Bruera et al. BMC Cancer 2010, 10:567 http://www.biomedcentral.com/1471-2407/10/567 first 15 enrolled pts were necessary for the first-step; to verify the alternative hypothesis of ORR 70%, 26 objec- tive responses among the total 43 pts enrolled were necessary; power (1 - b) 80%; error probability a 5%. p0 was considered as the activity of triplet combinations in MCRC (CPT-11/OHP/5-FU or BEV/CPT-11/5-FU) [17,18,20,11]; p1 as the projected ORR using the present Poker combination, increasing the activity ≥ 20%. In the first step of the study, a dose-finding was con- comitantly developed to verify recommended OHP dose by 3 escalating steps at 60, 70, 80 mg/m2, according to an intra-and inter-patient approach [26]. Results Patient Demographics From February 2006 to March 2009, 50 consecutive, unselected pts were enrolled (Table 1): Male/Female ratio, 31/19; median age, 63 years; 24 (48%) young- elderly pts (65 < 75 y); WHO Performance Status 0/1-2, 48/2; metastatic disease metachronous in 15 pts, syn- chronous in 35 pts. Metastatic sites: liver 33 pts (66%), lung 10 pts (20%), lymph nodes 17 pts, (34%); local recurrence 10 pts (20%). Metastatic site was single in 32 pts (64%), multiple in 18 pts (36%). Single metastatic sites were: liver 22 pts (44%), lung 3 pts (6%), lymph nodes 3 pts (6%), local recurrence 4 pts (8%). Liver metastases were single in 11 pts (22%) and multiple in 22 pts (44%). Dose finding In the first step of the study, a concomitant dose-finding was conducted in order to assess the recommended OHP dose. At the first dose-level, 9 pts were enrolled and 12 cycles were administered; a DLT, G3 diarrhea, was observed in 1 out of 9 pts (11%). At the second dose level, 11 pts were treated (3 new pts); no DLT was observed. At the third dose level, 14 pts were treated (3 new pts); a DLT (7%) was observed, characterized by G3 mucositis (G3 stomatitis and G2 diarrhea, associated with G2 hypoalbuminemia). Thus, 2 DLTs were observed out of 15 pts (13%) and out of 37 cycles of treatment (5%). The OHP dose-finding established that the maximum tolerated dose (MTD) was not reached at the third dose level [Additional file 1: Supplemental Table S1]; thus, the recommended dose of OHP was 80 mg/m2 day 8 and 22, every 4 weeks. Activity and efficacy The preliminary analysis of efficacy, according to the two-steps Simon’s design, was conducted among the first 15 patients: 14 patients were evaluable as treated and one patient did not received at least three cycles of treatment. ORR was 93% (a 0.05, CI ± 13) (14 objective responses): 12 partial responses (80%); 2 complete Table 1 Patients’ features Male/Female No. of patients Sex Age, years median range ≥ 65 years WHO Performance Status 0 1-2 Metastatic disease metachronous synchronous Primary tumor colon rectum Sites of metastases liver lung lymph nodes local Other No. of involved sites 1 ≥ 2 Single metastatic sites liver lung lymph nodes local Liver metastases single multiple Previous adjuvant chemotherapy: FA/5-FU bolus Capecitabine FOLFOX4 Previous radiotherapy: RT alone RT+CT (5-FU c.i.) RT+CT (XELOX) Page 3 of 10 Total N. (%) 50 31/19 63 40-73 24 (48) 48 (96) 2 (4) 15 (30) 35 (70) 24 (48) 26 (52) 33 (66) 10 (20) 17 (34) 10 (20) 5 (10) 32 (64) 18 (36) 22 (44) 3 (6) 3 (6) 4 (8) 11 (22) 22 (44) 9 (18) 4 (8) 1 (2) 4 (8) 6 (12) 2 (4) 3 (6) 1 (2) Abbreviation: WHO, World Health Organization; c.i., continous infusion. responses (13%); 1 progressive disease (7%) [Additional file 1: Supplemental Table S2]. Overall, 50 pts were enrolled to achieve 43 evaluable pts (Table 2). In the intent-to-treat analysis 49 pts were evalu- able (one patient lost to follow-up): ORR was 82% (a 0.05, CI ± 11). We observed 40 objective responses: 36 partial responses (73%) and 4 complete responses (CR 8%); 2