Abstract: We screened 1796 records and identified five eligible trials in total i.e. one trial could be added on the previous review. These trials included only adults (16 to 65 years of age). We included all five trials with 3427 people in the meta-analyses: the HD9 and HD14 trials were co-ordinated in Germany, the HD2000 and GSM-HD trials were performed in Italy and the EORTC 20012 was conducted in Belgium. The overall risk of performance and detection bias was low for overall survival (OS), but was high for other outcomes, as therapy blinding was not feasible. The remaining 'Risk of bias' domains were low and unclear. All trials reported results for OS and progression-free survival (PFS). In contrast to the our first published review (2011) the addition of results from the EORTC 20012 BEACOPP escalated increases OS (3142 participants; HR 0.74 (95% confidence interval (CI) 0.57 to 0.97; high-quality evidence). This means that only 90 (70 to 117) patients will die after five years in the BEACOPP escalated arm compared to 120 in the ABVD arm. This survival advantage is also reflected in an increased PFS with BEACOPP escalated (3142 participants; HR 0.54 (95% CI 0.45 to 0.64); moderate-quality evidence), meaning that after five years only 144 (121 to 168) patients will experience a progress, relapse or death in the BEACOPP escalated arm compared to 250 in the ABVD arm. There is no evidence for a difference for treatment-related mortality (2700 participants, RR 2.15 (95% CI = 0.93 to 4.95), low-quality evidence). Although the occurrence of MDS or AML may increase with BEACOPP escalated (3332 participants, RR 3.90 (95% CI 1.36 to 11.21); low-quality evidence)), there is no evidence for a difference between both regimens for overall secondary malignancies (3332 participants, RR 1.00 (95% CI 0.68 to 1.48), low-quality evidence). However, the observation time of the studies included in the review is too short to be expected to demonstrate differences with respect to second solid tumours which would not be expected to show significance until around 15 years after treatment. We are very uncertain how many female patients will be infertile due to chemotherapy and which arm might be favoured (106 participants, RR 1.37 (95% CI 0.83 to 2.26), very low-quality evidence). This is a very small sample, and the age of the patients was not detailed. No analysis of male fertility was provided. Five trials reported adverse events and the analysis shows that the escalated BEACOPP regimens probably causes more haematological toxicities WHO grade III or IV ((anaemia: 2425 participants, RR 10.67 (95% CI 7.14 to 15.93); neutropenia: 519 participants, RR 1.80 (95% CI 1.52 to 2.13); thrombocytopenia: 2425 participants, RR 18.12 (95% CI 11.77 to 27.92); infections: 2425 participants, RR 3.73 (95% CI 2.58 to 5.38), all low-quality evidence). Only one trial (EORTC 20012) planned to assess quality of life, however, no results were reported. This meta-analysis provides moderate- to high-quality evidence that adult patients between 16 and 60 years of age with early unfavourable and advanced stage HL benefit regarding OS and PFS from first-line chemotherapy including escalated BEACOPP. The proven benefit in OS for patients with advanced HL is a new finding of this updated review due to the inclusion of the results from the EORTC 20012 trial. Furthermore, there is only low-quality evidence of a difference in the total number of secondary malignancies, as the follow-up period might be too short to detect meaningful differences. Low-quality evidence also suggests that people treated with escalated BEACOPP may have a higher risk to develop secondary AML or MDS. Due to the availability of only very low-quality evidence available, we are unable to come to a conclusion in terms of infertility. This review does for the first time suggest a survival benefit. However, it is clear from this review that BEACOPP escalated may be more toxic that ABVD, and very important long-term side effects of second malignancies and infertility have not been sufficiently analysed yet.

Plain-language summary: We found five eligible trials by the date of this updated review (search date March 2017). These trials included 3427 patients adult patients (16 to 65 years of age). For this updated review there are new data available resulting in a benefit in terms of overall survival (OS) for people with early unfavourable and advanced HL receiving BEACOPP escalated for first-line treatment. Furthermore, the analysis shows a better chance of avoiding recurrence of the tumour in patients who received chemotherapy including BEACOPP escalated. We analysed the following harms potentially caused by both regimens. There is no evidence for a difference for treatment-related mortality. There is evidence for a higher risk of secondary acute myeloid leukaemia (AML) or myelodysplastic syndromes (MDS) in patients receiving BEACOPP escalated, but the total number of secondary malignancies does not show evidence for a difference between both treatment groups. However, the observation time of the studies included in the review is too short to be expected to demonstrate differences with respect to second solid tumours. We are very uncertain how many female patients will be infertile due to chemotherapy and which arm might be favoured, as the evaluated sample is very small. No data for male patients and risk for infertility was provided. Treatment with BEACOPP escalated caused a higher risk of adverse events such as anaemia, neutropenia, thrombocytopenia and infections. Quality of life was not reported by any of the included trials. One trial stated it would assess quality of life, however, there were no results reported. We assessed the quality of the evidence as high relating to overall survival, as moderate for progression-free survival and as low for secondary AML or MDS, secondary malignancies and treatment-related mortality and adverse events. The quality of evidence is very low for infertility.