Bruera et al. BMC Cancer 2010, 10:567 http://www.biomedcentral.com/1471-2407/10/567 Table 4 Cumulative toxicity Patients Number 50 NCI-CTC Grade 1 2 Nausea (%) 23 (46) 15 (30) Vomiting (%) 10 (20) 6 (12) Diarrhea (%) 20 (40) 12(24) Hypoalbuminemia (%) 2 (4) 1 (2) Constipation (%) 17 (34) 1 (2) Stomatitis/mucositis (%) 16 (32) 2 (4) Erythema (%) 1 (2) - Asthenia (%) 13 (26) 20 (40) Neurotoxicity (%) 36(72) 5 (10) Hypertension (%) 15 (30) 4 (8) Hypotension (%) 1 (2) - Hematuria (%) 2 (4) 1 (2) Gengival recession/gengivitis (%) 7 (14) - Rhinitis (%) 38 (76) - Epistaxis (%) 31 (62) 2 (4) HFS (%) 2 (4) - Headache (%) 6 (12) - Hypokalemia (%) 3 (6) - Hypertransaminasemy (%) 3 (6) 2 (4) Hyperpigmentation (%) 6 (12) 2 (4) Fever without infection (%) 10 (20) - Alopecia (%) 5 (10) 9 (18) Anemia (%) 7 (14) 4 (8) Leucopenia (%) 13 (26) 17 (34) Neutropenia (%) 9 (18) 14 (28) Thrombocytopenia (%) 7 (14) 1 (2) Abbreviation: NCI-CTC, National Cancer Institute Common Toxicity Criteria. 3 3 (6) 2 (4) 14 (28) - - 3 (6) 1 (2) 3 (6) - 1 (2) - - - - - - - 1 (2) 1 (2) - - 3 (6) - - 5 (10) - 4 - - - - - - - - - - - - - - - - - - 1 (2) - - - - - - - 1 81 (33) 19 (8) 76 (30) 2 (1) 22 (9) 29 (12) 3 (1) 48 (19) 126(51) 27 (11) 1 (0.5) 3 (1) 10 (4) 110(44.5) 68 (27.5) 2 (1) 9 (4) 3 (1) 9 (4) 14 (6) 10 (4) 11 (4) 16 (6) 49 (20) 35 (14) 16 (6) Cycles 247 2 23 (9) 9 (4) 28 (11) 1 (0.5) 1 (0.5) 3 (1) - 38 (15) 6 (2) 4 (2) - 1 (0.5) - - 2 (1) - - - 6 (2) 5 (2) - 17 (7) 4 (2) 26 (10.5) 32 (13) 1 (0.5) 3 4 (2) 2 (1) 15 (6) - - 3 (1) 1 (0.5) 3 (1) - 1 (0.5) - - - - - - - 1 (0.5) 1 (0.5) - - 7 (3) - - 8 (3) - Page 7 of 10 4 - - - - - - - - - - - - - - - - - - 1 (0.5) - - - - - - - median OS was 28 months and 80% of pts (40 pts) were alive > 12 months. The subsequent generations of randomized studies [8,10,11,13,14,17,18] showed increased activity and effi- cacy starting from ORR ≤ 20%, PFS 5 months and OS Table 5 Limiting Toxicity Syndromes (LTS): overall and in young-elderly patients Overall N. % Patients 50 100 Limiting Toxicity Syndromes (LTS) 22 44 LTS single-site (LTS-ss) 10 20 LTS multiple-sites (LTS-ms) 12 24 Single DLT plus G2-3 10 20 Double DLTs 2 4 Abbreviation: DLT, dose-limiting toxicity; G, grade. Young-elderly N. % 24 100 11 46 2 8 9 37.5 7 29 2 8 ≤ 14 months of 5-FU alone. Doublets consisting of CPT-11, or OHP, or BEV associated to 5-FU or Capeci- tabine gained ORR 20.0-47.0%, PFS 5.9-9.0 months and OS 15.1-21.5 months, without demonstrating differences between 5-FU/BEV associations compared to 5-FU or Capecitabine with CPT-11 or OHP. Triplets consisting of chemotherapeutic drugs or doublets plus BEV obtained ORR 39.0-66.0%, PFS 8.3-10.6 months and OS 20.3-26.1 months. In particular, the addition of a third drug, either BEV or OHP, equivalently increased the efficacy of doublet combination associating 5FU/CPT- 11; 5-FU or Capecitabine and OHP plus BEV shows OS 20.4-26.1 months [13,14]. Based on these data, a phase II study of four drug association, adding BEV to FOL- FOXIRI, was recently proposed [27]. We previously showed that doublet and triplet che- motherapy using TFI/5-FU, without Leucovorin, accord- ing to the present schedule [19,20], obtained equivalent