Patients with advanced-stage Hodgkin's lymphoma can be cured with modern chemotherapy regimens.1, 2 The intensive eBEACOPP regimen (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone in escalated doses) developed by the German Hodgkin Study Group (GHSG) has produced excellent tumour control in the entire group of patients with advanced-stage Hodgkin's lymphoma.3, 4, 5 Favourable outcomes are, however, accompanied by a high incidence of severe acute and long-term toxicities, which can have a major effect on patients' lives even many years after treatment.6, 7, 8 Within the heterogeneous group of patients diagnosed with advanced-stage Hodgkin's lymphoma, a low individual risk of treatment failure might allow the use of a less intensive treatment to avoid toxicities. However, none of the established staging systems based on the Ann Arbor classification in combination with various clinical risk factors can reliably predict the individual risk of treatment failure.
The introduction of functional imaging using 18F-fluoro-2-deoxy-D-glucose (18F-FDG) PET for metabolic response assessment has opened up the possibility of a more individualised treatment approach.9 18F-FDG-PET response after two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) chemotherapy appears to overcome the prognostic effect of even the International Prognostic Score.10, 11, 12, 13 We thus hypothesised that interim PET imaging after two cycles of the GHSG standard regimen eBEACOPP (PET-2) might discriminate between low-risk and high-risk patients. Based on this hypothesis, the GHSG HD18 study aimed to answer two questions.
Research in context
Evidence before this study
Early interim 18F-fluoro-2-deoxy-D-glucose (18F-FDG PET) after two cycles of chemotherapy (PET-2) has shown a high positive and negative predictive value in patients with advanced-stage Hodgkin's lymphoma receiving ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine). Treatment modification based on PET-2 results might improve the outcome. We searched MEDLINE between Jan 1, 2000, and Jan 1, 2017, with the search terms “interim PET” or “PET-2” and “Hodgkin*” to identify studies that assessed the predictive effect of early interim functional imaging with PET-2. The results from both uncontrolled and controlled studies suggest that PET-2 has a high positive predictive value in advanced-stage Hodgkin's lymphoma after upfront ABVD, and that treatment intensification might be of moderate benefit in these patients. The negative predictive value in patients receiving upfront ABVD seems to be less robust. We found no evidence from controlled trials on the prognostic or predictive value of PET-2 for patients receiving BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) besides the HD18 study.
Added value of this study
A positive PET after two cycles of BEACOPP in escalated doses (eBEACOPP) did not identify a high-risk patient cohort in our phase 3 trial, neither in patients treated with a total of eight or six cycles. The negative predictive value of PET-2, however, allowed reduction from eight to four cycles of eBEACOPP without loss of tumour control. As a result from the reduced treatment intensity, the incidence of severe adverse events was significantly reduced and overall survival was significantly improved.
Implications of all the available evidence
PET-2 positivity does not identify a high-risk patient cohort when the current GHSG standard treatment is used. However, PET-2 negativity allows the reduction to a highly effective, short, and very safe treatment of only four cycles of eBEACOPP. To our knowledge, the survival outcomes of patients in the HD18 study exceed any data from controlled trials reported so far. Because a large number of contributing centres from different countries and all levels of care generated the presented data, the results of HD18 should be widely applicable in countries with access to 18FDG-PET for response assessment.
First, we wanted to assess whether treatment intensification with the addition of the anti-CD20 antibody rituximab to standard eBEACOPP would improve progression-free survival in presumably high-risk patients with positive PET-2. However, a pre-planned interim analysis showed no difference in progression-free survival at 3 years, futility was concluded, and results were published early.14
Second, assuming a favourable outcome in presumably low-risk patients with negative PET-2, we asked whether a substantial treatment reduction from eight to only four cycles of eBEACOPP would be possible without compromising progression-free survival in this patient group. With this treatment reduction, we intended to reduce the burden of therapy for our patients.
Here we report the final analysis of the GHSG HD18 study.