CAO/ARO/AIO-12
Induction chemotherapy before or after preoperative chemoradiotherapy and surgery for locally advanced rectal cancer: a randomized phase II trial of the German Rectal Cancer Study Group
Phase 2N = 311NCT02363374
- Population
- Patients with stage II or III (cT3-4 and/or node-positive) rectal adenocarcinoma
- Design
- Multicentre randomised phase 2 trial with a pick-the-winner design, built on the hypothesis of a pathological complete response rate of 25% after total neoadjuvant therapy compared with 15% for standard preoperative chemoradiotherapy. Patients had stage II or III rectal cancer. Group A: three cycles of fluorouracil, leucovorin and oxaliplatin before fluorouracil/oxaliplatin chemoradiotherapy (50.4 Gy). Group B: the same chemoradiotherapy first, then consolidation chemotherapy. Total mesorectal excision was scheduled on day 123 after the start of treatment in both groups. 311 patients were enrolled and 306 were evaluable (156 in group A, 150 in group B).
- Primary endpoint
- pCR
- Arms
- Induction chemotherapy then chemoradiotherapy (group A) (experimental, n = 156): Three cycles of fluorouracil, leucovorin and oxaliplatin, then fluorouracil/oxaliplatin chemoradiotherapy (50.4 Gy), then total mesorectal excision
- Chemoradiotherapy then consolidation chemotherapy (group B) (experimental, n = 150): Fluorouracil/oxaliplatin chemoradiotherapy (50.4 Gy), then consolidation chemotherapy, then total mesorectal excision
- People
- Fokas E
DFSHR 0.95 (95% CI 0.63–1.45)
Show the numbers
| Endpoint | Analysis | Induction chemotherapy then chemoradiotherapy (group A) / Chemoradiotherapy then consolidation chemotherapy (group B) | Control | Effect |
|---|---|---|---|---|
| pCRIntention-to-treat population (306 evaluable: 156 and 150)Pathological complete response (ypT0N0), the primary endpoint | primaryFokas 2019 | 17% | — | Each group was tested separately against the standard benchmark of 15%: group A P=0.210, group B P<0.001. There was no concurrent control group. |
| Grade 3-4 acute toxicityEvaluable patients (156 in group A, 150 in group B)Chemoradiotherapy-related grade 3 or 4 toxicity | primaryFokas 2019 | 37% | — | Full-dose radiotherapy, concomitant fluorouracil and concomitant oxaliplatin were received by 91%, 78% and 76% in group A and 97%, 87% and 93% in group B; 92% (group A) and 85% (group B) completed all induction or consolidation chemotherapy cycles. The median interval between the end of chemoradiotherapy and surgery was 90 days in group B and 45 days in group A, without a reported increase in surgical morbidity. |
| DFSEvaluable patients (306: 156 in group A, 150 in group B)3-year disease-free survival (secondary end point, prespecified) | long term-updatemedian follow-up 43 monthsFokas 2022 | 73% at 3 y | — | HR 0.95 (95% CI 0.63–1.45)P=0.82 |
| Locoregional failureEvaluable patients (306: 156 in group A, 150 in group B)3-year cumulative incidence of locoregional recurrence, as named in the abstract | long term-updatemedian follow-up 43 monthsFokas 2022 | 6% at 3 y | — | P=0.67 |
| Cumulative incidence of distant metastasesEvaluable patients (306: 156 in group A, 150 in group B) | long term-updatemedian follow-up 43 monthsFokas 2022 | 18% at 3 y | — | P=0.52Chronic toxicity grade 3 to 4 at 3 years occurred in 10 of 85 patients (11.8%) in group A and 8 of 66 patients (9.9%) in group B. |
| OSEligible patients (306)5-year overall survival | long term-updatemedian follow-up 60 monthsDiefenhardt 2025 | 85.8% at 5 y (80.2–91.8%) | — | General pairwise comparison across ranked outcomes (overall survival, locoregional recurrence, distant metastasis, pathological or clinical complete remission, long-term quality of life, toxicity): net treatment benefit -1.38% and win ratio 0.97, reported by the authors as no clinically meaningful overall difference between the two sequences. In the full text the rate of complete remission (pathological, or sustained clinical when the patient declined surgery) was 21% (32 of 156) in group A and 27% (41 of 150) in group B (pairwise-comparison delta 0.0682, 95% CI -0.0275 to 0.1627, P=0.16); 5-year local recurrence was 6.9% vs 5.9% and 5-year distant metastases 21.7% vs 23.76% (groups A vs B). |
| Endpoint | Analysis | Induction chemotherapy then chemoradiotherapy (group A) / Chemoradiotherapy then consolidation chemotherapy (group B) | Control | Effect |
|---|---|---|---|---|
| pCRIntention-to-treat population (306 evaluable: 156 and 150)Pathological complete response (ypT0N0), the primary endpoint | primaryFokas 2019 | 17% | — | Each group was tested separately against the standard benchmark of 15%: group A P=0.210, group B P<0.001. There was no concurrent control group. |
| Grade 3-4 acute toxicityEvaluable patients (156 in group A, 150 in group B)Chemoradiotherapy-related grade 3 or 4 toxicity | primaryFokas 2019 | 37% | — | Full-dose radiotherapy, concomitant fluorouracil and concomitant oxaliplatin were received by 91%, 78% and 76% in group A and 97%, 87% and 93% in group B; 92% (group A) and 85% (group B) completed all induction or consolidation chemotherapy cycles. The median interval between the end of chemoradiotherapy and surgery was 90 days in group B and 45 days in group A, without a reported increase in surgical morbidity. |
| DFSEvaluable patients (306: 156 in group A, 150 in group B)3-year disease-free survival (secondary end point, prespecified) | long term-updatemedian follow-up 43 monthsFokas 2022 | 73% at 3 y | — | HR 0.95 (95% CI 0.63–1.45)P=0.82 |
| Locoregional failureEvaluable patients (306: 156 in group A, 150 in group B)3-year cumulative incidence of locoregional recurrence, as named in the abstract | long term-updatemedian follow-up 43 monthsFokas 2022 | 6% at 3 y | — | P=0.67 |
| Cumulative incidence of distant metastasesEvaluable patients (306: 156 in group A, 150 in group B) | long term-updatemedian follow-up 43 monthsFokas 2022 | 18% at 3 y | — | P=0.52Chronic toxicity grade 3 to 4 at 3 years occurred in 10 of 85 patients (11.8%) in group A and 8 of 66 patients (9.9%) in group B. |
| OSEligible patients (306)5-year overall survival | long term-updatemedian follow-up 60 monthsDiefenhardt 2025 | 85.8% at 5 y (80.2–91.8%) | — | General pairwise comparison across ranked outcomes (overall survival, locoregional recurrence, distant metastasis, pathological or clinical complete remission, long-term quality of life, toxicity): net treatment benefit -1.38% and win ratio 0.97, reported by the authors as no clinically meaningful overall difference between the two sequences. In the full text the rate of complete remission (pathological, or sustained clinical when the patient declined surgery) was 21% (32 of 156) in group A and 27% (41 of 150) in group B (pairwise-comparison delta 0.0682, 95% CI -0.0275 to 0.1627, P=0.16); 5-year local recurrence was 6.9% vs 5.9% and 5-year distant metastases 21.7% vs 23.76% (groups A vs B). |
Data table
| Endpoint | HR | 95% CI |
|---|---|---|
| DFS | 0.95 | 0.63–1.45 |
Appears in
Sources
Fokas E, Allgäuer M, Polat B, Klautke G, Grabenbauer GG, Fietkau R, et al. Randomized Phase II Trial of Chemoradiotherapy Plus Induction or Consolidation Chemotherapy as Total Neoadjuvant Therapy for Locally Advanced Rectal Cancer: CAO/ARO/AIO-12. J Clin Oncol. 2019;37(34):3212-3222.
Fokas E, Schlenska-Lange A, Polat B, Klautke G, Grabenbauer GG, Fietkau R, et al. Chemoradiotherapy Plus Induction or Consolidation Chemotherapy as Total Neoadjuvant Therapy for Patients With Locally Advanced Rectal Cancer: Long-term Results of the CAO/ARO/AIO-12 Randomized Clinical Trial. JAMA Oncol. 2022;8(1):e215445.
Diefenhardt M, Kosmala R, Fleischmann M, Martin D, Hofheinz RD, Ghadimi M, et al. Chemotherapy before or after preoperative chemoradiotherapy and surgery for locally advanced rectal cancer: 5-year results of the CAO/ARO/AIO-12 trial - a general pairwise comparison. ESMO Open. 2025;10(3):104483.