Background
Phase 3, open-label RCT (UK NCRI RAPID). N=602 patients with newly diagnosed stage IA/IIA nonbulky classical Hodgkin lymphoma. All patients received 3 cycles of ABVD followed by interim PET scan (iPET). The 420 iPET-negative patients (Deauville score ≤2 on central review) were randomized; 182 iPET-positive patients received a 4th ABVD cycle plus IF-RT off-protocol.
Interventions and follow up
Arm A: Involved-field radiotherapy (IF-RT, 30 Gy) after 3×ABVD (n=209)
Arm B: No further therapy after 3×ABVD in iPET-negative patients (n=211)
Primary endpoint: PFS; noninferiority margin 10 percentage points at 3 years
Median follow-up: ~60 months
Arm B: No further therapy after 3×ABVD in iPET-negative patients (n=211)
Primary endpoint: PFS; noninferiority margin 10 percentage points at 3 years
Median follow-up: ~60 months
Results
3-yr PFS (RT vs no RT): 94.6% vs 90.8% — difference −3.8 pp (95% CI −8.8 to 1.3); noninferiority not met
3-yr OS: 99.0% both arms
iPET-positive patients (n=181, ABVD×4 + RT): 3-yr PFS 70.7%
3-yr OS: 99.0% both arms
iPET-positive patients (n=181, ABVD×4 + RT): 3-yr PFS 70.7%
Adverse events
Chemotherapy: Bleomycin-related pulmonary toxicity any grade ~6% during 3 cycles
Radiotherapy: RT acute toxicities (esophagitis, fatigue) mild, no grade 4 acute RT events; joint RAPID/H10 analysis (Fiaccadori 2023) confirmed excess early relapses at involved sites in the no-RT arm
Radiotherapy: RT acute toxicities (esophagitis, fatigue) mild, no grade 4 acute RT events; joint RAPID/H10 analysis (Fiaccadori 2023) confirmed excess early relapses at involved sites in the no-RT arm
Conclusions
Omission of IF-RT in iPET-negative early-stage cHL failed to meet the prespecified 10-percentage-point noninferiority margin for 3-year PFS, with a 3.8 pp PFS deficit. Combined modality therapy (3×ABVD + IF-RT) remains the standard of care, even in PET-negative patients by stringent Deauville criteria.
Key Limitations
The 10 pp noninferiority margin was considered generous; a 3.8 pp difference is clinically meaningful given 90%+ cure rates in this population. The PFS deficit was driven almost entirely by local relapses at initially involved sites — sites RT would have treated — highlighting the fundamental role of local consolidation. OS equivalence reflects effective salvage, not treatment equivalence. Three cycles of ABVD before PET (rather than the 2-cycle HD10 standard) limits direct applicability. No late-effect comparison between arms is available, which is the main potential benefit of RT omission.
Clinical Context
RAPID, together with H10, is the definitive evidence that RT cannot be safely omitted in PET-negative early-stage favorable cHL after standard ABVD — incorporated into ESMO guidelines maintaining combined modality therapy as standard. A joint RAPID/H10 analysis (Fiaccadori et al, BJH 2023) confirmed excess relapses without RT, predominantly at originally involved nodes. PET-adapted chemotherapy-only approaches using 4–6 cycles of ABVD remain under investigation.
References