Clinical trialPhase 2Colorectal cancer

Organ Preservation in Patients With Rectal Adenocarcinoma Treated With Total Neoadjuvant Therapy

J Clin Oncol · 2022324 patients

Garcia-Aguilar J, Patil S, Gollub MJ, et al. J Clin Oncol. 2022. 40:2546-2556

A newer report of this study has been published: Long-Term Results of Organ Preservation in Patients With Rectal Adenocarcinoma Treated With Total Neoadjuvant Therapy: The Randomized Phase II OPRA Trial (2024)

Study type: Clinical trial
Study name: OPRA
Phase: Phase 2
Design: Prospective randomised phase 2 trial, designed as two independent studies (each group compared with a null hypothesis based on historical data); decision for surgery (TME) or "watch and wait" based on tumour response
Sample size: 324 patients
Source: J Clin Oncol · 2022
Trial registration: NCT02008656

In plain words

In rectal cancer, surgery to remove the rectum can lead to a permanent bag (stoma) or to bowel and sexual problems. In the OPRA study, all the chemotherapy and radiotherapy were given before any decision about surgery. Patients whose tumour had disappeared completely or almost completely were followed with regular examinations, endoscopy and MRI instead of having surgery. About half of the patients (especially when chemotherapy was given after radiotherapy) still had their rectum after 3 years, without a lower chance of staying alive free of disease. If the tumour grows back, surgery is still possible, so keeping to regular follow-up visits is very important.

Key results

76% (INCT-CRT) and 76% (CRT-CNCT)

3-year disease-free survival

95% CI: 69 to 84 and 69 to 83; consistent with the historical rate of 75%; median follow-up 3 years

41% (INCT-CRT) vs 53% (CRT-CNCT)

3-year TME-free survival (rectal preservation)

95% CI: 33 to 50 and 45 to 62

No difference

Other outcomes

Local recurrence-free survival, distant metastasis-free survival and overall survival did not differ between the two groups

Drugs in this study:Capecitabine (Xeloda)Fluorouracil (5-FU)

Dose and schedule cards

Chemoradiotherapy followed by consolidation chemotherapy (OPRA; aiming at rectal preservation)

Stage II or III rectal adenocarcinoma; with a complete or near-complete response, nonoperative follow-up (watch and wait)On the page “Colorectal cancer” · Locally advanced rectal cancer: total neoadjuvant therapy (TNT) and immunotherapy

Stage II or III rectal adenocarcinoma; with a complete or near-complete response, nonoperative follow-up (watch and wait)

Drug	Dose	Route	Schedule
Phase 1: chemoradiotherapy
Radiotherapy	45 Gy in 25 fractions to the pelvis, with a boost to a total of 50 to 56 Gy to the tumour and involved nodes	External beam
Concurrent capecitabine (or continuous-infusion fluorouracil)	825 mg/m² twice daily	Oral	During radiotherapy
Phase 2: consolidation chemotherapy (about 4 months)
FOLFOX or CAPOX	8 two-weekly cycles of FOLFOX or 5 three-weekly cycles of CAPOX (doses as in the regimens above)	IV / oral

Cycle length: FOLFOX every 14 days; CAPOX every 21 days
Duration: About 6 weeks of chemoradiotherapy, then about 4 months of chemotherapy; then response assessment

Radiotherapy schedule and number of cycles from OPRA; capecitabine dose with radiotherapy from the FDA label.

On the page “Colorectal cancer” · Locally advanced rectal cancer: total neoadjuvant therapy (TNT) and immunotherapy

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Induction chemotherapy followed by chemoradiotherapy (INCT-CRT)

Induction chemotherapy (about 15 to 16 weeks): 8 two-weekly cycles of FOLFOX or 5 three-weekly cycles of CAPOX; then chemoradiotherapy: 45 Gy in 25 fractions to the pelvis and a total of 50 to 56 Gy to the primary tumour and involved nodes (simultaneous or sequential boost), with continuous-infusion fluorouracil or oral capecitabine. After restaging: complete or near-complete response → "watch and wait"; incomplete response → TME. Drug doses are not stated in the paper.

2Chemoradiotherapy followed by consolidation chemotherapy (CRT-CNCT)

Chemoradiotherapy (the same radiotherapy schedule, about 6 weeks, with continuous-infusion fluorouracil or capecitabine), then consolidation chemotherapy: 8 cycles of FOLFOX or 5 to 6 cycles of CAPOX (5 cycles according to the paper and 6 cycles according to ClinicalTrials.gov); then the same "watch and wait" or TME strategy based on response. Drug doses are not stated in the paper.

Source of the regimen details: Abstract of the paper, full text of the OPRA long-term report (PMC11578087, Methods section) and ClinicalTrials.gov NCT02008656; chemotherapy drug doses are not stated in the paper

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Patients with stage 2 or 3 rectal adenocarcinoma.

Endpoints

Primary endpoint: 3-year disease-free survival (for each group compared with a historical rate of 75%).

Secondary endpoint: TME-free survival, i.e. rectal preservation.

Safety and side effects

The abstract reports no adverse event data; details in the full text of the paper.

Clinical significance and place in guidelines

OPRA is the main basis of the organ-preservation strategy with TNT and "watch and wait". The ESMO guideline for localised rectal cancer (2025), for tumours of the middle or lower third when organ preservation is the aim, recommends TNT for high-risk patients and cT2 N+‎ or cT3 N any [I, A], states that upfront chemoradiotherapy followed by consolidation chemotherapy can be recommended to increase the likelihood of clinical complete response [I, B], and recommends a watch-and-wait strategy in clinical complete response [I, A].

Limitations

Phase 2 with no direct statistical comparison between the two groups and comparison with historical controls; 3-year follow-up is limited for assessing late regrowth; requires high-quality MRI and endoscopy and an experienced multidisciplinary team.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.