(NCCN

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 3.2021 — June 15, 2021

Continue

NCCN.org

NCCN Guidelines for Patients

available at www.nccn.org/patients

NCCN Guidelines Version 3.2021

Hepatobiliary Cancers

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

NCCN Guidelines Index

Table of Contents

Discussion

NCCN Guidelines Panel Disclosures

Continue

¤ 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

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

Comprehensive Cancer Center

Adam Yopp, MD ¶

UT Southwestern Simmons

Comprehensive Cancer Center

NCCN

Susan Darlow, PhD

Cindy Hochstetler, PhD

Liz Hollinger, BSN, RN

Nicole McMillian, MS

NCCN Guidelines Version 3.2021

Hepatobiliary Cancers

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

NCCN Guidelines Index

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 nd 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 Conrmed (HCC-3)

• Potentially Resectable or Transplantable, Operable by Performance Status or Comorbidity (HCC-4)

• Unresectable Hepatocellular Carcinoma (HCC-5)

• Liver-Conned 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

Biliary Tract Cancers

• Principles of Imaging (BIL-A)

• Principles of Radiation Therapy (BIL-B)

• Principles of Systemic Therapy (BIL-C)

Hepatobiliary Cancers

• 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 Guidelines Version 3.2021

Hepatobiliary Cancers

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NCCN Guidelines Index

Table of Contents

Discussion

UPDATES

Continued

Updates in Version 2.2021 of the NCCN Guidelines for Hepatobiliary Cancers from Version 1.2021 include:

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-conned 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 reect use on or after sorafenib in

patients who previously tolerated sorafenib at a dose of at least 400

mg per day.”

Updates in Version 1.2021 of the NCCN Guidelines for Hepatobiliary Cancers from Version 5.2020 include:

Biliary Tract Cancers

BIL-C 2 of 3

• Subsequent-Line Therapy for Biliary Tract Cancers if Disease Progression

Useful in Certain Circumstances: Added "Ingratinib" for cholangiocarcinoma with FGFR2 fusions or rearrangements.

BIL-C 3 of 3

Reference updated for Ingratinib: 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 reect 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

• The discussion section has been updated to reect the changes in the algorithm.

Updates in Version 3.2021 of the NCCN Guidelines for Hepatobiliary Cancers from Version 2.2021 include:

NCCN Guidelines Version 3.2021

Hepatobiliary Cancers

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

NCCN Guidelines Index

Table of Contents

Discussion

UPDATES

Continued

Updates in Version 1.2021 of the NCCN Guidelines for Hepatobiliary Cancers from Version 5.2020 include:

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:

◊ 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 conrm metastatic

disease for histologic conrmation 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-eectiveness has not been

established; and their use as supplementary surveillance tests is

optional."

HCC-B

• Initial biopsy

3rd sub-bullet revised, "Conrmation 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, specically

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."

Last bullet revised, "...benet 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.

Vilgrain V, Pereira H, Assenat E, et al. Ecacy 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-Pacic Patients With

Hepatocellular Carcinoma. J Clin Oncol 2018;36:1913-21.

Kulik LM, Carr BI, Mulcahy MF, et al. Safety and ecacy 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.

NCCN Guidelines Version 3.2021

Hepatobiliary Cancers

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

NCCN Guidelines Index

Table of Contents

Discussion

Updates in Version 1.2021 of the NCCN Guidelines for Hepatobiliary Cancers from Version 5.2020 include:

UPDATES

Continued

HCC-F (1 of 2)

• Treatment Modalities

1st paragraph heading modied, "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 reect 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.”

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 dene standard regimen or denitive

benet. 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..."

NCCN Guidelines Version 3.2021

Hepatobiliary Cancers

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

NCCN Guidelines Index

Table of Contents

Discussion

Updates in Version 1.2021 of the NCCN Guidelines for Hepatobiliary Cancers from Version 5.2020 include:

UPDATES

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/les/content-les/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-uorouracil + cisplatin (category 2B)

◊ Capecitabine + cisplatin (category 2B)

• Adjuvant Therapy; Other Recommended Regimens

Removed: 5-uorouracil + 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-uorouracil + 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) SCREENING

HCC-1

Ultrasound (US)

Alpha fetoprotein (AFP)

US nodule(s) <10 mm

US negative

Repeat US + AFP in 6 mo

AFP positive

US nodule(s) ≥10 mm

See Principles of Imaging (HCC-A).

Adapted with permission from Marrero JA, et al. Hepatology 2018;68:723-750.

Patients with cirrhosis or chronic hepatitis B viral infection should be enrolled in an HCC screening program (See Discussion).

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.

White DL, Clin Gastroenterol Hepatol 2012;10:1342-1359.

Beuers U, et al. Am J Gastroenterol 2015;110:1536-1538.

Schiff ER, Sorrell MF, and Maddrey WC. Schiff's Diseases of the Liver. Philadelphia: Lippincott Williams & Wilkins (LWW); 2007.

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.

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).

Positive or rising AFP should prompt CT or MRI regardness of US results.

US negative means no observation or only definitely benign observation(s).

Patients at risk for HCC:

• Cirrhosis

Hepatitis B, C

Alcohol

Genetic hemochromatosis

Non-alcoholic fatty liver disease (NAFLD)

d,e

Stage 4 primary biliary cholangitis

Alpha-1-antitrypsin deciency

Other causes of cirrhosis

• Without cirrhosis

Hepatitis B

c,h

Additional

workup

(See HCC-2)

Repeat US + AFP in 3–6 mo

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

NCCN Guidelines Version 3.2021

Hepatocellular Carcinoma

NCCN Guidelines Index

Table of Contents

Discussion

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.

HCC-2

DIAGNOSIS OF HCC

FINDINGSIMAGING

ADDITIONAL WORKUP

• Positive imaging result

• Suspicious abnormality

detected on imaging exam

done for other reasons

• Positive AFP

Abdominal

multiphasic CT

MRI

Observation(s)

detected

No observation

detected

Return to screening in

6 mo (See HCC-1)

Denitely HCC

Not denitely HCC,

not denitely benign

Denitely benign

HCC conrmed

(See HCC-3)

Individualized workup,

which may include

additional imaging

biopsy,

n,o

as informed by

multidisciplinary discussion

Return to screening

6 mo (See HCC-1)

(NCCN

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NCCN Guidelines Version 3.2021

Hepatocellular Carcinoma

NCCN Guidelines Index

Table of Contents

Discussion

See Principles of Imaging (HCC-A).

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.

An observation is an area identified at imaging that is distinctive from background liver. It may be a mass or a pseudo lesion.

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).

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.

See Principles of Biopsy (HCC-B).

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.

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.

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

NCCN Guidelines Version 3.2021

Hepatocellular Carcinoma

NCCN Guidelines Index

Table of Contents

Discussion

HCC-3

CLINICAL PRESENTATION WORKUP

HCC confirmed

Multidisciplinary evaluation

(assess liver reserve

and comorbidity) and staging:

• H&P

• Hepatitis panel

• Bilirubin, transaminases, alkaline phosphatase

• PT or INR, albumin, BUN, creatinine

• CBC, platelets

• AFP

• Chest CT

• Bone scan if clinically indicated

• Abdominal/pelvic CT or MRI with contrast, if not

previously done or needs updating

• 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)

See Principles of Imaging (HCC-A).

See NCCN Guidelines for Older Adult Oncology.

See Child-Pugh Score (HCC-C) and assessment of portal hypertension (eg, varices, splenomegaly, thrombocytopenia).

An appropriate hepatitis panel should preferably include:

• Hepatitis B surface antigen (HBsAg). If the HBsAg is positive, check HBeAg, HBeAb, and quantitative HBV DNA and refer to hepatologist.

• Hepatitis B surface antibody (for vaccine evaluation only).

• Hepatitis B core antibody (HBcAb) IgG. The HBcAb IgM should only be checked in cases of acute viral hepatitis. An isolated HBcAb IgG may still be chronic HBV 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-conned disease, inoperable by

performance status, comorbidity, or with

minimal or uncertain extrahepatic disease

(See HCC-6)

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.

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

NCCN Guidelines Version 3.2021

Hepatocellular Carcinoma

NCCN Guidelines Index

Table of Contents

Discussion

• UNOS criteria

v,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 criteria

HCC-4

CLINICAL PRESENTATION SURGICAL ASSESSMENT

t,u,v

TREATMENT SURVEILLANCE

Potentially resectable

or transplantable,

operable by

performance status

or comorbidity

• Child-Pugh Class A, B

No portal hypertension

• Suitable tumor location

• Adequate liver reserve

• Suitable liver remnant

If ineligible

for transplant

• Refer to liver

transplant

center

u,y

• Consider bridge

therapy as

indicated

Resection, if

feasible (preferred)

Locoregional

therapy

• Ablation

• Arterially directed

therapies

• External beam

radiation therapy

(EBRT)

• Imaging

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

scussion of surgical treatment with patient and determination of whether patient is amenable to surgery.

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.

See Principles of Surgery (HCC-D).

In highly selected Child-Pugh Class B patients with limited resection.

Extended criteria/downstaging protocols are available through UNOS. See https://optn.transplant.hrsa.gov/media/1200/optn_policies.pdf#nameddest=Policy_09.

Mazzaferro V, et al. N Engl J Med 1996;334:693-700.

Many transplant centers consider bridge therapy for transplant candidates (See Discussion).

See Principles of Locoregional Therapy (HCC-E).

In well-selected patients with small, properly located tumors ablation should be considered as definitive treatment in the context of a multidisciplinary review.

See Principles of Radiation Therapy (HCC-F).

Multiphasic abdominal MRI or multiphase CT scans for liver assessment, CT chest and CT/MRI pelvis. See Principles of Imaging (HCC-A).

Note: All recommendations are category 2A unless otherwise indicated.

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See Child-Pugh Score (HCC-C) and assessment of portal hypertension (eg, varices, splenomegaly, thrombocytopenia).

See Principles of Surgery (HCC-D).

Mazzaferro V, et al. N Engl J Med 1996;334:693-700.

Many transplant centers consider bridge therapy for transplant candidates (See Discussion).

See Principles of Locoregional Therapy (HCC-E).

See Principles of Radiation Therapy (HCC-F).

Multiphasic abdominal MRI or multiphase CT scans for liver assessment, CT chest and CT/MRI pelvis. See Principles of Imaging (HCC-A).

Order does not indicate preference. The choice of treatment modality may depend on extent/location of disease, hepatic reserve, and institutional capabilities.

Use of chemoembolization has also been supported by randomized controlled trials in selected populations over best supportive care.

See Principles of Systemic Therapy (HCC-G).

HCC-5

CLINICAL

PRESENTATION

TREATMENT SURVEILLANCE

Options:

• Locoregional

therapy preferred

aa,

Ablation

Arterially directed

therapies

EBRT

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

indicated

• Imaging

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

• Consider early imaging

per local protocol

Unresectable

• Inadequate

hepatic

reserve

• Tumor

location

Transplant

Progression

on or after

systemic

therapy

Options:

• Clinical trial

• Systemic therapy

• Best supportive care

Note: All recommendations are category 2A unless otherwise indicated.

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HCC-6

CLINICAL PRESENTATION TREATMENT

Liver-conned disease, inoperable by performance

status, comorbidity or with minimal or uncertain

extrahepatic disease

Metastatic disease

Extensive liver

tumor burden

Biopsy

for

histologic

conrmation if not

previously done

Options:

• Clinical trial

• Systemic therapy

• Best supportive care

Options:

• Locoregional therapy preferred

Ablation

Arterially directed therapies

EBRT

• Clinical trial

• Systemic therapy

• Best supportive care

See Principles of Biopsy (HCC-B).

See Principles of Locoregional Therapy (HCC-E).

See Principles of Radiation Therapy (HCC-F).

Order does not indicate preference. The choice of treatment modality may depend on extent/location of disease, hepatic reserve, and institutional capabilities.

See Principles of Systemic Therapy (HCC-G).

Progression on or

after systemic therapy

Progression on or

after systemic therapy

Note: All recommendations are category 2A unless otherwise indicated.

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PRINCIPLES OF IMAGING

Screening and Surveillance

Screening and surveillance for HCC is considered cost eective 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,

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).

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.

To standardize interpretation, the

AASLD,

EASL,

OPTN,

and LI-RADS

5,7

have adopted imaging criteria to diagnose HCC nodules ≥10 mm. Criteria have not been proposed

for nodules smaller than 10 mm as these are dicult to denitively 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.

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 suciently 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 specicity for HCC; thus, lesions meeting these

criteria can be assumed to represent HCC and may be treated as such without conrmatory 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.

• 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

scan

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.

HCC-A

1 OF 3

References

Note: All recommendations are category 2A unless otherwise indicated.

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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 suciently specic to permit noninvasive diagnosis.

7,9

Biopsy or

denitive 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.

Role of PET

PET/CT has limited sensitivity but high specicity, and may be considered when there is an equivocal nding.

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.

PRINCIPLES OF IMAGING

HCC-A

2 OF 3

References

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

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HCC-A

3 OF 3

PRINCIPLES OF IMAGING

REFERENCES

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Lamarca A, Barriuso J, Chander A, et al.

F-fluorodeoxyglucose positron emission tomography (

FDG-PET) for patients with biliary tract cancer: Systematic review

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

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

(NY) 2016;41:33-41.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

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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 criteria

for HCC.

Lesion meets imaging criteria

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 brosis, or cirrhosis due to a vascular disorder such as Budd-Chiari syndrome,

hereditary hemorrhagic telangiectasia, or nodular regenerative hyperplasia.

◊ Patient has elevated CA 19-9 or carcinoembryonic antigen (CEA) with suspicion of intrahepatic cholangiocarcinoma or cHCC-CCA.

Conrmation 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

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).

These conditions are associated with formation of nonmalignant nodules that may resemble HCC at imaging.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

HCC-C

CHILD-PUGH SCORE

Class A: Good operative risk

Class B: Moderate operative risk

Class C: Poor operative risk

Trey C, Burns DG, Saunders SJ. Treatment of hepatic coma by exchange blood transfusion. N Engl J Med 1966;274:473-481.

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)

None 1–2 3–4

Ascites Absent Slight Moderate

Albumin (g/dL) >3.5 2.8–3.5 <2.8

Prothrombin time

Seconds over control

INR

<1.7

4–6

1.7–2.3

>2.3

Bilirubin (mg/dL)

• For primary biliary cirrhosis

2–3

4–10

>10

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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.

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HCC-D

PRINCIPLES OF SURGERY

• Patients must be medically t 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)

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 inow/outow)

• 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.

• 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.

Furthermore, there are patients who are downstaged to within criteria that can also be considered for transplantation.

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 t 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 benet from liver resection or transplantation for HCC, but they need to be carefully selected, as

overall survival is lower than for younger patients.

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.

Brouquet A, Andreou A, Shindoh J, et al. Methods to improve resectability of hepatocellular carcinoma. Recent Results Cancer Res. 2013;190:57-67.

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].

Rudnick SR, Russo MW. Liver transplantation beyond or downstaging within the Milan criteria for hepatocellular carcinoma. Expert Rev Gastroenterol Hepatol

201812:265-275.

Kamath PS, Wiesner RH, Malinchoc M, et al. A model to predict survival in patients with end-stage liver disease. Hepatology 2001l33:464-570.

Faber W, Stockmann M, Schirmer C, et al. Significant impact of patient age on outcome after liver resection for HCC cirrhosis. Eur J Surg Oncol 2014;40:208-213.

Note: All recommendations are category 2A unless otherwise indicated.

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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

denitive 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.

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]

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.

RE with Y-90 microspheres has an increased risk of radiation-induced liver disease in patients with bilirubin >2 mg/dL.

With RE, delivery of ≥205 Gy to the tumor may be associated with increased overall survival.

• 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

specically patients with segmental or lobar portal vein, rather than main portal vein thrombosis.

• 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 ecacy of the use of sorafenib concomitantly with

arterially directed therapies has not been associated with signicant benet 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

1 OF 2

References

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

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HCC-E

2 OF 2

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.

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.

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.

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.

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.

Yamakado K, Nakatsuka A, Takaki H, et al. Early-stage hepatocellular carcinoma:

radiofrequency ablation combined with chemoembolization versus hepatectomy.

Radiology 2008;247:260-266.

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.

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.

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.

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.

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.

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.

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.

Ramsey DE, Kernagis LY, Soulen MC, Geschwind J-FH. Chemoembolization of

hepatocellular carcinoma. J Vasc Interv Radiol 2002;13:211-221.

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.

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.

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.

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.

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.

PRINCIPLES OF LOCOREGIONAL THERAPY

REFERENCES

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

NCCN Guidelines Version 3.2021

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Table of Contents

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 photons

or protons

2,3

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 sucient 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 modications and strict dose constraint adherence.

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 specic 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

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.

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

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NCCN Guidelines Index

Table of Contents

Discussion

HCC-F

2 OF 2

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

PRINCIPLES OF RADIATION THERAPY

REFERENCES

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

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NCCN Guidelines Index

Table of Contents

Discussion

PRINCIPLES OF SYSTEMIC THERAPY

HCC-G

1 OF 2

An FDA-approved biosimilar is an appropriate substitute for bevacizumab.

See NCCN Guidelines for Management of Immunotherapy-Related Toxicities.

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.

See Child-Pugh Score (HCC-C) and assessment of portal hypertension (eg, varices, splenomegaly, thrombocytopenia).

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.

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).

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.)

There are no data to define optimal treatment for those who progress after first-line systemic therapy, other than sorafenib or nivolumab.

The data reflect use on or after sorafenib in patients who previously tolerated sorafenib at a dose of at least 400 mg per day.

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.

Consider if MSI-H HCC.

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)

• Nivolumab

b,6

(if ineligible for tyrosine kinase inhibitors

[TKIs] or other anti-angiogenic agents)

(Child-Pugh Class A or B) (category 2B)

• FOLFOX (category 2B)

Subsequent-Line Therapy

if Disease Progression

Other Recommended Regimens

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

(Child-Pugh Class A or B)

b,j,10-12

• Nivolumab + ipilimumab

(Child-Pugh Class A only)

b,i,13

• Pembrolizumab

(Child-Pugh Class A only)

b,j,k,14

(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.

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

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Discussion

PRINCIPLES OF SYSTEMIC THERAPY

REFERENCES

HCC-G

2 OF 2

Finn RS, Qin S, Ikeda M, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med 2020;382:1894-1905.

Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008;359:378-390.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

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NCCN Guidelines Index

Table of Contents

Discussion

GALL-1

PRESENTATION POSTOPERATIVE WORKUP

PRIMARY TREATMENT

Incidental

nding at

surgery

• Intraoperative

staging

• Frozen section

of resected

gallbladder +

suspicious

lymph node

Multiphasic

abdominal/pelvic

CT/MRI with IV

contrast, chest CT

± contrast

Cholecystectomy

b,f

+ en bloc hepatic

resection + lymphadenectomy ± bile duct

excision for malignant involvement

Resectable

b,c

Options:

• Systemic therapy

(preferred)

• Clinical trial (preferred)

• Palliative RT

• Best supportive care

See Adjuvant

Treatment

and

Surveillance

(GALL-5)

Incidental

nding on

pathologic

review

See GALL-2

See Principles of Imaging (BIL-A).

See Principles of Surgery and Pathology (GALL-A).

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).

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.

Testing may include NTRK gene fusion testing

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.

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

See Principles of Systemic Therapy (BIL-C).

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) testing

• Additional molecular

testing

Tumor mutational

burden (TMB)

testing

Progression

on or after

systemic

therapy

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.

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

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Discussion

PRESENTATION POSTOPERATIVE

WORKUP

PRIMARY TREATMENT

GALL-2

Incidental

nding on

pathologic

review

T1a (with

negative

margins)

T1b or

greater

Multiphasic abdominal/pelvic

CT/MRI with IV contrast, chest

CT ± contrast

• Consider staging

laparoscopy

Resectable

b,c

Unresectable

• MSI/MMR testing

• Additional

molecular testing

TMB testing

Observe

Hepatic resection

+ lymphadenectomy

± bile duct excision for

malignant involvement

Options:

• Systemic therapy

(preferred)

• Clinical trial (preferred)

• Palliative RT

• Best supportive care

See Adjuvant

Treatment and

Surveillance

(GALL-5)

See Principles of Imaging (BIL-A).

See Principles of Surgery and Pathology (GALL-A).

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).

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.

Testing may include NTRK gene fusion testing.

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

See Principles of Systemic Therapy (BIL-C).

See Principles of Radiation Therapy (BIL-B).

Consider multidisciplinary review.

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 ± contrast

• Consider staging

laparoscopy

• MSI/MMR testing

Consider neoadjuvant

chemotherapy

Clinical trial

Progression on

or after systemic

therapy

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.

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

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Discussion

PRESENTATION AND WORKUP

GALL-3

PRIMARY TREATMENT

Mass on

imaging

• H&P

• Multiphasic

abdominal/pelvic

CT/MRI with IV contrast

• Chest CT + contrast

• Liver function tests

(LFTs)

• Surgical consultation

• Assessment of hepatic

reserve

• Consider CEA

• Consider CA 19-9

• Consider staging

laparoscopy

Resectable

b,c

Unresectable

Biopsy

• MSI/MMR testing

• Additional

molecular testing

TMB testing

Cholecystectomy

+ 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

See Principles of Imaging (BIL-A).

See Principles of Surgery and Pathology (GALL-A).

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).

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.

Testing may include NTRK gene fusion testing.

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

See Principles of Systemic Therapy (BIL-C).

See Principles of Radiation Therapy (BIL-B).

CEA and CA 19-9 are baseline tests and should not be done to confirm diagnosis.

Options:

• Systemic therapy

(preferred)

• Clinical trial (preferred)

• Palliative RT

• Best supportive care

Progression on

or after systemic

therapy

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.

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

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Table of Contents

Discussion

GALL-4

PRIMARY TREATMENT

Jaundice

• H&P

• LFTs

• Chest CT ± contrast

• Multiphasic abdominal/

pelvic CT/MRI with IV

contrast

• Cholangiography

• Surgical consultation

• Consider CEA

• Consider CA 19-9

• Consider staging

laparoscopy

• Biliary drainage

Resectable

Unresectable

Biopsy

• MSI/MMR testing

• Additional

molecular testing

TMB testing

Cholecystectomy

+ en bloc hepatic

resection

+ lymphadenectomy

+ bile duct excision

See Adjuvant

Treatment and

Surveillance

(GALL-5)

Options:

• Systemic therapy

(preferred)

• Clinical trial (preferred)

• Palliative RT

• Best supportive care

Options:

• Systemic therapy

(preferred)

• Clinical trial (preferred)

• Best supportive care

Metastatic disease

See Principles of Imaging (BIL-A).

See Principles of Surgery and Pathology (GALL-A).

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).

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.

Testing may include NTRK gene fusion testing.

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

See Principles of Systemic Therapy (BIL-C).

See Principles of Radiation Therapy (BIL-B).

CEA and CA 19-9 are baseline tests and should not be done to confirm diagnosis.

Magnetic resonance cholangiopancreatography (MRCP) is preferred. Endoscopic retrograde cholangiopancreatography/percutaneous transhepatic cholangiography

(ERCP/PTC) are used more for therapeutic intervention.

Consult with a multidisciplinary team.

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)

• Clinical trial

Biopsy

• MSI/MMR testing

• Additional

molecular testing

TMB testing

Progression on

or after systemic

therapy

Progression on

or after systemic

therapy

PRESENTATION AND WORKUP

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.

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and this illustration may not be reproduced in any form without the express written permission of NCCN.

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Discussion

GALL-5

TREATMENT

SURVEILLANCE

• Consider imaging

every 3–6 mo for

2 y, then every

6–12 months for

up to 5 years,

or as clinically

indicated

• 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)

See Principles of Imaging (BIL-A).

See Principles of Systemic Therapy (BIL-C).

See Principles of Radiation Therapy (BIL-B).

Management of patients with R1 or R2 resections should be evaluated by a multidisciplinary team.

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).

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).

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).

There are no data to support a specific surveillance schedule or tests for monitoring. Physicians should discuss appropriate follow-up schedules/imaging with patients.

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

Carcinoma in situ at margin

Resected, positive margin (R1)

Positive regional nodes

• Observe

• Systemic therapy

(preferred)

• Clinical trial (preferred)

• Fluoropyrimidine-based chemoradiation

i,r

• Systemic therapy

(preferred)

• Clinical trial (preferred)

• Fluoropyrimidine-based chemoradiation

i,r

• Fluoropyrimidine- or gemcitabine-

based chemotherapy

followed by

uoropyrimidine-based chemoradiation

• Fluoropyrimidine-based chemoradiation

i,r

followed by uoropyrimidine- or

gemcitabine-based chemotherapy

Resected gross residual

disease (R2)

See treatment for unresectable disease

(GALL-1)

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.

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and this illustration may not be reproduced in any form without the express written permission of NCCN.

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Discussion

Incidental Finding at Surgery:

• If expertise is unavailable, document all relevant ndings 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 denitive 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 denitive 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 dierentiated 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.

• Repeat cross-sectional imaging of the chest, abdomen, and pelvis should be performed prior to denitive 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 eective, as the presence of a port site implant is a surrogate marker of underlying

disseminated disease and has not been shown to improve outcomes.

PRINCIPLES OF SURGERY AND PATHOLOGY

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.

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.

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.

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

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.

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

NCCN Guidelines Version 3.2021

Biliary Tract Cancers: Gallbladder Cancer

NCCN Guidelines Index

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 denitive resection should be carried out.

• Diagnostic laparoscopy is recommended prior to denitive 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 denitive resection during the same setting if pathology conrms 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.

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.

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.

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

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.

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

NCCN Guidelines Version 3.2021

Biliary Tract Cancers: Intrahepatic Cholangiocarcinoma

NCCN Guidelines Index

Table of Contents

Discussion

Options:

• Systemic therapy

• Clinical trial

• Consider locoregional therapy

m,n

EBRT

Arterially directed therapies

• Best supportive care

INTRA-1

PRESENTATION WORKUP PRIMARY TREATMENT

Isolated intrahepatic

mass

(imaging

characteristics

consistent with

malignancy but

not consistent

with hepatocellular

carcinoma)

(See NCCN

Guidelines for

Occult Primary

Cancers)

• H&P

• Multiphasic abdominal/pelvic

CT/MRI

with IV contrast

• Chest CT +/- contrast

• Consider CEA

• Consider CA 19-9

• LFTs

• Surgical consultation

• Esophagogastroduodenoscopy

(EGD) and colonoscopy

• Consider viral hepatitis

serologies

• Consider biopsy

• Consider AFP

• Consider referral to a

hepatologist

Resectable

Unresectable

• MSI/MMR

testing

• Additional

molecular

testing

TMB

testing

Metastatic

disease

• MSI/MMR

testing

• Additional

molecular

testing

TMB

testing

• Consider staging laparoscopy

• Resection

and regional

lymphadenectomy

See Additional

Therapy and

Surveillance

(INTRA-2)

Options:

• Systemic therapy

• Clinical trial

• EBRT with concurrent uoropyrimidine

k,l

Consider locoregional therapy

m,n

EBRT

Arterially directed therapies

• Best supportive care

See Principles of Surgery (INTRA-A).

See Principles of Imaging (HCC-A).

CEA and CA 19-9 are baseline tests and should not be done to confirm diagnosis.

Consult with multidisciplinary team.

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

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.

Testing may include NTRK gene fusion testing.

Laparoscopy may be done in conjunction with surgery if no distant metastases

are found.

Order does not indicate preference. The choice of treatment modality may depend

on extent/location of disease and institutional capabilities.

See Principles of Systemic Therapy (BIL-C).

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).

See Principles of Radiation Therapy (BIL-B).

Intra-arterial chemotherapy (with or without systemic chemotherapy) may be

used in a clinical trial or at experienced centers.

Principles of Locoregional Therapy (HCC-E).

Progression

on or after

systemic

therapy

Progression

on or after

systemic

therapy

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.

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

NCCN Guidelines Version 3.2021

Biliary Tract Cancers: Intrahepatic Cholangiocarcinoma

NCCN Guidelines Index

Table of Contents

Discussion

Post

resection

status

No residual

local disease

(R0 resection)

Options:

• Observe

• Systemic therapy

• Clinical trial

Consider multiphasic

abdominal/pelvic CT/MRI

with IV contrast

and chest

CT + contrast

every 3–6

mo for 2 y, then every 6–12

months for up to 5 years, or

as clinically indicated

Microscopic

margins (R1)

Positive

regional nodes

Options:

• Systemic therapy

• Fluoropyrimidine-based chemoradiation

k,l

• Fluoropyrimidine-based or gemcitabine-based chemotherapy

followed by uoropyrimidine-based chemoradiation

• Fluoropyrimidine-based chemoradiation

k,l

followed by

uoropyrimidine-based or gemcitabine-based chemotherapy

• Clinical trial

See Principles of Imaging (HCC-A).

Consult with multidisciplinary team.

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

See Principles of Systemic Therapy (BIL-C).

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).

See Principles of Radiation Therapy (BIL-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 (Horgan AM, et al. J Clin Oncol 2012;30:1934-1940).

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).

There are no data to support a specific surveillance schedule or tests for monitoring. Physicians should discuss appropriate follow-up schedules/imaging with patients.

Based on surveillance schedule used in the phase III BILCAP trial. Primrose JN, et al. Lancet Oncol 2019;20:663-673.

TREATMENT

Residual

local disease

(R2 resection)

SURVEILLANCE

INTRA-2

See treatment for unresectable disease (INTRA-1)

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.

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

NCCN Guidelines Version 3.2021

Biliary Tract Cancers: Intrahepatic Cholangiocarcinoma

NCCN Guidelines Index

Table of Contents

Discussion

PRINCIPLES OF SURGERY

1,2

General Principles

• A preoperative biopsy is not always necessary before proceeding with a denitive, 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.

Endo I, Gonen M, Yopp A. Intrahepatic cholangiocarcinoma: Rising frequency, improved survival and determinants of outcome after resection. Ann Surg 2008;248:84-96.

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

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.

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

NCCN Guidelines Version 3.2021

Biliary Tract Cancers: Extrahepatic Cholangiocarcinoma

NCCN Guidelines Index

Table of Contents

Discussion

PRESENTATION AND WORKUP

PRIMARY TREATMENT

• Pain

• Jaundice

• Abnormal

LFTs

• Obstruction

abnormality

on imaging

• H&P

• Multiphasic abdominal/

pelvic CT/MRI (assess

for vascular invasion)

with IV contrast

• Chest CT +/- contrast

• Cholangiography

• Consider CEA

• Consider CA 19-9

• LFTs

• Consider endoscopic

ultrasound (EUS) after

surgical consultation

• Consider serum IgG4

to rule out autoimmune

cholangitis

Unresectable

• Biliary drainage,

if indicated

• Biopsy

(only after determining

transplant status)

MSI/MMR testing

Additional molecular testing

◊ TMB testing

• Consider referral to transplant

center

Metastatic

disease

• Surgical exploration

• Consider laparoscopic staging

• Consider preoperative biliary

drainage

• Multidisciplinary review

• Biliary drainage,

if indicated

• Biopsy

MSI/MMR testing

Additional molecular testing

◊ TMB testing

See Principles of Imaging (BIL-A).

Magnetic resonance cholangiopancreatography (MRCP) is preferred.

Endoscopic retrograde cholangiopancreatography/percutaneous transhepatic

cholangiography (ERCP/PTC) are used more for therapeutic intervention.

CEA and CA 19-9 are baseline tests and should not be done to confirm diagnosis.

Patients with IgG-4–related cholangiopathy should be referred to an expert

center.

See Principles of Surgery (EXTRA-A).

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.

Surgery may be performed when index of suspicion is high; biopsy is not

required.

Consider biliary drainage for patients with jaundice prior to instituting

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

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.

Testing may include NTRK gene fusion testing.

Order does not indicate preference. The choice of treatment modality may

depend on extent/location of disease and institutional capabilities.

See Principles of Systemic Therapy (BIL-C).

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).

See Principles of Radiation Therapy (BIL-B).

Options:

• Systemic therapy

• Clinical trial

• EBRT with concurrent

uoropyrimidine

m,n

• Palliative EBRT

• Best supportive care

Unresectable, see below

Resectable

Resection

See Adjuvant

Treatment

and

Surveillance

(EXTRA-2)

Options:

• Systemic therapy

• Clinical trial

• Best supportive care

EXTRA-1

Progression

on or after

systemic

therapy

Resectable

Progression

on or after

systemic

therapy

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.

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

NCCN Guidelines Version 3.2021

Biliary Tract Cancers: Extrahepatic Cholangiocarcinoma

NCCN Guidelines Index

Table of Contents

Discussion

TREATMENT

SURVEILLANCE

Post

resection

status

Resected, negative margin (R0),

Negative regional nodes

Carcinoma in situ at margin

Resected, positive margin (R1)

Positive regional nodes

• Observe

• Systemic therapy

• Fluoropyrimidine chemoradiation

m,n

• Clinical trial

• Systemic therapy

• Fluoropyrimidine-based chemoradiation

m,n

• Fluoropyrimidine-based or gemcitabine-

based chemotherapy

followed by

uoropyrimidine-based chemoradiation

• Fluoropyrimidine-based chemoradiation

m,n

followed by uoropyrimidine-based or

gemcitabine-based chemotherapy

• Clinical trial

Consider imaging every

3–6 mo for 2 y, then every

6–12 months for up to 5

years,

or as clinically

indicated

See Principles of Imaging (BIL-A).

See Principles of Systemic Therapy (BIL-C).

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).

See Principles of Radiation Therapy (BIL-B).

Management of patients with R1 or R2 resections should be evaluated by a multidisciplinary team.

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).

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).

There are no data to support a specific surveillance schedule or tests for monitoring. Physicians should discuss appropriate follow-up schedules/imaging with patients.

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)

See treatment for unresectable disease (EXTRA-1)

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.

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

NCCN Guidelines Version 3.2021

Biliary Tract Cancers: Extrahepatic Cholangiocarcinoma

NCCN Guidelines Index

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 denitive, 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 signicant 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 inow 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 ndings

contraindicate resection. Further exploration must conrm local resectability.

• Since hilar tumors, by denition, abut or invade the central portion of the liver they require major hepatic resections on the involved side to

encompass the biliary conuence 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

Nishio H, Nagino M, Nimura Y. Surgical management of hilar cholangiocarcinoma: the Nagoya experience. HPB (Oxford) 2005;7:259-262.

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.

Jarnagin WR, Fong Y, DeMatteo RP, et al. Staging, resectability, and outcome in 225 patients with hilar cholangiocarcinoma. Ann Surg 2001;234:507-517.

Nimura Y. Preoperative biliary drainage before resection for cholangiocarcinoma. HPB (Oxford) 2008;10:130-133.

Kennedy TJ, Yopp A, Qin Y, et al. Role of preoperative biliary drainage of live remnant prior to extended liver resection for hilar cholangiocarcinoma. HPB (Oxford)

2009;11:445-451.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

NCCN Guidelines Version 3.2021

Biliary Tract Cancers

NCCN Guidelines Index

Table of Contents

Discussion

PRINCIPLES OF IMAGING

1-4

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.

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.

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.

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.

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 specicity and may be considered when there is an equivocal nding.

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 dicult, 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, specically 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 specically 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.

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.

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

NCCN Guidelines Version 3.2021

Biliary Tract Cancers

NCCN Guidelines Index

Table of Contents

Discussion

BIL-B

PRINCIPLES OF RADIATION THERAPY

General Principles

• IGRT is strongly recommended when using EBRT, IMRT, and SBRT to improve treatment accuracy and reduce treatment-related toxicity.

• Adjuvant EBRT

1,2

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 uoropyrimidine-based chemotherapy

to standard or high dose is acceptable

for intrahepatic and extrahepatic tumors.

Hypofractionation with photons

or protons

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.

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.

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.

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.

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.

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.

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

See Principles of Systemic Therapy (BIL-C).

References

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

NCCN Guidelines Version 3.2021

Biliary Tract Cancers

NCCN Guidelines Index

Table of Contents

Discussion

BIL-C

1 OF 3

PRINCIPLES OF SYSTEMIC THERAPY

Neoadjuvant Therapy

Preferred Regimens Other Recommended Regimens Useful in Certain Circumstances

• None • 5-uorouracil + oxaliplatin

• Capecitabine + oxaliplatin

• Gemcitabine + capecitabine

• Gemcitabine + cisplatin

• Gemcitabine + cisplatin + albumin-bound paclitaxel

(category 2B)

• Gemcitabine + oxaliplatin (category 2B)

• Single agents:

5-uorouracil

Capecitabine

Gemcitabine

• None

Adjuvant Therapy

b,2

Preferred Regimens Other Recommended Regimens Useful in Certain Circumstances

• Capecitabine

c,3

(category 1)

• 5-uorouracil + oxaliplatin

• Capecitabine + oxaliplatin

• Gemcitabine + capecitabine

• Gemcitabine + cisplatin

• Capecitabine + cisplatin (category 3)

• Single agents:

5-uorouracil

Gemcitabine

• None

Agents Used with Concurrent Radiation

• 5-uorouracil

• Capecitabine

There are limited clinical trial data to define a standard regimen or definitive benefit. Clinical trial participation is encouraged.

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.

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.

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.

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

NCCN Guidelines Version 3.2021

Biliary Tract Cancers

NCCN Guidelines Index

Table of Contents

Discussion

BIL-C

2 OF 3

PRINCIPLES OF SYSTEMIC THERAPY

Subsequent-Line Therapy for Biliary Tract Cancers if Disease Progression

Preferred Regimens Other Recommended Regimens Useful in Certain Circumstances

• FOLFOX

• FOLFIRI

(category 2B)

• Regorafenib

(category 2B)

• See also: Preferred and Other Recommended Regimens for

Unresectable and Metastatic Disease above

• For NTRK gene fusion-positive tumors:

Entrectinib

5-7

Larotrectinib

• For MSI-H/dMMR tumors/TMB-H tumors:

Pembrolizumab

d,e,9,13,14

• For cholangiocarcinoma with FGFR2

fusions or rearrangements:

Pemigatinib

Ingratinib

• For cholangiocarcinoma with IDH1

mutations

Ivosidenib

• For BRAF-V600E mutated tumors

Dabrafenib + trametinib

18,19

• Nivolumab

e,20

(category 2B)

• Lenvatinib + pembrolizumab

e,21

(category 2B)

Primary Treatment for Unresectable and Metastatic Disease

Preferred Regimens Other Recommended Regimens Useful in Certain Circumstances

• Gemcitabine + cisplatin

(category 1)

• 5-uorouracil + oxaliplatin

• 5-uorouracil + cisplatin (category 2B)

• Capecitabine + cisplatin (category 2B)

• Capecitabine + oxaliplatin

• Gemcitabine + albumin-bound paclitaxel

• Gemcitabine + capecitabine

• Gemcitabine + oxaliplatin

• Gemcitabine + cisplatin + albumin-bound paclitaxel

(category 2B)

• Single agents:

5-uorouracil

Capecitabine

Gemcitabine

• For NTRK gene fusion-positive tumors:

Entrectinib

5-7

Larotrectinib

• For MSI-H/dMMR tumors:

Pembrolizumab

d,e,9

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.

See NCCN Guidelines for Management of Immunotherapy-Related Toxicities.

Treatment selection depends on clinical factors including previous treatment regimen/agent and extent

of liver dysfunction.

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.

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

NCCN Guidelines Version 3.2021

Biliary Tract Cancers

NCCN Guidelines Index

Table of Contents

Discussion

BIL-C

3 OF 3

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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

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.

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

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.

Subbiah V, Lassen U, Élez E, et al. Dabrafenib plus trametinib in patients with BRAF

V600E

-mutated biliary tract cancer (ROAR): a phase 2, open-label, single-arm,

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

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.

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.

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.

PRINCIPLES OF SYSTEMIC THERAPY

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 dierentiated

G2 Moderately dierentiated

G3 Poorly dierentiated

G4 Undierentiated

Fibrosis Score (F)

The brosis score as dened 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 brosis)

F1 Fibrosis score 5-6 (severe brosis or cirrhosis)

Table 1. Denitions 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

Distant metastasis

American Joint Committee on Cancer (AJCC)

TNM Staging for Hepatocellular Cancer (8th ed., 2017)

NCCN Guidelines Version 3.2021

Hepatobiliary Cancers

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

NCCN Guidelines Index

Table of Contents

Discussion

Continued

ST-2

Table 4. AJCC Prognostic Groups

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

Histologic Grade (G)

GX Grade cannot be assessed

G1 Well dierentiated

G2 Moderately dierentiated

G3 Poorly dierentiated

Table 3. Denitions for T, N, M

T Primary Tumor

TX Primary tumor cannot be assessed

T0 No evidence of 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

American Joint Committee on Cancer (AJCC)

TNM Staging for Gallbladder Carcinoma (8th ed., 2017)

N Regional Lymph Nodes

NX Regional lymph nodes cannot be assessed

N0 No regional lymph node metastasis

N1 Metastases to one to three regional lymph nodes

N2 Metastases to four or more regional lymph nodes

M Distant Metastasis

M0 No distant metastasis

M1 Distant metastasis

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.

NCCN Guidelines Version 3.2021

Hepatobiliary Cancers

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

NCCN Guidelines Index

Table of Contents

Discussion

Continued

ST-3

Table 6. AJCC Prognostic Groups

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

Histologic Grade (G)

GX Grade cannot be assessed

G1 Well dierentiated

G2 Moderately dierentiated

G3 Poorly dierentiated

Table 5. Denitions for T, N, M

T Primary Tumor

TX Primary tumor cannot be assessed

T0 No evidence of 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

N Regional Lymph Nodes

NX Regional lymph nodes cannot be assessed

N0 No regional lymph node metastasis

N1 Regional lymph node metastasis present

M Distant Metastasis

M0 No distant metastasis

M1 Distant metastasis present

American Joint Committee on Cancer (AJCC)

TNM Staging for Intrahepatic Bile Duct Tumors (8th ed., 2017)

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.

NCCN Guidelines Version 3.2021

Hepatobiliary Cancers

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

NCCN Guidelines Index

Table of Contents

Discussion

Continued

ST-4

M Distant Metastasis

M0 No distant metastasis

M1 Distant metastasis

Table 8. AJCC Prognostic Groups

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

Histologic Grade (G)

GX Grade cannot be assessed

G1 Well dierentiated

G2 Moderately dierentiated

G3 Poorly dierentiated

Table 7. Denitions for T, N, M

T Primary Tumor

TX Primary tumor cannot be assessed

T0 No evidence of primary tumor

Tis Carcinoma in situ/high-grade dysplasia

T1 Tumor conned to the bile duct, with extension up to the muscle

layer or brous 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

N Regional Lymph Nodes

NX Regional lymph nodes cannot be assessed

N0 No regional lymph node metastasis

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

American Joint Committee on Cancer (AJCC)

TNM Staging for Perihilar Bile Duct Tumors (8th ed., 2017)

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.

NCCN Guidelines Version 3.2021

Hepatobiliary Cancers

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

NCCN Guidelines Index

Table of Contents

Discussion

ST-5

Table 10. AJCC Prognostic Groups

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

Histologic Grade (G)

GX Grade cannot be assessed

G1 Well dierentiated

G2 Moderately dierentiated

G3 Poorly dierentiated

Table 9. Denitions for T, N, M

T Primary Tumor

TX Primary tumor cannot be assessed

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

N Regional Lymph Nodes

NX Regional lymph nodes cannot be assessed

N0 No regional lymph node metastasis

N1 Metastasis in one to three regional lymph nodes

N2 Metastasis in four or more regional lymph nodes

M Distant Metastasis

M0 No distant metastasis

M1 Distant metastasis

American Joint Committee on Cancer (AJCC)

TNM Staging for Distal Bile Ducts Tumors (8th ed., 2017)

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.

NCCN Guidelines Version 3.2021

Hepatobiliary Cancers

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

NCCN Guidelines Index

Table of Contents

Discussion

NCCN Guidelines Version 3.2021

Hepatobiliary Cancers

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

NCCN Guidelines Index

Table of Contents

Discussion

NCCN Categories of Evidence and Consensus

Category 1 Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Category 2A Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Category 2B Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.

Category 3 Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.

All recommendations are category 2A unless otherwise indicated.

NCCN Categories of Preference

Preferred intervention

Interventions that are based on superior ecacy, safety, and evidence; and, when appropriate,

aordability.

Other recommended

intervention

Other interventions that may be somewhat less ecacious, more toxic, or based on less mature data;

or signicantly less aordable for similar outcomes.

Useful in certain

circumstances

Other interventions that may be used for selected patient populations (dened with recommendation).

All recommendations are considered appropriate.

CAT-1