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4007 Background: PRODIGE 23 investigated the role of neoadjuvant mFOLFIRINOX before preoperative (preop) chemoradiation (CRT), with TME-surgery and adjuvant chemotherapy (CT) in resectable locally advanced rectal cancer. Methods: PRODIGE 23 is a phase III multicenter randomized clinical trial. Eligible pts had cT3 or cT4, M0 rectal adenocarcinomas <15 cm from the anal verge, age 18-75 years, and WHO PS ≤1. Randomization was stratified by center, T stage, N status, tumor location, and perirectal fat extramural extension. Primary endpoint was 3-yr disease-free survival (DFS). Main secondary endpoints were ypT0N0 rate, overall survival (OS) and metastasis-free survival (MFS). 460 pts were required to observe 136 events to show a gain in 3-year DFS from 75% to 85% (HR=0.56) with a 2-sided α=0.05 and 90% power. HR and 95% CI were estimated by a stratified Cox proportional hazard model. Arm A pts received preop CRT (50 Gy, 2 Gy/fraction [fr]; 25 fr + capecitabine), surgery, then adjuvant CT for 6 months (mos). Arm B pts received 6 cycles of mFOLFIRINOX (oxaliplatin 85 mg/m², leucovorin 400 mg/m², irinotecan 180 mg/m² D1, and 5-FU 2.4 g/m² over 46 h) every 14 days, followed by the same preop CRT, surgery and 3 mos of adjuvant CT. Adjuvant CT consisted of mFOLFOX6 or capecitabine, depending on the centre’s choice for all pts. Imaging work-up, operative and pathology reports were centrally reviewed. Results: (ITT) Between 6/2012 and 6/2017, 230 and 231 pts were randomly assigned in Arm A/B, respectively by 35 participating centers. Pts characteristics were well balanced. Neoadjuvant mFOLFIRINOX and CRT in both arms were well tolerated. Compliance to CRT and to adjuvant CT was not hampered by neoadjuvant CT. Surgical morbidity did not differ between the 2 arms. The ypT0N0 rate was 11.7 vs 27.5% in Arm A/B (p<0.001). Median follow-up was 46.5 mos. 136 DFS events was reported. 3-yr DFS was significantly increased in arm B (HR 0.69, 95% CI 0.49-0.97, p=0.034): 68.5% (CI: 61.9-74.2) vs 75.7% (CI: 69.4-80.8) in arm A/B. The subgroup analysis showed no evidence of heterogeneity of the effect size of treatment on DFS. 3-yr MFS was also significantly higher in arm B: 71.7 in arm A vs 78.8% (HR 0.64, CI 0.44-0.93, p<0.02) in arm B. 3-yr OS was 87.7 vs 90.8% (HR 0.65, CI 0.40-1.05, p=0.077) in arm A/B, with 54.2% of the pts with recurrence being alive. Conclusions: Neoadjuvant mFOLFIRINOX plus CRT is safe, and significantly increased ypCR rate, DFS and MFS. OS data are not mature. Clinical trial information: NCT01804790 .

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BackgroundOptimization of chemotherapy effectiveness in metastatic colorectal cancers (mCRC) is a major endpoint to enhance the possibility of curative intent surgery. FOLFIRI3 has shown promising results as second-line chemotherapy for mCRC patients previously exposed to oxaliplatin. The clinical efficacy of FOLFIRI3 was never determined in association with bevacizumab in non-previously treated mCRC patients.MethodsWe conducted a phase II clinical trial to characterize the response rate and toxicity profile of FOLFIRI3-bevacizumab as initial treatment for mCRC. Sixty-one patients enrolled in 3 investigation centers were treated with FOLFIRI3-bevacizumab (median of 10 cycles) followed by a maintenance therapy combining bevacizumab and capecitabine. Levels of plasma angiopoietin-2 (Ang-2) were measured by enzyme-linked immunosorbent assay at baseline.ResultsOverall response rate (ORR) was 66.7% (8% of complete and 58% of partial responses). The disease control rate was 91.7%. After a median time of follow-up of 46.7 months, 56 patients (92%) had progressed or died. The median progression free survival (PFS) was 12.7 months (95% confidence interval (CI) 9.7-15.8 months). The median overall survival (OS) was 24.5 months (95% CI: 10.6-38.3 months). Twenty-one patients underwent curative intent-surgery including 4 patients with disease initially classified as unresectable. Most common grade III-IV toxicities were diarrhea (15%), neutropenia (13%), asthenia (10%), and infections (4%). Hypertension-related medications needed to be increased in 3 patients. In multivariate analysis, surgery of metastases and Ang-2 levels were the only independent prognostic factors for PFS and OS. Indeed, baseline level of Ang-2 above 5 ng/mL was confirmed as an independent prognostic factor for progression free survival (HR = 0.357; 95% CI: 0.168-0.76, p = 0.005) and overall survival (HR = 0.226; 95% CI: 0.098-0.53, p = 0.0002).ConclusionsAs front-line therapy, FOLFIRI-3-bevacizumab is associated with an acceptable toxicity and induced promising objective response rates. However, unfavorable clinical outcomes were observed in patients with high levels of angiopoietin-2.

Docetaxel, cisplatin, and 5‐fluorouracil (DCF) significantly improved overall survival in metastatic gastroesophageal adenocarcinoma (GEA). The aim of this study was to assess efficacy of DCF regimen as perioperative chemotherapy compared with surgery alone in patients with resectable GEA. We identified 789 patients who underwent surgery alone and 62 patients who received at least one cycle of DCF regimen consisting of docetaxel (75 mg/m2 on day 1), cisplatin (75 mg/m2 on day 1), and 5‐fluorouracil (750 mg/m2/day on continuous perfusion on days 1 to 5), every 3 weeks. Overall survival was compared using Cox proportional hazards regression model with adjustments for confounding factors provided by two propensity score methods: inverse probability of treatment weighting (IPTW) and matched‐pair analysis. In Cox multivariate analysis weighted by IPTW, DCF group was associated with favorable overall survival (OS) compared with the surgery group (HR = 0.59; 95% CI, 0.45–0.78; P = 0.0003). For the matched‐pair analysis (comparing 41 patients for each group with the same baseline characteristics), median OS was 22 months and 57 months for the surgery group and DCF group, respectively (log‐rank P = 0.0011). In Cox multivariate analysis, DCF group was associated with favorable OS compared with the surgery group (HR = 0.29; 95% IC, 0.14–0.64; P = 0.0019). In the matched‐pair population, major complications (Dindo‐Clavien grade 3–5) arose in six patients (14.63%) in the DCF group and seven patients (17.07%) in the surgery group (P = 1). Perioperative DCF chemotherapy is superior to surgery alone in terms of OS. A randomized phase III trial should compare DCF to standard perioperative regimens.