The goals of total neoadjuvant therapy (TNT) are to increase response by integrating systemic therapy before surgery, to reduce the risk of distant metastasis, to improve OS, and to improve quality of life by organ-preserving strategies (sphincter-preserving surgery, watch-and-wait for clinically complete response). Currently, several encouraging prospective studies with different TNT concepts and inclusion criteria have been published, but the heterogeneity of protocols make the comparison and interpretation of data rather complex (Table
1). In the Prodige-23 study [
14] and the RAPIDO study [
15], a significant improvement in DFS or disease-related treatment failure (DRFT) was demonstrated by induction chemotherapy with 6x FOLFIRINOX followed by radiochemotherapy (Prodige-23 study) or by short-term radiation followed by consolidation therapy with 6x CAPOX or 9x FOLFOX (Rapido study) compared with standard radiochemotherapy. Both trials showed more than a doubling of the pCR rate and a reduction of distant metastases. Data on OS from the Prodige-23 trial were presented at ASCO 2023, showing a significant survival benefit in favor of induction chemotherapy [
16]. No improvement in OS was shown in the RAPIDO trial. The German CAO/ARO/AIO-12 trial [
17] and the OPRA trial [
18] compared induction and consolidation chemotherapy. The CAO/ARO/AIO-12 trial compared 3 cycles of induction chemotherapy with FOLFOX followed by radiochemotherapy (oxaliplatin, 5‑FU) versus radiochemotherapy followed by consolidation chemotherapy with FOLFOX [
17]. Consolidation chemotherapy was superior in terms of increased pCR rates but there were comparable rates of DFS, local recurrence, and distant metastasis. Toxicities were lower and compliance higher in the consolidation group. The ongoing ACO/ARO/AIO-18.1 trial is investigating whether short-term radiation or radiochemotherapy should be used before consolidation chemotherapy. In the OPRA trial, 8 cycles of FOLFOX or 5 cycles of CAPOX were administered as either induction or consolidation chemotherapy and radiochemotherapy. A watch-and-wait strategy was offered to patients with a clinically complete remission. Both groups were formally compared with a historical control group. The aim of the study was to evaluate the optimal sequence of TNT in terms of DFS and organ preservation. The primary endpoint of the study, improvement in DFS, was not met and was comparable in both arms. However, 3‑year TME-free survival was better with consolidation chemotherapy. The STELLAR trial [
19] compared short-term radiation followed by 4 cycles of CAPOX, surgery, and 2 cycles of adjuvant CAPOX therapy with radiotherapy followed by TME and 6 cycles of adjuvant CAPOX therapy. There was no difference in DFS but the pCR rates and OS were significantly better in the experimental arm. By contrast, no difference was found in the incidence of distant metastases, R0 resection rates, and local recurrence.
Table 1
Overview of study details
Prodige 23 | 6x mFOLFIRINOX → CRT → 6x mFOLFOX6 versus CRT → TME → 12x mFOLFOX6 or 8x Cap | MRI | < 15 cm anal verge cT3 (at risk of local recurrence) cT4 | 231 vs. 230 | DFS at 3 years |
Rapido | RT → 6x CAPOX or 9x FOLFOX4 → TME versus CRT → TME → 8x CAPOX or 12x FOLFOX4 (optional) | MRI | < 16 cm anal verge cT4a/b EMVI cN2 MRF+ Enlarged lateral lymph node | 468 vs. 452 | DRTF |
OPRA | 8x FOLFOX or 5x CAPEOX → CRT → W&W or TME versus CRT → 8x FOLFOX or 5x CAPEOX → W&W or TME | MRI | cT3/4N0 cTxN1‑2 | 158 vs. 166 | DFS |
CAO/ARO/AIO-12 | 3xFOLFOX → CRT—(45d) → TME versus CRT (90d) → 3x FOLFOX → TME | MRI | < 12 cm anal verge cT3 < 6 cm from the anal verge cT3 c/d cT4 or N+ | 156 vs. 150 | pCR |
STELLAR | SCRT (21w) → 4x CAPOX → TME → 2x CAPOX versus CRT (14w) → TME → 6x CAPOX | MRI | < 10 cm cT3/4 and/or N+ | 302 vs. 297 | DFS |