EuroNet-PHL-C1

Satisfactory disease control rates (>90%) can be achieved in paediatric Hodgkin’s lymphoma with established therapeutic modalities (documented for the GPOH-HD study group since the DAL-HD-82 study). The remaining challenges for further treatment optimisation are
- Reduction of acute and long-term toxicity of the chemotherapy and radiotherapy employed.
- Reduction of the amount of treatment in those children who are currently over-treated.

Meanwhile FDG-PET has become available and is routinely used in most clinics. FDG-PET can better distinguish between vital and fibrotic/necrotic residual masses and thus may resolve the specificity problem of CT/MRI. To further increase sensitivity response assessment should be performed early, e.g. after 2 OEPA. FDG-PET is now formally integrated into staging and response assessment and used to implement a modified STAR strategy:
- Patients with an adequate response after 2 OEPA (roughly: CR or PR but PET-negative, details see chapter 7.2) will not be irradiated. This holds for all treatment groups.

This study aims to eliminate Procarbazine from chemotherapy. Procarbazine is gonadotoxic and may lead to male infertility and premature menopauses. Previous studies (DAL-HD 85 and DAL-HD 87) have shown that Procarbazine is a very effective drug in Hodgkin’s Lymphoma and cannot safely be omitted:
- Intensified OEPA using Etoposide instead of Procarbazine replaces OPPA for both boys and girls in the first two cycles.
- COPDAC in which Dacarbazine replaces Procarbazine is compared to standard COPP chemotherapy using a randomised study design.

In contrast to many other malignant diseases, patients with Hodgkin’s lymphoma in first relapse have a realistic chance of cure. The number of relapses is expected to be small.
Patients are now stratified based on the dominant prognostic factor “time to first treatment failure” (Schellong 2005). Some
patients (late relapse from TG-1) are expected to have very good results with standard 2 (IEPABVD) + radiotherapy. High risk patients (progression during or up to three months after first line treatment) have an unsatisfactory prognosis with standard salvage therapy. Therefore in this group high dose BEAM chemotherapy with autologous stem cell transplantation is introduced after 2 (IEP-ABVD). In all other patients (early relapse or late relapse after TG-2 or TG-3) early response assessment with FDG-PET after one double cycle of (IEP-ABVD) decides whether standard chemotherapy with two (IEP-ABVD) is completed with radiotherapy (adequate response) or treatment is intensified with high dose BEAM chemotherapy and autologous stem cell transplantation (inadequate or unclear response).

Primary objectives

• Is a 5 year event free survival (EFS) rate estimates in patients with adequate response after 2 OEPA treated without radiotherapy consistent with a target event free survival (EFS) rate of 90% in TG-1 and TG-2 & TG-3?
• Can Procarbazine be safely replaced by Dacarbazine in therapy groups 2 and 3 without a deterioration of EFS (randomised comparison of COPDAC and COPP).
• Description of treatment outcome to a standardised risk adapted relapse strategy

Secondary objectives

• Is the 5 year event free survival (EFS) rate in patients with inadequate response after 2 OEPA who receive standard involved field radiotherapy consistent with a target EFS rate of 90% estimates in TG-1 and TG-2 & TG-3?
• Does a positive PET finding before planned high-dose chemotherapy with autologous stem cell transplantation have a negative prognostic significance?
• Does substitution of Dacarbazine for Procarbazine in TG-2 and -3 patients decrease the rate of infertility in males and premature menopause for females?

Tertiary Objectives

The exploration of the impact of real-time central staging and response assessment on treatment outcome is a further objective of the trial.

• diagnosis of classic Hodgkin’s lymphoma
• patient aged under 18 years at time of diagnosis
• written informed consent of the patient and/or the patient’s parents or guardian according to national laws
• patients with a first relapse of a classic Hodgkin’s lymphoma who received as a first-line therapy EuroNet-PHL-C1 or a comparable other treatment