Stein et al. BMC Cancer 2012, 12:356 http://www.biomedcentral.com/1471-2407/12/356 Page 5 of 10 Therapy-naive, unresectable metastatic CRC ECOG≤2 n=250 R FOLFOX+Bevacizumab 6 months FOLFOXIRI+Bevacizumab 6 months Maintenance until PD or toxicity after secondary resection maximum of 12 months Bevacizumab+5FU/LV or Capecitabine Strata: clinical groups unresectable liver and/or lung metastasis potentially resectable after treatment induced downsizing, comorbidities allowing surgery multiple metastasis, rapid progression, risk of rapid deterioration, unlikely to become resectable never resectable and no symptoms or risk of deterioration Figure 1 overview CHARTA trial. 48 hours (day 1–3) and bevacizumab at a dose of 5 mg/kg iv over 30 to 90 min (day 1) with or without irinotecan at a dose of 165 mg/m2 iv over one hour (day 1) in a bi- weekly schedule will be administered followed by main- tenance with either 5-FU/LV and bevacizumab (same dosage and schedule as above) or capecitabine at a dose of 1600 mg/m2 in two doses po day 1 to 14 and bevaci- zumab at a dose of 7.5 mg/kg iv over 30 to 90 min (day 1) every three weeks (choice of 5-FU or capecitabine is at the discretion of the investigator). Treatment with FOLFOX and bevacizumab +/− irinotecan will be administered until progression, intolerable toxicity, and secondary resection or for a maximum of 12 cycles (6 months). After 6 months of treatment and/or no progression patients will continue with a maintenance regimen with bevacizumab and a fluoropyrimidine for up to 12 months in the absence of progression or intolerable toxicity. Maximum treatment duration is 18 months (6 months of FOLFOX and bevaci- zumab +/− irinotecan followed by 12 months of mainten- ance). In case of secondary resection (at any time point) treatment should be resumed 4–8 weeks postoperatively for a total of 6 months FOLFOX and bevacizumab +/− irinotecan (pre- and postoperative treatment), followed by maintenance treatment for total treatment duration of up to 12 months in the absence of progression or in- tolerable toxicity. Reintroduction of oxaliplatin +/− iri- notecan or restart of treatment in case of progressive Therapy-naive CRC with resectable liver metastases ECOG≤1 n=130 Stratification criteria CLM ≤3 vs. >3 Fong score <2 vs.2 R Figure 2 overview PERIMAX trial. disease during maintenance or complete break after 18 months of treatment is at the investigators discretion. PERIMAX trial The same regimens as in the CHARTA trial will be administered, although the postoperative treatment in arm A is FOLFOX without bevacizumab. In arm A FOLFOX will be administered for 12 cycles (6 months) postoperatively starting 6 +/−2 weeks after surgery. In the perioperative arm (B) FOLFOXIRI and bevacizumab will be administered for 6 cycles (last cycle without bev- acizumab) (3 months) preoperatively, followed by liver surgery within 6+/−2 weeks after last treatment FOLFOX- IRI (without bevacizumab), followed by 6 cycles (3 months) 6+/−2 weeks postoperatively. Bevacizumab should be withheld for at least 5 weeks before conducting surgery. The first cycle of FOLFOXIRI in both trials can be administered with 75% of dosage, if no diarrhoea or other significant toxicities ≥ grade 2 occurs, following cycles should be administered in full dosage. Dose reduction and escalation is at the discretion of the inves- tigator. Preoperative dose modifications should be main- tained for postoperative treatment in the PERIMAX trial. If a patient was treated with full dose preopera- tively, dose reduction to 75% for the first cycle and subsequent escalation might be applied similar to pre- operative treatment. Doses of drugs will be reduced in Surgery FOLFOX 6 months pre- and/or postoperative 6+/-2 weeks intervall FOLFOXIRI +bevacizumab 3 months Surgery FOLFOXIRI +bevacizumab 3 months