Cancer Chemotherapy and Pharmacology

, Volume 69, Issue 5, pp 1127–1133

A phase I study for adjuvant chemotherapy of gemcitabine plus S-1 in curatively resected patients with biliary tract cancer: adjusting the dose of adjuvant chemotherapy according to the surgical procedures

  • Takeshi Takahara
  • Hiroyuki Nitta
  • Yasushi Hasegawa
  • Naoko Itou
  • Masahiro Takahashi
  • Satoshi Nishizuka
  • Go Wakabayashi
Original Article

Abstract

Purpose

We conducted a phase I study for adjuvant chemotherapy of gemcitabine (GEM) plus S-1 in order to determine the maximum tolerated dose and the recommended dose (RD) and to evaluate the efficacy and toxicity of the regimen in curatively resected patients with biliary cancer.

Methods

The study included 34 patients with adequate organ functions, Eastern Cooperative Oncology Group PS 0-1, under 80 years of age, who had curative resection after August, 2007. Patients received GEM on day 1 and day 15, and S-1 from day 1 to day 14. Dose-limiting toxicities were determined during first two treatment cycles. After determining RD, a feasibility study was continued in the following four treatment cycles.

Results

Hematological toxicity, particularly neutropenia and thrombocytopenia, was the most pronounced toxic effect of gemcitabine and S-1 adjuvant combination chemotherapy. The RD after pancreatoduodenectomy is GEM 1,000 mg/m2 + S-1 80 mg/m2, and RD after hemihepatectomy is GEM 800 mg/m2 + S-1 60 mg/m2.

Conclusions

The pharmacokinetics of GEM and S-1 indicate that changing the dose of adjuvant chemotherapy based on the operation method for biliary cancers is reasonable. We believe that this regimen will be established as an effective adjuvant chemotherapy for biliary cancer in the future.

Keywords

Biliary tract cancer Adjuvant chemotherapy Gemcitabine and S-1 Phase I study 

References

  1. 1.
    Sobin LH, Wittekind CH (eds) (2002) UICC TNM Classification of malignant tumors. Liver. 6th edn. Wiley-Liss, New York, pp 81–92Google Scholar
  2. 2.
    De Groen PC, Gores GJ, LaRusso NF, Gunderson LL, Nagorney DM (1999) Biliary tract cancers. New Engl J Med 341:1368–1378PubMedCrossRefGoogle Scholar
  3. 3.
    Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, Thun MJ (2008) Cancer statistics, 2008. CA Cancer J Clin 58:71–96PubMedCrossRefGoogle Scholar
  4. 4.
    Okusaka T (2002) Chemotherapy for biliary tract cancer in Japan. Semin Oncol 29:51–53PubMedGoogle Scholar
  5. 5.
    Patel T (2002) Worldwide trends in mortality from biliary tract malignancies. BMC Cancer 2:10PubMedCrossRefGoogle Scholar
  6. 6.
    Shaib Y, El-Serag HB (2004) The epidemiology of cholangiocrcinoma. Semin Liver Dis 24:115–125PubMedCrossRefGoogle Scholar
  7. 7.
    National Cancer Center (2007) Cancer statistics in Japan. http://www.fpcr.or.jp/publivation/statistics.html
  8. 8.
    Jarnagin WR, Fong Y, De Matteo RP, Gonen M, Burke EC, Bodniewicz BSJ, Youssef BAM, Klimstra D, Blumgart LH (2001) Staging, resectability, and outcome in 225 patients with hilar cholangiocarcinoma. Ann Surg 234:507–517PubMedCrossRefGoogle Scholar
  9. 9.
    Nimura Y, Kamiya J, Kondo S, Nagino M, Uesaka K, Oda K, Sano T, Yamamoto H, Hayakawa N (2000) Aggressive preoperative management and extended surgery for hilar cholangiocarcinoma: Nagoya experience. J Hepatobiliary Pancreat Surg 7:155–162PubMedCrossRefGoogle Scholar
  10. 10.
    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 95:1685–1695Google Scholar
  11. 11.
    Nakeeb A, Tran KQ, Black MJ, Erickson BA, Ritch PS, Quebbeman EJ, Wilson SD, Demeure MJ, Rilling WS, Dua KS, Pitt HA (2002) Improved survival in resected biliary malignancies. Surgery 132:555–564PubMedCrossRefGoogle Scholar
  12. 12.
    Nelson JW, Ghofoori AP, Willett CG, Tyler DS, Pappas TN, Clary BM, Hurwitz HI, Bendell JC, Morse MA, Clough RW, Czito BG (2009) Concurrent chemoradiotherapy in resected extrahepatic cholangiocarcinoma. Int J Radiat Oncol Biol Phys 73:148–153PubMedCrossRefGoogle Scholar
  13. 13.
    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):950–956PubMedCrossRefGoogle Scholar
  14. 14.
    Eng C, Ramanathan RK, Wong MK, Remick SC, Dai L, Wade-Oliver KT, Mani S, Kindler HL (2004) A phase II trial of fixed dose rate gemcitabine in patients with advanced biliary tree carcinoma. Am J Clin Oncol 27:565–569PubMedCrossRefGoogle Scholar
  15. 15.
    Eckel F, Schmid RM (2007) Chemotherapy in advanced biliary tract carcinoma: a pooled analysis of clinical traials. Br J Cancer 96:896–902PubMedCrossRefGoogle Scholar
  16. 16.
    Andre T, Tournigand C, Rosmorduc O, Provent S, Maindrault-Goebel F, Avenin D, Selle F, Paye F, Hannoun L, Houry S, Gayet B, Lotz JP, de Gramont A, Louvet C, GERCOR Group (2004) Gemcitabine combined with oxaliplatin (GEMOX) in advanced biliary tract adenocarcinoma: a GERCOR study. Ann Oncol 15:1339–1343PubMedCrossRefGoogle Scholar
  17. 17.
    Knox JJ, Hedley D, Oza A, Feld R, Siu LL, Chen E, Nematollahi M, Pond GR, Zhang J, Moore MJ (2005) Combining gemcitabine and capecitabine in patients with advanced biliary cancer: a phase II trial. J Clin Oncol 23:2332–2338PubMedCrossRefGoogle Scholar
  18. 18.
    Sakuramoto S, Sasako M, Yamaguchi T, Kinoshita T, Fujii M, Nashimoto A, Furukawa H, Nakajima T, Ohashi Y, Imamura H, Higashino M, Yamamura Y, Kurita A, Arai K, ACTS-GC Group (2007) Adjuvant chemotherapy for gastric cancer with S-1, an oral fluoropyrimidine. N Engl J Med 357:1810–1820PubMedCrossRefGoogle Scholar
  19. 19.
    Boku N, Yamamoto S, Fukuda H, Shirao K, Doi T, Sawaki A, Koizumi W, Saito H, Yamaguchi K, Takiuchi H, Nasu J, Ohtsu Ohtsu, Gastrointestinal Oncology Study Group of the Japan Clinical Oncology Group (2009) Fluorouracil versus combination of irinotecan plus cisplatin versus S-1 in metastatic gastric cancer: a randomized phase 3 study. Lancet Oncol 10:1063–1069PubMedCrossRefGoogle Scholar
  20. 20.
    Morizane C, Okusaka T, Furuse J, Ishii H, Ueno H, Ikeda M, Nakachi K, Najima M, Ogura T, Suzuki E (2009) A phase II study of S-1 in gemcitabine-refractory metastatic pancreatic cancer. Cancer Chemother Pharmacol 63:313–319PubMedCrossRefGoogle Scholar
  21. 21.
    Furuse J, Okusaka T, Boku N, Ohkawa S, Sawaki A, Masumoto T, Funakoshi A (2008) S-1 monotherapy as first-line treatment in patients with advanced biliary tract cancer: a multicenter phase II study. Cancer Chemother Pharmacol 62:849–855PubMedCrossRefGoogle Scholar
  22. 22.
    Ueno H, Okusaka T, Ikeda M, Takezako Y, Morizane C (2004) Phase II study of S-1 in patients with advanced biliary tract cancer. Br J Cancer 91:1769–1774PubMedCrossRefGoogle Scholar
  23. 23.
    Valle JW, 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 362:1273–1281PubMedCrossRefGoogle Scholar
  24. 24.
    Okusaka T, Nakachi K, Fukutomi A, Mizuno N, Ohkawa S, Funakoshi A, Nagino M, Kondo S, Nagaoka S, Funai J, Koshiji M, Nambu Y, Furuse J, Miyazaki M, Nimura Y (2010) Gemcitabine alone or in combination with cisplatin in patients with biliary tract cancer: a comparative multicentre study in Japan. Br J Cancer 103:469–474PubMedCrossRefGoogle Scholar
  25. 25.
    Nakamura K, Yamaguchi T, Ishihara T, Sudo K, Kato H, Saisho H (2006) Phase II trial of oral S-1 combined with gemcitabine in metastatic pancreatic cancer. Br J Cancer 94:1575–1579PubMedGoogle Scholar
  26. 26.
    Nakai Y, Isayama H, Sasaki T, Sasahira N, Ito Y, Kogure H, Togawa O, Matsubara S, Arizumi T, Yagioka H, Yashima Y, Kawakubo K, Mizuno S, Yamamoto K, Hirano K, Tsujino T, Ijichi H, Toda N, Tada M, Kawabe T, Omata M (2009) A pilot study for combination chemotherapy using gemcitabine and S-1 for advanced pancreatic cancer. Oncology 77(5):300–303PubMedCrossRefGoogle Scholar
  27. 27.
    Sasaki T, Isayama H, Nakai Y, Ito Y, Kogure H, Togawa O, Toda N, Yasuda I, Hasebe O, Maetani I, Sasahira N, Hirano K, Tsujino T, Tada M, Omata M (2010) Multicenter, phase II study of gemcitabine and S-1 combination chemotherapy in patients with advanced biliary tract cancer. Cancer Chemother Pharmarcol 65:1101–1107CrossRefGoogle Scholar
  28. 28.
    Kanai M, Yoshimura K, Tsumura T, Asada M, Suzuki C, Niimi M, Matsumoto S, Nishimura T, Nitta T, Yasuchika K, Taura K, Mori Y, Hamada A, Inoue N, Tada S, Yanagihara K, Yazumi S, Osaki Y, Chiba T, Ikai I, Fukushima M, Uemoto S, Hatano E (2011) A multi-institution phase II study of gemcitabine/S-1 combination chemotherapy for patients with advanced biliary tract cancer. Cancer Chemother Pharmarcol 67:1429–1434CrossRefGoogle Scholar
  29. 29.
    Takashima A, Morizane C, Ishii H, Nakamura K, Fukuda H, Okusaka T, Furuse J (2010) Randomized phase II study of gemcitabine plus S-1 combination therapy versus S-1 in advanced biliary tract cancer: Japan Clinical Oncology Group Study (JCOG0805). Jpn J Clin Oncol 40:1189–1191PubMedCrossRefGoogle Scholar
  30. 30.
    Murakami Y, Uemura K, Sudo T, Hayashidani Y, Hashimoto Y, Nakamura H, Nakashima A, Sueda T (2009) Gemcitabine-based adjuvant chemotherapy improved survival after aggressive surgery for hilar cholangiocarcinoma. J Gastrointest Surg 13:1470–1479PubMedCrossRefGoogle Scholar
  31. 31.
    Ren Q, Kao V, Grem JL (1998) Cytotoxicity and DNA fragmentation associated with sequential gemcitabine and 5-fluoro-2′-deoxyuridine in HT-29 colon cancer cells. Clin Cancer Res 4:2811–2818PubMedGoogle Scholar
  32. 32.
    Rothenberg ML, Moore MJ, Cripps MC, Andersen JS, Portenoy RK, Burris HA III, Green MR, Tarassoff PG, Brown TD, Casper ES, Storniolo AM, Von Hoff DD (1996) A phase II trial of gemcitabine in patients with 5-FU-refractory pancreas cancer. Ann Oncol 7:347–353PubMedCrossRefGoogle Scholar
  33. 33.
    Heinemann V, Xu YZ, Chubb S, Sen A, Hertel LW, Grindey GB, Plunkett W (1990) Inhibition of ribonucleotide reduction in CCRF-CEM cells by 2′,2′-difluorodeoxycytidine. Mol Pharmocol 38:567–572Google Scholar
  34. 34.
    Madajewicz S, Hentschel P, Burns P, Caruso R, Fiore J, Fried M, Malhotra H, Ostrow S, Sugarman S, Viola M (2000) Phase I chemotherapy study of biochemical modulation of folinic acid and fluorouracil by gemcitabine in patients with solid tumor malignancies. J Clin Oncol 18:3553–3557PubMedGoogle Scholar
  35. 35.
    Pressacco J, Mirovski B, Erlichman C, Hedley DW (1995) Effects of thymidylate synthase inhibition on thymidine kinase activity and nucleoside transporter expression. Cancer Res 55:1505–1508PubMedGoogle Scholar
  36. 36.
    Nakahira S, Nakamori S, Tsujie M, Takeda S, Sugimoto K, Takahashi Y, Okami J, Marubashi S, Miyamoto A, Takeda Y, Nagano H, Dono K, Umeshita K, Sakon M, Monden M (2008) Pretreatment with S-1, an oral derivative of 5-fluorouracil, enhances gemcitabine effects in pancreatic cancer xenografts. Anticancer Res 28:179–186PubMedGoogle Scholar
  37. 37.
    Floyd FJ, Hornbeck CL, Byfield JE, Griffiths JC, Frankel SS (1982) Clearance of continuously infused 5-fluoraouracil in adults having lung or gastrointestinal carcinoma with or without hepatic metastases. Drug Intell Clin Pharm 16:665–667PubMedGoogle Scholar
  38. 38.
    Yoon DH, Lee HJ, Hong YS, Kim K, Lee SS, Lee JL, Chang HM, Ryu MH, Kang YK, Lee JS, Kim TW (2011) A phase I study of S-1 treatment with a 3 week schedule in advanced biliary cancer with or without hepatic dysfunction. Invest New Drugs 29:332–339PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Takeshi Takahara
    • 1
  • Hiroyuki Nitta
    • 1
  • Yasushi Hasegawa
    • 1
  • Naoko Itou
    • 1
  • Masahiro Takahashi
    • 1
  • Satoshi Nishizuka
    • 1
  • Go Wakabayashi
    • 1
  1. 1.Department of SurgeryIwate Medical University School of MedicineMoriokaJapan

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