Cancer Chemotherapy and Pharmacology

, Volume 73, Issue 2, pp 389–396 | Cite as

Randomized controlled study of gemcitabine plus S-1 combination chemotherapy versus gemcitabine for unresectable pancreatic cancer

  • Kentaro Sudo
  • Takeshi Ishihara
  • Nobuto Hirata
  • Fumiaki Ozawa
  • Tadashi Ohshima
  • Ryosaku Azemoto
  • Kenji Shimura
  • Takeshi Nihei
  • Takayoshi Nishino
  • Akihiko Nakagawa
  • Kazuyoshi Nakamura
  • Taro Hara
  • Motohisa Tada
  • Rintaro Mikata
  • Katsunobu Tawada
  • Osamu Yokosuka
  • So Nakaji
  • Taketo Yamaguchi
Original Article

Abstract

Purpose

The aim of this study was to evaluate efficacy and safety of gemcitabine plus S-1 (GS) combination chemotherapy in patients with unresectable pancreatic cancer.

Methods

Patients were randomly assigned to receive GS (oral S-1 60 mg/m2 daily on days 1–15 every 3 weeks and gemcitabine 1,000 mg/m2 on days 8 and 15) or gemcitabine (1,000 mg/m2 on days 1, 8, and 15 every 4 weeks). The primary endpoint was progression-free survival (PFS).

Results

One hundred and one patients were randomly assigned. PFS was significantly longer in the GS arm with an estimated hazard ratio (HR) of 0.65 (95 % CI 0.430.98; P = 0.039; median 5.3 vs 3.8 months). Objective response rate (ORR) was also better in the GS arm (21.6 vs 6 %, P = 0.048). Median survival was 8.6 months for GS and 8.6 months for GEM (HR 0.93; 95 % CI 0.611.41; P = 0.714). Grade 3–4 neutropenia (44 vs 19.6 %, P = 0.011) and thrombocytopenia (26 vs 8.7 %, P = 0.051) were more frequent in the GS arm.

Conclusions

GS therapy improved PFS and ORR with acceptable toxicity profile in patients with unresectable pancreatic cancer.

Keywords

Pancreatic cancer S-1 Gemcitabine Randomized controlled study 

Notes

Acknowledgments

This study was performed according to the guidelines of the Declaration of Helsinki. The protocol was approved by the institutional review board of participating institutions. Written informed consent was obtained from all patients before their inclusion into the study. This manuscript has not been published and is not under consideration for publication elsewhere.

Conflict of interest

No financial support for this study was provided. The authors report no conflict of interest.

References

  1. 1.
    Burris HA III, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, Cripps MC, Portenoy RK, Storniolo AM, Tarassoff P, Nelson R, Dorr FA, Stephens CD, Von Hoff DD (1997) Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol 15:2403–2413PubMedGoogle Scholar
  2. 2.
    Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, Au HJ, Murawa P, Walde D, Wolff RA, Campos D, Lim R, Ding K, Clark G, Voskoglou-Nomikos T, Ptasynski M, Parulekar W (2007) Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 25:1960–1966PubMedCrossRefGoogle Scholar
  3. 3.
    Conroy T, Desseigne F, Ychou M, Bouche O, Guimbaud R, Becouarn Y, Adenis A, Raoul JL, Gourgou-Bourgade S, de la Fouchardiere C, Bennouna J, Bachet JB, Khemissa-Akouz F, Pere-Verge D, Delbaldo C, Assenat E, Chauffert B, Michel P, Montoto-Grillot C, Ducreux M (2011) FOLFIRINOX vs gemcitabine for metastatic pancreatic cancer. N Engl J Med 364:1817–1825PubMedCrossRefGoogle Scholar
  4. 4.
    Shirasaka T, Shimamato Y, Ohshimo H, Yamaguchi M, Kato T, Yonekura K, Fukushima M (1996) Development of a novel form of an oral 5-fluorouracil derivative (S-1) directed to the potentiation of the tumor selective cytotoxicity of 5-fluorouracil by two biochemical modulators. Anticancer Drugs 7:548–557PubMedCrossRefGoogle Scholar
  5. 5.
    Tatsumi K, Fukushima M, Shirasaka T, Fujii S (1987) Inhibitory effects of pyrimidine, barbituric acid and pyridine derivatives on 5-fluorouracil degradation in rat liver extracts. Jpn J Cancer Res 78:748–755PubMedGoogle Scholar
  6. 6.
    Shirasaka T, Shimamoto Y, Fukushima M (1993) Inhibition by oxonic acid of gastrointestinal toxicity of 5-fluorouracil without loss of its antitumor activity in rats. Cancer Res 53:4004–4009PubMedGoogle Scholar
  7. 7.
    Okusaka T, Funakoshi A, Furuse J, Boku N, Yamao K, Ohkawa S, Saito H (2008) A late phase II study of S-1 for metastatic pancreatic cancer. Cancer Chemother Pharmacol 61:615–621PubMedCrossRefGoogle Scholar
  8. 8.
    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
  9. 9.
    Sudo K, Yamaguchi T, Nakamura K, Denda T, Hara T, Ishihara T, Yokosuka O (2011) Phase II study of S-1 in patients with gemcitabine-resistant advanced pancreatic cancer. Cancer Chemother Pharmacol 67:249–254PubMedCrossRefGoogle Scholar
  10. 10.
    Sudo K, Yamaguchi T, Ishihara T, Nakamura K, Hara T, Denda T, Tawada K, Imagumbai T, Araki H, Sakai M, Hatano K, Kawakami H, Uno T, Ito H, Yokosuka O (2011) Phase II study of oral S-1 and concurrent radiotherapy in patients with unresectable locally advanced pancreatic cancer. Int J Radiat Oncol Biol Phys 80:119–125PubMedCrossRefGoogle Scholar
  11. 11.
    Uesaka K, Fukutomi A, Boku N, Kanemoto H, Konishi M, Matsumoto I, Kaneoka Y, Shimizu Y, Nakamori S, Sakamoto H, Morinaga S, Kainuma O, Imai K, Sata N, Hishinuma S, Nakamura T, Kanai M, Hirano S, Yoshikawa Y, Ohashi Y (2012) Randomized phase III trial of adjuvant chemotherapy with gemcitabine versus S-1 for patients with resected pancreatic cancer (JASPAC-01 study). J Clin Oncol 30 (Suppl; abstr 145)Google Scholar
  12. 12.
    Nakamura K, Yamaguchi T, Ishihara T, Kobayashi A, Tadenuma H, Sudo K, Kato H, Saisho H (2005) Phase I trial of oral S-1 combined with gemcitabine in metastatic pancreatic cancer. Br J Cancer 92:2134–2139PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    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 94:1575–1579PubMedCentralPubMedGoogle Scholar
  14. 14.
    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
  15. 15.
    Ozaka M, Matsumura Y, Ishii H, Omuro Y, Itoi T, Mouri H, Hanada K, Kimura Y, Maetani I, Okabe Y, Tani M, Ikeda T, Hijioka S, Watanabe R, Ohoka S, Hirose Y, Suyama M, Egawa N, Sofuni A, Ikari T, Nakajima T (2012) Randomized phase II study of gemcitabine and S-1 combination versus gemcitabine alone in the treatment of unresectable advanced pancreatic cancer (Japan Clinical Cancer Research Organization PC-01 study). Cancer Chemother Pharmacol 69:1197–1204PubMedCrossRefGoogle Scholar
  16. 16.
    Ueno H, Ioka T, Ikeda M, Ohkawa S, Yanagimoto H, Boku N, Fukutomi A, Sugimori K, Baba H, Yamao K, Shimamura T, Sho M, Kitano M, Cheng AL, Mizumoto K, Chen JS, Furuse J, Funakoshi A, Hatori T, Yamaguchi T, Egawa S, Sato A, Ohashi Y, Okusaka T, Tanaka M (2013) Randomized phase III study of gemcitabine plus S-1, S-1 alone, or gemcitabine alone in patients with locally advanced and metastatic pancreatic cancer in Japan and Taiwan: GEST study. J Clin Oncol 31:1640–1648PubMedCrossRefGoogle Scholar
  17. 17.
    Nakai Y, Isayama H, Sasaki T, Sasahira N, Tsujino T, Toda N, Kogure H, Matsubara S, Ito Y, Togawa O, Arizumi T, Hirano K, Tada M, Omata M, Koike K (2012) A multicenter randomized phase II trial of gemcitabine alone vs gemcitabine and S-1 combination therapy in advanced pancreatic cancer: GEMSAP study. Br J Cancer 106:1934–1939PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Rauchwerger DR, Firby PS, Hedley DW, Moore MJ (2000) Equilibrative-sensitive nucleoside transporter and its role in gemcitabine sensitivity. Cancer Res 60:6075–6079PubMedGoogle Scholar
  19. 19.
    Lee GW, Kim HJ, Ju JH, Kim SH, Kim HG, Kim TH, Kim HJ, Jeong CY, Kang JH (2009) Phase II trial of S-1 in combination with gemcitabine for chemo-naïve patients with locally advanced or metastatic pancreatic cancer. Cancer Chemother Pharmacol 64:707–713PubMedCrossRefGoogle Scholar
  20. 20.
    Ueno H, Okusaka T, Furuse J, Yamao K, Funakoshi A, Boku N, Ohkawa S, Yokosuka O, Tanaka K, Moriyasu F, Nakamori S, Sato T (2011) Multicenter phase II study of gemcitabine and S-1 combination therapy (GS therapy) in patients with metastatic pancreatic cancer. Jpn J Clin Oncol 41:953–958PubMedCrossRefGoogle Scholar
  21. 21.
    Satouchi M, Kotani Y, Katakami N, Shimada T, Urata Y, Yoshimura S, Funada Y, Hata A, Ando M, Negoro S (2010) Randomized phase II study of two different schedules of gemcitabine and oral S-1 in chemo-naïve patients with advanced non-small cell lung cancer. J Thorac Oncol 5:696–701PubMedGoogle Scholar
  22. 22.
    Colucci G, Giuliani F, Gebbia V, Biglietto M, Rabitti P, Uomo G, Cigolari S, Testa A, Maiello E, Lopez M (2002) Gemcitabine alone or with cisplatin for the treatment of patients with locally advanced and/or metastatic pancreatic carcinoma: a prospective, randomized phase III study of the Gruppo Oncologia dell’Italia Meridionale. Cancer 94:902–910PubMedCrossRefGoogle Scholar
  23. 23.
    Reni M, Cordio S, Milandri C, Passoni P, Bonetto E, Oliani C, Luppi G, Nicoletti R, Galli L, Bordonaro R, Passardi A, Zerbi A, Balzano G, Aldrighetti L, Staudacher C, Villa E, Di Carlo V (2005) Gemcitabine versus cisplatin, epirubicin, fluorouracil, and gemcitabine in advanced pancreatic cancer: a randomized controlled multicenter phase III trial. Lancet Oncol 6:369–376PubMedCrossRefGoogle Scholar
  24. 24.
    Berlin JD, Catalano P, Thomas JP, Kugler JW, Haller DG, Benson AB 3rd (2002) Phase III study of gemcitabine in combination with fluorouracil versus gemcitabine alone in patients with advanced pancreatic carcinoma: Eastern Cooperative Oncology Group trial E2297. J Clin Oncol 20:3270–3275PubMedCrossRefGoogle Scholar
  25. 25.
    Herrmann R, Bodoky G, Ruhstaller T, Glimelius B, Bajetta E, Schüller J, Saletti P, Bauer J, Figer A, Pestalozzi B, Köhne CH, Mingrone W, Stemmer SM, Tàmas K, Kornek GV, Koeberle D, Cina S, Bernhard J, Dietrich D, Scheithauer W, Swiss Group for Clinical Cancer Research, Central European Cooperative Oncology Group (2007) Gemcitabine plus capecitabine compared with gemcitabine alone in advanced pancreatic cancer: a randomized, multicenter, phase III trial of the Swiss Group for Clinical Cancer Research and the Central European Cooperative Oncology Group. J Clin Oncol 2007(25):2212–2217CrossRefGoogle Scholar
  26. 26.
    Cunningham D, Chau I, Stocken DD, Valle JW, Smith D, Steward W, Harper PG, Dunn J, Tudur-Smith C, West J, Falk S, Crellin A, Adab F, Thompson J, Leonard P, Ostrowski J, Eatock M, Scheithauer W, Herrmann R, Neoptolemos JP (2009) Phase III randomized comparison of gemcitabine versus gemcitabine plus capecitabine in patients with advanced pancreatic cancer. J Clin Oncol 27:5513–5518PubMedCrossRefGoogle Scholar
  27. 27.
    Von Hoff DD, Ervin TJ, Arena FP, Chiorean EG, Infante JR, Moore MJ, Seay TE, Tjulandin S, Ma WW, Saleh MN, Harris M, Reni M, Ramanathan RK, Tabernero J, Hidalgo M, Cutsem EV, Goldstein D, Wei X, Iglesias JL, Renschler MF (2012) Randomized phase III study of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone in patients with metastatic adenocarcinoma of the pancreas (MPACT). J clin Oncol 30(suppl; abstr LBA148)Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Kentaro Sudo
    • 1
  • Takeshi Ishihara
    • 2
  • Nobuto Hirata
    • 3
  • Fumiaki Ozawa
    • 4
  • Tadashi Ohshima
    • 5
  • Ryosaku Azemoto
    • 6
  • Kenji Shimura
    • 7
  • Takeshi Nihei
    • 8
  • Takayoshi Nishino
    • 9
  • Akihiko Nakagawa
    • 10
  • Kazuyoshi Nakamura
    • 1
  • Taro Hara
    • 1
  • Motohisa Tada
    • 2
  • Rintaro Mikata
    • 2
  • Katsunobu Tawada
    • 2
  • Osamu Yokosuka
    • 2
  • So Nakaji
    • 3
  • Taketo Yamaguchi
    • 1
  1. 1.Department of GastroenterologyChiba Cancer CenterChuo-ku, ChibaJapan
  2. 2.Department of Gastroenterology and Nephrology, Graduate School of MedicineChiba UniversityChibaJapan
  3. 3.Department of GastroenterologyKameda Medical CenterKamogawaJapan
  4. 4.Department of Hepato-biliary-pancreatic Surgery, Saitama Medical CenterSaitama Medical UniversityKawagoeJapan
  5. 5.Department of GastroenterologySaitama Red Cross HospitalSaitamaJapan
  6. 6.Department of GastroenterologyKimitsu Chuo HospitalKisarazuJapan
  7. 7.Department of GastroenterologyAsahi General HospitalAsahiJapan
  8. 8.Department of Internal MedicineMito Saiseikai General HospitalMitoJapan
  9. 9.Department of GastroenterologyTokyo Women’s Medical University Yachiyo Medical CenterYachiyoJapan
  10. 10.Department of GastroenterologyNumazu City HospitalNumazuJapan

Personalised recommendations