Stein et al. BMC Cancer 2012, 12:356 http://www.biomedcentral.com/1471-2407/12/356 free survival (DFS) could be shown in the French trial, with a 5-year DFS rate of 26.7 vs. 33.5% (p=0.028), favouring the group with adjuvant treatment [25]. The ENG (EORTC/NCI-CTG/GIVIO) trial, still not fully published, showed a non-significant trend towards a pro- longation of DFS (median 39 vs. 20 months; p=0.35) and an increase in overall survival (median 53 vs. 43 months; p = 0.39) [26]. The combined analysis of both trials (n=278 patients) showed a non-significant prolongation of DFS from 18.8 to 27.9 months (p = 0.058) and OS from 47.3 to 62.2 months (p=0.095) [27]. Both trials were using a (non-contemporary) 5-FU bolus regimen. Intensification of postoperative treatment by 5-FU/LV plus irinotecan in a prematurely stopped, randomized phase III trial revealed no additional benefit com- pared to 5-FU/LV alone in terms of DFS (21.6 vs. 24.7 months, p=0.47) and OS (3-year rate of 71.6 vs. 72.7%, p=0.69) [28]. The Dutch HEPATICA trial, prematurely stopped after 74 randomized patients, indicated that postoperative treatment with capecitabine and oxaliplatin for 6 months and bevacizumab for 12 months might be beneficial with a trend in DFS rate at 2 years of 50 vs. 72% (p=0.074), although this trend needs to be carefully interpreted in regard of the known only transient benefit achieved with prolonged bevacizumab in stage II/III colon can- cer [29-31]. First line treatment for mCRC Several first-line treatment options are currently available incorporating fluoropyrimidines, irinotecan, oxaliplatin, bevacizumab and EGFR antibodies (e.g. cetuximab and panitumumab) for KRAS wildtype patients [32-37]. Bevacizumab based first line treatment for mCRC A variety of trials and registry analyses evaluated the effi- cacy of bevacizumab-containing first-line regimens. The addition of bevacizumab to 5FU bolus and irinotecan regimen (IFL) significantly increased ORR and pro- longed OS and PFS [38]. The NO16966 study was ini- tially designed to prove non-inferiority of the XELOX regimen compared with FOLFOX-4, but the addition of bevacizumab in a 2x2 factorial design was amended after the above-mentioned results. Although ORR in this trial was not different between the bevacizumab and the pla- cebo arms, potentially curative surgery was performed in 55 (9.6%) patients on bevacizumab vs. 38 (6.6%) on placebo (p=0.061) in the per protocol population. PFS was significantly increased in the bevacizumab group, 9.4 vs. 8.0 months in the placebo group (HR 0.83, 97.5% CI 0.72 to 0.95; p=0.0023). However, OS was 21.3 months in the bevacizumab group and 19.9 months in the placebo group (HR 0.89, 97.5% CI 0.76 to 1.03; p=0.077) [34]. Several observational phase IIIb/IV trials Page 3 of 10 (e.g., First BEAT, BriTE) confirmed the safety profile of bevacizumab in first-line mCRC patients receiving a var- iety of chemotherapy regimens, namely FOLFOX, XELOX, FOLFIRI, or capecitabine [39,40]. Four drug regimens for mCRC After the negative trials combining a chemo-doublet with bevacizumab and EGFR antibodies, four drug regi- mens focused on a chemo-triplet in combination with a targeted drug [41,42]. Several chemo-triplet schedules with 5FU/LV or capecitabine, irinotecan and oxaliplatin were evaluated with the Italian FOLFOXIRI demonstrat- ing the most efficacious and reliable data [37,43-46]. The FOLFOXIRI regimen by Falcone et al. significantly increased ORR (34 vs. 60%, p<0.0001), PFS (6.9 vs. 9.8 months, p=0.0006), and OS (16.7 vs. 22.6 months, p=0.032) compared to FOLFIRI in a phase III trial with 244 patients. Furthermore, the FOLFOXIRI regimen resulted in an increased R0 secondary resection rate (6% vs. 15%, p=0.033, among all 244 patients; and 12 vs. 36%, p=0.017 among patients with CLM only) [37]. Administration of second line does not seem to be rele- vantly impaired by first line FOLFOXIRI according to recently presented data demonstrating feasibility and efficacy of second line treatment with either oxaliplatin or irinotecan based doublet (38%), rechallenge with FOLFOXIRI (24%) or fluoropyrimidine with or without mitomycin [47]. Retreatment with FOLFOXIRI was associated with significantly prolonged survival. Several single arm phase II trials with different 5FU/LV, irinotecan and oxaliplatin schedules were performed in combination with either bevacizumab or cetuximab resulting in high ORR of 75-82% [48-53]. However, in the absence of comparative data, toxicity profile (especially grade 3/4 diarrhoea) seems to favour bevacizumab-containing regimens (14-28%) compared to 36-93% observed with cetuximab combinations even after dose reduction of chemotherapy. In a recently published single arm phase II trial, an ORR of 77% in all patients and 80% in the liver-only population (n=30) was achieved with the combination of FOLFOXIRI and bevacizumab. R0 resections were performed in 40% (n=12) of the liver-only population. Disease control rate was 100%. PFS and OS were 13.1 and 30.9 months, respectively. Treatment was well tol- erated with the major grade 3/4 toxicity being neutro- penia in 49% of patients (compared to 50% with FOLFOXIRI alone), which was well manageable with sec- ondary G-CSF prophylaxis leading to only one case of fe- brile neutropenia. Further G3/4 toxicities were diarrhoea in 14%, hypertension in 11%, and asthenia as well as deep vein thrombosis in 7% of patients [52]. Similar results could be achieved in another 5FU/LV, irinotecan and oxa- liplatin regimen (weekly alternating “Poker” schedule) with