Bahadoer 2021 — RAPIDO Trial

Citation: Bahadoer RR, Dijkstra EA, van Etten B, et al; RAPIDO collaborative investigators. Short-course radiotherapy followed by chemotherapy before total mesorectal excision (TME) versus preoperative chemoradiotherapy, TME, and optional adjuvant chemotherapy in locally advanced rectal cancer (RAPIDO): a randomised, open-label, phase 3 trial. Lancet Oncol. 2021;22(1):29-42. doi:10.1016/S1470-2045(20)30555-6.

Study design

• Multicentre, open-label, randomised, phase 3 trial — 54 hospitals/radiotherapy centres in 7 countries (Netherlands, Sweden, Spain, Slovenia, Denmark, Norway, USA). 920 patients randomized 1:1 (June 2011-June 2016); 912 eligible (462 experimental / 450 standard of care).
• Population: high-risk locally advanced rectal adenocarcinoma on pelvic MRI — at least one of: cT4a/T4b, extramural vascular invasion (EMVI+), cN2, involved mesorectal fascia (MRF), or enlarged lateral lymph nodes considered metastatic. Notably a higher-risk population than PRODIGE 23 or STELLAR.
• Experimental (TNT) arm: short-course radiotherapy (SCRT, 5×5 Gy over ≤8 days) → 6 cycles CAPOX or 9 cycles FOLFOX4 → total mesorectal excision (TME).
• Standard-of-care arm: long-course chemoradiotherapy (CRT, 28fx×1.8Gy to 50.4Gy or 25fx×2.0Gy to 50Gy + concurrent capecitabine) → TME → optional adjuvant chemotherapy (8 cycles CAPOX or 12 cycles FOLFOX4, per hospital policy — not mandated).
• Primary endpoint: disease-related treatment failure (DrTF) at 3 years — first occurrence of locoregional failure, distant metastasis, new primary colorectal tumour, or treatment-related death. (Endpoint was changed from disease-free survival to DrTF via protocol amendment in 2016, approved by the ethics committee/DSMB before unblinding — because standard DFS was judged inappropriate for a neoadjuvant trial where patients aren’t disease-free at baseline.)
• Median follow-up 4.6 years.

Key findings

Outcome (3-year)	Experimental (TNT)	Standard of care	HR (95% CI)	p
Disease-related treatment failure	23.7%	30.4%	0.75 (0.60–0.95)	.019
Distant metastases	20.0%	26.8%	0.69 (0.54–0.90)	.0048
Locoregional failure	8.3%	6.0%	1.42 (0.91–2.21)	.12
Pathological complete response	28% (120/423)	14% (57/398)	OR 2.37 (1.67–3.37)	<.0001
Overall survival	89.1%	88.8%	0.92 (0.67–1.25)	.59

• The DrTF benefit was driven almost entirely by fewer distant metastases, not by better local control.
• Locoregional failure was numerically higher — not lower — with TNT (8.3% vs 6.0%), though not statistically significant at this 3-year primary analysis (p=.12). The paper’s discussion flags this explicitly as a point of caution, and notes a subsequent 5-year follow-up publication (Dijkstra et al., Ann Surg 2023) reportedly found this difference became statistically significant. That follow-up paper is now independently ingested — Dijkstra 2023 - RAPIDO 5-Year Locoregional Failure confirms the trade-off became statistically significant at 5.6 years (10.2% vs 6.1%, P=0.027), and further establishes it as RAPIDO-specific rather than a general TNT effect (not replicated in PRODIGE 23, STELLAR, or POLISH II).
• No difference in overall survival at 3 years — the DrTF/metastasis benefit did not translate to a survival benefit in this report. The PRODIGE 23 long-term follow-up paper attributes this partly to an “ATRESS phenomenon” (neoadjuvant-therapy-related shortening of survival after metastatic relapse) observed in RAPIDO but not in PRODIGE 23 — see that source page.
• Grade ≥3 adverse events during preoperative therapy: 48% (experimental) vs 25% (standard of care) — more toxicity during the neoadjuvant phase of the experimental arm, but note this pools full preoperative treatment (SCRT+chemo) against CRT alone; the standard-of-care arm’s toxicity burden shifts partly to its (optional, ~59% uptake) adjuvant phase.
• Surgery with curative intent within 6 months: 92% (experimental) vs 89% (standard of care).
• Treatment-related deaths: 4 in each group.

Limitations

• High-risk-only population (by design) — findings should not be extrapolated to lower-risk LARC (e.g., the PROSPECT trial population) or automatically to different TNT regimens (chemotherapy- first, as in PRODIGE 23).
• Primary endpoint changed mid-trial (DFS → DrTF) — appropriately pre-registered and blinded before the change, but worth noting when comparing across trials with different endpoint definitions.
• No OS benefit demonstrated (contrast with PRODIGE 23’s 7-year OS benefit) — despite a clear reduction in distant metastases, likely related to the ATRESS phenomenon and/or immature follow-up (median 4.6 years vs PRODIGE 23’s 6.8 years).
• Numerically worse local control with TNT is the central caution from this trial — unresolved whether this is a true SCRT-specific effect, a radiotherapy-technique artifact, or a TME-quality confounder (all explored inconclusively per the discussion section).

Relevance

Closes the primary-literature gap flagged in Total Neoadjuvant Therapy (TNT) and Rectal Cancer’s Open items — previously only available via the Boublikova 2023 - TNT in Rectal Cancer Review secondary review, whose Table 1 figures (pCR 28% vs 14%, 3y-DFS ~76% vs ~70%, 3y-OS 89% vs 89%) are confirmed accurate against this primary source. Establishes the “trade-off” framing (distant control gained at a possible cost to local control) that TNT.md already carried from the secondary review — now grounded in primary data, though the statistical significance of that locoregional trade-off at longer follow-up rests on a paper not yet in this wiki. Contrasts informatively with Conroy 2024 - PRODIGE 23 Long-Term Results (chemotherapy-first TNT, no locoregional trade-off, real OS benefit) and Jin 2022 - STELLAR Trial (also SCRT-based TNT, but without RAPIDO’s locoregional trade-off) — suggesting the trade-off may not be a generic SCRT effect but something more specific to RAPIDO’s population or protocol details; this cross-trial inconsistency should be flagged rather than resolved.