High efficacy of sequential chemotherapy (CT) with dose-dense modified TCF regimen (TCF-DD) followed by CT with Oxaliplatin, Folinic Acid (FA), 5-Fluorouracil (5-FU) and Irinotecan (COFFI) in metastatic gastric cancer (MGC)

Background: Previous phase II trials made by our group showed that COFFI and TCFDD regimens are very active in MGC. Based on these studies we tested a sequential CT in order to avoid the occurrence of drug resistance. Methods: chemo-naı¨ve patients (pts) with MGC, PS ‡1, received in 16 weeks: 4 cycles of TCF-DD (Docetaxel 70 mg/m2 day [d] 1, Cisplatin 60 mg/m2 d 1, l-FA 100 mg/m2 d 1 and 2, 5-FU 400 mg/m2 bolus and then 600 mg/m2 as a 22 h c.i. d 1 and 2, every 14 days) followed by 4 cycles of COFFI (Oxaliplatin 85 mg/m2 d 1, Irinotecan 140 mg/m2 d 1, l-FA 200 mg/m2 d 1, 5-FU bolus 400 mg/m2 d 1 and then 2,400 mg/m2 as a 48 h c.i. every 14 days). In both regimens pegfilgrastim 6 mg on d 4 was included. End points were response rate (ORR) and TTP (RECIST criteria and ITT principle). Results: 40 consecutive pts were enrolled; in 8 pts CT is ongoing. Median age: 64, range 40-81; 63% male. 11/32 pts required a dose reduction of TCF-DD, mostly because of grade 3-4 haematologic, gastrointestinal toxicity and asthenia. 25/32 completed the 4 cycles of TCF-DD and 12/32 respected the schedule. 28 were evaluated for response (2 early suspension: 1 allergic reaction to Docetaxel and 1 severe toxicity; 2 early deaths: 1 bowel perforation and 1 sepsis): 2 CR, 16 PR, 7 SD and 3 PD were observed, for an ORR of 56% (95% CI, 39-73). 21 pts proceeded to COFFI. 2 required a dose reduction because of diarrhoea; all 21 pts were evaluated for response. The 2 CR observed after TCF-DD were maintained after COFFI. Among the 16 pts with PR after TCF-DD, 2 achieved CR, 5 further improved the response, 5 mantained PR, 2 progressed and 2 did not start COFFI (1 early death and 1 protocol violation). Among the 7 pts with SD after TCF-DD, 2 achieved PR, 2 mantained SD, 1 progressed and 2 did not start COFFI (1 protocol violation and 1 for other reasons). The ORR in the 32 pts was 63% (95% CI, 46%-79%). At a median f-up of 19 months (95% CI, 16-23) median TTP was 9 months (95% CI, 6-9,7). 1-year survival was 31%. 2 pts with multiple liver metastases mantained CR after 33 and 16 months. Conclusions: A sequential strategy using TCF-DD followed by COFFI is feasible, highly effective and deserves to be tested in randomized studies