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
The RAPIDO trial demonstrated that short-course radiotherapy followed by chemotherapy reduces 3-year disease-related treatment failure compared to standard preoperative chemoradiotherapy, primarily by decreasing distant metastases. This approach doubles the pathological complete response rate and offers an alternative treatment paradigm for high-risk locally advanced rectal cancer.
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 modest systemic 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 2012, the Rectal Cancer and Preoperative Induction Therapy Followed by Dedicated Operation Trial (RAPIDO) trial randomized, open-label, phase 3 trial included 912 eligible patients from 54 centers across seven countries. Patients were assigned to receive either short-course radiotherapy followed by six cycles of CAPOX or nine cycles of FOLFOX and TME, or the standard long-course chemoradiotherapy followed by TME and optional adjuvant chemotherapy. The primary endpoint, disease-related treatment failure at 3 years, favored the experimental group (23.7% vs. 30.4%; HR 0.75; p = 0.019). Distant metastases were significantly reduced in the experimental group (20.0% vs. 26.8%; HR 0.69; p = 0.0048), and the pathological complete response rate was higher (28% vs. 14%; OR 2.37; p < 0.0001). Locoregional control and 3-year overall survival rates were comparable between groups.
The trial provides evidence supporting short-course radiotherapy and chemotherapy as a new standard for high-risk locally advanced rectal cancer. However, criticisms include the variability in adjuvant chemotherapy policies across centers, potential biases in subgroup analyses, and the need for longer-term survival data.
Guidelines
Design
- Trial Type: Randomized, open-label, phase 3 trial
- N: 912 patients eligible for analysis
- Experimental Arm: Short-course radiotherapy → chemotherapy → TME (n=462)
- Standard Arm: 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: 3-year disease-related treatment failure
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
Experimental Arm:
- Short-course radiotherapy (5 × 5 Gy over ≤8 days)*
- Chemotherapy: six cycles of CAPOX or nine cycles of FOLFOX*
- TME after 2–4 weeks*
Standard Arm:
- Long-course chemoradiotherapy (50.0–50.4 Gy over 25–28 fractions) with oral capecitabine*
- TME after 6–10 weeks*
- Optional adjuvant chemotherapy (CAPOX or FOLFOX) per center policy*
Outcomes
Comparisons are short-course radiotherapy followed by chemotherapy vs. long-course chemoradiotherapy.
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.