Combining Gemcitabine and Capecitabine in Patients With Advanced Biliary Cancer: A Phase II Trial
http://www.100md.com
《临床肿瘤学》
the Departments of Hematology, Medical Oncology, and Biostatistics, Princess Margaret Hospital/University Health Network
Department of Medicine, University of Toronto
ABSTRACT
PURPOSE: Biliary cancer has a poor prognosis, and chemotherapy has had little impact. The objectives of this trial were to determine the response rate, time to disease progression, survival, and safety profile of the combination of gemcitabine and capecitabine (GemCap) in patients with advanced biliary cancer.
PATIENTS AND METHODS: Eligible patients had pathologically proven, locally advanced or metastatic adenocarcinoma arising from the intra- and extrahepatic bile ducts or gallbladder with no prior chemotherapy. Patients were treated on a 3-week cycle consisting of capecitabine at 650 mg/m2 orally twice a day for 14 days and gemcitabine at a fixed dose of 1,000 mg/m2 intravenously over 30 minutes on days 1 and 8.
RESULTS: Forty-five patients were enrolled between July 2001 and January 2004. Fifty-three percent of patients had cholangiocarcinoma, 47% had gallbladder cancer, and 89% had metastatic disease. The overall objective response rate was 31%, with an additional 42% of patients with stable disease, for a disease control rate of 73%. The median overall survival time was 14 months (95% CI, 7.3 months to not available), and the median progression-free survival time was 7 months (95% CI, 4.6 to 11.8 months). This chemotherapy combination was generally well tolerated. Transient neutropenia, thrombocytopenia, fatigue, and hand-foot syndrome were commonly observed but were easily managed without discontinuing further treatment.
CONCLUSION: The significant antitumor activity combined with a mild toxicity profile seen in this study argue that GemCap chemotherapy may benefit patients with advanced biliary cancer. This regimen warrants further evaluation in a randomized study with survival and quality of life end points.
INTRODUCTION
Adenocarcinomas of the gallbladder and bile ducts (cholangiocarcinoma) have a poor prognosis. Although surgical resection of the primary tumor is potentially curative therapy, less than 25% of patients will be resectable at presentation, and among those patients, relapse rates are high.1-4 Patients with unresectable disease will receive variable palliative therapy, with a median survival of less than 1 year. Biliary bypass or stenting is often required if chemotherapy is contemplated.
To date, chemotherapy has had limited impact on the natural history of this disease because of both the absence of agents with substantial activity and the overall morbidity of treatment in this patient population. No standard chemotherapy has been identified that can clearly prolong survival. Fluoropyrimidines have been considered the basis of palliative chemotherapy despite response rates (seen in small phase III trials) in the range of 0% to 10%.5-7 Older combination chemotherapy, including fluorouracil (FU), has not demonstrated a clear superiority over single-agent FU but has resulted in added toxicity. However, Glimelius et al8 showed there was improved quality of life for biliary cancer patients treated with FU-based chemotherapy versus best supportive care.
Clearly, improving outcomes for patients with this aggressive cancer will necessitate the use of more active and well-tolerated therapies. A number of recent phase II trials using newer chemotherapeutic agents suggest a level of chemosensitivity not previously seen. Gemcitabine,9-18 newer FU regimens,15-17 capecitabine,18-20 and platinum analogs20-25,13,14 all seem to be active and, perhaps, are more active in combinations. The larger phase II trials report objective response rates (ORRs) ranging from 15% to 45%. Differences in response rates between gallbladder and cholangiocarcinoma have not been seen; however, some series report poorer overall survival for patients with gallbladder cancer compared with cholangiocarcinoma.13,14 Regimens containing cisplatin or its analogs evaluated in phase II studies of biliary cancer have, in general, reported slightly higher response rates (20% to 45%) than those seen previously but also have significant toxicity (20% to 50% grade 3 toxicity), which may limit their applicability. The nucleoside analog gemcitabine is a chemotherapeutic agent with a favorable therapeutic profile. It has shown ORRs ranging from 15% to 35% in a number of phase II trials in biliary cancers and seems consistently active and well tolerated as a single agent.
The combination of gemcitabine and a fluoropyrimidine in biliary cancers is worthy of further evaluation. The toxicity profile of these agents are known to be nonoverlapping, and combinations have been well tolerated.26,27 Besides their known activity in a number of tumor types, both drugs interfere with the pyrimidine biosynthesis pathways and may act synergistically. Indeed, preclinical studies including xenograft models support this hypothesis.28,29 Clinically, Gebbia et al16 suggested improvement in response rates and median survival in biliary cancer with an infusional FU-gemcitabine combination over gemcitabine alone. We had also explored concurrent gemcitabine with continuous venous infusional (CVI) FU in biliary cancer with encouraging disease control rates (response rate, > 30%).30 Unfortunately, the treatment was associated with considerable central venous catheter–related adverse events. A strategy to reduce toxicity and, thereby, improve patient benefit was proposed with the substitution of capecitabine for the FU, thus eliminating the need for the central venous catheter. Capecitabine also seems to be active and well tolerated as a single agent in this disease (response rate, 19%)18 and has the advantage of easy oral administration. A gemcitabine-capecitabine (GemCap) regimen has been developed in a phase I trial for pancreas cancer patients,27 and thus, extrapolation to biliary cancer patients is reasonable.
We report the results of a single-institution phase II trial of GemCap combination for patients with advanced biliary cancer. The objectives of the trial were to determine the response rate, time to disease progression, survival, and safety profile.
PATIENTS AND METHODS
Patients were eligible if they had pathologically proven, measurable, unresectable, locally advanced or metastatic adenocarcinoma arising from the intra- and extrahepatic biliary ducts or gallbladder. No prior chemotherapy for advanced disease was allowed. Additional inclusion criteria included age 18 years, Eastern Cooperative Oncology Group (ECOG) performance status 2, and adequate organ functions (neutrophils 1.5 x 10/L, platelets 100 x 10/L, serum creatinine 160 μmol/L or actual or calculated creatinine clearance 60 mL/min, ALT 5 x upper limit of normal [ULN], and total bilirubin 3 x ULN and stable for 2 weeks). Written informed consent was obtained from each patient. The protocol and the informed consent form were approved by the Research Ethics Review Board of the Princess Margaret Hospital, Toronto, Canada.
Treatment Plan
Patients were treated on a 3-week cycle, with dosing based on the recommended phase II dose from Hess et al.27 Capecitabine was administered orally at 650 mg/m2 orally twice a day for 14 days every 21 days. Gemcitabine was administered intravenously over 30 minutes on days 1 and 8 of each cycle at a fixed dose of 1,000 mg/m2. Treatment was continued until progression, unacceptable toxicity, or withdrawal of patient consent. Adverse events were recorded according to the National Cancer Institute of Canada Common Toxicity Criteria (version 2).
Dose adjustments and delays were allowed for each drug. Gemcitabine was reduced by 25% on all subsequent cycles for febrile neutropenia, grade 4 hematologic toxicity lasting for more than 7 days, or bleeding-associated thrombocytopenia, and gemcitabine was reduced by 25% for grade 3 nonhematologic toxicity thought to be related to gemcitabine until recovery to grade 1 toxicity or baseline occurred. Gemcitabine doses were reduced by 25% on day 8 for an absolute neutrophil count of 500 to 1,000/μL or a platelet count of 50,000 to 100,000/μL. Capecitabine was held for any grade 4 hematologic or grade 3 nonhematologic toxicity and resumed if toxicity recovered to grade 1. Capecitabine was reduced by 25% for grade 3 nonhematologic toxicity that was likely related to capecitabine until recovery to grade 1.
Assessment
Tumor response was assessed using Response Evaluation Criteria in Solid Tumors,31 with computer tomography scans at baseline and every three cycles or 9 weeks of treatment. Responses were confirmed by computed tomography at least 4 weeks later. The primary investigation of interest was the tumor ORR, with secondary investigations including overall and progression-free survival, stable disease (SD) rate (> 3 months), time to progression, and safety and tolerability of this treatment. Summary statistics, such as the median, range, proportion, and frequency, were used to describe the patient sample. The Kaplan-Meier method was used to estimate overall and progression-free survival outcomes. Univariate Cox proportional hazards regression models were used to test selected variables as potential predictors of overall and progression-free survival. No multivariate analyses were undertaken because of the small sample size and exploratory nature of this modeling. Variables investigated were the patients' baseline age, weight, body-surface area, ECOG status, sex, tumor type, tumor extent (local v metastatic), and whether the patient had a biliary stent or experienced disease recurrence after a primary resection. All tests were two-sided, and a P .05 was considered statistically significant.
RESULTS
Forty-five patients with advanced biliary cancer were enrolled between July 2001 and January 2004. Demographics and other baseline characteristics are listed in Table 1. Fifty-one percent of patients had cholangiocarcinoma, and 49% had gallbladder cancer. Forty patients (89%) had metastatic disease, 10 of which experienced disease recurrence after a prior resection with curative intent. Eleven patients had undergone exploratory laparotomy to determine unresectability, whereas the remaining 24 were clearly unresectable based on radiologic evidence of distant metastatic disease. The five patients with locally advanced disease at baseline had cholangiocarcinomas. Most patients had good performance status at start of therapy (ECOG performance status of 0 to 1 in 82%), and the median age was 62 years (range, 38 to 84 years). Baseline median total bilirubin was 12 μmol/L (range, 5 to 62 μmol/L). All patients were assessable for efficacy and toxicity analysis. Nine patients received second-line treatments after progressive disease on GemCap (three patients received cisplatin-based chemotherapy, three received irinotecan-based chemotherapy, two received conformal radiotherapy to the primary tumor, and one received radiofrequency ablation to a residual liver metastasis).
Over 350 cycles of GemCap chemotherapy were delivered, with a median of seven cycles per patient (range, one to 24 cycles). Across all cycles, patients received more than 90% of initial prescribed chemotherapy. The primary reason for discontinuing treatment was progressive disease (86%, or 32 of the 37 patients who completed treatment). Three patients requested a break, and two discontinuations were at the physician's discretion because of other comorbidities. Eight patients remain on study treatment. Twenty-eight patients (62%) have died. Median follow-up time per patient is 11 months (range, 1.1 to 34 months.) Of the 17 patients who are still alive, the median duration of follow-up is 14 months (range, 9.6 to 34 months.)
Two patients achieved a complete response, and 12 patients achieved partial responses, for an overall ORR of 31% (Table 2). Four patients who met the criteria for response only did so after 6 months of treatment. The median time to progression for the responders was 13.8 months (range, 6.7 to 28.7 months.)
An additional 19 patients (42%) experienced SD for a median duration of 7 months (95% CI, 5.8 months to not available). Nine of the 19 patients with SD had minor responses where tumor shrinkage was less than 30% (range, 8% to 28%). Fifteen patients with SD have progressed (median, 6.1 months; range, 3.3 to 22 months), and four patients are progression free at 9.6, 11.3, 13, and 16 months.
The median overall survival time was 14 months (95% CI, 7.3 to not available), and the median progression-free survival time was 7 months (95% CI, 4.6 to 11.8 months; Figs 1 and 2). One-year progression-free survival and overall survival rates were 30% and 49%, respectively. Tumor type (cholangiocarcinoma v gallbladder cancer) was the only statistically significant predictor of overall survival in this series (hazard ratio = 3.61; 95% CI, 1.35 to 9.67; P = .011) or progression-free survival (hazard ratio = 2.37; 95% CI, 1.11 to 5.06; P = .026). As of this analysis, the median survival time for cholangiocarcinoma patients was 19 months v 6.6 months for gallbladder cancer patients. Progression-free survival time was 9.0 months for cholangiocarcinoma patients and 4.4 months for gallbladder cancer patients.
This combination of GemCap was generally well tolerated (Table 3). There were no treatment-related deaths. No patients discontinued treatment because of toxicity. Gemcitabine- or capecitabine-related specific toxicity resulted in at least one cycle delay or dose reduction in 53% and 29% of patients, respectively. Grade 3 and 4 toxicity was infrequent other than neutropenia, which was seen in 12% of all cycles delivered but resulted in only one brief episode of febrile neutropenia. Infectious complications (11% of patients) were not common or problematic despite the prevalence of biliary stents. Grade 2 and 3 hand-foot syndrome was observed in 29% of patients. Mild fatigue during treatment (grade 2) was reported in 42% of patients. There was no grade 3 or 4 gastrointestinal toxicity seen. The subset of patients whose baseline bilirubin was 1.5 to 3 x ULN (n = 8) did not have a toxicity profile different from the rest of the patients on study, including an absence of grade 4 toxicity. No treatment-related liver toxicity was observed in any of the patients on this study.
DISCUSSION
There is no current standard chemotherapy in advanced biliary cancer. Oncology practices vary considerably, and range from not offering patients chemotherapy because of concern over lack of efficacy and detrimental toxicity to offering patients multiple-drug regimens. Clinical trials in cholangiocarcinomas and gallbladder cancer have suffered from the relative rarity of these tumors and the generally morbid patient population. The recent surge of new phase II trials in biliary cancer reflects not only the lack of consensus on the best treatment but also an increase in research interest on how to manage this challenging disease. Table 4 lists the larger, more recent trials.
We report here one of the largest series in biliary cancer. This combination of GemCap is a conveniently administered, well-tolerated regimen. A response rate of 31% plus an additional disease stabilization rate of 42% gives an overall disease control rate of 73%. The group experiencing either ORRs or SD on GemCap had a median progression-free survival time of 10 months (range, 8.6 to 19 months), suggesting durable activity. The median overall survival time on study of 14 months is encouraging. These efficacy data compare favorably with other trials, including those with more toxic regimens (Table 4). The patients enrolled onto this trial reflect a fairly typical biliary cancer population considered for chemotherapy. Most patients had metastatic disease and presented with liver function abnormalities, which were stabilized with stenting before the start of chemotherapy.
It is also encouraging that the GemCap regimen was well tolerated in these patients with liver dysfunction and/or biliary stents. Transient neutropenia, thrombocytopenia, fatigue, and hand-foot syndrome were commonly observed but were easily managed without discontinuing the protocol. The high rate of venous thrombosis and line infections seen in our previous study of biliary cancer (26% total from CVI FU plus gemcitabine) was absent in this series, which substituted capecitabine for the CVI FU. An argument could be made that a more dose-intense regimen might be feasible and may produce slightly higher response rates, but almost certainly, this would come at the cost of more toxicity and perhaps fewer cycles of chemotherapy delivered on average. Indeed, other regimens, including those with platinum analogs, do not actually seem to provide significant improvements in response rates or prolonged median survivals when compared with older series or with this study (Table 4). In keeping with the preclinical data supporting synergy, lower than single-agent doses of both gemcitabine and capecitabine in this trial achieved a promising antitumor effect. The durable SD on this regimen may be impacting the encouraging observed median survival.
Carcinomas of the biliary tract and gallbladder may be biologically sufficiently different as to lead to different sensitivities to chemotherapy; however, this study shows responses to be similar (ORR, 34% v 27%, respectively), as do other trials. The shorter median survival for gallbladder cancer seen in this study compared with cholangiocarcinomas probably reflects a more aggressive biology of gallbladder cancer. Because of their relative rarity (4% of cancers of the gastrointestinal tract34), it may not be practical to separate the biliary cancers in clinical trials, but planned randomized studies should include biliary tumor type in the stratification strategy.
The amount of antitumor activity seen here combined with a tolerable toxicity profile argues that GemCap may yield benefit in this patient population. This regimen warrants further evaluation in a randomized study with survival end points to determine whether this combination is superior to a single agent. Given that gemcitabine is one of the better studied agents, with data supporting efficacy and tolerability in biliary cancer, it would make a reasonable comparative arm. The success of such a large trial would necessitate the participation of multiple centers or cooperative groups, yet it has the potential to change practice globally. Given its therapeutic profile, GemCap should also be evaluated in the adjuvant setting to attempt reduction of incurable recurrences. Preliminary data suggest targeted agents, such as epidermal growth factor receptor inhibitors, also have activity in advanced biliary cancer35 and should be explored in combination with GemCap.
Authors' Disclosures of Potential Conflicts of Interest
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Consultant/Advisory Role: Ron Feld, Amgen Canada, AstraZeneca Canada, Merck Frosst Canada. Honoraria: Ron Feld, EXIMIAS, Merck Frosst Canada. Research Funding: Ron Feld, AstraZeneca, EXIMIAS, GlaxoSmithKline; Eric Chen, Hoffman-La Roche. For a detailed description of these categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and Disclosures of Potential Conflicts of Interest found in Information for Contributors in the front of each issue.
Acknowledgment
We thank many local physicians for support of this study, especially S. Gallinger, P. Greig, P. Kortan, C.S. Ho, A. Wei, R. Hart, S. Berry, R. Haq, C. Law, and J. Kachura.
NOTES
Supported in part by Hoffman La Roche and Eli Lilly, Canada.
Presented in part at the 2004 Gastrointestinal Cancers Symposium: Current Status and Future Directions for Prevention and Management, San Francisco, CA, January 22-24, 2004; and at the 12th European Cancer Conference, Copenhagen, Denmark, September 21-25, 2003.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
REFERENCES
Oertli D, Herzog U, Tondelli P: Primary carcinoma of the gallbladder: Operative experience during a 16-year period. Eur J Surg 159:415-420, 1993
Alexander F, Rossi RL, O'Bryan M, et al: Biliary carcinoma: A review of 109 cases. Am J Surg 147:503-509, 1984
Wade TP, Prasad CN, Virgo KS, et al: Experience with distal bile duct cancers in US veterans affairs hospitals: 1987-1991. J Surg Oncol 64:242-245, 1997
De Groen PC, Gores GJ, La Russo NF, et al: Biliary tract cancers. N Engl J Med 341:1368-1378, 1999
Falkson G, Macintyre JM, Moertel CG: Eastern Cooperative Oncology Group experience with chemotherapy for inoperable gallbladder and bile duct cancer. Cancer 54:965-969, 1984
Takada T, Kato H, Matsushiro T, et al: Combination of 5-fluorouracil, doxorubicin and mitomycin C with 5-fluorouracil alone in the treatment of pancreatic–biliary carcinomas. Oncology 51:396-400, 1994
Kajanti M, Pyrhonen S: Epirubicin-sequential methotrexate-5-fluorouracil-leucovorin treatment in advanced cancer of the extrahepatic biliary system: A phase II study. Am J Clin Oncol 17:223-226, 1994
Glimelius B, Hoffman K, Sjoden PO: Chemotherapy improves survival and quality of life in advanced pancreatic and biliary cancer. Ann Oncol 7:593-600, 1996
Gallardo JO, Rubio B, Fodor M, et al: A phase II study of gemcitabine in gallbladder carcinoma. Ann Oncol 12:1403-1406, 2001
Dragovich T, Ramanathan R, Remick S, et al: Phase II trial of a weekly 150-minute gemcitabine infusion in patients with biliary tree carcinomas. Proc Am Soc Clin Oncol 19:264a, 2000 (abstr 1159)
Kubicka S, Rudolph KL, Tietze MK, et al: A phase II study of gemcitabine chemotherapy for advanced unresectable hepatobiliary carcinomas. Hepatogastroenterology 48:783-789, 2001
Penz M, Kornek GV, Raderer M, et al: Phase II trial of two-weekly gemcitabine in patients with advanced biliary tract cancer. Ann Oncol 12:183-186, 2001
Reyes-Vidal J, Gallardo J, Yanez E, et al: Gemcitabine and cisplatin in the treatment of patients with unresectable or metastatic gallbladder cancer: Results of the phase II Gocchi study 2000-13. Proc Am Soc Clin Oncol 22:273, 2003 (abstr 1095)
Dorval DC, Sekhon JS, Gupta SK, et al: A phase II study of gemcitabine and cisplatin in chemotherapy-naive, unresectable gall bladder cancer. Br J Cancer 90:1516-1520, 2004
Raderer M, Hejna MH, Valencak JB, et al: Two consecutive phase II studies of 5-FU/leucovorin/mitomycin and of gemcitabine in patients with advanced biliary cancer. Oncology 56:177-180, 1999
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 19:4089-4091, 2001
Hsu C, Shen Y-C, Yang C-H, et al: Weekly gemcitabine plus 24-h infusion of high-dose 5-fluorouracil/leucovorin for locally advanced or metastatic carcinoma of the biliary tract. Br J Cancer 90:1715-1719, 2004
Lozano RD, Patt YZ, MM Hassan, et al: Oral capecitabine (Xeloda) for the treatment of hepatobiliary cancers (hepatocellular carcinoma, cholangiocarcinoma and gallbladder cancer). Proc Am Soc Clin Oncol 19:264a, 2000 (abstr 1025)
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 randomized phase II trial. Ann Oncol 15:478-483, 2004
Nehls O, Oettle H, Hartmann J-T, et al: Multicenter phase II trial of oxaliplatin plus capecitabine (XELOX) in advanced biliary system adenocarcinomas (study CCC/GBC-01) Proc Am Soc Clin Oncol 22:280, 2003 (abstr 1126)
Taeb J, Mitry E, Boige V, et al: Optimization of 5-fluorouracil (5-FU)/cisplatin combination chemotherapy with a new schedule of leucovorin, 5-FU and cisplatin (LV5FU2-P regimen) in patients with biliary tract carcinoma. Ann Oncol 13:1192-1196, 2002
Sanz-Altamira P, Ferrante, Jenkins R: A phase II trial of 5-FU leucovorin and carboplatin in patients with unresectable biliary tree carcinoma. Cancer 82:2321-2325, 1998
Mitry E, Van Cutsem E, Van Laethem JL, et al: A randomized phase II trial of weekly high dose 5-FU (HD-FU) with and without folinic acid (FA) and cisplatin (P) in patients with advanced biliary tract carcinoma: The EORTC 40955 trial. Proc Am Soc Clin Oncol 21:175a, 2002 (abstr 698)
Patt YZ, Hassan MM, Lozano RD, et al: Phase II trial of cisplatin, interferon alpha-2b, doxorubicin, and fluorouracil for biliary tract cancer. Clin Cancer Res 7:3375-3380, 2001
Rao S, Cunningham D, Hawkins R, et al: Phase III trial comparing epirubicin, cisplatin and 5-FU (ECF) versus 5FU, etoposide and leucovorin (FELV) in previously untreated patients with advanced biliary cancer. Proc European Cancer Conference 12:S17, 2003 (abstr 44)
Hidalgo M, Castellano D, Pas-Ares L, et al: Phase I-II study of gemcitabine and fluorouracil as a continuous infusion in patients with pancreatic cancer. J Clin Oncol 17:585-592, 1999
Hess V, Salzberg M, Borner M, et al: Combining capecitabine and gemcitabine in patients with advanced pancreatic carcinoma: A phase I/II trial. J Clin Oncol 21:66-68, 2003
Schulz L, Schalhorn W, Wilmanns W, et al: Synergistic interaction of gemcitabine and 5-fluorouracil in colon cancer cells. Proc Am Soc Clin Oncol 17:251a, 1998 (abstr 965)
Sawada N, Fujimoto-Ouchi K, Ishikawa T, et al: Antitumor activity of combination therapy with capecitabine plus vinorelbine, and capecitabine plus gemcitabine in human tumor xenograft models. Proc Am Assoc Cancer Res 43:1088, 2002 (abstr 5388)
Knox JJ, Hedley D, Oza A, et al: Gemcitabine concurrent with continuous infusional 5-fluorouracil in advanced biliary cancers: A review of the Princess Margaret Hospital experience. Ann Oncol 15:770-774, 2004
Therasse P, Arbuck SG, Eisenhauer EA, et al: New guidelines to evaluate the response to treatment in solid tumors (RECIST) guidelines. J Natl Cancer Inst 92:205-216, 2000
Kuhn R, Hribaschek A, Eichelmann K, et al: Outpatient therapy with gemcitabine and docetaxel for gallbladder, biliary, and cholangio-carcinomas. Invest New Drugs 20:351-356, 2002
Andre T, Tournigand C, Rosmorduc O, et al: Gemcitabine combined with oxaliplatin (GEMOX) in advanced biliary tract adenocarcinoma: A GERCOR study. Ann Oncol 15:1339-1343, 2004
Greenlee RT, Hill-Harmon MB, Murray T, et al: Cancer statistics, 2001. CA Cancer J Clin 51:15-36, 2001
Philip PA, Mahoney M, Thomas J, et al: Phase II trial of erlotinib (OSI-774) in patients with hepatocellular or biliary cancer. Proc Am Soc Clin Oncol 23:318, 2004 (abstr 4025)(Jennifer J. Knox, David H)
Department of Medicine, University of Toronto
ABSTRACT
PURPOSE: Biliary cancer has a poor prognosis, and chemotherapy has had little impact. The objectives of this trial were to determine the response rate, time to disease progression, survival, and safety profile of the combination of gemcitabine and capecitabine (GemCap) in patients with advanced biliary cancer.
PATIENTS AND METHODS: Eligible patients had pathologically proven, locally advanced or metastatic adenocarcinoma arising from the intra- and extrahepatic bile ducts or gallbladder with no prior chemotherapy. Patients were treated on a 3-week cycle consisting of capecitabine at 650 mg/m2 orally twice a day for 14 days and gemcitabine at a fixed dose of 1,000 mg/m2 intravenously over 30 minutes on days 1 and 8.
RESULTS: Forty-five patients were enrolled between July 2001 and January 2004. Fifty-three percent of patients had cholangiocarcinoma, 47% had gallbladder cancer, and 89% had metastatic disease. The overall objective response rate was 31%, with an additional 42% of patients with stable disease, for a disease control rate of 73%. The median overall survival time was 14 months (95% CI, 7.3 months to not available), and the median progression-free survival time was 7 months (95% CI, 4.6 to 11.8 months). This chemotherapy combination was generally well tolerated. Transient neutropenia, thrombocytopenia, fatigue, and hand-foot syndrome were commonly observed but were easily managed without discontinuing further treatment.
CONCLUSION: The significant antitumor activity combined with a mild toxicity profile seen in this study argue that GemCap chemotherapy may benefit patients with advanced biliary cancer. This regimen warrants further evaluation in a randomized study with survival and quality of life end points.
INTRODUCTION
Adenocarcinomas of the gallbladder and bile ducts (cholangiocarcinoma) have a poor prognosis. Although surgical resection of the primary tumor is potentially curative therapy, less than 25% of patients will be resectable at presentation, and among those patients, relapse rates are high.1-4 Patients with unresectable disease will receive variable palliative therapy, with a median survival of less than 1 year. Biliary bypass or stenting is often required if chemotherapy is contemplated.
To date, chemotherapy has had limited impact on the natural history of this disease because of both the absence of agents with substantial activity and the overall morbidity of treatment in this patient population. No standard chemotherapy has been identified that can clearly prolong survival. Fluoropyrimidines have been considered the basis of palliative chemotherapy despite response rates (seen in small phase III trials) in the range of 0% to 10%.5-7 Older combination chemotherapy, including fluorouracil (FU), has not demonstrated a clear superiority over single-agent FU but has resulted in added toxicity. However, Glimelius et al8 showed there was improved quality of life for biliary cancer patients treated with FU-based chemotherapy versus best supportive care.
Clearly, improving outcomes for patients with this aggressive cancer will necessitate the use of more active and well-tolerated therapies. A number of recent phase II trials using newer chemotherapeutic agents suggest a level of chemosensitivity not previously seen. Gemcitabine,9-18 newer FU regimens,15-17 capecitabine,18-20 and platinum analogs20-25,13,14 all seem to be active and, perhaps, are more active in combinations. The larger phase II trials report objective response rates (ORRs) ranging from 15% to 45%. Differences in response rates between gallbladder and cholangiocarcinoma have not been seen; however, some series report poorer overall survival for patients with gallbladder cancer compared with cholangiocarcinoma.13,14 Regimens containing cisplatin or its analogs evaluated in phase II studies of biliary cancer have, in general, reported slightly higher response rates (20% to 45%) than those seen previously but also have significant toxicity (20% to 50% grade 3 toxicity), which may limit their applicability. The nucleoside analog gemcitabine is a chemotherapeutic agent with a favorable therapeutic profile. It has shown ORRs ranging from 15% to 35% in a number of phase II trials in biliary cancers and seems consistently active and well tolerated as a single agent.
The combination of gemcitabine and a fluoropyrimidine in biliary cancers is worthy of further evaluation. The toxicity profile of these agents are known to be nonoverlapping, and combinations have been well tolerated.26,27 Besides their known activity in a number of tumor types, both drugs interfere with the pyrimidine biosynthesis pathways and may act synergistically. Indeed, preclinical studies including xenograft models support this hypothesis.28,29 Clinically, Gebbia et al16 suggested improvement in response rates and median survival in biliary cancer with an infusional FU-gemcitabine combination over gemcitabine alone. We had also explored concurrent gemcitabine with continuous venous infusional (CVI) FU in biliary cancer with encouraging disease control rates (response rate, > 30%).30 Unfortunately, the treatment was associated with considerable central venous catheter–related adverse events. A strategy to reduce toxicity and, thereby, improve patient benefit was proposed with the substitution of capecitabine for the FU, thus eliminating the need for the central venous catheter. Capecitabine also seems to be active and well tolerated as a single agent in this disease (response rate, 19%)18 and has the advantage of easy oral administration. A gemcitabine-capecitabine (GemCap) regimen has been developed in a phase I trial for pancreas cancer patients,27 and thus, extrapolation to biliary cancer patients is reasonable.
We report the results of a single-institution phase II trial of GemCap combination for patients with advanced biliary cancer. The objectives of the trial were to determine the response rate, time to disease progression, survival, and safety profile.
PATIENTS AND METHODS
Patients were eligible if they had pathologically proven, measurable, unresectable, locally advanced or metastatic adenocarcinoma arising from the intra- and extrahepatic biliary ducts or gallbladder. No prior chemotherapy for advanced disease was allowed. Additional inclusion criteria included age 18 years, Eastern Cooperative Oncology Group (ECOG) performance status 2, and adequate organ functions (neutrophils 1.5 x 10/L, platelets 100 x 10/L, serum creatinine 160 μmol/L or actual or calculated creatinine clearance 60 mL/min, ALT 5 x upper limit of normal [ULN], and total bilirubin 3 x ULN and stable for 2 weeks). Written informed consent was obtained from each patient. The protocol and the informed consent form were approved by the Research Ethics Review Board of the Princess Margaret Hospital, Toronto, Canada.
Treatment Plan
Patients were treated on a 3-week cycle, with dosing based on the recommended phase II dose from Hess et al.27 Capecitabine was administered orally at 650 mg/m2 orally twice a day for 14 days every 21 days. Gemcitabine was administered intravenously over 30 minutes on days 1 and 8 of each cycle at a fixed dose of 1,000 mg/m2. Treatment was continued until progression, unacceptable toxicity, or withdrawal of patient consent. Adverse events were recorded according to the National Cancer Institute of Canada Common Toxicity Criteria (version 2).
Dose adjustments and delays were allowed for each drug. Gemcitabine was reduced by 25% on all subsequent cycles for febrile neutropenia, grade 4 hematologic toxicity lasting for more than 7 days, or bleeding-associated thrombocytopenia, and gemcitabine was reduced by 25% for grade 3 nonhematologic toxicity thought to be related to gemcitabine until recovery to grade 1 toxicity or baseline occurred. Gemcitabine doses were reduced by 25% on day 8 for an absolute neutrophil count of 500 to 1,000/μL or a platelet count of 50,000 to 100,000/μL. Capecitabine was held for any grade 4 hematologic or grade 3 nonhematologic toxicity and resumed if toxicity recovered to grade 1. Capecitabine was reduced by 25% for grade 3 nonhematologic toxicity that was likely related to capecitabine until recovery to grade 1.
Assessment
Tumor response was assessed using Response Evaluation Criteria in Solid Tumors,31 with computer tomography scans at baseline and every three cycles or 9 weeks of treatment. Responses were confirmed by computed tomography at least 4 weeks later. The primary investigation of interest was the tumor ORR, with secondary investigations including overall and progression-free survival, stable disease (SD) rate (> 3 months), time to progression, and safety and tolerability of this treatment. Summary statistics, such as the median, range, proportion, and frequency, were used to describe the patient sample. The Kaplan-Meier method was used to estimate overall and progression-free survival outcomes. Univariate Cox proportional hazards regression models were used to test selected variables as potential predictors of overall and progression-free survival. No multivariate analyses were undertaken because of the small sample size and exploratory nature of this modeling. Variables investigated were the patients' baseline age, weight, body-surface area, ECOG status, sex, tumor type, tumor extent (local v metastatic), and whether the patient had a biliary stent or experienced disease recurrence after a primary resection. All tests were two-sided, and a P .05 was considered statistically significant.
RESULTS
Forty-five patients with advanced biliary cancer were enrolled between July 2001 and January 2004. Demographics and other baseline characteristics are listed in Table 1. Fifty-one percent of patients had cholangiocarcinoma, and 49% had gallbladder cancer. Forty patients (89%) had metastatic disease, 10 of which experienced disease recurrence after a prior resection with curative intent. Eleven patients had undergone exploratory laparotomy to determine unresectability, whereas the remaining 24 were clearly unresectable based on radiologic evidence of distant metastatic disease. The five patients with locally advanced disease at baseline had cholangiocarcinomas. Most patients had good performance status at start of therapy (ECOG performance status of 0 to 1 in 82%), and the median age was 62 years (range, 38 to 84 years). Baseline median total bilirubin was 12 μmol/L (range, 5 to 62 μmol/L). All patients were assessable for efficacy and toxicity analysis. Nine patients received second-line treatments after progressive disease on GemCap (three patients received cisplatin-based chemotherapy, three received irinotecan-based chemotherapy, two received conformal radiotherapy to the primary tumor, and one received radiofrequency ablation to a residual liver metastasis).
Over 350 cycles of GemCap chemotherapy were delivered, with a median of seven cycles per patient (range, one to 24 cycles). Across all cycles, patients received more than 90% of initial prescribed chemotherapy. The primary reason for discontinuing treatment was progressive disease (86%, or 32 of the 37 patients who completed treatment). Three patients requested a break, and two discontinuations were at the physician's discretion because of other comorbidities. Eight patients remain on study treatment. Twenty-eight patients (62%) have died. Median follow-up time per patient is 11 months (range, 1.1 to 34 months.) Of the 17 patients who are still alive, the median duration of follow-up is 14 months (range, 9.6 to 34 months.)
Two patients achieved a complete response, and 12 patients achieved partial responses, for an overall ORR of 31% (Table 2). Four patients who met the criteria for response only did so after 6 months of treatment. The median time to progression for the responders was 13.8 months (range, 6.7 to 28.7 months.)
An additional 19 patients (42%) experienced SD for a median duration of 7 months (95% CI, 5.8 months to not available). Nine of the 19 patients with SD had minor responses where tumor shrinkage was less than 30% (range, 8% to 28%). Fifteen patients with SD have progressed (median, 6.1 months; range, 3.3 to 22 months), and four patients are progression free at 9.6, 11.3, 13, and 16 months.
The median overall survival time was 14 months (95% CI, 7.3 to not available), and the median progression-free survival time was 7 months (95% CI, 4.6 to 11.8 months; Figs 1 and 2). One-year progression-free survival and overall survival rates were 30% and 49%, respectively. Tumor type (cholangiocarcinoma v gallbladder cancer) was the only statistically significant predictor of overall survival in this series (hazard ratio = 3.61; 95% CI, 1.35 to 9.67; P = .011) or progression-free survival (hazard ratio = 2.37; 95% CI, 1.11 to 5.06; P = .026). As of this analysis, the median survival time for cholangiocarcinoma patients was 19 months v 6.6 months for gallbladder cancer patients. Progression-free survival time was 9.0 months for cholangiocarcinoma patients and 4.4 months for gallbladder cancer patients.
This combination of GemCap was generally well tolerated (Table 3). There were no treatment-related deaths. No patients discontinued treatment because of toxicity. Gemcitabine- or capecitabine-related specific toxicity resulted in at least one cycle delay or dose reduction in 53% and 29% of patients, respectively. Grade 3 and 4 toxicity was infrequent other than neutropenia, which was seen in 12% of all cycles delivered but resulted in only one brief episode of febrile neutropenia. Infectious complications (11% of patients) were not common or problematic despite the prevalence of biliary stents. Grade 2 and 3 hand-foot syndrome was observed in 29% of patients. Mild fatigue during treatment (grade 2) was reported in 42% of patients. There was no grade 3 or 4 gastrointestinal toxicity seen. The subset of patients whose baseline bilirubin was 1.5 to 3 x ULN (n = 8) did not have a toxicity profile different from the rest of the patients on study, including an absence of grade 4 toxicity. No treatment-related liver toxicity was observed in any of the patients on this study.
DISCUSSION
There is no current standard chemotherapy in advanced biliary cancer. Oncology practices vary considerably, and range from not offering patients chemotherapy because of concern over lack of efficacy and detrimental toxicity to offering patients multiple-drug regimens. Clinical trials in cholangiocarcinomas and gallbladder cancer have suffered from the relative rarity of these tumors and the generally morbid patient population. The recent surge of new phase II trials in biliary cancer reflects not only the lack of consensus on the best treatment but also an increase in research interest on how to manage this challenging disease. Table 4 lists the larger, more recent trials.
We report here one of the largest series in biliary cancer. This combination of GemCap is a conveniently administered, well-tolerated regimen. A response rate of 31% plus an additional disease stabilization rate of 42% gives an overall disease control rate of 73%. The group experiencing either ORRs or SD on GemCap had a median progression-free survival time of 10 months (range, 8.6 to 19 months), suggesting durable activity. The median overall survival time on study of 14 months is encouraging. These efficacy data compare favorably with other trials, including those with more toxic regimens (Table 4). The patients enrolled onto this trial reflect a fairly typical biliary cancer population considered for chemotherapy. Most patients had metastatic disease and presented with liver function abnormalities, which were stabilized with stenting before the start of chemotherapy.
It is also encouraging that the GemCap regimen was well tolerated in these patients with liver dysfunction and/or biliary stents. Transient neutropenia, thrombocytopenia, fatigue, and hand-foot syndrome were commonly observed but were easily managed without discontinuing the protocol. The high rate of venous thrombosis and line infections seen in our previous study of biliary cancer (26% total from CVI FU plus gemcitabine) was absent in this series, which substituted capecitabine for the CVI FU. An argument could be made that a more dose-intense regimen might be feasible and may produce slightly higher response rates, but almost certainly, this would come at the cost of more toxicity and perhaps fewer cycles of chemotherapy delivered on average. Indeed, other regimens, including those with platinum analogs, do not actually seem to provide significant improvements in response rates or prolonged median survivals when compared with older series or with this study (Table 4). In keeping with the preclinical data supporting synergy, lower than single-agent doses of both gemcitabine and capecitabine in this trial achieved a promising antitumor effect. The durable SD on this regimen may be impacting the encouraging observed median survival.
Carcinomas of the biliary tract and gallbladder may be biologically sufficiently different as to lead to different sensitivities to chemotherapy; however, this study shows responses to be similar (ORR, 34% v 27%, respectively), as do other trials. The shorter median survival for gallbladder cancer seen in this study compared with cholangiocarcinomas probably reflects a more aggressive biology of gallbladder cancer. Because of their relative rarity (4% of cancers of the gastrointestinal tract34), it may not be practical to separate the biliary cancers in clinical trials, but planned randomized studies should include biliary tumor type in the stratification strategy.
The amount of antitumor activity seen here combined with a tolerable toxicity profile argues that GemCap may yield benefit in this patient population. This regimen warrants further evaluation in a randomized study with survival end points to determine whether this combination is superior to a single agent. Given that gemcitabine is one of the better studied agents, with data supporting efficacy and tolerability in biliary cancer, it would make a reasonable comparative arm. The success of such a large trial would necessitate the participation of multiple centers or cooperative groups, yet it has the potential to change practice globally. Given its therapeutic profile, GemCap should also be evaluated in the adjuvant setting to attempt reduction of incurable recurrences. Preliminary data suggest targeted agents, such as epidermal growth factor receptor inhibitors, also have activity in advanced biliary cancer35 and should be explored in combination with GemCap.
Authors' Disclosures of Potential Conflicts of Interest
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Consultant/Advisory Role: Ron Feld, Amgen Canada, AstraZeneca Canada, Merck Frosst Canada. Honoraria: Ron Feld, EXIMIAS, Merck Frosst Canada. Research Funding: Ron Feld, AstraZeneca, EXIMIAS, GlaxoSmithKline; Eric Chen, Hoffman-La Roche. For a detailed description of these categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and Disclosures of Potential Conflicts of Interest found in Information for Contributors in the front of each issue.
Acknowledgment
We thank many local physicians for support of this study, especially S. Gallinger, P. Greig, P. Kortan, C.S. Ho, A. Wei, R. Hart, S. Berry, R. Haq, C. Law, and J. Kachura.
NOTES
Supported in part by Hoffman La Roche and Eli Lilly, Canada.
Presented in part at the 2004 Gastrointestinal Cancers Symposium: Current Status and Future Directions for Prevention and Management, San Francisco, CA, January 22-24, 2004; and at the 12th European Cancer Conference, Copenhagen, Denmark, September 21-25, 2003.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
REFERENCES
Oertli D, Herzog U, Tondelli P: Primary carcinoma of the gallbladder: Operative experience during a 16-year period. Eur J Surg 159:415-420, 1993
Alexander F, Rossi RL, O'Bryan M, et al: Biliary carcinoma: A review of 109 cases. Am J Surg 147:503-509, 1984
Wade TP, Prasad CN, Virgo KS, et al: Experience with distal bile duct cancers in US veterans affairs hospitals: 1987-1991. J Surg Oncol 64:242-245, 1997
De Groen PC, Gores GJ, La Russo NF, et al: Biliary tract cancers. N Engl J Med 341:1368-1378, 1999
Falkson G, Macintyre JM, Moertel CG: Eastern Cooperative Oncology Group experience with chemotherapy for inoperable gallbladder and bile duct cancer. Cancer 54:965-969, 1984
Takada T, Kato H, Matsushiro T, et al: Combination of 5-fluorouracil, doxorubicin and mitomycin C with 5-fluorouracil alone in the treatment of pancreatic–biliary carcinomas. Oncology 51:396-400, 1994
Kajanti M, Pyrhonen S: Epirubicin-sequential methotrexate-5-fluorouracil-leucovorin treatment in advanced cancer of the extrahepatic biliary system: A phase II study. Am J Clin Oncol 17:223-226, 1994
Glimelius B, Hoffman K, Sjoden PO: Chemotherapy improves survival and quality of life in advanced pancreatic and biliary cancer. Ann Oncol 7:593-600, 1996
Gallardo JO, Rubio B, Fodor M, et al: A phase II study of gemcitabine in gallbladder carcinoma. Ann Oncol 12:1403-1406, 2001
Dragovich T, Ramanathan R, Remick S, et al: Phase II trial of a weekly 150-minute gemcitabine infusion in patients with biliary tree carcinomas. Proc Am Soc Clin Oncol 19:264a, 2000 (abstr 1159)
Kubicka S, Rudolph KL, Tietze MK, et al: A phase II study of gemcitabine chemotherapy for advanced unresectable hepatobiliary carcinomas. Hepatogastroenterology 48:783-789, 2001
Penz M, Kornek GV, Raderer M, et al: Phase II trial of two-weekly gemcitabine in patients with advanced biliary tract cancer. Ann Oncol 12:183-186, 2001
Reyes-Vidal J, Gallardo J, Yanez E, et al: Gemcitabine and cisplatin in the treatment of patients with unresectable or metastatic gallbladder cancer: Results of the phase II Gocchi study 2000-13. Proc Am Soc Clin Oncol 22:273, 2003 (abstr 1095)
Dorval DC, Sekhon JS, Gupta SK, et al: A phase II study of gemcitabine and cisplatin in chemotherapy-naive, unresectable gall bladder cancer. Br J Cancer 90:1516-1520, 2004
Raderer M, Hejna MH, Valencak JB, et al: Two consecutive phase II studies of 5-FU/leucovorin/mitomycin and of gemcitabine in patients with advanced biliary cancer. Oncology 56:177-180, 1999
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 19:4089-4091, 2001
Hsu C, Shen Y-C, Yang C-H, et al: Weekly gemcitabine plus 24-h infusion of high-dose 5-fluorouracil/leucovorin for locally advanced or metastatic carcinoma of the biliary tract. Br J Cancer 90:1715-1719, 2004
Lozano RD, Patt YZ, MM Hassan, et al: Oral capecitabine (Xeloda) for the treatment of hepatobiliary cancers (hepatocellular carcinoma, cholangiocarcinoma and gallbladder cancer). Proc Am Soc Clin Oncol 19:264a, 2000 (abstr 1025)
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 randomized phase II trial. Ann Oncol 15:478-483, 2004
Nehls O, Oettle H, Hartmann J-T, et al: Multicenter phase II trial of oxaliplatin plus capecitabine (XELOX) in advanced biliary system adenocarcinomas (study CCC/GBC-01) Proc Am Soc Clin Oncol 22:280, 2003 (abstr 1126)
Taeb J, Mitry E, Boige V, et al: Optimization of 5-fluorouracil (5-FU)/cisplatin combination chemotherapy with a new schedule of leucovorin, 5-FU and cisplatin (LV5FU2-P regimen) in patients with biliary tract carcinoma. Ann Oncol 13:1192-1196, 2002
Sanz-Altamira P, Ferrante, Jenkins R: A phase II trial of 5-FU leucovorin and carboplatin in patients with unresectable biliary tree carcinoma. Cancer 82:2321-2325, 1998
Mitry E, Van Cutsem E, Van Laethem JL, et al: A randomized phase II trial of weekly high dose 5-FU (HD-FU) with and without folinic acid (FA) and cisplatin (P) in patients with advanced biliary tract carcinoma: The EORTC 40955 trial. Proc Am Soc Clin Oncol 21:175a, 2002 (abstr 698)
Patt YZ, Hassan MM, Lozano RD, et al: Phase II trial of cisplatin, interferon alpha-2b, doxorubicin, and fluorouracil for biliary tract cancer. Clin Cancer Res 7:3375-3380, 2001
Rao S, Cunningham D, Hawkins R, et al: Phase III trial comparing epirubicin, cisplatin and 5-FU (ECF) versus 5FU, etoposide and leucovorin (FELV) in previously untreated patients with advanced biliary cancer. Proc European Cancer Conference 12:S17, 2003 (abstr 44)
Hidalgo M, Castellano D, Pas-Ares L, et al: Phase I-II study of gemcitabine and fluorouracil as a continuous infusion in patients with pancreatic cancer. J Clin Oncol 17:585-592, 1999
Hess V, Salzberg M, Borner M, et al: Combining capecitabine and gemcitabine in patients with advanced pancreatic carcinoma: A phase I/II trial. J Clin Oncol 21:66-68, 2003
Schulz L, Schalhorn W, Wilmanns W, et al: Synergistic interaction of gemcitabine and 5-fluorouracil in colon cancer cells. Proc Am Soc Clin Oncol 17:251a, 1998 (abstr 965)
Sawada N, Fujimoto-Ouchi K, Ishikawa T, et al: Antitumor activity of combination therapy with capecitabine plus vinorelbine, and capecitabine plus gemcitabine in human tumor xenograft models. Proc Am Assoc Cancer Res 43:1088, 2002 (abstr 5388)
Knox JJ, Hedley D, Oza A, et al: Gemcitabine concurrent with continuous infusional 5-fluorouracil in advanced biliary cancers: A review of the Princess Margaret Hospital experience. Ann Oncol 15:770-774, 2004
Therasse P, Arbuck SG, Eisenhauer EA, et al: New guidelines to evaluate the response to treatment in solid tumors (RECIST) guidelines. J Natl Cancer Inst 92:205-216, 2000
Kuhn R, Hribaschek A, Eichelmann K, et al: Outpatient therapy with gemcitabine and docetaxel for gallbladder, biliary, and cholangio-carcinomas. Invest New Drugs 20:351-356, 2002
Andre T, Tournigand C, Rosmorduc O, et al: Gemcitabine combined with oxaliplatin (GEMOX) in advanced biliary tract adenocarcinoma: A GERCOR study. Ann Oncol 15:1339-1343, 2004
Greenlee RT, Hill-Harmon MB, Murray T, et al: Cancer statistics, 2001. CA Cancer J Clin 51:15-36, 2001
Philip PA, Mahoney M, Thomas J, et al: Phase II trial of erlotinib (OSI-774) in patients with hepatocellular or biliary cancer. Proc Am Soc Clin Oncol 23:318, 2004 (abstr 4025)(Jennifer J. Knox, David H)