Objectives: This phase II study was designed to evaluate the efficacy and safety of oral fluoropyrimidine S-1 plus irinotecan (IRIS regimen) in patients with previously untreated metastatic colorectal cancer. Methods: The response rate was the primary endpoint. Safety, progression-free survival time, and median survival time were secondary endpoints. The subjects were untreated patients with inoperable advanced colorectal cancer. Irinotecan was administered at a dose of 100 mg/m2 (on days 1 and 15). S-1 (40 mg/m2) was administered for 2 weeks (on days 1 to 14) and followed by a 2-week rest. Results: Forty patients were enrolled. Four patients had grade 4 neutropenia, and six patients had grade 3 diarrhea. No other serious hematologic or nonhematologic adverse reactions occurred, and all patients received IRIS safely on an outpatient basis. The response rate was 52.5% (95% confidence interval [CI], 36.1–68.5%). Median progression-free survival was 8.6 months (95% CI, 5.3–11.9), and median survival time was 23.4 months (95% CI, 15.9–30.8). Conclusions: IRIS produced a high response rate and could be given safely. IRIS may become a first-line treatment for inoperable or recurrent advanced colorectal cancer.

Keywords:
Irinotecan, Phase II study, Colorectal cancer, S-1
1.
Foundation for Promotion of Cancer Research: Cancer Statistics in Japan 2009. http://ganjoho.jp/public/statistics/backnumber/2009_en.html. Accessed 1 October 2010.
2.
Tournigand C, Andre T, Achille E, Lledo G, Flesh M, Mery-Mignard D, Quinaux E, Couteau C, Buyse M, Ganem G, Landi B, Colin P, Louvet C, de Gramont A: FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol 2004;22:229–237.
3.
Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J, Baron A, Griffing S, Holmgren E, Ferrara N, Fyfe G, Rogers B, Ross R, Kabbinavar F: Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004;350:2335–2342.
4.
Saltz LB, Clarke S, Diaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Lichinitser M, Yang TS, Rivera F, Couture F, Sirzen F, Cassidy J: Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol 2008;26:2013–2019.
5.
Van Cutsem E, Kohne CH, Hitre E, Zaluski J, Chang Chien CR, Makhson A, D’Haens G, Pinter T, Lim R, Bodoky G, Roh JK, Folprecht G, Ruff P, Stroh C, Tejpar S, Schlichting M, Nippgen J, Rougier P: Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med 2009;360:1408–1417.
6.
Cassidy J, Clarke S, Diaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Lichinitser M, Yang TS, Rivera F, Couture F, Sirzen F, Saltz L: 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;26:2006–2012.
7.
Shirasaka T, Shimamato Y, Ohshimo H, Yamaguchi M, Kato T, Yonekura K, Fukushima M: 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 1996;7:548–557.
8.
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: Adjuvant chemotherapy for gastric cancer with S-1, an oral fluoropyrimidine. N Engl J Med 2007;357:1810–1820.
9.
Koizumi W, Narahara H, Hara T, Takagane A, Akiya T, Takagi M, Miyashita K, Nishizaki T, Kobayashi O, Takiyama W, Toh Y, Nagaie T, Takagi S, Yamamura Y, Yanaoka K, Orita H, Takeuchi M: S-1 plus cisplatin versus S-1 alone for first-line treatment of advanced gastric cancer (SPIRITS trial): a phase III trial. Lancet Oncol 2008;9:215–221.
10.
Ohtsu A, Baba H, Sakata Y, Mitachi Y, Horikoshi N, Sugimachi K, Taguchi T: Phase II study of S-1, a novel oral fluorophyrimidine derivative, in patients with metastatic colorectal carcinoma. S-1 Cooperative Colorectal Carcinoma Study Group. Br J Cancer 2000;83:141–145.
11.
Shirao K, Ohtsu A, Takada H, Mitachi Y, Hirakawa K, Horikoshi N, Okamura T, Hirata K, Saitoh S, Isomoto H, Satoh A: Phase II study of oral S-1 for treatment of metastatic colorectal carcinoma. Cancer 2004;100:2355–2361.
12.
Komatsu Y, Yuki S, Fuse N, Kato T, Miyagishima T, Kudo M, Kunieda Y, Tateyama M, Wakahama O, Meguro T, Sakata Y, Asaka M: Phase 1/2 clinical study of irinotecan and oral S-1 (IRIS) in patients with advanced gastric cancer. Adv Ther 2010;27:483–492.
13.
Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG: 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;92:205–216.
14.
Yuuki S, Komatsu Y, Fuse N, Kato T, Miyagishima T, Kudo M, Watanabe M, Tateyama M, Kunieda Y, Wakahama O, Sakata Y, Asaka M: Modified-irinotecan/fluorouracil/levoleucovorin therapy as ambulatory treatment for metastatic colorectal cancer: results of phase I and II studies. Clin Drug Investig 2010;30:243–249.
15.
Saltz LB, Cox JV, Blanke C, Rosen LS, Fehrenbacher L, Moore MJ, Maroun JA, Ackland SP, Locker PK, Pirotta N, Elfring GL, Miller LL: Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group. N Engl J Med 2000;343:905–914.
16.
Borner MM, Schoffski P, de Wit R, Caponigro F, Comella G, Sulkes A, Greim G, Peters GJ, van der Born K, Wanders J, de Boer RF, Martin C, Fumoleau P: Patient preference and pharmacokinetics of oral modulated UFT versus intravenous fluorouracil and leucovorin: a randomised crossover trial in advanced colorectal cancer. Eur J Cancer 2002;38:349–358.
17.
Fuchs CS, Marshall J, Mitchell E, Wierzbicki R, Ganju V, Jeffery M, Schulz J, Richards D, Soufi-Mahjoubi R, Wang B, Barrueco J: Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: results from the BICC-C Study. J Clin Oncol 2007;25:4779–4786.
18.
Muro K, Boku N, Shimada Y, Tsuji A, Sameshima S, Baba H, Satoh T, Denda T, Ina K, Nishina T, Yamaguchi K, Takiuchi H, Esaki T, Tokunaga S, Kuwano H, Komatsu Y, Watanabe M, Hyodo I, Morita S, Sugihara K: Irinotecan plus S-1 (IRIS) versus fluorouracil and folinic acid plus irinotecan (FOLFIRI) as second-line chemotherapy for metastatic colorectal cancer: a randomised phase 2/3 non-inferiority study (FIRIS study). Lancet Oncol 2010;11:853–860.
19.
Goto A, Yamada Y, Yasui H, Kato K, Hamaguchi T, Muro K, Shimada Y, Shirao K: Phase II study of combination therapy with S-1 and irinotecan in patients with advanced colorectal cancer. Ann Oncol 2006;17:968–973.
20.
Tsunoda A, Yasuda N, Nakao K, Narita K, Watanabe M, Matsui N, Kusano M: Phase II study of S-1 combined with irinotecan (CPT-11) in patients with advanced colorectal cancer. Oncology 2009;77:192–196.
21.
Yoshioka T, Kato S, Gamoh M, Chiba N, Suzuki T, Sakayori N, Shibata H, Shimodaira H, Otsuka K, Kakudo Y, Takahashi S, Ishioka C: Phase I/II study of sequential therapy with irinotecan and S-1 for metastatic colorectal cancer. Br J Cancer 2009;101:1972–1977.
22.
Shiozawa M, Akaike M, Sugano N, Tsuchida K, Yamamoto N, Morinaga S: A phase II study of combination therapy with irinotecan and S-1 (IRIS) in patients with advanced colorectal cancer. Cancer Chemother Pharmacol 2010;66:987–992.
23.
Kohne CH, De Greve J, Hartmann JT, Lang I, Vergauwe P, Becker K, Braumann D, Joosens E, Muller L, Janssens J, Bokemeyer C, Reimer P, Link H, Spath-Schwalbe E, Wilke HJ, Bleiberg H, Van Den Brande J, Debois M, Bethe U, Van Cutsem E: Irinotecan combined with infusional 5-fluorouracil/folinic acid or capecitabine plus celecoxib or placebo in the first-line treatment of patients with metastatic colorectal cancer. EORTC study 40015. Ann Oncol 2008;19:920–926.
24.
Seymour MT, Maughan TS, Ledermann JA, Topham C, James R, Gwyther SJ, Smith DB, Shepherd S, Maraveyas A, Ferry DR, Meade AM, Thompson L, Griffiths GO, Parmar MK, Stephens RJ: Different strategies of sequential and combination chemotherapy for patients with poor prognosis advanced colorectal cancer (MRC FOCUS): a randomised controlled trial. Lancet 2007;370:143–152.
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2011
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