Bruera et al. BMC Cancer 2010, 10:567 http://www.biomedcentral.com/1471-2407/10/567 Median received dose intensities (rDI) per cycle were: 5-FU 1487 (480-1800) mg/m2/w, 82.6% of pro- jected-DI (pDI); CPT-11 66.7 (25-80) mg/m2/w, 83% of pDI; l-OHP 32 (8-40) mg/m2/w, 80% of pDI; BEV 2.1 (1-2.5) mg/kg/w, 84% of pDI (Table 3). Median rDI per patient were: 5-FU 1500 (955-1800) mg/m2/w, 83% of pDI; CPT-11 66 (45-80) mg/m2/w, 82.5% of pDI; l-OHP 32.5 (20.5-40) mg/m2/w, 81% of pDI; BEV 2 (1.5-2.5) mg/kg/w, 80% of pDI. In young elderly pts, median rDIs per cycle were: 5-FU 1420 (480-1800) mg/m2/w, 80% of pDI; CPT-11 61 (25-80) mg/m2/w, 76% of pDI; l-OHP 31.5 (8-40) mg/m2/w, 79% of pDI; BEV 2 (1-2.5) mg/kg/w, 80% of pDI. Toxicity Table 4 describes cumulative toxicities in enrolled pts and in 247 administered cycles. Two out of 50 patients (4%) discontinued FIr-B/FOx treatment due to limiting toxicity (grade 3 diarrhea). Cumulative G3-4 toxicities, by pts, were: nausea 3 pts (6%), vomiting 2 pts (4%), diarrhea 14 pts (28%), stomatitis/mucositis 3 pts (6%), erythema 1 patient (2%), asthenia 3 pts (6%), hypertension 1 patient (2%), hypokalemia 1 patient (2%), hypertransaminasemy 2 pts (4%), alopecia 3 pts (6%), neutropenia 5 pts (10%). The prevalent DLT was diarrhea, equally distributed among young-elderly and non-elderly pts: 6 pts (25%) and 8 pts (31%), respectively. Other G3-4 toxicities were mostly observed in the 24 young elderly pts, particularly nausea 2 pts, vomiting 2 pts, stomatitis/mucositis 3 pts, erythema 1 patient, asthenia 3 pts, alopecia 3 pts and neu- tropenia 3 pts. Cumulative G2 toxicities, by pts, were: nau- sea 15 pts (30%), vomiting 6 pts (12%), diarrhea 12 pts (24%), hypoalbuminemia 1 patient (2%), stomatitis/muco- sitis 2 pts (4%), asthenia 20 pts (40%), neurotoxicity 5 pts (10%), hypertension 4 pts (8%), hematuria 1 patient (2%), epistaxis 2 pts (4%), hypertransaminasemy 2 pts (4%), alopecia 9 pts (18%), neutropenia 14 pts (28%), thrombo- cytopenia 1 patient (2%). No case of thrombosis, hemor- rhage/bleeding, cardiac or cerebrovascular ischemia, G4 Table 3 Dose-intensity Page 6 of 10 neutropenia, febrile neutropenia, severe thrombocytope- nia, or toxic deaths were observed. Overall, LTS were observed in 22 pts (44%) (Table 5); 11 out of 24 young-eldely pts (46%). LTS-ss in 10 pts (20%); LTS-ms in 12 pts (24%). LTS-ms characterized by DLT associated to other, at least G2, non-limiting toxicities were detected in 10 pts (20%); ≥ 2 DLTs in 2 pts (4%). Among the 24 young-elderly pts the distribu- tion of LTS was: LTS-ss, 2 pts (8%), LTS-ms, 9 pts (37.5%). LTS-ms were characterized by: DLT associated to other, at least G2, non-limiting toxicities, 7 pts (29%); ≥ 2 DLTs, 2 pts (8%). The 10 LTS-ss were characterized by [Additional file 1: Supplemental Table S3]: G3 diar- rhea, 5 pts; G3 asthenia, 1 patient; G3 hypertension, 1 patient; G3 hypertransaminasemy, 1 patient; G3 neu- tropenia, 1 patient; G1 thrombocytopeny for > 2 weeks, 1 patient. The 10 LTS-ms, characterized by DLT asso- ciated to other, at least G2, non-limiting toxicities, were characterized by: G3 diarrhea associated with G2-3 nau- sea and/or G2-3 vomiting, 4 pts; G3 diarrhea associated with G2 vomiting and G2 neurotoxicity, 1 patient; G3 diarrhea associated with G2 stomatitis/mucositis and G2 asthenia, 1 patient; G3 diarrhea associated with G3 nau- sea and G2 asthenia, 1 patient; G3 diarrhea associated with G2 epistaxis, 1 patient; G4 hpertransaminasemy associated with G2 diarrhea, G2 nausea and G2 anemia, 1 patient; G3 stomatitis/mucositis and G2 asthenia, 1 patient. The 2 LTS-ms, with double DLTs, were observed in young-elderly pts and characterized by: lim- iting diarrhea associated with mucositis and mucositis associated with erythema. Discussion The present phase II study proposing FIr-B/FOx asso- ciation in first line treatment of consecutive, unselected MCRC pts, reached the primary endpoint: ORR 82% in the ITT and 84% in the as-treated analysis. After a med- ian follow-up of 21 months, median PFS was 12 months and 24% of pts were progression-free > 12 months; All patients DI/cycle mg/m2(or Kg)/w Young-elderly patients DI/cycle mg/m2(or Kg)/w Projected DI mg/m2(o Kg)/w Median (Range) Received DI (%) Median (Range) Received DI (%) 5-FU CPT-11 l-OHP BEV 1800 80 40 2.5 1487 (480-1800) 66.7 (25-80) 32 (8-40) 2.1 (1-2.5) 82,6 83 80 84 1420 (480-1800) 61 (25-80) 31.5 (8-40) 2 (1-2.5) 80 76 79 80 Abbreviation: DI, dose-intensity; 5-FU, 5-Fluorouracil; CPT-11, Irinotecan; l-OHP, Oxaliplatin; BEV, Bevacizumab.