Adjuvant chemoradiotherapy versus completion total mesorectal excision after local excision for early rectal cancer (TESAR): a multicentre, randomised, controlled, phase 3, non-inferiority trial
Mené sur 202 patients atteints d'un cancer du rectum de stade pT1 à haut risque ou pT2 à faible risque (durée médiane de suivi : 50 mois ; âge moyen : 64,7 % ; 40,1 % de femmes), cet essai international de phase III évalue la non-infériorité, du point de vue du taux de récidive locorégionale à 3 ans, d’une chimioradiothérapie adjuvante par rapport à une exérèse totale du mésorectum
Background: Completion total mesorectal excision (cTME) after local excision of early rectal cancer is associated with substantial morbidity and impaired functional outcomes. This study aimed to assess the oncological outcomes of adjuvant chemoradiotherapy as an organ-preserving alternative in patients with high-risk pT1 and low-risk pT2 rectal cancer.
Methods: This multicentre, open-label, randomised, controlled, phase 3, non-inferiority trial was conducted at 25 hospitals across the Netherlands and France. Patients aged 18 years or older with locally excised high-risk pT1 and low-risk pT2 rectal cancer located below the sigmoid takeoff were randomly assigned (1:1), via an interactive web-response system, to adjuvant chemoradiotherapy (25 × 1·8 Gy limited to the mesorectum, with oral capecitabine 825 mg/m2 twice daily) or cTME through an interactive web-response system. Randomisation was done via minimisation with stratification for age (<75 years vs ≥75 years), American Society of Anaesthesiologists (ASA) classification (ASA 1 vs ASA ≥2), type of local excision (surgical vs endoscopic), pathological tumour stage (high-risk pT1 vs low-risk pT2), and resection margin status (<1 mm vs ≥1 mm). The primary endpoint was 3-year locoregional recurrence, with a prespecified non-inferiority margin of 7%. Secondary endpoints included unsalvageable locoregional recurrence, disease-free survival, overall survival, treatment-related morbidity within 30 days (assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events criteria for adjuvant chemoradiotherapy and the Clavien–Dindo classification and the Comprehensive Complication Index for cTME), stoma rate, and quality of life. All comparative analyses were conducted according to the intention-to-treat (ITT) and per-protocol principles. The trial is registered on ClinicalTrials.gov, NCT02371304. On Oct 1, 2024, the trial was converted to a patient-preference design due to loss of equipoise before reaching its target sample size of 302 patients. The current analysis includes patients randomly assigned until this transition. Enrolment is ongoing within the patient-preference design.
Findings: Between Nov 1, 2015, and Sept 14, 2024, 202 patients were randomly assigned, of whom 197 were included in the ITT analysis (adjuvant chemoradiotherapy, n=101; cTME, n=96). Of these patients, 118 (59·9%) were male and 79 (40·1%) female; mean age was 64·7 years (SD 7·4), and mean BMI was 26·5 kg/m2 (SD 4·0). After a median follow-up of 50·0 months (IQR 27·0–62·0), five locoregional recurrences were reported: four in the adjuvant chemoradiotherapy group and one in the cTME group. Estimated 3-year locoregional recurrence rates were 5·0% (95% CI 1·6–11·3) after adjuvant chemoradiotherapy and 1·1% (0·0–5·5) after cTME. Adjuvant chemoradiotherapy did not meet the non-inferiority margin of 7% for 3-year locoregional recurrence (difference 3·9% [90% CI 0·0–9·4]; one-sided pnon-inferiority=0·16). However, four of the five locoregional recurrences (three in the adjuvant chemoradiotherapy group and one in the cTME group) were successfully salvaged, resulting in a 3-year unsalvageable locoregional recurrence rate of 1·3% (95% CI 0·1–6·1) after adjuvant chemoradiotherapy and 0·0% (0·0–5·6) after cTME. 3-year disease-free survival was 92·0% (95% CI 84·4–96·4) after adjuvant chemoradiotherapy compared with 96·3% (89·7–99·1) after cTME (hazard ratio [HR] 3·20 [95% CI 0·88–11·6]). 3-year overall survival was similar in both groups (98·9% [95% CI 94·1–99·9] for adjuvant chemoradiotherapy and 98·9% [93·7–99·9] for cTME; HR 1·64 [95% CI 0·22–18·0]). Treatment-related toxicity occurred in 82 (78%) of 105 patients after adjuvant chemoradiotherapy (grade ≥3 in ten [9·5%] of 105 patients). Post-operative complications occurred in 32 (43·8%) of 73 patients after cTME (Clavien–Dindo grade ≥IIIa in 11 [15·1%] patients; median Comprehensive Complication Index 21·8 [IQR 8·7–39·7]). 3-year stoma rates were significantly lower after adjuvant chemoradiotherapy (2·6% [95% CI 0·5–8·3]) versus cTME (45·4% [35·0–55·3]; p<0·0001). 1-year quality-of-life outcomes were comparable or favoured adjuvant chemoradiotherapy across nearly all domains.
Interpretation: Non-inferiority of adjuvant chemoradiotherapy compared with cTME for 3-year locoregional recurrence could not formally be demonstrated. However, loss of equipoise hampered patient accrual, precluding the trial from reaching its prespecified sample size. Although the 3-year locoregional recurrence rate numerically favoured cTME, adjuvant chemoradiotherapy resulted in low rates of unsalvageable locoregional recurrence, and substantially reduced treatment-related morbidity and stoma rates. These findings challenge cTME as the standard of care for patients with locally excised high-risk pT1 and low-risk pT2 rectal cancer.
The Lancet Gastroenterology & Hepatology , résumé, 2026