2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

Advanced Biliary Tract Cancers
By Laura Williams Goff, MD, and Jordan D. Berlin, MD
Overview: Single-agent management of metastatic biliary
tract cancers with 5-fluorouracil (5-FU) or gemcitabine has
shown limited efficacy, although 5-FU has been shown to be
more effective than best supportive care alone. An analysis
of phase II trials has suggested that platinums enhanced
the efficacy of single-agent fluoropyrimidines. In a phase III
randomized trial comparing single-agent gemcitabine with
gemcitabine plus cisplatin, the gemcitabine/cisplatin combination
significantly improved median overall survival (OS)
BILIARY TRACT cancers consist of a somewhat heterogeneous
group of tumors that include gallbladder cancer,
extrahepatic biliary tract cancer, and intrahepatic
cholangiocarcinoma. The exact incidence of each of these
cancers is difficult to discern from annual cancer statistics
because, for example, intrahepatic cholangiocarcinoma is
still combined with hepatocellular carcinoma despite the
fact that these are biologically distinct entities. In 2011,
9,250 new cases and 3,300 deaths from biliary tract cancers
and gallbladder cancer (excluding intrahepatic cholangiocrcinoma)
were anticipated. 1 Cancers of the biliary tract are
often found at late stages when resection is not feasible and
treatment options are limited. Overall, 5-year survival rates
are estimated to be approximately 15%.
Cytotoxic Chemotherapy
The systemic treatment of biliary tract cancers has largely
been based on cytotoxic chemotherapy. Data comparing
5-FU–based chemotherapy with best supportive care demonstrated
that median survival times are significantly prolonged
(6.0 months vs. 2.5 months) with treatment. 2 In
addition, the time before declines in quality of life was
prolonged with 5-FU–based chemotherapy. Rates of response
to either single-agent 5-FU or 5-FU with leucovorin
range up to approximately 20% with survival times up to
8 months. Similarly, single-agent gemcitabine has been
explored as an alternative treatment option for biliary tract
cancers. Response rates for single-agent gemcitabine have
ranged from 16% to 36% and survival times from 6 months
to 16 months. 3 Phase II study of combinations of gemcitabine
with either 5-FU or its oral prodrug, capecitabine, has
not clearly improved on the results of single-agent phase II
data. 4 The most promising results came from the combination
of gemcitabine and capecitabine with a response rate
of 31% in 45 patients and an OS of 14 months. 5
However, studies combining 5-FU or gemcitabine with
platinums have yielded very promising response rates. 4
Therefore, a study was undertaken to evaluate the effects of
gemcitabine plus cisplatin compared to gemcitabine alone. 6
This study had an initial randomized phase II portion
(ABC-01) and, when its endpoints were met, the trial proceeded
to phase III (ABC-02). The ABC-02 trial demonstrated
a significant benefit in both response rate and PFS
favoring the gemcitabine/cisplatin arm. Most importantly,
OS increased from 8.1 months for those treated with singleagent
gemcitabine to 11.7 months for those treated with
gemctiabine/cisplatin. These results have established the
standard of care for biliary tract cancers at the current time.
and progression-free survival (PFS), which established a new
option for standard of care. However, the future of cancer
medicine lies in newer, targeted agents. In the management of
biliary tract cancers, preliminary evidence with epidermal
growth factor receptor inhibitors has already demonstrated
activity. This article reviews systemic therapies for metastatic
biliary tract cancers as they relate to current and emerging
standards of care.
KEY POINTS
● Single-agent management of advanced biliary cancers
with 5-fluorouracil or gemcitabine yields short
survival times.
● Adding cisplatin to gemcitabine significantly improves
progression-free survival and overall survival
for patients with biliary tract cancers.
● Targeted therapies are being evaluated in patients
with biliary tract cancers, showing some preliminary
evidence of activity for epidermal growth factor receptor
inhibition.
Targeted Agents
Because of the limited likelihood that cytotoxic therapy
will substantially change the natural history of biliary tract
cancers, investigation is now focusing on the use of targeted
agents. One of the first agents studied in biliary tract
cancers was erlotinib, an oral tyrosine kinase inhibitor of
the epidermal growth factor receptor (EGFR). EGFR is
overexpressed in most biliary tract cancers. 7 In a singleagent,
multi-institutional study, erlotinib produced rare
responses (8%) in 42 patients. 8 Although the median time to
tumor progression was only 2.6 months, 17% of patients
were progression-free at 6 months and OS was 7.5 months.
Because adding EGFR inhibition to chemotherapy has
worked in other diseases such as colorectal cancer, investigators
have added cetuximab to gemcitabine and oxaliplatin
in a phase II study. A small randomized trial
comparing the combination of gemcitabine plus oxaliplatin
with gemcitabine/oxaliplatin plus erlotinib has been reported.
9 In the 133 randomly assigned patients, there was a
trend toward a PFS benefit from adding erlotinib, but OS
was identical for both arms at 9.5 months. However, the
EGFR pathway is actually a complex network and has
interactions with several other pathways. Others have tried
From the Vanderbilt Ingram Cancer Center, Nashville, TN.
Authors’ disclosures of potential conflicts of interest are found at the end of this article.
Address reprint requests to Jordan D. Berlin, MD, Vanderbilt Ingram Cancer Center, 777
Preston Research Building, 2220 Pierce Ave., Nashville, TN 37232-6307, email: jordan.
berlin@vanderbilt.edu.
© 2012 by American Society of Clinical Oncology.
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