Phase I/II study of metronomic chemotherapy using S-1 and irinotecan in patients with advanced colorectal cancer (KSCOG CR-01)

Abstract

2535 Background: The antiangiogenic efficacy of chemotherapy would seem to be optimized by administering comparatively lower dosages of drugs on a more frequent (daily, several times a week, or weekly) or continuous schedule, with no extended interruptions, sometimes referred to as ‘metronomic’ chemotherapy. This phase I/II study determine the recommended dose (RD), the efficacy and safety of the metronomic chemotherapy using oral fluoropyrimidine S-1 plus weekly irinotecan (CPT-11) in patients with previously untreated advanced or recurrent colorectal cancer. Methods: Patients received first-line chemotherapy comprising S-1 80 mg/m(2)/day given on days 3 to 7, 10 to 14, and 17 to 21 with escalating doses of CPT-11 (from 40 mg/m(2)) administered intravenously on day 1, 8, and 15 of a 28-day cycle. Eligibility criteria were standard. Patients were assigned on the basis of body surface area (BSA) to receive one of the following oral doses of S-1 twice daily: 40 mg (BSA < 1.25 m(2)), 50 mg (BSA ≥ 1.25 to < 1.50 m(2)), or 60 mg (BSA ≥ 1.50 m(2)). The RD was defined as the dose at which ≥ 50% of six patients experienced a skip of CPT-11 or S-1 during cycle 1 within the MTD. Results: The 60 mg/m (2) dose level was established as the RD of CPT-11 and expanded to 45 patients in whom treatment was generally well tolerated with a 92% in CPT-11 and a 95% in S-1 as dose intensity. One patient had complete response, and 21 had partial responses. The overall response rate was 48.9% (95% confidential interval, 33.7%-64.2%). Median progression-free survival was 7.6 months. The rates of grade 3 or 4 toxicity were as follows: neutropenia, 8.9%; anemia, 4.4%; anorexia, 6.7%; and diarrhea, 4.4%. Conclusions: Metronomic chemotherapy using S-1 and irinotecan is an effective, less toxic, and convenient regimen in patients with advanced colorectal cancer. Our findings suggest that this metronomic chemotherapy is a promising regimen, offering benefits in terms of safety and survival as compared with conventional regimens in patients with advanced colorectal cancer. No significant financial relationships to disclose.