Chemical catalogs abine was administered at a dose of 1,000 mg/m2 orally twice daily for 14 days. Capecitabine dose was reduced to 750 mg/m2 for patients over 65 years of age. Irinotecan was given at a dose of 200 mg/m2 intravenously on day 1. Bevacizumab was given at 7.5 mg/kg IV on day 1. The treatment cycle was repeated every 21 days. Dose modiWcations for capecitabine For grade 3 hematologic and non hematologic toxicities, the capecitabine dose was decreased by 25% from baseline on the Wrst occurrence, 50% from baseline on the 2nd occurrence, and capecitabine was permanently discontinued if it occurred a third time. For grade 4 hematologic and non hematologic toxicities, the dose was decreased by 50% from baseline on the Wrst occurrence and permanently stopped on the second occurrence. Dose modiWcations for irinotecan For grade 3 hematologic and non hematologic Clopidogrel toxicities, the irinotecan dose was decreased by 25 mg/m2 from baseline on the Wrst occurrence, 50 mg/m2 from baseline on the 2nd occurrence, and irinotecan was permanently discontinued if it occurred a third time.
For grade 4 hematologic and non hematologic toxicities, the dose was decreased by 50 mg/m2 from baseline on the Wrst occurrence and permanently stopped on the second occurrence. Capecitabine dose modiWcations for bevacizumab For the following events, bevacizumab was to be discontinued permanently: gastrointestinal perforation, arterial thromboembolic events, grade 3 or 4 hemorrhagic events, symptomatic grade 4 venous thromboembolic events, grade 4 hypertension, and grade 4 proteinuria. For grade 2 or 3 hypertension, bevacizumab was held until it improved to grade 1. For grade 3 and asymptomatic grade 4 venous thrombosis, bevacizumab was held for 2 weeks. Treatment of diarrhea The protocol recommended that patients with severe diarrhea be closely monitored and given electrolyte and Xuid replacement as medically indicated. Anti Phospholipases diarrheal treatments were recommendedto be promptly initiated as medically indicated. The use of subcutaneous octreotide was recommended for refractory chemotherapy induced diarrhea when hospitalization was required.
Study assessments Baseline radiological investigations were done within 28 days prior to study treatment. Radiological assessments for tumor measurements were conducted after every third cycle. Tumor responses were assessed by radiologists independent of study investigators. Study treatment continued until unacceptable toxicity, patient request, or progression. Statistical considerations The primary objective of this study was to determine the progression free survival of irinotecan, modiWed, and bevacizumab in patients with previously untreated mCRC. Secondary endpoints included overall survival, response rate, time to progression, and toxicity. In the study by Hurwitz et al., the median PFS was 6.2 months for patients treated with irinotecan and 5 FU, and 10.6 months for patients treated with irinotecan, 5 FU, and bevacizumab. In this study, PFS was estimated with the Kaplan Meier method and a 95% conWdence interval for the median PFS was constructed. The combination of irinotecan, capecitabine, and bevacizumab would be considered to be of interest if the lower bound of the 95% conWdence interval for the median PFS was 6.2 months. Since the Kaplan Meier meth.