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While none of the most active fluoropyrimidine regimens stands out as superior in terms of efficacy, the bolus 5-FU/LV Mayo Clinic regimen is used in a large proportion of centers owing to its confirmed activity and ease of administration compared with infusional regimens. Treatment consists of bolus LV 20 mg/m2 followed by iv bolus 5-FU 425 mg/m2 on days 1 to 5, repeated every 28 days. A number of randomized, phase III trials have been conducted to compare new fluoropyrimidine regimens with the Mayo Clinic regimen as first-line treatment for colorectal cancer. Dr. Twelves described the 4 fluoropyrimidine regimens that he was going to discuss in his presentation -- 2 oral fluoropyrimidines and 2 of the most active infusional 5-FU/LV regimens:
Before discussing the efficacy and safety data for the 4 regimens in detail, Dr. Twelves drew attention to some of the differences between the trials. He noted that in the de Gramont trial, which was not conducted for regulatory purposes, the analysis population was substantially smaller than the intent-to-treat population (448 patients randomized, 433 patients in the survival and time to disease progression (TTP) analyses, 348 patients in the response-rate analysis). He urged delegates to bear this in mind when comparing the trials. In the EORTC/AIO trial, only patients with measurable disease were included in the analysis of response rate. A notable difference in study design between the 4 studies was the longer interassessment intervals in the UFT/LV and de Gramont trials (8-10 and 12 weeks, respectively, compared with 6 and 4 weeks in the capecitabine and EORTC/AIO trials, respectively). The longer period between assessments results in cruder estimation of endpoints such as TTP. Another particularly important difference in the study designs in the context of this comparison, which was stressed later by Professor Jim Cassidy, is the different primary endpoints used in the 4 trials. For the UFT/LV, de Gramont, and EORTC/AIO trials, the primary endpoint was survival, whereas for the capecitabine analysis, the primary objective was to demonstrate at least equivalent efficacy in terms of response rate, with survival and TTP identified as secondary endpoints.
Median TTP (months) Relation to Mayo Clinic Regimen P value Capecitabine 4.6/4.7 Equivalent .95 UFT/LV 3.5/3.8 Inferior .01 de Gramont 6.3/5.0 Superior .001 EORTC/AIO
Both the de Gramont and EORTC/AIO infusional 5-FU/LV regimens offered modest but significant increases in TTP. Median TTP was 6.3 months with the de Gramont regimen compared with 5.0 months in the Mayo Clinic regimen arm (P = .001), and 6.3 vs 4.1 months with the EORTC/AIO (plus LV) regimen and Mayo Clinic regimen, respectively (P = .02). The de Gramont regimen also demonstrated a significant improvement in response rates compared with the Mayo Clinic regimen (33% vs 15%, P = .004), although Dr. Twelves reminded the audience that the response rate analysis was based on only three quarters of the randomized population. There was a large difference in response rates between the EORTC/AIO (20.5%) and the Mayo Clinic regimen (11.5%), but this difference did not reach statistical significance, possibly because of the relatively small number of patients with measurable disease.
Dr. Twelves also noted that in all 4 trials, the response rates achieved with Mayo Clinic regimen were consistently in the order of 12% to 15%, suggesting that the patient populations evaluated in the 4 trials were similar (Table 2).
Study Treatment Mayo Clinic Regimen P value Capecitabine 25.7 16.7 < .0002 UFT/LV 11.7 14.5 NS de Gramont 32.6 14.5 .004 EORTC/AIO
NS = not significant
Therefore, in terms of efficacy, concluded Dr. Twelves, none of the regimens provided a significant survival advantage over the Mayo Clinic regimen. However, capecitabine and the de Gramont regimen produced significant improvements in response rates, the infusional regimens provided significant improvements in TTP, and UFT/LV resulted in significantly inferior TTP.
One of the more frequent toxic effects associated with capecitabine therapy is cutaneous hand-foot syndrome, which affects palms and soles. However, this adverse event is usually mild to moderate in intensity, emphasized Dr. Twelves, and resulted in the hospitalization of only 2 of more than 600 patients treated with capecitabine in the 2 phase III trials. If patients and oncologists learn to recognize the early signs of mild or moderate hand-foot syndrome, development of severe hand-foot syndrome can usually be avoided by interrupting therapy, he added.
Patient preference must also be taken into consideration when choosing the ideal therapy: a questionnaire-based survey of 103 patients revealed that most patients prefer oral chemotherapy, provided this is not at the expense of efficacy. These results were supported by data from a recently reported, randomized, crossover study, in which patients showed a strong preference for oral vs iv therapy (84% in favor of oral therapy). The principal reasons stated for this preference were oral administration, home-based treatment, and ability to continue daily activities.