OPERA
Needs reviewEuropean Phase III Study Comparing a Radiation Dose Escalation Using 2 Different Approaches : External Beam Radiation Therapy Versus Endocavitary Radiation Therapy With Contact X-ray Brachytherapy 50 kiloVolts (kV) for Patients With Rectal Adenocarcinoma
Phase 3N = 148NCT02505750
- Population
- Operable adults with cT2, cT3a or cT3b adenocarcinoma of the low-mid rectum, tumours under 5 cm in diameter, and cN0 or cN1 nodes smaller than 8 mm
- Design
- Multicentre, open-label, randomised (1:1) phase 3 trial at 17 cancer centres. All patients had chemoradiotherapy (45 Gy external beam radiotherapy in 25 fractions with oral capecitabine) and then either a 9 Gy external beam boost in 5 fractions (group A) or a contact X-ray brachytherapy boost of 90 Gy in 3 fractions (group B). In group B the brachytherapy boost was given before chemoradiotherapy for tumours smaller than 3 cm. Randomisation was stratified by centre, cT2 versus cT3a/b, distance from the anal verge (under 6 cm versus 6 cm or more) and tumour diameter (under 3 cm versus 3 cm or more). Primary outcome: organ preservation at 3 years in the modified intention-to-treat population (141 of 148 randomised; 7 withdrew consent). The 5-year report extends follow-up of the same trial.
- Primary endpoint
- Organ preservation rate
- Arms
- Chemoradiotherapy with external beam boost (group A) (control, n = 74): Chemoradiotherapy (45 Gy in 25 fractions with oral capecitabine 825 mg/m2 twice daily) followed by an external beam radiotherapy boost of 9 Gy in 5 fractions
- Chemoradiotherapy with contact X-ray brachytherapy boost (group B) (experimental, n = 74): The same chemoradiotherapy plus a contact X-ray brachytherapy boost of 90 Gy in 3 fractions (given before chemoradiotherapy for tumours smaller than 3 cm)
- People
- Gerard JP, senior author Myint AS, ICONE group
Organ preservation rateHR 0.36 (95% CI 0.19–0.70)Δ 36-month Organ preservation rate+22 pointsOrgan preservation rateHR 0.07 (95% CI 0.01–0.57)Δ 36-month Organ preservation rate+34 pointsOrgan preservation rateHR 0.54 (95% CI 0.26–1.10)Δ 36-month Organ preservation rate+13 points
Show the numbers
| Endpoint | Analysis | Chemoradiotherapy with contact X-ray brachytherapy boost (group B) | Chemoradiotherapy with external beam boost (group A) | Effect |
|---|---|---|---|---|
| Organ preservation rateModified intention-to-treat population: 141 of 148 randomised patients (69 in group A, 72 in group B); 7 withdrew consentOrgan preservation at 3 years (primary outcome) | primarymedian follow-up 38.2 monthsGerard 2023 | 81% at 3 y (72–91%) | 59% at 3 y (48–72%) | HR 0.36 (95% CI 0.19–0.70)P=0.0026The abstract labels the hazard ratio 'HR' without stating its direction; the median follow-up was 38.2 months (IQR 34.2 to 42.5). |
| Organ preservation rateSubgroup with tumours under 3 cm in diameter (29 patients in group A, 32 in group B); tumour diameter was a stratification factorOrgan preservation at 3 years in the subgroup with tumours under 3 cm in diameter | exploratoryGerard 2023 | 97% at 3 y (91–100%) | 63% at 3 y (47–84%) | HR 0.07 (95% CI 0.01–0.57)P=0.012In group B these patients had the brachytherapy boost before chemoradiotherapy. The abstract does not say whether the subgroup analyses were prespecified. |
| Organ preservation rateSubgroup with tumours of 3 cm or larger (40 patients in group A, 40 in group B); tumour diameter was a stratification factorOrgan preservation at 3 years in the subgroup with tumours of 3 cm or larger | exploratoryGerard 2023 | 68% at 3 y (54–85%) | 55% at 3 y (41–74%) | HR 0.54 (95% CI 0.26–1.10)P=0.11The difference in this subgroup was not statistically significant. The abstract does not say whether the subgroup analyses were prespecified. |
| Late grade 1-2 rectal bleedingPatients with late-effect assessment as given in the abstract: 43 in group A, 59 in group BGrade 1-2 rectal bleeding due to telangiectasia, described as the main late side-effect | primaryGerard 2023 | 63% | 12% | P<0.0001Five of 43 patients in group A and 37 of 59 in group B. The abstract states that the bleeding subsided after 3 years. |
| Organ preservation rateEligible patients: 141 of 148 randomisedOrgan preservation at 5 years (updated analysis) | long term-updatemedian follow-up 61.1 monthsBaron 2025 | 79% at 5 y | 56% at 5 y | P=0.004No interval or hazard ratio is given in the abstract. Median follow-up 61.1 months, with the bracketed range 56.8 to 64.5 as printed in the abstract. |
| Organ preservation rateSubgroup with tumours under 3 cm in diameter among the 141 eligible patientsOrgan preservation at 5 years in the subgroup with tumours under 3 cm | exploratoryBaron 2025 | 93% at 5 y | 54% at 5 y | The abstract gives the two rates for tumours under 3 cm without an interval or a p value. |
| Cumulative incidence of local regrowthNot stated in the abstract: the 28 local regrowths reported in total are too few for 39% and 17% to be proportions of all 141 eligible patients5-year local regrowth as named in the abstract; the abstract does not say how it was estimated or in which patients | long term-updatemedian follow-up 61.1 monthsBaron 2025 | 17% at 5 y | 39% at 5 y | P=0.1The difference was not statistically significant. The abstract reports 28 local regrowths in total, 3 of them after 3 years of follow-up, and does not give the denominator of the 39% and 17%. If the denominators were the patients with a clinical complete or near-complete response (44 and 66), the percentages would correspond to about 17 and 11 regrowths, 28 in total; this is an inference from the abstract's numbers, not a statement by the authors. |
| Clinical complete or near-complete responseEligible patients: 141 of 148 randomisedClinical complete (or near) response observed between week 14 and week 24 | long term-updateBaron 2025 | 92% | 64% | P<0.00144 patients in group A and 66 in group B, as stated in the 5-year abstract. |
| Endpoint | Analysis | Chemoradiotherapy with contact X-ray brachytherapy boost (group B) | Chemoradiotherapy with external beam boost (group A) | Effect |
|---|---|---|---|---|
| Organ preservation rateModified intention-to-treat population: 141 of 148 randomised patients (69 in group A, 72 in group B); 7 withdrew consentOrgan preservation at 3 years (primary outcome) | primarymedian follow-up 38.2 monthsGerard 2023 | 81% at 3 y (72–91%) | 59% at 3 y (48–72%) | HR 0.36 (95% CI 0.19–0.70)P=0.0026The abstract labels the hazard ratio 'HR' without stating its direction; the median follow-up was 38.2 months (IQR 34.2 to 42.5). |
| Organ preservation rateSubgroup with tumours under 3 cm in diameter (29 patients in group A, 32 in group B); tumour diameter was a stratification factorOrgan preservation at 3 years in the subgroup with tumours under 3 cm in diameter | exploratoryGerard 2023 | 97% at 3 y (91–100%) | 63% at 3 y (47–84%) | HR 0.07 (95% CI 0.01–0.57)P=0.012In group B these patients had the brachytherapy boost before chemoradiotherapy. The abstract does not say whether the subgroup analyses were prespecified. |
| Organ preservation rateSubgroup with tumours of 3 cm or larger (40 patients in group A, 40 in group B); tumour diameter was a stratification factorOrgan preservation at 3 years in the subgroup with tumours of 3 cm or larger | exploratoryGerard 2023 | 68% at 3 y (54–85%) | 55% at 3 y (41–74%) | HR 0.54 (95% CI 0.26–1.10)P=0.11The difference in this subgroup was not statistically significant. The abstract does not say whether the subgroup analyses were prespecified. |
| Late grade 1-2 rectal bleedingPatients with late-effect assessment as given in the abstract: 43 in group A, 59 in group BGrade 1-2 rectal bleeding due to telangiectasia, described as the main late side-effect | primaryGerard 2023 | 63% | 12% | P<0.0001Five of 43 patients in group A and 37 of 59 in group B. The abstract states that the bleeding subsided after 3 years. |
| Organ preservation rateEligible patients: 141 of 148 randomisedOrgan preservation at 5 years (updated analysis) | long term-updatemedian follow-up 61.1 monthsBaron 2025 | 79% at 5 y | 56% at 5 y | P=0.004No interval or hazard ratio is given in the abstract. Median follow-up 61.1 months, with the bracketed range 56.8 to 64.5 as printed in the abstract. |
| Organ preservation rateSubgroup with tumours under 3 cm in diameter among the 141 eligible patientsOrgan preservation at 5 years in the subgroup with tumours under 3 cm | exploratoryBaron 2025 | 93% at 5 y | 54% at 5 y | The abstract gives the two rates for tumours under 3 cm without an interval or a p value. |
| Cumulative incidence of local regrowthNot stated in the abstract: the 28 local regrowths reported in total are too few for 39% and 17% to be proportions of all 141 eligible patients5-year local regrowth as named in the abstract; the abstract does not say how it was estimated or in which patients | long term-updatemedian follow-up 61.1 monthsBaron 2025 | 17% at 5 y | 39% at 5 y | P=0.1The difference was not statistically significant. The abstract reports 28 local regrowths in total, 3 of them after 3 years of follow-up, and does not give the denominator of the 39% and 17%. If the denominators were the patients with a clinical complete or near-complete response (44 and 66), the percentages would correspond to about 17 and 11 regrowths, 28 in total; this is an inference from the abstract's numbers, not a statement by the authors. |
| Clinical complete or near-complete responseEligible patients: 141 of 148 randomisedClinical complete (or near) response observed between week 14 and week 24 | long term-updateBaron 2025 | 92% | 64% | P<0.00144 patients in group A and 66 in group B, as stated in the 5-year abstract. |
Data table
| Endpoint | HR | 95% CI |
|---|---|---|
| Organ preservation rate | 0.36 | 0.19–0.7 |
| Organ preservation rate | 0.07 | 0.01–0.57 |
| Organ preservation rate | 0.54 | 0.26–1.1 |
Appears in
Sources
Gerard JP, Barbet N, Schiappa R, Magné N, Martel I, Mineur L, et al. Neoadjuvant chemoradiotherapy with radiation dose escalation with contact x-ray brachytherapy boost or external beam radiotherapy boost for organ preservation in early cT2-cT3 rectal adenocarcinoma (OPERA): a phase 3, randomised controlled trial. Lancet Gastroenterol Hepatol. 2023;8(4):356-367.
Baron D, Pace Loscos T, Schiappa R, Barbet N, Dost E, Ben Dhia S, et al. A phase III randomised trial on the addition of a contact X-ray brachytherapy boost to standard neoadjuvant chemo-radiotherapy for organ preservation in early rectal adenocarcinoma: 5 year results of the OPERA trial. Ann Oncol. 2025;36(2):208-215.