Study protocol of the SACURA trial: a randomized phase III trial of efficacy and safety of UFT as adjuvant chemotherapy for stage II colon cancer

Megumi Ishiguro, Hidetaka Mochizuki, Naohiro Tomita, Yasuhiro Shimada, Keiichi Takahashi, Kenjiro Kotake, Masahiko Watanabe, Yukihide Kanemitsu, Hideki Ueno, Toshiaki Ishikawa, Hiroyuki Uetake, Shigeyuki Matsui, Satoshi Teramukai, Kenichi Sugihara, Megumi Ishiguro, Hidetaka Mochizuki, Naohiro Tomita, Yasuhiro Shimada, Keiichi Takahashi, Kenjiro Kotake, Masahiko Watanabe, Yukihide Kanemitsu, Hideki Ueno, Toshiaki Ishikawa, Hiroyuki Uetake, Shigeyuki Matsui, Satoshi Teramukai, Kenichi Sugihara

Abstract

Background: Adjuvant chemotherapy for stage III colon cancer is internationally accepted as standard treatment with established efficacy, but the usefulness of adjuvant chemotherapy for stage II colon cancer remains controversial. The major Western guidelines recommend adjuvant chemotherapy for "high-risk stage II" cancer, but this is not clearly defined and the efficacy has not been confirmed.

Methods/design: SACURA trial is a multicenter randomized phase III study which aims to evaluate the superiority of 1-year adjuvant treatment with UFT to observation without any adjuvant treatment after surgery for stage II colon cancer in a large population, and to identify "high-risk factors of recurrence/death" in stage II colon cancer and predictors of efficacy and adverse events of the chemotherapy. Patients aged between 20 and 80 years with curatively resected stage II colon cancer are randomly assigned to a observation group or UFT adjuvant therapy group (UFT at 500-600 mg/day as tegafur in 2 divided doses after meals for 5 days, followed by 2-day rest. This 1-week treatment cycle is repeated for 1 year). The patients are followed up for 5 years until recurrence or death. Treatment delivery and adverse events are entered into a web-based case report form system every 3 months. The target sample size is 2,000 patients. The primary endpoint is disease-free survival, and the secondary endpoints are overall survival, recurrence-free survival, and incidence and severity of adverse events. In an additional translational study, the mRNA expression of 5-FU-related enzymes, microsatellite instability and chromosomal instability, and histopathological factors including tumor budding are assessed to evaluate correlation with recurrences, survivals and adverse events.

Discussion: A total of 2,024 patients were enrolled from October 2006 to July 2010. The results of this study will provide important information that help to improve the therapeutic strategy for stage II colon cancer.

Trial registration: ClinicalTrials.gov NCT00392899.

Figures

Figure 1
Figure 1
Study schema.
Figure 2
Figure 2
Observation, examination, and report schedule.
Figure 3
Figure 3
Items included in additional translational study.

References

    1. Cancer statistics in Japan. , ; 2010. .
    1. Mamounas E, Wieand S, Wolmark N, Bear HD, Atkins JN, Song K, Jones J, Rockette H. Comparative efficacy of adjuvant chemotherapy in patients with Dukes' B versus Dukes' C colon cancer: results from four National Surgical Adjuvant Breast and Bowel Project adjuvant studies (C-01, C-02, C-03, and C-04) J Clin Oncol. 1999;17:1349–1355.
    1. Efficacy of adjuvant fluorouracil and folinic acid in colon cancer: International Multicentre Pooled Analysis of Colon Cancer Trials (IMPACT) investigators. Lancet. 1995;345:939–944.
    1. Schrag D, Rifas-Shiman S, Saltz L, Bach PB, Begg CB. Adjuvant chemotherapy use for Medicare beneficiaries with stage II colon cancer. J Clin Oncol. 2002;20:3999–4005.
    1. Sakamoto J, Ohashi Y, Hamada C, Buyse M, Burzykowski T, Piedbois P. Efficacy of oral adjuvant therapy after resection of colorectal cancer: 5-year results from three randomized trials. J Clin Oncol. 2004;22:484–492.
    1. Kato T, Ohashi Y, Nakazato H, Koike A, Saji S, Suzuki H, Takagi H, Nimura Y, Hasumi A, Baba S, Manabe T, Maruta M, Miura K, Yamaguchi A. Efficacy of oral UFT as adjuvant chemotherapy to curative resection of colorectal cancer: multicenter prospective randomized trial. Langenbecks Arch Surg. 2002;386:575–581.
    1. Hamaguchi T, Shirao K, Moriya Y, Yoshida S, Kodaira S, Ohashi Y. Final results of randomized trials by the National Surgical Adjuvant Study of Colorectal Cancer (NSAS-CC) Cancer Chemother Pharmacol. 2011;67:587–596.
    1. Sadahiro S, Ohki S, Yamaguchi S, Takahashi T, Otani Y, Tsukikawa S, Yamamura T, Takemiya S, Nagasaki H, Nishiyama K, Fukushima T, Hiki Y, Yamaguchi S, Kumada K, Shimada H, Mitomi T, Makuuchi H. Feasibility of a novel weekday-on/weekend-off oral UFT schedule as postoperative adjuvant chemotherapy for colorectal cancer. Cancer Chemother Pharmacol. 2000;46:180–184.
    1. Higuchi T, Sugihara K. Complete mesocolic excision (CME) with central vascular ligation (CVL) as standardized surgical technique for colonic cancer: a Japanese multicentre study [abstract] Dis Colon Rectum. 2010;53:176.
    1. Sobin LH, Gospodarowicz MK, Wittekind C. TNM Classification of Malignant Tumours. 7. Wiley-Blackwell, New York; 2009.
    1. Colon cancer version 2. , ; 2012. .
    1. Benson AB, Schrag D, Somerfield MR, Cohen AM, Figueredo AT, Flynn PJ, Krzyzanowska MK, Maroun J, McAllister P, Van Cutsem E, Brouwers M, Charette M, Haller DG. American Society of Clinical Oncology recommendations on adjuvant chemotherapy for stage II colon cancer. J Clin Oncol. 2004;22:3408–3419.
    1. Van Cutsem E, Oliveira J. Colon cancer: ESMO clinical recommendations for diagnosis, adjuvant treatment and follow-up. Ann Oncol. 2008;19(Suppl 2):ii29–ii30.
    1. Pocock SJ, Simon R. Sequential treatment assignment with balancing for prognostic factors in the controlled clinical trial. Biometrics. 1975;31:103–115.
    1. Watanabe M, Nishida O, Kunii Y, Kodaira S, Takahashi T, Tominaga T, Hojyo K, Kato T, Niimoto M, Kunitomo K, Isomoto H, Ohashi Y, Yasutomi M. Randomized controlled trial of the efficacy of adjuvant immunochemotherapy and adjuvant chemotherapy for colorectal cancer, using different combinations of the intracutaneous streptococcal preparation OK-432 and the oral pyrimidines 1-hexylcarbamoyl-5-fluorouracil and uracil/tegafur. Int J Clin Oncol. 2004;9:98–106.
    1. Schoenfeld DA, Richter JR. Nomograms for calculating the number of patients needed for a clinical trial with survival as an endpoint. Biometrics. 1982;38:163–170.
    1. JSCCR Guidelines 2010 for the Treatment of Colorectal Cancer. Kanehara & Co., Ltd, Tokyo; 2010.
    1. West NP, Hohenberger W, Weber K, Perrakis A, Finan PJ, Quirke P. Complete mesocolic excision with central vascular ligation produces an oncologically superior specimen compared with standard surgery for carcinoma of the colon. J Clin Oncol. 2010;28:272–278.
    1. West NP, Kobayashi H, Takahashi K, Perrakis A, Weber K, Hohenberger W, Sugihara K, Quirke P. Understanding optimal colonic cancer surgery. Comparison of Japanese D3 resection and European complete excision with central vascular ligation. J Clin Oncol. 2012;30:1763–1769.
    1. Ueno H, Murphy J, Jass JR, Mochizuki H, Talbot IC. Tumour 'budding' as an index to estimate the potential of aggressiveness in rectal cancer. Histopathology. 2002;40:127–132.
    1. Ueno H, Mochizuki H, Hashiguchi Y, Ishiguro M, Kajiwara Y, Sato T, Shimazaki H, Hase K, Talbot IC. Histological grading of colorectal cancer: a simple and objective method. Ann Surg. 2008;247:811–818.
    1. Graham DM, Appelman HD. Crohn's-like lymphoid reaction and colorectal carcinoma: a potential histologic prognosticator. Mod Pathol. 1990;3:332–335.
    1. Ueno H, Jones AM, Wilkinson KH, Jass JR, Talbot IC. Histological categorisation of fibrotic cancer stroma in advanced rectal cancer. Gut. 2004;53:581–586.
    1. Des Guetz G, Schischmanoff O, Nicolas P, Perret GY, Morere JF, Uzzan B. Does microsatellite instability predict the efficacy of adjuvant chemotherapy in colorectal cancer? A systematic review with meta-analysis. Eur J Cancer. 2009;45:1890–1896.
    1. Sargent DJ, Marsoni S, Monges G, Thibodeau SN, Labianca R, Hamilton SR, French AJ, Kabat B, Foster NR, Torri V, Ribic C, Grothey A, Moore M, Zaniboni A, Seitz JF, Sinicrope F, Gallinger S. Defective mismatch repair as a predictive marker for lack of efficacy of fluorouracil-based adjuvant therapy in colon cancer. J Clin Oncol. 2010;28:3219–3226.
    1. de la Chapelle A. Microsatellite instability. N Engl J Med. 2003;349:209–210.
    1. Walther A, Johnstone E, Swanton C, Midgley R, Tomlinson I, Kerr D. Genetic prognostic and predictive markers in colorectal cancer. Nat Rev Cancer. 2009;9:489–499.
    1. Van Cutsem E, Labianca R, Bodoky G, Barone C, Aranda E, Nordlinger B, Topham C, Tabernero J, Andre T, Sobrero AF, Mini E, Greil R, Di Costanzo F, Collette L, Cisar L, Zhang X, Khayat D, Bokemeyer C, Roth AD, Cunningham D. Randomized phase III trial comparing biweekly infusional fluorouracil/leucovorin alone or with irinotecan in the adjuvant treatment of stage III colon cancer: PETACC-3. J Clin Oncol. 2009;27:3117–3125.
    1. Koizumi W, Tanabe S, Azuma M, Ishido K, Nishimura K, Sasaki T, Nakatani K, Higuchi K, Nakayama N, Katada C. Impacts of fluorouracil-metabolizing enzymes on the outcomes of patients treated with S-1 alone or S-1 plus cisplatin for first-line treatment of advanced gastric cancer. Int J Cancer. 2010;126:162–170.
    1. Ichikawa W, Takahashi T, Suto K, Yamashita T, Nihei Z, Shirota Y, Shimizu M, Sasaki Y, Hirayama R. Thymidylate synthase predictive power is overcome by irinotecan combination therapy with S-1 for gastric cancer. Br J Cancer. 2004;91:1245–1250.

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