Table 1.

A summary of key trials of total neoadjuvant therapy in rectal cancer.

Trial name	Study type	Patients (n)	Inclusion	Treatment arm A	Treatment arm B	Toxicity, resection & surgical complications	Pathological/survival outcomes
POLISH II (2016) [94, 95]	Randomised, Phase III	515	cT3 or cT4 primary or recurrent rectal cancer	TNT: SCRT (5x5Gy) + 3 cycles FOLFOX4 then TME	CRT (50.4Gy + 5-FU, leucovorin + oxaliplatin) then TME	Toxicity: 75% vs 83% (P = 0.006) R0: 77% vs 71% (NS) Postoperative complications: 29% vs 25% (NS)	pCR 16% vs 12% (NS) 3Y OS: 73% vs 65% (P = 0.046) 3Y DFS: 53% vs 52% (NS) 8Y OS: 49% (both groups)
RAPIDO (2020) [7, 96]	Randomised, international, multicentre Phase III	912	High-risk rectal adenocarcinoma (one of): • cT4a or cT4b • Extramural vascular invasion • Node stage: cN2 • Involved mesorectal fascia • Enlarged lateral lymph nodes	TNT: SCRT (5x5Gy) + 6 cycles CAPOX or 9 cycles FOLFOX then TME	Capecitabine-based CRT (50Gy or 50.4Gy) then TME Adjuvant: 8 cycles CAPOX or 12 cycles FOLFOX	Serious adverse events: 38% vs 34% Toxicity ≥ grade 3: 48% vs 35% Compliance: 84% vs 58% No difference in resection rates or post-op complications. R0 90% in both groups.	pCR: 28.4% vs 14.3% (P<0.0001) 3Y DRTF: 23.7% vs 30.4% (P = 0.019) 3Y OS: 89.1% vs 88.8% (NS)
PRODIGE 23 (2022) [8, 97]	Randomised, Phase III	461	cT3 or cT4 rectal adenocarcinoma	TNT: 6 cycles mFOLFIRINOX + CRT (50 Gy + capecitabine) then TME Adjuvant chemotherapy: 6 cycles FOLFOX6 or 4 cycles capecitabine	CRT (50.4Gy + capecitabine) then TME Adjuvant chemotherapy: 12 cycles mFOXFOX6 or 8 cycles capecitabine	Serious adverse events: 27% vs 22% (NS) Progression to surgery: 92% vs 95% (NS) (more palliative surgery in CRT group) R0: 95% vs 94% (NS) Post-op complications: 29.3% vs 31.2% (NS)	pCR: 28% vs 12% (P<0.0001) 3Y DFS: 75.7% vs 68.5% (P = 0.034) 3Y OS: 90.8% vs 87.7% (NS) Median OS (months): 76.3 vs 71.9 (P = 0.033)
CAO/ARO/AIO-12 (2022) [98, 99]	Randomised, Phase II	306	cT3 or T4 or cN+ rectal adenocarcinoma	3 cycles FOLFOX then fluorouracil/oxaliplatin CRT (50.4Gy) followed by TME	Fluorouracil/oxaliplatin CRT (50.4Gy) then 3 cycles FOLFOX followed by TME	Grade 3 or 4 toxicity: 37% vs 27% Compliance with CRT: 91% vs 97% Compliance with chemo: 92% vs 85% Surgical complications: 46% vs 35%	pCR: 19% vs 27% 3Y DFS: 73% both groups Interval from end of CRT to surgery (days): 45 vs 90 → no increase in surgical morbidity
OPRA (2022) [20]	Randomised, Phase II	324	Stage II & III rectal cancer (T3/4, N+)	Induction FOLFOX/CAPOX (16-18 weeks) + CRT (50-56Gy + fluorouracil or capecitabine) then TME or watch-and-wait	CRT (50-56Gy + fluorouracil or capecitabine) + consolidation FOLFOX/CAPOX (16-18 weeks) then TME or watch-and-wait	3Y TME-free survival: 41% vs 53%	pCR: 17% (induction) vs 25% (consolidation) 3Y DFS: 76% in both groups

TNT total neoadjuvant therapy, SCRT short-course radiotherapy, CRT chemoradiotherapy, TME total mesorectal excision.