Capecitabine (Cape) versus 5-fluorouracil (5-FU)–based (neo)adjuvant chemoradiotherapy (CRT) for locally advanced rectal cancer (LARC): Long-term results of a randomized, phase III trial.

Abstract

3504 Background: 5-FU based CRT is regarded standard perioperative treatment in LARC. We report long-term data of a non-inferiority phase III trial investigating (neo-)adjuvant CRT with Cape in comparison with 5-FU. Methods: Patients (pts) aged ≥18 years with LARC UICC stages II or III were recruited into this two-arm, two-strata randomized phase-III trial (arm A: Cape, arm B: 5-FU; stratum [S] I: adjuvant, S II: neoadjuvant). Regimens: Arm A: CRT: 50.4 Gy + Cape 1,650 mg/m2 days 1-38 plus five courses of Cape 2,500 mg/m2 d 1-14, rep. d 22 (S I: 2 x Cape, CRT, 3 x Cape; S II: CRT, TME surgery, 5 x Cape). Arm B: CRT: 50.4 Gy + 5-FU 225 mg/m2 c.i. daily [S I] or 5-FU 1,000 mg/m2 c.i. d 1-5 and 29-33 [S II] plus 4 cycles of bolus 5-FU 500mg/m2 d 1-5, rep. d 29 (S I: 2 x 5-FU, CRT, 2 x 5-FU; S II: CRT, TME surgery, 4 x 5-FU). Primary endpoint was overall survival (OS), secondary endpoints comprised disease-free survival (DFS) and safety. Results: Of 401 randomized pts, 392 are evaluable (Arm A n=197, arm B n=195; S I n=231, S II n=161). Toxicity, treatment duration and downstaging in S II were reported at ASCO 2009. Briefly, pts receiving Cape had more hand-foot skin reactions (HFS), fatigue, and proctitis, while leukopenia was more frequent with 5-FU. Pts receiving Cape in S II had a significantly higher rate of ypN- tumors. At a median follow-up of 52 months, the local recurrence rate was equal (Cape 6%, 5-FU 7%, p=0.665), while significantly less pts developed distant metastases in the Cape arm (18.8% vs 27.7%; p=0.037). A total of 93 patients had died, 55 of whom in the 5-FU arm. Cape was non-inferior to 5-FU regarding 5-year OS (Cape 75.7% vs 5-FU 66.6%; p=0.0004). The test for superiority showed borderline significance in favor of Cape (p=0.053). 3-year DFS was significantly better with Cape (75.2% vs 66.6%; p=0.034). Cape pts developing HFS had better 3-year DFS (83.2%) and 5-year OS (91.4%) in comparison with the remaining pts (p=0.004 for DFS and p<0.0001 for OS). Conclusions: In view of the advantageous safety profile, an improved nodal-downstaging in neoadjuvant stratum and the favourable survival data Cape may replace 5-FU in the perioperative treatment of LARC.