A phase II study of capecitabine and oxaliplatin combination chemotherapy in patients with inoperable adenocarcinoma of the gall bladder or biliary tract

J S Graham, K Boyd, F Y Coxon, L R Wall, M M Eatock, T S Maughan, M Highley, E Soulis, S Harden, P Bützberger-Zimmerli, T R J Evans, J S Graham, K Boyd, F Y Coxon, L R Wall, M M Eatock, T S Maughan, M Highley, E Soulis, S Harden, P Bützberger-Zimmerli, T R J Evans

Abstract

Background: Advanced biliary tract carcinomas are associated with a poor prognosis, and palliative chemotherapy has only modest benefit. This multi-centre phase II study was conducted to determine the efficacy of capecitabine in combination with oxaliplatin in patients with inoperable gall bladder or biliary tract cancer.

Methods: This was a Phase II, non-randomised, two-stage Simon design, multi-centre study. Ethics approval was sought and obtained by the North West MREC, and then locally by the West Glasgow Hospitals Research Ethics Committee. Eligible patients with inoperable locally advanced or metastatic adenocarcinoma of the gall bladder or biliary tract and with adequate performance status, haematologic, renal, and hepatic function were treated with capecitabine (1000 mg/m(2) po, twice daily, days 1-14) and oxaliplatin (130 mg/m(2) i.v., day 1) every 3 weeks for up to six cycles. The primary objective of the study was to determine the objective tumour response rates (complete and partial). The secondary objectives included assessment of toxicity, progression-free survival, and overall survival.

Results: Forty-three patients were recruited between July 2003 and December 2005. The regimen was well tolerated with no grade 3/4 neutropenia or thrombocytopenia. Grade 3/4 sensory neuropathy was observed in six patients. Two-thirds of patients received their chemotherapy without any dose delays. Overall response rate was 23.8% (95% CI 12.05-39.5%). Stable disease was observed in a further 13 patients (31%) and progressive disease observed in 12 (28.6%) of patients. The median progression-free survival was 4.6 months (95% CI 2.8-6.4 months; Fig. 1) and the median overall survival 7.9 months (95% CI 5.3-10.4 months; Fig. 2). Fig. 1 Progression-free survival Fig. 2 Overall survival

Conclusion: Capecitabine combined with oxaliplatin has a lower disease control and shorter overall survival than the combination of cisplatin with gemcitabine which has subsequently become the standard of care in this disease. However, capecitabine in combination with oxaliplatin does have modest activity in this disease, and can be considered as an alternative treatment option for patients in whom cisplatin and/or gemcitabine are contra-indicated.

Keywords: Biliary tract; Capecitabine; Gall bladder; Oxaliplatin.

Figures

Fig. 1
Fig. 1
Progression-free survival
Fig. 2
Fig. 2
Overall survival

References

    1. Hejna M, Pruckmayer M, Raderer M. The role of chemotherapy and radiation in the management of biliary cancer: a review of the literature. Eur J Cancer. 1998;34(7):977–986. doi: 10.1016/S0959-8049(97)10166-6.
    1. Glimelius B, et al. Chemotherapy improves survival and quality of life in advanced pancreatic and biliary cancer. Ann Oncol. 1996;7(6):593–600. doi: 10.1093/oxfordjournals.annonc.a010676.
    1. Davis HL, Jr, Ramirez G, Ansfield FJ. Adenocarcinomas of stomach, pancreas, liver, and biliary tracts. Survival of 328 patients treated with fluoropyrimidine therapy. Cancer. 1974;33(1):193–197. doi: 10.1002/1097-0142(197401)33:1<193::AID-CNCR2820330128>;2-S.
    1. Falkson G, MacIntyre JM, Moertel CG. Eastern cooperative Oncology Group experience with chemotherapy for inoperable gallbladder and bile duct cancer. Cancer. 1984;54(6):965–969. doi: 10.1002/1097-0142(19840915)54:6<965::AID-CNCR2820540603>;2-X.
    1. Haskell CM. Cancer of the liver. In: Haskell CM, editor. Cancer Treatment. Philadelphia: WB Saunders; 1980.
    1. Kato K, et al. Efficacy of 48-hour infusion of 5-fluorouracil for gall bladder cancer. Gan To Kagaku Ryoho. 1993;20(15):2341–2344.
    1. Takada 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(5):396–400. doi: 10.1159/000227373.
    1. Schuller J, et al. Preferential activation of capecitabine in tumor following oral administration to colorectal cancer patients. Cancer Chemother Pharmacol. 2000;45(4):291–297. doi: 10.1007/s002800050043.
    1. Cassidy J, et al. Randomized phase III study of capecitabine plus oxaliplatin compared with fluorouracil/folinic acid plus oxaliplatin as first-line therapy for metastatic colorectal cancer. J Clin Oncol. 2008;26(12):2006–2012. doi: 10.1200/JCO.2007.14.9898.
    1. Cassidy J, et al. A Phase I study of capecitabine in combination with oral leucovorin in patients with intractable solid tumors. Clin Cancer Res. 1998;4(11):2755–2761.
    1. Comella P, et al. Capecitabine plus oxaliplatin for the first-line treatment of elderly patients with metastatic colorectal carcinoma: final results of the Southern Italy Cooperative Oncology Group Trial 0108. Cancer. 2005;104(2):282–289. doi: 10.1002/cncr.21167.
    1. Diaz-Rubio E, et al. Capecitabine (Xeloda) in combination with oxaliplatin: a phase I, dose-escalation study in patients with advanced or metastatic solid tumors. Ann Oncol. 2002;13(4):558–565. doi: 10.1093/annonc/mdf065.
    1. Ducreux M, et al. Capecitabine plus oxaliplatin (XELOX) versus 5-fluorouracil/leucovorin plus oxaliplatin (FOLFOX-6) as first-line treatment for metastatic colorectal cancer. Int J Cancer. 2010;128(3):682–690. doi: 10.1002/ijc.25369.
    1. Haller DG, et al. Capecitabine plus oxaliplatin compared with fluorouracil and folinic acid as adjuvant therapy for stage III colon cancer. J Clin Oncol. 2011;29(11):1465–1471. doi: 10.1200/JCO.2010.33.6297.
    1. Mackean M, et al. Phase I and pharmacologic study of intermittent twice-daily oral therapy with capecitabine in patients with advanced and/or metastatic cancer. J Clin Oncol. 1998;16(9):2977–2985.
    1. Blum JL, et al. Multicenter, Phase II study of capecitabine in taxane-pretreated metastatic breast carcinoma patients. Cancer. 2001;92(7):1759–1768. doi: 10.1002/1097-0142(20011001)92:7<1759::AID-CNCR1691>;2-A.
    1. Oshaughnessy JA, et al. Randomized, open-label, phase II trial of oral capecitabine (Xeloda) vs a reference arm of intravenous CMF (cyclophosphamide, methotrexate and 5-fluorouracil) as first-line therapy for advanced/metastatic breast cancer. Ann Oncol. 2001;12(9):1247–1254. doi: 10.1023/A:1012281104865.
    1. Okines AF, et al. Meta-analysis of the REAL-2 and ML17032 trials: evaluating capecitabine-based combination chemotherapy and infused 5-fluorouracil-based combination chemotherapy for the treatment of advanced oesophago-gastric cancer. Ann Oncol. 2009;20(9):1529–1534. doi: 10.1093/annonc/mdp047.
    1. Mathe G, et al. Oxalato-platinum or 1-OHP, a third-generation platinum complex: an experimental and clinical appraisal and preliminary comparison with cis-platinum and carboplatinum. Biomed Pharmacother. 1989;43(4):237–250. doi: 10.1016/0753-3322(89)90003-6.
    1. Diaz-Rubio E, et al. Phase III study of capecitabine plus oxaliplatin compared with continuous-infusion fluorouracil plus oxaliplatin as first-line therapy in metastatic colorectal cancer: final report of the Spanish Cooperative Group for the Treatment of Digestive Tumors Trial. J Clin Oncol. 2007;25(27):4224–4230. doi: 10.1200/JCO.2006.09.8467.
    1. Therasse P, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. 2000;92(3):205–216. doi: 10.1093/jnci/92.3.205.
    1. Gunnlaugsson A, et al. Multicentre phase I-II trial of capecitabine and oxaliplatin in combination with radiotherapy for unresectable pancreatic and biliary tract cancer: the CORGI-U study. Radiother Oncol. 2010;95(3):292–297. doi: 10.1016/j.radonc.2010.04.004.
    1. Manzione L, Romano R, Germano D. Chemotherapy with gemcitabine and oxaliplatin in patients with advanced biliary tract cancer: a single-institution experience. Oncology. 2007;73(5–6):311–315. doi: 10.1159/000134239.
    1. Karachaliou N, et al. A multicenter phase II trial with irinotecan plus oxaliplatin as first-line treatment for inoperable/metastatic cancer of the biliary tract. Oncology. 2010;78(5–6):356–360. doi: 10.1159/000320462.
    1. Kim HJ, et al. A phase II study of gemcitabine in combination with oxaliplatin as first-line chemotherapy in patients with inoperable biliary tract cancer. Cancer Chemother Pharmacol. 2009;64(2):371–377. doi: 10.1007/s00280-008-0883-7.
    1. Kim KP, et al. Phase II study of S-1 combined with oxaliplatin as therapy for patients with metastatic biliary tract cancer: influence of the CYP2A6 polymorphism on pharmacokinetics and clinical activity. Br J Cancer. 2011;104(4):605–612. doi: 10.1038/bjc.2011.17.
    1. Oh SY, et al. Phase II trial of S-1 in combination with oxaliplatin in previously untreated patients with recurrent or inoperable biliary tract cancer. Chemotherapy. 2008;54(6):479–484. doi: 10.1159/000159624.
    1. Nehls O, et al. Capecitabine plus oxaliplatin as first-line treatment in patients with advanced biliary system adenocarcinoma: a prospective multi centre phase II trial. Br J Cancer. 2008;98:309–313. doi: 10.1038/sj.bjc.6604178.
    1. Jarnagin WR, et al. Differential cell-cycle-regulatory protein expression in biliary tract adenocarcinoma; correlation with anatomic site, pathologic variables, and clinical outcome. J Clin Oncol. 2006;24:1151–1160. doi: 10.1200/JCO.2005.04.6631.
    1. Andre T, et al. Gemcitabine combined with oxaliplatin (GEMOX) in advanced biliary tract adenocarcinoma: a GERCOR study. Ann Oncol. 2004;15(9):1339–1343. doi: 10.1093/annonc/mdh351.
    1. Valle J, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med. 2010;362(14):1273–1281. doi: 10.1056/NEJMoa0908721.
    1. Taal BG, et al. Phase II trial of mitomycin C (MMC) in advanced gallbladder and biliary tree carcinoma. An EORTC Gastrointestinal Tract Cancer Cooperative Group Study. Ann Oncol. 1993;4(7):607–609.
    1. Patt YZ, et al. Phase II trial of intravenous flourouracil and subcutaneous interferon alfa-2b for biliary tract cancer. J Clin Oncol. 1996;14(8):2311–2315.
    1. Patt YZ, et al. Phase II trial of cisplatin, interferon alpha-2b, doxorubicin, and 5-fluorouracil for biliary tract cancer. Clin Cancer Res. 2001;7(11):3375–3380.
    1. Penz M, et al. Phase II trial of two-weekly gemcitabine in patients with advanced biliary tract cancer. Ann Oncol. 2001;12(2):183–186. doi: 10.1023/A:1008352123009.
    1. Murad AM, et al. Phase II trial of the use of gemcitabine and 5-fluorouracil in the treatment of advanced pancreatic and biliary tract cancer. Am J Clin Oncol. 2003;26(2):151–154. doi: 10.1097/00000421-200304000-00010.
    1. Kornek GV, 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(3):478–483. doi: 10.1093/annonc/mdh096.
    1. Ueno H, et al. Phase II study of S-1 in patients with advanced biliary tract cancer. Br J Cancer. 2004;91(10):1769–1774. doi: 10.1038/sj.bjc.6602208.
    1. Alberts SR, 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(1):111–118. doi: 10.1002/cncr.20753.
    1. Furuse J, 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(9):552–556. doi: 10.1093/jjco/hyl075.
    1. Kim ST, et al. A Phase II study of gemcitabine and cisplatin in advanced biliary tract cancer. Cancer. 2006;106(6):1339–1346. doi: 10.1002/cncr.21741.
    1. Okusaka T, et al. Phase II study of single-agent gemcitabine in patients with advanced biliary tract cancer. Cancer Chemother Pharmacol. 2006;57(5):647–653. doi: 10.1007/s00280-005-0095-3.
    1. Park BK, et al. Phase II study of gemcitabine and cisplatin in advanced biliary tract cancer. J Gastroenterol Hepatol. 2006;21(6):999–1003. doi: 10.1111/j.1440-1746.2006.04230.x.
    1. Hong YS, et al. Phase II study of capecitabine and cisplatin in previously untreated advanced biliary tract cancer. Cancer Chemother Pharmacol. 2007;60(3):321–328. doi: 10.1007/s00280-006-0380-9.
    1. Furuse J, et al. S-1 monotherapy as first-line treatment in patients with advanced biliary tract cancer: a multicenter phase II study. Cancer Chemother Pharmacol. 2008;62(5):849–855. doi: 10.1007/s00280-007-0673-7.
    1. Kim YJ, et al. A phase II trial of S-1 and cisplatin in patients with metastatic or relapsed biliary tract cancer. Ann Oncol. 2008;19(1):99–103. doi: 10.1093/annonc/mdm439.
    1. Furuse J, et al. A phase II study of uracil-tegafur plus doxorubicin and prognostic factors in patients with unresectable biliary tract cancer. Cancer Chemother Pharmacol. 2009;65(1):113–120. doi: 10.1007/s00280-009-1011-z.
    1. Sasaki T, et al. Multicenter, phase II study of gemcitabine and S-1 combination chemotherapy in patients with advanced biliary tract cancer. Cancer Chemother Pharmacol. 2009;65(6):1101–1107. doi: 10.1007/s00280-009-1115-5.
    1. Kanai M, et al. A multi-institution phase II study of gemcitabine/S-1 combination chemotherapy for patients with advanced biliary tract cancer. Cancer Chemother Pharmacol. 2010;67(6):1429–1434. doi: 10.1007/s00280-010-1443-5.
    1. Chung MJ, et al. Prospective phase II trial of gemcitabine in combination with irinotecan as first-line chemotherapy in patients with advanced biliary tract cancer. Chemotherapy. 2011;57(3):236–243. doi: 10.1159/000328021.

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