Introduction: The development of oxaliplatin (O) - 5-fluorouracil-leucovorin (FL) as the main chemotherapy for metastatic colorectal cancer (MCC) is based on Oxaliplatin safety and FLO efficacy of chronomodulated (chrono) delivery (JNCI 1990; 1994; Cancer 1992; Lancet 1997). The activity of this 3-drug regimen given for 4 days (chronoFLO4) (JCO 1996) or as 2-day FOLFOX2 (EJC 1997) led us to perform this international randomized trial testing the role of schedule for survival in MCC patients. Methods: The main goal was to increase 2-year survival by 10% with chronoFLO4. 564 MCC patients (226 women; 338 men) in 36 centres (10 countries) received either therapeutic schedule every 2 weeks, with the same initial doses (FU, 1700 mg/m2; LV, 1200 mg/m2; Ox, 100 mg/m2). Intrapatient FU escalation (200 mg/m2/ course) was performed if toxicity < grade 2. Results: Distinct tolerabilty profiles but no difference in overall survival were found as a function of schedule. The analysis of predictive factors for survival revealed that the most active schedule in women was the least active one in men and vice versa (p<0.01). Median survival (months) in women was 19.1 on FOLFOX2 [95% C.I: 17.6; 24.1] vs. 16.3 on chronoFLO4 [14.1; 19.6] (p = 0.027). Conversely, median survival in men was 18.3 [16.8; 20.5] on FOLFOX2 vs 21. 4 [19.3; 24.6] on chronoFLO4 (p= 0.018). Compared with FOLFOX2, chronoFLO4 increased the relative risk of an earlier death by 38% in women, but decreased it by 25% in men. This gender dependency was confirmed with multivariate analysis (p = 0.0012). Irrespective of schedule, the incidence of grade 3-4 toxicities was high and gender-dependent (73% in women vs 56% in men, p<0.001). Conclusions: This pragmatic trial identified gender as the main predictor of best scheduling of FU-LV-oxaliplatin for optimal survival. The biological hypotheses accounting for these gender dependencies are being explored in a translational project. Sex-related differences characterized the optimal timing of several cytotostatics in experimental models and FU clearance rhythm in cancer patients. Both recommended doses and best delivery schedule can differ between male and female cancer patients
GENDER-DEPENDENT OPTIMAL SCHEDULING OFCANCER CHRONOTHERAPEUTICS
TAMPELLINI, MARCO;
2006-01-01
Abstract
Introduction: The development of oxaliplatin (O) - 5-fluorouracil-leucovorin (FL) as the main chemotherapy for metastatic colorectal cancer (MCC) is based on Oxaliplatin safety and FLO efficacy of chronomodulated (chrono) delivery (JNCI 1990; 1994; Cancer 1992; Lancet 1997). The activity of this 3-drug regimen given for 4 days (chronoFLO4) (JCO 1996) or as 2-day FOLFOX2 (EJC 1997) led us to perform this international randomized trial testing the role of schedule for survival in MCC patients. Methods: The main goal was to increase 2-year survival by 10% with chronoFLO4. 564 MCC patients (226 women; 338 men) in 36 centres (10 countries) received either therapeutic schedule every 2 weeks, with the same initial doses (FU, 1700 mg/m2; LV, 1200 mg/m2; Ox, 100 mg/m2). Intrapatient FU escalation (200 mg/m2/ course) was performed if toxicity < grade 2. Results: Distinct tolerabilty profiles but no difference in overall survival were found as a function of schedule. The analysis of predictive factors for survival revealed that the most active schedule in women was the least active one in men and vice versa (p<0.01). Median survival (months) in women was 19.1 on FOLFOX2 [95% C.I: 17.6; 24.1] vs. 16.3 on chronoFLO4 [14.1; 19.6] (p = 0.027). Conversely, median survival in men was 18.3 [16.8; 20.5] on FOLFOX2 vs 21. 4 [19.3; 24.6] on chronoFLO4 (p= 0.018). Compared with FOLFOX2, chronoFLO4 increased the relative risk of an earlier death by 38% in women, but decreased it by 25% in men. This gender dependency was confirmed with multivariate analysis (p = 0.0012). Irrespective of schedule, the incidence of grade 3-4 toxicities was high and gender-dependent (73% in women vs 56% in men, p<0.001). Conclusions: This pragmatic trial identified gender as the main predictor of best scheduling of FU-LV-oxaliplatin for optimal survival. The biological hypotheses accounting for these gender dependencies are being explored in a translational project. Sex-related differences characterized the optimal timing of several cytotostatics in experimental models and FU clearance rhythm in cancer patients. Both recommended doses and best delivery schedule can differ between male and female cancer patients
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