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NCCN Clinical Practice Guidelines in Oncology™
Hepatobiliary
Cancers
V.2.2008
www.nccn.org
Version 2.2008, 10/31/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
Practice Guidelines
in Oncology – v.2.2008
Guidelines Index
Hepatobiliary Cancers TOC
Staging, MS, ReferencesNCCN
®
NCCN Hepatobiliary Cancers Panel Members
Al B. Benson, III, MD/Chair
Robert H. Lurie Comprehensive Cancer
Center of Northwestern University
Edgar Ben-Josef, MD
University of Michigan
Comprehensive Cancer Center
Mark Bloomston, MD
Arthur G. James Cancer Hospital & Richard
J. Solove Research Institute at The Ohio
State University
Jean F. Botha, MB, BCh
UNMC Eppley Cancer Center at
The Nebraska Medical Center
Bryan M. Clary, MD
Duke Comprehensive Cancer Center
Steven A. Curley, MD
The University of Texas
M. D. Anderson Cancer Center
Michael I. D’Angelica, MD
Memorial Sloan-Kettering Cancer Center
†
§
¶
¶
¶
¶
¶
James A. Posey, MD
University of Alabama at Birmingham
Comprehensive Cancer Center
Fred Hutchinson Cancer Research
Center/Seattle Cancer Care Alliance
†
Riad Salem, MD, MBA
Robert H. Lurie Comprehensive Cancer
Center of Northwestern University
Elin R. Sigurdson, MD, PhD
Fox Chase Cancer Center
Mika Sinanan, MD, PhD
Fred Hutchinson Cancer Research
Center/Seattle Cancer Care Alliance
Jean-Nicolas Vauthey, MD
The University of Texas
M. D. Anderson Cancer Center
Alan P. Venook, MD
UCSF Helen Diller Family
Comprehensive Cancer Center
Raymond S. W. Yeung, MD
Lawrence D. Wagman, MD
City of Hope
§
¶
¶
¶
† ‡
¶
¶
Hepatobiliary Cancers
William D. Ensminger, MD, PhD
University of Michigan
Comprehensive Cancer Center
Christopher Garrett, MD
John F. Gibbs, MD
Roswell Park Cancer Institute
Rene Davila, MD
St. Jude Children’s Research Hospital/
University of Tennessee Cancer Institute
Craig C. Earle, MD, MSc
Dana-Farber/ Brigham and Women’s
Cancer Center | Massachusetts General
Hospital Cancer Center
H. Lee Moffitt Cancer Center and Research
Institute at the University of South Florida
Daniel Laheru, MD
The Sidney Kimmel Comprehensive
Cancer Center at Johns Hopkins
Sean J. Mulvihill, MD
Huntsman Cancer Institute
at the University of Utah
Þ
†
†
¶
† Þ
¶
†
*
*
*
† Medical Oncology
§ Radiotherapy/Radiation Oncology/Interventional Radiology
¶ Surgery/Surgical Oncology
Þ Internal Medicine
‡ Hematology/Hematology Oncology
*Writing Committee Member
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Version 2.2008, 10/31/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
Practice Guidelines
in Oncology – v.2.2008
Guidelines Index
Hepatobiliary Cancers TOC
Staging, MS, ReferencesNCCN
®
This manuscript is being
updated to correspond
with the newly updated
algorithm.
Table of Contents
Hepatocellular Carcinoma:
Gallbladder Cancer:
NCCN Hepatobiliary Cancers Panel Members
Extrahepatic Cholangiocarcinoma (EXTRA-1)
Guidelines Index
Print the Hepatobiliary Cancers Guideline
Summary of Guidelines Updates
Clinical Presentation and Workup (HCC-1)
Potentially resectable, operable (HCC-2)
Unresectable or patient declines surgery (HCC-3)
Inoperable, local disease (HCC-4)
Metastatic disease (HCC-4)
CHILD-PUGH Score (HCC-A)
Incidental finding at surgery (GALL-1)
Incidental finding on pathologic review (GALL-1)
Mass on imaging (GALL-2)
Jaundice (GALL-2)
Metastatic disease (GALL-2)
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Intrahepatic Cholangiocarcinoma (INTRA-1)
These guidelines are a statement of consensus of the authors regarding their views of currently accepted approaches to treatment. Any clinician
seeking to apply or consult these 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 makes no representations nor warranties of any kind
whatsoever regarding their content, use, or application and disclaims any responsibility for their application or use in any way. These guidelines are
copyrighted by National Comprehensive Cancer Network. All rights reserved. These guidelines and the illustrations herein may not be reproduced in
any form without the express written permission of NCCN. ©2007.
For help using these
documents, please click here
Staging
Manuscript
References
Clinical Trials:
Categories of Evidence and
Consensus:
NCCN
The
believes that the best management
for any cancer patient is in a clinical
trial. Participation in clinical trials is
especially encouraged.
To find clinical trials online at NCCN
member institutions,
All recommendations
are Category 2A unless otherwise
specified.
See
NCCN
click here:
nccn.org/clinical_trials/physician.html
NCCN Categories of Evidence
and Consensus
Hepatobiliary Cancers
Version 2.2008, 10/31/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
Practice Guidelines
in Oncology – v.2.2008
Guidelines Index
Hepatobiliary Cancers TOC
Staging, MS, ReferencesNCCN
®
UPDATES
Hepatocellular Carcinoma
HCC-3
:
Footnote “e” regarding Child-Pugh score, now includes “and
assessment of portal hypertension (eg, varices, splenomegaly,
and thrombocytopenia).”
Surgical Evaluation, Bottom branch: Included “....or hepatitis C
antigen positive.”
Footnote “i”: Removed the word “cadaveric” so that text now
reads “Criteria for transplantation.” (Also for )
Footnote “k” that states, “For selected patients, a randomized
clinical trial has demonstrated survival benefits” is new to the
page.
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Treatment: The sorafenib recommendations now include Child-
Pugh Class A , with corresponding footnote “l” that states,
“There are limited safety data available for Child-Pugh Class B
patients. Use with extreme caution in patients with elevated
bilirubin levels.” Previously, the guidelines only recommended
sorafenib for Child-Pugh Class A patients. (Also for )
Treatment, Top branch: Sorafenib was added as a treatment
option for patients who are inoperable by performance status or
comorbidity (local disease only) and who present with cancer-
related symptoms.
or B
HCC-4
( )
( )
( )
( )
HCC-1
HCC-2
HCC-3
HCC-4
Summary of the Guidelines Updates
Note: All recommendations are category 2A unless otherwise indicated.
Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
Gallbladder Cancer
Intrahepatic Cholangiocarcinoma
Extrahepatic Cholangiocarcinoma
:
Top branch, second column: The phrase “Consider en bloc
resection” was changed to “Consider extended cholecystectomy.”
Postoperative Workup; Bottom branch: The recommendation
“Strongly consider staging laparoscopy” was added.
Resectable; Primary Treatment: Panel deleted the recommendation
“± resection of port sites for laparoscopic operations.”
Footnote “b” was amended with the following sentence: “Patients
with nodal disease outside this area are unresectable.”
Under Adjuvant Treatment: The panel changed
“...chemotherapy/RT” to “...chemotherapy ± RT”
:
:
Unresectable and metastatic pathways; Primary Treatment: The
panel changed the recommendation to “Biliary drainage,
Surgical Procedures for Resectable Disease box: Proximal Third:
The panel changed “± en bloc liver resection” to “+” en bloc liver
resection.
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Workup: After “Upper and lower endoscopy”, the panel deleted the
phrase “as indicated”
Primary Treatment, Unresectable: The panel deleted the
recommendation “Ablative or embolization therapy” along with its
corresponding footnote.
if
indicated”
( )
( )
( )
GALL-1
INTRA-1
EXTRA-1
( )GALL-3
Summary of the changes in the 1.2008 version of the Hepatobiliary Cancer guidelines from the 2.2007 version include:
Hepatobiliary Cancers
Summary of the changes in the 2.2008 version of the Hepatobiliary Cancer guidelines from the 1.2008 version include:
The addition of sorafenib as a treatment option for patients who are inoperable by performance status or comorbidity (local disease only)
and who do not present with cancer-related symptoms .
Footnote “l” revised to read “ : There are limited safety data available for Child-Pugh Class B patients. Use with extreme caution in
patients with elevated bilirubin levels” throughout the hepatocellular carcinoma guideline.
�
� Caution
( )HCC-4
Version 2.2008, 10/31/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
Practice Guidelines
in Oncology – v.2.2008
Guidelines Index
Hepatobiliary Cancers TOC
Staging, MS, ReferencesNCCN
®
Note: All recommendations are category 2A unless otherwise indicated.
Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
CLINICAL
PRESENTATION
Liver mass
suspicious
for hepatocellular
carcinoma (HCC)
or
Histologically
confirmed HCC
WORKUP
a
c
d
e
If ultrasound negative, CT/MRI should be performed.
Rule out germ cell tumor if clinically indicated. MRI or triple phase CT scan may be helpful.
An appropriate hepatitis panel should preferably include:
and assessment of portal hypertension (eg, varices, splenomegaly, thrombocytopenia).
bMRI/ CT scan to define extent and number of primary lesions, vascular anatomy, involvement with tumor, and extrahepatic disease; triphasic helical CT or MRI to
include early arterial phase enhancement.
� Hepatitis B surface antigen (HBsAg). HBe and anti-HBc (IgM) are included if HBsAg is positive
Hepatitis B surface antibody (for HBIG or vaccine evaluation only)
Hepatitis C virus antibodies. If low positive, recombinant immuno blot assay (RIBA) confirmation test is performed
�
�
See Child-Pugh Score (HCC-A)
Rising alpha-
fetoprotein (AFP)
Liver imaging
studiesa,b
INITIAL FINDINGS OF
TUMOR AND LIVER
FUNCTION
Metastatic See Metastatic
pathway (HCC-4)
SURGICAL
ASSESSMENT
Mass confirmed
No massc
Screen every 3 mo
with AFP, liver imaging
Follow pathway
for HCC, below
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H&P
Hepatitis panel
Bilirubin, trans-
aminases, alkaline
phosphatase, LDH,
PT or INR, albumin,
protein, BUN,
creatinine
CBC, platelets
AFP
CT/MRI
Chest x-ray
d
b
�
�
Hepatitis B
surface antigen
Hepatitis C
antibodies
Nonmetastatic
Assess liver reserve
and comorbidity
Additional imaging
as required:
e
�
�
�
�
�
Chest CT
Bone scan
CT/MRI
Arterial CT
Ultrasound
b
Unresectable
(See HCC-3)
Inoperable by
performance status
or comorbidity, local
disease only
(See HCC-4)
Metastatic
disease
(See HCC-4)
Potentially resectable,
operable liver mass
(See HCC-2)
HCC-1
Hepatocellular Carcinoma
Version 2.2008, 10/31/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
Practice Guidelines
in Oncology – v.2.2008
Guidelines Index
Hepatobiliary Cancers TOC
Staging, MS, ReferencesNCCN
®
Consider
biopsy
or
Surgical
evaluation
f
Note: All recommendations are category 2A unless otherwise indicated.
Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
SURGICAL EVALUATION
Potentially
resectable,
operable
liver mass
(non-metastatic
disease, liver
confined)
Surgical
evaluation
f
Positive
for HCC
Nondiagnostic
�
�
�
Imaging
follow-up
Rebiopsy
Surgery,
including
laparoscopy
AFP > 4,000 ng/mL,
surface antigen
positive
AFP > 400 ng/mL,
surface antigen
negative
AFP < 400 ng/mL
surface antigen
negative or
AFP < 4,000 ng/mL,
hepatitis B surface
antigen positive or
hepatitis C antigen
positive
Positive
for HCC
TREATMENT
Resectable:
Resection ±
ablation
or
Transplant
h
g
i
Unresectable
Ablation� g
Treatment
(See HCC-3)
See Surgical
evaluation,
above
f
g
i
Discussion of surgical treatment with patient and determination of whether patient is amenable to surgery.
Ablation or embolization options: radiofrequency, alcohol, cryotherapy, microwave or embolization (chemoembolization, radioembolization, bland embolization).
Consider interferon or other antiviral therapy for selected low risk hepatitis C patients with completely resected tumors and good performance status.
Criteria for transplantion (UNOS criteria):
Patient is not a liver resection candidate
Patient has a tumor 5 cm in diameter or 2-3 tumors 3 cm each
No macrovascular involvement
No extrahepatic spread of tumor to surrounding lymph nodes, lungs, abdominal organs, or bone
Mazzaferro V, Regalia E, Doci, R, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis.
N Engl J Med 1996;334(11):693-700.
h
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�
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SURVEILLANCE
�
�
Imaging every 3-6 mo
for 2 y, then annually
AFP, if initially
elevated, every 3 mo
for 2 y, then every
6 mo
For relapse, see initial
Workup (HCC-1)
CLINICAL
PRESENTATION
HCC-2
See Surgical
evaluation,
above
Patient
does not
agree to
surgery
Treatment
(See HCC-3)
or
Ablation
(category 2B)
g
Patient
agrees to
surgery
Hepatocellular Carcinoma
Version 2.2008, 10/31/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
Practice Guidelines
in Oncology – v.2.2008
Guidelines Index
Hepatobiliary Cancers TOC
Staging, MS, ReferencesNCCN
®
Note: All recommendations are category 2A unless otherwise indicated.
Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
Unresectable
or patient
declines
surgery
Extensive
Options:
�
�
�
�
�
�
�
�
�
Sorafenib (Child-Pugh Class A or B) ,
Chemoembolization
Clinical trial
Ablation
Chemotherapy + RT in clinical trial
RT (conformal or stereotactic)
Radioembolization
Supportive care
Systemic or intra-arterial chemotherapy in
clinical trial
e j,k,l
m
g
TREATMENT
�
�
Inadequate
hepatic
reserve
Tumor location
e
Evaluate
whether patient
a candidate for
transplanti
Cancer-related
symptoms absent
Sorafenib (Child-Pugh Class A or B) ,e j,k,l
or
Clinical trial
Transplant
candidate
Not a
transplant
candidate
Transplant
Cancer-related
symptoms present
(UNOS criteria):
Patient is not a liver resection candidate
Patient has a tumor 5 cm in diameter or 2-3 tumors 3 cm each
No macrovascular involvement
No extrahepatic spread of tumor to surrounding lymph nodes, lungs, abdominal organs, or bone
Contraindicated in cases of main portal thrombosis or Child-Pugh Class C.
e
j
k
l
g
i
m
Ablation or embolization options: radiofrequency, alcohol, cryotherapy, microwave or embolization (chemoembolization, radioembolization, bland embolization).
Criteria for transplantion
Mazzaferro V, Regalia E, Doci, R, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis.
N Engl J Med 1996;334(11):693-700.
The impact of sorafenib on patients potentially eligible for transplant is unknown. Data are inadequate to define dosing for patients with abnormal
liver function (Child-Pugh Class B or C).
. (Llovet J, Ricci S, Mazzaferro V, et al. Sorafenib improves survival in advanced
Hepatocellular Carcinoma (HCC): Results of a Phase III randomized placebo-controlled trial (SHARP trial). 2007 ASCO Annual Meeting Proceedings Part I.
J Clin Onc 2007, Vol 25, No. 18S (June 20 Supplement), 2007: LBA1)
Caution: There are limited safety data available for Child-Pugh Class B patients. Use with extreme caution in patients with elevated bilirubin levels. (Miller AA, Murry
K, Owzar DR, et al. Pharmacokinetic (PK) phase I study of sorafenib (S) for solid tumors and hematologic malignancies with hepatic or renal dysfunction (HD or RD):
CALGB 6031 2007 ASCO Annual Meeting Proceedings Part I. J Clin Onc 2007, Vol 25, No 18S (June 20 Supplement), 2007: 3538)
�
� � �
�
�
For selected patients, a randomized clinical trial has demonstrated survival benefits
See Child-Pugh Score (HCC-A).
SURVEILLANCE
�
�
Imaging every 3-6 mo for 2 y,
then annually
AFP, if initially elevated, every
3 mo for 2 y, then every 6 mo
CLINICAL
PRESENTATION
HCC-3
Hepatocellular Carcinoma
Version 2.2008, 10/31/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
Practice Guidelines
in Oncology – v.2.2008
Guidelines Index
Hepatobiliary Cancers TOC
Staging, MS, ReferencesNCCN
®
Note: All recommendations are category 2A unless otherwise indicated.
Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
Metastatic
disease
Inoperable by performance
status or comorbidity,
local disease only
�
�
AFP > 4,000 ng/mL,
surface antigen positive
(Biopsy not required)
AFP > 400 ng/mL,
surface antigen negative
(Biopsy not required)
AFP < 400 ng/mL
surface antigen negative
or
AFP < 4,000 ng/mL,
hepatitis B surface
antigen positive
Options:
�
�
�
�
�
�
�
Sorafenib (Child-Pugh Class A or B) ,
Clinical trial
Ablation
Chemoembolization
RT (conformal or stereotactic)
Radioembolization
Supportive care
e j,k,l
g
m
TREATMENT
Cancer-related
symptoms absent
Cancer-related
symptoms present
Consider
biopsy
HCC
confirmed
e
j
k
l
g
m
Ablation or embolization options: radiofrequency, alcohol, cryotherapy, microwave or embolization (chemoembolization, radioembolization, bland embolization)
The impact of sorafenib on patients potentially eligible for transplant is unknown. Data are inadequate to define dosing for patients with abnormal
liver function (Child-Pugh Class B or C).
. (Llovet J, Ricci S, Mazzaferro V, et al. Sorafenib improves survival in advanced
Hepatocellular Carcinoma (HCC): Results of a Phase III randomized placebo-controlled trial (SHARP trial). 2007 ASCO Annual Meeting Proceedings Part I. J Clin
Onc 2007, Vol 25, No. 18S (June 20 Supplement), 2007: LBA1.
Caution: There are limited safety data available for Child-Pugh Class B patients. Use with extreme caution in patients with elevated bilirubin levels. (Miller AA, Murry
K, Owzar DR, et al. Pharmacokinetic (PK) phase I study of sorafenib (S) for solid tumors and hematologic malignancies with hepatic or renal dysfunction (HD or RD):
CALGB 6031 2007 ASCO Annual Meeting Proceedings Part I. J Clin Onc 2007, Vol 25, No 18S (June 20 Supplement), 2007: 3538)
For selected patients, a randomized clinical trial has demonstrated survival benefits
Contraindicated in cases of main portal thrombosis or Child-Pugh Class C.
See Child-Pugh Score (HCC-A).
CLINICAL
PRESENTATION
HCC-4
Hepatocellular Carcinoma
Sorafenib (Child-Pugh Class A or B) ,e j,k,l
or
Supportive care
or
Clinical trial
Sorafenib (Child-Pugh Class A or B) ,e j,k,l
or
Ablation
or
Clinical trial
Version 2.2008, 10/31/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without t