 1-, 2-, and 5-year survival rates were 60.2%, 39.3%, and11.5%, respectively, for patients who underwent TAE. The corresponding
survival rates were 37.3%, 17.6%, and 2%, respectively, for patients who
underwent supportive care.336 In a multivariate analysis, tumor size <5 cm
and earlier CLIP stage were independent factors associated with a better
survival. In another retrospective analysis of 322 patients undergoing TAE
for the treatment of unresectable HCC in which a standardized technique(including small particles to cause terminal vessel blockade) was used, 1-,2-, and 3-year OS rates of 66%, 46%, and 33%, respectively, wereobserved. The corresponding survival rates were 84%, 66%, and 51%,
respectively, when only the subgroup of patients without extrahepatic
spread or portal vein involvement was considered.337 In multivariate
analysis, tumor size 5 cm or larger, 5 or more tumors, and extrahepaticdisease were identified as predictors of poor prognosis following TAE.
TACE is distinguished from TAE in that, in addition to arterial blockade,the goal is to also deliver a highly concentrated dose of chemotherapy totumor cells, prolong the contact time between the chemotherapeutic
agents and the cancer cells, and minimize systemic toxicity ofchemotherapy.339 The results of two RCTs and one retrospective casecontrol study have shown a survival benefit for TACE compared withsupportive care in patients with unresectable HCC.340-342 In one study that
randomized patients with unresectable HCC to TACE or best supportive
care, the actuarial survival was significantly better in the TACE group (1year, 57%; 2 years, 31%; 3 years, 26%) than in the control group (1 year,

32%; 2 years, 11%; 3 years, 3%; P = .002).340 Although death from liver
failure was more frequent in patients who received TACE, the liverfunction of the survivors was not significantly different between the twogroups. In the other randomized study, which compared TAE and TACE
with supportive care for patients with unresectable HCC, the 1- and 2-year
survival rates were 82%; 63%, 75%, and 50%; and 63% and 27% forpatients in the TACE, TAE, and supportive care arms, respectively.341 The
majority of the patients in the study had liver function classified asChild-Pugh class A, a performance status of 0, and a main tumor nodule
size of about 5 cm. For the group of evaluable patients receiving TACE or
TAE, partial response (PR) and CR rates sustained for at least 6 months
were observed in 35% (14/40) and 43% (16/37), respectively. However,this study was terminated early due to an obvious benefit associated with
TACE. Although this study demonstrated that TACE was significantly more
effective than supportive care (P = .009), there were insufficient patients in
the TAE group to make any statement regarding its effectivenesscompared to either TACE or supportive care. In a randomized trial, theeffectiveness of TAE was compared to that of doxorubicin-based TACE in
101 patients with HCC.343 Study investigators did not find statisticallysignificant differences in response, PFS, and OS between the two groups.
Some institutions prefer the use of bland embolization using particles
without chemotherapy.343
A retrospective analysis of patients with advanced HCC who had
undergone embolization in the past 10 years revealed that TACE (withdoxorubicin plus mitomycin C) is significantly associated with prolonged
PFS and TTP but not OS, as compared to TAE.344 In a multivariable
analysis, the type of embolization and CLIP score were significant
predictors of PFS and TTP, whereas CLIP score and AFP wereindependent predictors of OS.

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-22

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
Many of the clinical studies evaluating the effectiveness of TAE and/or
TACE in the treatment of patients with HCC are confounded by use of awide range of treatment strategies, including type of embolic particles,
type of chemotherapy and type of emulsifying agent (for studies involving
TACE), and number of treatment sessions. In a randomized trial, theeffectiveness of TAE was compared to that of doxorubicin-based TACE in
101 patients with HCC.343 Study investigators did not find statisticallysignificant differences in response, PFS, and OS between the two groups.
Complications common to TAE and TACE include non-target
embolization, liver failure, pancreatitis, and cholecystitis. Additional
complications following TACE include acute portal vein thrombosis (PVT),
bone marrow suppression, and pancreatitis (very rare), although thereported frequencies of serious adverse events vary across studies.77,345
Reported rates of treatment-related mortality for TAE and TACE areusually well under 5%.77,337,341,345 A transient post-embolization syndrome
involving fever, abdominal pain, and intestinal ileus is relatively common inpatients undergoing these procedures.77,345 A retrospective study from asingle institution in Spain showed that PVT and liver function categorized
as Child-Pugh class C were significant predictors of poor prognosis inpatients treated with TACE.346 However, TACE has since been shown tobe safe and feasible in highly selected patients with HCC and PVT,347
and results of a meta-analysis (5 prospective studies with 600 patients)
showed that TACE may improve survival in these patients, compared topatients who received control treatments.348 Therefore, the panel
considers TACE to be safe in highly selected patients who have limited
tumor invasion of the portal vein. TACE is not recommended in those withliver function characterized as Child-Pugh class C (absolutecontraindication). Because TAE can increase the risk of liver failure,
hepatic necrosis, and liver abscess formation in patients with biliary
obstruction, the panel recommends that a total bilirubin level >3 mg/mL
should be considered as a relative contraindication for TACE or TAE

unless segmental treatment can be performed. Furthermore, patients withprevious biliary enteric bypass have an increased risk of intrahepatic
abscess following TACE and should be considered for prolonged antibiotic
coverage at the time of the procedure.349,350
TACE causes increased hypoxia leading to an up-regulation of vascularendothelial growth factor receptor (VEGFR) and insulin-like growth factor
receptor 2 (IGFR-2).351 Increased plasma levels of VEGFR and IGFR-2
have been associated with the development of metastasis after
TACE.352,353 These findings have led to the evaluation of TACE in
combination with sorafenib in patients with residual or recurrent tumor not
amenable to additional locoregional therapies.354-361
DEB-TACE has also been evaluated in patients with unresectable
HCC.362-369 A randomized study (PRECISION V) of 212 patients withlocalized, unresectable HCC with Child-Pugh class A or B cirrhosis andwithout nodal involvement, showed no difference in CR, objective
response, and disease control between DEB TACE withdoxorubicin-eluting embolic beads and conventional TACE withdoxorubicin.364 Overall, DEB-TACE was not superior to conventional
TACE with doxorubicin (P = .11) in this study. In a subgroup analysis,
DEB-TACE was associated with a significant increase in objective
response (P = .038) compared to conventional TACE in patients withChild-Pugh class B, ECOG performance status 1, bilobar disease, andrecurrent disease. DEB-TACE was also associated with improved
tolerability with a significant reduction in serious liver toxicity and asignificantly lower rate of doxorubicin-related side effects, compared toconventional TACE.364 In another small prospective randomized study (n =83), Malagari et al also showed that DEB-TACE resulted in higher
response rates, lower recurrences, and longer TTP compared to TAE inpatients with intermediate-state HCC; however, this study also did notshow any OS benefit for DEB-TACE.365 A randomized study comparing

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-23

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
DEB-TACE to conventional TACE in 177 patients with intermediate stage,unresectable, persistent, or recurrent HCC revealed no significant efficacy
or safety differences between the two approaches; however, DEB-TACE
was associated with less post-procedural abdominal pain.369 Conversely,
Dhanasekaran et al reported a survival advantage for DEB-TACE overconventional TACE in a prospective randomized study of 71 patients withunresectable HCC.366 However, these results are from underpowered
studies and need to be confirmed in large prospective studies. The
findings from a meta-analysis of 28 studies suggest that DEB-TACE led tolonger OS compared to TARE and conventional TACE.370 However, there
were lower complications associated with TARE.
Sorafenib following arterially directed therapies may be appropriate inpatients with adequate liver function once bilirubin returns to baseline, if
there is evidence of residual or recurrent tumor not amenable to additional
locoregional therapies.356-358 Results from non-randomized phase II
studies and a retrospective analysis suggest that concurrent
administration of sorafenib with TACE or DEB-TACE may be a treatment
option for patients with unresectable HCC.355-361,371 A meta-analysis
including 14 studies with 1670 patients with advanced HCC examined theefficacy and safety of TACE combined with sorafenib.372 Results showedthat this combination was associated with greater 1-year OS, compared to
TACE alone (OR, 1.88; 95% CI, 1.39–2.53; P < .001), but combination
therapy also resulted in greater frequency of some adverse events (handfoot skin reaction, diarrhea, hypertension, fatigue, hepatotoxicity, andrash). This meta-analysis is limited by lack of an evaluation of a longer
follow-up period. One meta-analysis of 13 studies with 2,538 patientsfound that the combination of TACE with sorafenib improved OS in the
Asian regions but not in non-Asian areas373 while another did not find adifference in OS in either region but noted a longer time to diseaseprogression in the Asian population but not the European population.374 Ina phase III randomized trial, sorafenib, when given following treatment

with TACE did not significantly prolong TTP or OS in patients withunresectable HCC that responded to TACE.361 Another phase III trial
determined that the combination of sorafenib with DEB-TACE did not
improve PFS.375 Currently, the panel does not recommend sorafenib
following TACE, given the lack of evidence to support this treatment
sequence.
TARE is a method that involves internal delivery of high-dose beta
radiation to the tumor-associated capillary bed, thereby sparing the normalliver tissue.334,376 TARE is accomplished through the catheter-based
administration of microspheres (glass or resin microspheres) embeddedwith Y-90, an emitter of beta radiation. There is a growing body ofliterature to suggest that radioembolization might be an effective treatment
option for patients with liver-limited, unresectable disease,377-382 thoughadditional RCTs are needed to determine the relative risks and benefits ofTARE with Y-90 microspheres in patients with unresectable HCC andlong-term impact on liver function.383 Delivery of 205 Gy or greater to thetumor may be associated with increased OS.384 Althoughradioembolization with Y-90 microspheres, like TAE and TACE, involves
some level of particle-induced vascular occlusion, it has been proposedthat such occlusion is more likely to be microvascular than macrovascular,
and that the resulting tumor necrosis is more likely to be induced byradiation rather than ischemia.377 RCTs have shown that Y-90 is notsuperior to sorafenib for treating advanced HCC.385,386 Radioembolization
may be appropriate in some patients with advanced HCC,385,386 specificallypatients with segmental or lobar portal vein, rather than main PVT.377
Reported complications of TARE include cholecystitis/bilirubin toxicity,
gastrointestinal ulceration, radiation-induced liver disease, and abscessformation.377,379,387 A PR rate of 42.2% was observed in a phase II study of
108 patients with unresectable HCC with and without PVT treated withTARE and followed for up to 6 months.377 Grade 3/4 adverse events were

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-24

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
more common in patients with main PVT. However, patients with branch
PVT experienced a similar frequency of adverse events related to elevatedbilirubin levels as patients without PVT. Results from a single-center,
prospective longitudinal cohort study of 291 patients with HCC treated withTARE showed a significant difference in median survival times based onliver function level (17.2 months for Child-Pugh class A patients and 7.7
months for Child-Pugh class B patients; P = .002).379 Median survival forChild-Pugh class B patients and those with PVT was 5.6 months. A metaanalysis including 17 studies with 722 patients with HCC and PVT showedthat median TTP, CR rate, PR rate, stable disease (SD) rate, progressive
disease rate, and OS were 5.6 months, 3.2%, 16.5%, 31.3%, 28%, and
9.7 months, respectively.388 Median OS for patients with Child-Pugh Class
B liver function (6.1 months) was lower than for patients with Child-PughClass A liver function (12.1 months), and lower for patients with main PVT(6.1 months) than for patients with branch PVT (13.4 months). Toxicities
reported in these studies included fatigue (2.9%–67%), abdominal pain
(2.9%–57%), and nausea/vomiting (5.7%–28%). Results from this metaanalysis suggest that TARE is safe and effective for patients with HCC
who have PVT.
A multicenter study analyzed radiation segmentectomy, a selective TARE
approach that limits radioembolization to two or fewer hepatic segments.
This technique was evaluated in 102 patients with solitary unresectable
HCC not amenable to RFA treatment due to tumor proximity to criticalstructures. The procedure resulted in CR, PR, and SD in 47%, 39%, and
12% of patients, respectively.382
In a meta-analysis including five studies, patients with unresectable HCC(N = 553) treated with TACE or TARE with Y-90 microspheres had similar
survival times and response rates.389 However, TARE resulted in a longer
TTP, less toxicity, and less post-treatment pain than TACE.389 Further,
TACE requires a one-day hospital stay, while TARE is usually an

outpatient procedure.389 Another meta-analysis including 14 studies
compared DEB-TACE to TARE with Y-90 microspheres in patients with
HCC and found that DEB-TACE had a superior 1-year OS rate (79% vs.
55%, respectively; OR, 0.57; 95% CI, 0.36–0.92; P = .02), though thisdifference is no longer statistically significant for 2-year and 3-year OS.390
These findings need to be confirmed in large RCTs.
Two recent phase III RCTs compared the efficacy and safety of TARE with
Y-90 microspheres to sorafenib in patients with locally advanced
HCC.385,386 In both trials, OS rates were not significantly different between
the two treatment groups. However, adverse events grade 3 or higher (eg,diarrhea, fatigue, hand-foot skin reaction) were more frequent in patientsrandomized to receive sorafenib than in patients randomized to receive
TARE.
Radiation Therapy
Radiation therapy options for patients with unresectable or inoperable
HCC include EBRT and stereotactic body radiation therapy (SBRT). EBRT
allows focal administration of high-dose radiation to liver tumors whilesparing surrounding liver tissue, thereby limiting the risk ofradiation-induced liver damage in patients with unresectable or inoperable
HCC.391,392 Advances in EBRT, such as intensity-modulated radiation
therapy (IMRT) and image–guided radiotherapy, have allowed forenhanced delivery of higher radiation doses to the tumor while sparing
surrounding critical tissue. SBRT is an advanced technique of EBRT thatdelivers large ablative doses of radiation. There is growing evidence(primarily from non-RCTs) supporting the usefulness of SBRT for patientswith unresectable, locally advanced, or recurrent HCC.393-397

In a phase II trial of 50 patients with inoperable HCC treated with SBRT
after incomplete TACE, SBRT induced CRs and PRs in 38.3% of patients
within 6 months of completing SBRT.396 The 2-year local control rate, OS,
and PFS rates were 94.6%, 68.7%, and 33.8%, respectively. In anotherMS-25
Version 1.2022 © 2022 National Comprehensive Cancer Network (NCCN ), All rights reserved. NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
©

©

®

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
study that evaluated the long-term efficacy of SBRT for patients withprimarily small HCC ineligible for local therapy or surgery (42 patients),
SBRT induced an overall CR rate of 33%, with 1- and 3-year OS rates of
92.9% and 58.6%, respectively.393 In patients with recurrent HCC treatedwith SBRT, tumor size, recurrent stage, and Child-Pugh were identified as
independent prognostic factors for OS in multivariate analysis.395 In areport from Princess Margaret Cancer Centre on 102 patients treated with
SBRT for locally advanced HCC in sequential phase I and phase II trials,
Bujold et al reported a 1-year local control rate of 87% and a mediansurvival of 17 months. The majority of these patients were at high risk withrelatively advanced-stage tumors (55% of patients had tumor vascularthrombosis, and 61% of patients had multiple lesions with a median sumof largest diameter of almost 10 cm and a median diameter of 7.2 cm forthe largest lesion).397 A retrospective analysis comparing RFA and SBRTin 224 patients with inoperable, nonmetastatic HCC showed that SBRT
may be a preferred option for tumors 2 cm or larger.398 However, anotherretrospective analysis from the National Cancer Database including 3980
patients with stage I or II HCC showed that 5-year OS was greater forpatients who received RFA, compared to patients who received SBRT
(30% vs. 19%, P < .001).399 SBRT has also been shown to be an effective
bridging therapy for patients with HCC and cirrhosis awaiting livertransplant.400-402
Most tumors, irrespective of their location, may be amenable to SBRT,IMRT, or conformal EBRT. SBRT dosing is usually 30 to 50 Gy in 3 to 5
fractions, depending on the ability to meet normal organ constraints andunderlying liver function.393,394,398,403,404 Hypofractionated schedules may
also be considered.405 SBRT is often used for patients with 1 to 3 tumors
with minimal or uncertain extrahepatic disease. There is no strict size limit,
so SBRT may be used for larger lesions if there is sufficient uninvolved
liver and liver radiation dose constraints can be respected. The majority ofsafety and efficacy data on the use of SBRT are available for patients with

HCC and Child-Pugh A liver function; limited safety data are available forthe use of SBRT in patients with Child-Pugh B or poorer liverfunction.394,397,403,405,406 Those with Child-Pugh B cirrhosis may require
dose modifications and strict dose constraint adherence to increase safety
in this population. The safety of SBRT for patients with Child-Pugh C
cirrhosis has not been established, as there are not likely to be clinical
trials available for this group of patients with a very poor prognosis.
In 2014, ASTRO (American Society for Radiation Oncology) released amodel policy supporting the use of proton beam therapy (PBT) in someoncology populations.407 In a phase II study, 94.8% of patients withunresectable HCC who received high-dose hypofractionated PBT
demonstrated >80% local control after two years, as defined by RECIST
criteria.408 In a meta-analysis including 70 studies, charged particle
therapy (mostly including PBT) was compared to SBRT and conventional
radiotherapy.409 OS (RR, 25.9; 95% CI, 1.64–408.5; P = .02), PFS (RR,
1.86; 95% CI, 1.08–3.22; P = .013), and locoregional control (RR, 4.30;
95% CI, 2.09–8.84; P < .001) through 5 years were greater for charged
particle therapy than for conventional radiotherapy. There were no
significant differences between charged particle therapy and SBRT forthese outcomes. In a comparison of PBT and IMRT, PBT was linked withhigher OS (31 months vs. 14 months), which could be due to deceased
occurrence of liver decompensation.410 Analyses from a prospective RCT
including 69 patients with HCC showed that PBT tended to be
associated with improved 2-year local control (P = .06), better PFS (P =.06), and fewer hospitalization days following treatment (P < .001),
relative to patients who received TACE.411 The panel advises that PBTmay be considered and appropriate in select settings for treating HCC.
Several ongoing studies are continuing to investigate the impact ofhypofractionated PBT on HCC outcomes (eg, NCT02632864), including
randomized trials comparing PBT to RFA (NCT02640924) and PBT to
TACE (NCT00857805). Hypofractionated PBT was evaluated in a phase

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-26

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
II study with 45 patients with HCC.412 At 3 years, the local PFS and OS
were 95.2% (95% CI, 89.1%–100%) and 86.4% (95% CI, 72.9%–99.9%)
respectively.
Combinations of Locoregional Therapies
Results from retrospective analyses suggest that the combination of TACE
with RFA is more effective (both in terms of tumor response and OS) than
TACE or RFA alone or resection in patients with single or multiple tumors
fulfilling the UNOS or Milan criteria206,413 or in patients with single tumors
up to 7 cm.414,415 The principle behind the combination of RFA andembolization is that the focused heat delivery of RFA may be enhanced byvessel occlusion through embolization since blood circulation inside thetumor may interfere with the transfer of heat to the tumor.
However, randomized trials that have compared the combination ofablation and embolization with ablation or embolization alone have shownconflicting results. Combination therapy with TACE and PEI resulted insuperior survival compared to TACE or PEI alone in the treatment ofpatients with small HCC tumors, especially for patients with HCC tumors
measuring <2 cm.416,417 In another randomized study, Peng et al reported
that the combination of TACE and RFA was superior to RFA alone interms of OS and RFS for patients with tumors <7 cm, although this study
had several limitations (small sample size and the study did not include
TACE alone as one of the treatment arms, thus making it difficult toassess the relative effectiveness of TACE alone compared to the
combination of TACE and RFA).418 In a prospective randomized study,
Shibata et al reported that the combination of RFA and TACE was equally
as effective as RFA alone for the treatment of patients with small (≤3 cm)
tumors.419 Conversely, results from other randomized trials indicate thatthe survival benefit associated with the combination approach is limited
only to patients with tumors that are between 3 cm and 5 cm.420,421 In the
randomized prospective trial that evaluated sequential TACE and RFA

versus RFA alone in 139 patients with recurrent HCC ≤5 cm, thesequential TACE and RFA approach was better than RFA in terms of OS
and RFS only for patients with tumors between 3.1 and 5.0 cm (P = .002
and P < .001) but not for those with tumors 3 cm or smaller (P = .478 and
P = .204).421 In a small RCT including 50 patients with an unresectablesingle HCC lesion (ie, larger than 4 cm, serum bilirubin >1.2 mg/dL, and/or
presence of esophageal varices), patients received either TACE alone,
TACE following RFA, or TACE following MWA.422 Patients who received
TACE alone had a greater recurrence rate one month after intervention
completion, compared to patients who received TACE with RFA or MWA(30% vs. 5% vs. 0%, respectively; P = .027). However, at 3- and 6-monthfollow-up, recurrence rates between the three groups were no longer
statistically significant.
The results of a meta-analysis of 10 RCTs comparing the outcomes ofTACE plus percutaneous ablation with those of TACE or ablation alone
suggest that while there is a significant OS benefit for the combination of
TACE and PEI compared to TACE alone for patients with large HCC
tumors, there was no survival benefit for the combination of TACE and
RFA in the treatment of small lesions as compared with that of RFA
alone.423
Therefore, available evidence suggests that the combination of TACE with
RFA or PEI may be effective, especially for patients with larger lesions that
do not respond to either procedure alone. A meta-analysis including 25
studies with 2577 patients with unresectable HCC showed that TACE
combined with RT (eg, 3D-CRT, SBRT) was associated with a complete
tumor response (OR, 2.73; 95% CI, 1.95–3.81) and survival through 5
years (OR, 3.98; 95% CI, 1.89–8.50), compared with TACE delivered
alone.424 However, this combination was also associated with increased
gastroduodenal ulcers (OR, 12.80; 95% CI, 1.57–104.33), levels of ALT

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-27

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers(OR, 2.46; 95% CI, 1.30–4.65), and total bilirubin (OR, 2.16; 95% CI,
1.05–4.45).
A Cochrane review including nine RCTs with 879 patients withunresectable HCC showed that EBRT combined with TACE is associatedwith lower 1-year mortality (RR, 0.51; 95% CI, 0.41–0.62; P < .001) and abetter response rate (CR or PR; RR, 1.58; 95% CI, 1.40–1.78; P < .001),
compared to TACE alone.425 However, patients who received the
combination treatment had increased toxicity compared to patients who
received TACE alone, as illustrated by elevated alanine aminotransferase(RR, 1.41; 95% CI, 1.08–1.84; P = .01) and bilirubin (RR, 2.69; 95% CI,
1.34–5.40; P = .005). The investigators who conducted the review
cautioned that the quality of evidence for these findings was low to very
low. In a recent RCT, 90 patients with HCC confined to the liver and withmacroscopic vascular invasion were randomized to receive first-line
sorafenib or TACE combined with EBRT.426 The TACE/EBRT arm had
better median OS (55 weeks vs. 43 weeks, respectively; P = .04), 12-week
PFS (86.7% vs. 34.3%, respectively; P < .001), radiologic response(33.3% vs. 2.2%, respectively; P < .001), and median TTP (31 weeks vs.
12 weeks, respectively; P < .001) compared to the sorafenib arm.
NCCN Recommendations for Locoregional Therapies
The relative effectiveness of locoregional therapies compared to resection
or liver transplantation in the treatment of patients with HCC has not been
established. The consensus of the panel is that liver resection ortransplantation, if feasible, is preferred for patients who meet surgical ortransplant selection criteria since these are established potentially curative
therapies. Locoregional therapy (eg, ablation, arterially directed therapies,
EBRT/SBRT) is the preferred treatment approach for patients who are notamenable to surgery or liver transplantation.
All tumors considered for ablation should be amenable to complete
treatment with a margin of normal tissue around the tumor. Tumors should

be in a location accessible for percutaneous, laparoscopic, or open
approaches. Lesions abutting key structures such as the bile ducts,
stomach, bowel, gallbladder, or diaphragm may be difficult locations for
ablation although hydrodissection techniques can be used to safely treat insome instances. The panel emphasizes that caution should be exercisedwhen ablating lesions near these structures to decrease complications.
Similarly, ablative treatment of tumors located on the liver capsule may
cause tumor rupture with track seeding, especially with direct puncturetechniques. Tumor seeding along the needle track has been reported in<1% of patients with HCC treated with RFA.427-429 Lesions with
subcapsular location and poor differentiation seem to be at higher risk forthis complication.427 During an ablation procedure, major vessels in close
proximity to the tumor can absorb large amounts of heat (known as the“heat sink effect”), which can decrease the effectiveness and significantly
increase local recurrence rates.
The consensus of the panel is that ablation alone may be a curative
treatment for tumors ≤3 cm. In well-selected patients with small, properly
located tumors ablation should be considered as definitive treatment in thecontext of a multidisciplinary review.308,310 Tumors between 3 and 5 cm
may be treated with a combination of MWA and/or arterially directed
therapies to prolong survival, as long as the tumor location is favorable toablation and underlying liver function is adequate.420,421,430 The panel
recommends that patients with unresectable or inoperable lesions larger
than 5 cm should be considered for treatment using arterially directed
therapies, EBRT, or systemic therapy.
All HCC tumors, irrespective of location in the liver, may be amenable toarterially directed therapies, provided that the arterial blood supply to thetumor can be isolated.337,341,377,414 An evaluation of the arterial anatomy of
the liver, patient’s performance status, and liver function is necessary prior
to the initiation of arterially directed therapy. In addition, more

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-28

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
individualized patient selection that is specific to the particular arteriallydirected therapy being considered is necessary to avoid significant
treatment-related toxicity. General patient selection criteria for arteriallydirected therapies include unresectable or inoperable tumors not
amenable to ablation therapy only, and the absence of large-volume
extrahepatic disease. Minimal extrahepatic disease is considered a“relative” contraindication for arterially directed therapies.
All arterially directed therapies are relatively contraindicated in patientswith bilirubin >3 mg/dL unless segmental treatment can be performed.
Outside of segmental therapy, TARE with Y-90 microspheres has anincreased risk of radiation-induced liver disease in patients with bilirubin>2 mg/dL.379 Arterially directed therapies are safe to use in patients withlimited tumor invasion of the portal vein but are contraindicated inChild-Pugh Class C patients, unless the goal of therapy is to bridge thepatient to transplant. It is also important to note that the contrast agent
used may be nephrotoxic, and, thus, these therapies should not be used if
creatinine clearance is elevated.
The panel recommends that EBRT or SBRT be considered as analternative to ablation and/or embolization techniques when these
therapies have failed or are contraindicated (in patients with unresectabledisease characterized as extensive or otherwise not suitable for livertransplantation and those with local disease but who are not consideredcandidates for surgery due to performance status or comorbidity).
Radiotherapy should be guided by imaging to improve treatment accuracy
and reduce toxicity. Palliative EBRT is appropriate for symptom control
and/or prevention of complications from metastatic HCC lesions in bone orbrain.431 The panel encourages prospective clinical trials evaluating therole of SBRT in patients with unresectable, locally advanced, or recurrent
HCC.

Systemic Therapy

The majority of patients diagnosed with HCC have advanced disease, andonly a small percentage are eligible for potentially curative therapies.
Furthermore, with the wide range of locoregional therapies available totreat patients with unresectable HCC confined to the liver, systemic
therapy has often been a treatment of last resort for those patients withvery advanced disease. Until recently, sorafenib has been the only
systemic therapy option for patients with advanced disease. However,from a number of recent clinical trials, there is one new systemic therapy
option for upfront treatment of advanced or unresectable HCC and anumber of active agents for HCC that has progressed on or after previous
systemic treatment. In the 2021 update, combined atezolizumab andbevacizumab was listed as a preferred regimen while sorafenib andlenvatinib were listed as other recommended regimens.
Sorafenib
Sorafenib, an oral multikinase inhibitor that suppresses tumor cellproliferation and angiogenesis, was evaluated in two randomized,
placebo-controlled, phase III trials for the treatment of patients withadvanced or metastatic HCC.432,433
In one of these phase III trials (SHARP trial), 602 patients with advanced
HCC were randomly assigned to sorafenib or best supportive care. In thisstudy, advanced HCC was defined as patients not eligible for or those who
had disease progression after surgical or locoregional therapies.432 The
majority of the patients had preserved liver function (≥95% of patientsclassified as Child-Pugh class A) and good performance status (>90% of
patients had ECOG performance status of 0 or 1). Median OS wassignificantly longer in the sorafenib arm (10.7 months in the sorafenib arm
vs. 7.9 months in the placebo group; HR, 0.69; 95% CI, 0.55–0.87; P <.001).432 In the Asia-Pacific study, another phase III trial with a similar
design to the SHARP study, 226 patients were randomly assigned to

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-29

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
sorafenib or placebo arms (150 and 76 in sorafenib and placebo arms,
respectively).433 While the HR for the sorafenib arm compared with theplacebo arm (HR, 0.68; CI, 0.50–0.93; P = .014) was nearly identical tothat reported for the SHARP study, the median OS was strikingly lower inboth treatment and placebo groups in the Asia-Pacific study (6.5 months
vs. 4.2 months).
Data on the efficacy of sorafenib in patients with C-P class B liver function
are limited since only patients with preserved liver function (C-P class A)
were to be included in those trials.434,435 However, approximately 28% of
the 137 patients enrolled in a phase 2 trial evaluating sorafenib in thetreatment of HCC had C-P class B liver function.436 A subgroup analysis ofthese patients demonstrated a median OS for patients in the C-P class B
group of only 3.2 months compared to 9.5 months for those in the C-P
class A group.437 Other investigators have also reported lower median OS
for patients with C-P class B liver function.438-442 In the GIDEON registry,
the safety profile of sorafenib was generally similar for C-P class A andC-P class B, although OS was shorter in the patients with C-P class B liverfunction.441 In the final analysis of the trial, in the intent-to-treat population(3213 patients), the median OS was 13.6 months for the C-P class Agroup compared to 5.2 months for the C-P class B group;443 however, the
TTP was similar for the two groups (4.7 months and 4.4 months,
respectively). These unsurprising results reflect the balance between
cancer progression and worsening liver disease as competing causes ofdeath for patients with unresectable HCC and forms the basis for the
exclusion of patients with poorer liver function from these and other clinical
trials.
In addition to clinical outcome, impaired liver function may impact thedosing and toxicity of sorafenib. Abou-Alfa et al found higher levels ofhyperbilirubinemia, encephalopathy, and ascites in the group with C-Pclass B liver function, although it is difficult to separate the extent to which

treatment drug and underlying liver function contributed to these disease
manifestations.437 A pharmacokinetic and phase I study of sorafenib inpatients with hepatic and renal dysfunction showed an association
between elevated bilirubin levels and possible hepatic toxicity.444 Finally, it
is important to mention that sorafenib induces only rare objective
volumetric tumor responses, and this has led to a search for othervalidated criteria to evaluate tumor response (such as RECIST289,290 or
EASL criteria176).434
Sorafenib combined with erlotinib for patients with advanced HCC wasassessed in a phase III RCT (N = 720).445 Results showed that thiscombination did not significantly improve survival, relative to sorafenib
delivered with a placebo. Further, disease control rate was significantly
lower for patients who received the sorafenib/erlotinib combination,
relative to those in the comparison group (P = .021). Treatment duration
was shorter for those receiving the sorafenib/erlotinib combination (86 vs.
123 days).
Lenvatinib
Lenvatinib is an inhibitor of VEGFR, fibroblast growth factor receptor,
platelet-derived growth factor receptor (PDGFR), and other growthsignaling kinases. In the phase III randomized REFLECT trial, patientswith unresectable HCC (N = 954) were randomized to receive either
lenvatinib or sorafenib as first-line treatment.446 The trial was designed todemonstrate non-inferiority or superiority of lenvatinib; the prespecified
boundary for non-inferiority was met with median OS of 13.6 months in thelenvatinib arm compared to 12.3 months for sorafenib (HR, 0.92; 95% CI,
0.79–1.06). Based on results of the REFLECT trial, the FDA approved
lenvatinib in 2018 as first-line treatment of patients with unresectable
HCC.

The combination of lenvatinib and pembrolizumab, an anti-PD-1 antibody,was investigated in a phase Ib study with 104 patients with unresectable
MS-30
Version 1.2022 © 2022 National Comprehensive Cancer Network (NCCN ), All rights reserved. NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
©

©

®

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
HCC.447 Using mRECIST criteria, the ORR was 46.0% (95% CI, 36.0%56.3%). The median PFS and OS were 9.3 months and 22 months
respectively. This combination is under investigation in a randomized
phase III trial against lenvatinib alone for the frontline treatment ofunresectable or metastatic HCC (NCT03713593).
Atezolizumab and Bevacizumab
Bevacizumab, a VEGF inhibitor, has modest clinical activity as a single
agent or in combination with erlotinib or chemotherapy in phase II studies
in patients with advanced HCC.448-452 A published abstract reported that
atezolizumab combined with bevacizumab showed an ORR of 34% in thefirst-line treatment option for patients with unresectable or metastatic HCC
in a phase 1b trial.453 The IMbrave150 phase III trial enrolled 501 patientswith unresectable HCC and Child Pugh A liver function, withrandomization to either the combination of atezolizumab and bevacizumab
or sorafenib as first-line treatment. All patients were required to have an
upper endoscopy within 6 months prior to enrollment due to risk of uppergastrointestinal bleeding observed in prior phase 2 studies ofbevacizumab in HCC.449,454 The IMbrave150 study showed that the
combination of atezolizumab plus bevacizumab significantly improved
outcomes compared to sorafenib, with the 12-month OS (67.2% vs.
54.6%; HR, 0.58, P < .001) and median PFS (6.8 months vs. 4.3 months;
HR, 0.59).455 Analyses from an independent reviewer (using HCC RECIST
criteria) comparing the atezolizumab and bevacizumab combination tosorafenib showed an ORR of 27.3% versus 11.9% (5.5% vs. 0% CR,
21.8% vs. 11.9% PR), with SD in 46.3% versus 43.4% of patients andprogressive disease in 19.6% versus 24.5%. Duration of response was >6months was estimated to be 87.6% in the atezolizumab and bevacizumab
arm and 59.1% in the sorafenib arm. Updated data from a publishedabstract revealed a median OS of 19.2 months for patients in theatezolizumab and bevacizumab group versus 13.4 months for patients inthe sorafenib group (HR, 0.66; P = .0009).456 Prior to the initiation of theatezolizumab plus bevacizumab regimen, patients should have adequate
endoscopic evaluation and management for esophageal varices withinapproximately 6 months prior to treatment or according to institutional
practice and based on the assessment of bleeding risk.
Subsequent-Line Therapy if Disease Progression
Until recently, there have been no subsequent-line systemic therapy
options for patients with HCC who have disease progression on or after
sorafenib. Recent advancements have produced some effective systemic
therapy options for these patients. However, it should be noted that it isunclear what the benefits of these systemic therapy options are forpatients who receive the atezolizumab and bevacizumab regimen as afirst-line treatment option and what subsequent agents to use if thedisease progresses. The first drug to get approved for HCC after sorafenib
was regorafenib, an oral multi-kinase inhibitor with activity against
VEGFR1-3, PDGFRB, KIT, RET, RAF-1, and other growth signaling
kinases. The randomized, double-blind, placebo-controlled, international
phase III RESORCE trial assessed the efficacy and safety of regorafenibin 573 patients with HCC and C-P A liver function who progressed on
sorafenib and who tolerated sorafenib at a dose of 400 mg per day for atleast 20 of the prior 28 days of treatment.457 Compared to the placebo,
regorafenib improved median OS (10.6 months vs. 7.8 months,
respectively; HR, 0.63; 95% CI, 0.50–0.79; P < .001), median PFS by
mRECIST (3.1 months vs. 1.5 months; HR, 0.46; 95% CI, 0.37–0.56; P <.001), TTP by mRECIST (3.2 months vs. 1.5 months; HR, 0.44; 95% CI,
0.36–0.55; P < .001), objective response (11% vs. 4%; P = .005), anddisease control (65% vs. 36%; P < .001). Adverse events were universal
among patients randomized to receive regorafenib (n = 374), with themost frequent grade 3 or 4 treatment-related events being hypertension(15%), hand-foot skin reaction (13%), fatigue (9%), and diarrhea (3%).
Seven deaths that occurred were considered by the investigators to havebeen related to treatment with regorafenib. Based on the results of thisVersion 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-31

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
trial, the FDA approved regorafenib in 2017 for patients with HCC who
progressed on or after sorafenib.
Cabozantinib, another oral multikinase inhibitor with potent activity against
VEGFR1-3 and MET among other targets, was assessed in the phase III
randomized CELESTIAL trial including 707 patients with advanced HCC
who have progressed on or after sorafenib, with 7.6% of the sample
having received more than one line of previous treatment.458 Median OS
and PFS were significantly greater in patients randomized to receive
cabozantinib (10.2 months and 5.2 months, respectively), compared topatients randomized to receive a placebo (8.0 and 1.9 months,
respectively) (HR, 0.76; 95% CI, 0.63–0.92; P = .005 for OS; HR, 0.44;
95% CI, 0.36–0.52; P < .001 for PFS) as was the ORR (4% vs. 0.4%, P =.009). A subsequent analysis showed that the benefits of cabozantinib
spanned across a range of AFP levels.459 The on-treatment AFP response
was higher in the cabozantinib arm, which was linked to longer OS and
PFS. Cabozantinib was approved by the FDA in 2019 for patients with C-P
A liver function who have disease progression on or after sorafenib.
In a phase III randomized REACH trial, the monoclonal antibody against
VEGFR2, ramucirumab, was assessed as second-line therapy following
sorafenib in patients with advanced HCC (N = 565).460,461 Though thisregimen did not improve median OS (9.2 months vs. 7.6 months; HR,0.87), median PFS (HR, 0.63; 95% CI, 0.52–0.75; P < .001) and TTP (HR,0.59; 95% CI, 0.49–0.72; P < .001) were improved, relative to the placebogroup. A subgroup analysis in patients with a baseline AFP level of ≥400
ng/mL (n = 250) showed that the median OS and PFS were 7.8 months(HR, 0.67) and 2.7 months, respectively, for patients in the ramucirumab
arm, and 4.2 months and 1.5 months, respectively, for patients in theplacebo arm. Analyses of patient-focused outcomes showed that
deterioration of symptoms was not significantly different in patientsrandomized to receive ramucirumab, compared to the placebo group.461

Based on these findings, the REACH-2 randomized phase III trial
assessed the efficacy of ramucirumab in patients with HCC who had
disease progression on or after sorafenib who had a baseline AFP level of≥400 ng/mL (N = 292).462 OS and PFS were greater in patients who
received ramucirumab with best supportive care, compared to patientsrandomized to receive a placebo with best supportive care (median OS
8.5 months vs. 7.3 months, respectively; HR, 0.71; 95% CI, 0.53–0.95; P =.0199; median PFS 2.8 months vs. 1.6 months, respectively; HR, 0.45;
95% CI, 0.34–0.60; P < .0001). A pooled analysis of results from REACH
and REACH-2, including 542 patients with disease progression on or after
sorafenib who had a baseline AFP level of ≥400 ng/mL, showed thatmedian OS was greater for patients who received ramucirumab, comparedto patients who received the placebo (8.1 months vs. 5.0 months,
respectively; HR, 0.69; 95% CI, 0.57–0.84; P = .0002).462 Post hoc
analyses of the REACH and REACH-2 trials revealed the importance of
AFP as a prognostic factor as the AFP response was significantly higher inpatients treated with ramucirumab compared to placebo (P < .0001).463 An
AFP response was associated with significantly improved survival (13.6
months vs. 5.6 months; HR, 0.45; P < .0001).463
Based on the results from the CheckMate 040 trial, the FDA gave
accelerated approval for nivolumab in 2017 for patients with HCC who
progressed on or after sorafenib.464 These preliminary data led to theconfirmatory CheckMate 459, a randomized phase III trial comparing
nivolumab to sorafenib in the frontline treatment of advanced HCC.465 In
the published abstract by Yau et al,465 the median OS with nivolumab
versus sorafenib was 16.4 versus 14.7 months, respectively (HR, 0.85; P= .075) but the ORR was 15% versus 7%. The median PFS was 3.7
months for nivolumab versus 3.8 months for sorafenib. In 2021, the FDA’s
Oncologic Drugs Advisory Committee voted against maintaining theaccelerated approval of nivolumab as a single agent for patients withadvanced HCC who were previously treated with sorafenib.466 Based on

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-32

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
the FDA decision, the panel removed nivolumab as a subsequent-line
treatment option for patients with C-P A disease. As treatment options arelimited for patients with C-P B disease, the panel voted to maintainnivolumab as a subsequent-line treatment option for these patients.
Combination treatment with nivolumab and the CTLA-4 antibody
ipilimumab in 148 patients with advanced HCC who were previously
treated with sorafenib led to improved clinical responses.467 The results
showed a response rate of 32%, per RECIST version 1.1 as assessed byblinded independent central review, and a median OS of 22.8 months. The
results from a long-term follow-up of at least 44 months, published in an
abstract, demonstrated that durable responses were achieved and the
median OS was maintained at 22.2 months.468
Pembrolizumab, a anti-PD-1 antibody, was assessed in the nonrandomized, open-label, phase II KEYNOTE-224 trial, which included 104
patients with HCC who progressed on or were intolerant to sorafenib.469
About 17% of patients had an objective response (all PRs except for 1
patient who had a CR), 44% had SD, and 33% had progressive disease.
Median duration of response was not reached, and, at the time of
publication, assessment was ongoing in 12 of the 18 responders. The
safety profile was similar to that seen for this drug in other tumor types.
Based on these results, the FDA granted accelerated approval for
pembrolizumab for patients with HCC who were previously treated withsorafenib. However, the phase 3 KEYNOTE-240 trial comparing
pembrolizumab to a placebo in second-line HCC did not meet its primary
endpoints (OS and PFS) based on the rigorous statistical plan.470 Updated
data from the KEYNOTE-240 trial, published in an abstract, showed thatthe median OS with pembrolizumab versus placebo was 13.9 vs. 10.6
months, respectively (HR, 0.77) and the median PFS was 3.3 vs. 2.8
months, respectively (HR, 0.70).471 Also, a clinically meaningful differencein ORR was seen favoring pembrolizumab (18.3% vs. 4.4%), and the

median duration of response on pembrolizumab was 13.9 months.
Pembrolizumab has maintained its accelerated approval in patientspreviously treated with sorafenib.
Dostarlimab-gxly, another anti-PD-1 antibody, was assessed in an openlabel phase I study with 2 cohorts.472 One cohort had 103 patients withadvanced or recurrent microsatellite instability-high (MSI-H)/deficientmismatch repair (dMMR) endometrial cancer and another had 106
patients with advanced or recurrent MSI-H/dMMR or POLE-hypermutated
non-endometrial solid tumors (comprising mostly gastrointestinal tumors[93.4%] with 65.1% colorectal tumors). An interim analysis, published in an
abstract, revealed an ORR of 41.6% (95% CI, 34.9%–48.6%), per RECIST
v1.1. The ORR for the cohort with non-endometrial cancer was 38.7%(95% CI, 29.4%–48.6%). The median duration of response was notreached (median follow-up of 16.3 months for the cohort with endometrial
cancer and 12.4 months for the cohort with non-endometrial cancer). The
most frequent grade 3 or higher treatment-related adverse events wereanemia (2.2%), elevated lipase (1.9%), elevated alanine aminotransferase(1.1%), and diarrhea (1.1%). Another published abstract demonstrated
that among the cohort with non-endometrial cancer, patients withcolorectal cancer had an ORR of 36.2% (95% CI, 25.0%–48.7%).473 Thecohort also included two patients with liver cancer. One patient had apartial response while the other had progressive disease.
Other Agents and Emerging Therapies
FOLFOX4 (infusional fluorouracil, leucovorin, and oxaliplatin) was
compared to doxorubicin in a phase III trial including 371 Asian patientswith advanced HCC.474 The primary OS endpoint was not met, but PFS
was greater for FOLFOX4, relative to doxorubicin (HR, 0.62; 95% CI,
0.49–0.79; P < .001). Subgroup analyses from this trial including patientsfrom China (n = 279) showed both an OS and a PFS benefit of FOLFOX4
over doxorubicin (HR, 0.74; 95% CI, 0.55–0.98; P = .03 and HR, 0.55;

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-33

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
95% CI, 0.45–0.78; P < .001, respectively), with median OS and PFS of
5.7 and 2.4 months, respectively, for patients randomized to receive
FOLFOX4, and 4.3 and 1.7 months, respectively, for patients randomized
to receive doxorubicin.475 Though none of the patients in this sample had aCR, 8.6% of patients who received FOLFOX4 had a PR, compared to
1.4% of patients who received doxorubicin (P = .006). In a phase II
multicenter trial including 40 patients with advanced HCC, FOLFOX4
combined with sorafenib showed a median TTP of 7.7 months, an ORR of
18%, and a median OS of 15.1 months.476 Grade 3 and 4 adverse events
included elevated AST (28%) and ALT (15%), diarrhea (13%),
hyperbilirubinemia (10%), hand-foot syndrome (8%), and bleeding (8%).
In a phase III trial, linifanib, a VEGF and PDGF receptor inhibitor, wascompared to sorafenib in patients with advanced HCC (N = 1035).477
Patients who were randomized to receive linifanib had a greater objective
response rate (P = .018), but also a greater rate of serious adverse events(P < .001) and adverse events leading to dose reduction and drug
discontinuation (P < .001), compared to patients randomized to receive
sorafenib. Overall, survival did not significantly differ between the two
drugs.
An oral MET inhibitor, tivantinib, was compared to a placebo in a phase III
trial including 340 patients with HCC that was previously treated withsorafenib and had high MET expression,478 based on encouraging resultsfrom a randomized phase II trial.479 OS did not significantly differ between
patients randomized to receive tivantinib or placebo.
Data from a phase II trial have demonstrated potential activity of axitinib
and tolerability for patients with intermediate/advanced Child Pugh class A
disease as a second-line therapy.480 In a phase III study, patientspreviously treated with at least one line of systemic therapy wererandomized to receive apatinib or placebo.481 The results, only publishedin an abstract, showed that compared to the placebo arm, patients treatedwith apatinib had significantly improved median OS (8.7 months vs. 6.8
months; HR, 0.785; 95% CI, 0.617-0.998; P = .0476), median PFS (4.5months vs. 1.9 months; HR, 0.471; 95% CI, 0.369-0.601; P < .0001), andORR (10.7% vs. 1.5%).
For patients with advanced disease, providers may wish to consider
molecular profiling to determine eligibility for clinical trials of new moleculartargeted agents (ie, for agents targeting mutated versions of isocitrate
dehydrogenase 1 [IDH1], IDH2, FGF, and KRAS, among others).478,482,483
Management of Resectable Disease

Results of an RCT (N = 200) showed that partial hepatectomy was
associated with better OS and RFS, relative to combination TACE andRFA.484 In a meta-analysis of 18 studies with 5986 patients comparing
TACE to resection, the survival benefits were significantly higher in thehepatectomy study arm.485The consensus of the panel is that initial
treatment with either partial hepatectomy or transplantation should beconsidered for patients with liver function characterized by a Child-Pughclass A score, lack of portal hypertension, and who fit UNOS criteria. In
addition, patients must have operable disease on the basis of performancestatus and comorbidity.
Hepatic resection is a potentially curative treatment option and is thepreferred treatment for patients with the following disease characteristics:
adequate liver function (Child-Pugh class A and selected Child-Pugh class
B patients without portal hypertension), solitary mass without major
vascular invasion, and adequate liver remnant.486,487 Ablation may beconsidered in patients with tumors <3 cm in diameter who are notresection candidates due to age or comorbidity.326The presence of
extrahepatic metastasis is considered to be a contraindication forresection. Hepatic resection is controversial in patients with limited
multifocal disease as well as those with major vascular invasion. Liver

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-34

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
resection in patients with major vascular invasion should only be
performed in highly selected situations by experienced teams.
Transplantation should be considered for patients who meet the UNOS
criteria (AFP level ≤1000 ng/mL and radiologic evidence of either a single
lesion ≥2 cm and ≤5 cm in diameter, or 2–3 lesions ≥1 cm and ≤3 cm indiameter and no evidence of macrovascular involvement or extrahepaticdisease) or can be downstaged to within Milan Criteria. Transplant also
provides a curative intent option for patients with Child-Pugh class B andC cirrhosis who would not otherwise be surgical candidates. The
guidelines have included consideration of bridge therapy as clinicallyindicated for patients eligible for liver transplant. Patients with tumor
characteristics that are marginally outside of the UNOS guidelines may beconsidered for transplantation at select institutions. Additionally,transplantation can be considered for patients who have undergone
successful downstaging therapy (ie, tumor currently meeting Milancriteria). If transplant is not feasible, the panel recommends hepatic
resection for this group of patients.
Surveillance

Although data on the role of surveillance in patients with resected HCC arevery limited, recommendations are based on the consensus that earlier
identification of disease, primary or recurrent, may facilitate patienteligibility for investigational studies or other forms of life-prolonging
treatment. The panel recommends ongoing surveillance—specifically,
multiphasic, high-quality, cross-sectional imaging of the chest, abdomen,
and pelvis every 3 to 6 months for 2 years, then every 6 to 12 months.
Multiphasic cross-sectional imaging (ie, CT or MRI) is the preferred
method for surveillance following treatment because of its reliability inassessing arterial vascularity,74 which is associated with increased risk of
HCC recurrence following treatment.488,489 Elevated AFP levels areassociated with poor prognosis following treatment241,490,491 and should bemeasured every 3 months for 2 years, then every 6 to 12 months.
Re-evaluation according to the initial workup should be considered in theevent of disease recurrence. Early imaging per local protocol can beconsidered.
Management of Advanced Disease

Locoregional therapy (ablation, arterially directed therapies, or EBRT) is
the preferred treatment option for selected patients with unresectable orinoperable liver-confined disease. Based on clinical experience with nontransplant candidates, the panel considers locoregional therapy to be thepreferred approach for treating patients with unresectable liver-confineddisease, or for those patients with localized tumors who are medicallyinoperable due to comorbidity. This may include older patients, particularly
those with comorbidities or compromised performance status.250,492,493
Systemic therapy is also recommended for patients with advanced
disease, especially for those progressing on locoregional therapies and for
those with extrahepatic metastatic disease. Biopsy may be considered forhistologic confirmation prior to initiation of treatment. The combination of
atezolizumab plus bevacizumab is the preferred category 1 first-line
systemic therapy option for patients with Child Pugh A liver function based
upon significant survival improvement in the IMBrave150 trial.455
Sorafenib and lenvatinib are listed as other recommended options for firstline systemic therapy. Sorafenib is recommended as a category 1 option(for selected patients with Child-Pugh class A liver function) and as acategory 2A option (for selected patients with Child-Pugh class B7 liverfunction) with disease characterized as: unresectable (liver-confined) andextensive/not suitable for liver transplantation; local disease only inpatients who are not operable due to performance status or comorbidity;
or metastatic disease. The panel recommends caution when considering
use of sorafenib in patients with elevated bilirubin levels.444 First-line
lenvatinib is also included as a category 1 option for patients with C-P

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-35

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
class A liver function only. Nivolumab and FOLFOX are listed as “useful incertain circumstances”. Nivolumab465 is a first-line option (category 2B) for
patients with Child-Pugh Class A or B liver function who are ineligible fortyrosine kinase inhibitors or other anti-angiogenic agents. FOLFOX is
another first-line option, but this is a category 2B option due to the panel’s
concern regarding the control arm used in this study (doxorubicin) andlack of significant survival benefit in final analysis.474
The panel now recommends several subsequent-line therapy options fordisease progression following first-line systemic therapy. However, it
should be noted that it is unclear what the benefits of these systemic
therapy options are for patients who receive the atezolizumab andbevacizumab regimen as a first-line treatment option and what subsequent
agents to use if the disease progresses. Category 1 targeted therapy
options include regorafenib, cabozantinib, and ramucirumab. Regorafeniband cabozantinib are recommended only for patients with C-P A liverfunction, while ramucirumab is recommended only for patients with abaseline AFP level of 400 ng/mL or greater. Checkpoint inhibitors options
include nivolumab monotherapy, pembrolizumab monotherapy, andcombination therapy with nivolumab and ipilimumab. Combined nivolumab
and ipilimumab are recommended for patients with Child-Pugh A.
Pembrolizumab is a recommended treatment option for patients with orwithout MSI-H tumors who have not been previously treated with acheckpoint inhibitor.469,494 Based on data from the negative phase III
KEYNOTE-240 trial showing that pembrolizumab did not meet its primary
endpoints (OS and PFS), the panel changed its recommendation of thisdrug from category 2A to category 2B for patients with C-P Class A liverfunction.470 The NCCN Guidelines include combined nivolumab andipilimumab as well as pembrolizumab as “other recommended regimens.”
Nivolumab is a treatment option (category 2B, useful in certain
circumstances) for patients with C-P B liver disease progression following
first-line systemic therapy who have not been previously treated with acheckpoint inhibitor.495-497 Dostarlimab-gxly is a recommended treatment
option (category 2B, useful in certain circumstances) for patients with MSIH/dMMR recurrent or advanced tumors that have progressed on orfollowing prior treatment, who have no satisfactory alternative treatment
options, and who have not been previously treated with a checkpoint
inhibitor.472
The relatively rapid development of these numerous treatment options has
made it difficult to address the important question of sequencing them,other than for those that have been approved for use in patients withdisease progression on or following sorafenib. Sorafenib may be used inpatients with disease progression on or following first-line lenvatinib (C-P
Class A or B7 liver function only), but there are currently no data to
support the use of lenvatinib for patients with disease progression after
sorafenib.
For all patients with advanced stages of HCC treated with systemic
therapies, the panel recommends periodic response assessment withcross-sectional imaging of sites at risk for metastatic progression,
including chest, multiphase abdomen, and pelvis. In patients with elevated
AFP tumor marker at start of therapy, AFP changes on treatment haveshown association with treatment response and survival. 459,463,498
The panel recommends that best supportive care measures beadministered to patients with unresectable or metastatic disease,alongside cancer-directed therapies.

Biliary Tract Cancers
Gallbladder Cancer
Gallbladder cancer is the most common biliary tract cancer. The vast
majority of gallbladder cancers are adenocarcinomas.499 Incidence steadily
increases with age, women are more likely to be diagnosed with

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-36

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
gallbladder cancer than men, and incidence and mortality rates in the
United States are highest among American Indian and Alaska Native men
and women.500 However, the incidence of gallbladder cancer has
decreased in women but has gone up in the black population and thoseyounger than 45 years of age.500,501 Globally, there are pockets ofincreased incidence in Korea; Japan; some areas of Eastern Europe andSouth America, especially Bolivia, Chile, and Spain; and in women in
India, Pakistan, and Ecuador.502-504 Gallbladder cancer is characterized by
local and vascular invasion, extensive regional lymph node metastasis,and distant metastases. Gallbladder cancer is also associated with shorter
median survival duration, a much shorter TTR, and shorter survival
duration after recurrence than hilar cholangiocarcinoma.505
Risk Factors

Cholelithiasis with the presence of chronic inflammation is the mostprevalent risk factor for gallbladder cancer, and the risk increases withstone size.506,507 Calcification of the gallbladder wall (porcelain
gallbladder), a result of chronic inflammation of the gallbladder, has also
been regarded as a risk factor for gallbladder cancer, with historicalestimates of cancer in up to 22% of gallbladders with calcification.506 Morerecent reports, however, suggest that the risk of developing gallbladdercancer in patients with gallbladder calcification is lower than anticipated,with gallbladder cancer being present in 7% to 15% of these patients.508-510
Other risk factors include anomalous pancreaticobiliary duct junction,
gallbladder polyps (>1 cm), chronic typhoid infection, primary sclerosing
cholangitis, and inflammatory bowel disease.507,511-513 Adenomyomatosis of
the gallbladder is also a potential, albeit somewhat controversial, risk
factor. Prophylactic cholecystectomy is probably beneficial for patients
who are at high risk of developing gallbladder cancer (eg, porcelain
gallbladder, polyps > 1 cm).506 Patients with a history of chroniccholecystitis or pancreaticobiliary maljunction have a greater prevalence of
gallbladder cancers that are microsatellite instability-high,514 andHER2/neu overexpression has been found in 13% of gallbladder cancer
cases.515
Staging and Prognosis

In the AJCC staging system, gallbladder cancer is classified into fourstages based on the depth of invasion into the gallbladder wall and theextent of spread to surrounding organs and lymph nodes. In the revised 8thedition of the AJCC staging system, T2 gallbladder carcinoma was divided
into two groups: tumors on the peritoneal side (T2a) and tumors on thehepatic side (T2b).165 This revision is supported by two retrospective
studies showing that gallbladder tumors located on the hepatic side isassociated with worse prognosis, compared to tumors located on theperitoneal side.516,517 However, it is important to note that it can be difficult
to determine the location of the tumor, and gallbladder cancer can spreadbeyond the visible tumor, contributing to difficulty in predicting tumor
location. Regional lymph node involvement is now staged according to
number of positive nodes, as opposed to staging based on anatomic
location of involved lymph nodes.
Tumor stage is the strongest prognostic factor for patients with gallbladdercancer.518,519 Results from a retrospective analysis of 435 patients treatedat a single center showed a median OS of 10.3 months for the entire
cohort of patients.519 The median survival was 12.9 months and 5.8
months for those presenting with stage IA–III and stage IV disease,respectively. It is important to note, however, that this retrospective
analysis did not control well for treatment-related variables. 520
Diagnosis

Gallbladder cancer is often diagnosed at an advanced stage because it isoften asymptomatic in its early stages and has an aggressive nature thatcan spread rapidly. Another factor contributing to late diagnosis ofgallbladder cancer is a clinical presentation that mimics that of biliary colicor chronic cholecystitis. Hence, it is common for a diagnosis of gallbladder

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-37

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
cancer to be an incidental finding at cholecystectomy for presumed benign
gallbladder disease or, more frequently, on pathologic review following
cholecystectomy for symptomatic cholelithiasis. In a retrospective reviewof 435 patients diagnosed and treated with curative resection at a single
center during the period of 1995 to 2005, 123 patients (47%) werediagnosed with gallbladder cancer as an incidental finding after
laparoscopic cholecystectomy.519 Other possible clinical presentations ofgallbladder cancer include a suspicious mass detected on US or biliary
tract obstruction with jaundice or chronic right upper quadrant abdominal
pain. The presence of jaundice in patients with gallbladder cancer isassociated with a poor prognosis; patients with jaundice are more likely tohave advanced-stage disease (96% vs. 60%; P < .001) and significantly
lower disease-specific survival (6 months vs.16 months; P < .0001) thanthose without jaundice.521 In a sample of 82 patients with gallbladdercancer who presented with jaundice, the resectability rate was low (7%),
with even fewer having negative surgical margins (5%) and no diseasefree survivors at 2 years.521
Workup

The initial workup of patients presenting with a gallbladder mass ordisease suspicious for gallbladder cancer should include liver function
tests and an assessment of hepatic reserve. High-quality contrastenhanced cross-sectional imaging (CT and/or MRI) of the chest,
abdomen, and pelvis is recommended to evaluate tumor penetration
through the wall of the gallbladder and the presence of nodal and distantmetastases, and to detect the extent of direct tumor invasion of otherorgans/biliary system or major vascular invasion.522 CT is more useful than
US for the detection of lymph node involvement, adjacent organ invasion,and distant metastasis; MRI may be useful for distinguishing benign
conditions from gallbladder cancer.499 However, both techniques wereunreliable in the detection of lymph node metastases that were smaller
than 10 mm.523 Although the role of PET scan has not been established in

the evaluation of patients with gallbladder cancer, emerging evidence fromretrospective studies indicates that it may be useful for the detection ofradiologically occult regional lymph node and distant metastatic disease inpatients with otherwise potentially resectable disease.524,525,526,527
However, false positives related to an inflamed gallbladder are
problematic.
For patients presenting with jaundice, additional workup should include
cholangiography to evaluate for hepatic and biliary invasion of tumor.
Noninvasive magnetic resonance cholangiography (MRCP) is preferredover endoscopic retrograde cholangiopancreatography (ERCP) or
percutaneous transhepatic cholangiography (PTC), unless a therapeuticintervention is planned.522
CEA and CA 19-9 testing could be considered as part of initial workup (inconjunction with imaging studies). Elevated serum CEA levels (>4.0
ng/mL) or CA 19-9 levels (>20.0 units/mL) could be suggestive ofgallbladder cancer.528 While CA 19-9 tends to have higher specificity(92.7% vs. 79.2% for CEA), its sensitivity tends to be lower (50% vs.
79.4% for CEA). However, these markers are not specific for gallbladdercancer and CA 19-9 could also be elevated in patients with jaundice fromother causes. Therefore, the panel recommends carrying out these tests
as part of a baseline assessment, and not for diagnostic purposes.
Surgical Management

The surgical approach for the management of all patients with resectablegallbladder cancer is the same, with the exception that in patients with anincidental finding of gallbladder cancer on pathologic review, thegallbladder has been removed. Complete resection with negative margins
remains the only potentially curative treatment for patients with gallbladdercancer.529 The optimal resection consists of cholecystectomy with a limited
hepatic resection (typically segments IVB and V) and portal
lymphadenectomy to encompass the tumor with negative margins.530

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-38

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
Lymphadenectomy should include lymph nodes in the porta hepatis,
gastrohepatic ligament, and retroduodenal regions without routine
resection of the bile duct. Extended hepatic resections (beyond segments
IV B and V) and resection of the bile duct may be necessary in somepatients to obtain negative margins, depending on the stage and locationof the tumor, depth of tumor invasion, proximity to adjacent organs, andexpertise of the surgeon.
A simple cholecystectomy is an adequate treatment for patients with T1atumors, with the long-term survival rate approaching 100%.531
Cholecystectomy combined with hepatic resection and lymphadenectomy
is associated with an improved survival for patients with T2 or higher
tumors. There is some controversy regarding the benefit of radical
resection over simple cholecystectomy for patients with T1b tumors, andthere is some risk of finding residual nodal or hepatic disease when reresecting these patients.532-537 Some studies have demonstrated an
associated improvement in cancer-specific survival for patients with T1b
and T2 tumors and no improvement in survival for patients with T3
tumors.533-535 Other reports suggest that survival benefit associated withextended resection and lymphadenectomy is seen only in patients with T2
tumors and some T3 tumors with localized hepatic invasion and limited
regional node involvement.536,537 One meta-analysis noted that regional
lymphadenectomy was associated with prolonged survival in patients with
T1b, T2, and T3 tumors.538
Empiric major hepatic resection and bile duct resection have been shownto increase morbidity without any demonstrable difference in survival.530,539
Bile duct resection was also not associated with a higher lymph node
yield.540 A retrospective analysis of prospective data collected on 104
patients undergoing surgery for gallbladder cancer from 1990 to 2002
showed that in a multivariate analysis, higher T and N stage, poordifferentiation, and common bile duct involvement were independent

predictors of poor disease-specific survival.539 Major hepatectomy andcommon bile duct excision significantly increased overall perioperative
morbidity (53%) and were not independently associated with long-term
survival.539 Fuks et al from the AFS-GBC-2009 study group also reported
that bile duct resection resulted in a postoperative morbidity rate of 60% inpatients with an incidental finding of gallbladder cancer.530 However, forthese patients, it has been suggested that common duct resection shouldbe performed at the time of re-resection for those with positive cystic duct
margins due to the presence of residual disease.541 However, occasionallythe cystic duct stump can be re-resected to a negative margin.
With these data in mind, the guidelines recommend that extended hepatic
resections (beyond segments IV B and V) should be performed only whennecessary to obtain negative margins (R0 resection) in well-selectedclinical situations as discussed above.533,535-537 Bile duct excision should
only be performed in the presence of adherent nodal disease and/or
locally invasive disease or to obtain a negative cystic duct margin if
necessary.539
Among patients with an incidental finding of gallbladder cancer, there issome evidence that a delayed resection due to referral to a tertiary cancer
center or a radical resection following an initial noncurative procedure is
not associated with a survival deficit compared with immediate
resection.542,543 However, these comparisons are difficult to interpret due toselection bias. Nevertheless, in all patients with a convincing clinicalevidence of gallbladder cancer, the guidelines recommend that surgery
should be performed by an experienced surgeon who is prepared to do adefinitive resection of the tumor. If expertise is unavailable, patients should
be referred to a center with available expertise. The panel is also of theopinion that surgery should not be performed in situations where theextent and resectability of the disease has not been established with goodquality imaging. Consultation with a pathologist with expertise in the

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-39

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
hepatobiliary region should be considered, and careful review of thepathology report for T stage, cystic duct margin status, and other margins
following surgery is crucial. If an imaging study shows a suspicious
gallbladder mass, then the patient should be referred to an experienced
center where they may be considered for upfront definitive resection.
Management of Resectable Disease

All patients should undergo cross-sectional imaging (CT and/or MRI) of
the chest, abdomen, and pelvis prior to surgery to evaluate local extent ofdisease and the presence of distant metastases. Staging laparoscopy has
been shown to identify radiographically occult disseminated disease inpatients with primary gallbladder cancer.544 In a prospective study that
evaluated the role of staging laparoscopy in 409 patients diagnosed withprimary gallbladder cancer, Agarwal et al reported a significantly higher
yield in locally advanced tumors compared with early-stage tumors (25.2%
vs. 10.7%; P = .02); the accuracy for detecting unresectable disease and a
detectable lesion in locally advanced tumors (56.0% and 94.1%,
respectively) was similar to that in early-stage tumors (54.6% and 100%,
respectively).544 In this study, the use of staging laparoscopy obviated theneed for laparotomy in 55.9% of patients with unresectable disease.
Staging laparoscopy, however, is of relatively low yield in patients withincidental finding of gallbladder cancer, since disseminated disease isrelatively uncommon, and the patients have already had an assessment of
their peritoneal cavity at the time of cholecystectomy.545 Higher yields may
be obtained in patients who are at higher risk for disseminated metastases(those with poorly differentiated, T3 or higher tumors or margin-positive
tumors at cholecystectomy).545
In patients with a suspicious gallbladder mass, a definitive resection withcholecystectomy and en bloc hepatic resection and lymphadenectomy isrecommended. In cases where there is a gallbladder mass but thediagnosis is unclear, intraoperative staging and consideration of

intraoperative photography prior to definitive resection should beconsidered. In selected cases, a frozen section biopsy of the gallbladdercan be considered. In any case of gallbladder cancer, frozen section of
suspicious distant lymph node (ie, celiac, retropancreatic, aortocaval)
should also be obtained. Contraindications for resection include tumors
with distant lymph node metastases beyond the porta hepatis (mostcommonly the celiac axis or aortocaval groove [retropancreatic]) or distantmetastatic disease (ie, most commonly liver and peritoneal cavity).
Additionally, some tumors are unresectable based on local invasion of theporta hepatis and its vascular and biliary structures.
Among patients with an incidental finding of gallbladder cancer on
pathologic review, those with T1a lesions may be observed if the tumor
margins are negative since these tumors have not penetrated the muscle
layer and long-term survival approaches 100% with simple
cholecystectomy.531 In a sample of 122 patients with gallbladder cancer
diagnosed incidentally, identified in a prospectively maintained database,liver involvement at re-resection (after cholecystectomy) was associatedwith decreased RFS and disease-specific survival for patients with T2
tumors (median RFS was 12 months vs. not reached for patients without
liver involvement, P = .004; median was 25 months vs. not reached forpatients without liver involvement, P = .003) but not in patients with T1btumors.520
As mentioned above, hepatic resection and lymphadenectomy with orwithout bile duct excision is recommended for patients with T1b or greater
lesions.533,535,536 Re-resection to achieve negative margins is
recommended for these patients with incidental gallbladder cancer since asignificant percentage of these patients have been found to harbor
residual disease within the liver and common bile duct.519,541 Furthermore,
although randomized trials are lacking, re-resection is generally
associated with improved OS compared to cholecystectomy alone. Port

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-40

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
site disease is associated with disseminated peritoneal metastases, andprophylactic port site resection is not associated with improved survival ordisease recurrence in patients with incidental findings of gallbladdercancer and, thus, should not be considered during definitive
resection.546,547
For patients with a suspicious mass detected on imaging, the guidelines
recommend cholecystectomy plus en bloc hepatic resection, andlymphadenectomy, with or without bile duct excision. A biopsy is notnecessary in most cases and a diagnostic laparoscopy is recommended
prior to definitive resection.544 In selected patients where the diagnosis is
not clear it may be reasonable to perform a cholecystectomy (including
intraoperative frozen section) followed by the definitive resection during
the same setting if pathology confirms cancer. Jaundice in patients withgallbladder cancer is considered a relative contraindication to surgery, andoutcomes are generally poor in these patients; only a rare group ofpatients with localized node-negative disease potentially benefit fromcomplete resection.521,548-550 In patients with jaundice, if gallbladder cancer
is suspected, surgery should only be performed if a complete resection is
feasible. These patients should be carefully evaluated prior to surgery andreferral to an experienced center should be considered. The guidelines
recommend consideration of preoperative biliary drainage for patients withjaundice. However, caution should be exercised in patients with biliary
obstruction as drainage is not always feasible and can be dangerous.
Decisions regarding biliary drainage should be made by a multidisciplinary
team.
Although there are no definitive data, the panel recommends considerationof a course of neoadjuvant chemotherapy for patients with jaundice.
Gallbladder cancer that is locally advanced or has lymph node
involvement is associated with a poor prognosis, but neoadjuvant
chemotherapy may allow the oncologist to evaluate the biology of thetumor and identify patients who are most likely to benefit from surgicalintervention. A systematic review of eight studies found that only a third of
the 474 patients achieved a R0 resection with the use of neoadjuvant
chemotherapy or chemoradiotherapy.551 In a retrospective analysis of 74
patients with locally advanced or lymph node-positive disease who
received systemic therapy, 30% of patients underwent resection.552 Out of
the 22 patients who underwent resection, 45% underwent definitive
resection, with OS being significantly greater for patients who underwent
definitive resection compared to those who did not (51 months vs. 11
months, respectively; P = .003).
In patients for whom there is evidence of locoregionally advanced disease(ie, nodal disease or evidence of other high-risk disease), neoadjuvant
chemotherapy should be considered. Though clinical trials are needed toassess the efficacy of specific regimens and this concept, the following
regimens may be used for gallbladder cancer in the neoadjuvant setting:gemcitabine/cisplatin, gemcitabine/oxaliplatin, gemcitabine/capecitabine,
capecitabine/oxaliplatin, 5-fluorouracil (5-FU)/oxaliplatin, gemcitabine,
capecitabine, and 5-FU. The panel currently does not recommend
neoadjuvant chemoradiation for these patients, though a prospective
study including 28 patients with locally advanced gallbladder cancer
showed that an R0 resection was achieved in 14 patients, with good
local control (93%) and 5-year survival (47%), following treatment withgemcitabine with concurrent RT.553
Fluoropyrimidine chemoradiation and fluoropyrimidine or gemcitabine
chemotherapy are options for adjuvant treatment. See the section on
Adjuvant Chemotherapy and Chemoradiation for Biliary Tract Cancers.
Management of Unresectable or Metastatic Disease

Preoperative evaluation and a biopsy to confirm the diagnosis is
recommended for patients with unresectable (includes tumors with distantlymph node metastases in the celiac axis or aortocaval groove) or

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-41

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
metastatic disease (includes distant metastases, nodal metastases
beyond the porta hepatis, and extensive involvement of the porta hepatis
causing jaundice or vascular encasement). MSI, mismatch repair (MMR),
and tumor mutational burden (TMB) (defined as ≥10
mutations/megabase),554 testing should be performed on biopsied tumor
tissue, as cancers with MSI-H, dMMR, and TMB-high (TMB-H) may
benefit from programmed death receptor-1 (PD-1) blockade such as
pembrolizumab.494,555,556 Primary options for these patients include: 1)
clinical trial; 2) systemic therapy; 3) best supportive care. In addition,
palliative RT is included as an option for patients with unresectabledisease. See sections on Chemotherapy and Chemoradiation andRadiation Therapy for Treatment for Advanced Biliary Tract Cancers.
In patients with unresectable or metastatic gallbladder cancer andjaundice, biliary drainage is an appropriate palliative procedure and should
be done before instituting chemotherapy if technically feasible.548
However, caution should be exercised in patients with biliary obstruction
as drainage is not always feasible and can be dangerous. Decisions
regarding biliary drainage should be made by a multidisciplinary team.
Biliary drainage followed by chemotherapy can result in improved qualityof life. CA 19-9 testing can be considered after biliary decompression.
Surveillance

There are no data to support a specific surveillance schedule or tests
following resection of gallbladder cancer; determination of appropriate
follow-up schedule/imaging should include a careful patient/physician
discussion. It is recommended that follow-up of patients undergoing an
extended cholecystectomy for gallbladder cancer should include
consideration of imaging studies every 6 months for 2 years, then annually
up to 5 years or as clinically indicated. Assessment of CEA and CA 19-9
may also be considered as clinically indicated. Re-evaluation according to

the initial workup should be considered in the event of disease relapse orprogression.
Cholangiocarcinomas
Cholangiocarcinomas encompass all tumors originating in the epitheliumof the bile duct. More than 90% of cholangiocarcinomas areadenocarcinomas and are broadly divided into three histologic types
based on their growth patterns: mass-forming, periductal-infiltrating, andintraductal-growing.557 Cholangiocarcinomas are diagnosed throughout thebiliary tree and are typically classified as either intrahepatic or extrahepaticcholangiocarcinoma. Extrahepatic cholangiocarcinomas are morecommon than intrahepatic cholangiocarcinomas. Analyses of SEER datafrom 1973 to 2012 showed that incidence of intrahepaticcholangiocarcinoma increased dramatically, while incidence of
extrahepatic cholangiocarcinoma increased at a slower rate.558,559 The
increase in incidence of intrahepatic cholangiocarcinoma may have been
due to an improvement in the ability to accurately diagnose intrahepaticcholangiocarcinoma, such as with imaging, molecular diagnostics, andpathology.558 These cancers might have previously been diagnosed ascancers of unknown primary, in which incidence decreased from 1973 to2012 [annual percentage change (APC), -1.87%].558 Five-year OS rates
for cholangiocarcinoma improved from 1973 to 2008, likely due toimprovements in treatment for this disease.559
Intrahepatic cholangiocarcinomas are located within the hepatic
parenchyma and have also been called “peripheral cholangiocarcinomas”(Figure 1). Extrahepatic cholangiocarcinomas occur anywhere within theextrahepatic bile duct—from the junction of the right and left hepatic ducts
to the common bile duct, including the intrapancreatic portion (Figure 1)—
and are further classified into hilar or distal tumors. Hilar
cholangiocarcinomas (also called Klatskin tumors) occur at or near thejunction of the right and left hepatic ducts; distal cholangiocarcinomas are

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-42

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
extrahepatic lesions arising in the extrahepatic bile ducts above theampulla of Vater and below the confluence of the left and right bileducts.560 Hilar cholangiocarcinomas are the most common type of
extrahepatic cholangiocarcinomas.

associated with increased incidence of both intrahepatic (pooled adjusted
OR, 2.09; 95% CI, 1.49–2.91) and extrahepatic cholangiocarcinoma(pooled adjusted OR, 2.05; 95% CI, 1.59–2.64).567

The NCCN Guidelines discuss the clinical management of patients withintra- and extrahepatic cholangiocarcinomas including hilar
cholangiocarcinoma and the distal bile duct tumors. Tumors of the ampullaof Vater are not included in the NCCN Guidelines for Hepatobiliary
Cancers.

Intrahepatic Cholangiocarcinoma
In the 6th edition of the AJCC staging system, intrahepaticcholangiocarcinoma was staged identically to HCC. However, thisstaging system did not include predictive clinicopathologic features(multiple hepatic tumors, regional nodal involvement, and large tumorsize) that are specific to intrahepatic cholangiocarcinoma.568 In some
reports, tumor size had no effect on survival in patients undergoingcomplete resection.569,570 In a SEER database analysis of 598 patientswith intrahepatic cholangiocarcinoma who had undergone surgery,Nathan et al reported that multiple lesions and vascular invasion
predicted adverse prognosis following resection; lymph node status wasof prognostic significance among patients without distant metastases.569
In this study, tumor size had no independent effect on survival. Thesefindings were confirmed in a subsequent multi-institutional international
study of 449 patients undergoing surgery for intrahepaticcholangiocarcinoma.570 The 5-year survival rate was higher for patients
who lacked all three risk factors (multiple tumors, vascular invasion, andN1 disease) than for those with one or more risk factors (38.3%, 27.3%,
and 18.1%, respectively) and, more importantly, tumor number andvascular invasion were of prognostic significance only in patients with N0
disease. Although tumor size was associated with survival in theunivariate analysis, it was not of prognostic significance in a multivariate
analysis.

Risk Factors

No predisposing factors are identified in most patients diagnosed withcholangiocarcinoma,561 although there is evidence that particular risk
factors may be associated with the disease in some patients. These risk
factors, like those for gallbladder cancer, are associated with the presenceof chronic inflammation. Primary sclerosing cholangitis, chronic calculi of
the bile duct (hepatolithiasis), choledochal cysts, and liver fluke infections
are well-established risk factors for cholangiocarcinoma. Unlike
gallbladder cancer, however, cholelithiasis is not thought to be linked withcholangiocarcinoma.562 Inflammatory bowel disease may also be a risk
factor for cholangiocarcinoma, though this association may be confoundedby primary sclerosing cholangitis.563 Other risk factors for intrahepaticcholangiocarcinoma have been found to include HBV infection, cirrhosis,
diabetes, obesity, alcohol, and tobacco.564 A systematic review and metaanalysis reported that the strongest risk factors for both intrahepatic andextrahepatic cholangiocarcinoma included biliary cysts and stones,
cirrhosis, HBV, and HCV.565 This may be responsible for the increased
incidence of intrahepatic cholangiocarcinoma observed at some centers,
although future studies are needed to further explore this putative
association.566 A recent systematic review including seven case-control
studies (9102 patients and 129,111 controls) showed that NAFLD is

Staging and Prognosis

In the revised 7th edition of the AJCC staging system, intrahepaticcholangiocarcinoma had a new staging classification that was independentof the staging classification used for HCC.571 This classification focused on

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-43

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
multiple tumors, vascular invasion, and lymph node metastasis. Farges et
al from the AFC-IHCC study group validated this staging classification in
163 patients with resectable intrahepatic cholangiocarcinoma.572 The
revised classification was useful in predicting survival according to the
TNM staging. With a median follow-up of 34 months, the median survival
was not reached for patients with stage I disease, was 53 months for
those with stage II disease (P = .01), and was 16 months for those withstage III disease (P < .0001).

features such as vascular encasement, lymph node involvement, distantmetastases, and liver atrophy. In addition, both the AJCC and the
Bismuth-Corlette staging systems are not useful for predicting resectability
or survival. The Blumgart staging system is a useful preoperative staging
system that predicts resectability, likelihood of metastatic disease, andsurvival.576,577 In this staging system, hilar cholangiocarcinomas areclassified into three stages (T1–T3) based on the location and extent ofbile duct involvement, the presence or absence of portal venous invasion,and hepatic lobar atrophy.576 Negative histologic margins, concomitantpartial hepatectomy, and well-differentiated tumor histology wereassociated with improved outcome after resection; increasing T-stage
significantly correlated with reduced R0 resection rate, distant metastatic
disease, and lower median survival.577

In the revised 8th edition of the AJCC staging system, T1 disease (ie,solitary tumor without vascular invasion) should now be staged according
to tumor size (ie, T1a refers to a tumor that is ≤5 cm, while T1b refers to atumor that is >5 cm).165 T2 disease, on the other hand, is no longer divided
into T2a (solitary tumor with vascular invasion) and T2b (multiple tumors
with or without vascular invasion) disease.

Diagnosis

Extrahepatic Cholangiocarcinoma
The 7th edition of AJCC staging system included a separate TNM
classification for hilar and distal extrahepatic cholangiocarcinoma, basedon the extent of liver involvement and distant metastatic disease.571 In therevised 8th edition of the AJCC staging system, regional lymph node
involvement is now staged according to number of positive nodes.165
Depth of tumor invasion is as an independent predictor of outcome inpatients with distal as well as hilar cholangiocarcinomas.573,574 In therevised 8th edition of the AJCC staging system for cancer of the distal bileduct, depth of tumor invasion has been added to the categorization of T1,
T2, and T3 tumors.165

Workup

The modified Bismuth-Corlette staging system575 and the Blumgart staging
system576 are used for the classification of hilar cholangiocarcinomas. The
modified Bismuth-Corlette staging system classifies hilar
cholangiocarcinomas into four types based on the extent of biliary
involvement. However, this does not include other clinicopathologic

Early-stage cholangiocarcinoma may only manifest as mild changes inserum liver function tests. Patients with intrahepatic cholangiocarcinoma,
due to their often late presentation, are more likely to present with
nonspecific symptoms such as fever, weight loss, and/or abdominal pain;
symptoms of biliary obstruction are uncommon because these tumors do
not necessarily involve the common hepatic/bile duct. Intrahepaticcholangiocarcinoma may be detected incidentally as an isolated
intrahepatic mass on imaging.98 In contrast, patients with extrahepaticcholangiocarcinoma are likely to present with jaundice followed byevidence of a biliary obstruction or abnormality on subsequent imaging.
The initial workup should include liver function tests. CEA and CA 19-9
testing can be considered for baseline assessment, although thesemarkers are not specific for cholangiocarcinoma; they are also associatedwith other malignancies and benign conditions.578 CA 19-9 may be falsely
elevated due to jaundice.579 Viral hepatitis serologies should be

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-44

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
considered for intrahepatic cholangiocarcinoma. If hepatitis is diagnosed, itneeds to be monitored and managed following ASCO’s guidelines.580
Since the diagnosis of HCC versus intrahepatic cholangiocarcinoma canbe difficult, AFP testing may also be considered, especially in patients withchronic liver disease. Further, there are a number of mixed
HCC/intrahepatic cholangiocarcinoma cases in which AFP may beelevated. LI-RADS provides some guidance in distinguishing between
HCC and intrahepatic cholangiocarcinoma lesions.581
Early surgical consultation (prior to drainage in jaundiced patients) with amultidisciplinary team is recommended as part of the initial workup forassessment of resectability in intrahepatic and extrahepaticcholangiocarcinomas. The panel emphasizes that a multidisciplinary
review of imaging studies involving experienced radiologists and surgeons
is necessary to stage the disease and determine potential treatment
options (ie, resection or other approach). Providers should only proceedwith biopsy once transplant or resectability status has been determined.
For patients with hilar cholangiocarcinoma who may be transplantcandidates, transperitoneal biopsy is contraindicated and will likely
preclude transplantation based on current protocols.582 For patients
undergoing resection, biopsy is usually not necessary. When necessary,
intraluminal biopsy is the preferred biopsy approach for potential
transplant patients.
In patients who are not resectable, direct visualization of the bile duct withdirected biopsies is the ideal technique for the workup ofcholangiocarcinoma. Multiphasic CT/MRI with IV contrast of the abdomen
and pelvis to assess the involvement of the liver, major vessels, nearby
lymph nodes, and distant sites is also recommended when extrahepaticcholangiocarcinoma is suspected.583,584 There are no pathognomonic
CT/MRI features associated with intrahepatic cholangiocarcinoma, but
CT/MRI can indicate the involvement of major vessels and the presence ofvascular anomalies and satellite lesions.583 Therefore, multiphasic CT/MRI
with IV contrast is used to help determine tumor resectability bycharacterizing the primary tumor, its relationship to nearby major vessels
and the biliary tree, the presence of satellite lesions and distantmetastases in the liver, and lymph node involvement.98,583 In addition,
chest CT (with or without contrast) should be performed, and staging
laparoscopy may be considered in conjunction with surgery if no distantmetastasis is found. Endoscopic US may be useful for distal common bile
duct cancers for defining a mass or abnormal thickening, which can direct
biopsies. For hilar cholangiocarcinoma, endoscopic US should only bedone after surgical consultation to prevent jeopardizing a patient’s
candidacy for transplantation. EGD and colonoscopy are recommended aspart of initial workup for patients with intrahepatic cholangiocarcinoma
since a mass diagnosed as adenocarcinoma can be metastatic disease.
Pathologic workup can be suggestive of cholangiocarcinoma but is notdefinitive. IgG4-associated cholangitis, which presents with biliary
strictures and obstructive jaundice, may mimic extrahepaticcholangiocarcinoma.585,586 Therefore, serum IgG4 should be considered inpatients for whom a diagnosis of extrahepatic cholangiocarcinoma is notclear, in order to avoid an unnecessary surgical resection.587,588 Patientswith IgG4-related cholangiopathy should be referred to an expert center.
Contrast-enhanced MRCP and/or CT as a diagnostic modality is
recommended over direct cholangiography for the diagnosis of bile duct
cancers.589,590 MRCP has been shown to have a higher sensitivity,
specificity, and diagnostic accuracy compared to ERCP in the diagnosis
and pre-treatment staging of hilar cholangiocarcinomas.591 Data also
support the use of MRCP and CT as the preferred method ofcholangiography for the assessment of bile duct tumors.592 Direct
cholangiography should only be performed when necessary as adiagnostic procedure in patients who are not resectable or in patients inwhom a therapeutic intervention is necessary. ERCP/PTC is not

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-45

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
recommended for the diagnosis of extrahepatic cholangiocarcinoma, since
this is associated with complications and contamination of the biliary tree.
For distal bile duct tumors in which a diagnosis is needed or where
palliation is indicated, an ERCP allows for complete imaging of the bile
duct and stenting of the obstruction. In addition, brush cytology of the bile
duct can be obtained for pathologic evaluation. Since many of the patientswith extrahepatic cholangiocarcinoma present with jaundice, workup
should include noninvasive cholangiography with cross-sectional imaging
to evaluate local tumor extent.583 Although the role of PET imaging has notbeen established in the evaluation of patients with cholangiocarcinoma,
emerging evidence indicates that it may be useful for the detection ofregional lymph node metastases and distant metastatic disease in patientswith otherwise potentially resectable disease.524-526,593,594
Management of Intrahepatic Cholangiocarcinoma

Complete resection is the only potentially curative treatment for patientswith resectable disease, although most patients are not candidates forsurgery due to the presence of advanced disease at diagnosis. The
optimal surgical margin associated with improved survival and reduced
risk of recurrence in patients undergoing surgery remains uncertain, withsome reports documenting R0 resection as a significant predictor ofsurvival and recurrence,595-600 while others suggest that margin status is
not a significant predictor of outcome.601,602 Ribero et al from the ItalianIntrahepatic Cholangiocarcinoma Study Group reported thatmargin-negative resection was associated with significantly higher survival
rates (the estimated 5-year survival rates were 39.8% vs. 4.7% for patientswith a positive margin) and significantly lower recurrence rates (53.9% vs.
73.6% for those with a positive margin); however, in patients resected withnegative margins, the margin width had no long-term impact on survival (P= .61) or recurrence (P > .05) following resection.600 Farges et al from the
AFC-IHCC-2009 study group reported that although R1 resection was thestrongest independent predictor of poor outcome in pN0 patients

undergoing surgery, its prognostic impact on survival was very low in pN+
patients (median survival was 18 months and 13 months, respectively,
after R0 and R1 resections; P = .10).602 In this study, a margin width
greater than 5 mm was an independent predictor of survival among pN0
patients with R0 resections, which is in contrast to the findings reported byRibero et al.600 A retrospective analysis of 535 patients with intrahepaticcholangiocarcinoma who underwent resection showed that other factors
associated with worse survival post-resection include multifocal disease(HR, 1.49; 95% CI, 1.19–1.86; P = .01), lymph node metastasis (HR, 2.21;
95% CI, 1.67–2.93; P < .01), and vascular invasion (HR, 1.39; 95% CI,
1.10–1.75; P = .006).603
Available evidence (although not conclusive) supports therecommendation that hepatic resection with negative margins should be
the goal of surgical therapy for patients with potentially resectabledisease.604 Extensive hepatic resections are often necessary to achieve
clear margins since the majority of tumors present as large masses.600
Initial surgical exploration should include assessment of multifocal liverdisease, lymph node metastases, and distant metastases. Multifocal liverdisease, distant (beyond the porta hepatis) nodal metastases, and distantmetastases contraindicate surgery as these generally indicate advanced
incurable disease. In highly selected situations, resection can beconsidered. A preoperative biopsy is not always necessary prior todefinitive and potentially curative resection. Although limited multifocal
liver tumors (including satellite lesions) and gross lymph node metastases
to the porta hepatis are considered relative contraindications to surgery,
surgical approaches can be considered in selected patients. Patient
selection for surgery is facilitated by careful preoperative staging, which
may include laparoscopy to identify patients with unresectable ordisseminated metastatic disease.605,606 Staging laparoscopy has beenshown to identify peritoneal metastases and liver metastases with a

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-46

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
respective yield of 36% and 67% accuracy in patients with potentiallyresectable intrahepatic cholangiocarcinoma.605 A portal lymphadenectomy
helps provide accurate staging information.607 Lymph node metastasis is
an important prognostic indicator of survival.570,600 Therefore, regional
lymphadenectomy of the porta hepatis is recommended. It is important tonote, however, that there are no data to support a therapeutic benefit ofroutine lymph node dissection in patients undergoing surgery.608-611
The optimal adjuvant treatment strategy for patients with resected
intrahepatic cholangiocarcinoma has not been determined and there arelimited clinical trial data to support a standard regimen for adjuvant
treatment. Lymphovascular and perineural invasion, lymph nodemetastasis, and tumor size greater than or equal to 5 cm have beenreported as independent predictors of recurrence and reduced OS
following resection.612-614 Since recurrence following resection is common,these tumor-specific risk factors could be considered as criteria for
selection of patients for adjuvant treatment in clinical trials. See Adjuvant
Chemotherapy and Chemoradiation for Biliary Tract Cancers in this
discussion.
Primary treatment options for patients with unresectable or metastatic
disease include: 1) clinical trial; 2) systemic therapy; or 3) best supportive
care. In addition, fluoropyrimidine chemoradiation is included as an option
for patients with unresectable disease. See sections on Chemotherapy
and Chemoradiation and Radiation Therapy for Treatment for Advanced
Biliary Tract Cancers in this discussion.
Locoregional Therapy
Locoregional therapies such as RFA,615,616 TACE,617-619 DEB-TACE, or
TACE drug-eluting microspheres,618,620,621 and TARE with Y-90
microspheres619,622-627 have been shown to be safe and effective in a small
retrospective series of patients with unresectable intrahepaticcholangiocarcinomas. The results of two independent prospective studies

showed that the efficacy of TACE with irinotecan DEB was similar to thatof gemcitabine and oxaliplatin (GEMOX), but was superior to that of TACE
with mitomycin in terms of PFS and OS for patients with unresectable
intrahepatic cholangiocarcinoma.618 In a systematic review of 12 studies
with 298 patients, the effects of radioembolization with Y-90 microspheresin unresectable intrahepatic cholangiocarcinoma were assessed.628 The
overall weighted median survival for this treatment was 15.5 months,
partial tumor response was seen for 28% of patients, and SD was seen for
54% of patients. Other smaller series have also reported favorable
response rates and survival benefit for patients with unresectable
intrahepatic cholangiocarcinoma treated with TARE with Y-90
microspheres.622,625,627 Due to the rarity of this disease, none of these
locoregional approaches has been evaluated in RCTs. In the phase IIMISPHEC trial, investigators determined that the combination ofradioembolization with Y-90 microspheres with chemotherapy (cisplatin
and gemcitabine) as a first-line treatment option in 41 patients withunresectable intrahepatic cholangiocarcinoma resulted in a 39% response
rate, by RECIST criteria.629 The median PFS and OS were 14 months and
22 months, respectively. Additionally, 22% of patients were downstaged tosurgery.
Radiation therapy is a locoregional treatment option for unresectable
intrahepatic cholangiocarcinoma.630 A single-institution study including 79
patients with unresectable intrahepatic cholangiocarcinoma showed thathigher doses of RT (3D-CRT with photons or protons) were associatedwith better 3-year OS (73% vs. 38%, respectively; P = .017) and 3-year
local control (78% vs. 45%, respectively; P = .04), compared with lower
doses of RT.631 SBRT may also be used for patients with unresectable
intrahepatic cholangiocarcinoma.405 A non-randomized multi-institutional
trial including 39 patients with unresectable intrahepaticcholangiocarcinoma showed that hypofractionated proton therapy resulted
in a 2-year OS rate of 46.5% (median OS was 22.5 months) and a 2-year

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-47

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
PFS rate of 25.7%.408 Therefore, hypofractionated proton therapy may
also be considered for patients with unresectable intrahepaticcholangiocarcinoma, but this treatment should only be administered atexperienced centers.
Data from prospective studies support the use of hepatic arterial infusion(HAI) chemotherapy in patients with advanced, liver confined, andunresectable intrahepatic cholangiocarcinoma.632-636 In a meta-analysis
including 20 studies (N = 657), HAI was compared to TACE, DEB-TACE,
and TARE with Y-90 microspheres.637 OS and tumor response weregreatest for HAI, with a median tumor response rate of 57%, though grade
III/IV toxicity was also highest, relative to the other arterially directed
therapies. A retrospective analysis of 525 patients with intrahepaticcholangiocarcinoma showed that patients who received a combined
regimen of HAI and another chemotherapy agent (gemcitabine, irinotecan,
or 5-FU) had greater OS, relative to patients receiving chemotherapy
without HAI (30.8 vs. 18.4 months, P < .001).638
Based on the available evidence as discussed above, the panel has
included locoregional therapy as a treatment option that may beconsidered for patients with unresectable disease or metastatic cancer
without extrahepatic disease. Intra-arterial chemotherapy is recommended
only in the context of a clinical trial or at experienced centers for patientswith advanced disease confined to the liver.
Management of Extrahepatic Cholangiocarcinoma

Complete resection with negative margins is the only potentially curative
treatment for patients with resectable disease. The reported 5-year
survival rates following complete resection are in the range of 20% to 42%
and 16% to 52%, respectively, for patients with hilar and distal
cholangiocarcinomas.639,640

Surgical margin status and lymph node metastases are independent
predictors of survival following resection.599,641,642 Regional
lymphadenectomy of the porta hepatis (hilar cholangiocarcinoma) or in thearea of the head of the pancreas (distal cholangiocarcinoma) areconsidered standard parts of curative resections.643,644 Since these
surgical procedures are associated with postoperative morbidity, theyshould be carried out in patients who are medically fit for a major
operation. Surgery is contraindicated in patients with distant metastatic
disease to the liver, peritoneum, or distant lymph nodes beyond the porta
hepatis (or head of the pancreas for distal tumors).
The type of surgical procedure for a resectable tumor is based on its
anatomic location in the biliary tract. Resection of the involved biliary tractand en bloc liver resection (typically a major hepatectomy involving theright or left liver with the caudate lobe) is recommended for hilar tumors.
Bile duct excision with frozen section assessment of proximal and distalbile duct margins and pancreaticoduodenectomy can be attempted for mid
bile duct tumors not involving the liver or pancreas. However, mid bile duct
tumors that can be completely resected with an isolated bile duct resection
are uncommon. A combined pancreaticoduodenectomy and hepatic
resection is required, in rare instances, for a bile duct tumor with extensive
biliary tract involvement. This operation, however, is associated with highmorbidity and should only be considered in well-selected cases.645,646
Combined hepatic and pancreatic resections to clear distant nodal disease(as opposed to biliary extent) are not recommended, as these are highly
morbid procedures with no obvious associated survival advantage. The
guidelines recommend consideration of biliary drainage prior to definitive
resection for patients with jaundice. However, caution should be exercisedin patients with hilar biliary obstruction as drainage is not always simple
and can be associated with significant morbidity.647 Decisions about
whether preoperative biliary drainage is appropriate (and the type ofVersion 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-48

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
drainage) should be made by a multidisciplinary team at a high-volume
center.
In patients with hilar cholangiocarcinoma, extended hepatic resection (toencompass the biliary confluence) with caudate lobectomy isrecommended, since hilar tumors, by definition, abut or invade the central
portion of the liver. The recommendation for extended liver resection is
supported by retrospective analyses showing a higher rate of R0
resection, prolonged survival, and decreased hepatic recurrence
associated with extended hepatic resections as compared to bile duct
resections.648-652 Resection and reconstruction of the portal vein and/or
hepatic artery may be necessary for complete resection, especially inpatients with more advanced disease. This approach requires substantial
experience and appropriate surgical support for such technicaloperations.653,654 For adjuvant treatment of resected hilar
cholangiocarcinoma, see the section on Adjuvant Chemotherapy andChemoradiation for Biliary Tract Cancers.
Patient selection for surgery is facilitated by careful preoperative staging,surgical exploration, biopsy, and consideration of diagnostic laparoscopy
to identify patients with unresectable or distant metastatic disease. A
preoperative biopsy is not necessary if the index of suspicion is high.
Laparoscopy can identify the majority of patients with occult metastatic
hilar cholangiocarcinoma, albeit with a lower yield. A review including six
studies of staging laparoscopy in patients with hilar cholangiocarcinoma
showed a yield of 14% to 45% and an accuracy of 32% to 71%.655 The
decreasing yield of staging laparoscopy over time may be due toimprovements in imaging techniques.656
While not routinely used in all patients undergoing resection, theconsensus of the panel is that in patients with hilar cholangiocarcinoma,
preoperative treatments including biliary drainage targeted to the FLR(using ERCP or PTC]657-660 and contralateral PVE661,662 should beconsidered for patients with low FLR volumes. Patients with unresectableor metastatic disease should be considered for biliary drainage using
either surgical bypass (although rarely used) or ERCP or PTC, most often
involving biliary stent placement.663-666
In patients with unresectable or metastatic disease, biopsy isrecommended to confirm the diagnosis prior to the initiation of further
treatment. For patients with unresectable disease, biopsy is recommended
only after determining transplant status. Molecular testing is recommended
to potentially guide targeted treatment. Primary treatment options for thesepatients include: 1) clinical trial; 2) systemic therapy; or 3) best supportive
care. In addition, RT or fluoropyrimidine chemoradiation are also included
as options for patients with unresectable disease. Data to support
particular chemoradiation and chemotherapy regimens are limited. See
sections on Chemotherapy and Chemoradiation and Radiation Therapy for
Treatment of Advanced Biliary Tract Cancers.
Liver transplantation is a potentially curative option for selected patientswith lymph node-negative, non-disseminated, locally advanced hilar
cholangiocarcinomas.667-670 There is retrospective evidence suggestingthat neoadjuvant chemoradiation followed by liver transplantation iseffective for selected patients with hilar cholangiocarcinoma.671-673 Resultsfrom two studies suggest that the combination of liver transplantation andneoadjuvant and/or adjuvant chemoradiation is associated with higher
RFS than a potentially curative resection.674,675 However, in one of thesestudies, there were substantial differences in the characteristics of patientsin the two treatment groups.674 It is important to note that many of thesereports include patients with primary sclerosing cholangitis, and somehave not had a definitive histologic cancer diagnosis. Liver transplantation
should be considered only for highly selected patients (ie, tumor ≤3 cm inradial diameter, no intrahepatic or extrahepatic metastases, no nodal
disease) with either unresectable disease with otherwise normal biliary

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-49

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
and hepatic function or underlying chronic liver disease precluding
surgery. The panel encourages continuation of clinical research in thisarea, and referral of patients with unresectable disease to a transplant
center with an UNOS-approved protocol for transplant ofcholangiocarcinoma should be considered.
Photodynamic therapy (PDT) is an ablative therapy that involves
intravenous injection of a photosensitizing drug followed by selective
irradiation with light of a specific wavelength to initiate localized drug
activation, and has been used for palliation in patients with extrahepaticcholangiocarcinoma. The combination of PDT with biliary stenting wasreported to be associated with prolonged OS in patients with unresectablecholangiocarcinoma in two small RCTs.676,677
Surveillance

There are no data to support a specific surveillance schedule or tests inpatients undergoing resection of cholangiocarcinoma; determination of
appropriate follow-up schedule/imaging should include a carefulpatient/physician discussion. It is recommended that follow-up of patients
undergoing resection of cholangiocarcinoma should include considerationof imaging studies every 6 months for 2 years, then annually up to 5 years.
Re-evaluation according to the initial workup should be considered in theevent of disease progression.
Adjuvant Chemotherapy and Chemoradiation for Biliary Tract
Cancers
Recurrence following surgery is a primary limitation for cure in patientswith biliary tract cancers, which provides an important justification for theuse of adjuvant therapy. In a sample of 80 patients with extrahepaticcholangiocarcinoma who underwent resection, 48.8% died of disease by
28 months, while 11.3% died of other causes.576 The role of adjuvant
chemotherapy or chemoradiation therapy in patients with resected biliary
tract cancers is poorly defined, with a lack of data from phase III

RCTs.678,679 Due to the low incidence of biliary tract cancers, the efficacy
and safety of adjuvant chemotherapy or chemoradiation therapy in thesepatients have been evaluated mostly in retrospective studies that haveincluded only a small number of patients. Further, these studies often
combined patients with gallbladder and bile duct cancers (with a few
exceptions), which is problematic since the biology of these tumors iscompletely different. Despite the challenges associated with the accrual oflarge numbers of patients with biliary tract cancer for randomized phase III
trials, it is widely recognized that efforts should be made to conduct suchstudies in which the individual disease entities are evaluated separately.
Data supporting adjuvant chemotherapy in patients with resected biliary
tract cancer have come from two randomized phase III trials. In the phase
III BILCAP study, 447 patients with completely resectedcholangiocarcinoma or gallbladder cancer were randomized to receive
either adjuvant capecitabine or observation.680 RFS was significantly
greater for patients in the capecitabine arm in both the intent-to-treat
analysis (24.4 months vs. 17.5 months; HR, 0.75; 95% CI, 0.58–0.98; P =.033) and in the per-protocol analysis (n = 430; HR, 0.70; 95% CI, 0.54–
0.92; P = .009). Median OS was 51.1 months for the capecitabine arm and36.4 months for the observation arm. This difference was statisticallysignificant in the per-protocol analysis (HR, 0.75; 95% CI, 0.58–0.97; P =.028) but not in the intent-to-treat analysis.
In the second phase III randomized trial, 508 patients with resectedpancreaticobiliary cancer (139 patients had cholangiocarcinoma and 140
patients had gallbladder cancer) were randomly assigned to adjuvant
chemotherapy with fluorouracil and mitomycin C or to a control arm.681
Results from unplanned subgroup analyses showed a significantly better5-year DFS for patients with gallbladder cancer treated with chemotherapy(20.3% compared to 11.6% in the control group; P = .021), although nosignificant differences between the two treatment arms were observed for

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-50

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
all patients with biliary duct cancers. Results from this trial support thesuggestion that patients with gallbladder cancer undergoing resection may
derive survival benefit with adjuvant chemotherapy.
Negative results have been found for two gemcitabine-based regimens in
two randomized phase III trials. In the phase III PRODIGE 12-ACCORD
18 trial, 196 patients with R0 or R1 resected biliary tract cancer wererandomized to receive gemcitabine/oxaliplatin or surveillance alone.682 No
statistically significant differences were found between the study arms for
RFS and OS. Negative results for survival outcomes were also found in aphase III trial from Japan evaluating the efficacy of gemcitabine
monotherapy (compared to observation) in 226 patients with resected
extrahepatic cholangiocarcinoma.683
Retrospective studies that have combined patients with gallbladder cancer
and cholangiocarcinomas provide conflicting evidence regarding the roleof adjuvant therapy.505,684,685 It should be noted that the majority ofrecurrences after resection of gallbladder cancer involve distant sites,
supporting the idea of developing effective adjuvant systemic therapies.505
In a systematic review and meta-analysis of 6712 patients with biliary tract
cancers, Horgan et al reported an associated improvement in OS(although nonsignificant) with adjuvant therapy compared with surgery
alone, with no difference between patients with gallbladder cancer and bile
duct cancers.686 Chemotherapy or chemoradiation therapy was associatedwith statistically greater benefit than RT alone, with the greatest benefit
observed in patients with lymph node-positive disease and macroscopic
residual disease (R1 resection). Another systematic review and metaanalysis of 42,917 patients found a significantly higher OS with adjuvant
therapy after surgery compared with surgery alone.687 Ren et al reported ahigher 5-year OS with adjuvant radiotherapy post surgery in patients withgallbladder cancer or extrahepatic cholangiocarcinoma in a meta-analysisof 21 clinical trials.

In studies that included only patients with gallbladder cancer, a metaanalysis including 10 retrospective studies with 3191 patients showed thatadjuvant chemotherapy was associated with improved OS, compared toresection alone (HR, 0.42; 95% CI, 0.22–0.80).688 Subgroup analyses
showed that the patients who are most likely to benefit from adjuvant
therapy include those with a positive margin, those with nodal disease,and those with at least stage II disease. Retrospective studies haveconcluded that adjuvant chemotherapy or chemoradiation following R0
resection might improve OS in selected patients with T2 or T3 tumors andlymph node-positive gallbladder cancer.689-692
Retrospective studies that included only patients with resected
extrahepatic cholangiocarcinoma suggest that adjuvant chemoradiation
may improve local control and survival, although distant metastases was
the most common pattern of failure.693-696 Other studies have suggested
that adjuvant chemoradiation may have a significant survival benefit only
in a subgroup of patients with T3 or T4 tumors or those with a high risk oflocoregional recurrence (R1 resection or positive lymph nodes).695,697,698
Most of the collective experience of chemoradiation in biliary tract cancers
involves concurrent chemoradiation and fluorouracil. The phase II SWOG
S0809 trial, which enrolled patients with extrahepatic cholangiocarcinoma
or gallbladder cancer (N = 79), provided prospective data on adjuvant
chemotherapy/chemoradiation (ie, capecitabine/gemcitabine followed by
concurrent capecitabine and RT). Two-year OS was 65%, and mediansurvival was 35 months. A majority of patients enrolled in the trial (86%)
completed therapy, and the regimen was generally tolerable. Confirmatory
phase III trial data are needed. Concurrent chemoradiation withcapecitabine has been used in other studies.695,699 Concurrent
chemoradiation with gemcitabine is not recommended due to the limited
experience and toxicity associated with this treatment.700

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-51

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
Among patients with cancer of the gallbladder or extrahepatic bile duct,
those who have undergone an R0 resection and who have negative
regional nodes or those with carcinoma in situ at margin may be followedwith observation alone, receive fluoropyrimidine chemoradiation, or
receive fluoropyrimidine or gemcitabine chemotherapy. Patients withintrahepatic cholangiocarcinoma who have undergone an R0 resection
may be observed or treated with fluoropyrimidine or gemcitabine
chemotherapy. Chemoradiation is not a recommended treatment option
for these patients.
Recommended chemotherapy regimens for these patients include
gemcitabine monotherapy or combined with cisplatin or capecitabine,
capecitabine monotherapy or combined with cisplatin or oxaliplatin, and 5fluououracil monotherapy or combined with oxaliplatin. Besides
capecitabine monotherapy, whose use in this setting is supported by thephase III BILCAP study,680 data to support particular chemotherapy
regimens for adjuvant treatment of resected biliary tract cancer are limited
due to lack of clinical trial data and are based on the extrapolation of datafrom studies of patients with advanced disease. Additionally, some of therecommendations are based on practice patterns at NCCN Member
Institutions and retrospective studies from single-center experiences.
Besides gemcitabine monotherapy not being recommended for patientswith resected extrahepatic cholangiocarcinoma (based on the negative
results of a phase III Japanese trial683), the recommendations in the NCCN
Guidelines on the use of adjuvant chemotherapy are not specific to theparticular type of biliary tract cancer, due to the limited data and theheterogeneity of patient populations included in many of the publishedstudies. Based on the negative results of the randomized phase III
PRODIGE 12-ACCORD 18 trial,682 gemcitabine/oxaliplatin was removed
as a recommended regimen for resected biliary tract cancer in 2019.

Patients with microscopic positive tumor margins (R1), gross residual local
disease (R2), or positive regional lymph nodes after resection should be
evaluated by a multidisciplinary team to review the available treatment
options on a case-by-case basis. Treatment of patients with gross residual
disease (R2) should be consistent with treatment for unresectabledisease. For patients with R1 margins or positive regional nodes, theoptimal treatment strategy has not been established but may include
fluoropyrimidine-based or gemcitabine-based chemotherapy or
fluoropyrimidine chemoradiation. Fluoropyrimidine or gemcitabine-based
chemotherapy may be followed by fluoropyrimidine-based chemoradiation,and vice versa. There are limited data to support a specific chemoradiation
regimen. If radiotherapy is used, then EBRT using 3D-CRT and IMRT are
options.701,702 Dosing schedules may depend on margin positivity and may
include 45 Gy at 1.8 Gy/fraction or 50 to 60 Gy at 1.8 to 2.0 Gy/fraction (toallow for an integrated boost) to the tumor bed.679,703
Treatment for Advanced Biliary Tract Cancers
The prognosis of patients with advanced biliary tract cancers is poor andthe median survival for those undergoing supportive care alone is short.704
Treatment options for advanced biliary tract cancers include enrollment ina clinical trial, systemic therapy (gemcitabine- or fluoropyrimidine-based
chemotherapy, or pembrolizumab for patients with MSI-H/dMMR tumors),
fluoropyrimidine-based chemoradiation, and radiotherapy without
additional chemotherapy.
Chemotherapy

The survival benefit of chemotherapy (fluorouracil, leucovorin, andetoposide) over best supportive care for patients with advanced biliary
tract cancers was initially suggested in a phase III trial of 90 patients withadvanced pancreatic and biliary tract cancers, 37 of whom had advanced
biliary tract cancers.705 In a single-center randomized study of 81 patientswith unresectable gallbladder cancer, Sharma et al reported that modified

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-52

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
GEMOX improved PFS and OS compared to best supportive care or
fluorouracil.706 Median OS was 4.5, 4.6, and 9.5 months, respectively, forthe best supportive care, fluorouracil, and modified GEMOX arms (P =.039). The corresponding PFS was 2.8, 3.5, and 8.5 months (P < .001).
Several phase II studies have also demonstrated the efficacy ofchemotherapy for the treatment of patients with advanced biliary tract
cancers.707,708 The results of a pooled analysis of 104 trials that haveincluded 2810 patients with advanced biliary tract cancers showed that
response rates and tumor control were higher for the subgroup of patients
receiving a combination of gemcitabine and platinum-based agents.709 In a
retrospective study of 304 patients with unresectable biliary tract cancers
who were treated with gemcitabine alone, a cisplatin-based regimen, or afluoropyrimidine-based regimen, patients receiving gemcitabine wereshown to have a lower risk of death.710 Most importantly, the support for
the use of gemcitabine-based or fluoropyrimidine-based chemotherapy forpatients with advanced biliary tract cancers comes from four randomized
studies.711-714
The randomized, controlled, phase III ABC-02 study, which enrolled 410
patients with locally advanced or metastatic cholangiocarcinoma,
gallbladder cancer, or ampullary cancer, demonstrated that the
combination of gemcitabine and cisplatin improved OS and PFS by 30%
over gemcitabine alone.713 Median OS was 11.7 months and 8.1 months(HR, 0.64; 95% CI, 0.52–0.80; P < .001), and median PFS was 8.0
months vs. 5.0 months (HR, 0.63; 95% CI, 0.51–0.77; P < .001), both infavor of the combination arm. Although the rate of neutropenia was higher
in the group receiving gemcitabine and cisplatin, there was no significant
difference in the rate of neutropenia-associated infections between the twoarms. Okusaka et al also reported similar findings in a phase II
randomized study of 84 patients with advanced biliary tract cancers.714
Combined analyses from both of these trials (n = 227) showed thatderived neutrophil-to-lymphocyte ratio assessed at baseline wasassociated with greater long-term survival in those randomized to receive
gemcitabine/cisplatin (P < .01).715 Based on these results, the combinationof gemcitabine and cisplatin is considered to be the standard of care forfirst-line chemotherapy for patients with advanced or metastatic biliary
tract cancers. Results from the randomized phase III ABC-06 study
showed that compared to active symptom control alone, active symptom
control combined with FOLFOX in patients previously treated withcombined cisplatin and gemcitabine improved median OS (6.2 months vs.
5.3 months; adjusted HR, 0.69; P = .031).716 Second-line treatment withfluorouracil and irinotecan (FOLFIRI) also provided some benefits topatients.717
Examples of other gemcitabine-based or fluoropyrimidine (fluorouracil orcapecitabine)-based regimens with demonstrated activity in phase II trials
include: gemcitabine and cisplatin or oxaliplatin718-726; gemcitabine andfluoropyrimidine727-731; gemcitabine and albumin-bound paclitaxel (forcholangiocarcinoma)732; gemcitabine, cisplatin, and albumin-boundpaclitaxel733; gemcitabine and cetuximab734; and fluoropyrimidine andoxaliplatin or cisplatin.735-738 In the phase II trial examining the combinationof gemcitabine-cisplatin with albumin-bound paclitaxel, the disease statusof 20% of patients went from unresectable to resectable.733 A phase III
study showed that the combination of capecitabine and oxaliplatin was
non-inferior to the gemcitabine and oxaliplatin combination in terms of the
6-month PFS.739 Triple-drug chemotherapy regimens have also beenshown to be effective in patients with advanced biliary tract cancers, albeit
in a very small number of patients.740-742 The phase III trial that evaluatedfluorouracil, leucovorin, and etoposide versus fluorouracil, cisplatin, andepirubicin did not show one regimen to be significantly superior withrespect to OS (12 months vs. 9 months, respectively) in patients withadvanced biliary tract cancers, although the trial was underpowered todetect such a difference.740 In a phase II trial, the combination of

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-53

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
panitumumab, a monoclonal anti-EGFR antibody, with gemcitabine andirinotecan showed encouraging efficacy with good tolerability in patientswith advanced cholangiocarcinoma, with a 5-month PFS rate of 69%.743
The median PFS and OS were 9.7 months and 12.9 months, respectively.
The effects of other gemcitabine combination therapies have been
examined in phase II trials. In a randomized phase II study of 51 patients,
Kornek et al established the efficacy and tolerance of mitomycin in
combination with gemcitabine or capecitabine in previously untreatedpatients with advanced biliary tract cancers.711 Mitomycin and capecitabine
were associated with superior CR rate (31% vs. 20%), median PFS (5.3
months vs. 4.2 months), and OS (9.25 months vs. 6.7 months). The
results of the 40955 EORTC trial showed that cisplatin and fluorouracil
was more active than high-dose fluorouracil in terms of overall response
rates (19% and 7.1%, respectively) and OS (8 months and 5 months,
respectively), but the PFS was similar in both treatment arms (3.3months).712 In a randomized phase II trial, the combination of gemcitabineand sorafenib was compared to gemcitabine with a placebo in 102
patients with unresectable or metastatic biliary tract cancer.744 There wereno significant between-group differences for OS and PFS rates, butpatients who developed liver metastases following resection survived
longer if they received sorafenib, relative to patients who received theplacebo (P = .019). The gemcitabine/sorafenib combination was welltolerated. Data from phase III trials are needed.
The panel has included combination therapy with gemcitabine andcisplatin with a category 1 recommendation for patients with unresectableor metastatic biliary tract cancers. Based on the experiences from phase II
studies, the following gemcitabine-based and fluoropyrimidine-based
combination chemotherapy regimens are included with a category 2A
recommendation for the treatment of patients with advanced biliary tract
cancer: gemcitabine with oxaliplatin or capecitabine; capecitabine withoxaliplatin; fluorouracil with oxaliplatin; and single-agent fluorouracil,
capecitabine, and gemcitabine. Gemcitabine combined with albuminbound paclitaxel is an option for patients with unresectable or metastatic
biliary tract cancer. Capecitabine or fluorouracil, with cisplatin, areincluded as a category 2B recommendation. The combination of
gemcitabine and fluorouracil is not included due to the increased toxicity
and decreased efficacy observed with this regimen727 when compared withresults of studies of the gemcitabine and capecitabine regimen in thesetting of advanced biliary tract cancer.
In a systematic review including 23 studies (14 phase II clinical trials and 9
retrospective studies) with 761 patients with advanced biliary tract cancer,
the efficacy of second-line chemotherapy was examined.745 There isinsufficient evidence to recommend specific regimens for second-line
therapy in this group of patients, and prospective randomized trials areneeded.
Chemoradiation and Radiation Therapy

Chemoradiation in the setting of advanced biliary tract cancers canprovide control of symptoms due to local tumor effects and may prolong
OS. However, there are limited clinical trial data to define a standard
regimen or definitive benefit. In a retrospective analysis of 37 patientstreated with chemoradiation for unresectable extrahepaticcholangiocarcinoma, the actuarial OS rates at 1 and 2 years were 59%
and 22%, respectively, although effective local control was observed in the
majority of patients during this time period (actuarial local control rates of
90% and 71% at 1 and 2 years, respectively).746 The most extensively
investigated chemotherapeutic agent for use in concurrent chemoradiationin the treatment of biliary tract cancers has been fluorouracil,747,748
although capecitabine has been substituted for fluorouracil in somestudies.699 The panel recommends that concurrent chemoradiation (EBRT
guided by imaging) should be limited to either fluorouracil or capecitabine,

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-54

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
and that such treatment should be restricted to patients without evidenceof metastatic disease. Concurrent chemoradiation with gemcitabine is notrecommended due to the limited experience and toxicity associated withthis treatment.
RT with EBRT and SBRT may be used for patients with unresectablebiliary tract cancers. Evidence supports the consideration of RT fortreatment of unresectable and metastatic intrahepaticcholangiocarcinoma,405,408,631,749 but there is little evidence to support thistreatment option for gallbladder cancer and extrahepaticcholangiocarcinoma without concurrent chemotherapy and in patients withunresected disease.750,751
Targeted Therapy

There is an increasing role for molecular profiling of cholangiocarcinomas.
IDH1/2 mutations are found in 10% to 23% of intrahepaticcholangiocarcinomas.752-758 The prognostic effect of this mutation in
intrahepatic cholangiocarcinoma is uncertain,759 but the IDH1 mutation,
which accounts for 0.8% (95% CI, 0.4%–1.5%) of patients withextrahepatic cholangiocarcinoma,760 is associated with poor prognosis inthese patients.758 A phase III study with 185 patients with advanced IDH1mutant cholangiocarcinoma resulted in significant improvement in PFS(median 2.7 months vs. 1.4 months; HR, 0.37; P < .0001) when treatedwith ivosidenib, an IDH1 inhibitor, compared to placebo.761 The panel
voted to include ivosidenib as a subsequent-line treatment option “usefulin certain circumstances” for unresectable or metastatic
cholangiocarcinoma with IDH1 mutations following disease progression.
Mutations in FGFR2 fusions have been found in 13% to 14% of
intrahepatic cholangiocarcinomas.762-764 FGFR mutations may be
associated with a favorable prognosis.757,763 In the phase II FIGHT-202
clinical trial, pemigatinib, an FGFR inhibitor, demonstrated promisingtherapeutic potential, with 35.5% of patients with cholangiocarcinoma and

FGFR2 fusions or rearrangements achieving an objective response.765 In
another phase II study, published in an abstract, treatment with infigratinib,
an FGFR1-3 inhibitor, led to an ORR of 23.1% (95% CI, 15.6 %–32.2%) inpatients with previously treated advanced/metastatic cholangiocarcinoma
with FGFR2 fusions or rearrangements.766 The median duration of
response was 5.0 months and the median PFS was 7.3 months (95% CI,
5.6 months–7.6 months). The panel voted to include pemigatinib andinfigratinib as subsequent-line treatment options “useful in certain
circumstances” for unresectable or metastatic cholangiocarcinoma with
FGFR2 fusions or rearrangements following disease progression.
NTRK fusion genes were identified in 0.75% of patients with biliary tract
tumors.767 A few NTRK inhibitors such as entrectinib and larotrectinib haveshown efficacy against NTRK fusion-positive solid tumors.768-770 The panel
voted to include entrectinib and larotrectinib as first-line or subsequent-line(following disease progression) treatment options “useful in certain
circumstances” for unresectable or metastatic disease with NTRK genefusions. A study including 35 patients with resected intrahepaticcholangiocarcinoma showed that 17% of these tumors had an NRAS
mutation, and 14% had a BAP1 mutation.758 The same study also
analyzed the tumors of 38 patients with extrahepatic cholangiocarcinoma
and showed that 47% had a KRAS mutation, 24% had a TP53 mutation,and 16% had an ARID1A mutation. BRAF V600E mutation was a rareoccurrence and was restricted to intrahepatic cholangiocarcinoma.771,772 In
the phase II ROAR trial with 43 patients with BRAF V600E-mutated biliary
tract cancer, treatment with the oral combination of dabrafenib andtrametinib led to an ORR of 51% (95% CI, 36%–67%).773 Results from theSubprotocol H trial revealed an ORR of 38% (90% CI, 22.9%–54.9%, P <.0001) and a PFS of 11.4 months (90% CI, 8.4 months–16.3 months) in 29
patients.774 In the 2021 update, the panel voted to include the oral
combination of dabrafenib and trametinib as a subsequent-line treatment

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-55

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
option “useful in certain circumstances” for unresectable or metastatic
progressive disease with BRAF-V600E mutations.
HER2 gene amplification has been found in up to 18% of extrahepaticcholangiocarcinomas.775 In patients with lymph node metastases, HER2
gene amplification may be associated with poor prognosis.775 Other genemutations that may be associated with a poor prognosis are: ALK for
extrahepatic cholangiocarcinoma; ARID1A, PIK3C2G, STK11, andTGFBR2 for intrahepatic cholangiocarcinoma; and TP53 for intrahepaticand extrahepatic cholangiocarcinoma.758 Given emerging evidence
regarding actionable targets for treating cholangiocarcinoma, molecular
testing of unresectable and metastatic tumors is recommended.
Studies have indicated that MSI-H, dMMR, and TMB-H tumors are
sensitive to PD-1 blockade.494,555,556,776 The phase II KEYNOTE-158 study
investigated the use of pembrolizumab in patients with advanced
noncolorectal MSI-H/dMMR tumors.494 Analyses of a cholangiocarcinoma
subgroup revealed an ORR of 40.9% (95% CI, 20.7%-63.6%). The median
PFS and OS were 4.2 months and 24.3 months, respectively. Data fromthe study also revealed that patients with a TMB-H status could have arobust response to pembrolizumab.776 Twenty-nine percent of patients in
the TMB-H arm achieved an objective response compared to 6% in the
non TMB-H arm. Results were published from a study of patients withdMMR tumors of various disease sites.555 Among four patients with dMMR
cholangiocarcinoma who received pembrolizumab, one patient had a CR,
and the remaining patients had SD. Based on these studies, the FDA
expanded pembrolizumab approval in 2017 and 2020 to include treatmentof unresectable or metastatic, MSI-H, dMMR, or TMB-H solid tumors thathave progressed following prior treatment and that have no satisfactory
alternative treatment options. The panel voted to include pembrolizumab
as a first-line or subsequent-line (following disease progression and withno prior treatment with a checkpoint inhibitor) treatment option “useful incertain circumstances” for patients with unresectable or metastatic MSI-H,
dMMR, and TMB-H (for subsequent-line therapy) biliary tract tumors,
though cautions that data to support this recommendation are limited,particularly in the first-line setting.777
Dostarlimab-gxly, another anti-PD-1 antibody, was assessed in an openlabel phase I study with 2 cohorts.472 One cohort had 103 patients withadvanced or recurrent MSI-H/dMMR endometrial cancer and another had
106 patients with advanced or recurrent MSI-H/dMMR or POLEhypermutated non-endometrial solid tumors (comprising mostly
gastrointestinal tumors [93.4%] with 65.1% colorectal tumors). An interim
analysis, published in an abstract, revealed an ORR of 41.6% (95% CI,
34.9%–48.6%), per RECIST v1.1. The ORR for the cohort with nonendometrial cancer was 38.7% (95% CI, 29.4%–48.6%). The median
duration of response was not reached (median follow-up of 16.3 months
for the cohort with endometrial cancer and 12.4 months for the cohort with
non-endometrial cancer). The most frequent grade 3 or higher treatmentrelated adverse events were anemia (2.2%), elevated lipase (1.9%),
elevated alanine aminotransferase (1.1%), and diarrhea (1.1%). Anotherpublished abstract demonstrated that among the cohort with nonendometrial cancer, patients with colorectal cancer had an ORR of 36.2%(95% CI, 25.0%–48.7%).473 The cohort also included one patient withgallbladder cancer and 1 with biliary neoplasm. Both patients had acomplete response. The panel voted to include dostarlimab-gxly as acategory 2B subsequent-line treatment option “useful in certain
circumstances” for patients with MSI-H/dMMR recurrent or advanced
tumors that have progressed on or following prior treatment, who have nosatisfactory alternative treatment options, and who have not beenpreviously treated with a checkpoint inhibitor.
In a phase II trial with 46 evaluable patients with advanced biliary tract
cancers, an ORR of 22% and a disease control rate of 59% were

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-56

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
obtained, upon investigator assessment, with the use of nivolumab,
another anti-PD1 drug.778 With blinded independent central review, theORR was 11% and the disease control rate was 50%. In the intention-totreat cohort, the median PFS and median OS were 3.7 months (95% CI,
2.3–5.7 months) and 14.2 months (95% CI, 6.0 months–not reached),
respectively. The panel voted to include nivolumab as a category 2B
subsequent-line treatment option “useful in certain circumstances” forpatients with unresectable or metastatic progressive disease who have notbeen previously treated with a checkpoint inhibitor.
Initial results from the phase II LEAP-005 trial, published in an abstractthat examined the combination of lenvatinib with pembrolizumab as asubsequent therapy for patients with advanced biliary tract disease,demonstrated an ORR of 9.7% (95% CI, 2.0–25.8%), with a median PFS
of 6.1 months.779 The panel voted to include the combination of lenvatinib
and pembrolizumab as a category 2B subsequent-line treatment option“useful in certain circumstances” for patients with unresectable ormetastatic progressive disease who have not been previously treated witha checkpoint inhibitor.
In a retrospective review of eight patients with advanced gallbladdercancer and HER2/neu gene amplification or overexpression, five of theeight patients who received HER2/neu-directed therapy (trastuzumab)
experienced a PR or CR. No response was seen in five patients withcholangiocarcinoma who also received HER2/neu-directed therapy.780
Phase II studies are currently ongoing to investigate HER2-directed
treatment options for solid tumors (eg, NCT02465060, NCT02693535). Ina published abstract, pralsetinib, a selective RET inhibitor, demonstrated
an ORR of 50% (95% CI, 21%–79%) in patients with RET fusion-positive
tumors other than non-small cell lung cancer and thyroid.781 A response
was observed in the two patients who had cholangiocarcinoma. However,
RET mutations in cholangiocarcinoma are rare.782

In a phase II trial, regorafenib was found to have a disease control rate of
56% and could thus be useful in patients with disease refractory to
chemotherapy.783 Another phase II trial reported an ORR of 9.1% and adisease control rate of 64%.784 In the phase II REACHIN trial, patients withbiliary tract cancers were randomized to receive best supportive carealong with either regorafenib or placebo.785 The median PFS for patients in
the regorafenib arm was 3.0 months compared to 1.5 months for those in
the placebo arm. The median OS was 5.3 months for the regorafenib
group compared to 5.1 months for the placebo group. The panel voted toinclude regorafenib as a category 2B subsequent-line treatment option(“other recommended regimen”) for unresectable or metastatic
progressive disease.

Summary
Hepatobiliary cancers are associated with a poor prognosis. Many patientswith HCC are diagnosed at an advanced stage, and patients with biliary
tract cancers commonly present with advanced disease. In the past few
years, several advances have been made in the therapeutic approaches
for patients with hepatobiliary cancers.
Complete resection of the tumor in well-selected patients is currently thebest available potentially curative treatment. Liver transplantation is acurative option for select resectable patients. Bridge therapy can beconsidered for patients with HCC to decrease tumor progression and thedropout rate from the liver transplantation waiting list.
Locoregional therapies (ablation, arterially directed therapies, and RT) areoften the initial approach for patients with HCC who are not candidates forsurgery or liver transplantation. Ablation should be considered as definitive
treatment in the context of a multidisciplinary review in well-selectedpatients with small properly located tumors. Arterially directed therapies(TACE, DEB-TACE, or TARE with Y-90 microspheres) are appropriate for

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-57

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
patients with unresectable or inoperable tumors that are not amenable toablation therapy. SBRT can be considered as an alternative to ablation
and/or embolization techniques (especially for patients with 1–3 tumors
and minimal or no extrahepatic disease) or when these therapies havefailed or are contraindicated. Though it is currently rarely used, there are
emerging data supporting its usefulness. PBT may also be used in selectsettings. Locoregional therapy is also included as an option for patientswith unresectable or metastatic intrahepatic cholangiocarcinoma. RT with
EBRT and SBRT may be used in patients with unresectable gallbladdercancer or extrahepatic cholangiocarcinoma, though there is little evidence
to support this treatment option without concurrent chemotherapy and inpatients with unresected disease.

RCTs of patients with hepatobiliary cancers, and patient participation inprospective clinical trials is the preferred option for the treatment ofpatients with all stages of disease.

The combination of atezolizumab and bevacizumab is now the preferredfirst-line option for patients with HCC. Lenvatinib and sorafenib are listed
as other recommended first-line options. A number of agents haverecently been added to the NCCN Guidelines for subsequent-line therapy
for patients with disease progression. These options include regorafenib,cabozantinib, ramucirumab, nivolumab, combined nivolumab andipilimumab, pembrolizumab, and dostarlimab-gxly. The results of therandomized phase III ABC-02 study demonstrated a survival advantage
for the combination of gemcitabine and cisplatin over gemcitabine alone inpatients with advanced or metastatic biliary tract cancers. The combinationof gemcitabine and cisplatin is included as a category 1 recommendation
for this group of patients. Drugs such as entrectinib, larotrectinib,
pembrolizumab, dostarlimab-gxly pemigatinib, infigratinib, ivosidenib, andcombined dabrafenib and trametinib may benefit certain patients withspecific genomic mutations.
It is essential that all patients be evaluated by a multidisciplinary teamprior to initiation of treatment. Careful patient selection for treatment andpatient engagement are essential. There are relatively few high-quality
Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-58

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers

Figure 1: Classification of Cholangiocarcinoma

Reproduced with permission from Patel T. Cholangiocarcinoma. Nat Clin Pract Gastroenterol Hepatol 2006;3:33-42.

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-59

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
References
1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J
Clin 2020;70:7-30. Available at:https://www.ncbi.nlm.nih.gov/pubmed/31912902.
2. Fong ZV, Tanabe KK. The clinical management of hepatocellular
carcinoma in the United States, Europe, and Asia: a comprehensive andevidence-based comparison and review. Cancer 2014;120:2824-2838.
Available at: http://www.ncbi.nlm.nih.gov/pubmed/24897995.
3. U.S. National Library of Medicine-Key MEDLINE® Indicators. Available
at: http://www.nlm.nih.gov/bsd/bsd_key.html. Accessed July 24, 2014.
4. Ryerson AB, Eheman CR, Altekruse SF, et al. Annual Report to the
Nation on the Status of Cancer, 1975-2012, featuring the increasing
incidence of liver cancer. Cancer 2016;122:1312-1337. Available at:https://www.ncbi.nlm.nih.gov/pubmed/26959385.
5. The burden of primary liver cancer and underlying etiologies from 1990
to 2015 at the global, regional, and national level: results from the Global
Burden of Disease Study 2015. JAMA Oncol 2017;3:1683-1691. Available
at: https://www.ncbi.nlm.nih.gov/pubmed/28983565.
6. Marrero JA, Kulik LM, Sirlin CB, et al. Diagnosis, staging, andmanagement of hepatocellular carcinoma: 2018 Practice Guidance by theAmerican Association for the Study of Liver Diseases. Hepatology
2018;68:723-750. Available at:https://www.ncbi.nlm.nih.gov/pubmed/29624699.
7. Islami F, Miller KD, Siegel RL, et al. Disparities in liver cancer
occurrence in the United States by race/ethnicity and state. CA Cancer J
Clin 2017;67:273-289. Available at:https://www.ncbi.nlm.nih.gov/pubmed/28586094.
8. Melkonian SC, Jim MA, Reilley B, et al. Incidence of primary livercancer in American Indians and Alaska Natives, US, 1999-2009. Cancer
Causes Control 2018;29:833-844. Available at:https://www.ncbi.nlm.nih.gov/pubmed/30030669.

9. Petrick JL, Kelly SP, Altekruse SF, et al. Future of hepatocellular
carcinoma incidence in the United States forecast through 2030. J Clin
Oncol 2016;34:1787-1794. Available at:https://www.ncbi.nlm.nih.gov/pubmed/27044939.
10. Herbst DA, Reddy KR. Risk factors for hepatocellular carcinoma. Clin
Liver Dis (Hoboken) 2012;1:180-182. Available at:https://www.ncbi.nlm.nih.gov/pubmed/31186882.
11. Janevska D, Chaloska-Ivanova V, Janevski V. Hepatocellular
carcinoma: Risk factors, diagnosis and treatment. Open Access Maced J
Med Sci 2015;3:732-736. Available at:https://www.ncbi.nlm.nih.gov/pubmed/27275318.
12. Fattovich G, Stroffolini T, Zagni I, Donato F. Hepatocellular carcinoma
in cirrhosis: incidence and risk factors. Gastroenterology 2004;127:S3550. Available at: http://www.ncbi.nlm.nih.gov/pubmed/15508101.
13. de Martel C, Maucort-Boulch D, Plummer M, Franceschi S. World-wide
relative contribution of hepatitis B and C viruses in hepatocellular
carcinoma. Hepatology 2015;62:1190-1200. Available at:https://www.ncbi.nlm.nih.gov/pubmed/26146815.
14. Sun J, Althoff KN, Jing Y, et al. Trends in hepatocellular carcinoma
incidence and risk among persons with HIV in the US and Canada, 19962015. JAMA Netw Open 2021;4:e2037512. Available at:https://www.ncbi.nlm.nih.gov/pubmed/33595662.
15. Ganne-Carrie N, Nahon P. Hepatocellular carcinoma in the setting of
alcohol-related liver disease. J Hepatol 2019;70:284-293. Available at:https://www.ncbi.nlm.nih.gov/pubmed/30658729.
16. Kanwal F, Kramer JR, Mapakshi S, et al. Risk of hepatocellular cancer
in patients with non-alcoholic fatty liver disease. Gastroenterology
2018;155:1828-1837 e1822. Available at:https://www.ncbi.nlm.nih.gov/pubmed/30144434.
17. Ascha MS, Hanouneh IA, Lopez R, et al. The incidence and risk
factors of hepatocellular carcinoma in patients with nonalcoholic

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-60

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
steatohepatitis. Hepatology 2010;51:1972-1978. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/20209604.

study (JPHC Study). Cancer Lett 2011;300:173-179. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/21035947.

18. Elmberg M, Hultcrantz R, Ekbom A, et al. Cancer risk in patients withhereditary hemochromatosis and in their first-degree relatives.
Gastroenterology 2003;125:1733-1741. Available at:https://www.ncbi.nlm.nih.gov/pubmed/14724826.

26. Alter MJ. The epidemiology of acute and chronic hepatitis C. Clin Liver
Dis 1997;1:559-568. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/15560058.

19. Di Bisceglie AM, Lyra AC, Schwartz M, et al. Hepatitis C-related
hepatocellular carcinoma in the United States: influence of ethnic status.
Am J Gastroenterol 2003;98:2060-2063. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/14499788.
20. Chen CJ, Yu MW, Liaw YF. Epidemiological characteristics and risk
factors of hepatocellular carcinoma. J Gastroenterol Hepatol
1997;12:S294-308. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/9407350.
21. Yang HI, Lu SN, Liaw YF, et al. Hepatitis B e antigen and the risk ofhepatocellular carcinoma. N Engl J Med 2002;347:168-174. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/12124405.
22. Chen G, Lin W, Shen F, et al. Past HBV viral load as predictor ofmortality and morbidity from HCC and chronic liver disease in aprospective study. Am J Gastroenterol 2006;101:1797-1803. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/16817842.
23. Chen CJ, Yang HI, Su J, et al. Risk of hepatocellular carcinoma acrossa biological gradient of serum hepatitis B virus DNA level. JAMA
2006;295:65-73. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/16391218.
24. Lee MH, Yang HI, Lu SN, et al. Hepatitis C virus seromarkers andsubsequent risk of hepatocellular carcinoma: long-term predictors from acommunity-based cohort study. J Clin Oncol 2010;28:4587-4593.
Available at: http://www.ncbi.nlm.nih.gov/pubmed/20855826.
25. Ishiguro S, Inoue M, Tanaka Y, et al. Impact of viral load of hepatitis C
on the incidence of hepatocellular carcinoma: A population-based cohort

27. Ryder SD, Irving WL, Jones DA, et al. Progression of hepatic fibrosis
in patients with hepatitis C: a prospective repeat liver biopsy study. Gut
2004;53:451-455. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/14960533.
28. Falade-Nwulia O, Suarez-Cuervo C, Nelson DR, et al. Oral directacting agent therapy for hepatitis C virus infection: a systematic review.
Ann Intern Med 2017;166:637-648. Available at:https://www.ncbi.nlm.nih.gov/pubmed/28319996.
29. Suwanthawornkul T, Anothaisintawee T, Sobhonslidsuk A, et al.
Efficacy of second generation direct-acting antiviral agents for treatment
naive hepatitis C genotype 1: a systematic review and network metaanalysis. PLoS One 2015;10:e0145953. Available at:https://www.ncbi.nlm.nih.gov/pubmed/26720298.
30. Ogata F, Kobayashi M, Akuta N, et al. Outcome of all-oral direct-acting
antiviral regimens on the rate of development of hepatocellular carcinoma
in patients with hepatitis C virus genotype 1-related chronic liver disease.
Oncology 2017. Available at:https://www.ncbi.nlm.nih.gov/pubmed/28448999.
31. Carrat F, Fontaine H, Dorival C, et al. Clinical outcomes in patientswith chronic hepatitis C after direct-acting antiviral treatment: a prospective
cohort study. Lancet 2019;393:1453-1464. Available at:https://www.ncbi.nlm.nih.gov/pubmed/30765123.
32. Lavanchy D. Worldwide epidemiology of HBV infection, disease
burden, and vaccine prevention. J Clin Virol 2005;34 Suppl 1:1-3.
Available at: http://www.ncbi.nlm.nih.gov/pubmed/16461208.

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-61

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
33. Goldstein ST, Zhou F, Hadler SC, et al. A mathematical model toestimate global hepatitis B disease burden and vaccination impact. Int J
Epidemiol 2005;34:1329-1339. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/16249217.
34. Beasley RP, Hwang LY, Lin CC, Chien CS. Hepatocellular carcinoma
and hepatitis B virus. A prospective study of 22 707 men in Taiwan.
Lancet 1981;2:1129-1133. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/6118576.
35. Bruix J, Sherman M. Management of hepatocellular carcinoma: An
update. AASLD Practice Guidelines; 2010. Available at:
http://www.aasld.org/practiceguidelines/Documents/HCCUpdate2010.pdf.

2011;54:801-807. Available at:https://www.ncbi.nlm.nih.gov/pubmed/21618565.
41. Blonski W, Kotlyar DS, Forde KA. Non-viral causes of hepatocellular
carcinoma. World J Gastroenterol 2010;16:3603-3615. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/20677332.
42. Asare GA, Bronz M, Naidoo V, Kew MC. Synergistic interaction
between excess hepatic iron and alcohol ingestion in hepatic
mutagenesis. Toxicology 2008;254:11-18. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/18852013.
43. Singal AK, Anand BS. Mechanisms of synergy between alcohol andhepatitis C virus. J Clin Gastroenterol 2007;41:761-772. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/17700425.

36. Thiele M, Gluud LL, Fialla AD, et al. Large variations in risk ofhepatocellular carcinoma and mortality in treatment naive hepatitis B
patients: systematic review with meta-analyses. PLoS One
2014;9:e107177. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/25225801.

44. Volk ML, Marrero JA. Early detection of liver cancer: diagnosis andmanagement. Curr Gastroenterol Rep 2008;10:60-66. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/18417044.

37. Kim WR, Loomba R, Berg T, et al. Impact of long-term tenofovir
disoproxil fumarate on incidence of hepatocellular carcinoma in patientswith chronic hepatitis B. Cancer 2015;121:3631-3638. Available at:https://www.ncbi.nlm.nih.gov/pubmed/26177866.

45. Lok AS, McMahon BJ. Chronic hepatitis B: update 2009. AASLDPractice Guidelines (ed 2009/08/29); 2009. Available at:
http://www.aasld.org/practiceguidelines/Pages/SortablePracticeGuidelines
Alpha.aspx.

38. Chang MH, You SL, Chen CJ, et al. Decreased incidence ofhepatocellular carcinoma in hepatitis B vaccinees: a 20-year follow-up
study. J Natl Cancer Inst 2009;101:1348-1355. Available at:https://www.ncbi.nlm.nih.gov/pubmed/19759364.

46. Terrault NA, Bzowej NH, Chang KM, et al. AASLD guidelines fortreatment of chronic hepatitis B. Hepatology 2016;63:261-283. Available
at: http://www.ncbi.nlm.nih.gov/pubmed/26566064.

39. Chang MH, You SL, Chen CJ, et al. Long-term effects of hepatitis B
immunization of infants in preventing liver cancer. Gastroenterology
2016;151:472-480.e471. Available at:https://www.ncbi.nlm.nih.gov/pubmed/27269245.
40. McMahon BJ, Bulkow LR, Singleton RJ, et al. Elimination ofhepatocellular carcinoma and acute hepatitis B in children 25 years after ahepatitis B newborn and catch-up immunization program. Hepatology

47. Beaton MD, Adams PC. Prognostic factors and survival in patientswith hereditary hemochromatosis and cirrhosis. Can J Gastroenterol
2006;20:257-260. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/16609753.
48. Yeoman AD, Al-Chalabi T, Karani JB, et al. Evaluation of risk factors in
the development of hepatocellular carcinoma in autoimmune hepatitis:
Implications for follow-up and screening. Hepatology 2008;48:863-870.
Available at: http://www.ncbi.nlm.nih.gov/pubmed/18752332.

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-62

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
49. Tansel A, Katz LH, El-Serag HB, et al. Incidence and determinants ofhepatocellular carcinoma in autoimmune hepatitis: a systematic review
and meta-analysis. Clin Gastroenterol Hepatol 2017;15:1207-1217 e1204.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/28215616.
50. Gomaa AI, Khan SA, Toledano MB, et al. Hepatocellular carcinoma:
epidemiology, risk factors and pathogenesis. World J Gastroenterol
2008;14:4300-4308. Available at:https://www.ncbi.nlm.nih.gov/pubmed/18666317.
51. Arnaoutakis DJ, Mavros MN, Shen F, et al. Recurrence patterns andprognostic factors in patients with hepatocellular carcinoma in noncirrhotic
liver: a multi-institutional analysis. Ann Surg Oncol 2014;21:147-154.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/23959056.
52. Makarova-Rusher OV, Altekruse SF, McNeel TS, et al. Population
attributable fractions of risk factors for hepatocellular carcinoma in the
United States. Cancer 2016;122:1757-1765. Available at:https://www.ncbi.nlm.nih.gov/pubmed/26998818.
53. Pearson-Stuttard J, Zhou B, Kontis V, et al. Worldwide burden ofcancer attributable to diabetes and high body-mass index: a comparativerisk assessment. Lancet Diabetes Endocrinol 2018;6:95-104. Available at:https://www.ncbi.nlm.nih.gov/pubmed/29195904.
54. Alexander M, Loomis AK, van der Lei J, et al. Risks and clinicalpredictors of cirrhosis and hepatocellular carcinoma diagnoses in adults
with diagnosed NAFLD: real-world study of 18 million patients in four
European cohorts. BMC Med 2019;17:95. Available at:https://www.ncbi.nlm.nih.gov/pubmed/31104631.
55. Marchesini G, Bugianesi E, Forlani G, et al. Nonalcoholic fatty liver,steatohepatitis, and the metabolic syndrome. Hepatology 2003;37:917923. Available at: http://www.ncbi.nlm.nih.gov/pubmed/12668987.
56. Takamatsu S, Noguchi N, Kudoh A, et al. Influence of risk factors formetabolic syndrome and non-alcoholic fatty liver disease on the
progression and prognosis of hepatocellular carcinoma.

Hepatogastroenterology 2008;55:609-614. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/18613418.
57. Kim NG, Nguyen PP, Dang H, et al. Temporal trends in disease
presentation and survival of patients with hepatocellular carcinoma: A realworld experience from 1998 to 2015. Cancer 2018;124:2588-2598.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/29624631.
58. Younossi ZM. Review article: current management of non-alcoholic
fatty liver disease and non-alcoholic steatohepatitis. Aliment Pharmacol
Ther 2008;28:2-12. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/18410557.
59. White DL, Kanwal F, El-Serag HB. Association between nonalcoholic
fatty liver disease and risk for hepatocellular cancer, based on systematic
review. Clin Gastroenterol Hepatol 2012;10:1342-1359 e1342. Available
at: http://www.ncbi.nlm.nih.gov/pubmed/23041539.
60. Sanyal AJ, Banas C, Sargeant C, et al. Similarities and differences inoutcomes of cirrhosis due to nonalcoholic steatohepatitis and hepatitis C.
Hepatology 2006;43:682-689. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/16502396.
61. Yatsuji S, Hashimoto E, Tobari M, et al. Clinical features andoutcomes of cirrhosis due to non-alcoholic steatohepatitis compared withcirrhosis caused by chronic hepatitis C. J Gastroenterol Hepatol
2009;24:248-254. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/19032450.
62. Loomba R, Lim JK, Patton H, El-Serag HB. AGA clinical practice
update on screening and surveillance for hepatocellular carcinoma inpatients with nonalcoholic fatty liver disease: Expert review.
Gastroenterology 2020;158:1822-1830. Available at:https://www.ncbi.nlm.nih.gov/pubmed/32006545.
63. El-Serag HB, Davila JA. Is fibrolamellar carcinoma different fromhepatocellular carcinoma? A US population-based study. Hepatology
2004;39:798-803. Available at:https://www.ncbi.nlm.nih.gov/pubmed/14999699.

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-63

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
64. Stipa F, Yoon SS, Liau KH, et al. Outcome of patients withfibrolamellar hepatocellular carcinoma. Cancer 2006;106:1331-1338.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/16475212.
65. Mayo SC, Mavros MN, Nathan H, et al. Treatment and prognosis ofpatients with fibrolamellar hepatocellular carcinoma: a national
perspective. J Am Coll Surg 2014;218:196-205. Available at:https://www.ncbi.nlm.nih.gov/pubmed/24315886.
66. Groeschl RT, Miura JT, Wong RK, et al. Multi-institutional analysis ofrecurrence and survival after hepatectomy for fibrolamellar carcinoma. J
Surg Oncol 2014;110:412-415. Available at:https://www.ncbi.nlm.nih.gov/pubmed/24844420.
67. Lafaro KJ, Pawlik TM. Fibrolamellar hepatocellular carcinoma: current
clinical perspectives. J Hepatocell Carcinoma 2015;2:151-157. Available
at: https://www.ncbi.nlm.nih.gov/pubmed/27508204.
68. Honeyman JN, Simon EP, Robine N, et al. Detection of a recurrent
DNAJB1-PRKACA chimeric transcript in fibrolamellar hepatocellular
carcinoma. Science 2014;343:1010-1014. Available at:https://www.ncbi.nlm.nih.gov/pubmed/24578576.
69. Cornella H, Alsinet C, Sayols S, et al. Unique genomic profile offibrolamellar hepatocellular carcinoma. Gastroenterology 2015;148:806818.e810. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25557953.
70. Darcy DG, Chiaroni-Clarke R, Murphy JM, et al. The genomic
landscape of fibrolamellar hepatocellular carcinoma: whole genome
sequencing of ten patients. Oncotarget 2015;6:755-770. Available at:https://www.ncbi.nlm.nih.gov/pubmed/25605237.
71. Graham RP, Jin L, Knutson DL, et al. DNAJB1-PRKACA is specific forfibrolamellar carcinoma. Mod Pathol 2015;28:822-829. Available at:https://www.ncbi.nlm.nih.gov/pubmed/25698061.
72. Abou-Alfa GK, Mayer RJ, Cosgrove D, et al. Randomized phase II
study of everolimus (E), leuprolide + letrozole (LL), and E + LL (ELL) inpatients (pts) with unresectable fibrolamellar carcinoma (FLC). J Clin

Oncol 2015;33:e15149. Available at:https://ascopubs.org/doi/abs/10.1200/jco.2015.33.15_suppl.e15149.
73. Heimbach JK, Kulik LM, Finn RS, et al. AASLD guidelines for thetreatment of hepatocellular carcinoma. Hepatology 2018;67:358-380.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/28130846.
74. EASL-EORTC clinical practice guidelines: management of
hepatocellular carcinoma. J Hepatol 2012;56:908-943. Available at:https://www.ncbi.nlm.nih.gov/pubmed/22424438.
75. Zhang B-H, Yang B-H, Tang Z-Y. Randomized controlled trial ofscreening for hepatocellular carcinoma. J Cancer Res Clin Oncol
2004;130:417-422. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/15042359.
76. Chang P-E, Ong W-C, Lui H-F, Tan C-K. Is the prognosis of young
patients with hepatocellular carcinoma poorer than the prognosis of older
patients? A comparative analysis of clinical characteristics, prognostic
features, and survival outcome. J Gastroenterol 2008;43:881-888.
Available at: http://www.ncbi.nlm.nih.gov/pubmed/19012042.
77. El-Serag HB, Marrero JA, Rudolph L, Reddy KR. Diagnosis andtreatment of hepatocellular carcinoma. Gastroenterology 2008;134:17521763. Available at: http://www.ncbi.nlm.nih.gov/pubmed/18471552.
78. Waidely E, Al-Yuobi AR, Bashammakh AS, et al. Serum protein
biomarkers relevant to hepatocellular carcinoma and their detection.
Analyst 2016;141:36-44. Available at:https://www.ncbi.nlm.nih.gov/pubmed/26606739.
79. Zhang B, Yang B. Combined alpha fetoprotein testing andultrasonography as a screening test for primary liver cancer. J Med Screen
1999;6:108-110. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/10444731.
80. Tong MJ, Rosinski AA, Huynh CT, et al. Long-term survival aftersurveillance and treatment in patients with chronic viral hepatitis andVersion 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-64

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
hepatocellular carcinoma. Hepatol Commun 2017;1:595-608. Available at:https://www.ncbi.nlm.nih.gov/pubmed/29404481.
81. Pathologic diagnosis of early hepatocellular carcinoma: a report of theinternational consensus group for hepatocellular neoplasia. Hepatology
2009;49:658-664. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/19177576.
82. Lok AS, Sterling RK, Everhart JE, et al. Des-gamma-carboxy
prothrombin and alpha-fetoprotein as biomarkers for the early detection ofhepatocellular carcinoma. Gastroenterology 2010;138:493-502. Available
at: http://www.ncbi.nlm.nih.gov/pubmed/19852963.
83. Tangkijvanich P, Anukulkarnkusol N, Suwangool P, et al. Clinicalcharacteristics and prognosis of hepatocellular carcinoma: analysis basedon serum alpha-fetoprotein levels. J Clin Gastroenterol 2000;31:302-308.
Available at: http://www.ncbi.nlm.nih.gov/pubmed/11129271.
84. Tzartzeva K, Obi J, Rich NE, et al. Surveillance imaging and alphafetoprotein for early detection of hepatocellular carcinoma in patients withcirrhosis: a meta-analysis. Gastroenterology 2018;154:1706-1718.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/29425931.
85. Arrieta O, Cacho B, Morales-Espinosa D, et al. The progressive
elevation of alpha fetoprotein for the diagnosis of hepatocellular carcinoma
in patients with liver cirrhosis. BMC Cancer 2007;7:28. Available at:https://www.ncbi.nlm.nih.gov/pubmed/17288606.
86. Schiff ER, Sorrell MF, Maddrey WC. Schiff's Diseases of the Liver.
Philadelphia: Lippincott Williams & Wilkins (LWW); 2007.
87. Liver imaging reporting and data system version 2017. 2018. Available
at: http://www.acr.org/quality-safety/resources/LIRADS. Accessed April 2,
2019.
88. Luo JC, Hwang SJ, Wu JC, et al. Clinical characteristics and prognosisof hepatocellular carcinoma patients with paraneoplastic syndromes.
Hepatogastroenterology 2002;49:1315-1319. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/12239934.

89. Gera S, Ettel M, Acosta-Gonzalez G, Xu R. Clinical features, histology,
and histogenesis of combined hepatocellular-cholangiocarcinoma. World J
Hepatol 2017;9:300-309. Available at:https://www.ncbi.nlm.nih.gov/pubmed/28293379.
90. O'Connor K, Walsh JC, Schaeffer DF. Combined hepatocellularcholangiocarcinoma (cHCC-CC): a distinct entity. Ann Hepatol
2014;13:317-322. Available at:https://www.ncbi.nlm.nih.gov/pubmed/24756005.
91. Li DB, Si XY, Wang SJ, Zhou YM. Long-term outcomes of combined
hepatocellular-cholangiocarcinoma after hepatectomy or livertransplantation: A systematic review and meta-analysis. Hepatobiliary
Pancreat Dis Int 2019;18:12-18. Available at:https://www.ncbi.nlm.nih.gov/pubmed/30442549.
92. Li R, Yang D, Tang CL, et al. Combined hepatocellular carcinoma andcholangiocarcinoma (biphenotypic) tumors: clinical characteristics,
imaging features of contrast-enhanced ultrasound and computed
tomography. BMC Cancer 2016;16:158. Available at:https://www.ncbi.nlm.nih.gov/pubmed/26917546.
93. Kassahun WT, Hauss J. Management of combined hepatocellular andcholangiocarcinoma. Int J Clin Pract 2008;62:1271-1278. Available at:https://www.ncbi.nlm.nih.gov/pubmed/18284443.
94. Yano Y, Yamamoto J, Kosuge T, et al. Combined hepatocellular andcholangiocarcinoma: a clinicopathologic study of 26 resected cases. Jpn J
Clin Oncol 2003;33:283-287. Available at:https://www.ncbi.nlm.nih.gov/pubmed/12913082.
95. Yin X, Zhang BH, Qiu SJ, et al. Combined hepatocellular carcinoma
and cholangiocarcinoma: clinical features, treatment modalities, andprognosis. Ann Surg Oncol 2012;19:2869-2876. Available at:https://www.ncbi.nlm.nih.gov/pubmed/22451237.
96. Breedis C, Young G. The blood supply of neoplasms in the liver. Am J
Pathol 1954;30:969-977. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/13197542.

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-65

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
97. Marrero JA, Hussain HK, Nghiem HV, et al. Improving the prediction ofhepatocellular carcinoma in cirrhotic patients with an arterially-enhancing
liver mass. Liver Transpl 2005;11:281-289. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/15719410.
98. Miller G, Schwartz LH, D'Angelica M. The use of imaging in the
diagnosis and staging of hepatobiliary malignancies. Surg Oncol Clin N
Am 2007;16:343-368. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/17560517.
99. Forner A, Vilana R, Ayuso C, et al. Diagnosis of hepatic nodules 20
mm or smaller in cirrhosis: Prospective validation of the noninvasive
diagnostic criteria for hepatocellular carcinoma. Hepatology 2008;47:979104. Available at: http://www.ncbi.nlm.nih.gov/pubmed/18069697.
100. Choi JY, Lee JM, Sirlin CB. CT and MR imaging diagnosis andstaging of hepatocellular carcinoma: part II. Extracellular agents,
hepatobiliary agents, and ancillary imaging features. Radiology
2014;273:30-50. Available at:https://www.ncbi.nlm.nih.gov/pubmed/25247563.

104. Colli A, Fraquelli M, Casazza G, et al. Accuracy of ultrasonography,
spiral CT, magnetic resonance, and alpha-fetoprotein in diagnosing
hepatocellular carcinoma: a systematic review. Am J Gastroenterol
2006;101:513-523. Available at:https://www.ncbi.nlm.nih.gov/pubmed/16542288.
105. Sun DW, An L, Wei F, et al. Prognostic significance of parametersfrom pretreatment (18)F-FDG PET in hepatocellular carcinoma: a metaanalysis. Abdom Radiol (NY) 2016;41:33-41. Available at:https://www.ncbi.nlm.nih.gov/pubmed/26830609.
106. Lin CY, Chen JH, Liang JA, et al. 18F-FDG PET or PET/CT for
detecting extrahepatic metastases or recurrent hepatocellular carcinoma:a systematic review and meta-analysis. Eur J Radiol 2012;81:2417-2422.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/21899970.
107. Park JW, Kim JH, Kim SK, et al. A prospective evaluation of 18FFDG and 11C-acetate PET/CT for detection of primary and metastatic
hepatocellular carcinoma. J Nucl Med 2008;49:1912-1921. Available at:https://www.ncbi.nlm.nih.gov/pubmed/18997056.

101. Tang A, Bashir MR, Corwin MT, et al. Evidence supporting LI-RADS
major features for CT- and MR imaging-based diagnosis of hepatocellular
carcinoma: a systematic review. Radiology 2018;286:29-48. Available at:https://www.ncbi.nlm.nih.gov/pubmed/29166245.

108. Lee YJ, Lee JM, Lee JS, et al. Hepatocellular carcinoma: diagnostic
performance of multidetector CT and MR imaging-a systematic review andmeta-analysis. Radiology 2015;275:97-109. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/25559230.

102. Claudon M, Dietrich CF, Choi BI, et al. Guidelines and good clinicalpractice recommendations for contrast enhanced ultrasound (CEUS) in
the liver - update 2012: A WFUMB-EFSUMB initiative in cooperation withrepresentatives of AFSUMB, AIUM, ASUM, FLAUS and ICUS. Ultrasound
Med Biol 2013;39:187-210. Available at:https://www.ncbi.nlm.nih.gov/pubmed/23137926.

109. Roberts LR, Sirlin CB, Zaiem F, et al. Imaging for the diagnosis ofhepatocellular carcinoma: A systematic review and meta-analysis.
Hepatology 2018;67:401-421. Available at:https://www.ncbi.nlm.nih.gov/pubmed/28859233.

103. Chou R, Cuevas C, Fu R, et al. Imaging techniques for the diagnosisof hepatocellular carcinoma: a systematic review and meta-analysis. Ann
Intern Med 2015;162:697-711. Available at:https://www.ncbi.nlm.nih.gov/pubmed/25984845.

110. Kierans AS, Kang SK, Rosenkrantz AB. The diagnostic performanceof dynamic contrast-enhanced MR imaging for detection of small
hepatocellular carcinoma measuring up to 2 cm: a meta-analysis.
Radiology 2016;278:82-94. Available at:https://www.ncbi.nlm.nih.gov/pubmed/26098460.
111. Sangiovanni A, Manini MA, Iavarone M, et al. The diagnostic andeconomic impact of contrast imaging techniques in the diagnosis of small

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-66

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
hepatocellular carcinoma in cirrhosis. Gut 2010;59:638-644. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/19951909.
112. Schellhaas B, Wildner D, Pfeifer L, et al. LI-RADS-CEUS - proposal
for a contrast-enhanced ultrasound algorithm for the diagnosis ofhepatocellular carcinoma in high-risk populations. Ultraschall Med
2016;37:627-634. Available at:https://www.ncbi.nlm.nih.gov/pubmed/27486793.
113. Chang TT, Sawhney R, Monto A, et al. Implementation of amultidisciplinary treatment team for hepatocellular cancer at a Veterans
Affairs Medical Center improves survival. HPB (Oxford) 2008;10:405-411.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/19088925.

119. Gregory JJ, Jr., Finlay JL. Alpha-fetoprotein and beta-humanchorionic gonadotropin: their clinical significance as tumour markers.
Drugs 1999;57:463-467. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/10235686.
120. Torzilli G, Minagawa M, Takayama T, et al. Accurate preoperativeevaluation of liver mass lesions without fine-needle biopsy. Hepatology
1999;30:889-893. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/10498639.
121. Levy I, Greig PD, Gallinger S, et al. Resection of hepatocellular
carcinoma without preoperative tumor biopsy. Ann Surg 2001;234:206209. Available at: http://www.ncbi.nlm.nih.gov/pubmed/11505066.

114. Yopp AC, Mansour JC, Beg MS, et al. Establishment of amultidisciplinary hepatocellular carcinoma clinic is associated withimproved clinical outcome. Ann Surg Oncol 2014;21:1287-1295. Available
at: https://www.ncbi.nlm.nih.gov/pubmed/24318095.

122. Lok AS, Lai CL. alpha-Fetoprotein monitoring in Chinese patientswith chronic hepatitis B virus infection: role in the early detection ofhepatocellular carcinoma. Hepatology 1989;9:110-115. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/2461890.

115. Agarwal PD, Phillips P, Hillman L, et al. Multidisciplinary
management of hepatocellular carcinoma improves access to therapy andpatient survival. J Clin Gastroenterol 2017;51:845-849. Available at:https://www.ncbi.nlm.nih.gov/pubmed/28877082.

123. Bialecki ES, Di Bisceglie AM. Diagnosis of hepatocellular carcinoma.
HPB (Oxford) 2005;7:26-34. Available at:https://www.ncbi.nlm.nih.gov/pubmed/18333158.

116. Serper M, Taddei TH, Mehta R, et al. Association of provider
specialty and multidisciplinary care with hepatocellular carcinoma
treatment and mortality. Gastroenterology 2017;152:1954-1964. Available
at: https://www.ncbi.nlm.nih.gov/pubmed/28283421.
117. Farinati F, Marino D, De Giorgio M, et al. Diagnostic and prognostic
role of alpha-fetoprotein in hepatocellular carcinoma: both or neither? Am
J Gastroenterol 2006;101:524-532. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/16542289.
118. Trevisani F, D'Intino PE, Morselli-Labate AM, et al. Serum alphafetoprotein for diagnosis of hepatocellular carcinoma in patients withchronic liver disease: influence of HBsAg and anti-HCV status. J Hepatol
2001;34:570-575. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/11394657.

124. Debruyne EN, Delanghe JR. Diagnosing and monitoring
hepatocellular carcinoma with alpha-fetoprotein: new aspects andapplications. Clin Chim Acta 2008;395:19-26. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/18538135.
125. Durazo FA, Blatt LM, Corey WG, et al. Des-gammacarboxyprothrombin, alpha-fetoprotein and AFP-L3 in patients with chronic
hepatitis, cirrhosis and hepatocellular carcinoma. J Gastroenterol Hepatol
2008;23:1541-1548. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/18422961.
126. Marrero JA, Feng Z, Wang Y, et al. Alpha-fetoprotein, des-gamma
carboxyprothrombin, and lectin-bound alpha-fetoprotein in early
hepatocellular carcinoma. Gastroenterology 2009;137:110-118. Available
at: http://www.ncbi.nlm.nih.gov/pubmed/19362088.

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-67

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
127. Johnson PJ, Pirrie SJ, Cox TF, et al. The detection of hepatocellular
carcinoma using a prospectively developed and validated model based onserological biomarkers. Cancer Epidemiol Biomarkers Prev 2014;23:144153. Available at: https://www.ncbi.nlm.nih.gov/pubmed/24220911.

135. Stewart CJR, Coldewey J, Stewart IS. Comparison of fine needle
aspiration cytology and needle core biopsy in the diagnosis ofradiologically detected abdominal lesions. J Clin Pathol 2002;55:93-97.
Available at: http://www.ncbi.nlm.nih.gov/pubmed/11865001.

128. Berhane S, Toyoda H, Tada T, et al. Role of the GALAD and BALAD2 serologic models in diagnosis of hepatocellular carcinoma and predictionof survival in patients. Clin Gastroenterol Hepatol 2016;14:875-886 e876.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/26775025.

136. Pupulim LF, Felce-Dachez M, Paradis V, et al. Algorithm for
immediate cytologic diagnosis of hepatic tumors. AJR Am J Roentgenol
2008;190:208-212. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/18287414.

129. Yang JD, Addissie BD, Mara KC, et al. GALAD score forhepatocellular carcinoma detection in comparison with liver ultrasound andproposal of GALADUS score. Cancer Epidemiol Biomarkers Prev
2019;28:531-538. Available at:https://www.ncbi.nlm.nih.gov/pubmed/30464023.

137. Asmis T, Balaa F, Scully L, et al. Diagnosis and management of
hepatocellular carcinoma: results of a consensus meeting of The Ottawa
Hospital Cancer Centre. Curr Oncol 2010;17:6-12. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/20404972.

130. Best J, Bechmann LP, Sowa JP, et al. GALAD score detects early
hepatocellular carcinoma in an international cohort of patients withnonalcoholic steatohepatitis. Clin Gastroenterol Hepatol 2020;18:728-735
e724. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31712073.
131. Pomfret EA, Washburn K, Wald C, et al. Report of a national
conference on liver allocation in patients with hepatocellular carcinoma in
the United States. Liver Transpl 2010;16:262-278. Available at:https://www.ncbi.nlm.nih.gov/pubmed/20209641.
132. DeLeve LD, Valla DC, Garcia-Tsao G. Vascular disorders of the liver.
Hepatology 2009;49:1729-1764. Available at:https://www.ncbi.nlm.nih.gov/pubmed/19399912.
133. Malaguarnera G, Paladina I, Giordano M, et al. Serum markers of
intrahepatic cholangiocarcinoma. Dis Markers 2013;34:219-228. Available
at: https://www.ncbi.nlm.nih.gov/pubmed/23396291.
134. Khan SA, Thomas HC, Davidson BR, Taylor-Robinson SD.
Cholangiocarcinoma. Lancet 2005;366:1303-1314. Available at:https://www.ncbi.nlm.nih.gov/pubmed/16214602.

138. Renshaw AA, Haja J, Wilbur DC, Miller TR. Fine-needle aspirates of
adenocarcinoma/metastatic carcinoma that resemble hepatocellular
carcinoma: correlating cytologic features and performance in the Collegeof American Pathologists Nongynecologic Cytology Program. Arch Pathol
Lab Med 2005;129:1217-1221. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/16196506.
139. Pawlik TM, Gleisner AL, Anders RA, et al. Preoperative assessmentof hepatocellular carcinoma tumor grade using needle biopsy: implications
for transplant eligibility. Ann Surg 2007;245:435-442. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/17435551.
140. Ghany MG, Strader DB, Thomas DL, Seeff LB. Diagnosis,
management, and treatment of hepatitis C: an update. Hepatology
2009;49:1335-1374. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/19330875.
141. Katyal S, Oliver JH, Peterson MS, et al. Extrahepatic metastases ofhepatocellular carcinoma. Radiology 2000;216:698-703. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/10966697.
142. Natsuizaka M, Omura T, Akaike T, et al. Clinical features ofhepatocellular carcinoma with extrahepatic metastases. J Gastroenterol

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-68

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
Hepatol 2005;20:1781-1787. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/16246200.
143. Harding JJ, Abu-Zeinah G, Chou JF, et al. Frequency, morbidity, andmortality of bone metastases in advanced hepatocellular carcinoma. J NatlCompr Canc Netw 2018;16:50-58. Available at:https://www.ncbi.nlm.nih.gov/pubmed/29295881.
144. Dodd GD, 3rd, Baron RL, Oliver JH, 3rd, et al. Enlarged abdominal
lymph nodes in end-stage cirrhosis: CT-histopathologic correlation in 507
patients. Radiology 1997;203:127-130. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/9122379.
145. Cooper GS, Bellamy P, Dawson NV, et al. A prognostic model forpatients with end-stage liver disease. Gastroenterology 1997;113:12781288. Available at: http://www.ncbi.nlm.nih.gov/pubmed/9322523.
146. Bruix J, Castells A, Bosch J, et al. Surgical resection of hepatocellular
carcinoma in cirrhotic patients: prognostic value of preoperative portalpressure. Gastroenterology 1996;111:1018-1022. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/8831597.
147. Groszmann RJ, Wongcharatrawee S. The hepatic venous pressure
gradient: anything worth doing should be done right. Hepatology
2004;39:280-282. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/14767976.
148. Boyer TD. Changing clinical practice with measurements of portalpressure. Hepatology 2004;39:283-285. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/14767977.
149. Thalheimer U, Mela M, Patch D, Burroughs AK. Targeting portalpressure measurements: a critical reappraisal. Hepatology 2004;39:286290. Available at: http://www.ncbi.nlm.nih.gov/pubmed/14767978.
150. Kamath PS, Wiesner RH, Malinchoc M, et al. A model to predictsurvival in patients with end-stage liver disease. Hepatology 2001;33:464470. Available at: http://www.ncbi.nlm.nih.gov/pubmed/11172350.

151. Malinchoc M, Kamath PS, Gordon FD, et al. A model to predict poor
survival in patients undergoing transjugular intrahepatic portosystemic
shunts. Hepatology 2000;31:864-871. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/10733541.
152. Martin AP, Bartels M, Hauss J, Fangmann J. Overview of the MELD
score and the UNOS adult liver allocation system. Transplant Proc
2007;39:3169-3174. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/18089345.
153. Cholongitas E, Papatheodoridis GV, Vangeli M, et al. Systematic
review: The model for end-stage liver disease--should it replace ChildPugh's classification for assessing prognosis in cirrhosis? Aliment
Pharmacol Ther 2005;22:1079-1089. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/16305721.
154. Saxena V, Lai JC. Kidney failure and liver allocation: Current
practices and potential improvements. Adv Chronic Kidney Dis
2015;22:391-398. Available at:https://www.ncbi.nlm.nih.gov/pubmed/26311601.
155. Johnson PJ, Berhane S, Kagebayashi C, et al. Assessment of liverfunction in patients with hepatocellular carcinoma: a new evidence-based
approach-the ALBI grade. J Clin Oncol 2015;33:550-558. Available at:https://www.ncbi.nlm.nih.gov/pubmed/25512453.
156. Oikonomou T, Goulis L, Doumtsis P, et al. ALBI and PALBI grades
are associated with the outcome of patients with stable decompensatedcirrhosis. Ann Hepatol 2019;18:126-136. Available at:https://www.ncbi.nlm.nih.gov/pubmed/31113581.
157. Wan SZ, Nie Y, Zhang Y, et al. Assessing the prognostic
performance of the Child-Pugh, Model for End-Stage Liver Disease, andAlbumin-Bilirubin scores in patients with decompensated cirrhosis: A large
Asian cohort from gastroenterology department. Dis Markers
2020;2020:5193028. Available at:https://www.ncbi.nlm.nih.gov/pubmed/32148566.

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-69

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
158. Fan ST. Liver functional reserve estimation: state of the art andrelevance for local treatments: the Eastern perspective. J Hepatobiliary
Pancreat Sci 2010;17:380-384. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/19865790.

166. Okuda K, Ohtsuki T, Obata H, et al. Natural history of hepatocellular
carcinoma and prognosis in relation to treatment. Study of 850 patients.
Cancer 1985;56:918-928. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/2990661.

159. Fan ST, Lai EC, Lo CM, et al. Hospital mortality of major
hepatectomy for hepatocellular carcinoma associated with cirrhosis. Arch
Surg 1995;130:198-203. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/7848092.

167. Chevret S, Trinchet JC, Mathieu D, et al. A new prognostic
classification for predicting survival in patients with hepatocellular
carcinoma. Groupe d'Etude et de Traitement du Carcinome
Hepatocellulaire. J Hepatol 1999;31:133-141. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/10424293.

160. Kudo M, Izumi N, Kokudo N, et al. Management of hepatocellular
carcinoma in Japan: Consensus-Based Clinical Practice Guidelines
proposed by the Japan Society of Hepatology (JSH) 2010 updated
version. Dig Dis 2011;29:339-364. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/21829027.
161. Bruix J, Sherman M, Llovet JM, et al. Clinical management of
hepatocellular carcinoma. Conclusions of the Barcelona-2000 EASL
conference. European Association for the Study of the Liver. J Hepatol
2001;35:421-430. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/11592607.
162. Dohmen K. Many staging systems for hepatocellular carcinoma:
evolution from Child-Pugh, Okuda to SLiDe. J Gastroenterol Hepatol
2004;19:1227-1232. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/15482527.
163. Marrero JA, Fontana RJ, Barrat A, et al. Prognosis of hepatocellular
carcinoma: comparison of 7 staging systems in an American cohort.
Hepatology 2005;41:707-716. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/15795889.
164. Pugh RN, Murray-Lyon IM, Dawson JL, et al. Transection of theoesophagus for bleeding oesophageal varices. Br J Surg 1973;60:646649. Available at: http://www.ncbi.nlm.nih.gov/pubmed/4541913.
165. Amin MB, ed AJCC Cancer Staging Manual. In: Cancer AJCo, ed (ed8th). Chicago, IL: Springer; 2017.

168. Leung TWT, Tang AMY, Zee B, et al. Construction of the Chinese
University Prognostic Index for hepatocellular carcinoma and comparison
with the TNM staging system, the Okuda staging system, and the Cancerof the Liver Italian Program staging system: a study based on 926
patients. Cancer 2002;94:1760-1769. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/11920539.
169. Kudo M, Chung H, Osaki Y. Prognostic staging system forhepatocellular carcinoma (CLIP score): its value and limitations, and a
proposal for a new staging system, the Japan Integrated Staging Score(JIS score). J Gastroenterol 2003;38:207-215. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/12673442.
170. A new prognostic system for hepatocellular carcinoma: aretrospective study of 435 patients: the Cancer of the Liver Italian Program(CLIP) investigators. Hepatology 1998;28:751-755. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/9731568.
171. Llovet JM, Bru C, Bruix J. Prognosis of hepatocellular carcinoma: theBCLC staging classification. Semin Liver Dis 1999;19:329-338. Available
at: http://www.ncbi.nlm.nih.gov/pubmed/10518312.
172. Omagari K, Honda S, Kadokawa Y, et al. Preliminary analysis of a
newly proposed prognostic scoring system (SLiDe score) for
hepatocellular carcinoma. J Gastroenterol Hepatol 2004;19:805-811.
Available at: http://www.ncbi.nlm.nih.gov/pubmed/15209629.

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-70

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
173. Huo T-I, Lin H-C, Huang Y-H, et al. The model for end-stage liverdisease-based Japan Integrated Scoring system may have a better
predictive ability for patients with hepatocellular carcinoma undergoing
locoregional therapy. Cancer 2006;107:141-148. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/16708358.
174. Limquiaco JL, Wong GLH, Wong VWS, et al. Evaluation of model forend stage liver disease (MELD)-based systems as prognostic index for
hepatocellular carcinoma. J Gastroenterol Hepatol 2009;24:63-69.
Available at: http://www.ncbi.nlm.nih.gov/pubmed/19054256.
175. Nanashima A, Sumida Y, Abo T, et al. Modified Japan Integrated
Staging is currently the best available staging system for hepatocellular
carcinoma patients who have undergone hepatectomy. J Gastroenterol
2006;41:250-256. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/16699859.
176. Bruix J, Sherman M. Management of hepatocellular carcinoma.
Hepatology 2005;42:1208-1236. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/16250051.
177. Wang J-H, Changchien C-S, Hu T-H, et al. The efficacy of treatment
schedules according to Barcelona Clinic Liver Cancer staging forhepatocellular carcinoma - Survival analysis of 3892 patients. Eur J
Cancer 2008;44:1000-1006. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/18337087.
178. Kamarajah SK, Frankel TL, Sonnenday C, et al. Critical evaluation of
the American Joint Commission on Cancer (AJCC) 8th edition staging
system for patients with hepatocellular carcinoma (HCC): A Surveillance,
Epidemiology, End Results (SEER) analysis. J Surg Oncol 2018;117:644650. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29127719.
179. Vauthey J-N, Ribero D, Abdalla EK, et al. Outcomes of livertransplantation in 490 patients with hepatocellular carcinoma: validation ofa uniform staging after surgical treatment. J Am Coll Surg 2007;204:10161027. Available at: http://www.ncbi.nlm.nih.gov/pubmed/17481532.

180. Huitzil-Melendez FD, Capanu M, O'Reilly EM, et al. Advanced
hepatocellular carcinoma: which staging systems best predict prognosis?
J Clin Oncol 2010;28:2889-2895. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/20458042.
181. Cho YK, Chung JW, Kim JK, et al. Comparison of 7 staging systems
for patients with hepatocellular carcinoma undergoing transarterial
chemoembolization. Cancer 2008;112:352-361. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/18008352.
182. Collette S, Bonnetain F, Paoletti X, et al. Prognosis of advanced
hepatocellular carcinoma: comparison of three staging systems in two
French clinical trials. Ann Oncol 2008;19:1117-1126. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/18303031.
183. Cabibbo G, Enea M, Attanasio M, et al. A meta-analysis of survival
rates of untreated patients in randomized clinical trials of hepatocellular
carcinoma. Hepatology 2010;51:1274-1283. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/20112254.
184. Guglielmi A, Ruzzenente A, Pachera S, et al. Comparison of sevenstaging systems in cirrhotic patients with hepatocellular carcinoma in acohort of patients who underwent radiofrequency ablation with complete
response. Am J Gastroenterol 2008;103:597-604. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/17970836.
185. Vitale A, Morales RR, Zanus G, et al. Barcelona Clinic Liver Cancer
staging and transplant survival benefit for patients with hepatocellular
carcinoma: a multicentre, cohort study. The Lancet Oncology
2011;12:654-662. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/21684210.
186. Cho CS, Gonen M, Shia J, et al. A novel prognostic nomogram is
more accurate than conventional staging systems for predicting survival
after resection of hepatocellular carcinoma. J Am Coll Surg 2008;206:281291. Available at: http://www.ncbi.nlm.nih.gov/pubmed/18222381.

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-71

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
187. Nathan H, Schulick RD, Choti MA, Pawlik TM. Predictors of survival
after resection of early hepatocellular carcinoma. Ann Surg 2009;249:799805. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19387322.
188. Nathan H, Mentha G, Marques HP, et al. Comparative performancesof staging systems for early hepatocellular carcinoma. HPB (Oxford)
2009;11:382-390. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/19768142.
189. Truty MJ, Vauthey J-N. Surgical resection of high-risk hepatocellular
carcinoma: patient selection, preoperative considerations, and operativetechnique. Ann Surg Oncol 2010;17:1219-1225. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/20405326.
190. Pawlik TM, Poon RT, Abdalla EK, et al. Critical appraisal of theclinical and pathologic predictors of survival after resection of large
hepatocellular carcinoma. Arch Surg 2005;140:450-457. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/15897440.
191. Chok KS, Ng KK, Poon RT, et al. Impact of postoperativecomplications on long-term outcome of curative resection forhepatocellular carcinoma. Br J Surg 2009;96:81-87. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/19065644.
192. Kianmanesh R, Regimbeau JM, Belghiti J. Selective approach tomajor hepatic resection for hepatocellular carcinoma in chronic liverdisease. Surg Oncol Clin N Am 2003;12:51-63. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/12735129.
193. Llovet JM, Fuster J, Bruix J. Intention-to-treat analysis of surgicaltreatment for early hepatocellular carcinoma: resection versus
transplantation. Hepatology 1999;30:1434-1440. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/10573522.
194. Poon RT-P, Fan ST, Lo CM, et al. Long-term survival and pattern ofrecurrence after resection of small hepatocellular carcinoma in patientswith preserved liver function: implications for a strategy of salvagetransplantation. Ann Surg 2002;235:373-382. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/11882759.

195. Seo DD, Lee HC, Jang MK, et al. Preoperative portal vein
embolization and surgical resection in patients with hepatocellular
carcinoma and small future liver remnant volume: comparison withtransarterial chemoembolization. Ann Surg Oncol 2007;14:3501-3509.
Available at: http://www.ncbi.nlm.nih.gov/pubmed/17899289.
196. Wei AC, Tung-Ping Poon R, Fan ST, Wong J. Risk factors forperioperative morbidity and mortality after extended hepatectomy forhepatocellular carcinoma. Br J Surg 2003;90:33-41. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/12520572.
197. Faber W, Stockmann M, Schirmer C, et al. Significant impact ofpatient age on outcome after liver resection for HCC in cirrhosis. Eur J
Surg Oncol 2014;40:208-213. Available at:https://www.ncbi.nlm.nih.gov/pubmed/24275202.
198. Ribero D, Curley SA, Imamura H, et al. Selection for resection ofhepatocellular carcinoma and surgical strategy: indications for resection,
evaluation of liver function, portal vein embolization, and resection. Ann
Surg Oncol 2008;15:986-992. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/18236112.
199. Berzigotti A, Reig M, Abraldes JG, et al. Portal hypertension and theoutcome of surgery for hepatocellular carcinoma in compensated cirrhosis:
a systematic review and meta-analysis. Hepatology 2015;61:526-536.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/25212123.
200. Santambrogio R, Kluger MD, Costa M, et al. Hepatic resection forhepatocellular carcinoma in patients with Child-Pugh's A cirrhosis: isclinical evidence of portal hypertension a contraindication? HPB (Oxford)
2013;15:78-84. Available at:https://www.ncbi.nlm.nih.gov/pubmed/23216782.
201. Tsai TJ, Chau GY, Lui WY, et al. Clinical significance of microscopic
tumor venous invasion in patients with resectable hepatocellular
carcinoma. Surgery 2000;127:603-608. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/10840353.

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-72

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
202. Abdalla EK, Denys A, Hasegawa K, et al. Treatment of large andadvanced hepatocellular carcinoma. Ann Surg Oncol 2008;15:979-985.
Available at: http://www.ncbi.nlm.nih.gov/pubmed/18236115.
203. Jonas S, Bechstein WO, Steinmuller T, et al. Vascular invasion andhistopathologic grading determine outcome after liver transplantation forhepatocellular carcinoma in cirrhosis. Hepatology 2001;33:1080-1086.
Available at: http://www.ncbi.nlm.nih.gov/pubmed/11343235.
204. Vauthey J-N, Lauwers GY, Esnaola NF, et al. Simplified staging forhepatocellular carcinoma. J Clin Oncol 2002;20:1527-1536. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/11896101.
205. Glantzounis GK, Paliouras A, Stylianidi MC, et al. The role of liverresection in the management of intermediate and advanced stage
hepatocellular carcinoma. A systematic review. Eur J Surg Oncol
2018;44:195-208. Available at:https://www.ncbi.nlm.nih.gov/pubmed/29258719.
206. Yamakado K, Nakatsuka A, Takaki H, et al. Early-stage
hepatocellular carcinoma: radiofrequency ablation combined withchemoembolization versus hepatectomy. Radiology 2008;247:260-266.
Available at: http://www.ncbi.nlm.nih.gov/pubmed/18305190.
207. Kubota K, Makuuchi M, Kusaka K, et al. Measurement of liver volume
and hepatic functional reserve as a guide to decision-making in resectional
surgery for hepatic tumors. Hepatology 1997;26:1176-1181. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/9362359.
208. Kishi Y, Abdalla EK, Chun YS, et al. Three hundred and one
consecutive extended right hepatectomies: evaluation of outcome basedon systematic liver volumetry. Ann Surg 2009;250:540-548. Available at:https://www.ncbi.nlm.nih.gov/pubmed/19730239.
209. Zorzi D, Laurent A, Pawlik TM, et al. Chemotherapy-associatedhepatotoxicity and surgery for colorectal liver metastases. Br J Surg
2007;94:274-286. Available at:https://www.ncbi.nlm.nih.gov/pubmed/17315288.

210. Glantzounis GK, Tokidis E, Basourakos SP, et al. The role of portal
vein embolization in the surgical management of primary hepatobiliary
cancers. A systematic review. Eur J Surg Oncol 2017;43:32-41. Available
at: https://www.ncbi.nlm.nih.gov/pubmed/27283892.
211. Brouquet A, Andreou A, Shindoh J, Vauthey J-N. Methods to improve
resectability of hepatocellular carcinoma. In: Schlag PM, Senn H-J, eds.
Recent Results in Cancer Research. Vol. 190: Springer; 2013:57-67.
212. Chapelle T, Op de Beeck B, Roeyen G, et al. Measuring future liver
remnant function prior to hepatectomy may guide the indication for portal
vein occlusion and avoid posthepatectomy liver failure: a prospective
interventional study. HPB (Oxford) 2017;19:108-117. Available at:https://www.ncbi.nlm.nih.gov/pubmed/27956027.
213. Martel G, Cieslak KP, Huang R, et al. Comparison of techniques forvolumetric analysis of the future liver remnant: implications for major
hepatic resections. HPB (Oxford) 2015;17:1051-1057. Available at:https://www.ncbi.nlm.nih.gov/pubmed/26373675.
214. Roayaie S, Jibara G, Tabrizian P, et al. The role of hepatic resectionin the treatment of hepatocellular cancer. Hepatology 2015;62:440-451.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/25678263.
215. Bruix J, Takayama T, Mazzaferro V, et al. Adjuvant sorafenib forhepatocellular carcinoma after resection or ablation (STORM): a phase 3,
randomised, double-blind, placebo-controlled trial. Lancet Oncol
2015;16:1344-1354. Available at:https://www.ncbi.nlm.nih.gov/pubmed/26361969.
216. Qi YP, Zhong JH, Liang ZY, et al. Adjuvant transarterial
chemoembolization for patients with hepatocellular carcinoma involving
microvascular invasion. Am J Surg 2019;217:739-744. Available at:https://www.ncbi.nlm.nih.gov/pubmed/30103903.
217. Chen ZH, Zhang XP, Zhou TF, et al. Adjuvant transarterial
chemoembolization improves survival outcomes in hepatocellular
carcinoma with microvascular invasion: A systematic review and meta-

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-73

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
analysis. Eur J Surg Oncol 2019;45:2188-2196. Available at:https://www.ncbi.nlm.nih.gov/pubmed/31256949.
218. Yin J, Li N, Han Y, et al. Effect of antiviral treatment with
nucleotide/nucleoside analogs on postoperative prognosis of hepatitis B
virus-related hepatocellular carcinoma: a two-stage longitudinal clinicalstudy. J Clin Oncol 2013;31:3647-3655. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/24002499.
219. Huang G, Lau WY, Wang ZG, et al. Antiviral therapy improves
postoperative survival in patients with hepatocellular carcinoma: arandomized controlled trial. Ann Surg 2015;261:56-66. Available at:https://www.ncbi.nlm.nih.gov/pubmed/25072444.
220. Xu J, Li J, Chen J, Liu ZJ. Effect of adjuvant interferon therapy on
hepatitis b/c virus-related hepatocellular carcinoma after curative therapy meta-analysis. Adv Clin Exp Med 2015;24:331-340. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/25931368.
221. Xia BW, Zhang YC, Wang J, et al. Efficacy of antiviral therapy with
nucleotide/nucleoside analogs after curative treatment for patients with
hepatitis B virus-related hepatocellular carcinoma: A systematic review
and meta-analysis. Clin Res Hepatol Gastroenterol 2015;39:458-468.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/25650304.
222. Manthravadi S, Paleti S, Pandya P. Impact of sustained viral
response postcurative therapy of hepatitis C-related hepatocellular
carcinoma: a systematic review and meta-analysis. Int J Cancer
2017;140:1042-1049. Available at:https://www.ncbi.nlm.nih.gov/pubmed/27861842.
223. Reig M, Boix L, Bruix J. The impact of direct antiviral agents on thedevelopment and recurrence of hepatocellular carcinoma. Liver Int
2017;37 Suppl 1:136-139. Available at:https://www.ncbi.nlm.nih.gov/pubmed/28052619.
224. Torres HA, Shigle TL, Hammoudi N, et al. The oncologic burden ofhepatitis C virus infection: A clinical perspective. CA Cancer J Clin 2017.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/28683174.

225. Conti F, Buonfiglioli F, Scuteri A, et al. Early occurrence andrecurrence of hepatocellular carcinoma in HCV-related cirrhosis treatedwith direct-acting antivirals. J Hepatol 2016;65:727-733. Available at:https://www.ncbi.nlm.nih.gov/pubmed/27349488.
226. Furtado R, Crawford M, Sandroussi C. Systematic review and metaanalysis of adjuvant i(131) lipiodol after excision of hepatocellular
carcinoma. Ann Surg Oncol 2014;21:2700-2707. Available at:https://www.ncbi.nlm.nih.gov/pubmed/24743904.
227. Zhu GQ, Shi KQ, Yu HJ, et al. Optimal adjuvant therapy for resected
hepatocellular carcinoma: a systematic review with network meta-analysis.
Oncotarget 2015;6:18151-18161. Available at:https://www.ncbi.nlm.nih.gov/pubmed/26061709.
228. Lee JH, Lee JH, Lim YS, et al. Adjuvant immunotherapy withautologous cytokine-induced killer cells for hepatocellular carcinoma.
Gastroenterology 2015;148:1383-1391.e1386. Available at:https://www.ncbi.nlm.nih.gov/pubmed/25747273.
229. Watt KD, Pedersen RA, Kremers WK, et al. Evolution of causes andrisk factors for mortality post-liver transplant: results of the NIDDK longterm follow-up study. Am J Transplant 2010;10:1420-1427. Available at:https://www.ncbi.nlm.nih.gov/pubmed/20486907.
230. Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation for thetreatment of small hepatocellular carcinomas in patients with cirrhosis. N
Engl J Med 1996;334:693-699. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/8594428.
231. Mazzaferro V, Chun YS, Poon RTP, et al. Liver transplantation forhepatocellular carcinoma. Ann Surg Oncol 2008;15:1001-1007. Available
at: http://www.ncbi.nlm.nih.gov/pubmed/18236119.
232. OPTN/UNOS policy notice modification to hepatocellular carcinoma(HCC) extension criteria. Available at:https://optn.transplant.hrsa.gov/media/2411/modification-to-hcc-autoapproval-criteria_policy-notice.pdf.

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-74

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
233. Cha CH, Ruo L, Fong Y, et al. Resection of hepatocellular carcinoma
in patients otherwise eligible for transplantation. Ann Surg 2003;238:315321; discussion 321-313. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/14501497.
234. Poon RT, Fan ST, Lo CM, et al. Difference in tumor invasiveness incirrhotic patients with hepatocellular carcinoma fulfilling the Milan criteria
treated by resection and transplantation: impact on long-term survival. Ann
Surg 2007;245:51-58. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/17197965.
235. Shah SA, Cleary SP, Tan JC, et al. An analysis of resection vstransplantation for early hepatocellular carcinoma: defining the optimal
therapy at a single institution. Ann Surg Oncol 2007;14:2608-2614.
Available at: http://www.ncbi.nlm.nih.gov/pubmed/17522942.
236. Facciuto ME, Koneru B, Rocca JP, et al. Surgical treatment of
hepatocellular carcinoma beyond Milan criteria. Results of liver resection,
salvage transplantation, and primary liver transplantation. Ann Surg Oncol
2008;15:1383-1391. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/18320284.
237. OPTN Policies Effective as of June 8 2020 [Modify HOPE Act
Variance Correction]. Available at:https://optn.transplant.hrsa.gov/media/1200/optn_policies.pdf.
238. Ioannou GN, Perkins JD, Carithers RL. Liver transplantation forhepatocellular carcinoma: impact of the MELD allocation system andpredictors of survival. Gastroenterology 2008;134:1342-1351. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/18471511.
239. Volk ML, Vijan S, Marrero JA. A novel model measuring the harm oftransplanting hepatocellular carcinoma exceeding Milan criteria. Am J
Transplant 2008;8:839-846. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/18318783.
240. Duffy JP, Vardanian A, Benjamin E, et al. Liver transplantation criteria
for hepatocellular carcinoma should be expanded: a 22-year experience

with 467 patients at UCLA. Ann Surg 2007;246:502-509. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/17717454.
241. Yao FY, Ferrell L, Bass NM, et al. Liver transplantation forhepatocellular carcinoma: expansion of the tumor size limits does notadversely impact survival. Hepatology 2001;33:1394-1403. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/11391528.
242. Yao FY, Bass NM, Nikolai B, et al. Liver transplantation forhepatocellular carcinoma: analysis of survival according to the intention-totreat principle and dropout from the waiting list. Liver Transpl 2002;8:873883. Available at: http://www.ncbi.nlm.nih.gov/pubmed/12360427.
243. Volk M, Marrero JA. Liver transplantation for hepatocellular
carcinoma: who benefits and who is harmed? Gastroenterology
2008;134:1612-1614. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/18471530.
244. Lee S-G, Hwang S, Moon D-B, et al. Expanded indication criteria ofliving donor liver transplantation for hepatocellular carcinoma at one largevolume center. Liver Transpl 2008;14:935-945. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/18581465.
245. Wan P, Xia Q, Zhang JJ, et al. Liver transplantation for hepatocellular
carcinoma exceeding the Milan criteria: a single-center experience. J
Cancer Res Clin Oncol 2014;140:341-348. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/24374832.
246. Duvoux C, Roudot-Thoraval F, Decaens T, et al. Liver transplantation
for hepatocellular carcinoma: a model including alpha-fetoprotein improves
the performance of Milan criteria. Gastroenterology 2012;143:986994.e983; quiz e914-985. Available at:https://www.ncbi.nlm.nih.gov/pubmed/22750200.
247. Notarpaolo A, Layese R, Magistri P, et al. Validation of the AFPmodel as a predictor of HCC recurrence in patients with viral hepatitisrelated cirrhosis who had received a liver transplant for HCC. J Hepatol
2017;66:552-559. Available at:https://www.ncbi.nlm.nih.gov/pubmed/27899297.

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-75

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
248. Mehta N, Heimbach J, Harnois DM, et al. Validation of a risk
estimation of tumor recurrence after transplant (RETREAT) score forhepatocellular carcinoma recurrence after liver transplant. JAMA Oncol
2017;3:493-500. Available at:https://www.ncbi.nlm.nih.gov/pubmed/27838698.
249. Kim J, Ko ME, Nelson RA, et al. Increasing age and survival after
orthotopic liver transplantation for patients with hepatocellular cancer. J
Am Coll Surg 2014;218:431-438. Available at:https://www.ncbi.nlm.nih.gov/pubmed/24559955.
250. Kozyreva ON, Chi D, Clark JW, et al. A multicenter retrospective
study on clinical characteristics, treatment patterns, and outcome in elderly
patients with hepatocellular carcinoma. Oncologist 2011;16:310-318.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/21349948.
251. Zhao LY, Huo RR, Xiang X, et al. Hepatic resection for elderly
patients with hepatocellular carcinoma: a systematic review of more than
17,000 patients. Expert Rev Gastroenterol Hepatol 2018;12:1059-1068.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/30145919.
252. Fujiki M, Aucejo F, Kim R. General overview of neo-adjuvant therapy
for hepatocellular carcinoma before liver transplantation: necessity or
option? Liver Int 2011;31:1081-1089. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/22008644.
253. Xing M, Sakaria S, Dhanasekaran R, et al. Bridging locoregional
therapy prolongs survival in patients listed for liver transplant with
hepatocellular carcinoma. Cardiovasc Intervent Radiol 2017;40:410-420.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/27900445.
254. Llovet JM, Di Bisceglie AM, Bruix J, et al. Design and endpoints ofclinical trials in hepatocellular carcinoma. J Natl Cancer Inst2008;100:698-711. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/18477802.
255. Majno P, Giostra E, Mentha G. Management of hepatocellular
carcinoma on the waiting list before liver transplantation: time forcontrolled trials? Liver Transpl 2007;13:S27-35. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/17969086.
256. Pompili M, Mirante VG, Rondinara G, et al. Percutaneous ablation
procedures in cirrhotic patients with hepatocellular carcinoma submitted toliver transplantation: Assessment of efficacy at explant analysis and ofsafety for tumor recurrence. Liver Transpl 2005;11:1117-1126. Available
at: http://www.ncbi.nlm.nih.gov/pubmed/16123960.
257. Mazzaferro V, Battiston C, Perrone S, et al. Radiofrequency ablationof small hepatocellular carcinoma in cirrhotic patients awaiting livertransplantation: a prospective study. Ann Surg 2004;240:900-909.
Available at: http://www.ncbi.nlm.nih.gov/pubmed/15492574.
258. Yao FY, Bass NM, Nikolai B, et al. A follow-up analysis of the pattern
and predictors of dropout from the waiting list for liver transplantation inpatients with hepatocellular carcinoma: implications for the current organ
allocation policy. Liver Transpl 2003;9:684-692. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/12827553.
259. DuBay DA, Sandroussi C, Kachura JR, et al. Radiofrequency ablationof hepatocellular carcinoma as a bridge to liver transplantation. HPB(Oxford) 2011;13:24-32. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/21159100.
260. Tsochatzis E, Garcovich M, Marelli L, et al. Transarterial embolization
as neo-adjuvant therapy pretransplantation in patients with hepatocellular
carcinoma. Liver Int 2013;33:944-949. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/23530918.
261. Llovet JM, Bruix J. Systematic review of randomized trials forunresectable hepatocellular carcinoma: Chemoembolization improves
survival. Hepatology 2003;37:429-442. Available at:https://www.ncbi.nlm.nih.gov/pubmed/12540794.
262. Richard HM, Silberzweig JE, Mitty HA, et al. Hepatic arterial
complications in liver transplant recipients treated with pretransplantation
chemoembolization for hepatocellular carcinoma. Radiology

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-76

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
2000;214:775-779. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/10715045.

review and meta-analysis. Hepatology 2018;67:381-400. Available at:https://www.ncbi.nlm.nih.gov/pubmed/28859222.

263. Graziadei IW, Sandmueller H, Waldenberger P, et al.
Chemoembolization followed by liver transplantation for hepatocellular
carcinoma impedes tumor progression while on the waiting list and leads
to excellent outcome. Liver Transpl 2003;9:557-563. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/12783395.

270. Freeman RB, Steffick DE, Guidinger MK, et al. Liver and intestinetransplantation in the United States, 1997-2006. Am J Transplant
2008;8:958-976. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/18336699.

264. Hayashi PH, Ludkowski M, Forman LM, et al. Hepatic arterychemoembolization for hepatocellular carcinoma in patients listed for livertransplantation. Am J Transplant 2004;4:782-787. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/15084175.
265. Nicolini D, Svegliati-Baroni G, Candelari R, et al. Doxorubicin-eluting
bead vs conventional transcatheter arterial chemoembolization forhepatocellular carcinoma before liver transplantation. World J
Gastroenterol 2013;19:5622-5632. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/24039354.
266. Kulik LM, Atassi B, van Holsbeeck L, et al. Yttrium-90 microspheres(TheraSphere) treatment of unresectable hepatocellular carcinoma:downstaging to resection, RFA and bridge to transplantation. J Surg Oncol
2006;94:572-586. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/17048240.
267. Sandroussi C, Dawson LA, Lee M, et al. Radiotherapy as a bridge toliver transplantation for hepatocellular carcinoma. Transpl Int 2010;23:299306. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19843294.
268. Lu L, Zeng J, Wen Z, et al. Transcatheter arterial chemoembolisation
followed by three-dimensional conformal radiotherapy versus
transcatheter arterial chemoembolisation alone for primary hepatocellular
carcinoma in adults. Cochrane Database Syst Rev 2019;2:CD012244.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/30776082.
269. Kulik L, Heimbach JK, Zaiem F, et al. Therapies for patients with
hepatocellular carcinoma awaiting liver transplantation: A systematic

271. Campos BD, Botha JF. Transplantation for hepatocellular carcinoma
and cholangiocarcinoma. J Natl Compr Canc Netw 2009;7:409-416.
Available at: http://www.ncbi.nlm.nih.gov/pubmed/19406041.
272. Toso C, Mentha G, Kneteman NM, Majno P. The place ofdownstaging for hepatocellular carcinoma. J Hepatol 2010;52:930-936.
Available at: http://www.ncbi.nlm.nih.gov/pubmed/20385428.
273. Yao FY, Fidelman N. Reassessing the boundaries of livertransplantation for hepatocellular carcinoma: Where do we stand withtumor down-staging? Hepatology 2016;63:1014-1025. Available at:https://www.ncbi.nlm.nih.gov/pubmed/26560491.
274. Parikh ND, Waljee AK, Singal AG. Downstaging hepatocellular
carcinoma: A systematic review and pooled analysis. Liver Transpl
2015;21:1142-1152. Available at:https://www.ncbi.nlm.nih.gov/pubmed/25981135.
275. Ravaioli M, Grazi GL, Piscaglia F, et al. Liver transplantation forhepatocellular carcinoma: results of down-staging in patients initiallyoutside the Milan selection criteria. Am J Transplant 2008;8:2547-2557.
Available at: http://www.ncbi.nlm.nih.gov/pubmed/19032223.
276. Yao FY, Kerlan RK, Jr., Hirose R, et al. Excellent outcome following
down-staging of hepatocellular carcinoma prior to liver transplantation: an
intention-to-treat analysis. Hepatology 2008;48:819-827. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/18688876.
277. Chapman WC, Majella Doyle MB, Stuart JE, et al. Outcomes ofneoadjuvant transarterial chemoembolization to downstage hepatocellular

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-77

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
carcinoma before liver transplantation. Ann Surg 2008;248:617-625.
Available at: http://www.ncbi.nlm.nih.gov/pubmed/18936575.
278. Lewandowski RJ, Kulik LM, Riaz A, et al. A comparative analysis oftransarterial downstaging for hepatocellular carcinoma:
chemoembolization versus radioembolization. Am J Transplant
2009;9:1920-1928. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/19552767.
279. Yao FY, Mehta N, Flemming J, et al. Downstaging of hepatocellularcancer before liver transplant: long-term outcome compared to tumors
within Milan criteria. Hepatology 2015;61:1968-1977. Available at:https://www.ncbi.nlm.nih.gov/pubmed/25689978.

285. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response
evaluation criteria in solid tumours: revised RECIST guideline (version1.1). Eur J Cancer 2009;45:228-247. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/19097774.
286. Duke E, Deng J, Ibrahim SM, et al. Agreement between competing
imaging measures of response of hepatocellular carcinoma to yttrium-90
radioembolization. J Vasc Interv Radiol 2010;21:515-521. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/20172741.
287. Lencioni R, Llovet JM. Modified RECIST (mRECIST) assessment for
hepatocellular carcinoma. Semin Liver Dis 2010;30:52-60. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/20175033.

280. De Luna W, Sze DY, Ahmed A, et al. Transarterial chemoinfusion forhepatocellular carcinoma as downstaging therapy and a bridge toward
liver transplantation. Am J Transplant 2009;9:1158-1168. Available at:https://www.ncbi.nlm.nih.gov/pubmed/19344435.

288. Riaz A, Miller FH, Kulik LM, et al. Imaging response in the primary
index lesion and clinical outcomes following transarterial locoregional
therapy for hepatocellular carcinoma. JAMA 2010;303:1062-1069.
Available at: http://www.ncbi.nlm.nih.gov/pubmed/20233824.

281. Jang JW, You CR, Kim CW, et al. Benefit of downsizing
hepatocellular carcinoma in a liver transplant population. Aliment
Pharmacol Ther 2010;31:415-423. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/19821808.

289. Sato Y, Watanabe H, Sone M, et al. Tumor response evaluation
criteria for HCC (hepatocellular carcinoma) treated using TACE
(transcatheter arterial chemoembolization): RECIST (response evaluation
criteria in solid tumors) version 1.1 and mRECIST (modified RECIST):JIVROSG-0602. Ups J Med Sci 2013;118:16-22. Available at:https://www.ncbi.nlm.nih.gov/pubmed/23167460.

282. Millonig G, Graziadei IW, Freund MC, et al. Response to preoperative
chemoembolization correlates with outcome after liver transplantation inpatients with hepatocellular carcinoma. Liver Transpl 2007;13:272-279.
Available at: http://www.ncbi.nlm.nih.gov/pubmed/17256758.
283. Otto G, Herber S, Heise M, et al. Response to transarterial
chemoembolization as a biological selection criterion for livertransplantation in hepatocellular carcinoma. Liver Transpl 2006;12:12601267. Available at: http://www.ncbi.nlm.nih.gov/pubmed/16826556.
284. Mazzaferro V, Citterio D, Bhoori S, et al. Liver transplantation in
hepatocellular carcinoma after tumour downstaging (XXL): a randomised,
controlled, phase 2b/3 trial. Lancet Oncol 2020;21:947-956. Available at:https://www.ncbi.nlm.nih.gov/pubmed/32615109.

290. Takada J, Hidaka H, Nakazawa T, et al. Modified response
evaluation criteria in solid tumors is superior to response evaluation
criteria in solid tumors for assessment of responses to sorafenib inpatients with advanced hepatocellular carcinoma. BMC Res Notes
2015;8:609. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26502722.
291. Riaz A, Ryu RK, Kulik LM, et al. Alpha-fetoprotein response after
locoregional therapy for hepatocellular carcinoma: oncologic marker ofradiologic response, progression, and survival. J Clin Oncol 2009;27:57345742. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19805671.
292. Livraghi T, Goldberg SN, Lazzaroni S, et al. Small hepatocellular
carcinoma: treatment with radio-frequency ablation versus ethanol

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-78

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
injection. Radiology 1999;210:655-661. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/10207464.
293. Lencioni RA, Allgaier HP, Cioni D, et al. Small hepatocellular
carcinoma in cirrhosis: randomized comparison of radio-frequency thermal
ablation versus percutaneous ethanol injection. Radiology 2003;228:235240. Available at: http://www.ncbi.nlm.nih.gov/pubmed/12759473.
294. Lin S-M, Lin C-J, Lin C-C, et al. Radiofrequency ablation improves
prognosis compared with ethanol injection for hepatocellular carcinoma <or =4 cm. Gastroenterology 2004;127:1714-1723. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/15578509.
295. Lin SM, Lin CJ, Lin CC, et al. Randomised controlled trial comparing
percutaneous radiofrequency thermal ablation, percutaneous ethanol
injection, and percutaneous acetic acid injection to treat hepatocellular
carcinoma of 3 cm or less. Gut 2005;54:1151-1156. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/16009687.
296. Shiina S, Teratani T, Obi S, et al. A randomized controlled trial ofradiofrequency ablation with ethanol injection for small hepatocellular
carcinoma. Gastroenterology 2005;129:122-130. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/16012942.
297. Brunello F, Veltri A, Carucci P, et al. Radiofrequency ablation versus
ethanol injection for early hepatocellular carcinoma: A randomized
controlled trial. Scand J Gastroenterol 2008;43:727-735. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/18569991.
298. Giorgio A, Di Sarno A, De Stefano G, et al. Percutaneousradiofrequency ablation of hepatocellular carcinoma compared topercutaneous ethanol injection in treatment of cirrhotic patients: an Italianrandomized controlled trial. Anticancer Res 2011;31:2291-2295. Available
at: http://www.ncbi.nlm.nih.gov/pubmed/21737654.
299. Weis S, Franke A, Mossner J, et al. Radiofrequency (thermal)
ablation versus no intervention or other interventions for hepatocellular
carcinoma. Cochrane Database Syst Rev 2013;12:CD003046. Available
at: http://www.ncbi.nlm.nih.gov/pubmed/24357457.

300. Cho YK, Kim JK, Kim MY, et al. Systematic review of randomized
trials for hepatocellular carcinoma treated with percutaneous ablation
therapies. Hepatology 2009;49:453-459. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/19065676.
301. Orlando A, Leandro G, Olivo M, et al. Radiofrequency thermal
ablation vs. percutaneous ethanol injection for small hepatocellular
carcinoma in cirrhosis: meta-analysis of randomized controlled trials. Am J
Gastroenterol 2009;104:514-524. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/19174803.
302. Germani G, Pleguezuelo M, Gurusamy K, et al. Clinical outcomes ofradiofrequency ablation, percutaneous alcohol and acetic acid injection forhepatocelullar carcinoma: a meta-analysis. J Hepatol 2010;52:380-388.
Available at: http://www.ncbi.nlm.nih.gov/pubmed/20149473.
303. Peng ZW, Zhang YJ, Chen MS, et al. Radiofrequency ablation as
first-line treatment for small solitary hepatocellular carcinoma: long-term
results. Eur J Surg Oncol 2010;36:1054-1060. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/20846819.
304. Shiina S, Tateishi R, Arano T, et al. Radiofrequency ablation forhepatocellular carcinoma: 10-year outcome and prognostic factors. Am J
Gastroenterol 2012;107:569-577. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/22158026.
305. Brunello F, Cantamessa A, Gaia S, et al. Radiofrequency ablation:technical and clinical long-term outcomes for single hepatocellular
carcinoma up to 30 mm. Eur J Gastroenterol Hepatol 2013;25:842-849.
Available at: http://www.ncbi.nlm.nih.gov/pubmed/23442417.
306. Francica G, Saviano A, De Sio I, et al. Long-term effectiveness ofradiofrequency ablation for solitary small hepatocellular carcinoma: aretrospective analysis of 363 patients. Dig Liver Dis 2013;45:336-341.
Available at: http://www.ncbi.nlm.nih.gov/pubmed/23245589.
307. Huang G-T, Lee P-H, Tsang Y-M, et al. Percutaneous ethanol
injection versus surgical resection for the treatment of small hepatocellular

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-79

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
carcinoma: a prospective study. Ann Surg 2005;242:36-42. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/15973099.
308. Chen M-S, Li J-Q, Zheng Y, et al. A prospective randomized trial
comparing percutaneous local ablative therapy and partial hepatectomy
for small hepatocellular carcinoma. Ann Surg 2006;243:321-328. Available
at: http://www.ncbi.nlm.nih.gov/pubmed/16495695.
309. Huang J, Yan L, Cheng Z, et al. A randomized trial comparing
radiofrequency ablation and surgical resection for HCC conforming to the
Milan criteria. Ann Surg 2010;252:903-912. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/21107100.
310. Feng K, Yan J, Li X, et al. A randomized controlled trial ofradiofrequency ablation and surgical resection in the treatment of small
hepatocellular carcinoma. J Hepatol 2012;57:794-802. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/22634125.
311. Fang Y, Chen W, Liang X, et al. Comparison of long-term
effectiveness and complications of radiofrequency ablation with
hepatectomy for small hepatocellular carcinoma. J Gastroenterol Hepatol
2014;29:193-200. Available at:https://www.ncbi.nlm.nih.gov/pubmed/24224779.
312. Ng KKC, Chok KSH, Chan ACY, et al. Randomized clinical trial ofhepatic resection versus radiofrequency ablation for early-stage
hepatocellular carcinoma. Br J Surg 2017;104:1775-1784. Available at:https://www.ncbi.nlm.nih.gov/pubmed/29091283.
313. Feng Q, Chi Y, Liu Y, et al. Efficacy and safety of percutaneousradiofrequency ablation versus surgical resection for small hepatocellular
carcinoma: a meta-analysis of 23 studies. J Cancer Res Clin Oncol
2015;141:1-9. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/24889505.
314. Jia JB, Zhang D, Ludwig JM, Kim HS. Radiofrequency ablation
versus resection for hepatocellular carcinoma in patients with Child-PughA liver cirrhosis: a meta-analysis. Clin Radiol 2017;72:1066-1075.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/28851491.

315. Xu G, Qi F-Z, Zhang J-H, et al. Meta-analysis of surgical resection
and radiofrequency ablation for early hepatocellular carcinoma. World J
Surg Oncol 2012;10:163-163. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/22897815.
316. Cai H, Kong W, Zhou T, Qiu Y. Radiofrequency ablation versus
reresection in treating recurrent hepatocellular carcinoma: a metaanalysis. Medicine (Baltimore) 2014;93:e122. Available at:https://www.ncbi.nlm.nih.gov/pubmed/25396332.
317. Livraghi T, Goldberg SN, Lazzaroni S, et al. Hepatocellular
carcinoma: radio-frequency ablation of medium and large lesions.
Radiology 2000;214:761-768. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/10715043.
318. Vivarelli M, Guglielmi A, Ruzzenente A, et al. Surgical resection
versus percutaneous radiofrequency ablation in the treatment of
hepatocellular carcinoma on cirrhotic liver. Ann Surg 2004;240:102-107.
Available at: http://www.ncbi.nlm.nih.gov/pubmed/15213625.
319. Ruzzenente A, Guglielmi A, Sandri M, et al. Surgical resection versus
local ablation for HCC on cirrhosis: results from a propensity casematched study. J Gastrointest Surg 2012;16:301-311; discussion 311.
Available at: http://www.ncbi.nlm.nih.gov/pubmed/22095524.
320. Livraghi T, Meloni F, Di Stasi M, et al. Sustained complete response
and complications rates after radiofrequency ablation of very early
hepatocellular carcinoma in cirrhosis: Is resection still the treatment ofchoice? Hepatology 2008;47:82-89. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/18008357.
321. Peng ZW, Lin XJ, Zhang YJ, et al. Radiofrequency ablation versus
hepatic resection for the treatment of hepatocellular carcinomas 2 cm orsmaller: a retrospective comparative study. Radiology 2012;262:10221033. Available at: http://www.ncbi.nlm.nih.gov/pubmed/22357902.
322. Shibata T, Iimuro Y, Yamamoto Y, et al. Small hepatocellular
carcinoma: comparison of radio-frequency ablation and percutaneous

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-80

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
microwave coagulation therapy. Radiology 2002;223:331-337. Available
at: http://www.ncbi.nlm.nih.gov/pubmed/11997534.

2014;25:997-1011; quiz 1011. Available at:https://www.ncbi.nlm.nih.gov/pubmed/24656178.

323. Ding J, Jing X, Liu J, et al. Comparison of two different thermal
techniques for the treatment of hepatocellular carcinoma. Eur J Radiol
2013;82:1379-1384. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/23726122.

331. Cheung W, Kavnoudias H, Roberts S, et al. Irreversible
electroporation for unresectable hepatocellular carcinoma: initial
experience and review of safety and outcomes. Technol Cancer Res Treat
2013;12:233-241. Available at:https://www.ncbi.nlm.nih.gov/pubmed/23369152.

324. Groeschl RT, Pilgrim CHC, Hanna EM, et al. Microwave ablation forhepatic malignancies: a multiinstitutional analysis. Ann Surg 2013.
Available at: http://www.ncbi.nlm.nih.gov/pubmed/24096760.
325. Zhang L, Wang N, Shen Q, et al. Therapeutic efficacy of
percutaneous radiofrequency ablation versus microwave ablation forhepatocellular carcinoma. PLoS One 2013;8. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/24146824.
326. Shi J, Sun Q, Wang Y, et al. Comparison of microwave ablation andsurgical resection for treatment of hepatocellular carcinomas conforming
to Milan Criteria. J Gastroenterol Hepatol 2014. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/24628534.
327. Hsiao CY, Huang KW. Irreversible electroporation: a novel
ultrasound-guided modality for non-thermal tumor ablation. J Med
Ultrasound 2017;25:195-200. Available at:https://www.ncbi.nlm.nih.gov/pubmed/30065492.
328. Narayanan G, Froud T, Suthar R, Barbery K. Irreversible
electroporation of hepatic malignancy. Semin Intervent Radiol 2013;30:6773. Available at: https://www.ncbi.nlm.nih.gov/pubmed/24436519.
329. Lencioni R, Crocetti L, Narayanan G. Irreversible electroporation in
the treatment of hepatocellular carcinoma. Tech Vasc Interv Radiol
2015;18:135-139. Available at:https://www.ncbi.nlm.nih.gov/pubmed/26365542.
330. Scheffer HJ, Nielsen K, de Jong MC, et al. Irreversible
electroporation for nonthermal tumor ablation in the clinical setting: asystematic review of safety and efficacy. J Vasc Interv Radiol

332. Cannon R, Ellis S, Hayes D, et al. Safety and early efficacy ofirreversible electroporation for hepatic tumors in proximity to vital
structures. J Surg Oncol 2013;107:544-549. Available at:https://www.ncbi.nlm.nih.gov/pubmed/23090720.
333. Fruhling P, Nilsson A, Duraj F, et al. Single-center nonrandomized
clinical trial to assess the safety and efficacy of irreversible electroporation(IRE) ablation of liver tumors in humans: Short to mid-term results. Eur J
Surg Oncol 2017;43:751-757. Available at:https://www.ncbi.nlm.nih.gov/pubmed/28109674.
334. Liapi E, Geschwind J-FH. Intra-arterial therapies for hepatocellular
carcinoma: where do we stand? Ann Surg Oncol 2010;17:1234-1246.
Available at: http://www.ncbi.nlm.nih.gov/pubmed/20405328.
335. Rand T, Loewe C, Schoder M, et al. Arterial embolization ofunresectable hepatocellular carcinoma with use of microspheres, lipiodol,and cyanoacrylate. Cardiovasc Intervent Radiol 2005;28:313-318.
Available at: http://www.ncbi.nlm.nih.gov/pubmed/15886943.
336. Huang YH, Chen CH, Chang TT, et al. The role of transcatheter
arterial embolization for patients with unresectable hepatocellular
carcinoma: a nationwide, multicentre study evaluated by cancer stage.
Aliment Pharmacol Ther 2005;21:687-694. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/15771754.
337. Maluccio MA, Covey AM, Porat LB, et al. Transcatheter arterial
embolization with only particles for the treatment of unresectable
hepatocellular carcinoma. J Vasc Interv Radiol 2008;19:862-869. Available
at: http://www.ncbi.nlm.nih.gov/pubmed/18503900.

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-81

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
338. Bonomo G, Pedicini V, Monfardini L, et al. Bland embolization inpatients with unresectable hepatocellular carcinoma using precise, tightly
size-calibrated, anti-inflammatory microparticles: first clinical experienceand one-year follow-up. Cardiovasc Intervent Radiol 2010;33:552-559.
Available at: http://www.ncbi.nlm.nih.gov/pubmed/19957182.
339. Ramsey DE, Kernagis LY, Soulen MC, Geschwind J-FH.
Chemoembolization of hepatocellular carcinoma. J Vasc Interv Radiol
2002;13:211-221. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/12354839.
340. Lo C-M, Ngan H, Tso W-K, et al. Randomized controlled trial oftransarterial lipiodol chemoembolization for unresectable hepatocellular
carcinoma. Hepatology 2002;35:1164-1171. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/11981766.
341. Llovet JM, Real MI, Montana X, et al. Arterial embolisation or
chemoembolisation versus symptomatic treatment in patients withunresectable hepatocellular carcinoma: a randomised controlled trial.
Lancet 2002;359:1734-1739. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/12049862.
342. Kong JY, Li SM, Fan HY, et al. Transarterial chemoembolization
extends long-term survival in patients with unresectable hepatocellular
carcinoma. Medicine (Baltimore) 2018;97:e11872. Available at:https://www.ncbi.nlm.nih.gov/pubmed/30113483.
343. Brown KT, Do RK, Gonen M, et al. Randomized trial of hepatic artery
embolization for hepatocellular carcinoma using doxorubicin-eluting
microspheres compared with embolization with microspheres alone. J Clin
Oncol 2016;34:2046-2053. Available at:https://www.ncbi.nlm.nih.gov/pubmed/26834067.
344. Morse MA, Hanks BA, Suhocki P, et al. Improved time to progression
for transarterial chemoembolization compared with transarterial
embolization for patients with unresectable hepatocellular carcinoma. Clin
Colorectal Cancer 2012;11:185-190. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/22280845.

345. Molinari M, Kachura JR, Dixon E, et al. Transarterial
chemoembolisation for advanced hepatocellular carcinoma: results from a
North American cancer centre. Clin Oncol (R Coll Radiol) 2006;18:684692. Available at: http://www.ncbi.nlm.nih.gov/pubmed/17100154.
346. Llado L, Virgili J, Figueras J, et al. A prognostic index of the survivalof patients with unresectable hepatocellular carcinoma after transcatheter
arterial chemoembolization. Cancer 2000;88:50-57. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/10618605.
347. Han K, Kim JH, Ko GY, et al. Treatment of hepatocellular carcinoma
with portal venous tumor thrombosis: A comprehensive review. World J
Gastroenterol 2016;22:407-416. Available at:https://www.ncbi.nlm.nih.gov/pubmed/26755886.
348. Leng JJ, Xu YZ, Dong JH. Efficacy of transarterial
chemoembolization for hepatocellular carcinoma with portal veinthrombosis: a meta-analysis. ANZ J Surg 2016;86:816-820. Available at:https://www.ncbi.nlm.nih.gov/pubmed/25088384.
349. Kim W, Clark TW, Baum RA, Soulen MC. Risk factors for liverabscess formation after hepatic chemoembolization. J Vasc Interv Radiol
2001;12:965-968. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/11487677.
350. Mezhir JJ, Fong Y, Fleischer D, et al. Pyogenic abscess after hepatic
artery embolization: a rare but potentially lethal complication. J Vasc Interv
Radiol 2011;22:177-182. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/21195630.
351. Sergio A, Cristofori C, Cardin R, et al. Transcatheter arterial
chemoembolization (TACE) in hepatocellular carcinoma (HCC): the role ofangiogenesis and invasiveness. Am J Gastroenterol 2008;103:914-921.
Available at: http://www.ncbi.nlm.nih.gov/pubmed/18177453.
352. Xiong ZP, Yang SR, Liang ZY, et al. Association between vascularendothelial growth factor and metastasis after transcatheter arterial
chemoembolization in patients with hepatocellular carcinoma.

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-82

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
Hepatobiliary Pancreat Dis Int 2004;3:386-390. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/15313674.
353. Song BC, Chung YH, Kim JA, et al. Association between insulin-likegrowth factor-2 and metastases after transcatheter arterial
chemoembolization in patients with hepatocellular carcinoma: aprospective study. Cancer 2001;91:2386-2393. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/11413529.
354. Kudo M, Imanaka K, Chida N, et al. Phase III study of sorafenib after
transarterial chemoembolisation in Japanese and Korean patients withunresectable hepatocellular carcinoma. Eur J Cancer 2011;47:2117-2127.
Available at: http://www.ncbi.nlm.nih.gov/pubmed/21664811.
355. Erhardt A, Kolligs F, Dollinger M, et al. TACE plus sorafenib for thetreatment of hepatocellular carcinoma: results of the multicenter, phase II
SOCRATES trial. Cancer Chemother Pharmacol 2014;74:947-954.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/25173458.
356. Pawlik TM, Reyes DK, Cosgrove D, et al. Phase II trial of sorafenibcombined with concurrent transarterial chemoembolization with drugeluting beads for hepatocellular carcinoma. J Clin Oncol 2011;29 39603967. Available at: http://www.ncbi.nlm.nih.gov/pubmed/21911714.
357. Park J-W, Koh YH, Kim HB, et al. Phase II study of concurrent
transarterial chemoembolization and sorafenib in patients withunresectable hepatocellular carcinoma. J Hepatol 2012;56:1336-1342.
Available at: http://www.ncbi.nlm.nih.gov/pubmed/22314421.
358. Chung Y-H, Han G, Yoon J-H, et al. Interim analysis of START: studyin Asia of the combination of TACE (transcatheter arterial
chemoembolization) with sorafenib in patients with hepatocellular
carcinoma trial. Int J Cancer 2013;132:2448-2458. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/23129123.
359. Zhu K, Chen J, Lai L, et al. Hepatocellular carcinoma with portal veintumor thrombus: treatment with transarterial chemoembolization combinedwith sorafenib--a retrospective controlled study. Radiology 2014;272:284293. Available at: http://www.ncbi.nlm.nih.gov/pubmed/24708192.

360. Zhao Y, Wang WJ, Guan S, et al. Sorafenib combined withtransarterial chemoembolization for the treatment of advanced
hepatocellular carcinoma: a large-scale multicenter study of 222 patients.
Ann Oncol 2013;24:1786-1792. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/23508822.
361. Lencioni R, Llovet JM, Han G, et al. Sorafenib or placebo plus TACE
with doxorubicin-eluting beads for intermediate stage HCC: the SPACE
trial. J Hepatol 2016;64:1090-1098. Available at:https://www.ncbi.nlm.nih.gov/pubmed/26809111.
362. Poon RT, Tso WK, Pang RW, et al. A phase I/II trial ofchemoembolization for hepatocellular carcinoma using a novel intraarterial drug-eluting bead. Clin Gastroenterol Hepatol 2007;5:1100-1108.
Available at: http://www.ncbi.nlm.nih.gov/pubmed/17627902.
363. Reyes DK, Vossen JA, Kamel IR, et al. Single-center phase II trial oftransarterial chemoembolization with drug-eluting beads for patients withunresectable hepatocellular carcinoma: initial experience in the UnitedStates. Cancer J 2009;15:526-532. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/20010173.
364. Lammer J, Malagari K, Vogl T, et al. Prospective randomized study of
doxorubicin-eluting-bead embolization in the treatment of hepatocellular
carcinoma: results of the PRECISION V study. Cardiovasc Intervent
Radiol 2010;33:41-52. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/19908093.
365. Malagari K, Pomoni M, Kelekis A, et al. Prospective randomized
comparison of chemoembolization with doxorubicin-eluting beads andbland embolization with BeadBlock for hepatocellular carcinoma.
Cardiovasc Intervent Radiol 2010;33:541-551. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/19937027.
366. Dhanasekaran R, Kooby DA, Staley CA, et al. Comparison of
conventional transarterial chemoembolization (TACE) andchemoembolization with doxorubicin drug eluting beads (DEB) for
unresectable hepatocelluar carcinoma (HCC). J Surg Oncol

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-83

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
2010;101:476-480. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/20213741.

analysis. Jpn J Clin Oncol 2018;48:1058-1069. Available at:https://www.ncbi.nlm.nih.gov/pubmed/30272196.

367. Malagari K, Pomoni M, Moschouris H, et al. Chemoembolization withdoxorubicin-eluting beads for unresectable hepatocellular carcinoma: fiveyear survival analysis. Cardiovasc Intervent Radiol 2012;35:1119-1128.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/22614031.

374. Li L, Zhao W, Wang M, et al. Transarterial chemoembolization plus
sorafenib for the management of unresectable hepatocellular carcinoma: asystematic review and meta-analysis. BMC Gastroenterol 2018;18:138.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/30180810.

368. Song MJ, Chun HJ, Song do S, et al. Comparative study between
doxorubicin-eluting beads and conventional transarterial
chemoembolization for treatment of hepatocellular carcinoma. J Hepatol
2012;57:1244-1250. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/22824821.

375. Meyer T, Fox R, Ma YT, et al. Sorafenib in combination withtransarterial chemoembolisation in patients with unresectable
hepatocellular carcinoma (TACE 2): a randomised placebo-controlled,
double-blind, phase 3 trial. Lancet Gastroenterol Hepatol 2017;2:565-575.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/28648803.

369. Golfieri R, Giampalma E, Renzulli M, et al. Randomised controlled
trial of doxorubicin-eluting beads vs conventional chemoembolisation forhepatocellular carcinoma. Br J Cancer 2014;111:255-264. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/24937669.

376. Ibrahim SM, Lewandowski RJ, Sato KT, et al. Radioembolization for
the treatment of unresectable hepatocellular carcinoma: a clinical review.
World J Gastroenterol 2008;14:1664-1669. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/18350597.

370. Yang B, Liang J, Qu Z, et al. Transarterial strategies for the treatmentof unresectable hepatocellular carcinoma: A systematic review. PLoS One
2020;15:e0227475. Available at:https://www.ncbi.nlm.nih.gov/pubmed/32074102.

377. Kulik LM, Carr BI, Mulcahy MF, et al. Safety and efficacy of 90Y
radiotherapy for hepatocellular carcinoma with and without portal veinthrombosis. Hepatology 2008;47:71-81. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/18027884.

371. Chao Y, Chung YH, Han G, et al. The combination of transcatheter
arterial chemoembolization and sorafenib is well tolerated and effective in
Asian patients with hepatocellular carcinoma: final results of the START
trial. Int J Cancer 2015;136:1458-1467. Available at:https://www.ncbi.nlm.nih.gov/pubmed/25099027.

378. Woodall CE, Scoggins CR, Ellis SF, et al. Is selective internal
radioembolization safe and effective for patients with inoperable
hepatocellular carcinoma and venous thrombosis? J Am Coll Surg
2009;208:375-382. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/19317999.

372. Cai R, Song R, Pang P, et al. Transcatheter arterial
chemoembolization plus sorafenib versus transcatheter arterial
chemoembolization alone to treat advanced hepatocellular carcinoma: ameta-analysis. BMC Cancer 2017;17:714. Available at:https://www.ncbi.nlm.nih.gov/pubmed/29110700.

379. Salem R, Lewandowski RJ, Mulcahy MF, et al. Radioembolization forhepatocellular carcinoma using Yttrium-90 microspheres: acomprehensive report of long-term outcomes. Gastroenterology
2010;138:52-64. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/19766639.

373. Jin PP, Shao SY, Wu WT, et al. Combination of transarterial
chemoembolization and sorafenib improves outcomes of unresectable
hepatocellular carcinoma: an updated systematic review and meta-

380. Sangro B, Carpanese L, Cianni R, et al. Survival after yttrium-90
resin microsphere radioembolization of hepatocellular carcinoma acrossBarcelona clinic liver cancer stages: a European evaluation. Hepatology

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-84

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
2011;54:868-878. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/21618574.
381. Mazzaferro V, Sposito C, Bhoori S, et al. Yttrium-90
radioembolization for intermediate-advanced hepatocellular carcinoma: aphase 2 study. Hepatology 2013;57:1826-1837. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/22911442.
382. Vouche M, Habib A, Ward TJ, et al. Unresectable solitary
hepatocellular carcinoma not amenable to radiofrequency ablation:
multicenter radiology-pathology correlation and survival of radiation
segmentectomy. Hepatology 2014;60:192-201. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/24691943.
383. Abdel-Rahman OM, Elsayed Z. Yttrium-90 microsphereradioembolisation for unresectable hepatocellular carcinoma. Cochrane
Database Syst Rev 2016;2:Cd011313. Available at:https://www.ncbi.nlm.nih.gov/pubmed/26905230.
384. Garin E, Tselikas L, Guiu B, et al. Personalised versus standard
dosimetry approach of selective internal radiation therapy in patients withlocally advanced hepatocellular carcinoma (DOSISPHERE-01): a
randomised, multicentre, open-label phase 2 trial. Lancet Gastroenterol
Hepatol 2021;6:17-29. Available at:https://www.ncbi.nlm.nih.gov/pubmed/33166497.
385. Vilgrain V, Pereira H, Assenat E, et al. Efficacy and safety of
selective internal radiotherapy with yttrium-90 resin microspherescompared with sorafenib in locally advanced and inoperable hepatocellular
carcinoma (SARAH): an open-label randomised controlled phase 3 trial.
Lancet Oncol 2017;18:1624-1636. Available at:https://www.ncbi.nlm.nih.gov/pubmed/29107679.
386. Chow PKH, Gandhi M, Tan SB, et al. SIRveNIB: Selective internalradiation therapy versus sorafenib in Asia-Pacific patients with
hepatocellular carcinoma. J Clin Oncol 2018;36:1913-1921. Available at:https://www.ncbi.nlm.nih.gov/pubmed/29498924.

387. Atassi B, Bangash AK, Bahrani A, et al. Multimodality imaging
following 90Y radioembolization: a comprehensive review and pictorial
essay. Radiographics 2008;28:81-99. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/18203932.
388. Jia Z, Jiang G, Tian F, et al. A systematic review on the safety andeffectiveness of yttrium-90 radioembolization for hepatocellular carcinoma
with portal vein tumor thrombosis. Saudi J Gastroenterol 2016;22:353-359.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/27748320.
389. Lobo L, Yakoub D, Picado O, et al. Unresectable hepatocellular
carcinoma: radioembolization versus chemoembolization: a systematic
review and meta-analysis. Cardiovasc Intervent Radiol 2016;39:15801588. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27586657.
390. Ludwig JM, Zhang D, Xing M, Kim HS. Meta-analysis: adjusted
indirect comparison of drug-eluting bead transarterial chemoembolization
versus (90)Y-radioembolization for hepatocellular carcinoma. Eur Radiol
2017;27:2031-2041. Available at:https://www.ncbi.nlm.nih.gov/pubmed/27562480.
391. Hawkins MA, Dawson LA. Radiation therapy for hepatocellular
carcinoma: from palliation to cure. Cancer 2006;106:1653-1663. Available
at: http://www.ncbi.nlm.nih.gov/pubmed/16541431.
392. Hoffe SE, Finkelstein SE, Russell MS, Shridhar R. Nonsurgicaloptions for hepatocellular carcinoma: evolving role of external beam
radiotherapy. Cancer Control 2010;17:100-110. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/20404793.
393. Kwon JH, Bae SH, Kim JY, et al. Long-term effect of stereotactic
body radiation therapy for primary hepatocellular carcinoma ineligible for
local ablation therapy or surgical resection. Stereotactic radiotherapy forliver cancer. BMC Cancer 2010;10:475-475. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/20813065.
394. Andolino DL, Johnson CS, Maluccio M, et al. Stereotactic bodyradiotherapy for primary hepatocellular carcinoma. Int J Radiat Oncol Biol

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-85

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
Phys 2011;81:e447-453. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/21645977.

Biol Phys 2012;83:895-900. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/22172906.

395. Huang W-Y, Jen Y-M, Lee M-S, et al. Stereotactic body radiation
therapy in recurrent hepatocellular carcinoma. Int J Radiat Oncol Biol Phys
2012;84:355-361. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/22342300.

402. O'Connor JK, Trotter J, Davis GL, et al. Long-term outcomes ofstereotactic body radiation therapy in the treatment of hepatocellularcancer as a bridge to transplantation. Liver Transpl 2012;18:949-954.
Available at: http://www.ncbi.nlm.nih.gov/pubmed/22467602.

396. Kang J-K, Kim M-S, Cho CK, et al. Stereotactic body radiation
therapy for inoperable hepatocellular carcinoma as a local salvage
treatment after incomplete transarterial chemoembolization. Cancer
2012;118:5424-5431. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/22570179.

403. Cardenes HR, Price TR, Perkins SM, et al. Phase I feasibility trial ofstereotactic body radiation therapy for primary hepatocellular carcinoma.
Clin Transl Oncol 2010;12:218-225. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/20231127.

397. Bujold A, Massey CA, Kim JJ, et al. Sequential phase I and II trials of
stereotactic body radiotherapy for locally advanced hepatocellular
carcinoma. J Clin Oncol 2013;31:1631-1639. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/23547075.
398. Wahl DR, Stenmark MH, Tao Y, et al. Outcomes after stereotactic
body radiotherapy or radiofrequency ablation for hepatocellular carcinoma.
J Clin Oncol 2016;34:452-459. Available at:https://www.ncbi.nlm.nih.gov/pubmed/26628466.
399. Rajyaguru DJ, Borgert AJ, Smith AL, et al. Radiofrequency ablation
versus stereotactic body radiotherapy for localized hepatocellular
carcinoma in nonsurgically managed patients: analysis of the National
Cancer Database. J Clin Oncol 2018;36:600-608. Available at:https://www.ncbi.nlm.nih.gov/pubmed/29328861.
400. Facciuto ME, Singh MK, Rochon C, et al. Stereotactic body radiation
therapy in hepatocellular carcinoma and cirrhosis: evaluation ofradiological and pathological response. J Surg Oncol 2012;105:692-698.
Available at: http://www.ncbi.nlm.nih.gov/pubmed/21960321.
401. Katz AW, Chawla S, Qu Z, et al. Stereotactic hypofractionatedradiation therapy as a bridge to transplantation for hepatocellular
carcinoma: clinical outcome and pathologic correlation. Int J Radiat Oncol

404. Velec M, Haddad CR, Craig T, et al. Predictors of liver toxicity
following stereotactic body radiation therapy for hepatocellular carcinoma.
Int J Radiat Oncol Biol Phys 2017;97:939-946. Available at:https://www.ncbi.nlm.nih.gov/pubmed/28333016/.
405. Tse RV, Hawkins M, Lockwood G, et al. Phase I study ofindividualized stereotactic body radiotherapy for hepatocellular carcinoma
and intrahepatic cholangiocarcinoma. J Clin Oncol 2008;26:657-664.
Available at: http://www.ncbi.nlm.nih.gov/pubmed/18172187.
406. Tanguturi SK, Wo JY, Zhu AX, et al. Radiation therapy for liver
tumors: ready for inclusion in guidelines? Oncologist 2014;19:868-879.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/25001265.
407. Proton Beam Therapy. American Society for Radiation Oncology;
2014. Available at:
http://www.astro.org/uploadedFiles/Main_Site/Practice_Management/Reimbursement/ASTRO%20PBT%20Model%20Policy%20FINAL.pdf.
Accessed 11/26/18.
408. Hong TS, Wo JY, Yeap BY, et al. Multi-institutional phase II study ofhigh-dose hypofractionated proton beam therapy in patients with localized,
unresectable hepatocellular carcinoma and intrahepaticcholangiocarcinoma. J Clin Oncol 2016;34:460-468. Available at:https://www.ncbi.nlm.nih.gov/pubmed/26668346.

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-86

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
409. Qi WX, Fu S, Zhang Q, Guo XM. Charged particle therapy versus
photon therapy for patients with hepatocellular carcinoma: a systematic
review and meta-analysis. Radiother Oncol 2015;114:289-295. Available
at: https://www.ncbi.nlm.nih.gov/pubmed/25497556.
410. Sanford NN, Pursley J, Noe B, et al. Protons versus Photons forUnresectable Hepatocellular Carcinoma: Liver Decompensation andOverall Survival. Int J Radiat Oncol Biol Phys 2019;105:64-72. Available
at: https://www.ncbi.nlm.nih.gov/pubmed/30684667.
411. Bush DA, Smith JC, Slater JD, et al. Randomized clinical trial
comparing proton beam radiation therapy with transarterial
chemoembolization for hepatocellular carcinoma: results of an interim
analysis. Int J Radiat Oncol Biol Phys 2016;95:477-482. Available at:https://www.ncbi.nlm.nih.gov/pubmed/27084661.
412. Kim TH, Park JW, Kim BH, et al. Phase II study of hypofractionatedproton beam therapy for hepatocellular carcinoma. Front Oncol
2020;10:542. Available at:https://www.ncbi.nlm.nih.gov/pubmed/32411594.
413. Kirikoshi H, Saito S, Yoneda M, et al. Outcome of transarterial
chemoembolization monotherapy, and in combination with percutaneous
ethanol injection, or radiofrequency ablation therapy for hepatocellular
carcinoma. Hepatol Res 2009;39:553-562. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/19527484.
414. Maluccio M, Covey AM, Gandhi R, et al. Comparison of survival rates
after bland arterial embolization and ablation versus surgical resection fortreating solitary hepatocellular carcinoma up to 7 cm. J Vasc Interv Radiol
2005;16:955-961. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/16002503.
415. Elnekave E, Erinjeri JP, Brown KT, et al. Long-term outcomescomparing surgery to embolization-ablation for treatment of solitary HCC<7 cm. Ann Surg Oncol 2013. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/23563960.

416. Koda M, Murawaki Y, Mitsuda A, et al. Combination therapy withtranscatheter arterial chemoembolization and percutaneous ethanol
injection compared with percutaneous ethanol injection alone for patientswith small hepatocellular carcinoma: a randomized control study. Cancer
2001;92:1516-1524. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/11745230.
417. Becker G, Soezgen T, Olschewski M, et al. Combined TACE and PEI
for palliative treatment of unresectable hepatocellular carcinoma. World J
Gastroenterol 2005;11:6104-6109. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/16273634.
418. Peng Z-W, Zhang Y-J, Chen M-S, et al. Radiofrequency ablation withor without transcatheter arterial chemoembolization in the treatment of
hepatocellular carcinoma: a prospective randomized trial. J Clin Oncol
2013;31:426-432. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/23269991.
419. Shibata T, Isoda H, Hirokawa Y, et al. Small hepatocellular
carcinoma: is radiofrequency ablation combined with transcatheter arterial
chemoembolization more effective than radiofrequency ablation alone fortreatment? Radiology 2009;252:905-913. Available at:
http://radiology.rsna.org/content/252/3/905.full.pdf.
420. Kim JH, Won HJ, Shin YM, et al. Medium-sized (3.1-5.0 cm)
hepatocellular carcinoma: transarterial chemoembolization plus
radiofrequency ablation versus radiofrequency ablation alone. Ann Surg
Oncol 2011;18:1624-1629. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/21445671.
421. Peng ZW, Zhang YJ, Liang HH, et al. Recurrent hepatocellular
carcinoma treated with sequential transcatheter arterial
chemoembolization and RF ablation versus RF ablation alone: aprospective randomized trial. Radiology 2012;262:689-700. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/22157201.
422. Sheta E, El-Kalla F, El-Gharib M, et al. Comparison of single-session
transarterial chemoembolization combined with microwave ablation orradiofrequency ablation in the treatment of hepatocellular carcinoma: aVersion 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-87

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
randomized-controlled study. Eur J Gastroenterol Hepatol 2016;28:11981203. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27362551.
423. Wang W, Shi J, Xie WF. Transarterial chemoembolization in
combination with percutaneous ablation therapy in unresectable
hepatocellular carcinoma: a meta-analysis. Liver Int 2010;30:741-749.
Available at: http://www.ncbi.nlm.nih.gov/pubmed/20331507.
424. Huo YR, Eslick GD. Transcatheter arterial chemoembolization plus
radiotherapy compared with chemoembolization alone for hepatocellular
carcinoma: a systematic review and meta-analysis. JAMA Oncol
2015;1:756-765. Available at:https://www.ncbi.nlm.nih.gov/pubmed/26182200.
425. Abdel-Rahman O, Elsayed Z. External beam radiotherapy forunresectable hepatocellular carcinoma. Cochrane Database Syst Rev
2017;3:Cd011314. Available at:https://www.ncbi.nlm.nih.gov/pubmed/28267205.
426. Yoon SM, Ryoo BY, Lee SJ, et al. Efficacy and safety of transarterial
chemoembolization plus external beam radiotherapy vs sorafenib in
hepatocellular carcinoma with macroscopic vascular invasion: arandomized clinical trial. JAMA Oncol 2018;4:661-669. Available at:https://www.ncbi.nlm.nih.gov/pubmed/29543938.
427. Llovet JM, Vilana R, Bru C, et al. Increased risk of tumor seeding
after percutaneous radiofrequency ablation for single hepatocellular
carcinoma. Hepatology 2001;33:1124-1129. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/11343240.
428. Livraghi T, Solbiati L, Meloni MF, et al. Treatment of focal liver tumors
with percutaneous radio-frequency ablation: complications encountered ina multicenter study. Radiology 2003;226:441-451. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/12563138.
429. Lencioni R, Cioni D, Crocetti L, et al. Early-stage hepatocellular
carcinoma in patients with cirrhosis: long-term results of percutaneous
image-guided radiofrequency ablation. Radiology 2005;234:961-967.
Available at: http://www.ncbi.nlm.nih.gov/pubmed/15665226.

430. Zhang Y-J, Liang H-H, Chen M-S, et al. Hepatocellular carcinoma
treated with radiofrequency ablation with or without ethanol injection: aprospective randomized trial. Radiology 2007;244:599-607. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/17641378.
431. 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. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/24062394.
432. Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced
hepatocellular carcinoma. N Engl J Med 2008;359:378-390. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/18650514.
433. Cheng AL, Kang YK, Chen Z, et al. Efficacy and safety of sorafenib inpatients in the Asia-Pacific region with advanced hepatocellular
carcinoma: a phase III randomised, double-blind, placebo-controlled trial.
Lancet Oncol 2009;10:25-34. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/19095497.
434. Abou-Alfa GK. Selection of patients with hepatocellular carcinoma forsorafenib. J Natl Compr Canc Netw 2009;7:397-403. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/19406040.
435. Finn RS, Zhu AX, Farah W, et al. Therapies for advanced stage
hepatocellular carcinoma with macrovascular invasion or metastatic
disease: A systematic review and meta-analysis. Hepatology 2018;67:422435. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28881497.
436. Abou-Alfa GK, Schwartz L, Ricci S, et al. Phase II study of sorafenibin patients with advanced hepatocellular carcinoma. J Clin Oncol
2006;24:4293-4300. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/16908937.
437. Abou-Alfa GK, Amadori D, Santoro A, et al. Safety and efficacy ofsorafenib in patients with hepatocellular carcinoma (HCC) and Child-PughA versus B cirrhosis. Gastrointest Cancer Res 2011;4:40-44. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/21673874.

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-88

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
438. Pinter M, Sieghart W, Hucke F, et al. Prognostic factors in patientswith advanced hepatocellular carcinoma treated with sorafenib. Aliment
Pharmacol Ther 2011;34:949-959. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/21883324.
439. Hollebecque A, Cattan S, Romano O, et al. Safety and efficacy ofsorafenib in hepatocellular carcinoma: the impact of the Child-Pugh score.
Aliment Pharmacol Ther 2011;34:1193-1201. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/21958438.
440. Kim JE, Ryoo BY, Ryu MH, et al. Sorafenib for hepatocellular
carcinoma according to Child-Pugh class of liver function. Cancer
Chemother Pharmacol 2011;68:1285-1290. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/21445543.
441. Lencioni R, Kudo M, Ye SL, et al. First interim analysis of the
GIDEON (Global Investigation of therapeutic decisions in hepatocellular
carcinoma and of its treatment with sorafeNib) non-interventional study. Int
J Clin Pract 2012;66:675-683. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/22698419.
442. Chiu J, Tang YF, Yao T-J, et al. The use of single-agent sorafenib in
the treatment of advanced hepatocellular carcinoma patients with
underlying Child-Pugh B liver cirrhosis: a retrospective analysis of efficacy,
safety, and survival benefits. Cancer 2012;118:5293-5301. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/22517493.
443. Marrero JA, Lencioni R, Ye S-L, et al. Final analysis of GIDEON(Global Investigation of Therapeutic Decisions in Hepatocellular
Carcinoma [HCC] and of its treatment with sorafenib [sor]) in >3000 sortreated patients (pts): Clinical findings in pts with liver dysfunction[abstract]. J Clin Oncol 2013;31:Abstract 4126. Available at:
http://meeting.ascopubs.org/cgi/content/abstract/31/15_suppl/4126.
444. Miller AA, Murry DJ, Owzar K, et al. Phase I and pharmacokinetic
study of sorafenib in patients with hepatic or renal dysfunction: CALGB
60301. J Clin Oncol 2009;27:1800-1805. Available at:https://www.ncbi.nlm.nih.gov/pubmed/19255312.

445. Zhu AX, Rosmorduc O, Evans TR, et al. SEARCH: a phase III,randomized, double-blind, placebo-controlled trial of sorafenib plus
erlotinib in patients with advanced hepatocellular carcinoma. J Clin Oncol
2015;33:559-566. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/25547503.
446. Kudo M, Finn RS, Qin S, et al. Lenvatinib versus sorafenib in first-line
treatment of patients with unresectable hepatocellular carcinoma: arandomised phase 3 non-inferiority trial. Lancet 2018;391:1163-1173.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/29433850.
447. Finn RS, Ikeda M, Zhu AX, et al. Phase Ib study of lenvatinib plus
pembrolizumab in patients with unresectable hepatocellular carcinoma. J
Clin Oncol 2020;38:2960-2970. Available at:https://www.ncbi.nlm.nih.gov/pubmed/32716739.
448. Zhu AX, Blaszkowsky LS, Ryan DP, et al. Phase II study of
gemcitabine and oxaliplatin in combination with bevacizumab in patientswith advanced hepatocellular carcinoma. J Clin Oncol 2006;24:1898-1903.
Available at: http://www.ncbi.nlm.nih.gov/pubmed/16622265.
449. Siegel AB, Cohen EI, Ocean A, et al. Phase II trial evaluating theclinical and biologic effects of bevacizumab in unresectable hepatocellular
carcinoma. J Clin Oncol 2008;26:2992-2998. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/18565886.
450. Thomas MB, Morris JS, Chadha R, et al. Phase II trial of the
combination of bevacizumab and erlotinib in patients who have advanced
hepatocellular carcinoma. J Clin Oncol 2009;27:843-850. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/19139433.
451. Hsu CH, Yang TS, Hsu C, et al. Efficacy and tolerability ofbevacizumab plus capecitabine as first-line therapy in patients withadvanced hepatocellular carcinoma. Br J Cancer 2010;102:981-986.
Available at: http://www.ncbi.nlm.nih.gov/pubmed/20160718.
452. Sun W, Sohal D, Haller DG, et al. Phase 2 trial of bevacizumab,
capecitabine, and oxaliplatin in treatment of advanced hepatocellular

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-89

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
carcinoma. Cancer 2011;117:3187-3192. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/21264839.
453. Pishvaian MJ, Lee MS, Ryoo BY, et al. Updated safety and clinicalactivity results from a phase Ib study of atezolizumab + bevacizumab inhepatocellular carcinoma (HCC). ESMO 2018 Congress. Munich,Germany; 2018. Available at: https://oncologypro.esmo.org/MeetingResources/ESMO-2018-Congress/Updated-safety-and-clinical-activityresults-from-a-Phase-Ib-study-of-atezolizumab-bevacizumab-inhepatocellular-carcinoma-HCC.
454. Fang P, Hu JH, Cheng ZG, et al. Efficacy and safety of bevacizumab
for the treatment of advanced hepatocellular carcinoma: a systematic
review of phase II trials. PLoS One 2012;7:e49717. Available at:https://www.ncbi.nlm.nih.gov/pubmed/23284624.
455. Finn RS, Qin S, Ikeda M, et al. Atezolizumab plus bevacizumab inunresectable hepatocellular carcinoma. N Engl J Med 2020;382:18941905. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32402160.
456. Finn R, Qin S, Ikeda M, et al. IMbrave150: Updated overall survival(OS) data from a global, randomized, open-label phase III study of
atezolizumab (atezo) + bevacizumab (bev) versus sorafenib (sor) inpatients (pts) with unresectable hepatocellular carcinoma (HCC) [abstract].
J Clin Oncol 2021;39:Abstract 267. Available at:https://ascopubs.org/doi/abs/10.1200/JCO.2021.39.3_suppl.267.
457. Bruix J, Qin S, Merle P, et al. Regorafenib for patients with
hepatocellular carcinoma who progressed on sorafenib treatment(RESORCE): a randomised, double-blind, placebo-controlled, phase 3
trial. Lancet 2017;389:56-66. Available at:https://www.ncbi.nlm.nih.gov/pubmed/27932229.
458. Abou-Alfa GK, Meyer T, Cheng AL, et al. Cabozantinib in patientswith advanced and progressing hepatocellular carcinoma. N Engl J Med
2018;379:54-63. Available at:https://www.ncbi.nlm.nih.gov/pubmed/29972759.

459. Kelley RK, Meyer T, Rimassa L, et al. Serum Alpha-fetoprotein
Levels and Clinical Outcomes in the Phase III CELESTIAL Study ofCabozantinib versus Placebo in Patients with Advanced Hepatocellular
Carcinoma. Clin Cancer Res 2020;26:4795-4804. Available at:https://www.ncbi.nlm.nih.gov/pubmed/32636319.
460. Zhu AX, Park JO, Ryoo BY, et al. Ramucirumab versus placebo as
second-line treatment in patients with advanced hepatocellular carcinoma
following first-line therapy with sorafenib (REACH): a randomised, doubleblind, multicentre, phase 3 trial. Lancet Oncol 2015;16:859-870. Available
at: http://www.ncbi.nlm.nih.gov/pubmed/26095784.
461. Chau I, Peck-Radosavljevic M, Borg C, et al. Ramucirumab assecond-line treatment in patients with advanced hepatocellular carcinoma
following first-line therapy with sorafenib: Patient-focused outcome resultsfrom the randomised phase III REACH study. Eur J Cancer 2017;81:1725. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28591675.
462. Zhu AX, Kang YK, Yen CJ, et al. Ramucirumab after sorafenib inpatients with advanced hepatocellular carcinoma and increased alphafetoprotein concentrations (REACH-2): a randomised, double-blind,placebo-controlled, phase 3 trial. Lancet Oncol 2019;20:282-296.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/30665869.
463. Zhu AX, Finn RS, Kang YK, et al. Serum alpha-fetoprotein andclinical outcomes in patients with advanced hepatocellular carcinoma
treated with ramucirumab. Br J Cancer 2021;124:1388-1397. Available at:https://www.ncbi.nlm.nih.gov/pubmed/33531690.
464. FDA grants accelerated approval to nivolumab for HCC previously
treated with sorafenib. 2017. Available at:https://www.fda.gov/drugs/resources-information-approved-drugs/fdagrants-accelerated-approval-nivolumab-hcc-previously-treated-sorafenib.
Accessed July 30, 2021.
465. Yau T, Park JW, Finn RS, et al. CheckMate 459: a randomized, multicenter phase 3 study of nivolumab (NIVO) vs sorafenib (SOR) as first-line(1L) treatment in patients (pts) with advanced hepatocellular carcinoma

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-90

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers[abstract]. Ann Oncol 2019;30:Abstract LBA38_PR. Available at:https://www.annalsofoncology.org/article/S0923-7534(19)60389-3/fulltext.
466. Bristol Myers Squibb statement on Opdivo® (nivolumab)
monotherapy post-sorafenib hepatocellular carcinoma U.S. indication.
2021. Available at: https://news.bms.com/news/corporatefinancial/2021/Bristol-Myers-Squibb-Statement-on-Opdivo-nivolumabMonotherapy-Post-Sorafenib-Hepatocellular-Carcinoma-U.S.Indication/default.aspx. Accessed July 30, 2021.
467. Yau T, Kang YK, Kim TY, et al. Efficacy and safety of nivolumab plus
ipilimumab in patients with advanced hepatocellular carcinoma previously
treated with sorafenib: The CheckMate 040 randomized clinical trial. JAMA
Oncol 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33001135.
468. El-Khoueiry A, Yau T, Kang Y-K, et al. Nivolumab (NIVO) plus
ipilimumab (IPI) combination therapy in patients (Pts) with advanced
hepatocellular carcinoma (aHCC): Long-term results from CheckMate 040[abstract]. J Clin Oncol 2021;39:Abstract 269. Available at:https://ascopubs.org/doi/abs/10.1200/JCO.2021.39.3_suppl.269.
469. Zhu AX, Finn RS, Edeline J, et al. Pembrolizumab in patients withadvanced hepatocellular carcinoma previously treated with sorafenib(KEYNOTE-224): a non-randomised, open-label phase 2 trial. Lancet
Oncol 2018;19:940-952. Available at:https://www.ncbi.nlm.nih.gov/pubmed/29875066.
470. Finn RS, Ryoo BY, Merle P, et al. Pembrolizumab as second-line
therapy in patients with advanced hepatocellular carcinoma in KEYNOTE240: A randomized, double-blind, phase III trial. J Clin Oncol 2020;38:193202. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31790344.
471. Merle P, Edeline J, Bouattour M, et al. Pembrolizumab (pembro) vsplacebo (pbo) in patients (pts) with advanced hepatocellular carcinoma(aHCC) previously treated with sorafenib: Updated data from therandomized, phase III KEYNOTE-240 study [abstract]. J Clin Oncol
2021;39:Abstract 268. Available at:https://ascopubs.org/doi/abs/10.1200/JCO.2021.39.3_suppl.268.

472. Berton D, Banerjee SN, Curigliano G, et al. Antitumor activity of
dostarlimab in patients with mismatch repair-deficient/microsatellite
instability–high tumors: A combined analysis of two cohorts in the
GARNET study [abstract]. J Clin Oncol 2021;39:Abstract 2564. Available
at: https://ascopubs.org/doi/abs/10.1200/JCO.2021.39.15_suppl.2564.
473. Andre T, Berton D, Curigliano G, et al. Safety and efficacy of anti–
PD-1 antibody dostarlimab in patients (pts) with mismatch repair-deficient(dMMR) solid cancers: Results from GARNET study [abstract]. J Clin
Oncol 2021;39:Abstract 9. Available at:https://ascopubs.org/doi/abs/10.1200/JCO.2021.39.3_suppl.9.
474. Qin S, Bai Y, Lim HY, et al. Randomized, multicenter, open-label
study of oxaliplatin plus fluorouracil/leucovorin versus doxorubicin as
palliative chemotherapy in patients with advanced hepatocellular
carcinoma from Asia. J Clin Oncol 2013;31:3501-3508. Available at:https://www.ncbi.nlm.nih.gov/pubmed/23980077.
475. Qin S, Cheng Y, Liang J, et al. Efficacy and safety of the FOLFOX4
regimen versus doxorubicin in Chinese patients with advanced
hepatocellular carcinoma: a subgroup analysis of the EACH study.
Oncologist 2014;19:1169-1178. Available at:https://www.ncbi.nlm.nih.gov/pubmed/25223462.
476. Goyal L, Zheng H, Abrams TA, et al. A phase II and biomarker studyof sorafenib combined with modified FOLFOX in patients with advanced
hepatocellular carcinoma. Clin Cancer Res 2019;25:80-89. Available at:https://www.ncbi.nlm.nih.gov/pubmed/30190369.
477. Cainap C, Qin S, Huang WT, et al. Linifanib versus Sorafenib inpatients with advanced hepatocellular carcinoma: results of a randomized
phase III trial. J Clin Oncol 2015;33:172-179. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/25488963.
478. Rimassa L, Assenat E, Peck-Radosavljevic M, et al. Tivantinib forsecond-line treatment of MET-high, advanced hepatocellular carcinoma(METIV-HCC): a final analysis of a phase 3, randomised, placebocontrolled study. Lancet Oncol 2018;19:682-693. Available at:https://www.ncbi.nlm.nih.gov/pubmed/29625879.

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-91

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
479. Santoro A, Rimassa L, Borbath I, et al. Tivantinib for second-line
treatment of advanced hepatocellular carcinoma: a randomised, placebocontrolled phase 2 study. Lancet Oncol 2013;14:55-63. Available at:https://www.ncbi.nlm.nih.gov/pubmed/23182627.
480. Kang YK, Yau T, Park JW, et al. Randomized phase II study of
axitinib versus placebo plus best supportive care in second-line treatmentof advanced hepatocellular carcinoma. Ann Oncol 2015;26:2457-2463.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/26386123.
481. Li Q, Qin S, Gu S, et al. Apatinib as second-line therapy in Chinesepatients with advanced hepatocellular carcinoma: A randomized, placebocontrolled, double-blind, phase III study [abstract]. J Clin Oncol
2020;38:Abstract 4507. Available at:https://ascopubs.org/doi/abs/10.1200/JCO.2020.38.15_suppl.4507.
482. Sia D, Tovar V, Moeini A, Llovet JM. Intrahepaticcholangiocarcinoma: pathogenesis and rationale for molecular therapies.
Oncogene 2013;32:4861-4870. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/23318457.
483. Galuppo R, Ramaiah D, Ponte OM, Gedaly R. Molecular therapies inhepatocellular carcinoma: what can we target? Dig Dis Sci 2014;59:16881697. Available at: http://www.ncbi.nlm.nih.gov/pubmed/24573715.
484. Liu H, Wang ZG, Fu SY, et al. Randomized clinical trial ofchemoembolization plus radiofrequency ablation versus partial
hepatectomy for hepatocellular carcinoma within the Milan criteria. Br J
Surg 2016;103:348-356. Available at:https://www.ncbi.nlm.nih.gov/pubmed/26780107.
485. Hyun MH, Lee YS, Kim JH, et al. Hepatic resection compared tochemoembolization in intermediate- to advanced-stage hepatocellular
carcinoma: A meta-analysis of high-quality studies. Hepatology
2018;68:977-993. Available at:https://www.ncbi.nlm.nih.gov/pubmed/29543988.
486. Volk ML, Hernandez JC, Lok AS, Marrero JA. Modified Charlson
comorbidity index for predicting survival after liver transplantation. Liver

Transpl 2007;13:1515-1520. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/17969207.
487. Utsunomiya T, Shimada M, Kudo M, et al. Nationwide study of 4741
patients with non-B non-C hepatocellular carcinoma with special reference
to the therapeutic impact. Ann Surg 2014;259:336-345. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/23673768.
488. Roayaie S, Blume IN, Thung SN, et al. A system of classifying
microvascular invasion to predict outcome after resection in patients with
hepatocellular carcinoma. Gastroenterology 2009;137:850-855. Available
at: https://www.ncbi.nlm.nih.gov/pubmed/19524573.
489. Sumie S, Nakashima O, Okuda K, et al. The significance ofclassifying microvascular invasion in patients with hepatocellular
carcinoma. Ann Surg Oncol 2014;21:1002-1009. Available at:https://www.ncbi.nlm.nih.gov/pubmed/24254204.
490. Park H, Park JY. Clinical significance of AFP and PIVKA-II responses
for monitoring treatment outcomes and predicting prognosis in patientswith hepatocellular carcinoma. Biomed Res Int 2013;2013:310427.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/24455683.
491. Figueras J, Ibanez L, Ramos E, et al. Selection criteria for livertransplantation in early-stage hepatocellular carcinoma with cirrhosis:
results of a multicenter study. Liver Transpl 2001;7:877-883. Available at:https://www.ncbi.nlm.nih.gov/pubmed/11679986.
492. Mirici-Cappa F, Gramenzi A, Santi V, et al. Treatments forhepatocellular carcinoma in elderly patients are as effective as in younger
patients: a 20-year multicentre experience. Gut 2010;59:387-396.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/20207642.
493. Ozenne V, Bouattour M, Goutte N, et al. Prospective evaluation of
the management of hepatocellular carcinoma in the elderly. Dig Liver Dis
2011;43:1001-1005. Available at:https://www.ncbi.nlm.nih.gov/pubmed/21798829.

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-92

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
494. Marabelle A, Le DT, Ascierto PA, et al. Efficacy of pembrolizumab inpatients with noncolorectal high microsatellite instability/mismatch repairdeficient cancer: Results from the phase II KEYNOTE-158 study. J Clin
Oncol 2020;38:1-10. Available at:https://www.ncbi.nlm.nih.gov/pubmed/31682550.
495. El-Khoueiry AB, Sangro B, Yau T, et al. Nivolumab in patients withadvanced hepatocellular carcinoma (CheckMate 040): an open-label, noncomparative, phase 1/2 dose escalation and expansion trial. Lancet
2017;389:2492-2502. Available at:https://www.ncbi.nlm.nih.gov/pubmed/28434648.
496. Kambhampati S, Bauer KE, Bracci PM, et al. Nivolumab in patientswith advanced hepatocellular carcinoma and Child-Pugh class B cirrhosis:
safety and clinical outcomes in a retrospective case series. Cancer
2019;125:3234-3241. Available at:https://www.ncbi.nlm.nih.gov/pubmed/31154669.
497. Kudo M, Matilla A, Santoro A, et al. Checkmate-040: nivolumab(NIVO) in patients (pts) with advanced hepatocellular carcinoma (aHCC)
and Child-Pugh B (CPB) status. J Clin Oncol 2019;37:327-327. Available
at: https://ascopubs.org/doi/abs/10.1200/JCO.2019.37.4_suppl.327.
498. Kudo M, Okusaka T, Motomura K, et al. Ramucirumab after priorsorafenib in patients with advanced hepatocellular carcinoma and elevatedalpha-fetoprotein: Japanese subgroup analysis of the REACH-2 trial. J
Gastroenterol 2020;55:627-639. Available at:https://www.ncbi.nlm.nih.gov/pubmed/32107609.

501. Van Dyke AL, Shiels MS, Jones GS, et al. Biliary tract cancer
incidence and trends in the United States by demographic group, 19992013. Cancer 2019;125:1489-1498. Available at:https://www.ncbi.nlm.nih.gov/pubmed/30645774.
502. Randi G, Franceschi S, La Vecchia C. Gallbladder cancer worldwide:
geographical distribution and risk factors. Int J Cancer 2006;118:15911602. Available at: http://www.ncbi.nlm.nih.gov/pubmed/16397865.
503. Lazcano-Ponce EC, Miquel JF, Munoz N, et al. Epidemiology andmolecular pathology of gallbladder cancer. CA Cancer J Clin 2001;51:349364. Available at: http://www.ncbi.nlm.nih.gov/pubmed/11760569.
504. Miranda-Filho A, Pineros M, Ferreccio C, et al. Gallbladder andextrahepatic bile duct cancers in the Americas: Incidence and mortality
patterns and trends. Int J Cancer 2020;147:978-989. Available at:https://www.ncbi.nlm.nih.gov/pubmed/31922259.
505. Jarnagin WR, Ruo L, Little SA, et al. Patterns of initial disease
recurrence after resection of gallbladder carcinoma and hilar
cholangiocarcinoma: implications for adjuvant therapeutic strategies.
Cancer 2003;98:1689-1700. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/14534886.
506. Sheth S, Bedford A, Chopra S. Primary gallbladder cancer:
recognition of risk factors and the role of prophylactic cholecystectomy.
Am J Gastroenterol 2000;95:1402-1410. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/10894571.

499. Levy AD, Murakata LA, Rohrmann CA, Jr. Gallbladder carcinoma:
radiologic-pathologic correlation. Radiographics 2001;21:295-314;
questionnaire, 549-255. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/11259693.

507. Tazuma S, Kajiyama G. Carcinogenesis of malignant lesions of thegall bladder. The impact of chronic inflammation and gallstones.
Langenbecks Arch Surg 2001;386:224-229. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/11382326.

500. Henley SJ, Weir HK, Jim MA, et al. Gallbladder cancer incidence andmortality, United States 1999-2011. Cancer Epidemiol Biomarkers Prev
2015;24:1319-1326. Available at:https://www.ncbi.nlm.nih.gov/pubmed/26070529.

508. Khan ZS, Livingston EH, Huerta S. Reassessing the need forprophylactic surgery in patients with porcelain gallbladder: case series andsystematic review of the literature. Arch Surg 2011;146:1143-1147.
Available at: http://www.ncbi.nlm.nih.gov/pubmed/22006872.

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-93

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
509. Schnelldorfer T. Porcelain gallbladder: a benign process or concern
for malignancy? J Gastrointest Surg 2013. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/23423431.
510. Stephen AE, Berger DL. Carcinoma in the porcelain gallbladder: arelationship revisited. Surgery 2001;129:699-703. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/11391368.
511. Elnemr A, Ohta T, Kayahara M, et al. Anomalous pancreaticobiliary
ductal junction without bile duct dilatation in gallbladder cancer.
Hepatogastroenterology 2001;48:382-386. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/11379314.
512. Reid KM, Ramos-De la Medina A, Donohue JH. Diagnosis andsurgical management of gallbladder cancer: a review. J Gastrointest Surg
2007;11:671-681. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/17468929.
513. Hundal R, Shaffer EA. Gallbladder cancer: epidemiology andoutcome. Clin Epidemiol 2014;6:99-109. Available at:https://www.ncbi.nlm.nih.gov/pubmed/24634588.
514. Williams AS, Huang WY. The analysis of microsatellite instability inextracolonic gastrointestinal malignancy. Pathology 2013;45:540-552.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/24018804.
515. Roa I, de Toro G, Schalper K, et al. Overexpression of the HER2/neu
gene: a new therapeutic possibility for patients with advanced gallbladdercancer. Gastrointest Cancer Res 2014;7:42-48. Available at:https://www.ncbi.nlm.nih.gov/pubmed/24799970.
516. Shindoh J, de Aretxabala X, Aloia TA, et al. Tumor location is astrong predictor of tumor progression and survival in T2 gallbladdercancer: an international multicenter study. Ann Surg 2015;261:733-739.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/24854451.
517. Lee H, Choi DW, Park JY, et al. Surgical strategy for T2 gallbladdercancer according to tumor location. Ann Surg Oncol 2015;22:2779-2786.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/25519930.

518. Donohue JH, Stewart AK, Menck HR. The National Cancer Data
Base report on carcinoma of the gallbladder, 1989-1995. Cancer
1998;83:2618-2628. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/9874470.
519. Duffy A, Capanu M, Abou-Alfa GK, et al. Gallbladder cancer (GBC):
10-year experience at Memorial Sloan-Kettering Cancer Centre (MSKCC).
J Surg Oncol 2008;98:485-489. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/18802958.
520. Ito H, Ito K, D'Angelica M, et al. Accurate staging for gallbladdercancer: implications for surgical therapy and pathological assessment.
Ann Surg 2011;254:320-325. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/21617582.
521. Hawkins WG, DeMatteo RP, Jarnagin WR, et al. Jaundice predicts
advanced disease and early mortality in patients with gallbladder cancer.
Ann Surg Oncol 2004;11:310-315. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/14993027.
522. Furlan A, Ferris JV, Hosseinzadeh K, Borhani AA. Gallbladdercarcinoma update: multimodality imaging evaluation, staging, andtreatment options. AJR Am J Roentgenol 2008;191:1440-1447. Available
at: http://www.ncbi.nlm.nih.gov/pubmed/18941083.
523. de Savornin Lohman EAJ, de Bitter TJJ, van Laarhoven C, et al. The
diagnostic accuracy of CT and MRI for the detection of lymph nodemetastases in gallbladder cancer: A systematic review and meta-analysis.
Eur J Radiol 2019;110:156-162. Available at:https://www.ncbi.nlm.nih.gov/pubmed/30599854.
524. Petrowsky H, Wildbrett P, Husarik DB, et al. Impact of integrated
positron emission tomography and computed tomography on staging andmanagement of gallbladder cancer and cholangiocarcinoma. J Hepatol
2006;45:43-50. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/16690156.
525. Corvera CU, Blumgart LH, Akhurst T, et al. 18F-fluorodeoxyglucose
positron emission tomography influences management decisions in

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-94

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
patients with biliary cancer. J Am Coll Surg 2008;206:57-65. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/18155569.
526. Lee SW, Kim HJ, Park JH, et al. Clinical usefulness of 18F-FDG
PET-CT for patients with gallbladder cancer and cholangiocarcinoma. J
Gastroenterol 2010;45:560-566. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/20035356.
527. Lamarca A, Barriuso J, Chander A, et al. (18)F-fluorodeoxyglucose
positron emission tomography ((18)FDG-PET) for patients with biliary tract
cancer: Systematic review and meta-analysis. J Hepatol 2019;71:115-129.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/30797051.
528. Strom BL, Maislin G, West SL, et al. Serum CEA and CA 19-9:
potential future diagnostic or screening tests for gallbladder cancer? Int J
Cancer 1990;45:821-824. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/2335386.
529. Dixon E, Vollmer CM, Jr., Sahajpal A, et al. An aggressive surgicalapproach leads to improved survival in patients with gallbladder cancer: a
12-year study at a North American Center. Ann Surg 2005;241:385-394.
Available at: http://www.ncbi.nlm.nih.gov/pubmed/15729060.
530. Fuks D, Regimbeau JM, Le Treut YP, et al. Incidental gallbladdercancer by the AFC-GBC-2009 Study Group. World J Surg 2011;35:18871897. Available at: http://www.ncbi.nlm.nih.gov/pubmed/21547420.
531. Lee SE, Jang JY, Lim CS, et al. Systematic review on the surgicaltreatment for T1 gallbladder cancer. World J Gastroenterol 2011;17:174180. Available at: http://www.ncbi.nlm.nih.gov/pubmed/21245989.
532. Foster JM, Hoshi H, Gibbs JF, et al. Gallbladder cancer: Defining theindications for primary radical resection and radical re-resection. Ann Surg
Oncol 2007;14:833-840. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/17103074.
533. Coburn NG, Cleary SP, Tan JC, Law CH. Surgery for gallbladdercancer: a population-based analysis. J Am Coll Surg 2008;207:371-382.
Available at: http://www.ncbi.nlm.nih.gov/pubmed/18722943.

534. You DD, Lee HG, Paik KY, et al. What is an adequate extent ofresection for T1 gallbladder cancers? Ann Surg 2008;247:835-838.
Available at: http://www.ncbi.nlm.nih.gov/pubmed/18438121.
535. Jensen EH, Abraham A, Habermann EB, et al. A critical analysis of
the surgical management of early-stage gallbladder cancer in the UnitedStates. J Gastrointest Surg 2009;13:722-727. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/19083068.
536. Downing Sr CKOG, et al. Early-stage gallbladder cancer in thesurveillance, epidemiology, and end results database: Effect of extended
surgical resection. Archives of Surgery 2011;146:734-738. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/21690451.
537. Shirai Y, Sakata J, Wakai T, et al. "Extended" radicalcholecystectomy for gallbladder cancer: long-term outcomes, indications
and limitations. World J Gastroenterol 2012;18:4736-4743. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/23002343.
538. Widmann B, Warschkow R, Beutner U, et al. Effect oflymphadenectomy in curative gallbladder cancer treatment: a systematic
review and meta-analysis. Langenbecks Arch Surg 2020;405:573-584.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/32458141.
539. D'Angelica M, Dalal KM, DeMatteo RP, et al. Analysis of the extent ofresection for adenocarcinoma of the gallbladder. Ann Surg Oncol
2009;16:806-816. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/18985272.
540. Gani F, Buettner S, Margonis GA, et al. Assessing the impact ofcommon bile duct resection in the surgical management of gallbladdercancer. J Surg Oncol 2016;114:176-180. Available at:https://www.ncbi.nlm.nih.gov/pubmed/27198742.
541. Pawlik TM, Gleisner AL, Vigano L, et al. Incidence of finding residual
disease for incidental gallbladder carcinoma: implications for re-resection.
J Gastrointest Surg 2007;11:1478-1486; discussion 1486-1477. Available
at: http://www.ncbi.nlm.nih.gov/pubmed/17846848.

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-95

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
542. Fong Y, Jarnagin W, Blumgart LH. Gallbladder cancer: comparison ofpatients presenting initially for definitive operation with those presenting
after prior noncurative intervention. Ann Surg 2000;232:557-569. Available
at: http://www.ncbi.nlm.nih.gov/pubmed/10998654.
543. Shih SP, Schulick RD, Cameron JL, et al. Gallbladder cancer: therole of laparoscopy and radical resection. Ann Surg 2007;245:893-901.
Available at: http://www.ncbi.nlm.nih.gov/pubmed/17522515.
544. Agarwal AK, Kalayarasan R, Javed A, et al. Role of staging
laparoscopy in primary gall bladder cancer-an analysis of 409 patients: aprospective study to evaluate the role of staging laparoscopy in the
management of gallbladder cancer. Ann Surg 2012. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/23059504.
545. Butte JM, Gonen M, Allen PJ, et al. The role of laparoscopic staging
in patients with incidental gallbladder cancer. HPB (Oxford) 2011;13:463472. Available at: http://www.ncbi.nlm.nih.gov/pubmed/21689230.
546. Maker AV, Butte JM, Oxenberg J, et al. Is port site resection
necessary in the surgical management of gallbladder cancer? Ann Surg
Oncol 2012;19:409-417. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/21698501.
547. Fuks D, Regimbeau JM, Pessaux P, et al. Is port-site resection
necessary in the surgical management of gallbladder cancer? J Visc Surg
2013. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23665059.
548. Regimbeau JM, Fuks D, Bachellier P, et al. Prognostic value ofjaundice in patients with gallbladder cancer by the AFC-GBC-2009 study
group. Eur J Surg Oncol 2011;37:505-512. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/21514090.
549. Nishio H, Ebata T, Yokoyama Y, et al. Gallbladder cancer involving
the extrahepatic bile duct is worthy of resection. Ann Surg 2011;253:953960. Available at: https://www.ncbi.nlm.nih.gov/pubmed/21490453.
550. Dasari BVM, Ionescu MI, Pawlik TM, et al. Outcomes of surgicalresection of gallbladder cancer in patients presenting with jaundice: A

systematic review and meta-analysis. J Surg Oncol 2018;118:477-485.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/30259519.
551. Hakeem AR, Papoulas M, Menon KV. The role of neoadjuvant
chemotherapy or chemoradiotherapy for advanced gallbladder cancer - A
systematic review. Eur J Surg Oncol 2019;45:83-91. Available at:https://www.ncbi.nlm.nih.gov/pubmed/30287098.
552. Creasy JM, Goldman DA, Dudeja V, et al. Systemic chemotherapy
combined with resection for locally advanced gallbladder carcinoma:
surgical and survival outcomes. J Am Coll Surg 2017;224:906-916.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/28216422.
553. Engineer R, Goel M, Chopra S, et al. Neoadjuvant chemoradiation
followed by surgery for locally advanced gallbladder cancers: a newparadigm. Ann Surg Oncol 2016;23:3009-3015. Available at:https://www.ncbi.nlm.nih.gov/pubmed/27075323.
554. Merino DM, McShane LM, Fabrizio D, et al. Establishing guidelines toharmonize tumor mutational burden (TMB): in silico assessment ofvariation in TMB quantification across diagnostic platforms: phase I of the
Friends of Cancer Research TMB Harmonization Project. J Immunother
Cancer 2020;8. Available at:https://www.ncbi.nlm.nih.gov/pubmed/32217756.
555. Le DT, Durham JN, Smith KN, et al. Mismatch repair deficiency
predicts response of solid tumors to PD-1 blockade. Science
2017;357:409-413. Available at:https://www.ncbi.nlm.nih.gov/pubmed/28596308.
556. Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors withmismatch-repair deficiency. N Engl J Med 2015;372:2509-2520. Available
at: https://www.ncbi.nlm.nih.gov/pubmed/26028255.
557. Lim JH. Cholangiocarcinoma: morphologic classification according to
growth pattern and imaging findings. AJR Am J Roentgenol 2003;181:819827. Available at: http://www.ncbi.nlm.nih.gov/pubmed/12933488.

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-96

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
558. Saha SK, Zhu AX, Fuchs CS, Brooks GA. Forty-year trends incholangiocarcinoma incidence in the U.S.: intrahepatic disease on the rise.
Oncologist 2016;21:594-599. Available at:https://www.ncbi.nlm.nih.gov/pubmed/27000463.

566. Chang K-Y, Chang J-Y, Yen Y. Increasing incidence of intrahepaticcholangiocarcinoma and its relationship to chronic viral hepatitis. J NatlCompr Canc Netw 2009;7:423-427. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/19406042.

559. Mukkamalla SKR, Naseri HM, Kim BM, et al. Trends in incidence andfactors affecting survival of patients with cholangiocarcinoma in the UnitedStates. J Natl Compr Canc Netw 2018;16:370-376. Available at:https://www.ncbi.nlm.nih.gov/pubmed/29632056.

567. Wongjarupong N, Assavapongpaiboon B, Susantitaphong P, et al.
Non-alcoholic fatty liver disease as a risk factor for cholangiocarcinoma: asystematic review and meta-analysis. BMC Gastroenterol 2017;17:149.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/29216833.

560. DeOliveira ML, Cunningham SC, Cameron JL, et al.
Cholangiocarcinoma: thirty-one-year experience with 564 patients at asingle institution. Ann Surg 2007;245:755-762. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/17457168.

568. Endo I, Gonen M, Yopp AC, et al. Intrahepatic cholangiocarcinoma:rising frequency, improved survival, and determinants of outcome after
resection. Ann Surg 2008;248:84-96. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/18580211.

561. Chapman RW. Risk factors for biliary tract carcinogenesis. Ann Oncol
1999;10 Suppl 4:308-311. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/10436847.

569. Nathan H, Aloia TA, Vauthey J-N, et al. A proposed staging system
for intrahepatic cholangiocarcinoma. Ann Surg Oncol 2009;16:14-22.
Available at: http://www.ncbi.nlm.nih.gov/pubmed/18987916.

562. Tyson GL, El-Serag HB. Risk factors for cholangiocarcinoma.
Hepatology 2011;54:173-184. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/21488076.

570. de Jong MC, Nathan H, Sotiropoulos GC, et al. Intrahepaticcholangiocarcinoma: an international multi-institutional analysis ofprognostic factors and lymph node assessment. J Clin Oncol
2011;29:3140-3145. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/21730269.

563. Huai JP, Ding J, Ye XH, Chen YP. Inflammatory bowel disease andrisk of cholangiocarcinoma: evidence from a meta-analysis of populationbased studies. Asian Pac J Cancer Prev 2014;15:3477-3482. Available at:https://www.ncbi.nlm.nih.gov/pubmed/24870743.
564. Welzel TM, Graubard BI, El-Serag HB, et al. Risk factors for
intrahepatic and extrahepatic cholangiocarcinoma in the United States: apopulation-based case-control study. Clin Gastroenterol Hepatol
2007;5:1221-1228. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/17689296.
565. Clements O, Eliahoo J, Kim JU, et al. Risk factors for intrahepatic andextrahepatic cholangiocarcinoma: A systematic review and meta-analysis.
J Hepatol 2020;72:95-103. Available at:https://www.ncbi.nlm.nih.gov/pubmed/31536748.

571. Edge SB, Byrd DR, Compton CC, et al. AJCC Cancer Staging
Manual (ed 7). New York, NY: Springer; 2010.
572. Farges O, Fuks D, Le Treut Y-P, et al. AJCC 7th edition of TNM
staging accurately discriminates outcomes of patients with resectable
intrahepatic cholangiocarcinoma. Cancer 2011;117:2170-2177. Available
at: http://www.ncbi.nlm.nih.gov/pubmed/21523730.
573. de Jong MC, Hong S-M, Augustine MM, et al. Hilar
cholangiocarcinoma: tumor depth as a predictor of outcome. Arch Surg
2011;146:697-703. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/21690446.

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-97

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
574. Hong S-M, Pawlik TM, Cho H, et al. Depth of tumor invasion better
predicts prognosis than the current American Joint Committee on Cancer
T classification for distal bile duct carcinoma. Surgery 2009;146:250-257.
Available at: http://www.ncbi.nlm.nih.gov/pubmed/19628081.

582. Heimbach JK, Sanchez W, Rosen CB, Gores GJ. Trans-peritoneal
fine needle aspiration biopsy of hilar cholangiocarcinoma is associatedwith disease dissemination. HPB (Oxford) 2011;13:356-360. Available at:https://www.ncbi.nlm.nih.gov/pubmed/21492336.

575. Bismuth H, Nakache R, Diamond T. Management strategies inresection for hilar cholangiocarcinoma. Ann Surg 1992;215:31-38.
Available at: http://www.ncbi.nlm.nih.gov/pubmed/1309988.

583. Sainani NI, Catalano OA, Holalkere NS, et al. Cholangiocarcinoma:
current and novel imaging techniques. Radiographics 2008;28:1263-1287.
Available at: http://www.ncbi.nlm.nih.gov/pubmed/18794305.

576. Jarnagin WR, Fong Y, DeMatteo RP, et al. Staging, resectability, andoutcome in 225 patients with hilar cholangiocarcinoma. Ann Surg
2001;234:507-517; discussion 517-509. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/11573044.

584. Zhang H, Zhu J, Ke F, et al. Radiological imaging for assessing therespectability of hilar cholangiocarcinoma: a systematic review and metaanalysis. Biomed Res Int 2015;2015:497942. Available at:https://www.ncbi.nlm.nih.gov/pubmed/26448940.

577. Matsuo K, Rocha FG, Ito K, et al. The Blumgart preoperative staging
system for hilar cholangiocarcinoma: analysis of resectability andoutcomes in 380 patients. J Am Coll Surg 2012;215:343-355. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/22749003.

585. Zaydfudim VM, Wang AY, de Lange EE, et al. IgG4-associatedcholangitis can mimic hilar cholangiocarcinoma. Gut Liver 2015;9:556-560.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/26033685.

578. Aljiffry M, Walsh MJ, Molinari M. Advances in diagnosis, treatment
and palliation of cholangiocarcinoma: 1990-2009. World J Gastroenterol
2009;15:4240-4262. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/19750567.

586. Oh HC, Kim MH, Lee KT, et al. Clinical clues to suspicion of IgG4associated sclerosing cholangitis disguised as primary sclerosing
cholangitis or hilar cholangiocarcinoma. J Gastroenterol Hepatol
2010;25:1831-1837. Available at:https://www.ncbi.nlm.nih.gov/pubmed/21091993.

579. Mann DV, Edwards R, Ho S, et al. Elevated tumour marker CA19-9:
clinical interpretation and influence of obstructive jaundice. Eur J Surg
Oncol 2000;26:474-479. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/11016469.

587. Oseini AM, Chaiteerakij R, Shire AM, et al. Utility of serum
immunoglobulin G4 in distinguishing immunoglobulin G4-associatedcholangitis from cholangiocarcinoma. Hepatology 2011;54:940-948.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/21674559.

580. Hwang JP, Feld JJ, Hammond SP, et al. Hepatitis B Virus Screening
and Management for Patients With Cancer Prior to Therapy: ASCO
Provisional Clinical Opinion Update. J Clin Oncol 2020;38:3698-3715.
Available at: https://ascopubs.org/doi/pdf/10.1200/JCO.20.01757.

588. Xu WL, Ling YC, Wang ZK, Deng F. Diagnostic performance ofserum IgG4 level for IgG4-related disease: a meta-analysis. Sci Rep
2016;6:32035. Available at:https://www.ncbi.nlm.nih.gov/pubmed/27558881.

581. Fowler KJ, Potretzke TA, Hope TA, et al. LI-RADS M (LR-M): definite
or probable malignancy, not specific for hepatocellular carcinoma. Abdom
Radiol (NY) 2018;43:149-157. Available at:https://www.ncbi.nlm.nih.gov/pubmed/28580538.

589. Halefoglu AM. Magnetic resonance cholangiopancreatography: auseful tool in the evaluation of pancreatic and biliary disorders. World J
Gastroenterol 2007;13:2529-2534. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/17551999.

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-98

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
590. Hekimoglu K, Ustundag Y, Dusak A, et al. MRCP vs. ERCP in theevaluation of biliary pathologies: review of current literature. J Dig Dis
2008;9:162-169. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/18956595.

597. Paik KY, Jung JC, Heo JS, et al. What prognostic factors areimportant for resected intrahepatic cholangiocarcinoma? J Gastroenterol
Hepatol 2008;23:766-770. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/17868336.

591. Vogl TJ, Schwarz WO, Heller M, et al. Staging of Klatskin tumours(hilar cholangiocarcinomas): comparison of MR cholangiography, MR
imaging, and endoscopic retrograde cholangiography. Eur Radiol
2006;16:2317-2325. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/16622690.

598. Lang H, Sotiropoulos GC, Sgourakis G, et al. Operations for
intrahepatic cholangiocarcinoma: single-institution experience of 158
patients. J Am Coll Surg 2009;208:218-228. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/19228533.

592. Hyodo T, Kumano S, Kushihata F, et al. CT and MR
cholangiography: advantages and pitfalls in perioperative evaluation ofbiliary tree. Br J Radiol 2012;85:887-896. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/22422383.
593. Kim JY, Kim M-H, Lee TY, et al. Clinical role of 18F-FDG PET-CT insuspected and potentially operable cholangiocarcinoma: a prospective
study compared with conventional imaging. Am J Gastroenterol
2008;103:1145-1151. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/18177454.
594. Ruys AT, Bennink RJ, van Westreenen HL, et al. FDG-positronemission tomography/computed tomography and standardized uptake
value in the primary diagnosis and staging of hilar cholangiocarcinoma.
HPB (Oxford) 2011;13:256-262. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/21418131.
595. Nakagohri T, Asano T, Kinoshita H, et al. Aggressive surgicalresection for hilar-invasive and peripheral intrahepaticcholangiocarcinoma. World J Surg 2003;27:289-293. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/12607053.
596. Konstadoulakis MM, Roayaie S, Gomatos IP, et al. Fifteen-year,
single-center experience with the surgical management of intrahepaticcholangiocarcinoma: operative results and long-term outcome. Surgery
2008;143:366-374. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/18291258.

599. Murakami Y, Uemura K, Sudo T, et al. Prognostic factors after
surgical resection for intrahepatic, hilar, and distal cholangiocarcinoma.
Ann Surg Oncol 2011;18:651-658. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/20945107.
600. Ribero D, Pinna AD, Guglielmi A, et al. Surgical approach for longterm survival of patients with intrahepatic cholangiocarcinoma: a multiinstitutional analysis of 434 patients. Arch Surg 2012;147:1107-1113.
Available at: http://www.ncbi.nlm.nih.gov/pubmed/22910846.
601. Tamandl D, Herberger B, Gruenberger B, et al. Influence of hepatic
resection margin on recurrence and survival in intrahepaticcholangiocarcinoma. Ann Surg Oncol 2008;15:2787-2794. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/18685896.
602. Farges O, Fuks D, Boleslawski E, et al. Influence of surgical margins
on outcome in patients with intrahepatic cholangiocarcinoma: a multicenter
study by the AFC-IHCC-2009 study group. Ann Surg 2011;254:824-829;
discussion 830. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/22042474.
603. Spolverato G, Kim Y, Ejaz A, et al. Conditional probability of longterm survival after liver resection for intrahepatic cholangiocarcinoma: amulti-institutional analysis of 535 patients. JAMA Surg 2015;150:538-545.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/25831462.
604. Carpizo DR, D'Angelica M. Management and extent of resection for
intrahepatic cholangiocarcinoma. Surg Oncol Clin N Am 2009;18:289-305,
viii-ix. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19306813.

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-99

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
605. Goere D, Wagholikar GD, Pessaux P, et al. Utility of staging
laparoscopy in subsets of biliary cancers : laparoscopy is a powerful
diagnostic tool in patients with intrahepatic and gallbladder carcinoma.
Surg Endosc 2006;20:721-725. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/16508808.
606. Joseph S, Connor S, Garden OJ. Staging laparoscopy forcholangiocarcinoma. HPB (Oxford) 2008;10:116-119. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/18773068.
607. Weber SM, Ribero D, O'Reilly EM, et al. Intrahepaticcholangiocarcinoma: expert consensus statement. HPB (Oxford)
2015;17:669-680. Available at:https://www.ncbi.nlm.nih.gov/pubmed/26172134.
608. Shimada M, Yamashita Y, Aishima S, et al. Value of lymph nodedissection during resection of intrahepatic cholangiocarcinoma. Br J Surg
2001;88:1463-1466. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/11683741.
609. Choi S-B, Kim K-S, Choi J-Y, et al. The prognosis and survival
outcome of intrahepatic cholangiocarcinoma following surgical resection:
association of lymph node metastasis and lymph node dissection withsurvival. Ann Surg Oncol 2009;16:3048-3056. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/19626372.
610. Clark CJ, Wood-Wentz CM, Reid-Lombardo KM, et al.
Lymphadenectomy in the staging and treatment of intrahepaticcholangiocarcinoma: a population-based study using the National Cancer
Institute SEER database. HPB (Oxford) 2011;13:612-620. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/21843261.

cholangiocarcinoma: a multi-institution analysis. HPB (Oxford)
2012;14:514-522. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/22762399.
613. Hyder O, Hatzaras I, Sotiropoulos GC, et al. Recurrence after
operative management of intrahepatic cholangiocarcinoma. Surgery
2013;153:811-818. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/23499016.
614. Ribero D, Rosso S, Pinna AD, et al. Postoperative nomogram forpredicting survival after resection for intrahepatic cholangiocarcinoma[abstract]. J Clin Oncol 2013;31:Abstract 4129. Available at:
http://meeting.ascopubs.org/cgi/content/abstract/31/15_suppl/4129.
615. Carrafiello G, Lagana D, Cotta E, et al. Radiofrequency ablation of
intrahepatic cholangiocarcinoma: preliminary experience. Cardiovasc
Intervent Radiol 2010;33:835-839. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/20411389.
616. Kim JH, Won HJ, Shin YM, et al. Radiofrequency ablation for thetreatment of primary intrahepatic cholangiocarcinoma. AJR Am J
Roentgenol 2011;196:W205-209. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/21257864.
617. Kiefer MV, Albert M, McNally M, et al. Chemoembolization of
intrahepatic cholangiocarcinoma with cisplatinum, doxorubicin, mitomycin
C, ethiodol, and polyvinyl alcohol: a 2-center study. Cancer
2011;117:1498-1505. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/21425151.

611. Morine Y, Shimada M, Utsunomiya T, et al. Clinical impact of lymph
node dissection in surgery for peripheral-type intrahepaticcholangiocarcinoma. Surg Today 2012;42:147-151. Available at:https://www.ncbi.nlm.nih.gov/pubmed/22124809.

618. Kuhlmann JB, Euringer W, Spangenberg HC, et al. Treatment ofunresectable cholangiocarcinoma: conventional transarterial
chemoembolization compared with drug eluting bead-transarterial
chemoembolization and systemic chemotherapy. Eur J Gastroenterol
Hepatol 2012;24:437-443. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/22261548.

612. Fisher SB, Patel SH, Kooby DA, et al. Lymphovascular andperineural invasion as selection criteria for adjuvant therapy in intrahepatic

619. Hyder O, Marsh JW, Salem R, et al. Intra-arterial therapy foradvanced intrahepatic cholangiocarcinoma: a multi-institutional analysis.

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-100Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
Ann Surg Oncol 2013;20:3779-3786. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/23846786.

2013;36:440-448. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/22956045.

620. Poggi G, Quaretti P, Minoia C, et al. Transhepatic arterial
chemoembolization with oxaliplatin-eluting microspheres (OEM-TACE) for
unresectable hepatic tumors. Anticancer Res 2008;28:3835-3842.
Available at: http://www.ncbi.nlm.nih.gov/pubmed/19192637.

627. Mouli S, Memon K, Baker T, et al. Yttrium-90 radioembolization for
intrahepatic cholangiocarcinoma: safety, response, and survival analysis.
J Vasc Interv Radiol 2013;24:1227-1234. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/23602420.

621. Schiffman SC, Metzger T, Dubel G, et al. Precision hepatic arterial
irinotecan therapy in the treatment of unresectable intrahepaticcholangiocellular carcinoma: optimal tolerance and prolonged overall
survival. Ann Surg Oncol 2011;18:431-438. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/20862554.

628. Al-Adra DP, Gill RS, Axford SJ, et al. Treatment of unresectable
intrahepatic cholangiocarcinoma with yttrium-90 radioembolization: asystematic review and pooled analysis. Eur J Surg Oncol 2015;41:120127. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25449754.

622. Ibrahim SM, Mulcahy MF, Lewandowski RJ, et al. Treatment ofunresectable cholangiocarcinoma using yttrium-90 microspheres: resultsfrom a pilot study. Cancer 2008;113:2119-2128. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/18759346.
623. Saxena A, Bester L, Chua TC, et al. Yttrium-90 radiotherapy forunresectable intrahepatic cholangiocarcinoma: a preliminary assessmentof this novel treatment option. Ann Surg Oncol 2010;17:484-491. Available
at: http://www.ncbi.nlm.nih.gov/pubmed/19876691.
624. Wijlemans JW, Van Erpecum KJ, Lam MG, et al. Trans-arterial(90)yttrium radioembolization for patients with unresectable tumors
originating from the biliary tree. Ann Hepatol 2011;10:349-354. Available
at: http://www.ncbi.nlm.nih.gov/pubmed/21677339.
625. Hoffmann R-T, Paprottka PM, Schon A, et al. Transarterial hepatic
yttrium-90 radioembolization in patients with unresectable intrahepaticcholangiocarcinoma: factors associated with prolonged survival.
Cardiovasc Intervent Radiol 2012;35:105-116. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/21431970.
626. Rafi S, Piduru SM, El-Rayes B, et al. Yttrium-90 radioembolization forunresectable standard-chemorefractory intrahepatic cholangiocarcinoma:
survival, efficacy, and safety study. Cardiovasc Intervent Radiol

629. Edeline J, Touchefeu Y, Guiu B, et al. Radioembolization plus
chemotherapy for first-line treatment of locally advanced intrahepaticcholangiocarcinoma: A phase 2 clinical trial. JAMA Oncol 2019. Available
at: https://www.ncbi.nlm.nih.gov/pubmed/31670746.
630. Shinohara ET, Mitra N, Guo M, Metz JM. Radiation therapy is
associated with improved survival in the adjuvant and definitive treatment
of intrahepatic cholangiocarcinoma. Int J Radiat Oncol Biol Phys
2008;72:1495-1501. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/18472359.
631. 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. Available at:https://www.ncbi.nlm.nih.gov/pubmed/26503201.
632. Mambrini A, Guglielmi A, Pacetti P, et al. Capecitabine plus hepatic
intra-arterial epirubicin and cisplatin in unresectable biliary cancer: aphase II study. Anticancer Res 2007;27:3009-3013. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/17695488.
633. Inaba Y, Arai Y, Yamaura H, et al. Phase I/II study of hepatic arterial
infusion chemotherapy with gemcitabine in patients with unresectable
intrahepatic cholangiocarcinoma (JIVROSG-0301). Am J Clin Oncol

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-101

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
2011;34:58-62. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/20177362.
634. Kemeny NE, Schwartz L, Gonen M, et al. Treating primary livercancer with hepatic arterial infusion of floxuridine and dexamethasone:
does the addition of systemic bevacizumab improve results? Oncology
2011;80:153-159. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/21677464.
635. Jarnagin WR, Schwartz LH, Gultekin DH, et al. Regional
chemotherapy for unresectable primary liver cancer: results of a phase II
clinical trial and assessment of DCE-MRI as a biomarker of survival. Ann
Oncol 2009;20:1589-1595. Available at:https://www.ncbi.nlm.nih.gov/pubmed/19491285.
636. Konstantinidis IT, Do RK, Gultekin DH, et al. Regional chemotherapy
for unresectable intrahepatic cholangiocarcinoma: a potential role fordynamic magnetic resonance imaging as an imaging biomarker and asurvival update from two prospective clinical trials. Ann Surg Oncol
2014;21:2675-2683. Available at:https://www.ncbi.nlm.nih.gov/pubmed/24664624.
637. Boehm LM, Jayakrishnan TT, Miura JT, et al. Comparative
effectiveness of hepatic artery based therapies for unresectable
intrahepatic cholangiocarcinoma. J Surg Oncol 2015;111:213-220.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/25176325.
638. Konstantinidis IT, Groot Koerkamp B, Do RK, et al. Unresectable
intrahepatic cholangiocarcinoma: Systemic plus hepatic arterial infusion
chemotherapy is associated with longer survival in comparison withsystemic chemotherapy alone. Cancer 2016;122:758-765. Available at:https://www.ncbi.nlm.nih.gov/pubmed/26695839.
639. Akamatsu N, Sugawara Y, Hashimoto D. Surgical strategy for bile
duct cancer: Advances and current limitations. World J Clin Oncol
2011;2:94-107. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/21603318.

640. Nagino M, Ebata T, Yokoyama Y, et al. Evolution of surgicaltreatment for perihilar cholangiocarcinoma: a single-center 34-year review
of 574 consecutive resections. Ann Surg 2013;258:129-140. Available at:https://www.ncbi.nlm.nih.gov/pubmed/23059502.
641. Qiao Q-L, Zhang T-P, Guo J-C, et al. Prognostic factors afterpancreatoduodenectomy for distal bile duct cancer. Am Surg
2011;77:1445-1448. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/22196654.
642. Groot Koerkamp B, Wiggers JK, Gonen M, et al. Survival after
resection of perihilar cholangiocarcinoma-development and external
validation of a prognostic nomogram. Ann Oncol 2015;26:1930-1935.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/26133967.
643. Schwarz RE, Smith DD. Lymph node dissection impact on staging
and survival of extrahepatic cholangiocarcinomas, based on U.S.
population data. J Gastrointest Surg 2007;11:158-165. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/17390167.
644. Ito K, Ito H, Allen PJ, et al. Adequate lymph node assessment for
extrahepatic bile duct adenocarcinoma. Ann Surg 2010;251:675-681.
Available at: http://www.ncbi.nlm.nih.gov/pubmed/20224368.
645. Ota T, Araida T, Yamamoto M, Takasaki K. Operative outcome andproblems of right hepatic lobectomy with pancreatoduodenectomy foradvanced carcinoma of the biliary tract. J Hepatobiliary Pancreat Surg
2007;14:155-158. Available at:https://www.ncbi.nlm.nih.gov/pubmed/17384906.
646. Miwa S, Kobayashi A, Akahane Y, et al. Is major hepatectomy withpancreatoduodenectomy justified for advanced biliary malignancy? J
Hepatobiliary Pancreat Surg 2007;14:136-141. Available at:https://www.ncbi.nlm.nih.gov/pubmed/17384903.
647. Ribero D, Zimmitti G, Aloia TA, et al. Preoperative cholangitis andfuture liver remnant volume determine the risk of liver failure in patients
undergoing resection for hilar cholangiocarcinoma. J Am Coll Surg

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-102

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
2016;223:87-97. Available at:https://www.ncbi.nlm.nih.gov/pubmed/27049784.

2014;20:15153-15157. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/25386064.

648. Nishio H, Nagino M, Nimura Y. Surgical management of hilar
cholangiocarcinoma: the Nagoya experience. HPB (Oxford) 2005;7:259262. Available at: http://www.ncbi.nlm.nih.gov/pubmed/18333203.

656. Ruys AT, Busch OR, Gouma DJ, van Gulik TM. Staging laparoscopy
for hilar cholangiocarcinoma: is it still worthwhile? Indian J Surg Oncol
2012;3:147-153. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/23728233.

649. Ito F, Agni R, Rettammel RJ, et al. Resection of hilar
cholangiocarcinoma: concomitant liver resection decreases hepatic
recurrence. Ann Surg 2008;248:273-279. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/18650638.

657. Nimura Y. Preoperative biliary drainage before resection for
cholangiocarcinoma (Pro). HPB (Oxford) 2008;10:130-133. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/18773090.

650. van Gulik TM, Kloek JJ, Ruys AT, et al. Multidisciplinary managementof hilar cholangiocarcinoma (Klatskin tumor): extended resection isassociated with improved survival. Eur J Surg Oncol 2011;37:65-71.
Available at: http://www.ncbi.nlm.nih.gov/pubmed/21115233.

658. Kennedy TJ, Yopp A, Qin Y, et al. Role of preoperative biliary
drainage of liver remnant prior to extended liver resection for hilar
cholangiocarcinoma. HPB (Oxford) 2009;11:445-451. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/19768150.

651. Cheng QB, Yi B, Wang JH, et al. Resection with total caudate
lobectomy confers survival benefit in hilar cholangiocarcinoma of Bismuth
type III and IV. Eur J Surg Oncol 2012;38:1197-1203. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/22992326.

659. Liu F, Li Y, Wei Y, Li B. Preoperative biliary drainage before resection
for hilar cholangiocarcinoma: whether or not? A systematic review. Dig Dis
Sci 2011;56:663-672. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/20635143.

652. Cho MS, Kim SH, Park SW, et al. Surgical outcomes and predicting
factors of curative resection in patients with hilar cholangiocarcinoma: 10year single-institution experience. J Gastrointest Surg 2012;16:1672-1679.
Available at: http://www.ncbi.nlm.nih.gov/pubmed/22798185.

660. Farges O, Regimbeau JM, Fuks D, et al. Multicentre European studyof preoperative biliary drainage for hilar cholangiocarcinoma. Br J Surg
2013;100:274-283. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/23124720.

653. de Jong MC, Marques H, Clary BM, et al. The impact of portal vein
resection on outcomes for hilar cholangiocarcinoma: a multi-institutional
analysis of 305 cases. Cancer 2012;118:4737-4747. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/22415526.

661. Abulkhir A, Limongelli P, Healey AJ, et al. Preoperative portal vein
embolization for major liver resection: a meta-analysis. Ann Surg
2008;247:49-57. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/18156923.

654. Wu XS, Dong P, Gu J, et al. Combined portal vein resection for hilar
cholangiocarcinoma: a meta-analysis of comparative studies. J
Gastrointest Surg 2013;17:1107-1115. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/23592188.

662. Shindoh J, Vauthey J-N, Zimmitti G, et al. Analysis of the efficacy of
portal vein embolization for patients with extensive liver malignancy andvery low future liver remnant volume, including a comparison with theassociating liver partition with portal vein ligation for staged hepatectomy
approach. J Am Coll Surg 2013. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/23632095.

655. Cho A, Yamamoto H, Kainuma O, et al. Laparoscopy in the
management of hilar cholangiocarcinoma. World J Gastroenterol

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-103

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
663. Davids PH, Groen AK, Rauws EA, et al. Randomised trial of selfexpanding metal stents versus polyethylene stents for distal malignant
biliary obstruction. Lancet 1992;340:1488-1492. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/1281903.
664. Prat F, Chapat O, Ducot B, et al. A randomized trial of endoscopic
drainage methods for inoperable malignant strictures of the common bileduct. Gastrointest Endosc 1998;47:1-7. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/9468416.
665. Abraham NS, Barkun JS, Barkun AN. Palliation of malignant biliary
obstruction: a prospective trial examining impact on quality of life.
Gastrointest Endosc 2002;56:835-841. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/12447294.
666. Paik WH, Park YS, Hwang JH, et al. Palliative treatment with selfexpandable metallic stents in patients with advanced type III or IV hilar
cholangiocarcinoma: a percutaneous versus endoscopic approach.
Gastrointest Endosc 2009;69:55-62. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/18657806.
667. Robles R, Figueras J, Turrion VS, et al. Spanish experience in livertransplantation for hilar and peripheral cholangiocarcinoma. Ann Surg
2004;239:265-271. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/14745336.
668. Becker NS, Rodriguez JA, Barshes NR, et al. Outcomes analysis for
280 patients with cholangiocarcinoma treated with liver transplantation
over an 18-year period. J Gastrointest Surg 2008;12:117-122. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/17963015.
669. Kaiser GM, Sotiropoulos GC, Jauch KW, et al. Liver transplantation
for hilar cholangiocarcinoma: a German survey. Transplant Proc
2008;40:3191-3193. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/19010230.
670. Friman S, Foss A, Isoniemi H, et al. Liver transplantation for
cholangiocarcinoma: selection is essential for acceptable results. Scand J

Gastroenterol 2011;46:370-375. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/21073376.
671. Darwish Murad S, Kim WR, Harnois DM, et al. Efficacy ofneoadjuvant chemoradiation, followed by liver transplantation, for perihilar
cholangiocarcinoma at 12 US centers. Gastroenterology 2012;143:88-98.
Available at: http://www.ncbi.nlm.nih.gov/pubmed/22504095.
672. Panjala C, Nguyen JH, Al-Hajjaj AN, et al. Impact of neoadjuvant
chemoradiation on the tumor burden before liver transplantation forunresectable cholangiocarcinoma. Liver Transpl 2012;18:594-601.
Available at: http://www.ncbi.nlm.nih.gov/pubmed/22140024.
673. Duignan S, Maguire D, Ravichand CS, et al. Neoadjuvant
chemoradiotherapy followed by liver transplantation for unresectablecholangiocarcinoma: a single-centre national experience. HPB (Oxford)
2013. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23600750.
674. Rea DJ, Heimbach JK, Rosen CB, et al. Liver transplantation withneoadjuvant chemoradiation is more effective than resection for hilar
cholangiocarcinoma. Ann Surg 2005;242:451-458. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/16135931.
675. Hong JC, Jones CM, Duffy JP, et al. Comparative analysis ofresection and liver transplantation for intrahepatic and hilar
cholangiocarcinoma: a 24-year experience in a single center. Arch Surg
2011;146:683-689. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/21690444.
676. Ortner MEJ, Caca K, Berr F, et al. Successful photodynamic therapy
for nonresectable cholangiocarcinoma: a randomized prospective study.
Gastroenterology 2003;125:1355-1363. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/14598251.
677. Zoepf T, Jakobs R, Arnold JC, et al. Palliation of nonresectable bile
duct cancer: improved survival after photodynamic therapy. Am J
Gastroenterol 2005;100:2426-2430. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/16279895.

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-104

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
678. Cereda S, Belli C, Reni M. Adjuvant treatment in biliary tract cancer:
to treat or not to treat? World J Gastroenterol 2012;18:2591-2596.
Available at: http://www.ncbi.nlm.nih.gov/pubmed/22690066.
679. Mallick S, Benson R, Haresh KP, et al. Adjuvant radiotherapy in thetreatment of gall bladder carcinoma: What is the current evidence. J Egypt
Natl Canc Inst 2016;28:1-6. Available at:https://www.ncbi.nlm.nih.gov/pubmed/26265290.
680. Primrose JN, Fox RP, Palmer DH, et al. Capecitabine compared withobservation in resected biliary tract cancer (BILCAP): a randomised,
controlled, multicentre, phase 3 study. Lancet Oncol 2019;20:663-673.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/30922733.
681. Takada T, Amano H, Yasuda H, et al. Is postoperative adjuvant
chemotherapy useful for gallbladder carcinoma? A phase III multicenterprospective randomized controlled trial in patients with resectedpancreaticobiliary carcinoma. Cancer 2002;95:1685-1695. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/12365016.
682. Edeline J, Benabdelghani M, Bertaut A, et al. Gemcitabine andoxaliplatin chemotherapy or surveillance in resected biliary tract cancer(PRODIGE 12-ACCORD 18-UNICANCER GI): a randomized phase III
study. J Clin Oncol 2019;37:658-667. Available at:https://www.ncbi.nlm.nih.gov/pubmed/30707660.
683. Ebata T, Hirano S, Konishi M, et al. Randomized clinical trial of
adjuvant gemcitabine chemotherapy versus observation in resected bile
duct cancer. Br J Surg 2018;105:192-202. Available at:https://www.ncbi.nlm.nih.gov/pubmed/29405274.

intrahepatic bile ducts. Cancer 2018;124:74-83. Available at:https://www.ncbi.nlm.nih.gov/pubmed/28841223.
686. Horgan AM, Amir E, Walter T, Knox JJ. Adjuvant therapy in thetreatment of biliary tract cancer: a systematic review and meta-analysis.
Journal of Clinical Oncology 2012;30:1934-1940. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/22529261.
687. Rangarajan K, Simmons G, Manas D, et al. Systemic adjuvant
chemotherapy for cholangiocarcinoma surgery: A systematic review andmeta-analysis. Eur J Surg Oncol 2020;46:684-693. Available at:https://www.ncbi.nlm.nih.gov/pubmed/31761507.
688. Ma N, Cheng H, Qin B, et al. Adjuvant therapy in the treatment ofgallbladder cancer: a meta-analysis. BMC Cancer 2015;15:615. Available
at: https://www.ncbi.nlm.nih.gov/pubmed/26337466.
689. Gold DG, Miller RC, Haddock MG, et al. Adjuvant therapy for
gallbladder carcinoma: the Mayo Clinic Experience. Int J Radiat Oncol Biol
Phys 2009;75:150-155. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/19297105.
690. Cho SY, Kim SH, Park S-J, et al. Adjuvant chemoradiation therapy ingallbladder cancer. J Surg Oncol 2010;102:87-93. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/20578085.
691. Kim K, Chie EK, Jang JY, et al. Postoperative chemoradiotherapy for
gallbladder cancer. Strahlenther Onkol 2012;188:388-392. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/22402869.

684. Glazer ES, Liu P, Abdalla EK, et al. Neither neoadjuvant nor adjuvant
therapy increases survival after biliary tract cancer resection with wide
negative margins. J Gastrointest Surg 2012;16:1666-1671. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/22777053.

692. Kim Y, Amini N, Wilson A, et al. Impact of chemotherapy andexternal-beam radiation therapy on outcomes among patients withresected gallbladder cancer: a multi-institutional analysis. Ann Surg Oncol
2016;23:2998-3008. Available at:https://www.ncbi.nlm.nih.gov/pubmed/27169772.

685. Tran Cao HS, Zhang Q, Sada YH, et al. The role of surgery andadjuvant therapy in lymph node-positive cancers of the gallbladder and693. Hughes MA, Frassica DA, Yeo CJ, et al. Adjuvant concurrent
chemoradiation for adenocarcinoma of the distal common bile duct. Int J

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-105

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
Radiat Oncol Biol Phys 2007;68:178-182. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/17276614.

2005;28:234-241. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/15923794.

694. Nelson JW, Ghafoori AP, Willett CG, et al. Concurrent
chemoradiotherapy in resected extrahepatic cholangiocarcinoma. Int J
Radiat Oncol Biol Phys 2009;73:148-153. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/18805651.

701. Ben-Josef E, Guthrie KA, El-Khoueiry AB, et al. SWOG S0809: aphase II intergroup trial of adjuvant capecitabine and gemcitabine followedby radiotherapy and concurrent capecitabine in extrahepaticcholangiocarcinoma and gallbladder carcinoma. J Clin Oncol
2015;33:2617-2622. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/25964250.

695. Lim KH, Oh DY, Chie EK, et al. Adjuvant concurrent chemoradiation
therapy (CCRT) alone versus CCRT followed by adjuvant chemotherapy:
which is better in patients with radically resected extrahepatic biliary tract
cancer?: a non-randomized, single center study. BMC Cancer 2009;9:345.
Available at: http://www.ncbi.nlm.nih.gov/pubmed/19781103.
696. Kim TH, Han SS, Park SJ, et al. Role of adjuvant chemoradiotherapy
for resected extrahepatic biliary tract cancer. Int J Radiat Oncol Biol Phys
2011;81:e853-859. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/21497455.
697. Borghero Y, Crane CH, Szklaruk J, et al. Extrahepatic bile duct
adenocarcinoma: patients at high-risk for local recurrence treated withsurgery and adjuvant chemoradiation have an equivalent overall survival
to patients with standard-risk treated with surgery alone. Ann Surg Oncol
2008;15:3147-3156. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/18754070.
698. Park J-h, Choi EK, Ahn SD, et al. Postoperative chemoradiotherapy
for extrahepatic bile duct cancer. Int J Radiat Oncol Biol Phys
2011;79:696-704. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/20510541.
699. Das P, Wolff RA, Abbruzzese JL, et al. Concurrent capecitabine andupper abdominal radiation therapy is well tolerated. Radiat Oncol
2006;1:41-41. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/17062148.
700. Lin LL, Picus J, Drebin JA, et al. A phase II study of alternating cyclesof split course radiation therapy and gemcitabine chemotherapy forinoperable pancreatic or biliary tract carcinoma. Am J Clin Oncol

702. Wang SJ, Lemieux A, Kalpathy-Cramer J, et al. Nomogram forpredicting the benefit of adjuvant chemoradiotherapy for resected
gallbladder cancer. Journal of Clinical Oncology 2011;29:4627-4632.
Available at: http://www.ncbi.nlm.nih.gov/pubmed/22067404.
703. Jeong Y, Park JH, Lee YJ, et al. Postoperative radiotherapy for
gallbladder cancer. Anticancer Res 2014;34:5621-5629. Available at:https://www.ncbi.nlm.nih.gov/pubmed/25275065.
704. Park J, Kim MH, Kim KP, et al. Natural history and prognostic factorsof advanced cholangiocarcinoma without surgery, chemotherapy, orradiotherapy: a large-scale observational study. Gut Liver 2009;3:298-305.
Available at: http://www.ncbi.nlm.nih.gov/pubmed/20431764.
705. Glimelius B, Hoffman K, Sjoden PO, et al. Chemotherapy improves
survival and quality of life in advanced pancreatic and biliary cancer. Ann
Oncol 1996;7:593-600. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/8879373.
706. Sharma A, Dwary AD, Mohanti BK, et al. Best supportive carecompared with chemotherapy for unresectable gall bladder cancer: arandomized controlled study. Journal of Clinical Oncology 2010;28:45814586. Available at: http://www.ncbi.nlm.nih.gov/pubmed/20855823.
707. Hezel AF, Zhu AX. Systemic therapy for biliary tract cancers.
Oncologist 2008;13:415-423. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/18448556.

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-106

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
708. Geynisman DM, Catenacci DV. Toward personalized treatment ofadvanced biliary tract cancers. Discov Med 2012;14:41-57. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/22846202.
709. Eckel F, Schmid RM. Chemotherapy in advanced biliary tract
carcinoma: a pooled analysis of clinical trials. Br J Cancer 2007;96:896902. Available at: http://www.ncbi.nlm.nih.gov/pubmed/17325704.
710. Yonemoto N, Furuse J, Okusaka T, et al. A multi-center retrospective
analysis of survival benefits of chemotherapy for unresectable biliary tract
cancer. Jpn J Clin Oncol 2007;37:843-851. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/17942578.
711. Kornek GV, Schuell B, Laengle F, et al. Mitomycin C in combination
with capecitabine or biweekly high-dose gemcitabine in patients withadvanced biliary tract cancer: a randomised phase II trial. Ann Oncol
2004;15:478-483. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/14998852.
712. Ducreux M, Van Cutsem E, Van Laethem JL, et al. A randomised
phase II trial of weekly high-dose 5-fluorouracil with and without folinic acidand cisplatin in patients with advanced biliary tract carcinoma: results of
the 40955 EORTC trial. Eur J Cancer 2005;41:398-403. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/15691639.
713. Valle J, Wasan H, Palmer DH, et al. Cisplatin plus gemcitabine
versus gemcitabine for biliary tract cancer. N Engl J Med 2010;362:12731281. Available at: http://www.ncbi.nlm.nih.gov/pubmed/20375404.
714. Okusaka T, Nakachi K, Fukutomi A, et al. Gemcitabine alone or in
combination with cisplatin in patients with biliary tract cancer: acomparative multicentre study in Japan. Br J Cancer 2010;103:469-474.
Available at: http://www.ncbi.nlm.nih.gov/pubmed/20628385.
715. Grenader T, Nash S, Plotkin Y, et al. Derived neutrophil lymphocyte
ratio may predict benefit from cisplatin in the advanced biliary cancer: theABC-02 and BT-22 studies. Ann Oncol 2015;26:1910-1916. Available at:https://www.ncbi.nlm.nih.gov/pubmed/26037798.

716. 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. Available at:https://www.ncbi.nlm.nih.gov/pubmed/33798493.
717. Caparica R, Lengele A, Bekolo W, Hendlisz A. FOLFIRI as secondline treatment of metastatic biliary tract cancer patients. Autops Case Rep
2019;9:e2019087. Available at:https://www.ncbi.nlm.nih.gov/pubmed/31528622.
718. Doval DC, Sekhon JS, Gupta SK, et al. A phase II study of
gemcitabine and cisplatin in chemotherapy-naive, unresectable gall
bladder cancer. Br J Cancer 2004;90:1516-1520. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/15083178.
719. Thongprasert S, Napapan S, Charoentum C, Moonprakan S. Phase II
study of gemcitabine and cisplatin as first-line chemotherapy in inoperable
biliary tract carcinoma. Ann Oncol 2005;16:279-281. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/15668284.
720. Giuliani F, Gebbia V, Maiello E, et al. Gemcitabine and cisplatin for
inoperable and/or metastatic biliary tree carcinomas: a multicenter phase II
study of the Gruppo Oncologico dell'Italia Meridionale (GOIM). Ann Oncol
2006;17 Suppl 7:73-77. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/16760299.
721. Lee J, Kim T-Y, Lee MA, et al. Phase II trial of gemcitabine combinedwith cisplatin in patients with inoperable biliary tract carcinomas. Cancer
Chemother Pharmacol 2008;61:47-52. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/17364190.
722. Meyerhardt JA, Zhu AX, Stuart K, et al. Phase-II study of gemcitabineand cisplatin in patients with metastatic biliary and gallbladder cancer. Dig
Dis Sci 2008;53:564-570. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/17597402.
723. Andre T, Reyes-Vidal JM, Fartoux L, et al. Gemcitabine andoxaliplatin in advanced biliary tract carcinoma: a phase II study. Br J

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-107

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
Cancer 2008;99:862-867. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/19238628.

Cancer Research. J Clin Oncol 2008;26:3702-3708. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/18669455.

724. Harder J, Riecken B, Kummer O, et al. Outpatient chemotherapy withgemcitabine and oxaliplatin in patients with biliary tract cancer. Br J
Cancer 2006;95:848-852. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/16969352.

731. Iqbal S, Rankin C, Lenz H-J, et al. A phase II trial of gemcitabine andcapecitabine in patients with unresectable or metastatic gallbladder cancer
or cholangiocarcinoma: Southwest Oncology Group study S0202. Cancer
Chemother Pharmacol 2011;68:1595-1602. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/21556747.

725. Kim HJ, Lee NS, Lee S-C, et al. A phase II study of gemcitabine in
combination with oxaliplatin as first-line chemotherapy in patients withinoperable biliary tract cancer. Cancer Chemother Pharmacol
2009;64:371-377. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/19142638.
726. Jang J-S, Lim HY, Hwang IG, et al. Gemcitabine and oxaliplatin inpatients with unresectable biliary cancer including gall bladder cancer: a
Korean Cancer Study Group phase II trial. Cancer Chemother Pharmacol
2010;65:641-647. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/19652971.
727. Alberts SR, Al-Khatib H, Mahoney MR, et al. Gemcitabine, 5fluorouracil, and leucovorin in advanced biliary tract and gallbladdercarcinoma: a North Central Cancer Treatment Group phase II trial. Cancer
2005;103:111-118. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/15558814.
728. Knox JJ, Hedley D, Oza A, et al. Combining gemcitabine andcapecitabine in patients with advanced biliary cancer: a phase II trial. J
Clin Oncol 2005;23:2332-2338. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/15800324.
729. Riechelmann RP, Townsley CA, Chin SN, et al. Expanded phase II
trial of gemcitabine and capecitabine for advanced biliary cancer. Cancer
2007;110:1307-1312. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/17628484.
730. Koeberle D, Saletti P, Borner M, et al. Patient-reported outcomes ofpatients with advanced biliary tract cancers receiving gemcitabine plus
capecitabine: a multicenter, phase II trial of the Swiss Group for Clinical732. Sahai V, Catalano PJ, Zalupski MM, et al. Nab-paclitaxel andgemcitabine as first-line treatment of advanced or metastatic
cholangiocarcinoma: a phase 2 clinical trial. JAMA Oncol 2018;4:17071712. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30178032.
733. Shroff RT, Javle MM, Xiao L, et al. Gemcitabine, cisplatin, and nabpaclitaxel for the treatment of advanced biliary tract cancers: a phase 2
clinical trial. JAMA Oncol 2019;5:824-830. Available at:https://www.ncbi.nlm.nih.gov/pubmed/30998813.
734. Borbath I, Ceratti A, Verslype C, et al. Combination of gemcitabineand cetuximab in patients with advanced cholangiocarcinoma: a phase II
study of the Belgian Group of Digestive Oncology. Ann Oncol
2013;24:2824-2829. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/23975665.
735. Nehls O, Klump B, Arkenau HT, et al. Oxaliplatin, fluorouracil andleucovorin for advanced biliary system adenocarcinomas: a prospective
phase II trial. Br J Cancer 2002;87:702-704. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/12232749.
736. Nehls O, Oettle H, Hartmann JT, et al. Capecitabine plus oxaliplatin
as first-line treatment in patients with advanced biliary systemadenocarcinoma: a prospective multicentre phase II trial. Br J Cancer
2008;98:309-315. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/18182984.
737. Kim TW, Chang HM, Kang HJ, et al. Phase II study of capecitabine
plus cisplatin as first-line chemotherapy in advanced biliary cancer. Ann

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-108

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
Oncol 2003;14:1115-1120. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/12853355.

biomarker and serum programme. Eur J Cancer 2014;50:3125-3135.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/25446376.

738. Kobayashi K, Tsuji A, Morita S, et al. A phase II study of LFP therapy(5-FU (5-fluorourasil) continuous infusion (CVI) and Low-dose consecutive(Cisplatin) CDDP) in advanced biliary tract carcinoma. BMC Cancer
2006;6:121-121. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/16677397.

745. Lamarca A, Hubner RA, David Ryder W, Valle JW. Second-line
chemotherapy in advanced biliary cancer: a systematic review. Ann Oncol
2014;25:2328-2338. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/24769639.

739. Kim ST, Kang JH, Lee J, et al. Capecitabine plus oxaliplatin versus
gemcitabine plus oxaliplatin as first-line therapy for advanced biliary tract
cancers: a multicenter, open-label, randomized, phase III, noninferiority
trial. Ann Oncol 2019;30:788-795. Available at:https://www.ncbi.nlm.nih.gov/pubmed/30785198.
740. Rao S, Cunningham D, Hawkins RE, et al. Phase III study of 5FU,
etoposide and leucovorin (FELV) compared to epirubicin, cisplatin and
5FU (ECF) in previously untreated patients with advanced biliary cancer.
Br J Cancer 2005;92:1650-1654. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/15856037.

746. Ghafoori AP, Nelson JW, Willett CG, et al. Radiotherapy in thetreatment of patients with unresectable extrahepatic cholangiocarcinoma.
Int J Radiat Oncol Biol Phys 2010. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/20864265.
747. Macdonald OK, Crane CH. Palliative and postoperative radiotherapy
in biliary tract cancer. Surg Oncol Clin N Am 2002;11:941-954. Available
at: http://www.ncbi.nlm.nih.gov/pubmed/12607581.
748. Czito BG, Anscher MS, Willett CG. Radiation therapy in the treatmentof cholangiocarcinoma. Oncology (Williston Park) 2006;20:873-884.
Available at: http://www.ncbi.nlm.nih.gov/pubmed/16922259.

741. Yamashita Y-i, Taketomi A, Fukuzawa K, et al. Gemcitabine
combined with 5-fluorouracil and cisplatin (GFP) in patients with advanced
biliary tree cancers: a pilot study. Anticancer Res 2006;26:771-775.
Available at: http://www.ncbi.nlm.nih.gov/pubmed/16739352.

749. Frakulli R, Buwenge M, Macchia G, et al. Stereotactic body radiation
therapy in cholangiocarcinoma: a systematic review. Br J Radiol
2019;92:20180688. Available at:https://www.ncbi.nlm.nih.gov/pubmed/30673295.

742. Wagner AD, Buechner-Steudel P, Moehler M, et al. Gemcitabine,
oxaliplatin and 5-FU in advanced bile duct and gallbladder carcinoma: twoparallel, multicentre phase-II trials. Br J Cancer 2009;101:1846-1852.
Available at: http://www.ncbi.nlm.nih.gov/pubmed/19904267.

750. Moureau-Zabotto L, Turrini O, Resbeut M, et al. Impact ofradiotherapy in the management of locally advanced extrahepaticcholangiocarcinoma. BMC Cancer 2013;13:568. Available at:https://www.ncbi.nlm.nih.gov/pubmed/24299517.

743. Sohal DP, Mykulowycz K, Uehara T, et al. A phase II trial of
gemcitabine, irinotecan and panitumumab in advanced
cholangiocarcinoma. Ann Oncol 2013;24:3061-3065. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/24146220.

751. Uno T, Itami J, Aruga M, et al. Primary carcinoma of the gallbladder:role of external beam radiation therapy in patients with locally advanced
tumor. Strahlenther Onkol 1996;172:496-500. Available at:https://www.ncbi.nlm.nih.gov/pubmed/8830812.

744. Moehler M, Maderer A, Schimanski C, et al. Gemcitabine plus
sorafenib versus gemcitabine alone in advanced biliary tract cancer: adouble-blind placebo-controlled multicentre phase II AIO study with

752. Mondesir J, Willekens C, Touat M, de Botton S. IDH1 and IDH2
mutations as novel therapeutic targets: current perspectives. J Blood Med

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-109Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
2016;7:171-180. Available at:https://www.ncbi.nlm.nih.gov/pubmed/27621679.
753. Borger DR, Tanabe KK, Fan KC, et al. Frequent mutation of isocitrate
dehydrogenase (IDH)1 and IDH2 in cholangiocarcinoma identified throughbroad-based tumor genotyping. Oncologist 2012;17:72-79. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/22180306.
754. Wang P, Dong Q, Zhang C, et al. Mutations in isocitrate
dehydrogenase 1 and 2 occur frequently in intrahepaticcholangiocarcinomas and share hypermethylation targets withglioblastomas. Oncogene 2013;32:3091-3100. Available at:https://www.ncbi.nlm.nih.gov/pubmed/22824796.
755. Voss JS, Holtegaard LM, Kerr SE, et al. Molecular profiling ofcholangiocarcinoma shows potential for targeted therapy treatment
decisions. Hum Pathol 2013;44:1216-1222. Available at:https://www.ncbi.nlm.nih.gov/pubmed/23391413.
756. Kipp BR, Voss JS, Kerr SE, et al. Isocitrate dehydrogenase 1 and 2
mutations in cholangiocarcinoma. Hum Pathol 2012;43:1552-1558.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/22503487.
757. Churi CR, Shroff R, Wang Y, et al. Mutation profiling incholangiocarcinoma: prognostic and therapeutic implications. PLoS One
2014;9:e115383. Available at:https://www.ncbi.nlm.nih.gov/pubmed/25536104.
758. Ruzzenente A, Fassan M, Conci S, et al. Cholangiocarcinoma
heterogeneity revealed by multigene mutational profiling: clinical andprognostic relevance in surgically resected patients. Ann Surg Oncol
2016;23:1699-1707. Available at:https://www.ncbi.nlm.nih.gov/pubmed/26717940.
759. Zhu AX, Borger DR, Kim Y, et al. Genomic profiling of intrahepaticcholangiocarcinoma: refining prognosis and identifying therapeutic targets.
Ann Surg Oncol 2014;21:3827-3834. Available at:https://www.ncbi.nlm.nih.gov/pubmed/24889489.

760. Boscoe AN, Rolland C, Kelley RK. Frequency and prognostic
significance of isocitrate dehydrogenase 1 mutations incholangiocarcinoma: a systematic literature review. J Gastrointest Oncol
2019;10:751-765. Available at:https://www.ncbi.nlm.nih.gov/pubmed/31392056.
761. Abou-Alfa G, Macarulla T, Javle MM, et al. Ivosidenib in IDH1mutant, chemotherapy-refractory cholangiocarcinoma (ClarlDHy): a
multicentre, randomized, double-blind, placebo-controlled, phase 3 study.
Lancet Oncol 2020. Available at:https://www.ncbi.nlm.nih.gov/pubmed/32416072.
762. Ross JS, Wang K, Gay L, et al. New routes to targeted therapy of
intrahepatic cholangiocarcinomas revealed by next-generation
sequencing. Oncologist 2014;19:235-242. Available at:https://www.ncbi.nlm.nih.gov/pubmed/24563076.
763. Graham RP, Barr Fritcher EG, Pestova E, et al. Fibroblast growth
factor receptor 2 translocations in intrahepatic cholangiocarcinoma. Hum
Pathol 2014;45:1630-1638. Available at:https://www.ncbi.nlm.nih.gov/pubmed/24837095.
764. Arai Y, Totoki Y, Hosoda F, et al. Fibroblast growth factor receptor 2tyrosine kinase fusions define a unique molecular subtype ofcholangiocarcinoma. Hepatology 2014;59:1427-1434. Available at:https://www.ncbi.nlm.nih.gov/pubmed/24122810.
765. Abou-Alfa GK, Sahai V, Hollebecque A, et al. Pemigatinib forpreviously treated, locally advanced or metastatic cholangiocarcinoma: amulticentre, open-label, phase 2 study. Lancet Oncol 2020. Available at:https://www.ncbi.nlm.nih.gov/pubmed/32203698.
766. Javle MM, Roychowdhury S, Kelley RK, et al. Final results from aphase 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 [abstract]. J Clin Oncol
2021;39:Abstract 265. Available at:https://ascopubs.org/doi/abs/10.1200/JCO.2021.39.3_suppl.265.

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-110Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
767. Demols A, Rocq L, Charry M, et al. NTRK gene fusions in biliary tract
cancers. J Clin Oncol 2020;38:574-574. Available at:https://ascopubs.org/doi/abs/10.1200/JCO.2020.38.4_suppl.574.
768. Drilon A, Siena S, Ou SI, et al. Safety and antitumor activity of themultitargeted pan-TRK, ROS1, and ALK inhibitor entrectinib: Combined
results from two phase I trials (ALKA-372-001 and STARTRK-1). Cancer
Discov 2017;7:400-409. Available at:https://www.ncbi.nlm.nih.gov/pubmed/28183697.
769. Doebele RC, Drilon A, Paz-Ares L, et al. Entrectinib in patients withadvanced or metastatic NTRK fusion-positive solid tumours: integrated
analysis of three phase 1-2 trials. Lancet Oncol 2020;21:271-282.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/31838007.
770. Drilon A, Laetsch TW, Kummar S, et al. Efficacy of larotrectinib in
TRK fusion-positive cancers in adults and children. N Engl J Med
2018;378:731-739. Available at:https://www.ncbi.nlm.nih.gov/pubmed/29466156.
771. Goeppert B, Frauenschuh L, Renner M, et al. BRAF V600E-specificimmunohistochemistry reveals low mutation rates in biliary tract cancer
and restriction to intrahepatic cholangiocarcinoma. Mod Pathol
2014;27:1028-1034. Available at:https://www.ncbi.nlm.nih.gov/pubmed/24309328.
772. Wainberg ZA, Lassen UN, Elez E, et al. Efficacy and safety ofdabrafenib (D) and trametinib (T) in patients (pts) with BRAF V600E–
mutated biliary tract cancer (BTC): A cohort of the ROAR basket trial. J
Clin Oncol 2019;37:187-187. Available at:https://ascopubs.org/doi/abs/10.1200/JCO.2019.37.4_suppl.187.
773. Subbiah V, Lassen U, Elez E, et al. Dabrafenib plus trametinib inpatients with BRAF(V600E)-mutated biliary tract cancer (ROAR): a phase2, open-label, single-arm, multicentre basket trial. Lancet Oncol
2020;21:1234-1243. Available at:https://www.ncbi.nlm.nih.gov/pubmed/32818466.

774. Salama AKS, Li S, Macrae ER, et al. Dabrafenib and trametinib inpatients with tumors with BRAF(V600E) mutations: Results of the NCIMATCH trial Subprotocol H. J Clin Oncol 2020;38:3895-3904. Available at:https://www.ncbi.nlm.nih.gov/pubmed/32758030.
775. Kim HJ, Yoo TW, Park DI, et al. Gene amplification and protein
overexpression of HER-2/neu in human extrahepatic cholangiocarcinoma
as detected by chromogenic in situ hybridization andimmunohistochemistry: its prognostic implication in node-positive patients.
Ann Oncol 2007;18:892-897. Available at:https://www.ncbi.nlm.nih.gov/pubmed/17322545.
776. Marabelle A, Fakih M, Lopez J, et al. Association of tumour
mutational burden with outcomes in patients with advanced solid tumours
treated with pembrolizumab: prospective biomarker analysis of themulticohort, open-label, phase 2 KEYNOTE-158 study. Lancet Oncol
2020;21:1353-1365. Available at:https://www.ncbi.nlm.nih.gov/pubmed/32919526.
777. Sicklick JK, Kato S, Okamura R, et al. Molecular profiling of cancer
patients enables personalized combination therapy: the I-PREDICT study.
Nat Med 2019;25:744-750. Available at:https://www.ncbi.nlm.nih.gov/pubmed/31011206.
778. Kim RD, Chung V, Alese OB, et al. A phase 2 multi-institutional studyof nivolumab for patients with advanced refractory biliary tract cancer.
JAMA Oncol 2020;6:888-894. Available at:https://www.ncbi.nlm.nih.gov/pubmed/32352498.
779. Lwin Z, Gomez-Roca C, Saada-Bouzid E, et al. LEAP-005: Phase II
study of lenvatinib (len) plus pembrolizumab (pembro) in patients (pts) withpreviously treated advanced solid tumours [abstract]. Ann Oncol
2020;31:Abstract LBA41. Available at:https://oncologypro.esmo.org/meeting-resources/esmo-virtual-congress2020/leap-005-phase-ii-study-of-lenvatinib-len-plus-pembrolizumabpembro-in-patients-pts-with-previously-treated-advanced-solid-tumours.

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-111

Printed by Lloyd Christmas on 7/4/2022 4:02:45 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2022
Hepatobiliary Cancers
780. Javle M, Churi C, Kang HC, et al. HER2/neu-directed therapy forbiliary tract cancer. J Hematol Oncol 2015;8:58. Available at:https://www.ncbi.nlm.nih.gov/pubmed/26022204.
781. Subbiah V, Hu MI-N, 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. Available at:https://ascopubs.org/doi/abs/10.1200/JCO.2021.39.3_suppl.467.
782. Kato S, Subbiah V, Marchlik E, et al. RET Aberrations in Diverse
Cancers: Next-Generation Sequencing of 4,871 Patients. Clin Cancer Res
2017;23:1988-1997. Available at:https://www.ncbi.nlm.nih.gov/pubmed/27683183.
783. Sun W, Patel A, Normolle D, et al. A phase 2 trial of regorafenib as asingle agent in patients with chemotherapy-refractory, advanced, andmetastatic biliary tract adenocarcinoma. Cancer 2019;125:902-909.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/30561756.
784. Kim RD, Sanoff HK, Poklepovic AS, et al. A multi-institutional phase 2
trial of regorafenib in refractory advanced biliary tract cancer. Cancer
2020;126:3464-3470. Available at:https://www.ncbi.nlm.nih.gov/pubmed/32453456.
785. Demols A, Borbath I, Van den Eynde M, et al. Regorafenib after
failure of gemcitabine and platinum-based chemotherapy for locallyadvanced/metastatic biliary tumors: REACHIN, a randomized, doubleblind, phase II trial. Ann Oncol 2020;31:1169-1177. Available at:https://www.ncbi.nlm.nih.gov/pubmed/32464280.

Version 1.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MS-112