Clinical trialPhase 2Colorectal cancer

Long-Term Results of Organ Preservation in Patients With Rectal Adenocarcinoma Treated With Total Neoadjuvant Therapy: The Randomized Phase II OPRA Trial

J Clin Oncol · 2024324 patients (158 INCT-CRT, 166 CRT-CNCT)

Verheij FS, Omer DM, Williams H, et al. J Clin Oncol. 2024. 42:500-506

Study type: Clinical trial
Study name: OPRA
Phase: Phase 2
Design: Update of a randomised phase 2 trial (Clinical Trial Update report); decision for surgery (TME) or "watch and wait" based on tumour response
Sample size: 324 patients (158 INCT-CRT, 166 CRT-CNCT)
Source: J Clin Oncol · 2024
Trial registration: NCT02008656

In plain words

This report followed the patients of the OPRA study for more than 5 years. In this approach, all the chemotherapy and radiotherapy are given before deciding about surgery, and if the tumour disappears, the patient is followed with regular examinations, endoscopy and MRI instead of having surgery. The result is encouraging: about half of the patients still had their rectum after 5 years, especially when chemotherapy was given after radiotherapy. Almost all cases of the tumour growing back happened in the first 2 to 3 years, and surgery at that point still worked well; so regular follow-up, especially in the first 2 years, is very important.

Key results

71% (INCT-CRT) and 69% (CRT-CNCT)

5-year disease-free survival

95% CI 64 to 79 and 62 to 77; P = .68; median follow-up 5.1 years

39% (INCT-CRT) vs 54% (CRT-CNCT)

TME-free survival (rectal preservation)

95% CI 32 to 48 and 46 to 62; P = .012

94% within the first 2 years and 99% within the first 3 years

Timing of tumour regrowth

In 81 patients with regrowth

64% vs 64%

Disease-free survival: TME after restaging vs TME after regrowth during watch and wait

95% CI 53 to 78 in both; P = .94

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: Full text of the paper (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 cancer.

Endpoints

Primary endpoint: disease-free survival (DFS).

Secondary endpoint: TME-free survival.

Safety and side effects

The abstract of this report provides no adverse event data; details in the full text of the paper.

Clinical significance and place in guidelines

These long-term data confirmed the durability of organ preservation with total neoadjuvant therapy and "watch and wait", strengthened the sequence of chemoradiotherapy followed by consolidation chemotherapy to increase the likelihood of rectal preservation, and showed that follow-up must be intensive in the first 2 to 3 years. The ESMO guideline for localised rectal cancer (2025) considers upfront chemoradiotherapy followed by consolidation chemotherapy recommendable to increase the likelihood of clinical complete response [I, B].

Limitations

A phase 2 trial not designed for direct comparison of the two groups; the comparison of TME-free survival between groups should be interpreted with caution; 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.