Nccn guidelines hepatobiliary 2.2021

Version 5.2021, 9/21/2021 © 2021 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.
NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®
)
Hepatobiliary Cancers
Version 5.2021 — September 21, 2021
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available at www.nccn.org/patients

NCCN Guidelines Version 5.2021
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NCCN Guidelines Index
Table of Contents
Discussion
NCCN Guidelines Panel Disclosures
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¤ Gastroenterology
‡ Hematology/Hematology
oncology
Þ Internal medicine
ф Interventional radiology
† Medical oncology
¥ Patient advocacy
≠ Pathology
§ Radiotherapy/Radiation
oncology
¶ Surgery/Surgical oncology
ξ Transplantation
* Discussion section writing
committee
*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 † ф
Vanderbilt-Ingram Cancer Center
Adam Burgoyne MD †
US San Diego Moores Cancer Center
Prabhleen Chahal, MD ¤
Case Comprehensive Cancer Center/
University Hospitals Seidman Cancer Center
and Cleveland Clinic Taussig Cancer Institute
Daniel T. Chang, MD §
Stanford Cancer Institute
Jordan Cloyd, MD ¶
The Ohio State University Comprehensive
Cancer Center - James Cancer Hospital
and Solove Research Institute
Jordan Cloyd, MD ¶
The Ohio State University Comprehensive
Cancer Center - James Cancer Hospital
and Solove Research Institute
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 †
Massachusetts General Hospital
Cancer Center
William G. Hawkins, MD ¶
Siteman Cancer Center at Barnes-
Jewish Hospital and Washington
University School of Medicine
Erika Hissong, MD ≠
University of Michigan Rogel Cancer Center
Renuka Iyer, MD Þ †
Roswell Park Cancer Institute
Rojymon Jacob, MD §
O'Neal Comprehensive
Cancer Center at UAB
R. Kate Kelley, MD † ‡
UCSF Helen Diller Family
Comprehensive Cancer Center
Robin Kim, MD ξ ¶
Huntsman Cancer Institute
at the University of Utah
Matthew Levine, MD, PhD ξ
Abramson Cancer Center
at the University of Pennsylvania
Manisha Palta, MD §
Duke Cancer Institute
James 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
Adam Yopp, MD ¶
UT Southwestern Simmons
NCCN
Susan Darlow, PhD
Cindy Hochstetler, PhD
Liz Hollinger, BSN, RN
Nicole McMillian, MS
Printed by LUIS NUNEZ on 2/11/2022 10:33:26 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.

(NCCN®
Table of Contents
Discussion
Clinical Trials: NCCN believes that the
best management for any patient with
cancer is in a clinical trial.
Participation in clinical trials is especially
encouraged.
To find clinical trials online at NCCN
Member Institutions, click here:
nccn.org/clinical_trials/member_
institutions.aspx.
NCCN Categories of Evidence and
Consensus: All recommendations are
category 2A unless otherwise indicated.
See NCCN Categories of Evidence
and Consensus.
NCCN Categories of Preference:
All recommendations are considered
appropriate. See NCCN Categories of
Preference.
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 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)
The NCCN Guidelines®
are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to treatment.
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. ©2021.
Biliary Tract Cancers
• Principles of Imaging (BIL-A)
• Principles of Radiation Therapy (BIL-B)
• Principles of Systemic Therapy (BIL-C)
• Staging (ST-1)
Biliary Tract Cancers: Extrahepatic
Cholangiocardinoma
• Presentation, Workup, Primary
Treatment (EXTRA-1)
• Adjuvant Treatment, Surveillance
(EXTRA-2)
• Principles of Surgery (EXTRA-A)

(NCCN®
Table of Contents
Discussion
UPDATES
Continued
Updates in Version 2.2021 of the NCCN Guidelines for Hepatobiliary Cancers from Version 1.2021 include:
BIL-C 2 of 3
• Subsequent-Line Therapy for Biliary Tract Cancers if Disease Progression
Useful in Certain Circumstances: Added Infigratinib for
cholangiocarcinoma with FGFR2 fusions or rearrangements.
BIL-C 3 of 3
Reference updated for Infigratinib: 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.
MS-1
• The discussion section has been updated to reflect the changes in the
algorithm.
HCC-4
• Surgical Assessment: UNOS criteria:
Sub-bullet 1 revised: AFP level ≤1000 ng/mL and patient has a tumor
2-5 cm in diameter or 2-3 tumors ≤3 cm each 1-3 cm in diameter.
HCC-D
5th bullet revised: ...(UNOS) criteria ([AFP level ≤1000 ng/mL and single
lesion...]
MS-1
algorithm.
HCC-G (1 of 2)
• Subsequent-Line Therapy for Hepatocellular Carcinoma if Disease
Progression
Nivolumab (Child-Pugh Class B only) changed from category 2A to
category 2B and moved from Other Recommended Regimens to Useful
in Certain Circumstances.
Other Recommended Regimens: Nivolumab was removed as a
treatment option for patients with Child-Pugh Class A.
• Footnote
Footnote k revised: Consider if MSI-H HCC. Pembrolizumab is a
recommended treatment option for patients with or without MSI-H HCC.
MS-1
The discussion section has been updated to reflect the changes in the
algorithm.
HCC-G (1 of 2)
• Subsequent-Line Therapy If Disease Progression
Dostarlimab-gxly was added as a treatment option for patients
with MSI-H/dMMR tumors. This is a category 2B, Useful in Certain
Circumstances recommendation.
Footnote l added: Dostarlimab-gxly is a recommended treatment option
for patients with MSI-H/dMMR recurrent or advanced tumors that have
progressed on or following prior treatment and who have no satisfactory
alternative treatment options. (Also on BIL-C, 2 of 4)
HCC-G (2 of 2)
• The following references were added:
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. (Also on BIL-C, 4 of 4)
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. (Also on
BIL-C, 4 of 4)
BIL-C (2 of 4)
• Subsequent-Line Therapy for Biliary Tract Cancers If Disease Progression
Dostarlimab-gxly was added as a treatment option for patients with
MSI-H/dMMR recurrent or advanced tumors. This is a category 2B, Useful
in Certain Circumstances recommendation.
Footnote g added: For patients who have not been previously treated
with a checkpoint inhibitor because there is a lack of data for subsequent
use of immunotherapy in patients who have previously been treated with
a checkpoint inhibitor.
MS-1
algorithm.

(NCCN®
Table of Contents
Discussion
UPDATES
Continued
General
• The Principles of Radiation Therapy (HCC-F) has been separated out
from the Principles of Locoregional Therapy (HCC-E).
HCC-1
• Screening
2nd column revised, Ultrasound + Alpha fetoprotein changed to
Ultrasound + Alpha fetoprotein.
Footnote d revised, …outcomes for patients with HCC in the
setting of NAFLD/HBV/HCV cirrhosis when the NAFLD/HBV/HCV is
successfully treated.
Footnote j removed, AFP is considered optional for screening, (See
Principles of Imaging, HCC-A HCC-3
• Workup: Multidisciplinary evaluation
9th bullet revised, Abdominal/pelvic CT or MRI with contrast, if not
previously done or needs updating.
New bullet 10 added, Consider referral to a hepatologist.
Last column: “Liver-confined disease, inoperable by performance
status, or comorbidity, local disease only or with minimal or unknown
extrahepatic disease. (Also on HCC-6)
according to institutional practice and based on the assessment of
bleeding risk.”
2nd bullet, sub-bullet 1 added, Tumor mutational burden (TMB)
testing. (Also INTRA-1, EXTRA-1)
Footnote i revised, “The data reflect use on or after sorafenib in
patients who previously tolerated sorafenib at a dose of at least 400
mg per day.”
HCC-4
• Surgical Assessment
After UNOS criteria, 2nd bullet added: Extended criteria.
Surveillance
4th bullet revised, ...for carriers of hepatitis if not previously done.
• Footnote x revised, Extended criteria/downstaging protocols are
available at selected centers and through UNOS...
Footnote dd revised, Multiphasic abdominal/pelvic MRI or multi-phase
CT scans for liver assessment, are recommended. Consider CT chest
and CT/MRI pelvis (See Principles of Imaging, HCC-A) (Also on HCC-5).
HCC-5
• Treatment
After Not a transplant candidate the treatment options were
divided into two separate pathways:
After Not a transplant candidate the treatment options were divided
into two separate pathways:
◊ Upper pathway: Locoregional therapy preferred listed with
corresponding options.
◊ Lower pathway: Includes the options of clinical trial, systemic
therapy, and best supportive care. (Also HCC-6)
• Surveillance
4th bullet added, Consider early imaging per local protocol.
HCC-6
• Metastatic disease or Extensive liver tumor burden pathway:
Recommendation revised to Consider Biopsy to confirm metastatic
disease for histologic confirmation if not previously done.
HCC-A (1 of 3)
• Screening and surveillance
1st paragraph, last sentence changed, “Serum biomarkers such as
AFP may incrementally improve the performance of imaging-based
screening and surveillance, but their cost-effectiveness has not been
established; and their use as supplementary surveillance tests is
optional.
HCC-B
• Initial biopsy
3rd sub-bullet revised, Confirmation of metastatic disease could
change clinical decision-making including enrollment in clinical
trials.
Bullet removed, “Histologic grading or molecular characterization
is desired.
HCC-E (1 of 2)
• Arterially Directed Therapies
3rd bullet: New sub-bullet added, With RE, delivery of 205 Gy to the
tumor may be associated with increased overall survival.4th bullet:
New sub-bullet, added, Randomized controlled trials have shown
that Y-90 is not superior to sorafenib for treating advanced HCC. RE
may be appropriate in some patients with advanced HCC, specifically
patients with segmental or local portal vein, rather than main portal
vein thrombosis.
Bullet removed, The angiographic endpoint of embolization may be
chosed by the treating physician.

(NCCN®
Table of Contents
Discussion
UPDATES
Continued
Last bullet revised, ...benefit in two three randomized trials; other
randomized phase lll trials are ongoing to further investigate other
systemic therapies including immunotherapy in combination with
arterial therapies.
HCC-E (2 of 2)
• New references added,
Garin E, Tselikas L, Guiu B et al and the DOSISPHERE-01 Study
Group. Personalised versus standard dosimetry approach of
selective internal radiation 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. HCC-E (2 of 2)
Vilgrain V, Pereira H, Assenat E, et al. Efficacy and safety of selective
internal radiotherapy with yttrium-90 resin microspheres compared
with sorafenib in locally advanced and inoperable hepatocellular
carcinoma (SARAH): an open-label randomised controlled phase 3
trial. Lancet Oncol 2017;18:1624-36.
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;36:1913-21.
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.
Ricke J, Klümpen HJ, Amthauer H, et al. Impact of combined
selective internal radiation therapy and sorafenib on survival in
advanced hepatocellular carcinoma. J Hepatol 2019;71:1164-1174.
HCC-F (1 of 2)
• Treatment Modalities
1st paragraph heading modified, External Beam Radiation Therapy.
1st bullet, sub-bullet 6 revised, SBRT (1-5 fractions) typically 3–5
fractions is...
• Bullet 2, revised, Dosing for EBRT is generally 30–50 Gy in 3–5
fractions, depending on the ability to meet normal organ constraints
and underlying liver function. Other hypofractionated schedules 5
fractions may also be used if clinically indicated.
◊ New tertiary bullet 1 added, Initial volumes to 45 Gy in 1.8 Gy per
fraction.
◊ New tertiary bullet 2 added, Boost to 50 to 60 Gy in 1.8–2 Gy per
fraction.
Sub-bullet 2 revised, Dosing for SBRT.
◊ Tertiary bullet 1 revised, is generally 30-50 Gy (typically in 3-5
fractions)...
HCC-G (1 of 2)
• First-Line Therapy
Preferred Regimens: Sorafenib and lenvatinib have been moved
under, Other Recommended Regimens.
Under Useful in Certain Circumstances: The nivolumab
recommendation was revised to include (Child-Pugh Class A or B)
• Subsequent-Line Therapy If Disease Progression
The following were moved from the list of Options to under Other
Recommended Regimens.
◊ Nivolumab (Child-Pugh Class A or B);
◊ Nivolumab + ipilimumab (Child-Pugh Class A only);
◊ Pembrolizumab (Child-Pugh Class A only) (category 2B)
• Footnotes
Footnote c added, “Patients on atezolizumab + bevacizumab
should have adequate endoscopic evaluation and management
for esophageal varices within approximately 6 months prior to
treatment or according to institutional practice and based on the
assessment of bleeding risk.”
2nd bullet, sub-bullet 1 added, Tumor mutational burden (TMB)
testing. (Also INTRA-1, EXTRA-1)
Footnote i revised, “The data reflect use on or after sorafenib in
patients who previously tolerated sorafenib at a dose of at least
400 mg per day.” Footnote j revised, “For patients who have not
been previously treated with a checkpoint inhibitor because there
is a lack of data for subsequent use of immunotherapy in patients
who have previously been treated with a checkpoint inhibitor.
Footnote k added, “Consider if MSI-H HCC.”

(NCCN®
Table of Contents
Discussion
UPDATES
GALL-1
• Postoperative Workup
4th column: Unresectable, 2nd bullet revised, Consider Additional
molecular testing. (Also on GALL-2, GALL-3, GALL-4, INTRA-1,
EXTRA-1).
• Footnote
Footnote c revised, If there is evidence of For (high-risk)
locoregionally advanced disease, (big mass invading liver
and/or nodal disease, including cystic duct node positive),
consideration to consider neoadjuvant chemotherapy should
be given to largely to rule out rapid progression and avoid futile
surgery. There are limited clinical trial data to define standard
regimen or definitive benefit. See Principles of Systemic
Therapy (BIL-C). (Also on GALL-2, GALL-3, and GALL-4).
GALL-A (2 of 2)
• Mass on Imaging: Patients Presenting with Gallbladder Mass/
Disease Suspicious for Gallbladder Cancer:
1st bullet revised, “...carried out with multiphasic cross-sectional
imaging...
INTRA-1
• Primary Treatment
Resectable pathway, 2nd bullet revised: Resection and regional
lymphadenectomy.
◊ Sub-bullet removed, “Consider lymphadenectomy for accurate
staging.
• Footnote
Footnote e added, 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.
BIL-B
• Unresectable
1st sub-bullet revised, All tumors irrespective of the location may
be amenable to EBRT radiation therapy (3D-CRT, IMRT, or SBRT).
4th bullet revised, RT Dosing Dosing for SBRT for biliary tract
tumors.
◊ New sub-bullet, EBRT.

– Tertiary bullet 1 new, Initial volumes to 45 Gy in 1.8 Gy
fraction

– Tertiary bullet 2 new, Boost to 50 to 60 Gy in 1.8-2 Gy per
fraction
◊ New sub-bullet, SBRT.

– Tertiary bullet 1, revised, Dosing is generally 30-50 Gy
(typically in 3-5 fractions) depending ...

– Tertiary bullet 3 revised, For intrahepatic tumors, SBRT in 1-5
fractions (typically 3-5 fractions) ...
BIL-C (1 of 3)
• Heading revised, “Neoadjuvant Therapy (for gallbladder cancer
only).
• Neoadjuvant Therapy; Other Recommended Regimens:
Removed the following regimens:
◊ 5-fluorouracil + cisplatin (category 2B)
◊ Capecitabine + cisplatin (category 2B)
• Adjuvant Therapy; Other Recommended Regimens
Removed: 5-fluorouracil + cisplatin (category 3)
Single agents: Gemcitabine (gallbladder and intrahepatic
cholanciocarcinoma only)
BIL-C (2 of 3)
• Primary Treatment for Unresectable and Metastatic Disease
Other Recommended Regimens
◊ 5-fluorouracil + cisplatin changed from category 2A to category
2B recommendation
◊ Capecitabine + cisplatin changed from category 2A to category
2B recommendation
◊ Gemcitabine + albumin-bound paclitaxel (cholangiocarcinoma
only)
• Subsequent-line Therapy for Biliary Tract Cancers if Disease
Progression
Useful in Certain Circumstances
◊ 2nd bullet revised, For MSI-H/dMMR tumors/TMB-H tumors.
◊ 5th bullet added, “For BRAF-V600E mutated tumors: Dabrafenib
+ trametinib.
◊ 6th bullet added, “Nivolumab (category 2B)
◊ 7th bullet added, “Lenvatinib + pembrolizumab (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.
HEPATOCELLULAR CARCINOMA (HCC) SCREENINGa
HCC-1
Ultrasound (US)i
+
Alpha fetoprotein (AFP)a US nodule(s) 10 mm
US negativek Repeat US + AFP in 6 mo
AFP positivej
or
US nodule(s) ≥10 mm
a 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 White DL, Clin Gastroenterol Hepatol 2012;10:1342-1359.
f Beuers U, et al. Am J Gastroenterol 2015;110:1536-1538.
g Schiff ER, Sorrell MF, and Maddrey WC. Schiff's Diseases of the Liver. Philadelphia: Lippincott Williams Wilkins (LWW); 2007.
h 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.
i 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).
j Positive or rising AFP should prompt CT or MRI regardness of US results.
k US negative means no observation or only definitely benign observation(s).
Patients at risk for HCC:b
• Cirrhosisc
Hepatitis B, Cd
Alcohol
Genetic hemochromatosis
Non-alcoholic fatty liver disease (NAFLD)d,e
Stage 4 primary biliary cholangitisf
Alpha-1-antitrypsin deficiency
Other causes of cirrhosisg
• Without cirrhosis
Hepatitis Bc,h
Additional
workup
(See HCC-2)
Repeat US + AFP in 3–6 mo
(NCCN®
Hepatocellular Carcinoma
Table of Contents
Discussion

HCC-2
DIAGNOSIS OF HCCb
FINDINGS
IMAGINGa ADDITIONAL WORKUP
• Positive imaging result
• Suspicious abnormality
detected on imaging exam
done for other reasons
• Positive AFP
Abdominal
multiphasic CT
or
MRI
Observation(s)l
detected
No observationl
detected
Return to screening in
6 mo (See HCC-1)
Definitely HCCm
Not definitely HCC,
not definitely benign
Definitely benign
HCC confirmed
(See HCC-3)
Individualized workup,
which may include
additional imaginga or
biopsy,n,o as informed by
multidisciplinary discussion
Return to screeningp in
6 mo (See HCC-1)
(NCCN®
Table of Contents
Discussion
b Adapted with permission from 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.
l An observation is an area identified at imaging that is distinctive from background liver. It may be a mass or a pseudo lesion.
m 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).
n 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.
o See Principles of Biopsy (HCC-B).
p If no observations are detected at diagnostic imaging despite positive surveillance tests, then return to surveillance in 6 months if the most reasonable explanation is
that surveillance tests were false positive. Consider imaging with an alternative method +/- AFP if there is reasonable suspicion that the diagnostic imaging test was
false negative.

(NCCN®
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Discussion
HCC-3
CLINICAL PRESENTATION WORKUP
HCC confirmed
Multidisciplinary evaluationq
(assess liver reserver and comorbidity) and staging:
• HP
• Hepatitis panels
• 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 not
previously done or needs updatinga
• Consider referral to a hepatologist
Potentially resectable or transplantable,
operable by performance status or
comorbidity (See HCC-4)
Unresectable (See HCC-5)
Metastatic disease (See HCC-6)
qSee NCCN Guidelines for Older Adult Oncology.
r See Child-Pugh Score (HCC-C) and assessment of portal hypertension (eg, varices, splenomegaly, thrombocytopenia).
sAn 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 and
should prompt testing for a quantitative HBV DNA.
• Hepatitis C antibody. If positive, check quantitative HCV RNA and HCV genotype and refer to hepatologist.
Liver-confined disease, inoperable by
performance status, comorbidity, or with
minimal or uncertain extrahepatic disease
(See HCC-6)

(NCCN®
Table of Contents
Discussion
• UNOS criteriav,x
AFP level ≤1000 ng/mL
and patient has a tumor
2-5 cm in diameter or
2-3 tumors 1-3 cm in
diameter
No macrovascular
involvement
No extrahepatic disease
• Extended criteriax
HCC-4
CLINICAL PRESENTATION SURGICAL ASSESSMENTt,u,v TREATMENT SURVEILLANCE
Potentially resectable
or transplantable,
operable by
performance status
or comorbidity
• Child-Pugh Class A, Bw
No portal hypertension
• Suitable tumor location
• Adequate liver reserve
• Suitable liver remnant
If ineligible
for transplant
• Refer to liver
transplant
centeru,y
• Consider bridge
therapy as
indicatedz
Resection, if
feasible (preferred)v
or
Locoregional
therapyaa
• Ablationbb
• Arterially directed
therapies
• External beam
radiation therapy
(EBRT)cc
• Imagingdd every 3–6 mo
for 2 y, then every 6–12 mo
• AFP, every 3–6 mo for 2 y,
then every 6–12 mo
• See relevant pathway
(HCC-2 through HCC-6) if
disease recurs
• Refer to a hepatologist for
a discussion of antiviral
therapy for carriers of
hepatitis if not previously
done
For relapse, see Initial
Workup (HCC-3)
Transplant
t Discussion of surgical treatment with patient and determination of whether patient is amenable to surgery.
u 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 is
controversy over which initial strategy is preferable to treat such patients. These patients should be evaluated by a multidisciplinary team.
v See Principles of Surgery (HCC-D).
w In highly selected Child-Pugh Class B patients with limited resection.
x Extended criteria/downstaging protocols are available through UNOS. See https://optn.transplant.hrsa.gov/media/1200/optn_policies.pdf#nameddest=Policy_09.
y Mazzaferro V, et al. N Engl J Med 1996;334:693-700.
z Many transplant centers consider bridge therapy for transplant candidates (See Discussion).
aa See Principles of Locoregional Therapy (HCC-E).
bb In well-selected patients with small, properly located tumors ablation should be considered as definitive treatment in the context of a multidisciplinary review.
cc See Principles of Radiation Therapy (HCC-F).
dd Multiphasic abdominal MRI or multiphase CT scans for liver assessment, CT chest and CT/MRI pelvis. See Principles of Imaging (HCC-A).

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r See Child-Pugh Score (HCC-C) and assessment of portal hypertension (eg, varices, splenomegaly, thrombocytopenia).
v See Principles of Surgery (HCC-D).
y Mazzaferro V, et al. N Engl J Med 1996;334:693-700.
z Many transplant centers consider bridge therapy for transplant candidates (See Discussion).
dd Multiphasic abdominal MRI or multiphase CT scans for liver assessment, CT chest and CT/MRI pelvis. See Principles of Imaging (HCC-A).
ee Order does not indicate preference. The choice of treatment modality may depend on extent/location of disease, hepatic reserve, and institutional capabilities.
ff Use of chemoembolization has also been supported by randomized controlled trials in selected populations over best supportive care.
gg See Principles of Systemic Therapy (HCC-G).
HCC-5
CLINICAL
PRESENTATION
TREATMENT SURVEILLANCE
Options:ee
• Locoregional
therapy preferredaa,ff
Ablation
Arterially directed
therapies
EBRTcc
Evaluate whether
patient is a candidate
for transplant [See
UNOS criteria under
Surgical Assessment
(HCC-4)]v,y
Transplant
candidate
Not a transplant
candidate
• Refer to liver
transplant center
• Consider bridge
therapy as
indicatedz
• Imagingdd
every 3–6 mo for 2 y,
• AFP
every 3–6 mo for 2 y,
• See relevant pathway
(HCC-2 through HCC-6) if
disease recurs
• Consider early imaging
per local protocol
Unresectable
• Inadequate
hepatic
reserver
• Tumor
location
Transplant
Progression
on or after
systemic
therapygg
Options:ee
• Clinical trial
• Systemic therapygg
• Best supportive care

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HCC-6
CLINICAL PRESENTATION TREATMENT
Liver-confined disease, inoperable by performance
status, comorbidity or with minimal or uncertain
extrahepatic disease
Metastatic disease
or
Extensive liver
tumor burden
Biopsyo for
histologic
confirmation if not
previously done
Options:ee
• Clinical trial
Options:ee
• Locoregional therapy preferredaa
Ablation
Arterially directed therapies
EBRTcc
• Clinical trial
o See Principles of Biopsy (HCC-B).
ee Order does not indicate preference. The choice of treatment modality may depend on extent/location of disease, hepatic reserve, and institutional capabilities.
gg See Principles of Systemic Therapy (HCC-G).
Progression on or
after systemic therapygg
Progression on or
after systemic therapygg

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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 such as AFP
may incrementally improve the performance of imaging-based screening and surveillance.
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.5 To standardize interpretation, the
AASLD,1 EASL,2 OPTN,6 and LI-RADS5,7 have adopted imaging criteria to diagnose HCC nodules ≥10 mm. Criteria have not been proposed
for nodules smaller than 10 mm as these are difficult to definitively characterize at imaging. Major imaging features of HCC include arterial
phase hyperenhancement, nonperipheral venous or delayed phase washout appearance, enhancing capsule appearance, and threshold
growth.5,7 LI-RADS also provides imaging criteria to diagnose major vascular invasion.5 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 have
close 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 these
criteria 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.5
• 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
scan8 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.
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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 and
cHCC-CCAs tend to have malignant imaging features, the features are not sufficiently specific to permit noninvasive diagnosis.7,9 Biopsy 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 of
factors 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 of
indeterminate nodules. It is not suitable for whole-liver assessment, surveillance, or cancer staging.10
Role of PET
PET/CT has limited sensitivity but high specificity, and may be considered when there is an equivocal finding.11 When an HCC is detected
by 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.12
HCC-A
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References

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HCC-A
3 OF 3
REFERENCES
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: a
systematic review. Am J Gastroenterol 2006;101:513-23.
4
Korean Liver Cancer Association; National Cancer Center. 2018 Korean Liver Cancer Association-National Cancer Center Korea Practice Guidelines for the
Management of Hepatocellular Carcinoma. Gut Liver 2019;13(3):227-299.
5
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.
6 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;16:262-78.
7
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.
8
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.
9
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.
10
Claudon M, Dietrich CF, Choi BI, et al. Guidelines and good clinical practice recommendations for Contrast Enhanced Ultrasound (CEUS) in the liver - update 2012: A
WFUMB-EFSUMB initiative in cooperation with representatives of AFSUMB, AIUM, ASUM, FLAUS and ICUS. Ultrasound Med Biol 2013;39:187-210.
11
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.
12
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.

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HCC-B
PRINCIPLES OF BIOPSY
Indicators for consideration of biopsy, which may include:
• Initial 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, congential 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 intrahepatic cholangiocarcinoma or cHCC-CCA.
Confirmation of metastatic disease could change clinical decision-making including enrollment in clinical trials.
Surgical resection without biopsy should be considered with multidisciplinary review.
• Repeat biopsy
Non-diagnostic biopsy
Prior 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.

HCC-C
CHILD-PUGH SCORE
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 of
Surgery Society Ltd. Adapted with permission. Permission is granted by John Wiley Sons Ltd on behalf of the BJSS Ltd.
Class A = 5–6 points; Class B = 7–9 points; Class C = 10–15 points.
Chemical and Biochemical Parameters
Scores (Points) for Increasing Abnormality
1 2 3
Encephalopathy (grade)1 None 1–2 3–4
Ascites Absent Slight Moderate
Albumin (g/dL) 3.5 2.8–3.5 2.8
Prothrombin time2
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
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Discussion
HCC-D
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 with
mild 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 and
biliary 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
• 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 liver
transplants.3,5
MELD score can be determined using the MELD calculator: https://optn.transplant.hrsa.gov/resources/allocation-calculators/meld-
calculator/. 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 a
standardized 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 is
controversy 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) [Epub
ahead of print].
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 2001l33:464-570.
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.

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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 patients
for 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 ≤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 arterially directed 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 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 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 2 mg/dL.13
With RE, delivery of ≥205 Gy 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 with
advanced HCC,19,20 specifically patients with segmental or lobar portal vein, rather than main portal vein thrombosis.22
• Sorafenib may be appropriate following arterially directed therapies in patients with adequate liver function once bilirubin returns to baseline if there
is evidence of residual/recurrent tumor not amenable to additional local therapies. The safety and efficacy of the use of sorafenib concomitantly with
arterially directed therapies has not been associated with significant benefit in three randomized trials; other randomized phase lll trials are ongoing to
investigate other systemic therapies including immunotherapy in combination with arterial therapies.15-17,22
HCC-E
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References

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HCC-E
2 OF 2
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 ablation
and 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 treated
with 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 comparison
of 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 bland
arterial 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, double-
blind, 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 compared
with 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 for
hepatocellular carcinoma using Yttrium-90 microspheres: a comprehensive report
of long-term outcomes. Gastroenterology 2010;138:52-64.
14 Ramsey DE, Kernagis LY, Soulen MC, Geschwind J-FH. Chemoembolization of
hepatocellular 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 with
doxorubicin-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 combined
with concurrent transarterial chemoembolization with drug-eluting beads for
hepatocellular 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 internal
radiation 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 locally
advanced and inoperable hepatocellular carcinoma (SARAH): an open-label
randomised controlled phase 3 trial. Lancet Oncol 2017;18:1624-36.
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;36:1913-21.
21 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.
22 Ricke J, Klümpen HJ, Amthauer H, et al. Impact of combined selective internal
radiation therapy and sorafenib on survival in advanced hepatocellular carcinoma.
J Hepatol 2019;71:1164-1174.
PRINCIPLES OF LOCOREGIONAL THERAPY
REFERENCES

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Discussion
External Beam Radiation Therapy:
• Treatment Modalities:
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 improve
treatment accuracy and reduce treatment-related toxicity.
Hypofractionation with photons1 or protons2,3 is an acceptable option for intrahepatic tumors, though treatment at centers with experience
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 an
alternative 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 from
patients with Child-Pugh A liver disease; safety data are limited for patients with Child-Pugh B or poorer liver functon. Those with Child-
Pugh B cirrhosis can be safely treated, but they may require dose modifications and strict dose constraint adherence.6 The safety of liver
radiation for HCC in patients with Child-Pugh C cirrhosis has not been established, as there are not likely to be clinical trials available for
Child-Pugh C 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.
• RT Dosing:
EBRT:
◊ Initial volumes to 45 Gy in 1.8 Gy per fraction
◊ Boost to 50 to 60 Gy in 1.8–2 Gy per fraction
SBRT:
◊ 30–50 Gy (typically in 3–5 fractions), depending on the ability to meet normal organ constraints and underlying liver function.
◊ Other hypofractionated schedules 5 fractions may also be used if clinically indicated
HCC-F
1 OF 2
PRINCIPLES OF RADIATION THERAPY
See next page for
References

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Discussion
HCC-F
2 OF 2
1 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.
2 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.
3 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.
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.
REFERENCES

(NCCN®
Table of Contents
Discussion
PRINCIPLES OF SYSTEMIC THERAPY
HCC-G
1 OF 2
a An FDA-approved biosimilar is an appropriate substitute for bevacizumab.
b See NCCN Guidelines for Management of Immunotherapy-Related Toxicities.
c Patients on atezolizumab + bevacizumab should have adequate endoscopic evaluation
and management for esophageal varices within approximately 6 months prior to treatment
or according to institutional practice and based on the assessment of bleeding risk.
d See Child-Pugh Score (HCC-C) and assessment of portal hypertension (eg, varices,
splenomegaly, thrombocytopenia).
e Caution: There are limited safety data available for Child-Pugh Class B or C patients and
dosing is uncertain. Use with extreme caution in patients with elevated bilirubin levels.
(Miller AA, et al. J Clin Oncol 2009;27:1800-1805). The impact of sorafenib on patients
potentially eligible for transplant is unknown.
f 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).
g 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.)
h There are no data to define optimal treatment for those who progress after first-line
systemic therapy, other than sorafenib or nivolumab.
i The data reflect use on or after sorafenib in patients who previously tolerated sorafenib at a
dose of at least 400 mg per day.
j For patients who have not been previously treated with a checkpoint inhibitor because
there is a lack of data for subsequent use of immunotherapy in patients who have
previously been treated with a checkpoint inhibitor.
k Pembrolizumab is a recommended treatment option for patients with or without MSI-H
HCC.
l Dostarlimab-gxly is a recommended treatment option for patients with MSI-H/dMMR
recurrent or advanced tumors that have progressed on or following prior treatment and
who have no satisfactory alternative treatment options.
First-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
• Sorafenib
(Child-Pugh Class A)
[category 1] or B7)d,e,2,3
• Lenvatinib
(Child-Pugh Class A only)4,5
(category 1)
• Nivolumabb,6
(if ineligible for tyrosine kinase inhibitors
[TKIs] or other anti-angiogenic agents)
(Child-Pugh Class A or B) (category 2B)
• FOLFOX (category 2B)f
Subsequent-Line Therapyg if Disease Progressionh Other Recommended Regimens Useful in Certain Circumstances
Options
• Regorafenib (Child-Pugh Class A only) (category 1)i,7
• Cabozantinib (Child-Pugh Class A only) (category 1)i,8
• Ramucirumab (AFP ≥400 ng/mL only) (category 1)i,9
• Lenvatinib (Child-Pugh Class A only)
• Sorafenib (Child-Pugh Class A or B7)d,e
• Nivolumab + ipilimumab
(Child-Pugh Class A only)b,i,13
• Pembrolizumab
(Child-Pugh Class A only)b,j,k,14
(category 2B)
• Nivolumab
(Child-Pugh Class B only)b,j,10-12
(category 2B)
• Dostarlimab-gxlyb,j,l,15,16
for MSI-H/dMMR tumors
(category 2B)

(NCCN®
Table of Contents
Discussion
REFERENCES
HCC-G
2 OF 2
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. 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.
6 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.
7 Bruix J, Qin S, Merle P, et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomized, double-blind,
placebo-controlled, phase 3 trial. Lancet 2017;389:56-66.
8 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.
9 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.
10 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 escalation and expansion trial. Lancet 2017;389:2492-2502.
11 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.
12 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.
13 Yau T, Kang Y-K, Kim T-Y, 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(11):e204564.
14 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-label phase 2 trial. Lancet Oncol 2018;19:940-952.
15 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.
16 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.

(NCCN®
Table of Contents
Discussion
GALL-1
PRESENTATION POSTOPERATIVE WORKUPa PRIMARY TREATMENT
Incidental
finding at
surgery
• Intraoperative
staging
• Frozen section
of resected
gallbladder +
suspicious
lymph node
Multiphasic
abdominal/pelvic
CT/MRI with IV
contrast, chest CT
± contrast
Cholecystectomyb,f + en bloc hepatic
resection + lymphadenectomy ± bile duct
excision for malignant involvement
Resectableb,c
Options:g
• Systemic therapyh (preferred)
• Clinical trial (preferred)
• Palliative RTi
See Adjuvant
Treatment
and
Surveillance
(GALL-5)
Incidental
finding on
pathologic
review
See GALL-2
a See Principles of Imaging (BIL-A).
b See Principles of Surgery and Pathology (GALL-A).
c For locoregionally advanced disease, consider neoadjuvant chemotherapy to rule out rapid progression and avoid futile surgery. There are limited clinical trial data to
define a standard regimen or definitive benefit. See Principles of Systemic Therapy (BIL-C).
d 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.
e Testing may include NTRK gene fusion testing
f Depends on expertise of surgeon and/or resectability. Consider referral to surgeon with hepatobiliary expertise and consider intraoperative photography. If resectability
is not clear, close incision.
g Order does not indicate preference. The choice of treatment modality may depend on extent/location of disease and institutional capabilities.
h See Principles of Systemic Therapy (BIL-C).
i See Principles of Radiation Therapy (BIL-B).
Other Clinical
Presentations
See GALL-3
and GALL-4
Unresectable
• Microsatellite
instability (MSI) and/
or mismatch repair
(MMR) testingd
• Additional molecular
testinge
Tumor mutational
burden (TMB)
testing
Progression
on or after
systemic
therapyh

(NCCN®
Table of Contents
Discussion
PRESENTATION POSTOPERATIVE
WORKUPj
PRIMARY TREATMENT
GALL-2
Incidental
finding on
pathologic
reviewj
T1a (with
negative
margins)
T1b or
greater
Multiphasic abdominal/pelvic
CT/MRI with IV contrast, chest
CT ± contrasta
• Consider staging
laparoscopyk
Resectableb,c
Unresectable
• MSI/MMR testingd
• Additional
molecular testinge
TMB testing
Observe
Hepatic resectionb
+ lymphadenectomy
± bile duct excision for
malignant involvement
Options:g
• Palliative RTi
See Adjuvant
Treatment and
Surveillance
(GALL-5)
d 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.
e Testing may include NTRK gene fusion testing.
j Consider multidisciplinary review.
k Butte JM, et al. HPB (Oxford) 2011;13:463-472.
Other Clinical
Presentations
See GALL-3
and GALL-4
Cystic
duct
node
positive
Multiphasic abdominal/pelvic
CT/MRI with IV contrast, chest
CT ± contrasta
laparoscopyk
• MSI/MMR testing
Consider neoadjuvant
chemotherapyc,h
or
Clinical trial
Progression on
or after systemic
therapyh

(NCCN®
Table of Contents
Discussion
PRESENTATION AND WORKUP
GALL-3
PRIMARY TREATMENT
Mass on
imaging
• HP
• Multiphasic
abdominal/pelvic
CT/MRI with IV contrasta
• Chest CT + contrasta
• Liver function tests
(LFTs)
• Surgical consultation
• Assessment of hepatic
reserve
• Consider CEAl
• Consider CA 19-9l
laparoscopy
Resectableb,c
Unresectable
Biopsy
• Additional
molecular testinge
TMB testing
Cholecystectomyb
+ en bloc hepatic resection
+ lymphadenectomy
± bile duct excision for
malignant involvement
See Adjuvant
Treatment and
Surveillance
(GALL-5)
Other Clinical Presentations
See GALL-1, GALL-2,
and GALL-4
l CEA and CA 19-9 are baseline tests and should not be done to confirm diagnosis.
Options:g
• Palliative RTi
Progression on
or after systemic
therapyh

(NCCN®
Table of Contents
Discussion
GALL-4
PRIMARY TREATMENT
Jaundice
• HP
• LFTs
• Chest CT ± contrasta
• Multiphasic abdominal/
pelvic CT/MRI with IV
contrasta
• Cholangiographym
• Surgical consultationn
• Consider CEAl
• Consider CA 19-9l
laparoscopy
• Biliary drainageo
Resectableb
Unresectable
Biopsy
• Additional
molecular testinge
TMB testing
Cholecystectomyb
+ en bloc hepatic
resection
+ lymphadenectomy
+ bile duct excision
See Adjuvant
Treatment and
Surveillance
(GALL-5)
Options:g
• Palliative RTi
Options:g
Metastatic disease
l CEA and CA 19-9 are baseline tests and should not be done to confirm diagnosis.
m Magnetic resonance cholangiopancreatography (MRCP) is preferred. Endoscopic retrograde cholangiopancreatography/percutaneous transhepatic cholangiography
(ERCP/PTC) are used more for therapeutic intervention.
n Consult with a multidisciplinary team.
o Consider biliary drainage for patients with jaundice prior to resection and systemic therapy. Consider baseline CA 19-9 after biliary decompression. Other Clinical
Presentations
See GALL-2
and GALL-3
• Consider neoadjuvant
chemotherapy (category 2B)c,h
• Clinical trial
Biopsy
• Additional
molecular testinge
TMB testing
Progression on
or after systemic
therapyh
Progression on
or after systemic
therapyh
PRESENTATION AND WORKUP

(NCCN®
Table of Contents
Discussion
GALL-5
TREATMENTq SURVEILLANCEt
• Consider imaging
every 3–6 mo for
2 y, then every
6–12 months for
up to 5 years,a
or as clinically
indicatedu
• Consider CEA
and CA 19-9
as clinically
indicated
For relapse, see
Workup of the
following initial
clinical
presentations:
• Mass on imaging
(See GALL-3)
• Jaundice
(See GALL-4)
• Metastases
(See GALL-4)
p Management of patients with R1 or R2 resections should be evaluated by a multidisciplinary team.
q 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, J Clin Oncol 2012;30:1934-1940).
r There are limited clinical trial data to define a standard regimen or definitive benefit. Clinical trial participation is encouraged. (Macdonald OK, Crane CH. Surg Oncol
Clin N Am 2002;11:941-954).
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.
Post
resection
status
Resected, negative margin
(R0),
Negative regional nodes
or
Carcinoma in situ at margin
Resected, positive margin (R1)p
or
Positive regional nodes
• Observe
• Fluoropyrimidine-based chemoradiationi,r
• Fluoropyrimidine- or gemcitabine-
based chemotherapys followed by
fluoropyrimidine-based chemoradiationi
followed by fluoropyrimidine- or
gemcitabine-based chemotherapys
Resected gross residual
disease (R2)p
See treatment for unresectable disease
(GALL-1)

(NCCN®
Table of Contents
Discussion
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 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.
• The principles of resection are the same as below consisting of radical cholecystectomy including segments IV B and V and
lymphadenectomy 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 with
any 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 been
shown 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
PRINCIPLES OF SURGERY AND PATHOLOGY
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.
GALL-A
1 OF 2

(NCCN®
Table of Contents
Discussion
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 with
available 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.
PRINCIPLES OF SURGERY AND PATHOLOGY
GALL-A
2 OF 2

(NCCN®
Table of Contents
Discussion
Options:i
• Systemic therapyj
• Clinical trial
• Consider locoregional therapym,n
EBRTl
Arterially directed therapiesn
INTRA-1
PRESENTATION WORKUP PRIMARY TREATMENT
Isolated intrahepatic
massa (imaging
characteristics
consistent with
malignancy but
not consistent
with hepatocellular
carcinoma)
(See NCCN
Guidelines for
Occult Primary
Cancers)
• HP
• 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
• Consider AFP
• Consider referral to a
hepatologist
Resectablea
Unresectable
• MSI/MMR
testingf
• Additional
molecular
testingg
TMB
testing
Metastatic
disease
• MSI/MMR
testingf
• Additional
molecular
testingg
TMB
testing
• Consider staging laparoscopyh
• Resectiona and regional
lymphadenectomya
See Additional
Therapy and
Surveillance
(INTRA-2)
Options:i
• Clinical trial
• EBRT with concurrent fluoropyrimidinek,l
Consider locoregional therapym,n
EBRTl
Arterially directed therapiesn
a See Principles of Surgery (INTRA-A).
b See Principles of Imaging (HCC-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 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 Laparoscopy may be done in conjunction with surgery if no distant metastases
are found.
i Order does not indicate preference. The choice of treatment modality may depend
on extent/location of disease and institutional capabilities.
j See Principles of Systemic Therapy (BIL-C).
k There are limited clinical trial data to define a standard regimen or definitive
benefit. Participation in clinical trials is encouraged (Macdonald OK, Crane CH.
Surg Oncol Clin N Am 2002;11:941-954).
l See Principles of Radiation Therapy (BIL-B).
m Intra-arterial chemotherapy (with or without systemic chemotherapy) may be
used in a clinical trial or at experienced centers.
n Principles of Locoregional Therapy (HCC-E).
Progression
on or after
systemic
therapyj
Progression
on or after
systemic
therapyj

(NCCN®
Table of Contents
Discussion
Post
resection
status
No residual
local disease
(R0 resection)
Options:i
• Observe
• Clinical trial
Consider multiphasic
abdominal/pelvic CT/MRI
with IV contrastb and chest
CT + contrastb every 3–6
mo for 2 y, then every 6–12
months for up to 5 years, or
as clinically indicatedr
Microscopic
margins (R1)
or
Positive
regional nodes
Options:i
• Fluoropyrimidine-based chemoradiationk,l
• Fluoropyrimidine-based or gemcitabine-based chemotherapyp
followed by fluoropyrimidine-based chemoradiationl
• Fluoropyrimidine-based chemoradiationk,l followed by
fluoropyrimidine-based or gemcitabine-based chemotherapyp
• Clinical trial
b See Principles of Imaging (HCC-A).
d Consult with multidisciplinary team.
i Order does not indicate preference. The choice of treatment modality may depend on extent/location of disease and institutional capabilities
j See Principles of Systemic Therapy (BIL-C).
k There are limited clinical trial data to define a standard regimen or definitive benefit. Clinical trial participation is encouraged (Macdonald OK, Crane CH. Surg Oncol
Clin N Am 2002;11:941-954).
l See Principles of Radiation Therapy (BIL-B).
o 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).
p 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).
q There are no data to support a specific surveillance schedule or tests for monitoring. Physicians should discuss appropriate follow-up schedules/imaging with patients.
r Based on surveillance schedule used in the phase III BILCAP trial. Primrose JN, et al. Lancet Oncol 2019;20:663-673.
TREATMENTo
Residual
local diseased
(R2 resection)
SURVEILLANCEq
INTRA-2
See treatment for unresectable disease (INTRA-1)

(NCCN®
Table of Contents
Discussion
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 and
segmental 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 with
limited 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 selected
cases.
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.
INTRA-A

(NCCN®
Biliary Tract Cancers: Extrahepatic Cholangiocarcinoma
Table of Contents
Discussion
PRESENTATION AND WORKUP PRIMARY TREATMENT
• Pain
• Jaundice
• Abnormal
LFTs
• Obstruction
or
abnormality
on imaging
• HP
• 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
Unresectablef
• Biliary drainage,h if indicated
• Biopsyf (only after determining
transplant status)
MSI/MMR testingi
Additional molecular testingj
◊ TMB testing
• Consider referral to transplant
center
Metastatic
disease
• Surgical explorationg
• Consider laparoscopic staging
• Consider preoperative biliary
drainage
• Multidisciplinary review
• Biliary drainage,h if indicated
• Biopsy
MSI/MMR testingi
Additional molecular testingj
◊ TMB testing
b Magnetic resonance cholangiopancreatography (MRCP) is preferred.
Endoscopic retrograde cholangiopancreatography/percutaneous transhepatic
cholangiography (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 patient
is a potential transplant candidate, consider referral to transplant center before
biopsy. Unresectable perihilar or hilar cholangiocarcinomas that measure ≤3 cm
in radial diameter, with the absence of intrahepatic or extrahepatic metastases
and without nodal disease, as well as those with primary sclerosing cholangitis,
may be considered for liver transplantation at a transplant center that has an
UNOS-approved protocol for transplantation of cholangiocarcinoma.
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
chemotherapy. Consider baseline CA 19-9 after biliary decompression.
i 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.
j Testing may include NTRK gene fusion testing.
k Order does not indicate preference. The choice of treatment modality may
depend on extent/location of disease and institutional capabilities.
l See Principles of Systemic Therapy (BIL-C).
m There are limited clinical trial data to define a standard regimen or definitive
benefit. Clinical trial participation is encouraged (Macdonald OK, Crane CH. Surg
Oncol Clin N Am 2002;11:941-954).
n See Principles of Radiation Therapy (BIL-B).
Options:k
• Systemic therapyl
• Clinical trial
• EBRT with concurrent
fluoropyrimidinem,n
• Palliative EBRTn
Unresectable, see below
Resectablee Resectione
See Adjuvant
Treatment
and
Surveillance
(EXTRA-2)
Options:k
• Clinical trial
EXTRA-1
Progression
on or after
systemic
therapyl
Resectablee
Progression
on or after
systemic
therapyl

(NCCN®
Table of Contents
Discussion
TREATMENTp SURVEILLANCEr
Post
resection
status
Resected, negative margin (R0),
Negative regional nodes
or
Carcinoma in situ at margin
Resected, positive margin (R1)o
or
Positive regional nodes
• Observe
• Fluoropyrimidine chemoradiationm,n
• Clinical trial
• Fluoropyrimidine-based chemoradiationm,n
• Fluoropyrimidine-based or gemcitabine-
based chemotherapyq followed by
fluoropyrimidine-based chemoradiationn
• Fluoropyrimidine-based chemoradiationm,n
followed by fluoropyrimidine-based or
gemcitabine-based chemotherapyq
• Clinical trial
Consider imaging every
3–6 mo for 2 y, then every
6–12 months for up to 5
years,a or as clinically
indicateds
l See Principles of Systemic Therapy (BIL-C).
m There are limited clinical trial data to define a standard regimen or definitive benefit. Clinical trial participation is encouraged (Macdonald OK, Crane CH. Surg Oncol
Clin N Am 2002;11:941-954).
n See Principles of Radiation Therapy (BIL-B).
o Management of patients with R1 or R2 resections should be evaluated by a multidisciplinary team.
p Adjuvant chemotherapy or chemoradiation has been associated with survival benefit in patients with biliary tract cancers, especially in patients with lymph node-
positive disease (Horgan AM, et al. J Clin Oncol 2012;30:1934-1940).
q 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).
r There are no data to support a specific surveillance schedule or tests for monitoring. Physicians should discuss appropriate follow-up schedules/imaging with patients.
s Based on surveillance schedule used in the phase III BILCAP trial. Primrose JN, et al. Lancet Oncol 2019;20:663-673.
EXTRA-2
Resected gross residual disease (R2)o
See treatment for unresectable disease (EXTRA-1)

(NCCN®
Table of Contents
Discussion
PRINCIPLES OF SURGERY
General Principles
• The basic principle is a complete resection with negative margins and regional lymphadenectomy. This generally requires a
pancreaticoduodenectomy for distal bile duct tumors and a major hepatic resection for hilar tumors. Rarely, a mid bile duct tumor can be resected
with 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 pancreatic
resections 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 an
assessment of biliary drainage and volumetrics of the FLR. While not necessary in all cases, the use of preoperative biliary drainage of the FLR and
contralateral 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 to
encompass 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 these
procedures.
• 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.
EXTRA-A
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.

(NCCN®
Table of Contents
Discussion
PRINCIPLES OF IMAGING1-4
1 Srinivasa S, McEntee B, Koea JB. The role of PET scans in the management of
cholangiocarcinoma 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, Lourdusamy V, Sanaka MR. Endoscopic
ultrasound in the diagnosis of cholangiocarcinoma as the etiology of biliary
strictures: a systematic review and meta-analysis. 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 and meta-analysis. J Hepatol 2019;71:115-129.
BIL-A
General Principles
• CT of the chest with or without contrast and multiphasic contrast-enhanced CT or MRI of the abdomen and pelvis are recommended for
follow-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 examination
of the gallbladder.
• If gallbladder cancer is suspected preoperatively, multidetector multiphase CT of the abdomen (and pelvis) or contrast-enhanced MRI with
magnetic resonance cholangiopancreatography (MRCP) of the abdomen (and pelvis) and chest CT with or without contrast should be
performed. MRI is preferred for evaluating masses within the gallbladder and demonstrating bile duct involvement.
• 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.
Intrahepatic and Extrahepatic Cholangiocarcinoma
• Surgical management is based on the location and extent of the tumor.
• Preoperative imaging for accurate staging of extrahepatic cholangiocarcinoma 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 with thin cuts, or multiphase CT or MRI of the liver and biliary tree should specifically address the anatomy of the
biliary tree, hepatic arteries, and portal veins and their relationship to the tumor.
• 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 intrahepatic cholangiocarcinoma is suspected or confirmed.

(NCCN®
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Discussion
BIL-B
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 cholangiocarcinoma and
gallbladder cancer.3,4 Target volumes should cover the draining regional lymph nodes 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 acceptable
for intrahepatic and extrahepatic tumors.
Hypofractionation with photons5 or protons6 is an acceptable option for intrahepatic tumors, though 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 Dosing:
EBRT:
◊ Initial volumes to 45 Gy in 1.8 Gy per fraction
◊ Boost to 50 to 60 Gy in 1.8–2 Gy per fraction
SBRT:
◊ 30–50 Gy (typically in 3–5 fractions), depending on the ability to meet normal organ constraints and underlying liver function.
◊ Other hypofractionated schedules 5 fractions may also be used if clinically indicated
◊ For intrahepatic tumors, SBRT (typically 3–5 fractions) is an acceptable option.5
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 multi-
institutional 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 and
concurrent 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 intrahepatic
cholangiocarcinoma: 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.
Footnote
a See Principles of Systemic Therapy (BIL-C).
References

(NCCN®
Table of Contents
Discussion
BIL-C
1 OF 4
Neoadjuvant Therapya
• 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
• None
Adjuvant Therapyb,2
• Capecitabinec,3
(category 1) • 5-fluorouracil + oxaliplatin
• Gemcitabine + cisplatin
• Capecitabine + cisplatin (category 3)
• Single agents:
5-fluorouracil
Gemcitabine
• None
Agents Used with Concurrent Radiation
• 5-fluorouracil
• Capecitabine
a
There are limited clinical trial data to define a standard regimen or definitive benefit. Clinical trial participation is encouraged.
b
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.
c The phase III BILCAP study shows improved overall survival for adjuvant capecitabine in the per-protocol analysis, and the overall survival did not reach statistical 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 by radiotherapy and concurrent capecitabine in extrahepatic cholangiocarcinoma and gallbladder carcinoma. J Clin Oncol 2015;33:2617-2622.

(NCCN®
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Discussion
BIL-C
2 OF 4
Subsequent-Line Therapy for Biliary Tract Cancers if Disease Progression
Preferred Regimens Other Recommended Regimens Useful in Certain Circumstancesf
• FOLFOX10
• FOLFIRI11
(category 2B)
• Regorafenib12
(category 2B)
• See also: Preferred and Other Recommended Regimens for
Unresectable and Metastatic Disease abovef
• For NTRK gene fusion-positive tumors:
Entrectinib5-7
Larotrectinib8
• For MSI-H/dMMR tumors/TMB-H tumors:
Pembrolizumabd,e,g,9,13,14
• For cholangiocarcinoma with FGFR2
fusions or rearrangements:
Pemigatinib15
Infigratinib16
• For cholangiocarcinoma with IDH1
mutations
Ivosidenib17
• For BRAF-V600E mutated tumors
Dabrafenib + trametinib18,19
• Nivolumabe,g,20 (category 2B)
• Lenvatinib + pembrolizumabe,g,21
(category 2B)
• For MSI-H/dMMR tumors
Dostarlimab-gxlye,g,h,22,23
(category 2B)
Primary Treatment for Unresectable and Metastatic Disease
• Gemcitabine + cisplatin4
(category 1) • 5-fluorouracil + oxaliplatin
• 5-fluorouracil + cisplatin (category 2B)
• Capecitabine + cisplatin (category 2B)
• Gemcitabine + albumin-bound paclitaxel
• Gemcitabine + oxaliplatin
• Gemcitabine + cisplatin + albumin-bound paclitaxel1
(category 2B)
• Single agents:
5-fluorouracil
Capecitabine
Gemcitabine
• For NTRK gene fusion-positive tumors:
Entrectinib5-7
Larotrectinib8
• For MSI-H/dMMR tumors:
Pembrolizumabd,e,9
d 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.
e See NCCN Guidelines for Management of Immunotherapy-Related Toxicities.
f Treatment selection depends on clinical factors including previous treatment regimen/agent and extent of liver
dysfunction.
g For patients who have not been previously treated with a checkpoint inhibitor because there is a lack of data for
subsequent use of immunotherapy in patients who have previously been treated with a checkpoint inhibitor.
h Dostarlimab-gxly is a recommended treatment option for patients with MSI-H/dMMR recurrent or advanced tumors
that have progressed on or following prior treatment and who have no satisfactory alternative treatment options.

(NCCN®
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Discussion
BIL-C
3 OF 4
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 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.
6 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.
7 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.
8 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.
9 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.
10 Lamarca A, Palmer DH, Wasan HS, et al. ABC-06 | A randomised phase III, multi-centre, open-label study of active symptom control (ASC) alone or ASC with
oxaliplatin / 5-FU chemotherapy (ASC+mFOLFOX) for patients (pts) with locally advanced / metastatic biliary tract cancers (ABC) previously-treated with cisplatin/
gemcitabine (CisGem) chemotherapy [abstract]. J Clin Oncol 2019; 37(Suppl 15):Abstract 4003.
11 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.
12 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.
13 Marabelle A, Le DT, Ascierto PA, et al. Efficacy of pembrolizumab in patients with noncolorectal high microsatellite instability/mismatch repair-deficient cancer: Results
from the phase II KEYNOTE-158 study. J Clin Oncol 2020;38:1-10.
14 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
15 Abou-Alfa GK, Sahai V, Hollebecque A, et al. Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: a multicentre, open-label, phase
2 study. Lancet Oncol 2020;21:671-684.
16
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
17 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.
18 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.
19 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.
REFERENCES

(NCCN®
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Discussion
BIL-C
4 OF 4
20 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.
21 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 treated
advanced solid tumors. Ann. Oncol. 2020;31:S1142-S1215.
22
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.
23 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.
REFERENCES

ST-1
Continued
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.
Table 2. AJCC Prognostic Groups
T N M
Stage IA T1a N0 M0
Stage IB T1b N0 M0
Stage II T2 N0 M0
Stage IIIA T3 N0 M0
Stage IIIB T4 N0 M0
Stage IVA Any T N1 M0
Stage IVB Any T Any N M1
Histologic Grade (G)
GX Grade cannot be accessed
G1 Well differentiated
G2 Moderately differentiated
G3 Poorly differentiated
G4 Undifferentiated
Fibrosis 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 Fibrosis score 0-4 (none to moderate fibrosis)
F1 Fibrosis score 5-6 (severe fibrosis or cirrhosis)
Table 1. Definitions for T, N, M
T Primary Tumor
TX Primary tumor cannot be assessed
T0 No evidence of primary tumor
T1 Solitary tumor ≤2 cm, or 2 cm without vascular invasion
T1a Solitary tumor ≤2 cm
T1b Solitary tumor 2 cm without vascular invasion
T2 Solitary tumor 2 cm with vascular invasion, or multiple
tumors, none 5 cm
T3 Multiple tumors, at least one of which is 5 cm
T4 Single tumor or multiple tumors of any size involving a major
branch of the portal vein or hepatic vein, or tumor(s) with
direct invasion of adjacent organs other than the gallbladder
or with perforation of visceral peritoneum
N Regional Lymph Nodes
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Regional lymph node metastasis
M Distant Metastasis
M0 No distant metastasis
M1 Distant metastasis
American Joint Committee on Cancer (AJCC)
TNM Staging for Hepatocellular Cancer (8th ed., 2017)
(NCCN®
Table of Contents
Discussion

Continued
ST-2
T N M
Stage 0 Tis N0 M0
Stage I T1 N0 M0
Stage IIA T2a N0 M0
Stage IIB T2b N0 M0
Stage IIIA T3 N0 M0
Stage IIIB T1-3 N1 M0
Stage IVA T4 N0-1 M0
Stage IVB Any T N2 M0
Any T Any N M1
GX Grade cannot be assessed
T Primary Tumor
Tis Carcinoma in situ
T1 Tumor invades lamina propria or muscular layer
T1a Tumor invades lamina propria
T1b Tumor invades muscle layer
T2 Tumor invades the perimuscular connective tissue on the
peritoneal side, without involvement of the serosa (visceral
peritoneum) Or tumor invades the perimuscular connective
tissue on the hepatic side, with no extension into the liver
T2a Tumor invades the perimuscular connective tissue on the
peritoneal side, without involvement of the serosa (visceral
peritoneum)
T2b Tumor invades the perimuscular connective tissue on the
hepatic side, with no extension into the liver
T3 Tumor perforates the serosa (visceral peritoneum) and/
or directly invades the liver and/or one other adjacent
organ or structure, such as the stomach, duodenum, colon,
pancreas, omentum, or extrahepatic bile ducts
T4 Tumor invades main portal vein or hepatic artery or invades
two or more extrahepatic organs or structures
TNM Staging for Gallbladder Carcinoma (8th ed., 2017)
N1 Metastases to one to three regional lymph nodes
N2 Metastases to four or more regional lymph nodes
(NCCN®
Table of Contents
Discussion

Continued
ST-3
T N M
Stage 0 Tis N0 M0
Stage IA T1a N0 M0
Stage IB T1b N0 M0
Stage II T2 N0 M0
Stage IIIA T3 N0 M0
Stage IIIB T4 N0 M0
Any T N1 M0
Stage IV Any T Any N M1
T Primary Tumor
Tis Carcinoma in situ (intraductal tumor)
T1 Solitary tumor without vascular invasion, ≤5 cm or 5 cm
T1a Solitary tumor ≤5 cm without vascular invasion
T1b Solitary tumor 5 cm without vascular invasion
T2 Solitary tumor with intrahepatic vascular invasion or multiple
tumors, with or without vascular invasion
T3 Tumor perforating the visceral peritoneum
T4 Tumor involving local extrahepatic structures by direct invasion
N1 Regional lymph node metastasis present
M1 Distant metastasis present
TNM Staging for Intrahepatic Bile Duct Tumors (8th ed., 2017)
(NCCN®
Table of Contents
Discussion

Continued
ST-4
T N M
Stage 0 Tis N0 M0
Stage I T1 N0 M0
Stage II T2a-b N0 M0
Stage IIIA T3 N0 M0
Stage IIIB T4 N0 M0
Stage IIIC Any T N1 M0
Stage IVA Any T N2 M0
Stage IVB Any T Any N M1
T Primary Tumor
Tis Carcinoma in situ/high-grade dysplasia
T1 Tumor confined to the bile duct, with extension up to the muscle
layer or fibrous tissue
T2 Tumor invades beyond the wall of the bile duct to surrounding
adipose tissue, or tumor invades adjacent hepatic parenchyma
T2a Tumor invades beyond the wall of the bile duct to surrounding
adipose tissue
T2b Tumor invades adjacent hepatic parenchyma
T3 Tumor invades unilateral branches of the portal vein or hepatic artery
T4 Tumor invades main portal vein or its branches bilaterally, or the
common hepatic artery; or unilateral second-order biliary radicals
bilaterally with contralateral portal vein or hepatic artery involvement
N1 One to three positive lymph nodes typically involving the
hilar, cystic duct, common bile duct, hepatic artery, posterior
pancreatoduodenal, and portal vein lymph nodes
N2 Four or more positive lymph nodes from the sites described for N1
TNM Staging for Perihilar Bile Duct Tumors (8th ed., 2017)
(NCCN®
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Discussion

ST-5
T N M
Stage 0 Tis N0 M0
Stage I T1 N0 M0
Stage IIA T1 N1 M0
T2 N0 M0
Stage IIB T2 N1 M0
T3 N0 M0
T3 N1 M0
Stage IIIA T1 N2 M0
T2 N2 M0
T3 N2 M0
Stage IIIB T4 N0 M0
T4 N1 M0
T4 N2 M0
Stage IV Any T Any N M1
T Primary Tumor
Tis Carcinoma in situ/high-grade dysplasia
T1 Tumor invades the bile duct wall with a depth less than 5 mm
T2 Tumor invades the bile duct wall with a depth of 5–12 mm
T3 Tumor invades the bile duct wall with a depth greater than 12 mm
T4 Tumor involves the celiac axis, superior mesenteric artery, and/or
common hepatic artery
N1 Metastasis in one to three regional lymph nodes
N2 Metastasis in four or more regional lymph nodes
TNM Staging for Distal Bile Ducts Tumors (8th ed., 2017)
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Discussion

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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
intervention
Other interventions that may be somewhat less efficacious, more toxic, or based on less mature data;
or significantly less affordable for similar outcomes.
Useful in certain
circumstances
Other interventions that may be used for selected patient populations (defined with recommendation).
All recommendations are considered appropriate.
CAT-1

Version 5.2021 © 2021 National Comprehensive Cancer Network©
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Discussion
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
This discussion corresponds to the NCCN Guidelines for Hepatobiliary Cancers. Last updated: September 21st, 2021.

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Overview
Hepatobiliary cancers are highly lethal cancers including a spectrum of
invasive carcinomas arising in the liver (hepatocellular carcinoma; HCC),
gall bladder, and bile ducts (intrahepatic and extrahepatic
cholangiocarcinoma). Gallbladder cancer and cholangiocarcinomas are
collectively 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 the
members of the NCCN Hepatobiliary Cancers Guidelines Panel. The types
of 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 such
as 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 in
prospective clinical trials is the preferred option for treatment of patients
with 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 (liver
cancer) 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; Meta-
Analysis; 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 have
been included in this version of the Discussion section. Recommendations
for which high-level evidence is lacking are based on the panel’s review of
lower-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).
Risk Factors and Epidemiology
Incidence and mortality rates for most cancers are declining; however, the
incidence 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

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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 and
chronic 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 or
other 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 patients
with chronic hepatitis B viral infection.20,21
Data from large
population-based studies have also identified high serum HBV DNA and
HCV RNA viral load as independent risk factors for developing HCC in
patients 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 these
calculations difficult to interpret. Although it has been reported that the
number of cases of hepatitis C infection diagnosed per year in the United
States is declining, it is likely that the observed increase in the number of
cases 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 chronically
infected 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 among
individuals 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), with
higher 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 in
patients 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 HBV
vaccination 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

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alcohol-induced cirrhosis have been confounded by the presence of other
risk 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 with
chronic 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 HBV
DNA levels, and a family history of HCC.35,46
Asian males ≥40 years, Asian
females ≥50 years, and Black/African American men and women with
hepatitis B are also at increased risk for HCC.6
The presence of liver
cirrhosis is usually considered to be a prerequisite for development of
HCC in individuals with inherited metabolic diseases of the liver or liver
disease 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, the
presence of chronic liver disease represents a risk for development of
HCC.12
However, HCC may also develop in patients with normal livers and
no known risk factors.50,51
GH is a condition characterized by excess iron absorption due to the
presence of mutations in the HFE gene. A study from the National Center
for Health Statistics found that patients with a known diagnosis of
hemochromatosis 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-alcoholic
steatohepatitis (NASH, a spectrum of conditions characterized by
histologic 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 in
individuals with cirrhosis.16,59
However, several studies suggest that HCC
may be somewhat less likely to develop in the setting of NASH-associated
cirrhosis 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 in
patients with NAFLD with noninvasive markers that provide evidence of
advanced liver fibrosis or cirrhosis.
Fibrolamellar hepatocellular carcinoma (FLHC) is a variant of HCC that
makes 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 molecular
target 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

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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-free
survival (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 in
patients 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 that
ultrasound (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 of
age. 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 to
have 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 high
specificity (99%) but low sensitivity (31%).78
In a screening study involving
a large population of patients in China infected with HBV or those with
chronic hepatitis, and using an AFP cut-off of 20 ng/mL, the detection
rate, false-positive rate, and positive predictive value with AFP alone were
69%, 5.0%, and 3.3%; with US alone were 84%, 2.9%, and 6.6%; and with
the 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 after
surveillance with US and AFP had significantly longer overall survival (OS)
and disease-free survival (DFS), compared to patients who had no
surveillance 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 patients
with early-stage disease and its utility as a screening biomarker is
limited.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

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In these guidelines, the populations considered to be “at risk” for HCC and
likely 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) and
hepatitis B carriers without cirrhosis, regardless of cause. Other less
common causes of cirrhosis include secondary biliary cirrhosis, Wilson’s
disease, sclerosing cholangitis, granulomatous disease, type IV glycogen
storage 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 6
months) for patients with established risk factors for HCC. Additional
imaging (abdominal multiphasic CT or MRI) is recommended in the setting
of a rising serum AFP or following identification of a liver mass nodule ≥10
mm on US, based on AASLD and LI-RADS (Liver Imaging Reporting and
Data System) guidelines.6,87
It is also reasonable to screen patients with
cross-sectional imaging (CT or MRI), and this may be commonly
employed, though not well-studied in the United States. Cost and
availability limit the widespread use of screening using cross-sectional
imaging. Liver masses 10 mm are difficult to definitively characterize
through 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. Nonspecific
symptoms associated with more advanced HCC can include jaundice,
anorexia, weight loss, malaise, and upper abdominal pain. Physical signs
of 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 through
imaging is difficult since imaging characteristics consist of varying features
of 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 that
needle biopsies will not necessarily show both elements of the
malignancy.
Imaging
HCC lesions are characterized by arterial hypervascularity and “wash out”
on portal venous phases, since they derive most of their blood supply from
the 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 with
multiphasic (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 to
previous imaging as part of diagnosis using CT or MRI imaging.87
The LI-
RADS 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 of
expertise as a problem-solving tool for characterization of indeterminate
nodules, it is not recommended by the panel for whole-liver assessment,

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surveillance, or staging.102
A meta-analysis including 241 studies showed
that CT and MRI are more sensitive than US without contrast for detection
of HCC.103
Another meta-analysis that included only studies of patients
with cirrhosis or chronic hepatitis (N = 30) also showed that US is less
sensitive 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 patients
with 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 acceptable
sensitivity (78%) and excellent specificity (92%) when criteria are applied
in appropriate clinical context in patients with known liver disease.110
The
results of a prospective study evaluating the accuracy of CEUS and
dynamic contrast-enhanced MRI for the diagnosis of liver nodules 2 cm or
smaller 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 not
commonly utilized in the United States. Other investigators have
suggested 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 been
changed 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 the
setting of high clinical suspicion for HCC (eg, following identification of a
liver 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 an
incidental 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, and
extrahepatic 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 LI-
RADS interpretation. The quality of MRI is dependent on patient
compliance, since some patients may be unable to hold their breath. If no
mass is detected using multiphasic contrast-enhanced imaging, or if the
observed lesion is definitely benign, then the patients should return to a
screening program (ie, US and AFP in 6 months). If there is suspicion that
the 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), then
multidisciplinary 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, and
prolonged survival in advanced disease.113-116

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Serum Biomarkers
Although serum AFP has long been used as a marker for HCC, it is not a
sensitive or specific diagnostic test for HCC. Serum AFP levels 400
ng/mL are observed only in a small percentage of patients with HCC. In a
series of 1158 patients with HCC, only 18% of patients had values 400
ng/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 more
indicative of HCC than in non-infected patients.118
Furthermore, AFP can
also be elevated in pregnancy, and other cancers such as intrahepatic
cholangiocarcinoma, some metastases from colon cancer, lymphoma, and
germ cell tumors.35,119
AFP testing can be useful in conjunction with other
test 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 to
have a high positive predictive value for HCC in two retrospective
analyses involving small numbers of patients.120,121
However, the
diagnostic accuracy of an absolute AFP cutoff value has not been
validated in this setting, and such values may vary by institution and
patient 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 an
imaging finding of classic enhancement to be more definitive in the
diagnostic setting compared to AFP alone. Additional imaging studies (CT
or MRI) are recommended for patients with a rising serum AFP level in the
absence of a liver mass. If no liver mass is detected following
measurement of an elevated AFP level, the patient should be followed
with AFP testing and liver imaging. Further, assessment of AFP levels
may be helpful in monitoring treatment response as appropriate (see
Surveillance below).
Other serum biomarkers being studied in this setting include
des-gamma-carboxy prothrombin (DCP), also known as protein induced
by 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 the
large, randomized HALT-C trial who developed HCC showed that a
combination of AFP and DCP is superior to either biomarker alone as a
complementary assay to screening.82
The GALAD model, which accounts for gender, age, AFP-L3, AFP, and
des-carboxy-prothrombin, is a serum biomarker model used to assess the
risk of HCC in patients with chronic liver disease.127
In validation studies,
the GALAD model identified HCC cases in patients with chronic liver
disease or nonalcoholic steatohepatitis with a high degree of accuracy.128-
130
The GALADUS score, which combines the GALAD score and US, was
found to improve the performance of the GALAD score.129
Biopsy
A diagnosis of HCC can often be made noninvasively by imaging in
patients 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 be
considered. 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 in
this scenario, specifically the cost, emotional distress for the patient, risk of
complications, and potential sampling error for small lesions.73
Second,
biopsy may be done in patients who are not considered high risk for
developing HCC (ie, patients who do not have cirrhosis, chronic HBV, or a

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previous history of HCC). Third, biopsy may be indicated in patients with
conditions 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 disorder
such as Budd-Chiari syndrome, hereditary hemorrhagic telangiectasia, or
nodular regenerative hyperplasia.132
Finally, biopsy may be considered in
patients with elevated CA 19-9 or carcinoembryonic antigen (CEA), in
order to rule out intrahepatic cholangiocarcinoma or mixed HCC-
cholangiocarcinoma133,134
or in patients with history of another primary
malignancy at risk for metastatic disease. If transplant or resection is a
consideration, patients should be referred to a transplant center and/or
hepatic surgeon before biopsy since biopsy may not be necessary in
certain patients with resectable malignant-appearing masses.
Both core needle biopsy and fine-needle aspiration biopsy (FNAB) have
advantages and disadvantages in this setting. For example, FNAB may be
associated with a lower complication rate when sampling deeply situated
lesions 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 well
as the possibility of an upfront tentative diagnosis.135
However, FNAB is
highly dependent on the skill of the cytopathologist,136
and there are
reports of high false-negative rates99,137
as well as the possibility of
false-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, some
evidence 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 a
nondiagnostic 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 a
negative biopsy does not rule out HCC. Continual monitoring with a
multidisciplinary review including surgeons is recommended since
definitive resection may be considered.
Initial Workup
The foundation of initial workup for patients with suspected HCC is a
multidisciplinary evaluation including investigations of the etiologic origin of
liver 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 acute
viral hepatitis], and HCV antibodies), an assessment of the presence of
comorbidity; 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 of
viral load in patients who test positive for HBsAg, HBcAb IgG (since an
isolated HBcAb IgG may still indicate chronic HBV infection), and HCV
antibodies. If viral load is positive, patients should be evaluated by a
hepatologist 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 the
possibility 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
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metastatic disease, nodal disease, and vascular invasion; to assess
whether evidence of portal hypertension is present; to provide an estimate
of 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 an
estimate of the future liver remnant (FLR).98
Enlarged lymph nodes are
commonly seen in patients with viral hepatitis, primary biliary cirrhosis, and
other underlying liver disorders that predispose patients to HCC.144
Detection of nodal disease by cross-sectional imaging is non-specific and
can 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 as
international normalized ratio (INR), albumin, and platelet count (surrogate
for portal hypertension). Other recommended tests include complete blood
count (CBC), blood urea nitrogen (BUN), and creatinine to assess kidney
function; creatinine is also an established prognostic marker in patients
with liver disease.145
Further assessment of hepatic functional reserve
prior to hepatic resection in patients with cirrhosis may be performed with
different tools such as US and MRI elastography (which may provide and
quantify the degree of cirrhosis-related fibrosis), non-focal liver biopsy, and
transjugular liver biopsy with pressure measurements.
The Child-Pugh classification has been traditionally used for the
assessment 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 of
encephalopathy and ascites. It provides a general estimate of the liver
function by classifying patients as having compensated (class A) or
decompensated (classes B and C) cirrhosis. Advantages of the Child-Pugh
score include ease of performance (ie, can be done at the bedside) and
the inclusion of clinical parameters.
An important additional assessment of liver function not included in the
Child-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 using
esophagogastroduodenoscopy (EGD) or contrast-enhanced cross-
sectional imaging.
Model for End-Stage Liver Disease (MELD) is another system for the
evaluation 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) and
was 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 liver
transplantation waiting list according to their risk of death within 3
months.152
The MELD score has sometimes been used in place of the
Child-Pugh score to assess prognosis in patients with cirrhosis.
Advantages of the MELD score include the inclusion of a measurement of
renal function and an objective scoring system based on widely available
laboratory tests, although clinical assessments of ascites and
encephalopathy are not included. It is currently unclear whether the MELD
score is superior to the Child-Pugh score as a predictor of survival in
patients with liver cirrhosis. The MELD score has not been validated as a
predictor of survival in patients with cirrhosis who are not on a liver
transplantation waiting list.153
While the MELD model is used to stratify
organ access for transplantation, it also favors patients with renal

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dysfunction. Serum creatinine, an important component of the MELD
score, can be an unreliable marker of renal dysfunction, especially in
patients with cirrhosis.154
Albumin and bilirubin are objectively measured, while ascites and
encephalopathy, other scoring parameters used to calculate the Child-
Pugh score, are subjective. Therefore, another alternative to the Child-
Pugh 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 the
survival 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 three
risk 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.
The indocyanine green (ICG) clearance test is extensively used in Asia for
the assessment of liver function prior to hepatic resection in patients with
cirrhosis.158 159
The 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 to
surgery.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 and
is characterized by well-circumscribed nodules. The massive type of HCC,
usually associated with a non-cirrhotic liver, occupies a large area with or
without satellite nodules in the surrounding liver. The less common diffuse
type is characterized by diffuse hepatic involvement with many small
indistinct tumor nodules throughout the liver.
Staging
Clinical staging systems for the patient with cancer can provide a more
accurate 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 in
patients with HCC are the clinical stage, growth rate of the tumor, the
general health of the patient, the liver function of the patient, and the
treatments 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, the
Child-Pugh164
and MELD scores150
can be considered to be staging
systems that evaluate aspects of liver function.
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 the
Cancer 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,

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the BCLC system also incorporates the Okuda system, as well as other
tumor 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 have
been 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 of
studies 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 therapeutic
intervention. For example, the AJCC staging system has been shown to
accurately predict survival for patients who underwent orthotopic liver
transplantation.179
The CLIP, CUPI, and GRETCH staging systems have
been shown to perform well in predicting survival in patients with
advanced disease.180
The CLIP system has been specifically identified as being useful for
staging 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 a
meta-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 not
included 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 liver
transplantation, survival benefit for liver transplantation was seen in
patients with advanced liver cirrhosis and in those with intermediate
tumors (BCLC stage D and stages B–C, respectively), regardless of the
number 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 particular
clinicopathologic variables, including patient age, tumor size and margin
status, postoperative blood loss, the presence of satellite lesions and
vascular invasion, and serum AFP level, that was developed has been
shown to perform well in predicting postoperative outcome for patients
undergoing liver resection for HCC.186
In addition, another study showed
tumor 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 system
that could be used across all institutions in different countries. The BCLC
and the Hong Kong Liver Cancer staging systems are amongst the most
widely used. Although no particular staging system (with the exception of
the Child-Pugh score and TNM staging system) is currently used in these
guidelines, following an initial workup, patients are stratified into one of the
following four categories:

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• Potentially resectable or transplantable, operable by performance
status 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 is
complicated 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 and
pathologists with hepatobiliary cancer expertise, thereby requiring careful
coordination of care.44
Given the comorbidities associated with this
disease, patients need careful consideration of treatment choice given the
risk of potential toxicities from treatment and potential benefits.
Surgery
Partial hepatectomy is a potentially curative therapy for patients with a
solitary 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
Results
of 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 and
early-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 functional
liver parenchyma in the setting of underlying liver disease, careful patient
selection, based on patient characteristics as well as characteristics of the
liver and the tumor(s), is essential. Assessments of patient performance
status 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 to
have potentially resectable disease. Univariate analyses from a database
study 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 mass
index (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 for
liver resection (ie, serving as a means to identify patients with substantially
decompensated liver disease).198
An evaluation of the presence of
significant portal hypertension is also an important part of the surgical
assessment. A meta-analysis including 11 studies showed that clinically
significant 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 well
as 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 liver
resection is characterized by a Child-Pugh class A score and absence of

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portal hypertension. However, in highly selected cases, patients with a
Child-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 in
cases where portal hypertension is mild. A prospective observational study
of 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 that
albumin, but not portal hypertension, was significantly associated with
survival 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 size
of the HCC lesions in order to detect the presence of satellite nodules,
extrahepatic metastasis, and tumor invasion of the portal vein or the
hepatic veins/inferior vena cava, and to help establish the location of the
tumors with respect to vascular and biliary structures.
Optimal tumor characteristics for liver resection are solitary tumors without
major 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 vascular
invasion 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 role
of 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 for
patients with multinodular disease who underwent resection were 35%
and 22%, respectively.205
The authors also examined survival rates of
patients 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 and
total 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 for
liver resection, preoperative portal vein embolization (PVE) should be
considered. PVE is a safe and effective procedure for redirecting blood
flow 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 estimated
future liver remnant function (eFLRF), which accounts for individual
differences in body surface area, can also be calculated.212
A comparison
of 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

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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 a
treatment other than resection was associated with an increased risk of
mortality (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 other
treatments (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) and
transplantation (HR, 0.20; 95% CI, 0.14–0.27, P .001). Despite the fact
that these study results are powerfully influenced by selection bias, the
study 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 for
patients 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. Treatment-
emergent 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 between-
group 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 patients
with 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), and
improved 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 to
those 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 meta-
analysis including 10 studies with 1794 patients with HCV showed that
sustained 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 that
the rising use of DAAs might increase HCC recurrence or progression

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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 the
benefit of this treatment in patients with resected HCC.
Immunotherapy, or using the immune system to treat cancer, is beginning
to be investigated as adjuvant HCC treatment. A systematic review of
adjuvant treatment options for HCC including 14 studies (two
immunotherapy 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 specific
recommendations regarding immunotherapy treatment in an adjuvant
setting.
Liver Transplantation
Liver transplantation is a potentially curative therapeutic option for patients
with early HCC. It is especially appealing since it removes both detectable
and undetectable tumor lesions, treats underlying liver cirrhosis, and
avoids 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 in
diameter or no more than three nodules ≤3 cm in diameter in patients with
multiple tumors and no macrovascular invasion) for patients with
unresectable HCC and cirrhosis.230
The 4-year OS and RFS rates were
85% 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 liver
transplantation 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 no
evidence of macrovascular involvement or extrahepatic disease) specify
that patients eligible for liver transplantation should not be candidates for
liver resection.232
Therefore, liver transplantation has been generally
considered to be the initial treatment of choice for well selected patients
with early-stage HCC and moderate-to-severe cirrhosis (ie, patients with
Child-Pugh class B and C scores), with partial hepatectomy generally
accepted as the best option for the first-line treatment of patients with
early-stage HCC and Child-Pugh class A scores when tumor location is
amenable to resection. Retrospective studies have reported similar
survival rates for hepatic resection and liver transplantation in patients with
early-stage HCC when accounting for the fallout while on waiting lists for
transplantation.193,233-236
However, there are no prospective randomized
studies that have compared the effectiveness of liver resection and liver
transplantation for this group of patients.
The MELD score as a measure of liver function is also used as a measure
of 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

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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 and
Transplantation 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 is
controversial. Survival was also significantly lower for the subgroup of
patients with HCC tumors between 3 and 5 cm.
Expansion of the Milan/UNOS criteria to provide patients who have
marginally larger HCC tumors with liver transplant eligibility is an active
area of debate, with exceptional cases frequently prompting analysis and
revisions.176,231,239,240
An expanded set of criteria including patients with a
single HCC tumor ≤6.5 cm, with a maximum of 3 total tumors with no
tumor larger than 4.5 cm (and cumulative tumor size 8 cm) as liver
transplant candidates has been proposed by Yao et al at the University of
California at San Francisco (UCSF).241,242
Studies evaluating the post-
transplantation 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 the
Milan/UNOS criteria includes the general recognition that many patients
with HCC tumors exceeding the Milan criteria can be cured by liver
transplant. Opponents of an expansion of the Milan/UNOS criteria cite the
increased risk of vascular invasion and tumor recurrence associated with
larger tumors and higher HCC stage, the shortage of donor organs, and
taking 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 cm
compared with those who had smaller tumors.238
There is a risk of tumor recurrence following liver transplantation. A group
from France argued that the Milan criteria may be overly restrictive and
thus developed a predictive model of HCC recurrence that combines AFP
value with tumor size and number.246
Analyses from samples of patients
from France and Italy who underwent liver transplantation showed that this
AFP model predicted an increase in 5-year risk of recurrence and
decreased survival.246,247
The panel does not provide specific
recommendations regarding whether or not AFP should be considered a
transplant criterion, and this may depend on local practice. Another
analysis 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 were
associated with HCC recurrence.248
Resection or liver transplantation can be considered for patients with
Child-Pugh Class A liver function who meet UNOS criteria
(www.unos.org/) and are resectable. Controversy exists over which initial
strategy is preferable to treat such patients. The guidelines recommend
that 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 by
well-defined imaging from contrast-enhanced CT or MRI. OPTN also
provides guidance on equipment specifications and use of a standardized

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protocol. While the panel does not have a recommendation regarding liver
transplantation in older adults with HCC, some centers report transplant in
highly 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 for
patients who meet the transplant criteria. An analysis including 205
patients from a transplant center registry who had HCC showed that
bridging locoregional therapy was associated with survival following
transplant (P = .005).253
A number of studies have investigated the role of
locoregional 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 nature
of the study populations, and the absence of RCTs evaluating the utility of
bridge therapy for reducing the liver transplantation waiting list drop-out
rate, limit the conclusions that can be drawn.269-271
Nevertheless, the use
of 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 selected
patients with more advanced HCC (without distant metastasis) who are
beyond the accepted transplant criteria with the goal of future
transplant.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) post-
transplant, compared to transplant alone.269
Downstaging therapy did not
significantly increase RFS. However, the three studies included in these
analyses 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 have
lesions 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, with
at 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 ≤8
cm.237
The UCSF criteria can be used as the current limit for consideration
of downstaging and potential candidates for this therapy should be
assessed by a transplant center.
Prospective studies have demonstrated that downstaging (prior to
transplant) 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 and
recurrence following transplant. However, such studies have used different

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selection criteria for the downstaging therapy and different transplant
criteria after successful downstaging. In some studies, response to
locoregional 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. Liver
transplantation was then performed in one group.284
The results showed
that 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 select
institutions. For patients with initial tumor characteristics beyond the Milan
criteria 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 by
locoregional therapy is typically estimated by the extent to which contrast
uptake on dynamic CT/MRI is diminished at a specified time following the
treatment when compared with pretreatment imaging findings. The
absence of contrast uptake within the treated tumor is believed to be an
indication of tumor necrosis. A number of factors are involved in
measuring the effectiveness of locoregional therapies, and the criteria for
evaluating tumor response are evolving.161,285-288
A few studies have
shown that the use of modified RECIST (mRECIST) is more suitable than
RECIST.289,290
AFP response after locoregional therapy has also been
reported 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-Pugh
class 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 Italian
randomized 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 for
tumors larger than 2 cm.300-302
Results of some long-term studies show

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survival rates of greater than 50% at 5 years for patients with early HCC
treated with RFA.303-306
The reported OS and recurrence rates vary widely across the studies for
patients treated with RFA, which is most likely due to differences in the
size 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 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 that
have compared RFA and resection have failed to provide conclusive
evidence (reviewed by Weis et al299
). RFA and liver resection in the
treatment of patients with HCC have been compared in randomized
prospective studies.308-312
The results of one randomized trial showed a
significant survival benefit for resection over RFA in 235 patients with
small 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 to
follow-up than the RFA group. Conversely, other randomized studies
demonstrated that percutaneous local ablative therapy with RFA is as
effective 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 the
small number of patients (180 patients and 168 patients, respectively) and
the lack of a non-inferiority design. Nevertheless, results from these
studies support ablation as an alternative to resection in patients with
small (3 cm), properly located tumors.
RFA has been compared to resection in some meta-analyses, which have
shown that resection is generally associated with better survival outcomes
than RFA313-315
but is associated with more complications and morbidity
from 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) showed
that 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
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 were
significantly higher with surgery compared to percutaneous RFA. The
advantage of surgery was more evident for Child-Pugh class A patients
with single tumors 3 cm in diameter, and the results were similar in 2
groups for Child-Pugh class B patients.318
In another retrospective analysis
of 40 Child-Pugh class A or B patients with HCC treated with
percutaneous ablative procedures, the overall rate of complete necrosis
was 53%, which increased to 62% when considering only the subset of
tumors 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

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resection and ablation for tumors that met the Milan criteria; however,
resection was associated with significantly improved long-term survival for
patients 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 an
accessible 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 for
patients with central HCC tumors 2 cm.321
The 5-year OS rates in
patients with central HCC tumors were 80% for RFA compared to 62% for
resection (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 or
unresectable HCC.322-326
So far, only two randomized trials have compared
MWA with resection and RFA.322,326
In the RCT that compared RFA with
percutaneous microwave coagulation, no significant differences were
observed 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 associated
with 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 and
the ability to treat near vessels, bile ducts, and other critical
structures.328,329
However, IRE can cause cardiac arrhythmias and
uncontrolled muscle contractions.330
Some small studies have shown that
IRE 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 6-
month follow-up.333
Recurrences have been reported following IRE for
larger tumors.330,332
Larger studies are needed to determine the
effectiveness 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 on
tumor 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 other
organs and major vessels/bile ducts, with the best outcomes in tumors 2
cm.
Arterially Directed Therapies
Arterially directed therapy involves the selective catheter-based infusion of
particles 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.

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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 an
effective 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%, and
11.5%, 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, were
observed. 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 extrahepatic
disease 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 to
tumor cells, prolong the contact time between the chemotherapeutic
agents and the cancer cells, and minimize systemic toxicity of
chemotherapy.339
The results of two RCTs and one retrospective case-
control study have shown a survival benefit for TACE compared with
supportive 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 (1
year, 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 liver
function of the survivors was not significantly different between the two
groups. 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% for
patients in the TACE, TAE, and supportive care arms, respectively.341
The
majority of the patients in the study had liver function classified as
Child-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 effectiveness
compared to either TACE or supportive care. In a randomized trial, the
effectiveness of TAE was compared to that of doxorubicin-based TACE in
101 patients with HCC.343
Study investigators did not find statistically
significant 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 (with
doxorubicin 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 were
independent predictors of OS.

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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 a
wide 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, the
effectiveness of TAE was compared to that of doxorubicin-based TACE in
101 patients with HCC.343
Study investigators did not find statistically
significant 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 the
reported frequencies of serious adverse events vary across studies.77,345
Reported rates of treatment-related mortality for TAE and TACE are
usually well under 5%.77,337,341,345
A transient post-embolization syndrome
involving fever, abdominal pain, and intestinal ileus is relatively common in
patients undergoing these procedures.77,345
A retrospective study from a
single institution in Spain showed that PVT and liver function categorized
as Child-Pugh class C were significant predictors of poor prognosis in
patients treated with TACE.346
However, TACE has since been shown to
be 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 to
patients 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 with
liver function characterized as Child-Pugh class C (absolute
contraindication). 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 with
previous 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 vascular
endothelial 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 with
localized, unresectable HCC with Child-Pugh class A or B cirrhosis and
without nodal involvement, showed no difference in CR, objective
response, and disease control between DEB TACE with
doxorubicin-eluting embolic beads and conventional TACE with
doxorubicin.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 with
Child-Pugh class B, ECOG performance status 1, bilobar disease, and
recurrent disease. DEB-TACE was also associated with improved
tolerability with a significant reduction in serious liver toxicity and a
significantly lower rate of doxorubicin-related side effects, compared to
conventional 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 in
patients with intermediate-state HCC; however, this study also did not
show any OS benefit for DEB-TACE.365
A randomized study comparing

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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 over
conventional TACE in a prospective randomized study of 71 patients with
unresectable 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 to
longer OS compared to TARE and conventional TACE.370
However, there
were lower complications associated with TARE.
Sorafenib following arterially directed therapies may be appropriate in
patients 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 the
efficacy and safety of TACE combined with sorafenib.372
Results showed
that 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 (hand-
foot skin reaction, diarrhea, hypertension, fatigue, hepatotoxicity, and
rash). 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 patients
found that the combination of TACE with sorafenib improved OS in the
Asian regions but not in non-Asian areas373
while another did not find a
difference in OS in either region but noted a longer time to disease
progression in the Asian population but not the European population.374
In
a phase III randomized trial, sorafenib, when given following treatment
with TACE did not significantly prolong TTP or OS in patients with
unresectable 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 normal
liver tissue.334,376
TARE is accomplished through the catheter-based
administration of microspheres (glass or resin microspheres) embedded
with Y-90, an emitter of beta radiation. There is a growing body of
literature to suggest that radioembolization might be an effective treatment
option for patients with liver-limited, unresectable disease,377-382
though
additional RCTs are needed to determine the relative risks and benefits of
TARE with Y-90 microspheres in patients with unresectable HCC and
long-term impact on liver function.383
Delivery of 205 Gy or greater to the
tumor may be associated with increased OS.384
Although
radioembolization with Y-90 microspheres, like TAE and TACE, involves
some level of particle-induced vascular occlusion, it has been proposed
that such occlusion is more likely to be microvascular than macrovascular,
and that the resulting tumor necrosis is more likely to be induced by
radiation rather than ischemia.377
RCTs have shown that Y-90 is not
superior to sorafenib for treating advanced HCC.385,386
Radioembolization
may be appropriate in some patients with advanced HCC,385,386
specifically
patients 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 abscess
formation.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 with
TARE and followed for up to 6 months.377
Grade 3/4 adverse events were

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more common in patients with main PVT. However, patients with branch
PVT experienced a similar frequency of adverse events related to elevated
bilirubin levels as patients without PVT. Results from a single-center,
prospective longitudinal cohort study of 291 patients with HCC treated with
TARE showed a significant difference in median survival times based on
liver 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 for
Child-Pugh class B patients and those with PVT was 5.6 months. A meta-
analysis including 17 studies with 722 patients with HCC and PVT showed
that 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-Pugh
Class 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 meta-
analysis 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 critical
structures. 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 this
difference 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 patients
randomized 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 while
sparing surrounding liver tissue, thereby limiting the risk of
radiation-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 for
enhanced delivery of higher radiation doses to the tumor while sparing
surrounding critical tissue. SBRT is an advanced technique of EBRT that
delivers large ablative doses of radiation. There is growing evidence
(primarily from non-RCTs) supporting the usefulness of SBRT for patients
with 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 another

(NCCN©
MS-26
study that evaluated the long-term efficacy of SBRT for patients with
primarily 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 treated
with SBRT, tumor size, recurrent stage, and Child-Pugh were identified as
independent prognostic factors for OS in multivariate analysis.395
In a
report 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 median
survival of 17 months. The majority of these patients were at high risk with
relatively advanced-stage tumors (55% of patients had tumor vascular
thrombosis, and 61% of patients had multiple lesions with a median sum
of largest diameter of almost 10 cm and a median diameter of 7.2 cm for
the largest lesion).397
A retrospective analysis comparing RFA and SBRT
in 224 patients with inoperable, nonmetastatic HCC showed that SBRT
may be a preferred option for tumors 2 cm or larger.398
However, another
retrospective analysis from the National Cancer Database including 3980
patients with stage I or II HCC showed that 5-year OS was greater for
patients 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 liver
transplant.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 and
underlying 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 of
safety 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 for
the use of SBRT in patients with Child-Pugh B or poorer liver
function.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 a
model policy supporting the use of proton beam therapy (PBT) in some
oncology populations.407
In a phase II study, 94.8% of patients with
unresectable 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 for
these outcomes. In a comparison of PBT and IMRT, PBT was linked with
higher 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 PBT
may be considered and appropriate in select settings for treating HCC.
Several ongoing studies are continuing to investigate the impact of
hypofractionated 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

(NCCN©
MS-27
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 and
embolization is that the focused heat delivery of RFA may be enhanced by
vessel occlusion through embolization since blood circulation inside the
tumor may interfere with the transfer of heat to the tumor.
However, randomized trials that have compared the combination of
ablation and embolization with ablation or embolization alone have shown
conflicting results. Combination therapy with TACE and PEI resulted in
superior survival compared to TACE or PEI alone in the treatment of
patients 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 in
terms 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 to
assess 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 that
the 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, the
sequential 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 unresectable
single 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-month
follow-up, recurrence rates between the three groups were no longer
statistically significant.
The results of a meta-analysis of 10 RCTs comparing the outcomes of
TACE 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

(NCCN©
MS-28
(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 with
unresectable HCC showed that EBRT combined with TACE is associated
with lower 1-year mortality (RR, 0.51; 95% CI, 0.41–0.62; P .001) and a
better 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 with
macroscopic 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 or
transplantation, if feasible, is preferred for patients who meet surgical or
transplant 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 not
amenable 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 in
some instances. The panel emphasizes that caution should be exercised
when 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 puncture
techniques. 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 for
this 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 the
context 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 to
ablation 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 to
arterially directed therapies, provided that the arterial blood supply to the
tumor 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

(NCCN©
MS-29
individualized patient selection that is specific to the particular arterially
directed therapy being considered is necessary to avoid significant
treatment-related toxicity. General patient selection criteria for arterially
directed 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 patients
with bilirubin 3 mg/dL unless segmental treatment can be performed.
Outside of segmental therapy, TARE with Y-90 microspheres has an
increased risk of radiation-induced liver disease in patients with bilirubin
2 mg/dL.379
Arterially directed therapies are safe to use in patients with
limited tumor invasion of the portal vein but are contraindicated in
Child-Pugh Class C patients, unless the goal of therapy is to bridge the
patient 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 an
alternative to ablation and/or embolization techniques when these
therapies have failed or are contraindicated (in patients with unresectable
disease characterized as extensive or otherwise not suitable for liver
transplantation and those with local disease but who are not considered
candidates 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 or
brain.431
The panel encourages prospective clinical trials evaluating the
role of SBRT in patients with unresectable, locally advanced, or recurrent
HCC.
Systemic Therapy
The majority of patients diagnosed with HCC have advanced disease, and
only a small percentage are eligible for potentially curative therapies.
Furthermore, with the wide range of locoregional therapies available to
treat patients with unresectable HCC confined to the liver, systemic
therapy has often been a treatment of last resort for those patients with
very 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 a
number of active agents for HCC that has progressed on or after previous
systemic treatment. In the 2021 update, combined atezolizumab and
bevacizumab was listed as a preferred regimen while sorafenib and
lenvatinib were listed as other recommended regimens.
Sorafenib
Sorafenib, an oral multikinase inhibitor that suppresses tumor cell
proliferation and angiogenesis, was evaluated in two randomized,
placebo-controlled, phase III trials for the treatment of patients with
advanced 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 this
study, 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 patients
classified as Child-Pugh class A) and good performance status (90% of
patients had ECOG performance status of 0 or 1). Median OS was
significantly 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

(NCCN©
MS-30
sorafenib or placebo arms (150 and 76 in sorafenib and placebo arms,
respectively).433
While the HR for the sorafenib arm compared with the
placebo arm (HR, 0.68; CI, 0.50–0.93; P = .014) was nearly identical to
that reported for the SHARP study, the median OS was strikingly lower in
both 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 the
treatment of HCC had C-P class B liver function.436
A subgroup analysis of
these 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 and
C-P class B, although OS was shorter in the patients with C-P class B liver
function.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 A
group 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 of
death 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 the
dosing and toxicity of sorafenib. Abou-Alfa et al found higher levels of
hyperbilirubinemia, encephalopathy, and ascites in the group with C-P
class 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 in
patients 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 other
validated criteria to evaluate tumor response (such as RECIST289,290
or
EASL criteria176
).434
Sorafenib combined with erlotinib for patients with advanced HCC was
assessed in a phase III RCT (N = 720).445
Results showed that this
combination 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 growth
signaling kinases. In the phase III randomized REFLECT trial, patients
with unresectable HCC (N = 954) were randomized to receive either
lenvatinib or sorafenib as first-line treatment.446
The trial was designed to
demonstrate non-inferiority or superiority of lenvatinib; the prespecified
boundary for non-inferiority was met with median OS of 13.6 months in the
lenvatinib 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

(NCCN©
MS-31
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 of
unresectable 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 the
first-line treatment option for patients with unresectable or metastatic HCC
in a phase 1b trial.453
The IMbrave150 phase III trial enrolled 501 patients
with unresectable HCC and Child Pugh A liver function, with
randomization 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 upper
gastrointestinal bleeding observed in prior phase 2 studies of
bevacizumab 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 to
sorafenib 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 and
progressive disease in 19.6% versus 24.5%. Duration of response was 6
months was estimated to be 87.6% in the atezolizumab and bevacizumab
arm and 59.1% in the sorafenib arm. Updated data from a published
abstract revealed a median OS of 19.2 months for patients in the
atezolizumab and bevacizumab group versus 13.4 months for patients in
the sorafenib group (HR, 0.66; P = .0009).456
Prior to the initiation of the
atezolizumab plus bevacizumab regimen, patients should have adequate
endoscopic evaluation and management for esophageal varices within
approximately 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 is
unclear what the benefits of these systemic therapy options are for
patients who receive the atezolizumab and bevacizumab regimen as a
first-line treatment option and what subsequent agents to use if the
disease 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 regorafenib
in 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 at
least 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), and
disease control (65% vs. 36%; P .001). Adverse events were universal
among patients randomized to receive regorafenib (n = 374), with the
most 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 have
been related to treatment with regorafenib. Based on the results of this

(NCCN©
MS-32
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 to
patients 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 this
regimen 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 placebo
group. 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 the
placebo arm. Analyses of patient-focused outcomes showed that
deterioration of symptoms was not significantly different in patients
randomized 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 patients
randomized 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 that
median OS was greater for patients who received ramucirumab, compared
to 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 in
patients 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 the
confirmatory 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 the
accelerated approval of nivolumab as a single agent for patients with
advanced HCC who were previously treated with sorafenib.466
Based on

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the FDA decision, the panel removed nivolumab as a subsequent-line
treatment option for patients with C-P A disease. As treatment options are
limited for patients with C-P B disease, the panel voted to maintain
nivolumab 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 by
blinded 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 non-
randomized, 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 with
sorafenib. 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 that
the 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 difference
in 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 patients
previously treated with sorafenib.
Dostarlimab-gxly, another anti-PD-1 antibody, was assessed in an open-
label phase I study with 2 cohorts.472
One cohort had 103 patients with
advanced or recurrent microsatellite instability-high (MSI-H)/deficient
mismatch 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 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 treatment-related adverse events were
anemia (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 with
colorectal cancer had an ORR of 36.2% (95% CI, 25.0%–48.7%).473
The
cohort also included two patients with liver cancer. One patient had a
partial 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 patients
with 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 patients
from 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;

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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 a
CR, 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, was
compared 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 with
sorafenib and had high MET expression,478
based on encouraging results
from 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, patients
previously treated with at least one line of systemic therapy were
randomized to receive apatinib or placebo.481
The results, only published
in an abstract, showed that compared to the placebo arm, patients treated
with 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 (4.5
months vs. 1.9 months; HR, 0.471; 95% CI, 0.369-0.601; P .0001), and
ORR (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 molecular
targeted 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 and
RFA.484
In a meta-analysis of 18 studies with 5986 patients comparing
TACE to resection, the survival benefits were significantly higher in the
hepatectomy study arm.485
The consensus of the panel is that initial
treatment with either partial hepatectomy or transplantation should be
considered for patients with liver function characterized by a Child-Pugh
class A score, lack of portal hypertension, and who fit UNOS criteria. In
addition, patients must have operable disease on the basis of performance
status and comorbidity.
Hepatic resection is a potentially curative treatment option and is the
preferred 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 be
considered in patients with tumors 3 cm in diameter who are not
resection candidates due to age or comorbidity.326
The presence of
extrahepatic metastasis is considered to be a contraindication for
resection. Hepatic resection is controversial in patients with limited
multifocal disease as well as those with major vascular invasion. Liver

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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 in
diameter and no evidence of macrovascular involvement or extrahepatic
disease) or can be downstaged to within Milan Criteria. Transplant also
provides a curative intent option for patients with Child-Pugh class B and
C cirrhosis who would not otherwise be surgical candidates. The
guidelines have included consideration of bridge therapy as clinically
indicated for patients eligible for liver transplant. Patients with tumor
characteristics that are marginally outside of the UNOS guidelines may be
considered for transplantation at select institutions. Additionally,
transplantation can be considered for patients who have undergone
successful downstaging therapy (ie, tumor currently meeting Milan
criteria). 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 are
very limited, recommendations are based on the consensus that earlier
identification of disease, primary or recurrent, may facilitate patient
eligibility 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 in
assessing arterial vascularity,74
which is associated with increased risk of
HCC recurrence following treatment.488,489
Elevated AFP levels are
associated with poor prognosis following treatment241,490,491
and should be
measured every 3 months for 2 years, then every 6 to 12 months.
Re-evaluation according to the initial workup should be considered in the
event of disease recurrence. Early imaging per local protocol can be
considered.
Management of Advanced Disease
Locoregional therapy (ablation, arterially directed therapies, or EBRT) is
the preferred treatment option for selected patients with unresectable or
inoperable liver-confined disease. Based on clinical experience with non-
transplant candidates, the panel considers locoregional therapy to be the
preferred approach for treating patients with unresectable liver-confined
disease, or for those patients with localized tumors who are medically
inoperable 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 for
histologic 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 first-
line systemic therapy. Sorafenib is recommended as a category 1 option
(for selected patients with Child-Pugh class A liver function) and as a
category 2A option (for selected patients with Child-Pugh class B7 liver
function) with disease characterized as: unresectable (liver-confined) and
extensive/not suitable for liver transplantation; local disease only in
patients 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

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class A liver function only. Nivolumab and FOLFOX are listed as “useful in
certain circumstances”. Nivolumab465
is a first-line option (category 2B) for
patients with Child-Pugh Class A or B liver function who are ineligible for
tyrosine 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) and
lack of significant survival benefit in final analysis.474
The panel now recommends several subsequent-line therapy options for
disease 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 and
bevacizumab 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. Regorafenib
and cabozantinib are recommended only for patients with C-P A liver
function, while ramucirumab is recommended only for patients with a
baseline AFP level of 400 ng/mL or greater. Checkpoint inhibitors options
include nivolumab monotherapy, pembrolizumab monotherapy, and
combination 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 or
without MSI-H tumors who have not been previously treated with a
checkpoint 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 this
drug from category 2A to category 2B for patients with C-P Class A liver
function.470
The NCCN Guidelines include combined nivolumab and
ipilimumab 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 a
checkpoint inhibitor.495-497
Dostarlimab-gxly is a recommended treatment
option (category 2B, useful in certain circumstances) for patients with MSI-
H/dMMR recurrent or advanced tumors that have progressed on or
following 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 with
disease progression on or following sorafenib. Sorafenib may be used in
patients 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 with
cross-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 have
shown association with treatment response and survival. 459,463,498
The panel recommends that best supportive care measures be
administered to patients with unresectable or metastatic disease,
alongside cancer-directed therapies.
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

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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 those
younger than 45 years of age.500,501
Globally, there are pockets of
increased incidence in Korea; Japan; some areas of Eastern Europe and
South 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 most
prevalent risk factor for gallbladder cancer, and the risk increases with
stone 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 historical
estimates of cancer in up to 22% of gallbladders with calcification.506
More
recent reports, however, suggest that the risk of developing gallbladder
cancer 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 chronic
cholecystitis or pancreaticobiliary maljunction have a greater prevalence of
gallbladder cancers that are microsatellite instability-high,514
and
HER2/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 four
stages based on the depth of invasion into the gallbladder wall and the
extent of spread to surrounding organs and lymph nodes. In the revised 8th
edition of the AJCC staging system, T2 gallbladder carcinoma was divided
into two groups: tumors on the peritoneal side (T2a) and tumors on the
hepatic side (T2b).165
This revision is supported by two retrospective
studies showing that gallbladder tumors located on the hepatic side is
associated with worse prognosis, compared to tumors located on the
peritoneal 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 spread
beyond 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 gallbladder
cancer.518,519
Results from a retrospective analysis of 435 patients treated
at 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 is
often asymptomatic in its early stages and has an aggressive nature that
can spread rapidly. Another factor contributing to late diagnosis of
gallbladder cancer is a clinical presentation that mimics that of biliary colic
or chronic cholecystitis. Hence, it is common for a diagnosis of gallbladder

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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 review
of 435 patients diagnosed and treated with curative resection at a single
center during the period of 1995 to 2005, 123 patients (47%) were
diagnosed with gallbladder cancer as an incidental finding after
laparoscopic cholecystectomy.519
Other possible clinical presentations of
gallbladder 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 is
associated with a poor prognosis; patients with jaundice are more likely to
have advanced-stage disease (96% vs. 60%; P .001) and significantly
lower disease-specific survival (6 months vs.16 months; P .0001) than
those without jaundice.521
In a sample of 82 patients with gallbladder
cancer who presented with jaundice, the resectability rate was low (7%),
with even fewer having negative surgical margins (5%) and no disease-
free survivors at 2 years.521
Workup
The initial workup of patients presenting with a gallbladder mass or
disease suspicious for gallbladder cancer should include liver function
tests and an assessment of hepatic reserve. High-quality contrast-
enhanced 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 distant
metastases, and to detect the extent of direct tumor invasion of other
organs/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 were
unreliable 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 from
retrospective studies indicates that it may be useful for the detection of
radiologically occult regional lymph node and distant metastatic disease in
patients 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 preferred
over endoscopic retrograde cholangiopancreatography (ERCP) or
percutaneous transhepatic cholangiography (PTC), unless a therapeutic
intervention is planned.522
CEA and CA 19-9 testing could be considered as part of initial workup (in
conjunction with imaging studies). Elevated serum CEA levels (4.0
ng/mL) or CA 19-9 levels (20.0 units/mL) could be suggestive of
gallbladder 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 gallbladder
cancer and CA 19-9 could also be elevated in patients with jaundice from
other 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 resectable
gallbladder cancer is the same, with the exception that in patients with an
incidental finding of gallbladder cancer on pathologic review, the
gallbladder has been removed. Complete resection with negative margins
remains the only potentially curative treatment for patients with gallbladder
cancer.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

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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 some
patients to obtain negative margins, depending on the stage and location
of the tumor, depth of tumor invasion, proximity to adjacent organs, and
expertise of the surgeon.
A simple cholecystectomy is an adequate treatment for patients with T1a
tumors, 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, and
there is some risk of finding residual nodal or hepatic disease when re-
resecting 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 with
extended 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 shown
to 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, poor
differentiation, and common bile duct involvement were independent
predictors of poor disease-specific survival.539
Major hepatectomy and
common 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% in
patients with an incidental finding of gallbladder cancer.530
However, for
these patients, it has been suggested that common duct resection should
be performed at the time of re-resection for those with positive cystic duct
margins due to the presence of residual disease.541
However, occasionally
the 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 when
necessary to obtain negative margins (R0 resection) in well-selected
clinical 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 is
some 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 to
selection bias. Nevertheless, in all patients with a convincing clinical
evidence of gallbladder cancer, the guidelines recommend that surgery
should be performed by an experienced surgeon who is prepared to do a
definitive resection of the tumor. If expertise is unavailable, patients should
be referred to a center with available expertise. The panel is also of the
opinion that surgery should not be performed in situations where the
extent and resectability of the disease has not been established with good
quality imaging. Consultation with a pathologist with expertise in the

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hepatobiliary region should be considered, and careful review of the
pathology 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 of
disease and the presence of distant metastases. Staging laparoscopy has
been shown to identify radiographically occult disseminated disease in
patients with primary gallbladder cancer.544
In a prospective study that
evaluated the role of staging laparoscopy in 409 patients diagnosed with
primary 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 the
need for laparotomy in 55.9% of patients with unresectable disease.
Staging laparoscopy, however, is of relatively low yield in patients with
incidental finding of gallbladder cancer, since disseminated disease is
relatively 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 with
cholecystectomy and en bloc hepatic resection and lymphadenectomy is
recommended. In cases where there is a gallbladder mass but the
diagnosis is unclear, intraoperative staging and consideration of
intraoperative photography prior to definitive resection should be
considered. In selected cases, a frozen section biopsy of the gallbladder
can 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 (most
commonly the celiac axis or aortocaval groove [retropancreatic]) or distant
metastatic disease (ie, most commonly liver and peritoneal cavity).
Additionally, some tumors are unresectable based on local invasion of the
porta 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 associated
with 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 for
patients without liver involvement, P = .003) but not in patients with T1b
tumors.520
As mentioned above, hepatic resection and lymphadenectomy with or
without 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 a
significant 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

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site disease is associated with disseminated peritoneal metastases, and
prophylactic port site resection is not associated with improved survival or
disease recurrence in patients with incidental findings of gallbladder
cancer 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, and
lymphadenectomy, with or without bile duct excision. A biopsy is not
necessary 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 with
gallbladder cancer is considered a relative contraindication to surgery, and
outcomes are generally poor in these patients; only a rare group of
patients with localized node-negative disease potentially benefit from
complete 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 and
referral to an experienced center should be considered. The guidelines
recommend consideration of preoperative biliary drainage for patients with
jaundice. 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 consideration
of 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 the
tumor and identify patients who are most likely to benefit from surgical
intervention. 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 to
assess 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 with
gemcitabine 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 distant
lymph node metastases in the celiac axis or aortocaval groove) or

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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 unresectable
disease. See sections on Chemotherapy and Chemoradiation and
Radiation Therapy for Treatment for Advanced Biliary Tract Cancers.
In patients with unresectable or metastatic gallbladder cancer and
jaundice, 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 quality
of 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 or
progression.
Cholangiocarcinomas
Cholangiocarcinomas encompass all tumors originating in the epithelium
of the bile duct. More than 90% of cholangiocarcinomas are
adenocarcinomas and are broadly divided into three histologic types
based on their growth patterns: mass-forming, periductal-infiltrating, and
intraductal-growing.557
Cholangiocarcinomas are diagnosed throughout the
biliary tree and are typically classified as either intrahepatic or extrahepatic
cholangiocarcinoma. Extrahepatic cholangiocarcinomas are more
common than intrahepatic cholangiocarcinomas. Analyses of SEER data
from 1973 to 2012 showed that incidence of intrahepatic
cholangiocarcinoma 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 intrahepatic
cholangiocarcinoma, such as with imaging, molecular diagnostics, and
pathology.558
These cancers might have previously been diagnosed as
cancers of unknown primary, in which incidence decreased from 1973 to
2012 [annual percentage change (APC), -1.87%].558
Five-year OS rates
for cholangiocarcinoma improved from 1973 to 2008, likely due to
improvements 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 the
extrahepatic 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 the
junction of the right and left hepatic ducts; distal cholangiocarcinomas are

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extrahepatic lesions arising in the extrahepatic bile ducts above the
ampulla of Vater and below the confluence of the left and right bile
ducts.560
Hilar cholangiocarcinomas are the most common type of
extrahepatic cholangiocarcinomas.
The NCCN Guidelines discuss the clinical management of patients with
intra- and extrahepatic cholangiocarcinomas including hilar
cholangiocarcinoma and the distal bile duct tumors. Tumors of the ampulla
of Vater are not included in the NCCN Guidelines for Hepatobiliary
Cancers.
Risk Factors
No predisposing factors are identified in most patients diagnosed with
cholangiocarcinoma,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 presence
of 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 with
cholangiocarcinoma.562
Inflammatory bowel disease may also be a risk
factor for cholangiocarcinoma, though this association may be confounded
by primary sclerosing cholangitis.563
Other risk factors for intrahepatic
cholangiocarcinoma have been found to include HBV infection, cirrhosis,
diabetes, obesity, alcohol, and tobacco.564
A systematic review and meta-
analysis reported that the strongest risk factors for both intrahepatic and
extrahepatic 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
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
Staging and Prognosis
Intrahepatic Cholangiocarcinoma
In the 6th
edition of the AJCC staging system, intrahepatic
cholangiocarcinoma was staged identically to HCC. However, this
staging system did not include predictive clinicopathologic features
(multiple hepatic tumors, regional nodal involvement, and large tumor
size) that are specific to intrahepatic cholangiocarcinoma.568
In some
reports, tumor size had no effect on survival in patients undergoing
complete resection.569,570
In a SEER database analysis of 598 patients
with intrahepatic cholangiocarcinoma who had undergone surgery,
Nathan et al reported that multiple lesions and vascular invasion
predicted adverse prognosis following resection; lymph node status was
of prognostic significance among patients without distant metastases.569
In this study, tumor size had no independent effect on survival. These
findings were confirmed in a subsequent multi-institutional international
study of 449 patients undergoing surgery for intrahepatic
cholangiocarcinoma.570
The 5-year survival rate was higher for patients
who lacked all three risk factors (multiple tumors, vascular invasion, and
N1 disease) than for those with one or more risk factors (38.3%, 27.3%,
and 18.1%, respectively) and, more importantly, tumor number and
vascular invasion were of prognostic significance only in patients with N0
disease. Although tumor size was associated with survival in the
univariate analysis, it was not of prognostic significance in a multivariate
analysis.
In the revised 7th
edition of the AJCC staging system, intrahepatic
cholangiocarcinoma had a new staging classification that was independent
of the staging classification used for HCC.571
This classification focused on

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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 with
stage III disease (P .0001).
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 a
tumor 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.
Extrahepatic Cholangiocarcinoma
The 7th
edition of AJCC staging system included a separate TNM
classification for hilar and distal extrahepatic cholangiocarcinoma, based
on the extent of liver involvement and distant metastatic disease.571
In the
revised 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 in
patients with distal as well as hilar cholangiocarcinomas.573,574
In the
revised 8th
edition of the AJCC staging system for cancer of the distal bile
duct, depth of tumor invasion has been added to the categorization of T1,
T2, and T3 tumors.165
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
features such as vascular encasement, lymph node involvement, distant
metastases, 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, and
survival.576,577
In this staging system, hilar cholangiocarcinomas are
classified into three stages (T1–T3) based on the location and extent of
bile duct involvement, the presence or absence of portal venous invasion,
and hepatic lobar atrophy.576
Negative histologic margins, concomitant
partial hepatectomy, and well-differentiated tumor histology were
associated with improved outcome after resection; increasing T-stage
significantly correlated with reduced R0 resection rate, distant metastatic
disease, and lower median survival.577
Diagnosis
Early-stage cholangiocarcinoma may only manifest as mild changes in
serum 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. Intrahepatic
cholangiocarcinoma may be detected incidentally as an isolated
intrahepatic mass on imaging.98
In contrast, patients with extrahepatic
cholangiocarcinoma are likely to present with jaundice followed by
evidence of a biliary obstruction or abnormality on subsequent imaging.
Workup
The initial workup should include liver function tests. CEA and CA 19-9
testing can be considered for baseline assessment, although these
markers are not specific for cholangiocarcinoma; they are also associated
with other malignancies and benign conditions.578
CA 19-9 may be falsely
elevated due to jaundice.579
Viral hepatitis serologies should be

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considered for intrahepatic cholangiocarcinoma. If hepatitis is diagnosed, it
needs to be monitored and managed following ASCO’s guidelines.580
Since the diagnosis of HCC versus intrahepatic cholangiocarcinoma can
be difficult, AFP testing may also be considered, especially in patients with
chronic liver disease. Further, there are a number of mixed
HCC/intrahepatic cholangiocarcinoma cases in which AFP may be
elevated. LI-RADS provides some guidance in distinguishing between
HCC and intrahepatic cholangiocarcinoma lesions.581
Early surgical consultation (prior to drainage in jaundiced patients) with a
multidisciplinary team is recommended as part of the initial workup for
assessment of resectability in intrahepatic and extrahepatic
cholangiocarcinomas. 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 proceed
with biopsy once transplant or resectability status has been determined.
For patients with hilar cholangiocarcinoma who may be transplant
candidates, 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 with
directed biopsies is the ideal technique for the workup of
cholangiocarcinoma. 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 extrahepatic
cholangiocarcinoma 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 of
vascular anomalies and satellite lesions.583
Therefore, multiphasic CT/MRI
with IV contrast is used to help determine tumor resectability by
characterizing the primary tumor, its relationship to nearby major vessels
and the biliary tree, the presence of satellite lesions and distant
metastases 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 distant
metastasis 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 be
done after surgical consultation to prevent jeopardizing a patient’s
candidacy for transplantation. EGD and colonoscopy are recommended as
part 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 not
definitive. IgG4-associated cholangitis, which presents with biliary
strictures and obstructive jaundice, may mimic extrahepatic
cholangiocarcinoma.585,586
Therefore, serum IgG4 should be considered in
patients for whom a diagnosis of extrahepatic cholangiocarcinoma is not
clear, in order to avoid an unnecessary surgical resection.587,588
Patients
with 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 of
cholangiography for the assessment of bile duct tumors.592
Direct
cholangiography should only be performed when necessary as a
diagnostic procedure in patients who are not resectable or in patients in
whom a therapeutic intervention is necessary. ERCP/PTC is not

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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 patients
with 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 not
been established in the evaluation of patients with cholangiocarcinoma,
emerging evidence indicates that it may be useful for the detection of
regional lymph node metastases and distant metastatic disease in patients
with otherwise potentially resectable disease.524-526,593,594
Management of Intrahepatic Cholangiocarcinoma
Complete resection is the only potentially curative treatment for patients
with resectable disease, although most patients are not candidates for
surgery 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, with
some reports documenting R0 resection as a significant predictor of
survival and recurrence,595-600
while others suggest that margin status is
not a significant predictor of outcome.601,602
Ribero et al from the Italian
Intrahepatic Cholangiocarcinoma Study Group reported that
margin-negative resection was associated with significantly higher survival
rates (the estimated 5-year survival rates were 39.8% vs. 4.7% for patients
with a positive margin) and significantly lower recurrence rates (53.9% vs.
73.6% for those with a positive margin); however, in patients resected with
negative 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 the
strongest 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 by
Ribero et al.600
A retrospective analysis of 535 patients with intrahepatic
cholangiocarcinoma 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 the
recommendation that hepatic resection with negative margins should be
the goal of surgical therapy for patients with potentially resectable
disease.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 liver
disease, lymph node metastases, and distant metastases. Multifocal liver
disease, distant (beyond the porta hepatis) nodal metastases, and distant
metastases contraindicate surgery as these generally indicate advanced
incurable disease. In highly selected situations, resection can be
considered. A preoperative biopsy is not always necessary prior to
definitive 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 or
disseminated metastatic disease.605,606
Staging laparoscopy has been
shown to identify peritoneal metastases and liver metastases with a

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respective yield of 36% and 67% accuracy in patients with potentially
resectable 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 to
note, however, that there are no data to support a therapeutic benefit of
routine 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 are
limited clinical trial data to support a standard regimen for adjuvant
treatment. Lymphovascular and perineural invasion, lymph node
metastasis, and tumor size greater than or equal to 5 cm have been
reported 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 intrahepatic
cholangiocarcinomas. The results of two independent prospective studies
showed that the efficacy of TACE with irinotecan DEB was similar to that
of 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 microspheres
in 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 II
MISPHEC trial, investigators determined that the combination of
radioembolization with Y-90 microspheres with chemotherapy (cisplatin
and gemcitabine) as a first-line treatment option in 41 patients with
unresectable 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 to
surgery.
Radiation therapy is a locoregional treatment option for unresectable
A single-institution study including 79
patients with unresectable intrahepatic cholangiocarcinoma showed that
higher doses of RT (3D-CRT with photons or protons) were associated
with 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
A non-randomized multi-institutional
trial including 39 patients with unresectable intrahepatic
cholangiocarcinoma 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

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PFS rate of 25.7%.408
Therefore, hypofractionated proton therapy may
also be considered for patients with unresectable intrahepatic
cholangiocarcinoma, but this treatment should only be administered at
experienced centers.
Data from prospective studies support the use of hepatic arterial infusion
(HAI) chemotherapy in patients with advanced, liver confined, and
unresectable 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 were
greatest 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 intrahepatic
cholangiocarcinoma 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 be
considered 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 patients
with 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 the
area of the head of the pancreas (distal cholangiocarcinoma) are
considered standard parts of curative resections.643,644
Since these
surgical procedures are associated with postoperative morbidity, they
should 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 tract
and en bloc liver resection (typically a major hepatectomy involving the
right or left liver with the caudate lobe) is recommended for hilar tumors.
Bile duct excision with frozen section assessment of proximal and distal
bile 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 high
morbidity 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 exercised
in 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 of

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drainage) should be made by a multidisciplinary team at a high-volume
center.
In patients with hilar cholangiocarcinoma, extended hepatic resection (to
encompass the biliary confluence) with caudate lobectomy is
recommended, 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 in
patients with more advanced disease. This approach requires substantial
experience and appropriate surgical support for such technical
operations.653,654
For adjuvant treatment of resected hilar
cholangiocarcinoma, see the section on Adjuvant Chemotherapy and
Chemoradiation 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 to
improvements in imaging techniques.656
While not routinely used in all patients undergoing resection, the
consensus 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 be
considered for patients with low FLR volumes. Patients with unresectable
or 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 is
recommended 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 these
patients 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 patients
with lymph node-negative, non-disseminated, locally advanced hilar
cholangiocarcinomas.667-670
There is retrospective evidence suggesting
that neoadjuvant chemoradiation followed by liver transplantation is
effective for selected patients with hilar cholangiocarcinoma.671-673
Results
from two studies suggest that the combination of liver transplantation and
neoadjuvant and/or adjuvant chemoradiation is associated with higher
RFS than a potentially curative resection.674,675
However, in one of these
studies, there were substantial differences in the characteristics of patients
in the two treatment groups.674
It is important to note that many of these
reports include patients with primary sclerosing cholangitis, and some
have not had a definitive histologic cancer diagnosis. Liver transplantation
should be considered only for highly selected patients (ie, tumor ≤3 cm in
radial diameter, no intrahepatic or extrahepatic metastases, no nodal
disease) with either unresectable disease with otherwise normal biliary

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and hepatic function or underlying chronic liver disease precluding
surgery. The panel encourages continuation of clinical research in this
area, and referral of patients with unresectable disease to a transplant
center with an UNOS-approved protocol for transplant of
cholangiocarcinoma 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 extrahepatic
cholangiocarcinoma. The combination of PDT with biliary stenting was
reported to be associated with prolonged OS in patients with unresectable
cholangiocarcinoma in two small RCTs.676,677
Surveillance
There are no data to support a specific surveillance schedule or tests in
patients undergoing resection of cholangiocarcinoma; determination of
appropriate follow-up schedule/imaging should include a careful
patient/physician discussion. It is recommended that follow-up of patients
undergoing resection of cholangiocarcinoma should include consideration
of 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 the
event of disease progression.
Adjuvant Chemotherapy and Chemoradiation for Biliary Tract
Cancers
Recurrence following surgery is a primary limitation for cure in patients
with biliary tract cancers, which provides an important justification for the
use of adjuvant therapy. In a sample of 80 patients with extrahepatic
cholangiocarcinoma 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 these
patients have been evaluated mostly in retrospective studies that have
included 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 is
completely different. Despite the challenges associated with the accrual of
large numbers of patients with biliary tract cancer for randomized phase III
trials, it is widely recognized that efforts should be made to conduct such
studies 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 resected
cholangiocarcinoma 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 and
36.4 months for the observation arm. This difference was statistically
significant 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 resected
pancreaticobiliary 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 better
5-year DFS for patients with gallbladder cancer treated with chemotherapy
(20.3% compared to 11.6% in the control group; P = .021), although no
significant differences between the two treatment arms were observed for

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all patients with biliary duct cancers. Results from this trial support the
suggestion 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 were
randomized 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 a
phase 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 role
of adjuvant therapy.505,684,685
It should be noted that the majority of
recurrences 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 associated
with 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 meta-
analysis of 42,917 patients found a significantly higher OS with adjuvant
therapy after surgery compared with surgery alone.687
Ren et al reported a
higher 5-year OS with adjuvant radiotherapy post surgery in patients with
gallbladder cancer or extrahepatic cholangiocarcinoma in a meta-analysis
of 21 clinical trials.
In studies that included only patients with gallbladder cancer, a meta-
analysis including 10 retrospective studies with 3191 patients showed that
adjuvant chemotherapy was associated with improved OS, compared to
resection 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 have
concluded that adjuvant chemotherapy or chemoradiation following R0
resection might improve OS in selected patients with T2 or T3 tumors and
lymph 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 of
locoregional 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 median
survival 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 with
capecitabine 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

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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 followed
with observation alone, receive fluoropyrimidine chemoradiation, or
receive fluoropyrimidine or gemcitabine chemotherapy. Patients with
intrahepatic 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 5-
fluououracil monotherapy or combined with oxaliplatin. Besides
capecitabine monotherapy, whose use in this setting is supported by the
phase 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 data
from studies of patients with advanced disease. Additionally, some of the
recommendations are based on practice patterns at NCCN Member
Institutions and retrospective studies from single-center experiences.
Besides gemcitabine monotherapy not being recommended for patients
with 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 the
particular type of biliary tract cancer, due to the limited data and the
heterogeneity of patient populations included in many of the published
studies. 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 unresectable
disease. For patients with R1 margins or positive regional nodes, the
optimal 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 (to
allow 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 and
the median survival for those undergoing supportive care alone is short.704
Treatment options for advanced biliary tract cancers include enrollment in
a 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, and
etoposide) over best supportive care for patients with advanced biliary
tract cancers was initially suggested in a phase III trial of 90 patients with
advanced pancreatic and biliary tract cancers, 37 of whom had advanced
biliary tract cancers.705
In a single-center randomized study of 81 patients
with unresectable gallbladder cancer, Sharma et al reported that modified

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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, for
the 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 of
chemotherapy for the treatment of patients with advanced biliary tract
cancers.707,708
The results of a pooled analysis of 104 trials that have
included 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 a
fluoropyrimidine-based regimen, patients receiving gemcitabine were
shown to have a lower risk of death.710
Most importantly, the support for
the use of gemcitabine-based or fluoropyrimidine-based chemotherapy for
patients 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 in
favor 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 two
arms. 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 that
derived neutrophil-to-lymphocyte ratio assessed at baseline was
associated with greater long-term survival in those randomized to receive
gemcitabine/cisplatin (P .01).715
Based on these results, the combination
of gemcitabine and cisplatin is considered to be the standard of care for
first-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 with
combined cisplatin and gemcitabine improved median OS (6.2 months vs.
5.3 months; adjusted HR, 0.69; P = .031).716
Second-line treatment with
fluorouracil and irinotecan (FOLFIRI) also provided some benefits to
patients.717
Examples of other gemcitabine-based or fluoropyrimidine (fluorouracil or
capecitabine)-based regimens with demonstrated activity in phase II trials
include: gemcitabine and cisplatin or oxaliplatin718-726
; gemcitabine and
fluoropyrimidine727-731
; gemcitabine and albumin-bound paclitaxel (for
cholangiocarcinoma)732
; gemcitabine, cisplatin, and albumin-bound
paclitaxel733
; gemcitabine and cetuximab734
; and fluoropyrimidine and
oxaliplatin or cisplatin.735-738
In the phase II trial examining the combination
of gemcitabine-cisplatin with albumin-bound paclitaxel, the disease status
of 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 been
shown 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 evaluated
fluorouracil, leucovorin, and etoposide versus fluorouracil, cisplatin, and
epirubicin did not show one regimen to be significantly superior with
respect to OS (12 months vs. 9 months, respectively) in patients with
advanced biliary tract cancers, although the trial was underpowered to
detect such a difference.740
In a phase II trial, the combination of

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panitumumab, a monoclonal anti-EGFR antibody, with gemcitabine and
irinotecan showed encouraging efficacy with good tolerability in patients
with 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 untreated
patients 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 (3.3
months).712
In a randomized phase II trial, the combination of gemcitabine
and sorafenib was compared to gemcitabine with a placebo in 102
patients with unresectable or metastatic biliary tract cancer.744
There were
no significant between-group differences for OS and PFS rates, but
patients who developed liver metastases following resection survived
longer if they received sorafenib, relative to patients who received the
placebo (P = .019). The gemcitabine/sorafenib combination was well-
tolerated. Data from phase III trials are needed.
The panel has included combination therapy with gemcitabine and
cisplatin with a category 1 recommendation for patients with unresectable
or 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 with
oxaliplatin; fluorouracil with oxaliplatin; and single-agent fluorouracil,
capecitabine, and gemcitabine. Gemcitabine combined with albumin-
bound paclitaxel is an option for patients with unresectable or metastatic
biliary tract cancer. Capecitabine or fluorouracil, with cisplatin, are
included 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 with
results of studies of the gemcitabine and capecitabine regimen in the
setting 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 is
insufficient evidence to recommend specific regimens for second-line
therapy in this group of patients, and prospective randomized trials are
needed.
Chemoradiation and Radiation Therapy
Chemoradiation in the setting of advanced biliary tract cancers can
provide 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 patients
treated with chemoradiation for unresectable extrahepatic
cholangiocarcinoma, 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 chemoradiation
in the treatment of biliary tract cancers has been fluorouracil,747,748
although capecitabine has been substituted for fluorouracil in some
studies.699
The panel recommends that concurrent chemoradiation (EBRT
guided by imaging) should be limited to either fluorouracil or capecitabine,

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and that such treatment should be restricted to patients without evidence
of metastatic disease. Concurrent chemoradiation with gemcitabine is not
recommended due to the limited experience and toxicity associated with
this treatment.
RT with EBRT and SBRT may be used for patients with unresectable
biliary tract cancers. Evidence supports the consideration of RT for
treatment of unresectable and metastatic intrahepatic
cholangiocarcinoma,405,408,631,749
but there is little evidence to support this
treatment option for gallbladder cancer and extrahepatic
cholangiocarcinoma without concurrent chemotherapy and in patients with
unresected 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 intrahepatic
cholangiocarcinomas.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 with
extrahepatic cholangiocarcinoma,760
is associated with poor prognosis in
these patients.758
A phase III study with 185 patients with advanced IDH1-
mutant cholangiocarcinoma resulted in significant improvement in PFS
(median 2.7 months vs. 1.4 months; HR, 0.37; P .0001) when treated
with ivosidenib, an IDH1 inhibitor, compared to placebo.761
The panel
voted to include ivosidenib as a subsequent-line treatment option “useful
in 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 promising
therapeutic 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%) in
patients 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 and
infigratinib 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 have
shown 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 gene
fusions. A study including 35 patients with resected intrahepatic
cholangiocarcinoma 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 rare
occurrence 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 and
trametinib led to an ORR of 51% (95% CI, 36%–67%).773
Results from the
Subprotocol 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

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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 extrahepatic
cholangiocarcinomas.775
In patients with lymph node metastases, HER2
gene amplification may be associated with poor prognosis.775
Other gene
mutations that may be associated with a poor prognosis are: ALK for
extrahepatic cholangiocarcinoma; ARID1A, PIK3C2G, STK11, and
TGFBR2 for intrahepatic cholangiocarcinoma; and TP53 for intrahepatic
and 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 from
the study also revealed that patients with a TMB-H status could have a
robust 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 with
dMMR 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 treatment
of unresectable or metastatic, MSI-H, dMMR, or TMB-H solid tumors that
have 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 with
no prior treatment with a checkpoint inhibitor) treatment option “useful in
certain 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 open-
label phase I study with 2 cohorts.472
One cohort had 103 patients with
advanced or recurrent MSI-H/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 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 treatment-
related adverse events were anemia (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 with colorectal cancer had an ORR of 36.2%
(95% CI, 25.0%–48.7%).473
The cohort also included one patient with
gallbladder cancer and 1 with biliary neoplasm. Both patients had a
complete response. The panel voted to include dostarlimab-gxly as a
category 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 no
satisfactory alternative treatment options, and who have not been
previously 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

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obtained, upon investigator assessment, with the use of nivolumab,
another anti-PD1 drug.778
With blinded independent central review, the
ORR was 11% and the disease control rate was 50%. In the intention-to-
treat 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” for
patients with unresectable or metastatic progressive disease who have not
been previously treated with a checkpoint inhibitor.
Initial results from the phase II LEAP-005 trial, published in an abstract
that examined the combination of lenvatinib with pembrolizumab as a
subsequent 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 or
metastatic progressive disease who have not been previously treated with
a checkpoint inhibitor.
In a retrospective review of eight patients with advanced gallbladder
cancer and HER2/neu gene amplification or overexpression, five of the
eight patients who received HER2/neu-directed therapy (trastuzumab)
experienced a PR or CR. No response was seen in five patients with
cholangiocarcinoma 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). In
a 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 a
disease control rate of 64%.784
In the phase II REACHIN trial, patients with
biliary tract cancers were randomized to receive best supportive care
along 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 to
include 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 patients
with 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 the
best available potentially curative treatment. Liver transplantation is a
curative option for select resectable patients. Bridge therapy can be
considered for patients with HCC to decrease tumor progression and the
dropout rate from the liver transplantation waiting list.
Locoregional therapies (ablation, arterially directed therapies, and RT) are
often the initial approach for patients with HCC who are not candidates for
surgery or liver transplantation. Ablation should be considered as definitive
treatment in the context of a multidisciplinary review in well-selected
patients with small properly located tumors. Arterially directed therapies
(TACE, DEB-TACE, or TARE with Y-90 microspheres) are appropriate for

(NCCN©
MS-58
patients with unresectable or inoperable tumors that are not amenable to
ablation 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 have
failed or are contraindicated. Though it is currently rarely used, there are
emerging data supporting its usefulness. PBT may also be used in select
settings. Locoregional therapy is also included as an option for patients
with unresectable or metastatic intrahepatic cholangiocarcinoma. RT with
EBRT and SBRT may be used in patients with unresectable gallbladder
cancer or extrahepatic cholangiocarcinoma, though there is little evidence
to support this treatment option without concurrent chemotherapy and in
patients with unresected disease.
The combination of atezolizumab and bevacizumab is now the preferred
first-line option for patients with HCC. Lenvatinib and sorafenib are listed
as other recommended first-line options. A number of agents have
recently been added to the NCCN Guidelines for subsequent-line therapy
for patients with disease progression. These options include regorafenib,
cabozantinib, ramucirumab, nivolumab, combined nivolumab and
ipilimumab, pembrolizumab, and dostarlimab-gxly. The results of the
randomized phase III ABC-02 study demonstrated a survival advantage
for the combination of gemcitabine and cisplatin over gemcitabine alone in
patients with advanced or metastatic biliary tract cancers. The combination
of 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, and
combined dabrafenib and trametinib may benefit certain patients with
specific genomic mutations.
It is essential that all patients be evaluated by a multidisciplinary team
prior to initiation of treatment. Careful patient selection for treatment and
patient engagement are essential. There are relatively few high-quality
RCTs of patients with hepatobiliary cancers, and patient participation in
prospective clinical trials is the preferred option for the treatment of
patients with all stages of disease.

(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
Figure 1: Classification of Cholangiocarcinoma
Reproduced with permission from Patel T. Cholangiocarcinoma. Nat Clin Pract Gastroenterol Hepatol 2006;3:33-42.

(NCCN©
MS-60
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