CHICAGO—Capecitabine therapy demonstrated statistically significant three-year disease free survival (DFS) rates, significantly improved five-year overall survival (OS) and improved nodal-downstaging in patients with locally advanced rectal cancer as compared with 5-fluorouracil (5-FU), according to study data presented at the American Society of Clinical Oncology’s 2011 Annual Meeting.

Ralf Hofheinz, MD, of the Day Treatment Centre at the Interdisciplinary Tumour Centre Mannheim, Germany, and colleagues reported on long-term data from this noninferiority, two-arm, two-strata (adjuvant and neoadjuvant) randomized, Phase 3 trial with primary endpoints of overall survival (OS) and secondary endpoints of disease-free survival and safety data. Inclusion criteria included age ≥18 years, histologically proven rectal cancer (0–16 cm ab ano), no distant metastases, adequate hematological parameters, and adequate liver and renal function. Patients were treated in the adjuvant stratum if a total mesorectal resection had been performed (R0-resection) and were classified with tumor stages pT3/4 Nany MO or pTany N+ MO. Patients were treated in the neoadjuvant stratum if a total mesorectal excision was mandatory and their disease was classified as stages uT3/4 uNany MO or uTany uN+ MO.

Patients in Arm A received chemoradiotherapy (CRT): 50.4 Gy + capecitabine 1,650 mg/m2 Days 1–38 + 5 courses of capecitabine 2,500 mg/m2 Days 1–14, repeat on Day 22 (stratum (S) adjuvant (I): 2 x capecitabine, CRT, 3 x capecitabine; S neoadjuvant (II): CRT, TME surgery, 5 x capecitabine). Patients in Arm B received: CRT: 50.4 Gy + 5-FU 225mg/m2 continuous infusion daily [S I] or 5-FU 1,000 mg/m2 continuous infusion Days 1–5 and 29–33 [S II] + 4 cycles of bolus 5-FU 500mg/m2 Days 1–5, repeat. Day 29 (S I: 2 x 5-FU, CRT, 2 x 5-FU; S II: CRT, TME surgery, 4 x 5-FU).

Of 401 randomized patients, 392 were evaluable (Arm A n=197, arm B n=195; S I n=231, S II n=161). At a median follow-up of 52 months, the local recurrence rate was equal (capecitabine 6.1%, 5-FU 7.2%, P=0.7795), while significantly fewer patients developed distant metastases in the capecitabine arm (18.8% vs. 27.7%; P=0.0367). Capecitabine was found to be non-inferior to 5-FU regarding the 5-year OS rate (capecitabine 75.7% vs. 5-FU 66.6%; P=0.0004). The test for superiority showed borderline significance in favor of capecitabine (P=0.053). The 3-year and 5-year disease-free survival was significantly better with capecitabine (75.2% vs. 66.6% and 67.8% vs. 54.1%; P=0.035 for both). Safety data was reported at the ASCO 2009 Annual Meeting. However, patients receiving capecitabine had more hand-foot skin reactions, diarrhea, fatigue, proctitis, while leukopenia and alopecia was more frequent with 5-FU. Dr. Hofheinz noted, however, that capecitabine patients developing hand-foot skin reactions had better 3-year DFS (83.2%) and 5-year OS (91.4%) in comparison to 5-FU patients (P=0.004 for DFS and P<0.0001 for OS).

A trend of improved downstaging was observed in the S II arm. Patients receiving capecitabine in S II had a significantly lower rate of ypN-positive tumors (P=0.09), improved T-downstaging (ie, ypT 0–2) (P=0.07), and more pCR (ypT0 ypN0) (13.2% vs. 5.4%; P=0.16). A total of 93 patients had died, 55 of who were in the 5-FU arm.

Dr. Hofheinz et al concluded that capecitabine is safe and efficacious, and may replace 5-FU for the perioperative treatment of locally advanced rectal cancer.