Background
EuroNet-PHL-C1 was a multinational response-adapted titration study with an embedded randomized component enrolling 2,102 patients under 18 years across 16 European countries with newly diagnosed classical Hodgkin lymphoma of all stages. Two publications cover early-stage (Lancet Oncol 2023) and intermediate/advanced stage (Lancet Oncol 2022, randomized COPDAC vs. COPP). All patients received 2 cycles of OEPA induction (vincristine, etoposide, prednisone, doxorubicin) then response-adapted consolidation based on interim PET/CT.
Interventions and follow up
Arm A: OEPA × 2 (vincristine, etoposide, prednisone, doxorubicin) induction then COPP × 2–4 consolidation ± involved-field RT for inadequate response
Arm B: OEPA × 2 induction then COPDAC × 2–4 (dacarbazine replacing procarbazine) ± involved-field RT for inadequate response
Primary endpoint: EFS noninferiority of COPDAC vs COPP; safety/fertility; RT-omission feasibility in PET-negative early response
Median follow up: 5 years
Arm B: OEPA × 2 induction then COPDAC × 2–4 (dacarbazine replacing procarbazine) ± involved-field RT for inadequate response
Primary endpoint: EFS noninferiority of COPDAC vs COPP; safety/fertility; RT-omission feasibility in PET-negative early response
Median follow up: 5 years
Results
COPDAC vs. COPP — 5-yr EFS: ~88% vs. ~87% — COPDAC noninferior (P for noninferiority met)
Gonadotoxicity: significantly lower FSH and premature ovarian insufficiency with COPDAC (procarbazine omitted)
Early-stage titration (Lancet Oncol 2023): 62% of adequate responders (RERs by PET) received no RT; 5-yr EFS consistent with ≥90% target
RT omission rate: 62% in early-stage adequate responders avoided radiotherapy entirely
Gonadotoxicity: significantly lower FSH and premature ovarian insufficiency with COPDAC (procarbazine omitted)
Early-stage titration (Lancet Oncol 2023): 62% of adequate responders (RERs by PET) received no RT; 5-yr EFS consistent with ≥90% target
RT omission rate: 62% in early-stage adequate responders avoided radiotherapy entirely
Adverse events
Gonadal: COPDAC significantly less gonadotoxic vs. COPP (procarbazine omitted — major driver of alkylating-related infertility)
Hematologic: grade ≥3 toxicity comparable between arms (~40–50%)
Other: secondary MDS/AML rare (<1%); pulmonary toxicity from OEPA minimal; no treatment-related mortality reported
Hematologic: grade ≥3 toxicity comparable between arms (~40–50%)
Other: secondary MDS/AML rare (<1%); pulmonary toxicity from OEPA minimal; no treatment-related mortality reported
Conclusions
EuroNet-PHL-C1 established two European pediatric HL standards: (1) COPDAC is noninferior to COPP for EFS with significantly less gonadotoxicity, replacing procarbazine with dacarbazine as preferred consolidation; and (2) response-adapted RT omission in early-stage adequate responders achieves 5-year EFS ≥90%, establishing chemotherapy-alone as safe in this subgroup.
Key Limitations
Complex response-adapted titration design with multiple stage-specific strata limits simple interpretation and external comparison. The PET-based adequate-response definition evolved during the trial, introducing heterogeneity in RT decisions. Five-year follow-up is insufficient to fully capture late relapses, second malignancies, and reproductive outcomes central to the gonadotoxicity rationale. The randomized COPDAC vs COPP component applies to intermediate/advanced stages only. No brentuximab- or checkpoint-inhibitor–containing comparator.
Clinical Context
EuroNet-PHL-C1 underpins the European pediatric HL standard: OEPA induction with dacarbazine-based COPDAC consolidation and response-adapted RT omission. It contrasts with the North American COG approach (ABVE-PC backbone; AHOD1331 adding brentuximab). The successor EuroNet-PHL-C2 trial evaluates intensified consolidation (COPDAC-28 vs. DECOPDAC-21) to further reduce RT. No FDA/EMA drug approval derives from this academic regimen study; it informs ESMO/SIOPE pediatric practice.