Andrea Bonetti

Primary Tumor Response to Preoperative Chemoradiation With or Without Oxaliplatin in Locally Advanced Rectal Cancer: Pathologic Results of the STAR-01 Randomized Phase III Trial

PURPOSE To investigate oxaliplatin combined with fluorouracil-based chemoradiotherapy as preoperative treatment for locally advanced rectal cancer. PATIENTS AND METHODS Seven hundred forty-seven patients with resectable, locally advanced (cT3-4 and/or cN1-2) adenocarcinoma of the mid-low rectum were randomly assigned to receive pelvic radiation (50.4 Gy in 28 daily fractions) and concomitant infused fluorouracil (225 mg/m(2)/d) either alone (arm A, n = 379) or combined with oxaliplatin (60 mg/m(2) weekly × 6; arm B, n = 368). Overall survival is the primary end point. A protocol-planned analysis of response to preoperative treatment is reported here. RESULTS Grade 3 to 4 adverse events during preoperative treatment were more frequent with oxaliplatin plus fluorouracil and radiation than with radiation and fluorouracil alone (24% v 8% of treated patients; P < .001). In arm B, 83% of the patients treated with oxaliplatin had five or more weekly administrations. Ninety-one percent, compared with 97% in the control arm, received ≥ 45 Gy (P < .001). Ninety-six percent versus 95% of patients underwent surgery with similar rates of abdominoperineal resections (20% v 18%, arm A v arm B). The rate of pathologic complete responses was 16% in both arms (odds ratio = 0.98; 95% CI, 0.66 to 1.44; P = .904). Twenty-six percent versus 29% of patients had pathologically positive lymph nodes (arm A v arm B; P = .447), 46% versus 44% had tumor infiltration beyond the muscularis propria (P = .701), and 7% versus 4% had positive circumferential resection margins (P = .239). Intra-abdominal metastases were found at surgery in 2.9% versus 0.5% of patients (arm A v arm B; P = .014). CONCLUSION Adding oxaliplatin to fluorouracil-based preoperative chemoradiotherapy significantly increases toxicity without affecting primary tumor response. Longer follow-up is needed to assess the impact on efficacy end points.

Randomized multicenter Phase II trial of two different schedules of irinotecan combined with capecitabine as first-line treatment in metastatic colorectal carcinoma.

The aim of the current randomized Phase II study was to investigate the efficacy and safety of capecitabine combined with irinotecan as first‐line treatment in metastatic colorectal carcinoma (CRC).

Continuation or reintroduction of bevacizumab beyond progression to first-line therapy in metastatic colorectal cancer: final results of the randomized BEBYP trial

BACKGROUND The combination of bevacizumab with fluorouracil-based chemotherapy is a standard first-line treatment option in metastatic colorectal cancer (mCRC). We studied the efficacy of continuing or reintroducing bevacizumab in combination with second-line chemotherapy after progression to bevacizumab-based first-line therapy. PATIENTS AND METHODS In this phase III study, patients with mCRC treated with fluoropyrimidine-based first-line chemotherapy plus bevacizumab were randomized to receive in second-line mFOLFOX-6 or FOLFIRI (depending on first-line regimen) with or without bevacizumab. The primary end point was progression-free survival. To detect a hazard ratio (HR) for progression of 0.70 with an α and β error of 0.05 and 0.20, respectively, 262 patients were required. RESULTS In consideration of the results of the ML18147 trial, the study was prematurely stopped. Between April 2008 and May 2012, a total of 185 patients were randomized. Bevacizumab-free interval was longer than 3 months in 43% of patients in chemotherapy alone arm and in 50% of patients in the bevacizumab arm. At a median follow-up of 45.3 months, the median progression-free survival was 5.0 months in the chemotherapy group and 6.8 months in the bevacizumab group [adjusted HR = 0.70; 95% confidence interval (CI) 0.52-0.95; stratified log-rank P = 0.010]. Subgroup analyses showed a consistent benefit in all subgroups analyzed and in particular in patients who had continued or reintroduced bevacizumab. An improved overall survival was also observed in the bevacizumab arm (adjusted HR = 0.77; 95% CI 0.56-1.06; stratified log-rank P = 0.043). Responses (RECIST 1.0) were similar in the chemotherapy and bevacizumab groups (17% and 21%; P = 0.573). Toxicity profile was consistent with previously reported data. CONCLUSIONS This study demonstrates that the continuation or the reintroduction of bevacizumab with second-line chemotherapy beyond first progression improves the outcome and supports the use of this strategy in the treatment of mCRC. ClinicalTrials.gov number: NCT00720512.

517PFOLFOXIRI PLUS BEVACIZUMAB (BEV) AS FIRST-LINE TREATMENT OF RAS WILD-TYPE (WT) METASTATIC COLORECTAL CANCER (MCRC) PATIENTS (PTS)

ABSTRACT Aim: Phase III TRIBE trial demonstrated that FOLFOXIRI plus bev provides a significant advantage in PFS, response rate and OS as compared to FOLFIRI plus bev. No interaction between RAS mutational status and treatment effect was reported. The aim of the present analysis is to describe the clinical outcome of RAS wt pts treated with the triplet plus bev. Methods: Patients not bearing KRAS or NRAS codon 12, 13 and 61 mutations were defined as RAS wt. Best response according to RECIST, early response and deepness of response (DoR) were analysed. Patients achieving a >20% reduction in the sum of longest diameters of RECIST target lesions at week 8 compared to baseline were defined as early responders. A further analysis was performed in the RAS and BRAF wt subgroup. Results: Seventy-eight RAS wt patients received first-line FOLFOXIRI plus bev. BRAF mutation was detected in 14 (18%) RAS wt patients. Fifty-one (65%) out of 78 pts achieved RECIST response and 21 (27%) reported a disease stabilization for an overall disease control rate of 92%. Early response was reported in 44 (63%) out of 70 evaluable pts. The median DoR was 43.5% (range 100%/-38.2%). Twenty-three patients (29%) underwent a secondary resection with curative intent (R0/R1/R2) and a R0 resection was performed in 14 patients (18%). Median PFS and OS were 12.8 and 36.0 months, respectively. Out of 64 RAS and BRAF wt pts, RECIST response rate was 69% and median PFS and OS were 13.3 and 41.7 months, respectively. Conclusions: RAS wt pts treated with the triplet plus bev in the TRIBE trial achieved notable results in terms of RECIST response, PFS and OS. Though acknowledging limitations of cross-trial comparisons, these results compare favourably with those reported in phase III trials with first-line doublets plus an anti-EGFR monoclonal antibody, in particular for PFS. Disclosure: A. Falcone: Consultant, honoraria and research funding for Roche, Merck and Amgen. Consultant and honoraria fro Sanofi-Aventis, Bayer and Celgene.All other authors have declared no conflicts of interest.