Adding Oxaliplatin to Preoperative Chemoradiotherapy and Postoperative Chemotherapy Improves Disease-Free Survival in Locally Advanced Rectal Cancer
Final results of the German phase III CAO/ARO/AIO-04 trial reported in The Lancet Oncology by Rödel et al showed that adding oxaliplatin to fluorouracil (5-FU)–based neoadjuvant chemoradiation and postoperative chemotherapy improved disease-free survival in patients with locally advanced rectal cancer.
Study Details
In this open-label trial, 1,236 patients with clinical stage T3–4 or any node-positive disease from 88 sites in Germany took part. Between July 2006 and February 2010, they were randomly assigned to receive preoperative radiotherapy of 50.4 Gy in 28 fractions plus infusional 5-FU 1,000 mg/m2 on days 1 to 5 and 29 to 33 followed by total mesorectal excision and four cycles of bolus 5-FU (500 mg/m2) on days 1 to 5 and 29 (control group, n = 623) or the same preoperative radiotherapy plus infusional 5-FU 250 mg/m² on days 1 to 14 and 22 to 35 and oxaliplatin 50 mg/m² on days 1, 8, 22, and 29 followed by surgery and eight cycles of oxaliplatin 100 mg/m² on days 1 and 15, leucovorin 400 mg/m² on days 1 and 15, and infusional 5-FU 2,400 mg/m² on days 1 to 2 and 15 to 16 (investigational group, n = 613). The primary endpoint was disease-free survival in the intent-to-treat population.
Disease-Free Survival
Median follow-up was 50 months. In total, 21% of the investigational group and 22% of the control group did not start postoperative chemotherapy. Complete locoregional resection was achieved in 567 (95%) of 596 operated patients in the investigational group and in 584 (95%) of 615 operated patients in the control group.
Disease-free survival at 3 years was 75.9% (95% confidence interval [CI] = 72.4%–79.5%) in the investigational group vs 71.2% (95% CI = 67.6%–74.9%) in the control group (hazard ratio [HR] = 0.79, P = .03). Hazard ratios favored investigational treatment in most predefined subgroups, with a significant benefit observed in younger patients (< 61 years); male patients; and patients with clinically node-negative disease, low-lying tumors (< 5 cm from the anal verge), and abdominoperineal resection surgery.
Three-year overall survival was 88.7% (95% CI = 86.0%–91.3%) in the investigational group and 88.0% (95% CI = 85.3%–90.7%) in the control group (HR = 0.96, 95% CI = 0.72–1.26). Follow-up for overall survival continues.
Adverse Events
Preoperative grade 3 or 4 adverse events occurred in 144 (24%) of 607 patients who received 5-FU and oxaliplatin during chemoradiotherapy and in 128 (20%) of 625 patients who received 5-FU chemoradiotherapy. Postoperative grade 3 or 4 adverse events occurred in 158 (36%) of 445 patients who received adjuvant 5-FU, leucovorin, and oxaliplatin and in 170 (36%) of 470 who received adjuvant 5-FU.
Late grade 3 to 4 adverse events in patients who received the protocol-specified preoperative and postoperative treatments occurred in 112 (25%) of 445 patients in the investigational group and in 100 (21%) of 470 patients in the control group.
The investigators concluded: “Adding oxaliplatin to [5-FU]–based neoadjuvant chemoradiotherapy and adjuvant chemotherapy (at the doses and intensities used in this trial) significantly improved disease-free survival of patients with clinically staged cT3-4 or cN1-2 rectal cancer compared with our former [5-FU]–based combined modality regimen (based on CAO/ARO/AIO-94). The regimen established by CAO/ARO/AIO-04 can be deemed a new treatment option for patients with locally advanced rectal cancer.”
Claus Rödel, MD, of University of Frankfurt, is the corresponding author of The Lancet Oncology article.
The study was funded by German Cancer Aid (Deutsche Krebshilfe). For full disclosures of the study authors, visit www.thelancet.com/journals/lanonc/.
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