Clinical trialPhase 3Colorectal cancer

Short-course radiotherapy followed by chemotherapy before total mesorectal excision (TME) versus preoperative chemoradiotherapy, TME, and optional adjuvant chemotherapy in locally advanced rectal cancer (RAPIDO): a randomised, open-label, phase 3 trial

Lancet Oncol · 2021920 patients randomised; 912 eligible patients (462 experimental group, 450 standard group)

Bahadoer RR, Dijkstra EA, van Etten B, et al. Lancet Oncol. 2021. 22:29-42

Study type: Clinical trial
Study name: RAPIDO
Phase: Phase 3
Design: Randomised, open-label, multicentre trial (54 centres in the Netherlands, Sweden, Spain, Slovenia, Denmark, Norway and the USA); 1:1 randomisation
Sample size: 920 patients randomised; 912 eligible patients (462 experimental group, 450 standard group)
Source: Lancet Oncol · 2021
Trial registration: NCT01558921

In plain words

In high-risk advanced rectal cancer, the older approach was to give 5 to 6 weeks of radiotherapy with chemotherapy tablets first, then surgery, and chemotherapy at the end. In RAPIDO, all the chemotherapy was given before surgery, after a short one-week course of radiotherapy (5 sessions). With this approach, the chance of the disease coming back or spreading within 3 years was lower (about 24% vs 30%). However, longer follow-up showed that the disease came back in the pelvis slightly more often with this approach, so the choice should be made at a multidisciplinary meeting based on the features of the tumour.

Key results

23.7% vs 30.4%

Disease-related treatment failure at 3 years

HR 0.75 (95% CI 0.60–0.95); p=0.019; median follow-up 4.6 years

18% vs 9%

Grade 3 or higher diarrhoea during preoperative treatment

81 of 460 vs 41 of 441 patients

10% vs 6%

Locoregional recurrence after R0/R1 resection (5-year follow-up, Dijkstra et al, Ann Surg 2023)

44 of 431 vs 26 of 428; P=0.027 — increased local recurrence in the experimental group

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

Dose and schedule cards

Short-course radiotherapy followed by CAPOX or FOLFOX4 (RAPIDO)

High-risk locally advanced rectal adenocarcinoma on MRI (at least one of: cT4a/b, extramural vascular invasion, cN2, mesorectal fascia involvement or enlarged lateral lymph nodes); ECOG 0–1On the page “Colorectal cancer” · Locally advanced rectal cancer: total neoadjuvant therapy (TNT) and immunotherapy

High-risk locally advanced rectal adenocarcinoma on MRI (at least one of: cT4a/b, extramural vascular invasion, cN2, mesorectal fascia involvement or enlarged lateral lymph nodes); ECOG 0–1

Drug	Dose	Route	Schedule
Phase 1
Short-course radiotherapy	5 × 5 Gy	Pelvis	Within a maximum of 8 days
Phase 2: 6 cycles of CAPOX (every 21 days)
Oxaliplatin	130 mg/m²	IV	Day 1
Capecitabine	1000 mg/m² twice daily	Oral	Days 1–14
Or phase 2: 9 cycles of FOLFOX4 (every 14 days)
Oxaliplatin	85 mg/m²	IV	Day 1
Leucovorin	200 mg/m²	IV	Days 1 and 2
Fluorouracil	400 mg/m² bolus, then 600 mg/m² over 22 hours	IV	Days 1 and 2

Cycle length: CAPOX every 21 days; FOLFOX4 every 14 days
Duration: Radiotherapy, then 6 cycles of CAPOX or 9 cycles of FOLFOX4, followed by total mesorectal excision (TME)

Doses and schedule from the RAPIDO publication.

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

RAPIDO

High-risk rectal cancerOn the page “Total neoadjuvant therapy (TNT) in rectal cancer: the RAPIDO regimen”

High-risk rectal cancer

Drug	Dose	Route	Schedule
Phase 1
Short-course radiotherapy	5 Gy × 5 fractions		One week
Phase 2: 6 cycles
Oxaliplatin	130 mg/m²	IV	Day 1 every 21 days
Capecitabine	1000 mg/m² twice a day	Oral	Days 1 to 14

Cycle length: CAPOX every 21 days (or FOLFOX4 every 14 days, 9 cycles)
Duration: Chemotherapy 11 to 18 days after radiotherapy; surgery 2 to 4 weeks after the last cycle

As in RAPIDO.

On the page “Total neoadjuvant therapy (TNT) in rectal cancer: the RAPIDO regimen”

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

1Experimental group: short-course radiotherapy + chemotherapy, then TME

Short-course radiotherapy 5 × 5 Gy (over a maximum of 8 days), then 6 cycles of CAPOX (capecitabine 1000 mg/m² orally twice daily, days 1 to 14; oxaliplatin 130 mg/m² IV on day 1; rest days 15 to 21) or 9 cycles of FOLFOX4 (oxaliplatin 85 mg/m² IV on day 1; leucovorin 200 mg/m² IV on days 1 and 2; fluorouracil 400 mg/m² bolus and 600 mg/m² over 22 hours on days 1 and 2; rest days 3 to 14), then total mesorectal excision (TME).

2Standard group: chemoradiotherapy, TME and optional adjuvant chemotherapy

Radiotherapy in 28 fractions of 1.8 Gy to 50.4 Gy or 25 fractions of 2 Gy to 50 Gy with oral capecitabine 825 mg/m² twice daily, then TME and, if hospital policy, adjuvant chemotherapy with 8 cycles of CAPOX or 12 cycles of FOLFOX4.

Source of the regimen details: Doses and schedules from the published abstract of the paper (Lancet Oncol 2021), which gives the regimens in full

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

Adults (18 or older) with ECOG 0 or 1 and newly diagnosed, primary, locally advanced rectal adenocarcinoma that was "high risk" on pelvic MRI, meaning at least one of: cT4a or cT4b, extramural vascular invasion (EMVI), cN2, mesorectal fascia involvement, or enlarged lateral lymph nodes.

Endpoints

Primary outcome: disease-related treatment failure at 3 years (first occurrence of locoregional failure, distant metastasis, new primary colorectal tumour or treatment-related death) in the intention-to-treat population.

Safety and side effects

The most common grade 3 or higher adverse event during preoperative treatment in both groups was diarrhoea (18% in the experimental group versus 9% in the standard group). In the standard group, neurotoxicity during adjuvant chemotherapy occurred in 9% (16 of 187). Serious adverse events occurred in 38% of the experimental group and in 34% of patients in the standard group with or without adjuvant chemotherapy. 4 treatment-related deaths were reported in each group.

Clinical significance and place in guidelines

RAPIDO, together with PRODIGE 23, established the concept of total neoadjuvant therapy (TNT) in high-risk rectal cancer. The ESMO guideline for localised rectal cancer (2025) recommends that TNT be offered for mid or low tumours with high-risk features [I, A], and the radiotherapy can be long-course chemoradiotherapy or short-course radiotherapy (25 Gy in 5 fractions) [I, A]. Five-year follow-up (Ann Surg 2023) showed an increase in locoregional recurrence after R0/R1 resection in the experimental group (10% versus 6%), while the reduction in distant metastases was maintained.

Limitations

Open-label design; adjuvant chemotherapy in the standard group was optional and depended on hospital policy; overall survival showed no difference; increased local recurrence in the experimental group on longer follow-up.

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.