Stein et al. BMC Cancer 2012, 12:356 http://www.biomedcentral.com/1471-2407/12/356 case of undue toxicity. Treatment will be delayed until adequate recovery from toxicity. Assessments/follow up Tolerability will be evaluated at every visit including physical examination, vital signs, clinical laboratory pro- file, and adverse events, which will be graded according to NCI-CTCAE v.4.0 and correlated to the administered treatment or performed study procedure. Treatment related Serious Adverse Events (SAE) considered pos- sibly, probably or definitely related to treatment, will be determined. In both trials the investigator will assess tumour response according to RECIST v1.1 and CEA (optional CA 19–9). CT and/or MRI scans will be independently reviewed e.g. for resectability (both trials) and allocation to the clinical groups (CHARTA). In the CHARTA trial imaging of all sites of disease will be performed at baseline and every 4 cycles (8 weeks) thereafter for the first 6 months (induction treatment) and afterwards every 3 months (dur- ing and after maintenance) until progression. Radiological imaging in the PERIMAX trial (CT-scan of the chest, CT or MRI-scan of the abdomen) should be done at baseline and/or preoperatively, postopera- tively (prior to the start of postoperative treatment) and afterwards every three months for two years and every 6 month thereafter in both arms. In the preoperatively treated arm, an additional radiological imaging after the 3rd cycle (6 weeks) should be done to avoid clinically complete response. In case of CEA elevation without progressive disease defined by RECIST, further examina- tions must be performed searching for local recurrence or metastatic progression of disease. Diagnosis of recur- rence could either be made by radiological imaging or by positive cytology or biopsy. After progression, patients will be followed every 3 months for disease sta- tus, protracted toxicities, further treatment, and survival. Quality of life will be assessed together with tumour assessment using the EORTC QLQ-C30, and the mod- ules CR29 and CIPN20 in the CHARTA and the module LMC21 in the PERIMAX. Formalin fixed and paraffin embedded (FFPE) tumour tissue obtained at baseline (if available) and serum obtained at baseline and before the 3rd and the 7th cycle will be evaluated for KRAS and BRAF-status (FFPE) and angiogenic markers (FFPE and serum) in the CHARTA trial. In addition to KRAS and BRAF in PERIMAX evaluation of pathohistological response rate and further analyses are planned, thus either paraffin embedded or preferably fresh frozen tissue of primary tumour and hepatic metastases should be obtained in patients con- senting. Furthermore, serum obtained at baseline, during preoperative treatment, postoperatively and at follow up will be evaluated for circulating tumour DNA. Page 6 of 10 Statistical considerations and sample size estimation CHARTA trial First line therapy with FOLFOX and bevacizumab displays a median PFS of 9,4 months [34], leading to a PFS Rate at 9 months (PFSR@9) of approximately 55%. The four-drug combination treatment should produce a PFSR@9 of at least 71.3%. The risk of estimating the four-drug combin- ation treatment as active although the PFSR@9 is less than 71.3% should be 10%. The risk of rejecting the therapy although the PFSR@9 is more than 71.3% should be 20%, which leads to a power of 80%. The planned number of patients to answer this question in a two-sided (continuity corrected) Chi-square test will be 120 and with a dropout rate of 4% the number to be included will be 125 patients per arm. Analysis will be performed by logistic regression to account for the stratification. PERIMAX trial Perioperative chemotherapy with 5-FU/LV with or without oxaliplatin in a prognostic favourable group of patients with up to 4 CLM led to a FFS rate at 18 months (FFSR@18) of 50-65% [22,25]. However, in the trial by Portier et al.. solely patients after R0 resection were included, whereas in the EORTC study 51% and 27% of patients had one or two CLM, respectively. In this trial, patients with unlimited number of CLM, fulfilling the local judgement for resectability will be included. Therefore, FFSR@18 is expected to be 40% with current treatment strategies (postoperative FOLFOX). The inves- tigational treatment (perioperative FOLFOXIRI and beva- cizumab) should produce a FFSR@18 of at least 60%, to be regarded as promising for further evaluation and of major clinical relevance. The trial should achieve 80% power to detect differences between the treatments and keeping the type I error level below 10% in a one-sided (continuity corrected) Chi-square test. The planned num- ber of patients to answer this question with a drop out rate of about 14% will be 65 patients per arm. The trial uses a randomized parallel arm phase II design. Quality assurance/safety Patient data are collected in a case report form at the data centre of the clinical research organisation (Koordinierungszentrum für Klinische Studien Halle). Consistency checks will be performed on newly entered forms and queries issued in case of inconsistencies. On- site monitoring will be performed adapted according to the site accrual. Data safety monitoring boards will review the data from both trials on a regular basis. Discussion The CHARTA and PERIMAX trials are designed to evaluate the benefits and limitations of a highly active four-drug regimen in different treatment situations of