Safety and Efficacy of Oxaliplatin and Fluoropyrimidine Regimens With or Without Bevacizumab As First-Line Treatment of Metastatic Colorectal Cancer: Results of the TREE Study

To evaluate the safety and efficacy of three oxaliplatin and fluoropyrimidine regimens, with or without bevacizumab, as first-line treatment for metastatic colorectal cancer (CRC).Patients with histologically documented metastatic or recurrent CRC and no prior treatment for advanced disease were randomly assigned to mFOLFOX6 (bolus and infusion fluorouracil [FU] and leucovorin [LV] with oxaliplatin), bFOL (bolus FU and low-dose LV with oxaliplatin), or CapeOx (capecitabine with oxaliplatin), respectively (Three Regimens of Eloxatin Evaluation [TREE-1]). The study was later modified such that subsequent patients were randomized to the same regimens plus bevacizumab (TREE-2).A total of 150 and 223 patients were randomly assigned in the TREE-1 and TREE-2 cohorts, respectively. Incidence of grade 3/4 treatment-related adverse events during the first 12 weeks of treatment were 59%, 36%, and 67% for mFOLFOX6, bFOL, and CapeOx, respectively, (TREE-1) and 59%, 51%, and 56% for the corresponding treatments plus bevacizumab (TREE-2; primary end point). CapeOx toxicity in TREE-1 included grade 3/4 diarrhea (31%) and dehydration (27%); capecitabine dose reduction to 1,700 mg/m(2)/d in TREE-2 resulted in improved tolerance. Overall response rates were 41%, 20%, and 27% (TREE-1) and 52%, 39%, and 46% (TREE-2); median overall survival (OS) was 19.2, 17.9, and 17.2 months (TREE-1) and 26.1, 20.4, and 24.6 months (TREE-2). For all treated patients, median OS was 18.2 months (95% CI, 14.5 to 21.6; TREE-1) and 23.7 months (95% CI, 21.3 to 26.8; TREE-2).The addition of bevacizumab to oxaliplatin and fluoropyrimidine regimens is well tolerated as first-line treatment of mCRC and does not markedly change overall toxicity. CapeOx tolerability and efficacy is improved with reduced-dose capecitabine. First-line oxaliplatin and fluoropyrimidine-based therapy plus bevacizumab resulted in a median OS of approximately 2 years.