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Completed trials in detail

Since its foundation in 1978, the German Hodgkin Study Group has been conducting clinical trials on Hodgkin lymphoma in cooperation with hospitals and oncology practices in Germany and other European countries. In the following you will find a summary of the results from the GHSG’s completed trials. 

Early stages

In the late 1970s, the standard treatment for early stage Hodgkin lymphoma was extended-field radiotherapy (EF-RT) of the affected regions. But then the results of the GHSG’s trials showed that a combination of chemotherapy and radiotherapy leads to a clearly better outcome, particularly in terms of relapse rates. The trials also evidenced that an irradiation restricted to the so-called involved field (IF-RT) is equally effective as EF-RT. Due to these findings, IF-RT was adopted as standard radiotherapy, leading to a reduction in radiation exposure for patients.

The results of the HD7 trial (1994-1998) showed that a combination of chemotherapy and radiotherapy is more effective than radiotherapy alone. The HD10 trial (1998-2002) proved that 4 cycles of ABVD do not lead to better results than 2 cycles of ABVD. The trial also evidenced the non-inferiority of a total dose of 20 Gy IF radiotherapy compared to 30 Gy (publication on the HD7 trial).

Therefore, the current standard treatment in early stage Hodgkin lymphoma consists of 2 cycles of ABVD and subsequent 20 Gy IF-RT. (publication on the HD10 trial).

Intermediate stages

Therapy for patients with intermediate stage Hodgkin lymphoma also underwent changes in recent years. In the first trials of the GHSG, these patients were usually treated with 2 cycles of COPP/ABVD, followed by 30 Gy EF-RT and 40 Gy RT of the bulk. In the course of time, EF-RT was replaced by IF-RT, which exposes patients to less radiation while treatment efficacy is maintained. The HD8 trial (1993-1998) produced groundbreaking results in this connection. The standard chemotherapy regimens for intermediate stage Hodgkin lymphoma also changed over the years. Instead of 2 cycles of COPP/ABVD (HD5 and HD8), 4 cycles of ABVD were used, followed by radiotherapy.

In order to optimize relapse rates, the HD14 trial investigated the option of a treatment intensification by means of 2 cycles of escalated BEACOPP, followed by 2 cycles of ABVD and subsequent 30 Gy IF-RT. The arm in which 2 cycles of escalated BEACOPP and 2 cycles of ABVD were given proved to be superior to the so far used standard of 4 cycles of ABVD. Therefore, this treatment regimen (2 cycles of escalated BEACOPP + 2 cycles of ABVD, followed by 30 Gy IF-RT) has been the GHSG’s standard treatment for intermediate stages since 2010
(publication on the HD14 trial).

Advanced stages

The most impressive therapeutic progress could be made in the treatment of advanced stage Hodgkin lymphoma. While in 1975, a complete recovery was only achieved in 50% of all advanced stage patients, 80-90% of affected patients can be cured today. The HD9 trial (1993-1998), in which the escalated BEACOPP chemotherapy regimen was introduced, has decisively contributed to this development.

In the 1970s, the MOPP and the COPP scheme were considered as standard treatment for advanced stage Hodgkin lymphoma. In the first two trial generations for advanced stage patients, HD3 (1982-1988) and HD6 (1988-1993), different numbers of cycles (3-4 cycles) of COPP/ABVD with and without subsequent radiotherapy were compared to each other. The cure rates could be improved with the new therapy compared to treatment with MOPP or COPP, but they were still not satisfying.

Therefore, in the HD9 trial the BEACOPP regimen was introduced. This treatment scheme consists of almost the same drugs as COPP and ABVD, but they are administered at different doses and times. Moreover, a highly efficacious substance, etoposide, was added to the scheme. Baseline BEACOPP and escalated BEACOPP (which uses increased doses for adriamycin, cyclophosphamide and etoposide) were tested as new schemes and compared to the COPP/ABVD standard. With a 5-year survival rate of 91%, it could be shown that escalated BEACOPP is superior to the so far used regimens.

The escalated BEACOPP regimen is highly effective, however, it is also hematotoxic (damaging to the bone marrow) and it has a higher potential for causing late effects. The HD15 trial (2003-2008) was designed to find out whether it is possible to reduce the number of patients who receive additional radiotherapy. This was the first time when the PET examination technique came into use for diagnostic purposes. 

The trial showed above all that radiotherapy can be omitted in patients with a negative PET result after chemotherapy without increasing the risk for progress or early relapse of the disease. It also evidenced that 6 cycles of escalated BEACOPP are more effective and less toxic for patients with advanced stage Hodgkin lymphoma.(publication on the HD15 trial). Therefore, the current standard treatment for advanced stage Hodgkin lymphoma consists in 6 cycles of escalated BEACOPP plus subsequent 30 Gy RT in case of PET-positive residual tumor masses ≥ 2,5 cm in size.

Studies on relapsed Hodgkin lymphoma

The HD-R1 study showed that a high-dose chemotherapy followed by autologous stem cell transplantation is more effective than 4 cycles of Dexa-BEAM. The HD-R2 study, which was conducted in cooperation with the European Organisation for Research and Treatment of Cancer, investigated whether 2 cycles of DHAP followed by a sequential high-dose chemotherapy with cyclophosphamide, methotrexate/vincristine and etoposide, and subsequent administration of BEAM and autologous stem cell transplantation are more effective than 2 cycles of DHAP directly followed by BEAM high dose chemotherapy and subsequent autologous stem cell transplantation.

Studies on advanced stage Hodgkin patients aged over 60

The escalated BEACOPP regimen, which is widely used for patients under 60 years of age, is too toxic for most patients over 60. In the BACOPP21 trial and the PVAG Pilot trial for intermediate stage Hodgkin lymphoma, different treatment schemes for patients of this age group were evaluated.

Studies on nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL)

In terms of lymphocyte-predominant Hodgkin lymphoma at stage IA without risk factors, the LPHD study was designed to compare different therapeutic approaches retrospectively, since there weren’t any respective randomized trials at this time. The analysis of the data from 131 patients showed that involved field (IF) radiotherapy is as effective as extended-field (EF) radiotherapy or a combined treatment (randomization to either 2 x ABVD + IF or 4 x ABVD + IF). However, in order to determine the optimal therapy, longer follow-up times are necessary. 

In the RIPL study, the efficacy of the anti-CD20 antibody, rituximab, was tested in relapsed lymphocyte-predominant Hodgkin lymphoma. It was found that rituximab can be a safe and highly effective alternative. 

Study on the preservation of ovarian fertility

The PROFE study was conducted to compare oral contraceptives and the GnRH analogue, goserelin, regarding their ability to reduce ovarian toxicity and thus treatment-induced infertility. Hormonal co-treatment did not show any protective effects on the ovarian reserve. It is essential to inform young female Hodgkin lymphoma patients on potential treatment-induced damage to the ovaries and to explain ways to preserve ovarian fertility, e.g. cryopreservation of oocytes.
(publication on the PROFE study)