Stein et al. BMC Cancer 2012, 12:356 http://www.biomedcentral.com/1471-2407/12/356 metastatic CRC with nearly 200 patients randomized to an experimental treatment with FOLFOXIRI and bevaci- zumab vs. what is considered a standard approach. Perioperative treatment in resectable CLM, especially its sequence (peri- vs. postoperative treatment) and intensity, is still a matter of debate. The PERIMAX trial design represents the agreement on a multidisciplinary trial by surgical and medical oncologists in Germany and reflects the ongoing discussion about timing of peri- operative chemotherapy. In regard of the high recur- rence rate after resection with curative intent and the results of four drug combinations including bevacizumab in mCRC, further intensification of the perioperative treatment to improve patients’ prognosis by increasing the rate of long-term survivors seems to be a feasible op- tion. Despite the lack of data for FOLFOX for purely postoperative treatment after resection of CLM, this regimen was chosen in regard of the beneficial trend for 5FU/LV in this setting and the data obtained in stage III disease with oxaliplatin [27,56,57]. Furthermore, this treatment approach is widely used for patients receiving upfront resection of CLM, and is considered a ‘current standard’ for this patient group. However, the PERIMAX trial has several variables (sequence and intensity) and is therefore of an exploratory nature focusing on the effi- cacy and feasibility of perioperative FOLFOXIRI and bevacizumab in this setting. The randomized design was chosen to collect data albeit limited by the low number of patients on the comparative efficacy in terms of sur- vival in order to reduce the bias that is associated with a comparison to historical controls, which are only avail- able for 5FU/LV in this setting [58]. Number of CLM with a cut-off value of 3 was added to the widely accepted stratification according to the Fong score. Although already part of the Fong score, this cut off value has recently demonstrated high prognostic value [15]. The composite endpoint FFS was chosen to adapt to the specific situation in this trial with half of the patients being disease-free within the first months after randomization, compared to the other half receiving 3 months of preoperative treatment. In order to ensure comparability with available data, e.g. EORTC 40983 (PFS), and to gain information about tolerability and QoL with the four-drug regimen secondary endpoints include these parameters. Perioperative treatment was limited to 6 months, as no conclusive data about pro- longed treatment is currently available [30]. The trial also offers the unique opportunity of collecting tissue from liver metastases and primary tumours either untreated or treated. Therefore, fresh frozen and paraffin embedded tissue will be collected and stored for further analyses. The CHARTA trial will evaluate the efficacy of a max- imal intensive first line regimen compared to a standard first line regimen in patients with unresectable metastatic Page 7 of 10 CRC. The intensification of first line treatment is believed to increase the rate of patients amenable for a secondary curative approach and even if surgery might not be an option this treatment approach could result in improved long-term disease control. Especially for clin- ical group 2 and 3, if amenable for intensive first line treatment, disease control after induction chemotherapy could result in long intervals of either low toxic mainten- ance therapy or complete treatment discontinuation and might thus be a reasonable long-term approach. Fur- thermore, the magnitude and point in time of tumour response has demonstrated significant impact on prog- nosis, underlining the need for an intensive first line regimen inducing early tumour shrinkage [59]. Eligible patients will be stratified according to clinical groups in order to balance the arms especially for potentially secondary resectable patients. PFS-rate at 9 months was chosen as primary endpoint to gain information about the comparative efficacy in terms of a survival endpoint, taking into account the inclusion of all metastatic and not only potentially resectable patients. Treatment dur- ation is limited to a maximum of 6 months FOLFOX and bevacizumab +/− irinotecan, followed by up to 12 months of maintenance with fluoropyrimidine and beva- cizumab. According to current clinical standard oxalipla- tin should be discontinued at least after 6 months of treatment due to significant cumulative side effects, par- ticularly peripheral neuropathy. None of the available trials with FOLFOXIRI with or without bevacizumab continued treatment beyond 12 cycles (6 months), as tolerability will be significantly impaired and achieve- ment of secondary resectability with prolonged treatment beyond 6 months seems unlikely [37,52]. In the CELIM trial for example median time to resection or exploration was 5.1 months, with a median number of 8 treatment cycles until intervention [60]. Current data support the use of maintenance treatment after first line chemo- therapy, though the choice of regimen is not yet clear [61-64]. However, results of ongoing trials (e.g. AIO 0207 and CAIRO3) might help clarifying this question and potentially the choice of maintenance regimen as well (biological +/− fluoropyrimidine. In regard of the higher intensity of the four-drug combination not only in terms of response but as well in terms of toxicity QoL evalu- ation is performed during the trial. With overall 380 previously untreated metastatic CRC patients classified for resectability, stratified for clinical grouping and randomized, the CHARTA and PERIMAX trials will give further information about the benefit and tolerability of FOLFOXIRI and bevaci- zumab in these distinct disease settings. Abbreviations 5-FU, 5-fluorouracil; 5-yOSR, 5 year overall survival rate; AE, Adverse event; ALT, Alanin-aminotransferase; AST, Aspartat-aminotransferase; aPTT, Activated