Capecitabine Better Than, Not Inferior to, Fluorouracil in Perioperative Treatment of Rectal Cancer
Capecitabine Better Than, Not Inferior to, Fluorouracil in Perioperative Treatment of Rectal Cancer
Abstract & Commentary
Synopsis:In a multicenter, Phase 3 trial, perioperative chemoradiotherapy with capecitabine proved safe and equivalently effective as fluorouracil in reducing local recurrence. In fact, post hoc analysis demonstrated better disease-free and overall survival for those treated with capecitabine. This is a finding that will resonate in the offices of community-based oncologists.
Source:Hofheintz RD, et al. Chemoradiotherapy with capecitabine versus fluorouracil for locally advanced rectal cancer: A randomized, multicenter, non-inferiority Phase 3 trial. Lancet Oncol 2012;13:579-588.
Fluorouracil (FU)-based chemoradiotherapy has been regarded as a standard perioperative treatment for locally advanced rectal cancer.1 However, capecitabine, a fluorpyrimidine derivative that has proven equally effective as FU plus folinic acid for adjuvant treatment of stage III colon cancer2 also may be equally effective in this setting, and offers the advantage of oral administration. To address this, Hofheintz and colleagues throughout Germany conducted an industry-sponsored, multicenter, randomized, Phase 3 trial in patients with pathological stage II–III locally advanced rectal cancer from 35 German institutions. The trial was initiated in 2002 before neoadjuvant chermoradiotherapy was common practice. However, the protocol was amended in 2005 to include patients receiving preoperative chemoradiotherapy (neoadjuvant cohort).
Patients enrolled in the "adjuvant" (i.e., postoperative) cohorts received either two cycles of capecitabine (2500 mg/m2 days 1-14, repeated day 22), followed by chemoradiotherapy (50.4 Gy plus capecitabine 1650 mg/m2 days 1-38), then three cycles of capecitabine or two cycles of bolus fluorouracil (500 mg/m2 days 1-5, repeated day 29), followed by chemoradiotherapy (50.4 Gy plus infusional fluorouracil 225 mg/m2 daily), then two cycles of bolus fluorouracil. Upon amendment, those who were included as "neoadjuvant" received chemoradiotherapy (50.4 Gy plus capecitabine 1650 mg/m2 daily) followed by radical surgery and five cycles of capecitabine (2500 mg/m2 per day for 14 days) or chemoradiotherapy (50.4 Gy plus infusional fluorouracil 1000 mg/m days 1-5 and 29-33) followed by radical surgery and four cycles of bolus fluorouracil (500 mg/m2 for 5 days). The primary endpoint was overall survival; analyses were done based on all patients with post-randomization data. Non-inferiority of capecitabine in terms of 5-year overall survival was tested with a 12.5% margin.
A total of 401 patients were randomly allocated; 392 patients were evaluable (197 in the capecitabine group, 195 in the FU group), with a median follow-up of 52 months (IQR 41-72). Five-year overall survival in the capecitabine group was non-inferior to that in the FU group (76% [95% CI 67-82] vs 67% [58-74]; P = 0.0004; post-hoc test for superiority P = 0.05). Three-year disease-free survival was 75% (95% CI 68-81) in the capecitabine group and 67% (59-73) in the fluorouracil group (P = 0.07). Similar numbers of patients had local recurrences in each group (12 [6%] in the capecitabine group vs 14 [7%] in the fluorouracil group, P = 0.67), but fewer patients developed distant metastases in the capecitabine group (37 [19%] vs 54 [28%]; P = 0.04). Diarrhea was the most common adverse event in both groups (any grade: 104 [53%] patients in the capecitabine group vs 85 [44%] in the fluorouracil group). Patients in the capecitabine group had more hand-foot skin reactions (62 [31%] vs three [2%]), whereas leucopenia was more frequent with fluorouracil than with capecitabine (68 [35%] any grade, 16 [8%] grade 3-4 vs 50 [25%] any grade, three [2%] grade 3-4).
Commentary
This study resulted in findings very similar to the X-ACT trial demonstrating non-inferiority of capecitabine when compared with FU in the adjuvant treatment of stage III colon cancer.2,3 In the present study, when examined by post hoc analysis, those receiving capecitabine had better disease-free and overall survival with equivalent (low) rates of local recurrence. Current investigations are underway to examine the role of additional chemotherapeutic agents in the neoadjuvant setting, including prominently, oxaliplatin.4 In the meantime, clinicians can be reassured that substituting capecitabine for FU, a choice with the obvious advantage of oral administration, comes at no cost in terms of safety or efficacy. In fact, there is now evidence in terms of disease-free and overall survival that it may be better.
References
1. Sauer R, et al. N Engl J Med 2004;351:1731-1740.
2. Twelves C, et al. N Engl J Med 2005;352:2696-2704.
3. Twelves C, et al. Ann Oncol 2012;23:1190-1197.
4. Aschele C, et al. J Clin Oncol 2011;29:2773-2780.
In a multicenter, Phase 3 trial, perioperative chemoradiotherapy with capecitabine proved safe and equivalently effective as fluorouracil in reducing local recurrence. In fact, post hoc analysis demonstrated better disease-free and overall survival for those treated with capecitabine. This is a finding that will resonate in the offices of community-based oncologists.Subscribe Now for Access
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