Bruera et al. BMC Cancer 2010, 10:567 http://www.biomedcentral.com/1471-2407/10/567 efficacy to other reported schedules (ORR 40% and 66.7%, PFS 10 and 12 months, OS 21 and 20 months, respectively) and demonstrated a good tolerability pro- file [19,20,28]. In this scenario, Poker combination, add- ing BEV to FIr-FOx association, in first line treatment of MCRC, increased activity compared to triplet associa- tions and it also increased efficacy; the 48% young elderly pts enrolled showed equivalent activity and efficacy. Randomized studies of doublets (5-FU plus CPT-11 or OHP) adding Cetuximab (an EGFR-inhibitor) in EGFR- overexpressing pts, showed equivalent efficacy to other triplet combinations [29,30]; in these studies, k-ras wild- type status was reported as a statistically relevant predic- tive biomarker of higher activity and efficacy. Preliminary data of a phase III trial may also confirm this with Pani- tumumab plus FOLFOX4 [31]. The effectiveness of BEV- containing treatments was maintained in k-ras wild-type as it was in k-ras mutated pts [32]. Liver metastasectomies were performed in 26% of MCRC pts and 39% of pts with liver metastases. Moreover, 54% of pts with liver-only metastases and 50% of pts with initially unresectable liver metastases underwent surgical resection. Liver metastasectomies were reported in 8-11% of pts treated with triplet chemotherapy (36% in liver-only pts) [17,18] and in 7.6% of pts in BEV-containing associa- tions (15.2% in liver-only pts) [16]; in pts with potentially curable liver metastases, they were 92.8% [15]. In Cetuxi- mab-containing associations [29,30], metastasectomies were performed in 7% and 4.7% of overall pts [29,30]; 9.8% of KRAS wt pts [30]. More, using neoadjuvant Cetuximab with either FOLFOX6 or FOLFIRI for unresectable color- ectal liver metastases, metastasectomies were performed in 38% and 30% of pts, respectively [33]. Our data show that more active first line treatment of MCRC [34], such as Poker combination, contribute to increase efficacy also by raising surgical resection of liver metastases. Median rDIs per cycle and per patient were > 80% for each drug; in young elderly pts, only the rDI of CPT-11 was lower than 80% (76%; 61 mg/m2/w). Cumulative G3-4 toxicities were prevalently represented by diarrhea (28%), stomatitis/mucositis (6%), asthenia (6%), hyperten- sion (2%), hypertransaminasemy (4%), neutropenia (10%). Cumulative G3-4 toxicities reported with the schedule associating BEV to 5-FU/Leucovorin or IFL were repre- sented by equivalent prevalence of, respectively: diarrhea 28.5% and 32.4%; hypertension 8.5% and 11%; thrombotic events 14.2% and 19.4% [8,11]. Cumulative G3-4 toxici- ties reported with FOLFOXIRI schedules [17,18] were prevalently represented by, respectively: diarrhea 20% and 27.7%, stomatitis/mucositis 5% and 5%, asthenia 6% and 5.6%, neutropenia 50% and 35%, febrile neutropenia 5% and 7%, neurotoxicity 2% and 5.8%. Thus, gastroin- testinal toxicities were not quite different in patients Page 8 of 10 treated with 5-FU and CPT-11 as doublet, or associated to BEV, or OHP, or BEV and OHP as in the present study. Preliminary safety data of the phase III trial evalu- ating BEV plus FOLFOXIRI versus BEV plus FOLFIRI, show cumulative G3-4 toxicities prevalently represented by diarrhea (18%), stomatitis/mucositis (8%), asthenia (4%), hypertension (2%), trombotic events (8%), neutro- penia (53%), febrile neutropenia (6%); a treatment-related death was reported in 1 patient (gastrointestinal bleeding; 2%). Thus, FIr-B/FOx schedule determined only 10% G3- 4 neutropenia, while FOLFOXIRI schedule, added or not to BEV [35,17], prevalently induced it (53% and 50%, respectively) and also febrile neutropenia (6% and 5%, respectively). Cumulative G3-4 toxicities in young-elderly pts were prevalently represented by diarrhea (25%), hypertransa- minasemy (4%), neutropenia 12.5%, stomatitis/mucositis (12.5%), asthenia (12.5%). Souglakos et al reported a sig- nificantly higher incidence of G3-4 diarrhea in elderly versus non-elderly pts either in the FOLFIRI or in the FOLFOXIRI arm [18]. In our study, DLT was observed in 44% of pts and in 46% of young-elderly pts, with no differences of cumulative G3-4 toxicities by pts and by cycles. The innovative clinical evaluation of LTS, con- sisting of at least the DLT associated or not to other G2 or limiting toxicities, was introduced to better evalu- ate, in the individual patient, the presence of DLT alone, LTS-ss, or the association of major toxicities in different sites, LTS-ms: overall, they were 20% and 24% respectively; among young-elderly pts, they were 8% and 37.5%, respectively. Most LTS-ms (2 double DLTs and 7 out of 10 DLT associated to other, at least G2, non- limiting toxicities) were observed in this subgroup. LTS- ms were mostly represented by diarrhea and/or stomati- tis/mucositis associated to nausea, vomiting and/or asthenia. Conclusions Randomized trials will confirm if intensive chemother- apy approaches, such as Poker association, increase effi- cacy, also by raising surgical resection of liver metastases, as first line treatment of MCRC. The present schedule is feasible, also in young-elderly pts, with man- ageable toxicity. Young-elderly pts show equivalent effi- cacy and cumulative toxicity, with a prevalence of LTS- ms associating the DLT with other moderate/severe toxicities. Additional material Additional file 1: Oxaliplatin dose-finding, activity in the first step of the study (Simon’s design) and Limiting Toxicity Syndromes (LTS). Supplemental Table S1 reports results of the dose-finding planned in order to assess the recommended Oxaliplatin dose. Supplemental