Expanded Phase II Trial of Gemcitabine and Capecitabine for Advanced Biliary Cancer

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1 1307 Expanded Phase II Trial of Gemcitabine and Capecitabine for Advanced Biliary Cancer Rachel P. Riechelmann, MD 1 Carol A. Townsley, MD 2 Sheray N. Chin, MD 2 Gregory R. Pond, MD 3 Jennifer J. Knox, MD 2 1 Department of Medical Oncology, Albert Einstein Hospital, Sao Paulo, Brazil. 2 Department of Medical Oncology and Hematology, Princess Margaret Hospital, University of Toronto, Toronto, Ontario, Canada. 3 Department of Biostatistics, Princess Margaret Hospital, University of Toronto, Toronto, Ontario, Canada. BACKGROUND. A phase 2 trial of gemcitabine and capecitabine (GemCap) in patients with advanced biliary cancer led to an objective response in approximately 30% of patients and a median survival of 14 months. In the current study, the authors report further efficacy data of a larger cohort of such patients treated with the GemCap regimen. METHODS. Patients aged >18 years and who had a diagnosis of locally advanced biliary cancer received first-line treatment with capecitabine at a dose of 650 mg/m 2 twice daily for 14 days and gemcitabine at a dose of 1000 mg/m 2 on Day 1 and Day 8, every 3 weeks until disease progression. Tumor response was assessed by Response Evaluation Criteria In Solid Tumors (RECIST) criteria. RESULTS. Between July 2001 and January 2005, 75 patients were enrolled in the study. At a median follow-up of 9.5 months, the overall response rate was 29% (95% confidence interval [95% CI], %), with a median duration of 9.7 months (range, 3 36 months). Three patients achieved complete responses, with a median duration of 17 months (range, 9 27 months). The median progressionfree survival and overall survivals were 6.2 months (95% CI, months) and 12.7 months (95% CI, months), respectively. CONCLUSIONS. The GemCap regimen is active in patients with biliary cancer. Randomized trials are warranted to define the impact of such a regimen on patient survival and quality of life. Cancer 2007;110: Ó 2007 American Cancer Society. Address for reprints: Jennifer J. Knox, MD, Department of Medical Oncology, Princess Margaret Hospital, 610 University Avenue, Suite 5-210, Toronto, ON, Canada M5G2M9; Fax: (416) ; Jennifer.Knox@uhn.on.ca Received March 8, 2007; revision received May 14, 2007; accepted May 15, KEYWORDS: gemcitabine, capecitabine, advanced biliary cancer, overall survival, progression-free survival, objective response. Biliary cancers are among the most lethal gastrointestinal cancers, 1 and their incidence is rising. 2 The prognosis of biliary cancers (adenocarcinoma of the gallbladder, intrahepatic and extrahepatic cholangiocarcinoma) is dismal, with <5% of patients alive at 5 years after first diagnosis. 1 The median survival of patients with metastatic biliary tumors is usually <1 year, and the majority of these patients die as a consequence of cholangitis, hepatic failure, or cancer-related general consumption. To our knowledge, complete surgical ressection is the only curative modality and, to date, there is no definite evidence that chemotherapy adds to survival or quality of life compared with best supportive care. In the past, biliary cancer was considered a chemoresistant disease because 5-fluorouracil-based regimens led to tumor responses in <10% of patients. 3,4 However, in the last 10 years, several phase 2 trials with new chemotherapeutic agents have demonstrated tumor response in 20% to 35% of patients treated with single agents (gemcitabine 5,6 or capecitabine 7 ), and in 20% to 45% of patients treated with chemotherapy combinations Among these studies, Knox ª 2007 American Cancer Society DOI /cncr Published online 12 July 2007 in Wiley InterScience (

2 1308 CANCER September 15, 2007 / Volume 110 / Number 6 et al. 14 reported that the combination of gemcitabine and capecitabine (GemCap) in 45 patients with locally advanced or metastatic biliary tumors led to objective responses in 30% of patients with cholangiocarcinoma and in 23% of patients with tumors arising from the gallbladder, with a median survival of 14 months. 14 After the publication of this study, and while developing the next clinical trial, the Gem- Cap regimen phase 2 trial was expanded to 75 patients with advanced biliary cancers, all of whom were treated as per protocol at the Princess Margaret Hospital, Toronto, Ontario, Canada. The objective of the current study was to report further data concerning efficacy in an expanded cohort of patients treated with the GemCap regimen. MATERIALS AND METHODS Study The current study was an expanded nonrandomized, single-institution phase 2 clinical trial of gemcitabine combined with capecitabine for patients with advanced biliary tumors. The primary outcome was the proportion of patients with an objective response; secondary endpoints included the median progression-free survival and overall survival of the entire cohort and by type of cancer. Patients Patients aged >18 years with pathologically confirmed, unresectable, locally advanced or metastatic adenocarcinoma of the intrahepatic and extrahepatic biliary ducts or gallbladder were considered eligible. Patients had to have measurable disease. Additional inclusion criteria were no prior systemic antineoplastic therapy, an Eastern Cooperative Oncology Group (ECOG) performance status 2, and adequate organ function (neutrophil count /L, platelet count /L, serum creatinine 160 lmol/l or actual or calculated creatinine clearance 60 ml/ min, alanine aminotransferase 5 times the upper limit of normal [ULN], total bilirubin 3 times ULN, and stable disease for 2 weeks, especially after stenting). Each patient provided written informed consent. The study was approved by the Research Ethics Review Board of the Princess Margaret Hospital, Toronto, Ontario, Canada. Patients were treated as previously reported. 14 Capecitabine at a dose of 650 mg/m 2 orally was given twice daily for 14 consecutive days and gemcitabine at a dose of 1000 mg/m 2 was administered intravenously over 30 minutes on Days 1 and 8; both drugs were given at 3-week intervals. Treatment was continued until disease progression, unacceptable toxicity, physician decision to remove the patient, or withdrawal of patient consent. Information regarding adverse events (recorded according to the Common Toxicity Criteria of the National Cancer Institute of Canada [version 2]), dose adjustments, and delays have been previously reported and were not updated for the current study. 14 For the expanded cohort, patients were assessed for toxicity at routine medical visits and case report forms were not formally completed. Baseline evaluation included medical history, physical examination, and assessment of tumor dimensions (using computed tomography [CT] or magnetic resonance imaging [MRI] scans of the chest, abdomen, and pelvis performed within 28 days of study entry); CT/ MRI scans of the brain and bone scans were performed if indicated by clinical findings. Tumor response was assessed using Response Evaluation Criteria in Solid Tumors (RECIST) criteria, 15 with CT or MRI scans repeated every 3 cycles of treatment. Responses were evaluated by investigators. Progression-free survival was defined as the time from Day 1 of Cycle 1 of GemCap to the first documentation of progressive disease or death from any cause (whichever came first), with patients being censored on the last day of study follow-up if no disease progression had occurred. Summary statistics were used to describe the medians, range, proportions, and frequencies. The Kaplan-Meier method was used to estimate time-to-event outcomes. RESULTS Between July 2001 and January 2005, 75 patients were enrolled in the current expanded phase 2 trial. The charateristics of the patients are described in Table 1. The median age was 61 years (range, years) and greater than half of the patients were male. Approximately 60% of patients had cholangiocarcinoma and 85% had metastatic disease at the time of study enrollment. The great majority of patients (98%) had not received any form of anticancer therapy; 1 patient with locally advanced cholangiocarcinoma received local external beam radiation and 1 patient received postoperative radiation concurrently with gemcitabine for positive surgical margins. Greater than 60% of patients had undergone biliary decompression either by stenting or bypass surgery prior to the initiation of the study chemotherapy. The total number of cycles delivered was 609 and the median duration of treatment was 6 months (range, 5 weeks to 40 months). All 75 patients were evaluable for efficacy outcomes. The proportion of

3 Gemcitabine and Capecitabine for Biliary CA/Riechelmann et al TABLE 1 Charateristics of Patients TABLE 2 Best Response by RECIST Criteria Characteristic No. Percentage Total Median age (range), y 61 (37 84) Sex Male Female Cancer type Bile duct Gallbladder Ampulla of Vater 3 4 Extension of disease at study entry Locally advanced Metastatic Primary ressection Prior systemic therapy None Adjuvant chemoradiation 1 1 Local radiation 1 1 patients achieving best response as per RECIST criteria is described in Table 2. At a median follow-up of 9.5 months (range, 1 49 months), the overall response rate was 29% (95% confidence interval [95% CI], %), with a median duration of 9.7 months (range, 3 36 months). Three patients achieved a complete response (1 patient with cholangiocarcinoma, 1 with gallbladder cancer, and 1 patient with an ampullary tumor), with a median duration of response of 17 months (range, 9 27 months). The overall disease control (proportion of patients who achieved tumor response and stable disease) was 78%. The proportion of patients who achieved an objective response was slightly higher for gallbladder cancer patients than for cholangiocainoma patients (33% vs 24%); more patients with gallbladder cancer developed early disease progression at 9 weeks (37% vs 16%) and had less stable disease (30% vs 60%) compared with cholangiocarcinoma patients. The median progression-free survival and overall survival for the entire cohort were 6.2 months (95% CI, months) and 12.7 months (95% CI, months), respectively. The estimated 2-year progression-free survival and overall survival rates were 9.8% (95% CI, 4 23%) and 39% (95% CI, 29 53%), respectively. The median overall survival was 15.5 months (95% CI, 12.3 months to not reached) for patients with cholangiocarcinoma and was 7.7 months (95% CI, 4.6 months to not reached) for patients with gallbladder tumors. The median progression-free survival was 6.5 months (95% CI, months) for cholangiocarcinoma patients and 4.4 months (95% Best response on treatment Cancer type All Bile duct Gallbladder Ampullary Total, No. (%) 75 (100) 45 (100) 27 (100) 3 (100) Overall 22 (29) 11 (24) 09 (33) 2 (67) Complete response 3 (4) 01 (2) 01 (4) 1 (33) Partial response 19 (25) 10 (22) 08 (30) 1 (33) Stable disease 37 (49) 27 (60) 08 (30) 1 (33) Early progression 16 (21) 07 (16) 10 (37) RECIST indicates Response Evaluation Criteria In Solid Tumors. CI, months) for gallbladder cancer patients. Of 75 patients, 73 developed disease progression during the study period; 12 patients (16%) progressed locoregionally, 27 patients (37%) progressed at distant sites, and 34 patients (47%) progressed in both local and distant sites. Twenty-one patients (6 patients with gallbladder cancer and 15 patients with cholangiocarcinoma) received 2 lines of anticancer therapy. As per RECIST criteria evaluation, no objective responses were observed. Seven patients were treated with phase 1 drugs, 5 patients were rechallenged with GemCap, 3 patients received cisplatin combined with 5-flurororacil, 2 patients received gemcitabine alone, and 1 patient each received cisplatin and gemcitabine, cisplatin and irinotecan, the ECF regimen (epirubicin, cisplatin, and 5-fluorouracil), and gefitinib. The phase 1 drugs that patients received included a vasopressin V1-A receptor antagonist combined with irinotecan (3 patients) and tyrosine kynase inhibitors (2 patients), and 1 patient each received an antisense oligonucleotide targeting BCL-2 plus doxorubicin, a histone deacetylase inhibitor agent, an oral topoisomerase inhibitor, and a metaloproteinase inhibitor. Of the 5 patients who received second-line GemCap after a median treatment break of 4 months (range, 3 14 months), 4 patients achieved stable disease for a median of 10 months (range, 4 11 months) and 1 patient developed disease progression after 2 cycles. These 5 patients were rechallenged with Gem- Cap because of progressive disease and their best tumor responses with first-line GemCap were as follows: 3 patients achieved stable disease for a median of 18 months (range, months), 1 patient achieved a complete response lasting 27 months, and 1 patient achieved a partial response lasting 12 months. Reasons for discontinuing treatment included progressive disease in 62 patients (83%), a chemo-

4 1310 CANCER September 15, 2007 / Volume 110 / Number 6 TABLE 3 Recent Clinical Trials of Biliary Cancer Reference Regimen No. of patients Tumor site Response rate, % Median survival, mo Randomized Trials Kornek et al., Mitomycin/gemcitabine vs. 51 Bile duct mitomycin/capecitabine 31 9* Ducreux et al., FU vs. 5-FU/cisplatin 58 Bile duct * 8* Rao et al., FU/leucovorin/etoposide vs. ECF 54 Bile duct * 9* Valle et al., Gemcitabine vs. gemcitabine/cisplatin 86 Both 15 NR 24 Phase II Trials Lozano et al., Capecitabine 26 Both 19 7 Gallardo et al., Gemcitabine 26 Gallbladder Taieb et al., Cisplatin/5-FU 29 Both Kuhn et al., Gemcitabine/docetaxel 43 Both 9 11 Nehls et al., Capecitabine/oxaliplatin 29 Both Kim et al., Cisplatin/capecitabine 42 Bile duct Reyes-Vidal et al., Gemcitabine/cisplatin 44 Gallbladder 45 7 Eng et al., Fixed-dose gemcitabine 15 Bile duct 0 5 Knox et al., Gemcitabine/capecitabine 45 Both Andre et al., Gemcitabine/oxaliplatin 45 Both Lee et al., Gemcitabine/cisplatin 24 Bile duct Julka et al., Gemcitabine/carboplatin 20 Gallbladder 36.7 NR (<1 y) Phillip et al., Erlotinib 42 Bile duct 7 NR 5-FU indicates 5-fluorouracil; ECF: epirubicin, cisplatin, and 5-FU; NR: not reported. * P was not significant. therapy break in 7 patients with stable disease (9%), a chemotherapy break in 3 patients with a complete response (4%), adverse events in 2 patients (3%; 1 patient had grade 3 thrombocytopenia and neutropenia and 1 patient had gastrointestinal bleeding), and the development of sepsis in 1 patient (1%). Transient neutropenia, thrombocytopenia, fatigue, and hand-foot syndrome were commonly observed, but were easily managed without discontinuing further treatment. In this expanded cohort, the investigators did not observe any adverse events that were not in keeping with that which had been reported previously in the initial sample of 45 patients. DISCUSSION This expanded phase 2 trial lends further evidence that the GemCap regimen is effective in patients with advanced biliary cancers, with nearly one-third of patients achieving an objective response and a median overall survival of nearly 13 months. At a total of 75 patients, the outcomes remain encouraging and consistent with what was demonstrated within the first 45-patient cohort. 14 Patients with gallbladder tumors had shorter overall and progression-free survival compared with patients with cholangiocarcinoma. No objective responses were observed among patients who received 2 lines of therapy. A few patients who achieved long-term disease control with first-line GemCap benefited from second-line Gem- Cap in terms of disease stabilization. To our knowledge, there is currently no standard chemotherapy regimen for advanced biliary cancer. Historically, chemotherapy has had little impact on the natural history of this disease. This is because of several reasons: a lack of active agents, the overall morbidity of treatment and consequent reduced dose intensity, and the grouping together of different cancer types with different biologies such as pancreatic cancers and hepatocellular carcinomas. Older chemotherapy combinations with 5-fluorouracil have demonstrated response rates of 0% to 10%. To our knowledge, only 1 randomized study published to date demonstrated an improvement in quality of life for biliary cancer patients treated with 5-fluorouracilbased chemotherapy versus best supportive care, although no difference in overall survival was observed. 4 Regimens containing new agents such as gemcitabine, capecitabine, and oxaliplatin have demonstrated objective responses in 20% to 45% of patients and a median survival of 8 to 14 months (Table 3). 12,16 The preliminary results of a large

5 Gemcitabine and Capecitabine for Biliary CA/Riechelmann et al randomized phase 2 trial of gemcitabine versus gemcitabine combined with cisplatin demonstrated that both arms were active, although time to disease progression was longer in the combination arm (5.5 months vs 8 months). 17 Many advances, including the blockade of angiogenesis-related signaling and epidermal growth factor receptor (EGFR) signaling, are being made in several cancer types, including biliary cancer. Philip et al. evaluated the oral EGFR tyrosine kinase inhibitor erlotinib in 42 patients with advanced biliary cancers. 18 Approximately 60% of patients had received 1 prior chemotherapy regimen and 81% had tumors expressing EGFR as detected by immunohistochemistry. In that study, 3 patients achieved a partial response (7%) and 17% of patients were progression free at 6 months. 18 These results suggest a therapeutic benefit for EGFR blockade with erlotinib in some patients with biliary cancers. The GemCap regimen has consistenly shown promising results, as demonstrated by our expanded phase 2 trial, which to our knowledge is 1 of the largest trials published to date regarding this disease, as well as by other studies. 19,20 Although the impact of this regimen on patient survival warrants further evaluation in a randomized study, the results presented herein suggest that GemCap may improve the survival of biliary cancer patients, as evidenced by a reported median survival of nearly 13 months (patients with advanced biliary tumors usually survive <1year). In addition, patients who achieved a complete response had a median duration of response of 17 months. We did not observe responses among those patients who received 2 lines of anticancer therapy. Four of 5 patients who received second-line therapy with Gem- Cap had disease stabilization for a median of 10 months, although these numbers are too small to draw any conclusions and evidence of a benefit for second-line therapy in biliary cancers currently is anecdotal. 21,22 We observed that patients with gallbladder tumors developed more early disease progression and less stable disease, and had shorter survival than patients with cholangiocarcinoma. In the initial cohort treated with GemCap, gallbladder cancer patients also appeared to have a worse outcome, as demonstrated by a Cox regression multivariate analysis. 14 Limitations of the current study should be noted. First, this was single-institution trial and patient selection bias was possible. Second, we did not update data regarding patient safety. The evaluation of adverse events occurring in the expanded cohort was performed at routine follow-up visits; however, the formal collection of toxicity data into the case report forms was not undertaken because of logistic matters. However, the study team did not identify differences with regard to the type or frequency of drug-related adverse events in comparison with what has been reported previously. 14 Lastly, the serum tumor marker CA 19-9 was not routinely available for use during the current study and therefore no evaluation as to its usefulness in monitoring patient outcomes was performed. In conclusion, encouraging antitumor activity as reinforced by this larger patient cohort coupled with a mild toxicity profile 14 suggest that the GemCap chemotherapy regimen may benefit patients with advanced biliary cancers. The National Cancer Institute of Canada s Clinical Trials Group will conduct a randomized clinical trial to compare the GemCap combination with single-agent gemcitabine, with overall survival being the primary endpoint. Secondary endpoints will include response and quality of life. The study will stratify for cancer type (gallbladder vs bile duct cancer), performance status, and extent of disease and will include a tumor banking component. The trial will begin accrual in the second semester of 2007 with the goal of establishing a chemotherapy standard of care for patients with biliary cancers. REFERENCES 1. Khan SA, Thomas HC, Davidson BR, Taylor-Robinson SD. Cholangiocarcinoma. Lancet. 2005;366: Patel T. Worldwide trends in mortality from biliary tract malignancies. BMC Cancer. 2002;2: Falkson G, MacIntyre JM, Moertel CG. Eastern Cooperative Oncology Group experience with chemotherapy for inoperable gallbladder and bile duct cancer. 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