CAO/ARO/AIO-04
Prospective randomised multicenter phase-III-study: preoperative radiochemotherapy and adjuvant chemotherapy with 5-fluorouracil plus oxaliplatin versus preoperative radiochemotherapy and adjuvant chemotherapy with 5-fluorouracil for locally advanced rectal cancer
Phase 3N = 1,265NCT00349076
- Population
- Patients with rectal adenocarcinoma, clinically staged cT3-4 or any node-positive disease
- Design
- Multicentre, open-label, randomised phase 3 study in patients with rectal adenocarcinoma, clinically staged cT3-4 or any node-positive disease. Control group: preoperative radiotherapy 50.4 Gy in 28 fractions plus infusional fluorouracil (1000 mg/m2 on days 1-5 and 29-33), surgery, then four cycles of bolus fluorouracil (500 mg/m2 on days 1-5 and 29). Investigational group: the same radiotherapy plus infusional fluorouracil (250 mg/m2 on days 1-14 and 22-35) and oxaliplatin (50 mg/m2 on days 1, 8, 22 and 29), surgery, then eight cycles of oxaliplatin (100 mg/m2), leucovorin (400 mg/m2) and infusional fluorouracil (2400 mg/m2) on days 1-2 and 15-16. 1265 patients were initially enrolled; 1236 were assessable (613 investigational, 623 control). Primary endpoint: disease-free survival (time from randomisation to R2 resection, locoregional recurrence after R0/1 resection, metastatic disease or progression, or death).
- Primary endpoint
- DFS
- Arms
- Fluorouracil chemoradiotherapy and adjuvant fluorouracil (control, n = 623): Preoperative radiotherapy 50.4 Gy in 28 fractions with infusional fluorouracil, surgery, then four cycles of bolus fluorouracil
- Fluorouracil and oxaliplatin chemoradiotherapy and adjuvant fluorouracil, leucovorin and oxaliplatin (experimental, n = 613): Preoperative radiotherapy 50.4 Gy in 28 fractions with infusional fluorouracil and oxaliplatin, surgery, then eight cycles of oxaliplatin, leucovorin and infusional fluorouracil
- People
- Rödel C
DFSHR 0.79 (95% CI 0.64–0.98)Δ 36-month DFS+4.7 pointsΔ Grade 3-4 acute toxicity+4 pointsΔ pCR+4 points
Show the numbers
| Endpoint | Analysis | Fluorouracil and oxaliplatin chemoradiotherapy and adjuvant fluorouracil, leucovorin and oxaliplatin | Fluorouracil chemoradiotherapy and adjuvant fluorouracil | Effect |
|---|---|---|---|---|
| DFSIntention-to-treat analysis of assessable patients (1236: 613 investigational, 623 control)3-year disease-free survival (primary endpoint) | finalmedian follow-up 50 monthsRödel 2015 | 75.9% at 3 y (72.4–79.5%) | 71.2% at 3 y (67.6–74.9%) | HR 0.79 (95% CI 0.64–0.98)P=0.03Median follow-up 50 months (IQR 38-61). Oxaliplatin was added to both the preoperative chemoradiotherapy and the postoperative chemotherapy, and the control group received a different fluorouracil schedule. |
| Grade 3-4 acute toxicityPatients who actually received fluorouracil and oxaliplatin (607) or fluorouracil (625) chemoradiotherapyPreoperative grade 3-4 toxic effects | finalRödel 2015 | 24% | 20% | Adjuvant grade 3-4 toxic effects occurred in 158 (36%) of 445 patients who received the oxaliplatin-containing adjuvant chemotherapy and 170 (36%) of 470 who received adjuvant fluorouracil. Late grade 3-4 adverse events in patients who received the protocol-specified preoperative and postoperative treatment occurred in 112 (25%) of 445 patients in the investigational group and 100 (21%) of 470 in the control group. |
| pCRPatients who underwent surgery (591 investigational, 606 control)Pathological complete response (secondary endpoint, initial report) | interimRödel 2012 | 17% | 13% | P=0.038Odds ratio 1.40 (95% CI 1.02-1.92). The 2012 report is an initial analysis of secondary endpoints; disease-free survival, the primary endpoint, was reported in 2015. |
| Endpoint | Analysis | Fluorouracil and oxaliplatin chemoradiotherapy and adjuvant fluorouracil, leucovorin and oxaliplatin | Fluorouracil chemoradiotherapy and adjuvant fluorouracil | Effect |
|---|---|---|---|---|
| DFSIntention-to-treat analysis of assessable patients (1236: 613 investigational, 623 control)3-year disease-free survival (primary endpoint) | finalmedian follow-up 50 monthsRödel 2015 | 75.9% at 3 y (72.4–79.5%) | 71.2% at 3 y (67.6–74.9%) | HR 0.79 (95% CI 0.64–0.98)P=0.03Median follow-up 50 months (IQR 38-61). Oxaliplatin was added to both the preoperative chemoradiotherapy and the postoperative chemotherapy, and the control group received a different fluorouracil schedule. |
| Grade 3-4 acute toxicityPatients who actually received fluorouracil and oxaliplatin (607) or fluorouracil (625) chemoradiotherapyPreoperative grade 3-4 toxic effects | finalRödel 2015 | 24% | 20% | Adjuvant grade 3-4 toxic effects occurred in 158 (36%) of 445 patients who received the oxaliplatin-containing adjuvant chemotherapy and 170 (36%) of 470 who received adjuvant fluorouracil. Late grade 3-4 adverse events in patients who received the protocol-specified preoperative and postoperative treatment occurred in 112 (25%) of 445 patients in the investigational group and 100 (21%) of 470 in the control group. |
| pCRPatients who underwent surgery (591 investigational, 606 control)Pathological complete response (secondary endpoint, initial report) | interimRödel 2012 | 17% | 13% | P=0.038Odds ratio 1.40 (95% CI 1.02-1.92). The 2012 report is an initial analysis of secondary endpoints; disease-free survival, the primary endpoint, was reported in 2015. |
Data table
| Endpoint | HR | 95% CI |
|---|---|---|
| DFS | 0.79 | 0.64–0.98 |
Appears in
Sources
Rödel C, Graeven U, Fietkau R, Hohenberger W, Hothorn T, Arnold D, et al. Oxaliplatin added to fluorouracil-based preoperative chemoradiotherapy and postoperative chemotherapy of locally advanced rectal cancer (the German CAO/ARO/AIO-04 study): final results of the multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2015;16(8):979-89.
Rödel C, Liersch T, Becker H, Fietkau R, Hohenberger W, Hothorn T, et al. Preoperative chemoradiotherapy and postoperative chemotherapy with fluorouracil and oxaliplatin versus fluorouracil alone in locally advanced rectal cancer: initial results of the German CAO/ARO/AIO-04 randomised phase 3 trial. Lancet Oncol. 2012;13(7):679-87.