Click here to read this article as a CME course
The Oncologist, Vol. 13, No. 4, 415-423, April 2008; doi:10.1634/theoncologist.2007-0252
© 2008 AlphaMed Press
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
|
|---|
After completing this course, the reader will be able to:- Assess the clinical and molecular heterogeneity of BTCs.
- Exploit the chemotherapy responsiveness of these tumors to improve the quality of life and extend the survival of patients with BTC.
- Administer the most current systemic therapy in BTC patients, including the appropriate first-line treatment options.
- 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
|
|---|
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
|
|---|
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?
|
|---|
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
|
|---|
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
|
|---|
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.
|
GEMCITABINE-BASED REGIMENS
|
|---|
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.
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).
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
|
|---|
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).
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
|
|---|
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
|
|---|
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
|
|---|
- Jemal A, Siegel R, Ward E et al. Cancer statistics, 2007. CA Cancer J Clin 2007;57:43–66.[Abstract/Free Full Text]
- Shaib Y, El-Serag HB. The epidemiology of cholangiocarcinoma. Semin Liver Dis 2004;24:115–125.[CrossRef][Medline]
- Khan SA, Thomas HC, Davidson BR et al. Cholangiocarcinoma. Lancet 2005;366:1303–1314.[CrossRef][Medline]
- Thomas MB. Biological characteristics of cancers in the gallbladder and biliary tract and targeted therapy. Crit Rev Oncol Hematol 2007;61:44–51.[CrossRef][Medline]
- Olnes MJ, Erlich R. A review and update on cholangiocarcinoma. Oncology 2004;66:167–179.[CrossRef][Medline]
- Anderson CD, Pinson CW, Berlin J et al. Diagnosis and treatment of cholangiocarcinoma. The Oncologist 2004;9:43–57.[Abstract/Free Full Text]
- Glimelius B, Hoffman K, Sjoden PO et al. Chemotherapy improves survival and quality of life in advanced pancreatic and biliary cancer. Ann Oncol 1996;7:593–600.[Abstract/Free Full Text]
- Ducreux M, Van Cutsem E, Van Laethem JL et al. A randomised phase II trial of weekly high-dose 5-fluorouracil with and without folinic acid and cisplatin in patients with advanced biliary tract carcinoma: Results of the 40955 EORTC trial. Eur J Cancer 2005;41:398–403.[CrossRef][Medline]
- Kornek GV, Schuell B, Laengle F et al. Mitomycin C in combination with capecitabine or biweekly high-dose gemcitabine in patients with advanced biliary tract cancer: A randomised phase II trial. Ann Oncol 2004;15:478–483.[Abstract/Free Full Text]
- Rao S, Cunningham D, Hawkins RE et al. Phase III study of 5FU, etoposide and leucovorin (FELV) compared to epirubicin, cisplatin and 5FU (ECF) in previously untreated patients with advanced biliary cancer. Br J Cancer 2005;92:1650–1654.[CrossRef][Medline]
- Choi CW, Choi IK, Seo JH et al. Effects of 5-fluorouracil and leucovorin in the treatment of pancreatic-biliary tract adenocarcinomas. Am J Clin Oncol 2000;23:425–428.[CrossRef][Medline]
- Ducreux M, Rougier P, Fandi A et al. Effective treatment of advanced biliary tract carcinoma using 5-fluorouracil continuous infusion with cisplatin. Ann Oncol 1998;9:653–656.[Abstract/Free Full Text]
- Ellis PA, Norman A, Hill A et al. Epirubicin, cisplatin and infusional 5-fluorouracil (5-FU) (ECF) in hepatobiliary tumours. Eur J Cancer 1995;31A:1594–1598.[CrossRef]
- Lee MA, Woo IS, Kang JH et al. Epirubicin, cisplatin, and protracted infusion of 5-FU (ECF) in advanced intrahepatic cholangiocarcinoma. J Cancer Res Clin Oncol 2004;130:346–350.[CrossRef][Medline]
- Mitry E, Taieb J, Artru P et al. Combination of folinic acid, 5-fluorouracil bolus and infusion, and cisplatin (LV5FU2-P regimen) in patients with advanced gastric or gastroesophageal junction carcinoma. Ann Oncol 2004;15:765–769.[Abstract/Free Full Text]
- Takada T, Kato H, Matsushiro T et al. Comparison of 5-fluorouracil, doxorubicin and mitomycin C with 5-fluorouracil alone in the treatment of pancreatic-biliary carcinomas. Oncology 1994;51:396–400.[Medline]
- Feisthammel J, Schoppmeyer K, Mossner J et al. Irinotecan with 5-FU/FA in advanced biliary tract adenocarcinomas: A multicenter phase II trial. Am J Clin Oncol 2007;30:319–324.[CrossRef][Medline]
- Hong YS, Lee J, Lee SC et al. Phase II study of capecitabine and cisplatin in previously untreated advanced biliary tract cancer. Cancer Chemother Pharmacol 2007;60:321–328.[CrossRef][Medline]
- Kim TW, Chang HM, Kang HJ et al. Phase II study of capecitabine plus cisplatin as first-line chemotherapy in advanced biliary cancer. Ann Oncol 2003;14:1115–1120.[Abstract/Free Full Text]
- Park SH, Park YH, Lee JN et al. Phase II study of epirubicin, cisplatin, and capecitabine for advanced biliary tract adenocarcinoma. Cancer 2006;106:361–365.[Medline]
- Ueno H, Okusaka T, Ikeda M et al. Phase II study of S-1 in patients with advanced biliary tract cancer. Br J Cancer 2004;91:1769–1774.[CrossRef][Medline]
- Furuse J, Okusaka T, Funakoshi A et al. Early phase II study of uracil-tegafur plus doxorubicin in patients with unresectable advanced biliary tract cancer. Jpn J Clin Oncol 2006;36:552–556.[Abstract/Free Full Text]
- Park KH, Choi IK, Kim SJ et al. The efficacy of epirubicin, cisplatin, uracil/tegafur, and leucovorin in patients with advanced biliary tract carcinoma. Cancer 2005;103:2338–2343.[Medline]
- Chen JS, Yang TS, Lin YC et al. A phase II trial of tegafur-uracil plus leucovorin (LV) in the treatment of advanced biliary tract carcinomas. Jpn J Clin Oncol 2003;33:353–356.[Abstract/Free Full Text]
- Ikeda M, Okusaka T, Ueno H et al. A phase II trial of uracil-tegafur (UFT) in patients with advanced biliary tract carcinoma. Jpn J Clin Oncol 2005;35:439–443.[Abstract/Free Full Text]
- Burris HA 3rd, Moore MJ, Andersen J et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: A randomized trial. J Clin Oncol 1997;15:2403–2413.[Abstract/Free Full Text]
- Oettle H, Post S, Neuhaus P et al. Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: A randomized controlled trial. JAMA 2007;297:267–277.[Abstract/Free Full Text]
- Raderer M, Hejna MH, Valencak JB et al. Two consecutive phase II studies of 5-fluorouracil/leucovorin/mitomycin C and of gemcitabine in patients with advanced biliary cancer. Oncology 1999;56:177–180.[CrossRef][Medline]
- Gebbia V, Giuliani F, Maiello E et al. Treatment of inoperable and/or metastatic biliary tree carcinomas with single-agent gemcitabine or in combination with levofolinic acid and infusional fluorouracil: Results of a multicenter phase II study. J Clin Oncol 2001;19:4089–4091.[Free Full Text]
- Kubicka S, Rudolph KL, Tietze MK et al. Phase II study of systemic gemcitabine chemotherapy for advanced unresectable hepatobiliary carcinomas. Hepatogastroenterology 2001;48:783–789.[Medline]
- Penz M, Kornek GV, Raderer M et al. Phase II trial of two-weekly gemcitabine in patients with advanced biliary tract cancer. Ann Oncol 2001;12:183–186.[Abstract/Free Full Text]
- Valencak J, Raderer M et al. Gemcitabine for the treatment of advanced biliary tract carcinomas: Evaluation of two different dose regimens. Onkologie 1999;22:498–501.[Medline]
- Mezger JS, Ko Y. A phase II trial of gemcitabine in gallbladder and biliary tract carcinomas. Oncologie 1998;21:232–234.[CrossRef]
- Dingle BH, Rumble RB, Brouwers MC. Cancer Care Ontario's Program in Evidence-Based Care's Gastrointestinal Cancer Disease Site Group. The role of gemcitabine in the treatment of cholangiocarcinoma and gallbladder cancer: A systematic review. Can J Gastroenterol 2005;19:711–716.[Medline]
- Sultana A, Smith CT, Cunningham D et al. Meta-analyses of chemotherapy for locally advanced and metastatic pancreatic cancer. J Clin Oncol 2007;25:2607–2615.[Abstract/Free Full Text]
- Bria E, Milella M, Gelibter A et al. Gemcitabine-based combinations for inoperable pancreatic cancer: Have we made real progress? A meta-analysis of 20 phase 3 trials. Cancer 2007;110:525–533.[Medline]
- Meyerhardt JA, Zhu AX, Stuart K et al. Phase-II study of gemcitabine and cisplatin in patients with metastatic biliary and gallbladder cancer. Dig Dis Sci 2008;53:564–570.[CrossRef][Medline]
- Thongprasert S, Napapan S, Charoentum C et al. Phase II study of gemcitabine and cisplatin as first-line chemotherapy in inoperable biliary tract carcinoma. Ann Oncol 2005;16:279–281.[Abstract/Free Full Text]
- Lee GW, Kang JH, Kim HG et al. Combination chemotherapy with gemcitabine and cisplatin as first-line treatment for immunohistochemically proven cholangiocarcinoma. Am J Clin Oncol 2006;29:127–131.[CrossRef][Medline]
- Kim ST, Park JO, Lee J et al. A phase II study of gemcitabine and cisplatin in advanced biliary tract cancer. Cancer 2006;106:1339–1346.[CrossRef][Medline]
- Androulakis N, Aravantinos G, Syrigos K et al. Oxaliplatin as first-line treatment in inoperable biliary tract carcinoma: A multicenter phase II study. Oncology 2006;70:280–284.[CrossRef][Medline]
- Andre T, Tournigand C, Rosmorduc O et al. Gemcitabine combined with oxaliplatin (GEMOX) in advanced biliary tract adenocarcinoma: A GERCOR study. Ann Oncol 2004;15:1339–1343.[Abstract/Free Full Text]
- Harder J, Riecken B, Kummer O et al. Outpatient chemotherapy with gemcitabine and oxaliplatin in patients with biliary tract cancer. Br J Cancer 2006;95:848–852.[CrossRef][Medline]
- Gebbia N, Verderame F, Di Leo R et al. A phase II study of oxaliplatin (O) and gemcitabine (G) first line chemotherapy in patients with advanced biliary tract cancers. J Clin Oncol 2005;23(suppl 16S, Abstract 4132.
- Alberts SR, Al-Khatib H, Mahoney MR et al. Gemcitabine, 5-fluorouracil, and leucovorin in advanced biliary tract and gallbladder carcinoma: A North Central Cancer Treatment Group phase II trial. Cancer 2005;103:111–118.[CrossRef][Medline]
- Knox JJ, Hedley D, Oza A et al. Combining gemcitabine and capecitabine in patients with advanced biliary cancer: A phase II trial. J Clin Oncol 2005;23:2332–2338.[Abstract/Free Full Text]
- Cho JY, Paik YH, Chang YS et al. Capecitabine combined with gemcitabine (CapGem) as first-line treatment in patients with advanced/metastatic biliary tract carcinoma. Cancer 2005;104:2753–2758.[CrossRef][Medline]
- Riechelmann RP, Townsley CA, Chin SN et al. Expanded phase II trial of gemcitabine and capecitabine for advanced biliary cancer. Cancer 2007;110:1307–1312.[CrossRef][Medline]
- Bhargava P, Jani CR, Savarese DM et al. Gemcitabine and irinotecan in locally advanced or metastatic biliary cancer: Preliminary report. Oncology (Williston Park) 2003;17(suppl 8):23–26.
- Eckel F, Schmid RM. Chemotherapy in advanced biliary tract carcinoma: A pooled analysis of clinical trials. Br J Cancer 2007;96:896–902.[CrossRef][Medline]
- Yonemoto N, Furuse J, Okusaka T et al. A multi-center retrospective analysis of survival benefits of chemotherapy for unresectable biliary tract cancer. Jpn J Clin Oncol 2007;37:843–851.[Abstract/Free Full Text]
- Tannapfel A, Benicke M, Katalinic A et al. Frequency of p16(INK4A) alterations and K-ras mutations in intrahepatic cholangiocarcinoma of the liver. Gut 2000;47:721–727.[Abstract/Free Full Text]
- Tannapfel A, Weinans L, Geissler F et al. Mutations of p53 tumor suppressor gene, apoptosis, and proliferation in intrahepatic cholangiocellular carcinoma of the liver. Dig Dis Sci 2000;45:317–324.[CrossRef][Medline]
- Watanabe M, Asaka M, Tanaka J et al. Point mutation of K-ras gene codon 12 in biliary tract tumors. Gastroenterology 1994;107:1147–1153.[Medline]
- Tannapfel A, Sommerer F, Benicke M et al. Mutations of the BRAF gene in cholangiocarcinoma but not in hepatocellular carcinoma. Gut 2003;52:706–712.[Abstract/Free Full Text]
- Leone F, Cavalloni G, Pignochino Y et al. Somatic mutations of epidermal growth factor receptor in bile duct and gallbladder carcinoma. Clin Cancer Res 2006;12:1680–1685.[Abstract/Free Full Text]
- Gwak GY, Yoon JH, Shin CM et al. Detection of response-predicting mutations in the kinase domain of the epidermal growth factor receptor gene in cholangiocarcinomas. J Cancer Res Clin Oncol 2005;131:649–652.[CrossRef][Medline]
- Philip PA, Mahoney MR, Allmer C et al. Phase II study of erlotinib in patients with advanced biliary cancer. J Clin Oncol 2006;24:3069–3074.[Abstract/Free Full Text]
- Lynch TJ, Bell DW, Sordella R et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004;350:2129–2139.[Abstract/Free Full Text]
- Nakazawa K, Dobashi Y, Suzuki S et al. Amplification and overexpression of c-erbB-2, epidermal growth factor receptor, and c-met in biliary tract cancers. J Pathol 2005;206:356–365.[CrossRef][Medline]
- Paule B, Herelle MO, Rage E et al. Cetuximab plus gemcitabine-oxaliplatin (GEMOX) in patients with refractory advanced intrahepatic cholangiocarcinomas. Oncology 2007;72:105–110.[CrossRef][Medline]
- Sprinzl MF, Schimanski CC, Moehler M et al. Gemcitabine in combination with EGF-receptor antibody (cetuximab) as a treatment of cholangiocarcinoma: A case report. BMC Cancer 2006;6:190.[CrossRef][Medline]
- Ramanathan RK, Belani CP, Singh DA et al. Phase II study of lapatinib, a dual inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase 1 and 2 (Her2/Neu) in patients (pts) with advanced biliary tree cancer (BTC) or hepatocellular cancer (HCC). A California Consortium (CCC-P) Trial. J Clin Oncol 2006;24(suppl 18S, Abstract 4010.
- Hida Y, Morita T, Fujita M et al. Vascular endothelial growth factor expression is an independent negative predictor in extrahepatic biliary tract carcinomas. Anticancer Res 1999;19:2257–2260.[Medline]
- Clark JW, Meyerhardt JA, Sahani DV et al. Phase II study of gemcitabine, oxaliplatin in combination with bevacizumab (GEMOX-B) in patients with unresectable or metastatic biliary tract and gallbladder cancers. J Clin Oncol 2007;25(suppl 18S, Abstract 4625.
- El-Khoueiry AB, Rankin C, Lenz HJ et al. A phase II study of sorafenib (BAY 43–9006) as single agent in patients (pts) with unresectable or metastatic gallbladder cancer or cholangiocarcinomas. J Clin Oncol 2007;25(suppl 18S, Abstract 4639.
- Falkson G, MacIntyre JM, Moertel CG. Eastern Cooperative Oncology Group experience with chemotherapy for inoperable gallbladder and bile duct cancer. Cancer 1984;54:965–969.[CrossRef][Medline]
- Mani S, Sciortino D, Samuels B et al. Phase II trial of uracil/tegafur (UFT) plus leucovorin in patients with advanced biliary carcinoma. Invest New Drugs 1999;17:97–101.[CrossRef][Medline]
- Arroyo G, Gallardo J, Rubio B et al. Gemcitabine (GEM) in advanced biliary tract cancer (ABTC). Experience from Chile and Argentina in phase II trials. Proc Am Soc Clin Oncol 2001;157a; (Abstract 626).
- Iyer RV, Gibbs J, Kuvshinoff B et al. A phase II study of gemcitabine and capecitabine in advanced cholangiocarcinoma and carcinoma of the gallbladder: A single-institution prospective study. Ann Surg Oncol 2007;14:3202–3209.[Abstract/Free Full Text]
Top
Learning Objectives
Abstract
