Phase I study of adjuvant chemotherapy with gemcitabine plus cisplatin in patients with biliary tract cancer undergoing curative resection without major hepatectomy (KHBO1004)

Masanori Toyoda, Tetsuo Ajiki, Yutaka Fujiwara, Hiroaki Nagano, Shogo Kobayashi, Daisuke Sakai, Etsuro Hatano, Masashi Kanai, Shoji Nakamori, Atsushi Miyamoto, Akihito Tsuji, Satoshi Kaihara, Hisashi Ikoma, Shigekazu Takemura, Hideyoshi Toyokawa, Hiroaki Terajima, Satoshi Morita, Tatsuya Ioka, Masanori Toyoda, Tetsuo Ajiki, Yutaka Fujiwara, Hiroaki Nagano, Shogo Kobayashi, Daisuke Sakai, Etsuro Hatano, Masashi Kanai, Shoji Nakamori, Atsushi Miyamoto, Akihito Tsuji, Satoshi Kaihara, Hisashi Ikoma, Shigekazu Takemura, Hideyoshi Toyokawa, Hiroaki Terajima, Satoshi Morita, Tatsuya Ioka

Abstract

Purpose: We conducted a phase I study to determine the maximum tolerated dose and recommended dose (RD) of this gemcitabine plus cisplatin (GC) combination in the adjuvant setting for biliary tract cancer (BTC). GC has become a standard chemotherapy regimen for patients with locally advanced or metastatic BTC; however, the benefit of adjuvant therapy for BTC is unclear.

Methods: Patients with BTC were eligible if they met the following criteria: Stage IB or higher; and undergoing resection without major hepatectomy. The starting dose matched the standard dose of gemcitabine (1,000 mg/m(2)) and cisplatin (25 mg/m(2)) on days 1 and 8, every 3 weeks for up to 24 weeks. The dose limiting toxicities (DLTs) were determined during the first 6 weeks, and a 3+3 dose finding design with cohorts of 3-6 patients was used. Further cohort expansion took place.

Results: One DLT, namely grade 4 neutropenia, was observed among six patients at the starting dosages. Then, we expanded the cohort with a total of eighteen patients to evaluate RD and no further DLTs were observed. During the entire study, the most common grade 3/4 adverse events were neutropenia (94 %) and leucopenia (56 %). Non-hematological toxicities were manageable.

Conclusions: We defined the standard dose of GC as the RD for adjuvant chemotherapy for BTC treated by curative resection without major hepatectomy. Further study is warranted to clarify the safety and efficacy of this regimen for all patients.

Trial registration: ClinicalTrials.gov NCT01297998.

References

    1. Randi G, Malvezzi M, Levi F, Ferlay J, Negri E, Franceschi S, La Vecchia C. Epidemiology of biliary tract cancers: an update. Ann Oncol. 2009;20:146–159. doi: 10.1093/annonc/mdn533.
    1. Labour and Welfare Ministry of Health (2010) Handbook of health and welfare statistics.
    1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin. 2013;63:11–30. doi: 10.3322/caac.21166.
    1. Anderson CD, Pinson CW, Berlin J, Chari RS. Diagnosis and treatment of cholangiocarcinoma. Oncologist. 2004;9:43–57. doi: 10.1634/theoncologist.9-1-43.
    1. Howlader N, Noone AM, Krapcho M et al. SEER cancer static tics review, 1975–2008, National Cancer Institute.
    1. Miyakawa S, Ishihara S, Horiguchi A, Takada T, Miyazaki M, Nagakawa T. Biliary tract cancer treatment: 5,584 results from the Biliary Tract Cancer Statistics Registry from 1998 to 2004 in Japan. J Hepatobiliary Pancreat Surg. 2009;16:1–7. doi: 10.1007/s00534-008-0015-0.
    1. Takada T, Amano H, Yasuda H, Yasuda H, Nimura Y, Matsushiro T, Kato H, Nagakawa T, Nakayama T. Is postoperative adjuvant chemotherapy useful for gallbladder carcinoma? A phase III multicenter prospective randomized controlled trial in patients with resected pancreaticobiliary carcinoma. Cancer. 2002;95:1685–1695. doi: 10.1002/cncr.10831.
    1. Neoptolemos JP, Moore MJ, Cox TF, et al. Effect of adjuvant chemotherapy with fluorouracil plus folinic acid or gemcitabine vs observation on survival in patients with resected periampullary adenocarcinoma. JAMA. 2012;308:147–156. doi: 10.1001/jama.2012.7352.
    1. Horgan AM, Amir E, Walter T, Knox JJ. Adjuvant therapy in the treatment of biliary tract cancer: a systematic review and meta-analysis. J Clin Oncol. 2012;30:1934–1940. doi: 10.1200/JCO.2011.40.5381.
    1. Bariani GM, Braghiroli MI, Riechelmann RP. Poor evidence to standardize adjuvant treatment for patients with biliary tract cancer. J Clin Oncol. 2012;30:4173. doi: 10.1200/JCO.2012.44.1634.
    1. Network NCC, NCCN clinical Practice Guidelines in Oncology; Hepatobiliary Cancers. Version 2. 2013
    1. Furuse J, Takada T, Miyazaki M, et al. Guidelines for the management of biliary tract and ampullary carcinomas: surgical treatment. J Hepatobiliary Pancreat Surg. 2008;15:55–62. doi: 10.1007/s00534-007-1280-z.
    1. Valle J, Wasan H, Palmer DH, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med. 2010;362:1273–1281. doi: 10.1056/NEJMoa0908721.
    1. Okusaka T, Nakachi K, Fukutomi A, et al. Gemcitabine alone or in combination with cisplatin in patients with biliary tract cancer: a comparative multicenter study in Japan. Br J Cancer. 2010;103:469–474. doi: 10.1038/sj.bjc.6605779.
    1. Plunkett W, Huang P, Gandhi V (1995) Preclinical characteristics of gemcitabine. Anticancer Drugs 6(Suppl 6):7–13
    1. Watanabe S, Uchida T. Expression of cytidine deaminase in human solid tumors and its regulation by 1 alpha, 25-dihydroxyvitamin D3. Biochim Biophys Acta. 1996;1312:99–104. doi: 10.1016/0167-4889(96)00024-9.
    1. Ho DH. Distribution of kinase and deaminase of 1-beta-D-arabinofuranosylcytosine in tissues of man and mouse. Cancer Res. 1973;33:2816–2820.
    1. Venook AP, Egorin MJ, Rosner GL, et al. Phase I and pharmacokinetic trial of gemcitabine in patients with hepatic or renal dysfunction: cancer and Leukemia Group B 9565. J Clin Oncol. 2000;18:2780–2787.
    1. Hall KS, Lien B, Endresen L, Bergan A, Rugstad HE. Changes in pharmacokinetics of cisplatin after hepatic resection in rats. Drug Metab Dispos. 1991;19:725–728.

Source: PubMed

Sponsor e collaboratori

Condizioni mediche

Interventi farmacologici

3
Sottoscrivi