A Study of Neoadjuvant Chemoradiotherapy With 5-FU/Leucovorin (FL) vs. TS-1/Irinotecan in Patients With Locally Advanced Rectal Cancer

This is an open-label, randomized phase II study. Patients will be randomly assigned to either FL or TS-1/irinotecan preoperative chemotherapy regimens by stratification. Patients in FL group will be treated with bolus injections of 5-FU 400 mg/m2/day and LV 20 mg/m2/day for 3 consecutive days every 4 weeks for 2 cycles, and patients in TS-1/irinotecan will be treated with irinotecan 40 mg/m2/day on days 1, 8, 15, 22, 29. TS-1 at a dose of 35mg/m2 was administered orally twice a day after a meal on the day of irradiation (Monday-Friday) concurrent with radiotherapy.

This is an open-label, randomized phase II study. Patients will be randomly assigned to either FL or TS-1/irinotecan preoperative chemotherapy regimens by stratification. Patients in FL group will be treated with bolus injections of 5-FU 400 mg/m2/day and LV 20 mg/m2/day for 3 consecutive days every 4 weeks for 2 cycles, and patients in TS-1/irinotecan will be treated with irinotecan 40 mg/m2/day on days 1, 8, 15, 22, 29. TS-1 at a dose of 35mg/m2 was administered orally twice a day after a meal on the day of irradiation (Monday-Friday) concurrent with radiotherapy. Total 45-50.4 Gy radiations in 25-28 fractions to tumor and draining lymph nodes will be delivered concurrently. Curative surgery (especially total mesorectal excision will be considered as 1st choice of surgical procedure) will be performed for about 4-8 weeks after the completion of chemoradiotherapy. Postoperative chemotherapy regimen is 5-FU plus leucovorin.

Eligibility Criteria:
Inclusion Criteria:

* Histologically confirmed adenocarcinoma of the rectum
* AJCC/UICC pathologic stages of cT3-4 or cN plus
* Male or female patients, 18 years of age or older
* Be ambulatory and have an Eastern Cooperative Oncology Group (ECOG) performance status 0-1.
* No prior chemotherapy, radiotherapy and immunotherapy
* Adequate major organ functions as following: Hematopoietic function: ANC (absolute neutrophil count)1,500/mm3, Platelet 100,000/mm3, and Hepatic function: serum bilirubin \< 1.5 x ULN, AST/ALT levels \< 2.5 x ULN, and Renal function: serum creatinine \< 1.5 x ULN or Ccr 50 ml/min by Cockcroft formula
* Be willing and able to comply with the protocol for the duration of the study.
* Give written informed consent prior to study-specific screening procedures, with the understanding that the patient has the right to withdraw from the study at any time, without prejudice.

Exclusion Criteria:

* Any histologic feature other than adenocarcinoma or arisen from chronic inflammatory bowel disease
* Patients treated with previous surgery, chemotherapy and/or radiotherapy
* Uncontrolled or severe cardiovascular disease: New York Heart Association class III or IV heart disease, and Unstable angina or myocardial infarction within the past 6 months, and History of significant ventricular arrhythmia requiring medication with antiarrhythmics or significant conduction system abnormality.
* Serious concurrent infection or nonmalignant illness that is uncontrolled or whose control may be jeopardized by complications of study therapy.
* Other malignancy within the past 5 years except non-melanomatous skin cancer or carcinoma in situ of the cervix.
* Organ allografts requiring immunosuppressive therapy.
* Psychiatric disorder or uncontrolled seizure that would preclude compliance.
* Pregnant, nursing women or patients with reproductive potential without contraception.
* Patients receiving a concomitant treatment with drugs interacting with 5-FU or irinotecan such as flucytosine, phenytoin, or warfarin et al.
* Prior unanticipated severe reaction to fluoropyrimidine therapy, or known dihydropyrimidine dehydrogenase (DPD) deficiency.
* Known hypersensitivity to any of the components of the study medications.
* Received any investigational drug or agent within 4 weeks before beginning treatment with study drug.