Author:

Justin Ferdinandus

Abstract

The BEACOPP regimen, developed by the German Hodgkin Study Group (GHSG) under Volker Diehl's leadership, represents a significant milestone in the treatment of advanced Hodgkin lymphoma. This article traces the history of BEACOPP’s introduction and development, its scientific rationale and its clinical impact. Designed to intensify therapy and eliminate resistant clones upfront, BEACOPP demonstrated superior efficacy in the landmark HD9 trial, setting a new benchmark for primary cure. Decades of research led by Diehl and his successor Andreas Engert significantly improved the tolerability of BEACOPP and the regimen’s legacy continues to shape Hodgkin lymphoma treatment through ongoing refinements and integration of novel therapies.

Introduction

By the late 20th century, Hodgkin lymphoma had transitioned from a universally fatal to a potentially curable disease, thanks to advances in radiation therapy and combination chemotherapy. The ABVD regimen, developed in Italy, had emerged as the standard treatment for many patients (Bonnadonna, 1975). However, for those with advanced or high-risk disease, outcomes remained suboptimal. The challenge was clear: develop a more intensive regimen to improve survival in these patients without unacceptable toxicity.

The German Hodgkin Study Group

In 1978 the German Ministry of Research and Technology (BMFT) started an initiative to improve clinical research in Germany by allocating 15 million Deutsche Mark for clinical trials. A meeting was held on the development of clinical trials in 1978 at Schloss Reisensburg near Ulm, Germany, and young clinical scientists were asked to initiate cooperative clinical studies in all disciplines of medicine, including hemato-oncology, rheumatology, cardiology, and psychiatry/neurology.

At that time, the pediatric and adult hemato-oncology groups were the first that successfully started the planning and performance of prospective well-controlled clinical trials in different tumor groups, in close cooperation with corresponding disciplines. The task and responsibility for initiating studies in Hodgkin lymphoma were given to Volker Diehl.

The BMFT funding provided biostatistical and documentation support in a very limited amount, but this minimal support was sufficient to start the first multicenter studies in Hannover in 1978, beginning with 5 centers and a yearly recruitment of less than 20 patients, at a time when neither doctors nor patients were familiar with or enthusiastic about clinical trials in Germany.

The group in Hannover had established the first in vitro cultures of Hodgkin-Reed-Sternberg cells in 1978, in cooperation with Harald Stein and Hilmar Lemke. The CD30 antigen and Ki-67 antigen were detected on L-428 cells, and the first monoclonal antibodies against the CD30 antigen were produced.

In 1983, Volker Diehl was offered the Chair of the Department of Internal Medicine at the University Clinics in Cologne, and the GHSG study center was moved from Hannover to Cologne. The group in Cologne was instrumental in initiating the evolution of GHSG studies under the leadership of Volker Diehl. Key contributors included clinicians Michael Schaadt, Rüdiger Mohr, Bernd Lathan, and Michael Pfreundschuh, and biomathematicians and biostatisticians such as Markus Löffler, Dirk Hasenclever, and Erich Backes.

Under the leadership of Volker Diehl, treatment strategies were gradually more risk-adapted and in five generations of consecutive studies, therapy switched from the sole use of radiotherapy to a balanced application of combining polychemotherapy and reduced radiation.

The Development of BEACOPP

By the 1990s, the GHSG had identified a critical need for a regimen that could deliver higher efficacy in advanced disease, and BEACOPP was born out of this ambition. After years of in vivo experiments, retrospective analyses, mathematical models and clinical trials it was hypothesized that more rapid administration, and more importantly, a moderate dose escalation could significantly improve cure rates..

The BEACOPP regimen—an acronym for bleomycin, etoposide, doxorubicin (adriamycin), cyclophosphamide, vincristine, procarbazine, and prednisone—was designed to intensify therapy and eliminate resistant clones upfront. The concept was coined by Volker Diehl as the “Kairos principle” and became a hallmark of the GHSG’s systematic approach. The backbone was the COPP-ABVD regimen and featured increased doses and addition of etoposide over three days and the use of granulocyte colony-stimulating factor (G-CSF) to mitigate the risk for infection.

The GHSG developed the dose-dense regimen BEACOPP in both a baseline-dose (bBEACOPP) and an escalated-dose version (eBEACOPP). The HD9 trial first compared both variants to the standard at that time, which was cyclophosphamide, vincristine, procarbazine, and prednisone (COPP) alternating with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) (Diehl, 2003). This three-armed randomized multicenter trial demonstrated superiority of eight cycles of eBEACOPP over eight cycles of COPP/ABVD or bBEACOPP, and established eBEACOPP as new standard of care for advanced-stage Hodgkin lymphoma. The 5-year results for the primary endpoint freedom from treatment failure were 87%, 76% and 69% eBEACOPP, bBEACOPP and COPP/ABVD, respectively. The 5-year overall survival rate of 91% following eBEACOPP was superior to the former standard regimen, COPP/ABVD, which had a 5-year overall survival of 83% (p=0.002). The benefit of eBEACOPP was confirmed in a ten-year follow-up analysis (Engert, 2009).

Improving BEACOPP

However, the improved efficacy came at a cost. BEACOPP, particularly in its escalated form, was associated with increased hematological toxicity, gonadal function impairment including infertility and a heightened risk of secondary malignancies. BEACOPP thus required more health-care resources, in the form of transfusions or hospitalizations potentially limiting its feasibility in some countries. Recognizing these challenges, the GHSG undertook further studies to refine the regimen, including shortened and response-adapted strategies.

As the successor to Prof. Diehl, Andreas Engert led multiple treatment optimization trials and was instrumental to improve BEACOPP. The subsequent HD15 trial compared eight cycles of eBEACOPP used in HD9 with six cycles of eBEACOPP and eight cycles of BEACOPP-14, a time-dense variant of bBEACOPP (Engert, 2012). Its aim was to reduce chemotherapy and the associated side effects while maintaining treatment results. The HD15 trial was the first to employ 18F-fluordeoxyglucose positron emission tomography (PET) for treatment stratification.

Patients with increased FDG accumulation in remaining tissue (PET positive) received consolidating radiotherapy, while patients without metabolic activity (PET negative) were not. Two important conclusions can be drawn from the results of the HD15 trial: first, six cycles of eBEACOPP are superior to eight, and second, the decision whether a patient should receive radiotherapy can be based on the PET EOT-examination. The HD18 trial implemented interim PET after two cycles of chemotherapy (PET-2) and aimed at a further reduction of chemotherapy for PET-2-negative patients to a total of only four cycles (Borchmann, 2017). In PET-2-negative patients, four cycles of eBEACOPP were non-inferior to six or eight cycles of eBEACOPP in terms of progression-free survival (PFS) : 5-year PFS for 8/6x eBEACOPP 91.2%; 5-year PFS for four cycles eBEACOPP 91.8%. In terms of OS (overall survival), four cycles of eBEACOPP were even superior with 5-year estimates of 97.6% for 4x eBEACOPP and 95.4% for 8/6x eBEACOPP and treatment-related morbidity was significantly reduced. HD18 provides a clear rational to reduce eBEACOPP from eight to only four cycles of in well-responding patients.

Next to advanced stages, BEACOPP improved cure rates in early-stage unfavorable Hodgkin Lymphoma. The HD14 trial was pivotal in exploring the role of eBEACOPP in patients with early unfavorable Hodgkin lymphoma (von Tresckow, 2014). The trial demonstrated that two cycles of eBEACOPP followed by two cycles of ABVD (“2+2”) provided superior progression-free survival compared to four cycles of ABVD (5y-PFS: 95.4% vs. 89.1%; p<0.001), without significantly increasing toxicity. Building on this, the HD17 trial further refined the approach by integrating PET-guided treatment strategies. This trial confirmed that the “2+2”-approach followed by PET-adapted therapy allows for effective treatment de-escalation while maintaining high cure rates.

The BrECADD regimen (brentuximab vedotin, etoposide, cyclophosphamide, doxorubicin, procarbazine, dexamethasone) builds on the principles of BEACOPP and incorporates brentuximab vedotin, an antibody-drug conjugate targeting CD30 (Eichenauer, 2017). The HD21 trial demonstrated that PET-2 guided BrECADD not only matches the efficacy of eBEACOPP but surpasses it with higher progression-free survival (Borchmann et al. 2024). Importantly, patients treated with BrECADD experienced significantly fewer severe toxicities, including reduced rates of myelosuppression and gonadal dysfunction. By standing on the shoulders of BEACOPP, BrECADD exemplifies the iterative nature of scientific progress within the GHSG.

Conclusion

By setting a new benchmark for primary cure, the introduction of BEACOPP in the early 2000s was a landmark achievement in the treatment of advanced and early unfavorable Hodgkin lymphoma. The development of BEACOPP in the following decades reflects the best of European oncology: multidisciplinary approach, scientific translational rigor, innovation, and a commitment to improving patient outcomes and individual wellbeing.

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