nach oben

Erschienen in:

01.10.2014 | Original Article

Phase I study of adjuvant gemcitabine or S-1 in patients with biliary tract cancers undergoing major hepatectomy: KHBO1003 study

verfasst von: Shogo Kobayashi, Hiroaki Nagano, Daisuke Sakai, Hidetoshi Eguchi, Etsuro Hatano, Masashi Kanai, Satoru Seo, Kojiro Taura, Yutaka Fujiwara, Tetsuo Ajiki, Shigekazu Takemura, Shoji Kubo, Hiroaki Yanagimoto, Hideyoshi Toyokawa, Akihito Tsuji, Hiroaki Terajima, Satoshi Morita, Tatsuya Ioka

Erschienen in: Cancer Chemotherapy and Pharmacology | Ausgabe 4/2014

Einloggen, um Zugang zu erhalten

Abstract

Background

Standardized adjuvant therapy is not performed after major hepatectomy for biliary tract cancer (BTC) because of frequent adverse events, which may be caused by insufficient liver function. Therefore, the aim of this multicenter study (KHBO1003) was to determine the safety protocol for adjuvant chemotherapy after major hepatectomy.

Methods

Within 12 weeks of R0 or R1 major hepatectomy (hemihepatectomy or trisectionectomy) for BTC, the following adjuvant chemotherapy was performed for 6 months: 800–1,000 mg/m² gemcitabine on days 1, 8, and 15 and then every 3–4 weeks or 40–80 mg/m²/day S-1 on days 1–28 and every 3–6 weeks. Major dose-limited toxicity (DLT) was defined as grade 4 hematotoxicity, grade 3/4 febrile neutropenia, grade 3/4 non-hematotoxicity, skipped gemcitabine on days 8 and 15, or halting the course at or after 14 days. Dose-escalation and de-escalation decisions were based on the continual reassessment method. Every three patients were alternately assigned to each arm.

Results

Thirty-three patients (14 intrahepatic bile duct, 1 gall bladder, 18 extrahepatic bile duct) were enrolled in this study from February 2011 to July 2012 (n = 18 gemcitabine, n = 15 S-1). At 10 % of DLT, the recommended dose was 1,000 mg/m² gemcitabine biweekly and 80 mg/m²/day S-1 on days 1–28 and every 6 weeks. Major DLT and adverse drug reactions were neutropenia. No grade 3 or 4 non-hematological adverse events were noted.

Conclusion

We determined RDs for gemcitabine and S-1 adjuvant chemotherapy after major hepatectomy with a DLT that does not exceed 10 %.

Yamanaka K, Hatano E, Kanai M, Tanaka S, Yamamoto K, Narita M, Nagata H, Ishii T, Machimoto T, Taura K, Uemoto S (2014) A single-center analysis of the survival benefits of adjuvant gemcitabine chemotherapy for biliary tract cancer. Int J Clin Oncol 19(3):485–489

Kobayashi S, Nagano H, Marubashi S, Wada H, Eguchi H, Takeda Y, Tanemura M, Umeshita K, Doki Y, Mori M (2011) Treatment of borderline cases for curative resection of biliary tract cancer. J Surg Oncol 104(5):499–503PubMedCrossRef

Miyakawa S, Ishihara S, Horiguchi A, Takada T, Miyazaki M, Nagakawa T (2009) Biliary tract cancer treatment: 5,584 results from the Biliary Tract Cancer Statistics Registry from 1998 to 2004 in Japan. J Hepatobiliary Pancreat Surg 16:1–7PubMedCrossRef

Hasegawa S, Ikai I, Fujii H, Hatano E, Shimahara Y (2007) Surgical resection of hilar cholangiocarcinoma. Analysis of survival and postoperative complications. World J Surg 31(6):1256–1263PubMedCrossRef

Takada T, Amano H, Yasuda H, Nimura Y, Matsushiro T, Kato H, Nagakawa T, Nakayama T, Study Group of Surgical Adjuvant Therapy for Carcinomas of the Pancreas and Biliary Tract (2002) Is postoperative adjuvant chemotherapy useful for gallbladder carcinoma? A phase III multicenter prospective randomized controlled trial in patients with resected pancreaticobiliary carcinoma. Cancer 95(8):1685–1695PubMedCrossRef

Kobayashi S, Nagano H, Marubashi S, Takeda Y, Tanemura M, Konishi K, Yoshioka Y, Inoue T, Doki Y, Mori M (2009) Impact of postoperative irradiation after non-curative resection of hilar biliary cancer. J Surg Oncol 100(8):657–662PubMedCrossRef

Neoptolemos JP, Moore MJ, Cox TF, Valle JW, Palmer DH, McDonald AC, Carter R, Tebbutt NC, Dervenis C, Smith D, Glimelius B, Charnley RM, Lacaine F, Scarfe AG, Middleton MR, Anthoney A, Ghaneh P, Halloran CM, Lerch MM, Oláh A, Rawcliffe CL, Verbeke CS, Campbell F, Büchler MW, European Study Group for Pancreatic Cancer (2012) Effect of adjuvant chemotherapy with fluorouracil plus folinic acid or gemcitabine vs observation on survival in patients with resected periampullary adenocarcinoma: the ESPAC-3 periampullary cancer randomized trial. JAMA 308(2):147–156PubMedCrossRef

Kobayashi S, Miyamoto A, Shimizu J, Kashiwazaki M, Takeda Y, Ueshima S, Kim Y, Kitagawa T, Dono K, Mori M, Doki Y, Nagano H (2011) Comparison of 4-weekly vs 3-weekly gemcitabine as adjuvant chemotherapy following curative resection for biliary tract cancer: a prospective randomized controlled trial. J Cancer Ther 2:703–709CrossRef

Maeda A, Boku N, Fukutomi A, Kondo S, Kinoshita T, Nagino M, Uesaka K (2008) Randomized phase III trial of adjuvant chemotherapy with gemcitabine versus S-1 in patients with resected pancreatic cancer: Japan Adjuvant Study Group of Pancreatic Cancer (JASPAC-01). Jpn J Clin Oncol 38(3):227–229PubMedCrossRef

10.

Ueno H, Kosuge T, Matsuyama Y, Yamamoto J, Nakao A, Egawa S, Doi R, Monden M, Hatori T, Tanaka M, Shimada M, Kanemitsu K (2009) A randomised phase III trial comparing gemcitabine with surgery-only in patients with resected pancreatic cancer: Japanese Study Group of Adjuvant Therapy for Pancreatic Cancer. Br J Cancer 101(6):908–915PubMedCrossRefPubMedCentral

11.

Oettle H, Post S, Neuhaus P, Gellert K, Langrehr J, Ridwelski K, Schramm H, Fahlke J, Zuelke C, Burkart C, Gutberlet K, Kettner E, Schmalenberg H, Weigang-Koehler K, Bechstein WO, Niedergethmann M, Schmidt-Wolf I, Roll L, Doerken B, Riess H (2007) Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial. JAMA 297(3):267–277PubMedCrossRef

12.

Morizane C, Okusaka T, Mizusawa J, Takashima A, Ueno M, Ikeda M, Hamamoto Y, Ishii H, Boku N, Furuse J (2013) Randomized phase II study of gemcitabine plus S-1 versus S-1 in advanced biliary tract cancer: a Japan Clinical Oncology Group trial (JCOG 0805). Cancer Sci 104(9):1211–1216PubMedCrossRef

13.

Suzuki E, Ikeda M, Okusaka T, Nakamori S, Ohkawa S, Nagakawa T, Boku N, Yanagimoto H, Sato T, Furuse J (2013) A multicenter phase II study of S-1 for gemcitabine-refractory biliary tract cancer. Cancer Chemother Pharmacol 71(5):1141–1146PubMedCrossRefPubMedCentral

14.

Konishi M (2012) Adjuvant chemotherapy for resectable biliary tract cancer: current status and future direction. J Hepatobiliary Pancreat Sci 19(4):301–305PubMedCrossRef

15.

Belghiti J, Clavien PA, Gadzijev E, Garden JO, Lau WY, Makuuchi M, Strong RW (2000) The Brisbane 2000 terminology of liver anatomy and resections. HPB 2(3):333–339

16.

O’Quigley J, Pepe M, Fisher L (1990) Continual reassessment method: a practical design for phase 1 clinical trials in cancer. Biometrics 46:33–48PubMedCrossRef

17.

Ono T, Yamanoi A, Nazmy El Assal O, Kohno H, Nagasue N (2001) Adjuvant chemotherapy after resection of hepatocellular carcinoma causes deterioration of long-term prognosis in cirrhotic patients: metaanalysis of three randomized controlled trials. Cancer 91(12):2378–2385PubMedCrossRef

18.

Lai EC, Lo CM, Fan ST, Liu CL, Wong J (1998) Postoperative adjuvant chemotherapy after curative resection of hepatocellular carcinoma: a randomized controlled trial. Arch Surg 133(2):183–188PubMedCrossRef

19.

Hasegawa K, Takayama T, Ijichi M, Matsuyama Y, Imamura H, Sano K, Sugawara Y, Kokudo N, Makuuchi M (2006) Uracil-tegafur as an adjuvant for hepatocellular carcinoma: a randomized trial. Hepatology 44(4):891–895PubMedCrossRef

20.

Murakami Y, Uemura K, Sudo T, Hayashidani Y, Hashimoto Y, Nakamura H, Nakashima A, Sueda T (2009) Adjuvant gemcitabine plus S-1 chemotherapy improves survival after aggressive surgical resection for advanced biliary carcinoma. Ann Surg 250(6):950–956PubMedCrossRef

21.

Murakami Y, Uemura K, Sudo T, Hayashidani Y, Hashimoto Y, Nakamura H, Nakashima A, Sueda T (2009) Gemcitabine-based adjuvant chemotherapy improves survival after aggressive surgery for hilar cholangiocarcinoma. J Gastrointest Surg 13(8):1470–1479PubMedCrossRef

22.

Kobayashi S, Wada H, Hama N, Akita H, Kawamoto K, Eguchi H, Umeshita K, Doki Y, Mori M, Nagano H (2013) Evaluation of safety parameters and changes of serum concentration in liver transplant recipients treated with doxorubicin during the anhepatic period. Cancer Chemother Pharmacol 72(6):1325–1333PubMedCrossRef

23.

Ku Y, Kusunoki N, Kitagawa T, Maeda I, Fukumoto T, Iwasaki T et al (1997) Pharmacokinetics of adriamycin and cisplatin for anhepatic chemotherapy during liver transplantation. Cancer Chemother Pharmacol 40(6):457–462PubMedCrossRef

24.

Kitagawa T, Ku Y, Kusunoki N, Tominaga M, Maeda I, Fukumoto T et al (1996) Pharmacokinetics of intravenous adriamycin for anhepatic chemotherapy during liver transplantation. Transpl Int 9(Suppl 1):S105–S108PubMedCrossRef

25.

Furuse J, Kasuga A, Takasu A, Kitamura H, Nagashima F (2012) Role of chemotherapy in treatments for biliary tract cancer. J Hepatobiliary Pancreat Sci 19(4):337–341PubMedCrossRef

26.

Bridgewater JA, Stubbs C, Stocken DD, Fox RP, Primrose JN (2011) BILCAP: A randomized clinical trial evaluating adjuvant chemotherapy with capecitabine compared to expectant treatment alone following curative surgery for biliary tract cancers. J Clin Oncol Abstr 4125

27.

Ramírez-Merino N, Aix SP, Cortés-Funes H (2013) Chemotherapy for cholangiocarcinoma: an update. World J Gastrointest Oncol 5(7):171–176PubMedCrossRefPubMedCentral

28.

Valle J, Wasan H, Palmer DH, Cunningham D, Anthoney A, Maraveyas A, Madhusudan S, Iveson T, Hughes S, Pereira SP, Roughton M, Bridgewater J, ABC-02 Trial Investigators (2010) Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med 362(14):1273–1281PubMedCrossRef

29.

Toyoda M, Ajiki T, Fujiwara Y, Nagano H, Kobayashi S, Sakai D, Hatano E, Kanai M, Nakamori S, Miyamoto A, Tsuji A, Kaihara S, Ikoma H, Takemura S, Toyokawa H, Terajima H, Morita S, Ioka T (2014) Phase I study of adjuvant chemotherapy with gemcitabine plus cisplatin in patients with biliary tract cancer undergoing curative resection without major hepatectomy (KHBO1004). Cancer Chemother Pharmacol 73(6):1295–1301PubMedCrossRefPubMedCentral

30.

Goodman SN, Zahurak ML, Piantadosi S (1995) Some practical improvements in the continual reassessment method for phase I studies. Stat Med 14:1149–1161PubMedCrossRef

Titel: Phase I study of adjuvant gemcitabine or S-1 in patients with biliary tract cancers undergoing major hepatectomy: KHBO1003 study
verfasst von: Shogo Kobayashi
Hiroaki Nagano
Daisuke Sakai
Hidetoshi Eguchi
Etsuro Hatano
Masashi Kanai
Satoru Seo
Kojiro Taura
Yutaka Fujiwara
Tetsuo Ajiki
Shigekazu Takemura
Shoji Kubo
Hiroaki Yanagimoto
Hideyoshi Toyokawa
Akihito Tsuji
Hiroaki Terajima
Satoshi Morita
Tatsuya Ioka
Publikationsdatum: 01.10.2014
Verlag: Springer Berlin Heidelberg
Erschienen in: Cancer Chemotherapy and Pharmacology / Ausgabe 4/2014
Print ISSN: 0344-5704
Elektronische ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-014-2543-4

Springer Medizin

Phase I study of adjuvant gemcitabine or S-1 in patients with biliary tract cancers undergoing major hepatectomy: KHBO1003 study