Response-adapted omission of radiotherapy and comparison of consolidation chemotherapy in children and adolescents with intermediate-stage and advanced-stage classical Hodgkin lymphoma (EuroNet-PHL-C1): a titration study with an open-label, embedded, multinational, non-inferiority, randomised controlled trial

Abstract

Summary Background Children and adolescents with intermediate-stage and advanced-stage classical Hodgkin lymphoma achieve an event-free survival at 5 years of about 90% after treatment with vincristine, etoposide, prednisone, and doxorubicin (OEPA) followed by cyclophosphamide, vincristine, prednisone, and procarbazine (COPP) and radiotherapy, but long-term treatment effects affect survival and quality of life. We aimed to investigate whether radiotherapy can be omitted in patients with morphological and metabolic adequate response to OEPA and whether modified consolidation chemotherapy reduces gonadotoxicity. Methods Our study was designed as a titration study with an open-label, embedded, multinational, non-inferiority, randomised controlled trial, and was carried out at 186 hospital sites across 16 European countries. Children and adolescents with newly diagnosed intermediate-stage (treatment group 2) and advanced-stage (treatment group 3) classical Hodgkin lymphoma who were younger than 18 years and stratified according to risk using Ann Arbor disease stages IIAE, IIB, IIBE, IIIA, IIIAE, IIIB, IIIBE, and all stages IV (A, B, AE, and BE) were included in the study. Patients with early disease (treatment group 1) were excluded from this analysis. All patients were treated with two cycles of OEPA (1·5 mg/m 2 vincristine taken intravenously capped at 2 mg, on days 1, 8, and 15; 125 mg/m 2 etoposide taken intravenously on days 1–5; 60 mg/m 2 prednisone taken orally on days 1–15; and 40 mg/m 2 doxorubicin taken intravenously on days 1 and 15). Patients were randomly assigned to two (treatment group 2) or four (treatment group 3) cycles of COPP (500 mg/m 2 cyclophosphamide taken intravenously on days 1 and 8; 1·5 mg/m 2 vincristine taken intravenously capped at 2 mg, on days 1 and 8; 40 mg/m 2 prednisone taken orally on days 1 to 15; and 100 mg/m 2 procarbazine taken orally on days 1 to 15) or COPDAC, which was identical to COPP except that 250 mg/m 2 dacarbazine administered intravenously on days 1 to 3 replaced procarbazine. The method of randomisation (1:1) was minimisation with stochastic component and was centrally stratified by treatment group, country, trial sites, and sex. The primary endpoint was event-free survival, defined as time from treatment start until the first of the following events: death from any cause, progression or relapse of classical Hodgkin lymphoma, or occurrence of secondary malignancy. The primary objectives were maintaining 90% event-free survival at 5 years in patients with adequate response to OEPA treated without radiotherapy and to exclude a decrease of 8% in event-free survival at 5 years in the embedded COPDAC versus COPP randomisation to show non-inferiority of COPDAC. Efficacy ana...

Guideline for the first‐line management of Classical Hodgkin Lymphoma — A British Society for Haematology guideline

“…A large paediatric trial has shown that substituting dacarbazine for procarbazine as part of consolidation chemotherapy does not compromise event‐free survival (EFS), although the results from a subgroup analysis of patients treated without radiotherapy were less clear 32 . However, this trial confirmed considerably reduced gonadotoxicity and neutropenia in dacarbazine‐treated patients.…”

“…42 Paediatric trials have also placed greater reliance on combined-modality therapy and in the EuroNet-PHL-C1 trial, with over 2000 patients aged up to 18, the six-year EFS was 91.6% for the intermediate-stage group and 86.6% for the advanced-stage group with 60% receiving radiotherapy as per trial protocol. 32 Children treated with these regimens appeared to show better outcomes than adults with equivalentstage disease treated with ABVD, but it is unclear if this reflects the biology of the disease or the treatments used. The successor trial, EuroNet-PHL-C2, included patients up to 25 and uses PET to guide a randomised escalation in chemotherapy and need for radiotherapy (EuroNet-PHL-C2 trial, NCT02684708).…”

“…Compared with ABVD, paediatric regimens include corticosteroids, have a higher initial dose intensity but lower cumulative dose of anthracycline, and increased exposure to vinca alkaloids 42 . Paediatric trials have also placed greater reliance on combined‐modality therapy and in the EuroNet‐PHL‐C1 trial, with over 2000 patients aged up to 18, the six‐year EFS was 91.6% for the intermediate‐stage group and 86.6% for the advanced‐stage group with 60% receiving radiotherapy as per trial protocol 32 . Children treated with these regimens appeared to show better outcomes than adults with equivalent‐stage disease treated with ABVD, but it is unclear if this reflects the biology of the disease or the treatments used.…”

Advances in Hodgkin Lymphoma: Including the Patient’s Voice

“…Table 1 reviews some of these more recent studies from pediatric and adult cooperative groups (9)(10)(11)(12)(13)(14)(15)(16). The next generation of investigation builds upon these studies with incorporation of more biologically-targeted approaches.…”

The EHA Research Roadmap: Malignant Lymphoid Diseases

“…In adolescents and young adults (AYA), to limit gonadal damage and second malignancies, the European trial EuroNet PHL C1 24 lead to the replacement of procarbazine with dacarbazine and to restriction of RT indications to patients with an adequate response after 2 first cycles of OEPA. EuroNet PHL C2 explores moderate treatment intensification in order to further limit RT indications.…”