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The Oncologist, Vol. 13, No. 4, 415-423, April 2008; doi:10.1634/theoncologist.2007-0252
© 2008 AlphaMed Press

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Hepatobiliary

Systemic Therapy for Biliary Tract Cancers

Aram F. Hezel, Andrew X. Zhu

Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts, USA

Key Words. Cholangiocarcinoma • Gallbladder cancer • Chemotherapy • Bile duct cancer

Correspondence: Aram F. Hezel, M.D., or Andrew X. Zhu, M.D., Ph.D., Tucker Gosnell Center for Gastrointestinal Cancers, Massachusetts General Hospital Cancer Center, Lawrence House/POB 232, Boston, Massachusetts 02114, USA. Telephone: 617-724-3853; Fax: 617-724-3166; e-mail: ahezel{at}partners.org or azhu{at}partners.org

Received December 23, 2007; accepted for publication February 27, 2008.

Disclosure: A.F.H. has received consulting fees from Vion Pharmaceuticals. A.X.Z. has acted as a consultant for Genentech (bevacizumab). This article discusses bevacizumab manufactured by Genentech. No other potential conflicts of interest were reported by the authors, planners, reviewers, or staff managers of this article.


   LEARNING OBJECTIVES
Top
 Learning Objectives
Abstract
 Introduction
 Can Chemotherapy Improve...
 Randomized Trials in BTC
 Fluoropyrimidine-Based Regimens
 Gemcitabine-Based Regimens
 Molecular Features and Targeted...
 Conclusions and Recommendations
 Author Contributions
 References
 
After completing this course, the reader will be able to:

  1. Assess the clinical and molecular heterogeneity of BTCs.
  2. Exploit the chemotherapy responsiveness of these tumors to improve the quality of life and extend the survival of patients with BTC.
  3. Administer the most current systemic therapy in BTC patients, including the appropriate first-line treatment options.
  4. Explain the rationale for developing and discuss the current status of molecularly targeted agents in BTC.

Access and take the CME test online and receive 1 AMA PRA Category 1 CreditTM at CME.TheOncologist.com


   ABSTRACT
Top
 Learning Objectives
 Abstract
Introduction
 Can Chemotherapy Improve...
 Randomized Trials in BTC
 Fluoropyrimidine-Based Regimens
 Gemcitabine-Based Regimens
 Molecular Features and Targeted...
 Conclusions and Recommendations
 Author Contributions
 References
 
Biliary tract cancers (BTCs) are invasive carcinomas that arise from the epithelial lining of the gallbladder and bile ducts. These include intrahepatic, perihilar, and distal biliary tree cancers as well as carcinoma arising from the gallbladder. Complete surgical resection offers the only chance for cure; however, only 10% of patients present with early-stage disease and are considered surgical candidates. Among those patients who do undergo "curative" resection, recurrence rates are high; thus, for the majority of BTC patients, systemic chemotherapy is the mainstay of their treatment plan. Patients with unresectable or metastatic BTC have a poor prognosis, with a median overall survival time of <1 year. Despite a paucity of randomized phase III data, a consensus on first-line systemic therapy is emerging. In this review, we discuss the clinical experience with systemic treatment of BTC, focusing on the rationale for a first-line regimen as well as future directions in the field.


   INTRODUCTION
Top
 Learning Objectives
 Abstract
 Introduction
Can Chemotherapy Improve...
 Randomized Trials in BTC
 Fluoropyrimidine-Based Regimens
 Gemcitabine-Based Regimens
 Molecular Features and Targeted...
 Conclusions and Recommendations
 Author Contributions
 References
 
Biliary tract cancers (BTCs) are invasive carcinomas that arise from the epithelial lining of the gallbladder and bile ducts. The term BTC includes both cholangiocarcinoma, which has been used to refer to cancers arising in the intrahepatic, perihilar, or distal biliary tree, and carcinoma arising from the gallbladder. The vast majority of cholangiocarcinomas and gallbladder cancers are adenocarcinoma. BTCs affect approximately 12,000 people in the U.S. annually [1]. Although the incidence of extrahepatic cholangiocarcinoma has remained constant, the incidence of intrahepatic cholangiocarcinoma has increased in the U.S. [2]. This group of tumors is characterized by regional lymph node metastasis, vascular encasement, and distant metastases. Complete surgical resection offers the only chance for cure; however, only 10% of patients present with early-stage disease and are considered surgical candidates. Among those patients who do undergo "curative" resection, recurrence rates are high; thus, for the majority of BTC patients, systemic chemotherapy is the mainstay of their treatment plan. Patients with unresectable or metastatic BTC have a poor prognosis with a median overall survival (OS) time of <1 year. Among the BTCs, there are differences with respect to disease course, responsiveness to chemotherapy, and, correspondingly, molecular profiles based on the site of disease—intrahepatic, distal biliary tree, or gallbladder. Thus, while these entities have traditionally been included together in clinical trials, it is widely appreciated that efforts should be made to segregate these diseases in future studies. Despite a paucity of randomized phase III data, a consensus on first-line systemic therapy is emerging. Below, we review the clinical experience with systemic treatment of BTC, focusing on the rationale for a first-line regimen as well as future directions in the field. Other excellent reviews have recently summarized other aspects of BTCs, including the molecular biology, epidemiology, staging, and surgical management of these cancers, to which we refer the reader [3–6].


   CAN CHEMOTHERAPY IMPROVE SURVIVAL?
Top
 Learning Objectives
 Abstract
 Introduction
 Can Chemotherapy Improve...
Randomized Trials in BTC
 Fluoropyrimidine-Based Regimens
 Gemcitabine-Based Regimens
 Molecular Features and Targeted...
 Conclusions and Recommendations
 Author Contributions
 References
 
Because of the smaller numbers of patients and heterogeneous patient population in BTC as compared with other more common malignancies, randomized phase III studies have been a challenge to conduct. Most of the clinical experience and data are derived from smaller phase II trials, and it is largely from these experiences that clinical standards have been adopted by the gastrointestinal (GI) oncology community.

The advantages of systemic chemotherapy over supportive care alone in improving quality of life (QOL) and survival among BTC patients was first suggested in an evaluation of 5-fluorouracil (5-FU) plus leucovorin (LV) and etoposide therapy versus best supportive care among a mixed population of pancreatic and BTC patients [7]. In that trial, conducted prior to the widespread adoption of gemcitabine-based chemotherapy regimens for locally advanced and metastatic disease, 90 patients, including 53 pancreatic cancer and 37 BTC patients, were randomized to best supportive care versus chemotherapy. The OS time was significantly longer in the chemotherapy group than in the best supportive care group (median, 6 months versus 2.5 months; p < .01). Furthermore, treatment was associated with an improvement in QOL as evaluated by the European Organization for Research and Treatment of Cancer (EORTC) QOL questionnaire EORTC-QLQ-C30. Subgroup analysis supported the applicability of these findings to both pancreatic cancer patients and BTC patients with similar degrees of benefits, although the p-value of 0.1 did not reach a predefined significance level of < .05 among the BTC subgroup, likely as a result of the small sample size. Despite the limitation of this study, because of ethical and practical considerations, this will likely represent the only study comparing the relative benefits of chemotherapy with those of best supportive care in advanced BTC.


   RANDOMIZED TRIALS IN BTC
Top
 Learning Objectives
 Abstract
 Introduction
 Can Chemotherapy Improve...
 Randomized Trials in BTC
Fluoropyrimidine-Based Regimens
 Gemcitabine-Based Regimens
 Molecular Features and Targeted...
 Conclusions and Recommendations
 Author Contributions
 References
 
Three randomized trials have been conducted comparing chemotherapy regimens in BTC. A randomized phase II trial comparing high-dose 5-FU with 5-FU, LV, and cisplatin involving 58 patients was conducted by the EORTC [8]. Patients with locally advanced or metastatic BTC were randomized to either arm A, consisting of cycles of continuous infusion 5-FU at 3 g/m2 weekly for 6 weeks followed by 1 week of rest, every 7 weeks, or arm B, consisting of cycles of continuous infusion 5-FU at 2.0 g/m2, LV at 500 mg/m2 given with a 2-hour infusion weekly, and cisplatin at 50 mg/m2 once every 2 weeks, for 6 weeks, followed by 1 week of rest, every 7 weeks. The combination therapy in arm B demonstrated a higher response rate (RR) (19% versus 7%) and a trend toward a longer OS time compared with arm A (8 months versus 5 months). However, the rate of disease stabilization was not different between the two arms, and the toxicity of the combined therapy in arm B was significant, with higher incidences of grade 3 and 4 neutropenia and GI toxicities, and thus the authors concluded that the combination regimen with 5-FU, LV, and cisplatin did not warrant further investigation.

A randomized phase II trial compared the relative tolerability and efficacy of mitomycin C (MMC) plus gemcitabine versus MMC plus capecitabine [9]. In total, 51 patients were randomly allocated to treatment with MMC, 8 mg/m2 on day 1, in combination with gemcitabine, 2,000 mg/m2 on days 1 and 15, every 4 weeks, or MMC, 8 mg/m2 on day 1, plus capecitabine, 2,000 mg/m2 per day on days 1–14, every 4 weeks. The MMC plus capecitabine treatment was associated with a higher RR (31% versus 20%), longer time to progression (TTP) (5.3 months versus 4.2 months), and longer OS time (9.3 months versus 6.7 months) compared with the MMC plus gemcitabine treatment.

The only phase III trial in BTC to date compared etoposide, 5-FU, and LV (FELV) with epirubicin, cisplatin, and 5-FU (ECF) [10]. As a result of poor recruitment (54 of the planned 119 patients), the trial was underpowered to detect a significant difference in OS. The median OS time for ECF was 9.02 months (95% confidence interval [CI], 6.46–11.51) and for FELV it was 12.03 months (95% CI, 9.3–14.7), with a p-value of .2059. Objective RRs were similar for both arms: ECF, 19.2% (95% CI, 6.55%–39.3%); FELV, 15% (95% CI, 3.2%–37.9). Overall nonhematological toxicities were similar for both regimens. However, there was a significantly higher incidence of grade 3–4 neutropenia with FELV than with ECF (53.8% versus 29.5%, respectively; p = .020).

These trials, and particularly their associated QOL measures and toxicity data, provide evidence for the safe and efficacious use of traditional cytotoxic chemotherapy in BTC. Modest but reproducible RRs were observed in these trials, and the OS times for the tested arms were consistently >6 months. None of these studies have, however, provided a clear standard of care for BTC.


   FLUOROPYRIMIDINE-BASED REGIMENS
Top
 Learning Objectives
 Abstract
 Introduction
 Can Chemotherapy Improve...
 Randomized Trials in BTC
 Fluoropyrimidine-Based Regimens
Gemcitabine-Based Regimens
 Molecular Features and Targeted...
 Conclusions and Recommendations
 Author Contributions
 References
 
5-FU and 5-FU–based regimens were among the first reported in BTC and have in part been described above because they are the backbone of the regimens tested in a randomized fashion. Other single-arm phase II studies with 5-FU alone and with other agents reflect the level of activity described above. 5-FU plus LV has a demonstrated RR of 32% and OS time of 6 months [11]. Combination therapy with cisplatin consistently yields response rates of 10%–40% and median OS times somewhat better than those observed with 5-FU alone [12–15]. 5-FU combinations with taxanes, etoposide, streptozotocin, methyl-1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea, and irinotecan have not shown convincing superiority over 5-FU alone in BTC [7, 16, 17]. Similar to the experience with 5-FU plus cisplatin combinations, two phase II studies of capecitabine plus cisplatin in BTC, divided between cholangiocarcinoma and gallbladder cancer, demonstrated somewhat higher RRs of 21% and 40% and median OS times of 9.1 and 12.4 months [18, 19]. No grade 4 toxicities were reported. An earlier study evaluating epirubicin, cisplatin, and capecitabine exhibited an impressive RR of 40% but with an unremarkable median OS duration of 8 months and a significant incidence grade 3–4 mucositis (19%) and neutropenia (26%) [20]. Capecitabine has also been evaluated in combination with gemcitabine and is discussed below.

The fluoropyrimidines uracil-tegafur (UFT) and S-1 have also been evaluated in BTC. UFT is an oral combination of two drugs—tegafur, a prodrug that is converted by the liver to 5-FU, and uracil, a competitive inhibitor of dihydropyrimidine dehydrogenase (DPD), the enzyme responsible for fluorouracil catabolism. S-1 is a combination of tegafur, 5-chloro-2,4-dihydroxypyridine (known as CDHP, also an inhibitor of DPD) and potassium oxonate, which may reduce diarrhea related to tegafur. As evidenced by a number of phase II studies, the activity of single agents mirrors the experience described with 5-FU and capecitabine and is slightly better with the addition of cisplatin [21–25]. These studies are detailed in Table 1.


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  		Table 1. 5-FU–based regimens

 

   GEMCITABINE-BASED REGIMENS
Top
 Learning Objectives
 Abstract
 Introduction
 Can Chemotherapy Improve...
 Randomized Trials in BTC
 Fluoropyrimidine-Based Regimens
 Gemcitabine-Based Regimens
Molecular Features and Targeted...
 Conclusions and Recommendations
 Author Contributions
 References
 
Gemcitabine, a nucleotide analogue determined to be active against advanced pancreatic cancer in both the metastatic and adjuvant settings, has been extensively evaluated in patients with metastatic biliary tract tumors [26, 27]. RRs with single-agent gemcitabine have varied in the range of 0%–30%, with median OS times in the range of 5–14 months [28–33] (Table 2). The rationale for gemcitabine-based chemotherapy in BTC was also recently reviewed [34]. Based on acceptable tolerability and promising RRs and OS times, more recent studies have focused on improving efficacy, by combining gemcitabine with other agents, while maintaining a tolerable toxicity profile.


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  		Table 2. Single-agent gemcitabine

 
Combinations of gemcitabine with platinum-based regimens have demonstrated efficacy in other diseases, including cancers of the aerodigestive tract and cervix. Though randomized trials in pancreatic cancer have not demonstrated a significant difference in OS for gemcitabine plus oxaliplatin versus gemcitabine alone, a recent meta-analysis of two gemcitabine plus oxaliplatin trials suggests a benefit with combination therapy [35, 36]. Gemcitabine and cisplatin or oxaliplatin combinations in BTC have been tested in at least eight published clinical trials to date, which have demonstrated RRs (21%–53%) and median OS times (~5–15 months) somewhat better than those from the preceding single-agent gemcitabine studies (Table 3).


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  		Table 3. Gemcitabine-based combination regimens

 
Four studies of gemcitabine plus cisplatin have been reported, with RRs of 21%–34.5% and median survival times of 9.3–11 months [37–40]. These studies were all conducted with a 21-day cycle consisting of gemcitabine (1,000–1,250 mg/m2) on days 1 and 8 and 30–70 mg/m2 of cisplatin on day 1. A multicenter study conducted in the U.S. demonstrated a RR of 21% and median OS time of 9.7 months. Despite a lower dose of cisplatin than in the other reported trials, >50% patients withdrew consent because of treatment-related hematologic and GI toxicities [37]. The toxicity data in that trial differed from other reports, in which therapy appeared to be better tolerated, even with higher doses of cisplatin [38]. Whether patient selection, population genetics and pharmacokinetic differences, or patient reporting played a role in these observed differences is unclear.

Gemcitabine–oxaliplatin combinations have been reported in three trials. Oxaliplatin alone has also been evaluated in a first-line setting with appreciable activity [41]. A Groupe Cooperateur Multidisciplinaire en Oncologie study evaluated 56 patients with BTC treated with gemcitabine (1,000 mg/m2) and oxaliplatin (100 mg/m2) every 2 weeks and stratified patients based on their Eastern Cooperative Oncology Group performance status (PS) score (0–2 versus >2) and bilirubin level (<2.5 mg/dl versus >2.5 mg/dl) [42]. The median OS time among good PS patients was double that of poor PS patients at 15.4 months versus 7.6 months. RRs were 36% and 22%, respectively. Importantly, this regimen was well tolerated, even among poor PS patients. Treatment on a 28-day cycle, with gemcitabine at 1,000 mg/m2 on days 1, 8, and 15 and oxaliplatin at 100 mg/m2 on days 1 and 15, yielded a 26% RR and 11-month median OS time and was similarly well tolerated [43]. Finally, in a reported Italian study including nine gallbladder cancer patients and 15 cholangiocarcinoma patients, a 50% RR and 14-month median OS time were reported [44]. Among all these reported experiences, hematologic suppression and grade 1–2 peripheral neuropathy were the most significant toxicities reported.

Gemcitabine has also been evaluated in combination with fluorouracil [29, 45]. Gemcitabine plus capecitabine was initially evaluated in two single-arm phase II trials. Both trials were fairly large, with 44 and 45 patients, respectively, equally divided with respect to gallbladder and cholangiocarcinoma, and with the vast majority of patients having metastatic disease [46, 47]. This regimen was well tolerated, with neutropenia and thrombocytopenia as the most common grade 3–4 toxicities. The two trials demonstrated remarkably similar results; the median OS time in both trials was 14 months, and RRs of 31% and 32% were reported. An extension of one of these trials, with the addition of 30 patients, 75 in total, demonstrated similar efficacy, with a RR of 29% and median OS time of 12.7 months [48], and suggested a benefit comparable with that observed with oxaliplatin- and cisplatin-containing gemcitabine-based combinations. An interim report of gemcitabine plus irinotecan in BTC suggested significant neutropenia with only a modest level of activity [49].

More recently, a pooled analysis of 104 chemotherapy trials involving 1,368 BTC patients conducted between 1999 and 2006 both suggested a biologic difference between cholangiocarcinoma and gallbladder carcinoma and pointed toward gemcitabine as the most active agent [50]. Among all patients, the median TTP and OS time were 4.1 months and 8.2 months, respectively. Subgroup analysis of gallbladder carcinoma versus cholangiocarcinoma, however, demonstrated a significantly greater RR in gallbladder carcinoma patients, 36% versus 18%, while the median OS time was better for patients with cholangiocarcinoma, 9.3 months versus 7.2 months. Importantly, this study demonstrated that gemcitabine- and platinum-containing regimens produced a consistently higher RR and longer TTP for both gallbladder carcinoma and cholangiocarcinoma patients as compared with other therapies. The findings of this study were echoed in a recent retrospective analysis of BTC patients in Japan, in which treatment with gemcitabine-based chemotherapy was associated with a lower risk for death [51]. That study pointed toward a clinical standard of gemcitabine-based therapy and a possible benefit conferred by combination with platinum-containing regimens or with capecitabine. While gemcitabine-based regimens have been routinely used in clinical practice, the relative benefit of gemcitabine-based combination regimens versus gemcitabine alone needs to be tested in randomized controlled clinical trials.


   MOLECULAR FEATURES AND TARGETED THERAPIES IN BTC
Top
 Learning Objectives
 Abstract
 Introduction
 Can Chemotherapy Improve...
 Randomized Trials in BTC
 Fluoropyrimidine-Based Regimens
 Gemcitabine-Based Regimens
 Molecular Features and Targeted...
Conclusions and Recommendations
 Author Contributions
 References
 
BTCs share a largely common spectrum of mutations in cancer-related genes, including common activation of K-ras and loss of function of the P16INK4A, P53, and SMAD4 tumor suppressor genes [52–54]. Activating missense B-raf mutations were also identified in 22% of a series of cholangiocarcinomas. Importantly, these mutations were mutually exclusive of K-ras mutations, which occurred in 45% of tumors within this series, pointing toward obligate activation of the Raf/mitogen-activated protein kinase (MAPK) signaling pathway within a large set of these tumors [55]. Testing of Raf and MAPK/Erk kinase (MEK) inhibitors in this population should be a foremost priority (Table 4).


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  		Table 4. Targeted agents in development

 
Activating epidermal growth factor receptor (EGFR) mutations have also been identified in a subset (13.6%–15%) of BTCs, pointing toward a role for small-molecule inhibitors in a subset of these patients as well [56, 57]. A trial of 42 patients with BTC treated with single-agent erlotinib demonstrated a 17% 6-month progression-free survival (PFS) rate, and three patients had partial responses (PRs) as determined by the Response Evaluation Criteria in Solid Tumors. Of these patients, 57% had received first-line chemotherapy [58]. In this study, EGFR mutation status was not tested, and therefore it is unknown if the response correlated with EGFR mutation status in BTC. The clinical experience with erlotinib and the molecular studies suggesting a mutation rate on the order of 13%–15% beg the question of a highly susceptible EGFR mutant population of patients who would benefit from inhibitors, along the lines of non-small cell lung cancer patients [59]. EGFR gene amplification studies as well as case reports on the efficacy of cetuximab in combination with either gemcitabine or gemcitabine and oxaliplatin have also been published, further prompting investigation of EGFR inhibitors in BTC [60–62]. Lapatinib, a dual EGFR-1 and human epidermal growth factor receptor (HER)-2/Neu inhibitor, has been tested in a phase II trial including both BTCs and hepatocellular carcinoma [63]. In 17 evaluable patients with BTC, no responses were observed though five patients had stable disease (SD). Based on this, the authors concluded that this agent has no activity in BTC.

Additional molecular characteristics and associated targeting strategies in BTC were recently reviewed [4]. While agents targeting pathways such as those of the met proto-oncogene (hepatocyte growth factor receptor) and transforming growth factor β, etc., have yet to complete phase I testing, targeting vascular endothelial growth factor receptor (VEGF) has proven to be clinically significant in a number of other solid tumors. The expression of VEGF, a key mediator in tumor angiogenesis, has been detected in BTC. Higher VEGF expression levels have been correlated with advanced stage of disease and a poor prognosis [64]. Presently, bevacizumab, a humanized monoclonal antibody against VEGF, is being tested in combination with gemcitabine and oxaliplatin in BTC in a multicenter phase II trial [65]. Based on an early report, this combination appears to be safe and well tolerated. Of the first 24 patients analyzed, seven had PRs and six had SD. A fluorodeoxyglucose positron emission tomography analysis evaluating standardized uptake values from baseline to after two cycles of treatment was also promising, with 17 PRs, five cases of SD, and one case of progressive disease among the 23 patients analyzed based on EORTC criteria. Sorafenib, which most efficaciously targets VEGF receptor (VEGFR)-2 and VEGFR-3 and the platelet-derived growth factor receptor and less potently targets the B- and C-Raf kinases, was tested as a single agent in a phase II trial involving 31 evaluable patients [66]. Grade 3–4 toxicities were noted in 20 patients (66.7%) and included hand–foot syndrome, thrombosis/embolism, elevated liver transaminases, and abdominal pain. Two patients (6%) had an unconfirmed PR and nine patients (29%) had SD. At the time of the report, 27 patients had progressed on therapy, yielding a median PFS time of 2 months (95% CI, 2–4 months) and median survival duration estimate of 6 months (95% CI, 4–10 months). These studies suggest the importance of targeting angiogenesis in BTC. More definitive studies are required to define the role of antiangiogenic agents in advanced BTC. The limited RR of single-agent sorafenib should not dissuade further evaluation of more potent Raf kinase inhibitors in BTCs, particularly among those harboring K-ras mutations.


   CONCLUSIONS AND RECOMMENDATIONS
Top
 Learning Objectives
 Abstract
 Introduction
 Can Chemotherapy Improve...
 Randomized Trials in BTC
 Fluoropyrimidine-Based Regimens
 Gemcitabine-Based Regimens
 Molecular Features and Targeted...
 Conclusions and Recommendations
Author Contributions
 References
 
From the many clinical trials conducted in BTCs, we have achieved significant, albeit modest, efficacy of classic cytotoxic chemotherapy. The collected phase II experience and a more recent meta-analysis suggest that gemcitabine and gemcitabine-based platinum regimens offer a slight advantage over other regimens [50]. The reported experience with gemcitabine and capecitabine in combination is noteworthy both for the RR on par with gemcitabine plus cisplatin or oxaliplatin combinations and the relatively long median OS duration [48]. Among gemcitabine–cisplatin or gemcitabine–oxaliplatin combinations, which have similar reported RRs and median OS times, the toxicity and tolerability data tend to favor gemcitabine–oxaliplatin combinations. This is the backbone that we have used in the exploration of the added effects of newer target agents [65].

Understanding completely how tumor genetics predicts drug sensitivity is a key area to focus on in future trials. Evidence suggesting nonoverlapping spectra of key oncogenic mutations, including K-ras, EGFR, and B-raf, potentially offers a genetic basis for tailored first-line regimens with targeted agents in the future. Important questions include defining the relationship between activated EGFR mutations and erlotinib responsiveness as well as between ras mutation and lack of response to EGFR-blocking antibodies, as has been recently demonstrated in colorectal cancer. The relationship between ras mutation status and the sensitivity of tumors to EGFR antagonism (ras mutation predicts insensitivity) that is observed in other tumor types begs us to look at the relevance of this relationship in BTC. This is particularly compelling given the clinical evidence of responsiveness among subsets of patients with EGFR-targeting agents. Inhibitors of B-Raf or the downstream MAPK/MEK pathway will be important to test in BTC. Again, these studies should include corollary genetic analyses of tumors, allowing patterns of sensitivity to be established. Evidence of heterogeneity in chemotherapy response, genetics, and OS among cancers arising in the gallbladder and bile ducts and intrahepatic cholangiocarcinomas suggests that future trials should either stratify these entities or study one entity in a specific trial. Given the relatively small numbers of these cancers, such a trial design will be a challenge and will require a multicenter design to adequately power each subtype of BTC. While trial design and implementation provide statistical and logistical challenges, such integrated and coordinated efforts offer the hope of enriching populations of BTC subtypes, enabling the evaluation of targeted agents based on the molecular signature (EGFR or B-raf mutations).

Molecular and genetic profiles may ultimately dictate first-line therapy once the efficacy of genetic stratification in BTC is established. In the meantime, the community needs to proceed with the testing of first-line classic cytotoxic regimens to establish a standard of care. Data presented here suggest that establishing the value of combination therapy over gemcitabine alone is critical. Arms to consider include gemcitabine versus gemcitabine plus oxaliplatin versus gemcitabine plus capecitabine. Data on bevacizumab with gemcitabine plus oxaliplatin will be emerging. Integrating bevacizumab into future trials will be important if the RR, PFS time, and OS time appear superior from the current phase II study to the historical data described above.

Important work has provided insights into the clinical behavior, biology, genetics, and treatment of BTC. This should pave the way for future efforts in a very directed way. Given the relatively small number of BTCs and disease heterogeneity, integration and coordination of national and international clinical research efforts are of paramount importance to continued progress in this field and improved outcomes for our patients.


   AUTHOR CONTRIBUTIONS
Top
 Learning Objectives
 Abstract
 Introduction
 Can Chemotherapy Improve...
 Randomized Trials in BTC
 Fluoropyrimidine-Based Regimens
 Gemcitabine-Based Regimens
 Molecular Features and Targeted...
 Conclusions and Recommendations
 Author Contributions
References
 
Conception/design: Aram F. Hezel, Andrew X. Zhu

Financial support: Aram F. Hezel, Andrew X. Zhu

Administrative support: Aram F. Hezel, Andrew X. Zhu

Provision of study materials or patients: Aram F. Hezel, Andrew X. Zhu

Collection/assembly of data: Aram F. Hezel, Andrew X. Zhu

Data analysis and interpretation: Aram F. Hezel, Andrew X. Zhu

Manuscript writing: Aram F. Hezel, Andrew X. Zhu

Final approval of manuscript: Aram F. Hezel, Andrew X. Zhu


   REFERENCES
Top
 Learning Objectives
 Abstract
 Introduction
 Can Chemotherapy Improve...
 Randomized Trials in BTC
 Fluoropyrimidine-Based Regimens
 Gemcitabine-Based Regimens
 Molecular Features and Targeted...
 Conclusions and Recommendations
 Author Contributions
 References
 

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