RAPIDO
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Clinical Question
Does neoadjuvant short-course radiotherapy followed by chemotherapy reduce disease-related treatment failure compared to standard preoperative chemoradiotherapy in patients with locally advanced rectal cancer?
Bottom Line
For selected patients with locally advanced rectal cancer, neoadjuvant short-course RT followed by CAPEOX or FOLFOX improves disease control compared to conventional neoadjuvant long-course RT plus concurrent capecitabine and adjuvant chemotherapy.
Major Points
Neoadjuvant therapy for rectal cancer has historically included chemoradiotherapy followed by total mesorectal excision (TME) and optional adjuvant chemotherapy. Adjuvant chemotherapy, however, suffers from low compliance and offers only modest systemic disease control, with distant metastases remaining a significant clinical challenge. The RAPIDO trial sought to evaluate whether total neoadjuvant therapy using short-course radiotherapy followed by chemotherapy and delayed TME could reduce disease-related treatment failure without compromising locoregional control.
Published in 2021, the Rectal Cancer and Preoperative Induction Therapy Followed by Dedicated Operation Trial (RAPIDO) trial was a randomized, open-label, phase 3 trial of patients with newly diagnosed locally advanced rectal cancer. Approximately 900 patients were randomly assigned to experimental or control arms; in the experimental arm, patients received neoadjuvant short-course radiotherapy (25 Gy over 5 fractions) followed by, at the discretion of the treating physician, either six 21-day cycles of capecitabine plus oxaliplatin (CAPEOX) or nine 14-day cycles of FOLFOX; TME was planned 2-4 weeks after completion of neoadjuvant chemotherapy. In the control arm, patients received neoadjuvant chemoradiotherapy consisting of 50 Gy over 25-28 fractions plus concurrent capecitabine, with TME planned 6-10 weeks after the last dose of RT; additional systemic chemotherapy could be provided in the adjuvant setting based on institutional policy. The primary endpoint of disease-related treatment failure at 3 years favored the experimental group (23.7% vs. 30.4%), a difference which was driven primarily by distant mestastases (20.0% vs. 26.8%). The pathological complete response rate was higher in the experimental arm (28% vs. 14%). Locoregional control (8.3% vs. 6.0%) and 3-year overall survival rates (89.1% vs. 88.8%) were comparable between groups. Approximately half of participating instutitons offered adjuvant chemotherapy in the standard-of-care group, and receipt of adjuvant therapy did not alter disease-related treatment failure at 3 years.
When the study was published, there was enthusiasm that a new standard of care could be offered for patients with high-risk locally advanced rectal cancer. Limitations included the variability in receipt of adjuvant chemotherapy across centers, potential biases in subgroup analyses, and the need for longer term survival data. Importantly, with longer follow-up at 5 years, there were more locoregional recurrences with short-course RT than with conventional care (10% vs. 6%), a difference which reached statistical significance.[1] Risk factors for recurrence included lateral lymph node involvement, positive resection margin, tumor deposits, and pathologic node involvement.
Ultimately the RAPIDO trial demonstrates that total neoadjuvant therapy (TNT) with short-course RT may be offered to selected patients, acknowledging that locoregional recurrence risk may increase in patients with certain high-risk features.
Guidelines
NCCN Rectal Cancer (Version 2.2025, adapted)[1]
- For T1-2 N0 M0 rectal cancer, options include
- Transabdominal resection followed by adjuvant therapy
- Chemo/RT (capecitabine or 5FU), followed by FOLFOX or CAPEOX, followed by resection
- Short-course RT, followed by FOLFOX or CAPEOX, followed by resection
- Evaluation for short-course RT should be in a multidisciplinary setting, with a discussion fo the need for downstaging and the possibility of long-term toxicity.
- While short-course RT can be considered for preoperative radiation, for high-risk rectal cancer, the 5-year follow-up of the RAPIDO trial now indicates a statistically higher locoregional recurrence rate in the experimental arm (10%) compared to the control arm (6%).
Design
- Randomized, open-label, phase 3 trial
- N=920 patients with newly diagnosed locally advanced rectal cancer
- Experimental: Short-course radiotherapy → chemotherapy → TME (n=462)
- Control: Long-course chemoradiotherapy → TME → optional adjuvant chemotherapy (n=450)
- Setting: 54 centers in 7 countries
- Enrollment: June 2011 to June 2016
- Median follow-up: 4.6 years
- Analysis: Intention-to-treat
- Primary outcome: Disease-related treatment failure at 3 years
Population
Inclusion Criteria
- Adults with biopsy-proven high-risk locally advanced rectal cancer
- High-risk features on pelvic MRI (e.g., cT4, cN2, +MRF, lateral lymph node involvement)
- ECOG performance status 0–1
Exclusion Criteria
- Metastatic disease
- Tumor invasion into the sacral nerve roots
- Prior rectal cancer treatment
Baseline Characteristics
- Median age: 62 years
- Male sex: 65%
- Clinical T stage: 65% cT3, 32% cT4
- Clinical N stage: 65% cN2
- Mesorectal fascia involvement: 61%
Interventions
- Randomized to
- Experimental arm:
- Short-course RT (25 Gy over 5 fractions in ≤8 days)
- Chemotherapy: six cycles of CAPEOX or nine cycles of FOLFOX
- TME after 2–4 weeks
- Standard arm:
- Long-course chemoradiotherapy (50 Gy over 25-28 fractions) with oral capecitabine
- TME after 6–10 weeks
- Optional adjuvant chemotherapy (CAPEOX or FOLFOX) per center policy
- Experimental arm:
Outcomes
Comparisons are short-course RT vs. control arms.
Primary Outcome
- Disease-related treatment failure at 3 years
- 23.7% vs. 30.4% (HR 0.75; 95% CI 0.60–0.95; P=0.019)
Secondary Outcomes
- Distant metastases at 3 years
- 20.0% vs. 26.8% (HR 0.69; P=0.0048)
- Pathological complete response rate
- 28% vs. 14% (OR 2.37; P<0.0001)
- Locoregional failure at 3 years
- 8.3% vs. 6.0% (HR 1.42; P=0.12)
- 3-year overall survival
- 89.1% vs. 88.8% (HR 0.92; P=0.59)
Subgroup Analysis
Subgroup analyses consistently favored the experimental treatment for disease-related treatment failure, although they were not prespecified and may be hypothesis-generating.
Adverse Events
- Grade ≥3 diarrhea
- 16% vs. 9%
- Serious adverse events
- 38% vs. 34%
Criticisms
- Variability in adjuvant chemotherapy use across centers may have influenced outcomes.
- Long-term survival data and quality-of-life outcomes are not yet available.
- Subgroup analyses for disease-free survival were not prespecified, introducing potential biases.
- Protocol changes during the study (e.g., primary outcome redefinition) could impact interpretation.
Funding
Funded by the Dutch Cancer Foundation, Swedish Cancer Society, Spanish Ministry of Economy and Competitiveness, and Spanish Clinical Research Network.