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Andreas Engert - One of the best experts on this subject based on the ideXlab platform.

  • comparison of first line chemotherapy including escalated BEACOPP versus chemotherapy including abvd for people with early unfavourable or advanced stage hodgkin lymphoma
    Cochrane Database of Systematic Reviews, 2017
    Co-Authors: Nicole Skoetz, Andreas Engert, C. Brillant, Ina Monsef, Andrea Will, Bastian Von Tresckow
    Abstract:

    Background There are two different international standards for the treatment of early unfavourable and advanced stage Hodgkin lymphoma (HL): chemotherapy with escalated BEACOPP (bleomycin/etoposide/doxorubicin/cyclophosphamide/vincristine/procarbazine/prednisone) regimen and chemotherapy with ABVD (doxorubicin/bleomycin/vinblastine/dacarbazine) regimen. Objectives To determine the advantages and disadvantages of chemotherapy including escalated BEACOPP compared to chemotherapy including ABVD in the treatment of early unfavourable or advanced stage HL as first-line treatment. Search methods We searched for randomised controlled trials in MEDLINE, CENTRAL and conference proceedings (January 1985 to July 2013 and for the update to March 2017) and Embase (1985 to November 2008). Moreover we searched trial registries (March 2017; www.controlled-trials.com, www.clinicaltrialsregister.eu/ctr-search/search, clinicaltrials.gov, www.eortc.be, www.ghsg.org, www.ctc.usyd.edu.au, www.trialscentral.org/index.html) Selection criteria We included randomised controlled trials examining chemotherapy including at least two cycles of escalated BEACOPP regimens compared with chemotherapy including at least four cycles of ABVD regimens as first-line treatment for patients with early unfavourable stage or advanced stage HL. Data collection and analysis The effect measures we used were hazard ratios (HRs) for overall survival (OS), progression-free survival (PFS) and freedom from first progression. We used risk ratios (RRs) relative risks to analyse harms: treatment-related mortality, secondary malignancies (including myeloid dysplastic syndrome (MDS) or acute myeloid leukaemia (AML)), infertility and adverse events. Quality of life was not reported in any trial, therefore not analysed. Two review authors independently extracted data and assessed quality of trials. Main results 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. Authors' conclusions 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.

  • CLINICAL TRIALS AND OBSERVATIONS Fertility in male patients with advanced Hodgkin lymphoma treated with
    2016
    Co-Authors: Andreas Engert
    Abstract:

    To date, there is little information on the impact of more aggressive treatment regi-men such as BEACOPP (bleomycin, eto-poside, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) on the fertility of male patients with Hodgkin lymphoma (HL). We evaluated the impact of BEACOPP regimen on fertil-ity status in 38 male patients with ad-vanced-stage HL enrolled into trials of the German Hodgkin Study Group (GHSG). Before treatment, 6 (23%) patients had normozoospermia and 20 (77%) patients had dysspermia. After treatment, 34 (89%) patients had azoospermia, 4 (11%) had other dysspermia, and no patients had normozoospermia. There was no differ-ence in azoospermia rate between pa-tients treated with BEACOPP baseline and those given BEACOPP escalated (93% vs 87%, respectively; P>.999). After treat-ment, most of patients (93%) had abnor-mal values of follicle-stimulating hor-mone, whereas the number of patients with abnormal levels of testosterone and luteinizing hormone was less pro-nounced—57 % and 21%, respectively. In univariate analysis, none of the evaluated risk factors (ie, age, clinical stage, el-evated erythrocyte sedimentation rate, B symptoms, large mediastinal mass, ex-tranodal disease, and 3 or more lymph nodes) was statistically significant. Male patients with HL are at high risk of infertil-ity after treatment with BEACOPP. (Blood

  • ABVD or BEACOPP for Advanced Hodgkin Lymphoma
    Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2015
    Co-Authors: Andreas Engert
    Abstract:

    The development of multiagent chemotherapy dramatically changed the prognosis of patients with advanced-stage Hodgkin lymphoma (HL). Although almost all of these patients died when treated with radiotherapy or single-agent chemotherapy, the fourdrug regimen MOPP (mustargen, oncovin, procarbazine, and prednisone) led to remission rates of more than 50% and an overall survival (OS) rate of more than 60%. Shortly thereafter, ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) as an alternative anthracycline-containing regimen was introduced in the treatment of HL. It took 20 years before ABVD was accepted as better than MOPP or MOPP-based hybrid variants. In the meantime, multiagent regimens such as ChlVPP (chlorambucil, vinblastine, procarbazine, and prednisolone) plus EVA (etoposide, vinblastine, and doxorubicin) and Stanford V were evaluated but failed to improve outcomes of patients with advanced-stage HL. The quest for a more effective regimen in HLwas the rationale for the GermanHodgkin StudyGroup (GHSG) to design BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone)more than 20 years ago. This regimen was developed using baseline (BEACOPPbaseline) or escalated doses (BEACOPPescalated) and subsequently compared with the GHSG standard at that time, COPP (cyclophosphamide, vincristine, procarbazine, and prednisone) –ABVD, in the HD9 trial. With a total of 1,195 randomly assigned patients and 5 years of follow-up, BEACOPPescalated was found to be significantly better than BEACOPPbaseline and COPP-ABVD. The 10-year update confirmed and extended the initial findings, demonstrating an improvement of 18% in tumor control between BEACOPPescalated and COPP-ABVD as well as an OS difference of 11%. Because BEACOPPescalated was also associated withmore hematologic toxicity, infections, infertility, and secondary leukemia, there has been some controversy about this regimen since the initial publication. Themajority of patients treated with BEACOPPescalated in HD9 developed grade 3 to 4 leucopenia and thrombocytopenia, and 22% had infectious complications. However, this did not translate into higher treatment-associated mortality with BEACOPPescalated, as compared with the other two arms of the HD9 trial, BEACOPPbaseline and COPP-ABVD. In the 10-year update, the higher response rates in patients treated with BEACOPPescalated resulted in significantly lower overall mortality (12%) as compared with those in patients treated with BEACOPPbaseline (19%) or COPP-ABVD (24%). With this clear improvement in efficacy, the GHSG HD12 follow-up trial for advanced-stage HL aimed at reducing overall toxicity of BEACOPP by employing four cycles of BEACOPPescalated followed by four cycles of BEACOPPbaseline (ie, 41 4). However, this approach failed. It was the next-generation trial in advanced-stage HL, HD15, in which more than 2,100 patients were randomly assigned, that demonstrated the reduction to six cycles of BEACOPPescalated followed by radiation administered to residual positron emission tomography (PET) –positive disease $ 2.5 cm led to a significantly improved and less toxic regimen. With the disappearance of potential alternatives such as Stanford V, the choice of the best treatment for advanced-stage HL increasingly focused on the question of ABVD or BEACOPP. Subsequently, collaborative groups directly compared ABVD with BEACOPPescalated in four prospective trials. 10-13 Instead of using eight cycles of BEACOPPescalated, as in HD9, three of these trials used 41 4, similar to the experimental arms of the HD12 trial; the Italian HD2000 instead used four cycles of BEACOPPescalated followed by two cycles of BEACOPPbaseline (4 1 2). In these four trials, a total of 1,227 patients were randomly assigned to 41 4 or 4 1 2 BEACOPP variants and ABVD. All four trials reported significant improvements in tumor control, with 5-year progression-free survival (PFS) gains ranging between 12% and 18% and OS differences of 4% to 8% favoring BEACOPP. In the article accompanying this editorial, Merli et al report an update of their 2009 publication of the Italian HD2000 trial. This three-arm randomized trial registered 307 patients with HL, of whom 12 were subsequently excluded. The initial article, with a median follow-up of 42 months, also published in Journal of Clinical Oncology, had shown a significantly better PFS with BEACOPP 4 1 2 as compared with ABVD (81% v 68% P 5 .038). In the 10-year update, with a median follow-up of 120 months, PFS with ABVD, BEACOPP 4 1 2, and the 10-drug COPP-EBV-CAD (cyclophosphamide, lomustine, vindesine, melphalan, prednisone, epidoxorubicin, vincristine, procarbazine, vinblastine, and bleomycin) regimen was 69%, 75%, and 76%, respectively, with corresponding OS rates of 85%, 84%, and 86%. A total of 13 secondary neoplasias were reported, one after treatment with ABVD, six after BEACOPP, and six after COPP-EBV-CAD. The authors concluded that with longer follow-up, they were no longer able to confirm the superiority of BEACOPP 4 1 2 over ABVD in terms of PFS and that this was mainly because of higher mortality from secondary malignancies. However, with fewer

  • effect of initial treatment strategy on survival of patients with advanced stage hodgkin s lymphoma a systematic review and network meta analysis
    Lancet Oncology, 2013
    Co-Authors: Nicole Skoetz, Andreas Engert, Heinz Haverkamp, V Diehl, Sven Trelle, Michaela Rancea, Peter Borchmann
    Abstract:

    Summary Background Several treatment strategies are available for adults with advanced-stage Hodgkin's lymphoma, but studies assessing two alternative standards of care—increased dose bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP escalated ), and doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD)—were not powered to test differences in overall survival. To guide treatment decisions in this population of patients, we did a systematic review and network meta-analysis to identify the best initial treatment strategy. Methods We searched the Cochrane Library, Medline, and conference proceedings for randomised controlled trials published between January, 1980, and June, 2013, that assessed overall survival in patients with advanced-stage Hodgkin's lymphoma given BEACOPP baseline , BEACOPP escalated , BEACOPP variants, ABVD, cyclophosphamide (mechlorethamine), vincristine, procarbazine, and prednisone (C[M]OPP), hybrid or alternating chemotherapy regimens with ABVD as the backbone (eg, COPP/ABVD, MOPP/ABVD), or doxorubicin, vinblastine, mechlorethamine, vincristine, bleomycin, etoposide, and prednisone combined with radiation therapy (the Stanford V regimen). We assessed studies for eligibility, extracted data, and assessed their quality. We then pooled the data and used a Bayesian random-effects model to combine direct comparisons with indirect evidence. We also reconstructed individual patient survival data from published Kaplan-Meier curves and did standard random-effects Poisson regression. Results are reported relative to ABVD. The primary outcome was overall survival. Findings We screened 2055 records and identified 75 papers covering 14 eligible trials that assessed 11 different regimens in 9993 patients, providing 59 651 patient-years of follow-up. 1189 patients died, and the median follow-up was 5·9 years (IQR 4·9–6·7). Included studies were of high methodological quality, and between-trial heterogeneity was negligible (τ 2 =0·01). Overall survival was highest in patients who received six cycles of BEACOPP escalated (HR 0·38, 95% credibility interval [CrI] 0·20–0·75). Compared with a 5 year survival of 88% for ABVD, the survival benefit for six cycles of BEACOPP escalated is 7% (95% CrI 3–10)—ie, a 5 year survival of 95%. Reconstructed individual survival data showed that, at 5 years, BEACOPP escalated has a 10% (95% CI 3–15) advantage over ABVD in overall survival. Interpretation Six cycles of BEACOPP escalated significantly improves overall survival compared with ABVD and other regimens, and thus we recommend this treatment strategy as standard of care for patients with access to the appropriate supportive care. Funding None.

  • effect of initial treatment strategy on survival of patients with advanced stage hodgkin s lymphoma a systematic review and network meta analysis
    Lancet Oncology, 2013
    Co-Authors: Nicole Skoetz, Andreas Engert, Heinz Haverkamp, V Diehl, Sven Trelle, Michaela Rancea, Peter Borchmann
    Abstract:

    Summary Background Several treatment strategies are available for adults with advanced-stage Hodgkin's lymphoma, but studies assessing two alternative standards of care—increased dose bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP escalated ), and doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD)—were not powered to test differences in overall survival. To guide treatment decisions in this population of patients, we did a systematic review and network meta-analysis to identify the best initial treatment strategy. Methods We searched the Cochrane Library, Medline, and conference proceedings for randomised controlled trials published between January, 1980, and June, 2013, that assessed overall survival in patients with advanced-stage Hodgkin's lymphoma given BEACOPP baseline , BEACOPP escalated , BEACOPP variants, ABVD, cyclophosphamide (mechlorethamine), vincristine, procarbazine, and prednisone (C[M]OPP), hybrid or alternating chemotherapy regimens with ABVD as the backbone (eg, COPP/ABVD, MOPP/ABVD), or doxorubicin, vinblastine, mechlorethamine, vincristine, bleomycin, etoposide, and prednisone combined with radiation therapy (the Stanford V regimen). We assessed studies for eligibility, extracted data, and assessed their quality. We then pooled the data and used a Bayesian random-effects model to combine direct comparisons with indirect evidence. We also reconstructed individual patient survival data from published Kaplan-Meier curves and did standard random-effects Poisson regression. Results are reported relative to ABVD. The primary outcome was overall survival. Findings We screened 2055 records and identified 75 papers covering 14 eligible trials that assessed 11 different regimens in 9993 patients, providing 59 651 patient-years of follow-up. 1189 patients died, and the median follow-up was 5·9 years (IQR 4·9–6·7). Included studies were of high methodological quality, and between-trial heterogeneity was negligible (τ 2 =0·01). Overall survival was highest in patients who received six cycles of BEACOPP escalated (HR 0·38, 95% credibility interval [CrI] 0·20–0·75). Compared with a 5 year survival of 88% for ABVD, the survival benefit for six cycles of BEACOPP escalated is 7% (95% CrI 3–10)—ie, a 5 year survival of 95%. Reconstructed individual survival data showed that, at 5 years, BEACOPP escalated has a 10% (95% CI 3–15) advantage over ABVD in overall survival. Interpretation Six cycles of BEACOPP escalated significantly improves overall survival compared with ABVD and other regimens, and thus we recommend this treatment strategy as standard of care for patients with access to the appropriate supportive care. Funding None.

C. Brillant - One of the best experts on this subject based on the ideXlab platform.

  • comparison of first line chemotherapy including escalated BEACOPP versus chemotherapy including abvd for people with early unfavourable or advanced stage hodgkin lymphoma
    Cochrane Database of Systematic Reviews, 2017
    Co-Authors: Nicole Skoetz, Andreas Engert, C. Brillant, Ina Monsef, Andrea Will, Bastian Von Tresckow
    Abstract:

    Background There are two different international standards for the treatment of early unfavourable and advanced stage Hodgkin lymphoma (HL): chemotherapy with escalated BEACOPP (bleomycin/etoposide/doxorubicin/cyclophosphamide/vincristine/procarbazine/prednisone) regimen and chemotherapy with ABVD (doxorubicin/bleomycin/vinblastine/dacarbazine) regimen. Objectives To determine the advantages and disadvantages of chemotherapy including escalated BEACOPP compared to chemotherapy including ABVD in the treatment of early unfavourable or advanced stage HL as first-line treatment. Search methods We searched for randomised controlled trials in MEDLINE, CENTRAL and conference proceedings (January 1985 to July 2013 and for the update to March 2017) and Embase (1985 to November 2008). Moreover we searched trial registries (March 2017; www.controlled-trials.com, www.clinicaltrialsregister.eu/ctr-search/search, clinicaltrials.gov, www.eortc.be, www.ghsg.org, www.ctc.usyd.edu.au, www.trialscentral.org/index.html) Selection criteria We included randomised controlled trials examining chemotherapy including at least two cycles of escalated BEACOPP regimens compared with chemotherapy including at least four cycles of ABVD regimens as first-line treatment for patients with early unfavourable stage or advanced stage HL. Data collection and analysis The effect measures we used were hazard ratios (HRs) for overall survival (OS), progression-free survival (PFS) and freedom from first progression. We used risk ratios (RRs) relative risks to analyse harms: treatment-related mortality, secondary malignancies (including myeloid dysplastic syndrome (MDS) or acute myeloid leukaemia (AML)), infertility and adverse events. Quality of life was not reported in any trial, therefore not analysed. Two review authors independently extracted data and assessed quality of trials. Main results 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. Authors' conclusions 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.

  • comparison of chemotherapy including escalated BEACOPP versus chemotherapy including abvd for patients with early unfavourable or advanced stage hodgkin lymphoma
    Cochrane Database of Systematic Reviews, 2011
    Co-Authors: Andreas Engert, C. Brillant, Nicole Skoetz, Kathrin Bauer, Ina Monsef
    Abstract:

    Background There are two different international standards for the treatment of early unfavourable and advanced stage Hodgkin lymphoma (HL): chemotherapy with escalated BEACOPP (bleomycin/etoposide/doxorubicin/cyclophosphamide/vincristine/procarbazine/prednisone) regimen and chemotherapy with ABVD (doxorubicin/bleomycin/vinblastine/dacarbazine) regimen. Objectives To provide an evidence-based answer regarding the advantages and disadvantages of chemotherapy including escalated BEACOPP compared to chemotherapy including ABVD. Search methods We searched for randomised controlled trials in MEDLINE, CENTRAL and conference proceedings (January 1985 to November 2010) and EMBASE (1985 to November 2008). Selection criteria We included randomised controlled trials examining chemotherapy including at least two cycles of escalated BEACOPP regimens compared to chemotherapy including at least four cycles of ABVD regimens as first-line treatment for patients with early unfavourable stage or advanced stage HL. Data collection and analysis Effect measures used were hazard ratios (HR) for overall survival (OS), progression-free survival (PFS) and freedom from first progression. Relative risks were used to analyse complete response rate, treatment-related mortality and adverse events. Two independent review authors extracted data and assessed quality of trials. Main results A total of 790 records were screened. Five eligible trials (four published, one ongoing), were identified. These trials included only adult patients (16 to 60 years of age). Four trials with 2868 patients were included in the meta-analyses: the HD9 and HD14 trials from Germany, the HD2000 and GSM-HD trials from Italy. All trials reported results for PFS and OS. PFS was statistically significantly longer for escalated BEACOPP: HR was 0.53 (95% confidence interval (CI) 0.44 to 0.64, I2 = 0%). There was no statistically significant difference in OS between the comparators: HR was 0.80 (95% CI 0.59 to 1.09, I2 = 0%). Three trials reported adverse events: the escalated BEACOPP regimens caused statistically significantly more haematological toxicities WHO grade III or IV (anaemia P < 0.00001, neutropenia P = 0.007, thrombocytopenia P < 0.00001), infections (P < 0.00001)) and occurrence of myeloid dysplastic syndrome (MDS) or acute myeloid leukemia (AML) (P = 0.05). There were no differences between both regimens for secondary malignancies, treatment-related mortality or infertility. Authors' conclusions This meta-analysis showed that adult patients between 16 and 60 years of age with early unfavourable or advanced stage HL benefited from chemotherapy including escalated BEACOPP regarding PFS, but there was no significant difference in OS. Longer follow-up and the inclusion of the EORTC 20012 trial will lead to a more definitive answer with respect to OS.

  • Escalated BEACOPP Versus ABVD-Like Chemotherapy for Hodgkin Lymphoma Patients: a Cochrane Review.
    Blood, 2009
    Co-Authors: C. Brillant, Nicole Skoetz, Kathrin Bauer, Ina Monsef, Christine Herbst, Andreas Engert
    Abstract:

    Abstract 3705 Poster Board III-641 Introduction The main challenge in treating Hodgkin lymphoma (HL) is to find the optimal treatment with the best efficacy and least toxicity. So far there are two different international standards for the treatment of intermediate and advanced stage HL: chemotherapy with ABVD regime and chemotherapy with escalated BEACOPP regime. This review aims to clarify advantages and disadvantages of both treatments. Methods MEDLINE, CENTRAL and EMBASE were systematically searched for randomised controlled trials from 1985 to 2008. Trials comparing treatment with at least 2 cycles escalated BEACOPP versus chemotherapy with at least 4 cycles of ABVD within patients in intermediate or advanced stages HL were included. Trials without any published results will be excluded from the meta-analysis. Trial selection, quality assessment and data extraction were done independently by two review authors. Time-to-event outcome were analyzed with hazard ratios (HR) and 95% confidence interval (CI) in a fixed effects model. Results A total of 683 references were screened. Four eligible trials with 1970 patients were identified and included in the main analysis: the HD9 and HD14 trials from Germany, the HD2000 and GSM-HD trials from Italy. The escalated BEACOPP regime was more toxic during treatment than ABVD. Progression free survival (PFS) was statistically significantly longer for escalated BEACOPP: HR was 0.53 (95% CI [0.42, 0.67], I2=0%). In the main analysis of overall survival (OS), escalated BEACOPP was statistically significantly better than ABVD: HR was 0.70 (95% CI [0.50, 0.98], I2=0%). However, this result is not robust. In the OS-analysis restricted to advanced stage trials, the HR was 0.93 (95% CI [0.52, 1.04], I2=0%). Due to the high weight of the HD9 trial (57%), the OS-results are strongly influenced by this trial. In a sensitivity OS analysis without the HD9 trial the HR was 0.83 (95% CI [0.50, 1.38]). Only one trial (HD9) had a follow-up of over 5 years; the median of the other trials was approx. 3 years. Conclusions This meta-analysis showed a better PFS and suggests a benefit in OS for escalated BEACOPP in comparison to ABVD-like regimen. However, many trials had a short follow-up. Longer follow-up and the inclusion of the ongoing EORTC 20012 trial should allow a more definitive answer concerning OS. Disclosures: No relevant conflicts of interest to declare.

  • comparison of BEACOPP and abvd chemotherapy in intermediate stage hodgkin s lymphoma results of the fourth interim analysis of the hd 11 trial of the ghsg
    Journal of Clinical Oncology, 2005
    Co-Authors: Beate Klimm, Richard Herrmann, C. Brillant, A. Engert, Hans Theodor Eich, Wolfgang Hiddemann, Hans Konrad Muellerhermelink, Richard Greil
    Abstract:

    6507 Background: Combined modality treatment is the standard treatment for intermediate stage Hodgkin’s lymphoma (HL). Despite high complete remission (CR) rates, failure rates are remarkably higher in this group of patients. In the HD 11 multicenter trial of the GHSG the BEACOPP regimen was introduced to intermediate stages in an attempt to improve therapy outcome. Simultaneously, the possibility to reduce the IF-RT dose from 30 Gy to 20 Gy is evaluated. Methods: Between May 1998 and July 2002, 1363 patients (16–75 years old) with intermediate stage HL (CS I, IIA with risk factors or IIB with elevated ESR and/or >= 3 nodal areas) were randomised according to a 2 x 2 factorial design between: 4 ABVD + 30 Gy IF-RT (arm A), 4 ABVD + 20 Gy IF-RT (arm B), 4 BEACOPP basis + 30 Gy IF-RT (arm C), and 4 BEACOPP basis + 20 Gy IF-RT (arm D). Results: In the fourth interim analysis in August 2003, 1047 (77%) patients were evaluable for chemotherapy and 982 (72%) for radiotherapy. Patient characteristics were well ba...

  • BEACOPP chemotherapy for advanced hodgkin s disease results of further analyses of the hd9 and hd12 trials of the german hodgkin study group ghsg
    Blood, 2004
    Co-Authors: C. Brillant, Jeremy Franklin, Richard Greil, R. Hermann, A. Engert, Beate Pfistner
    Abstract:

    Background: The BEACOPP regimen has proved to be superior to the conventional drug combination COPP/ABVD in the HD9 trial. In the HD12 trial, the GHSG aimed to confirm these results but at the same time attempted to reduce acute and late toxicity. Objectives: HD 9: In the recent analysis of HD9, we aim to demonstrate the benefits of BEACOPP and of dose increase after longer follow-up. In particular, we reassess the occurrence of second malignancies and the impact on OS. HD12: The HD12 trial (closed in 1/2003) aimed at de-escalating chemotherapy by comparing 8 courses of escalated BEACOPP (8 esc.BEA) with 4 escalated and 4 baseline courses of BEACOPP (4+4BEA), with or without consolidatory radiation to initial bulky and residual disease. Methods: HD9: In 1993-98, 1201 eligible patients (aged 16-65, in stages IIB and IIIA with risk factors and stages IIIB and IV) were randomised to (A) 4 double cycles COPP/ABVD, (B) 8 cycles baseline BEACOPP or (C) 8 cycles esc.BEACOPP, followed by radiation of initial bulky or residual disease. HD12: In 1999-2002, 1396 eligible patients aged 16-65 with HL in stage IIB (large mediastinal mass and/or E-lesions) or stage III-IV were randomised according to a factorial design between: (A) 8 esc.BEA + RT, (B) 8 esc.BEA no RT, (C) 4+4BEA+ RT, (D) 4+4BEA no RT. An expert panel evaluated all cases immediately after chemotherapy and, where appropriate, recommended additional radiotherapy independent of randomisation. Results: HD9: In the recent update of this trial (7/2004) with a median follow-up of 82 months, the estimated FFTF and OS rates were: arm A 67% and 79%, arm B 75% and 84%, arm C 85% and 90% (p Conclusions: The results of the updated HD9 analysis convincingly demonstrate, despite an increased second leukemia rate, superior overall survival due to dose escalation of BEACOPP. Up to now the interim analysis of the HD12 trial shows no statistical difference between 8 cycles of escalated BEACOPP and 4 escalated and 4 baseline BEACOPP cycles. With a larger cohort of patients the excellent efficacy of the escalated BEACOPP regime for FFTF and OS seems to be confirmed in the HD12 trial.

Jeremy Franklin - One of the best experts on this subject based on the ideXlab platform.

  • escalated dose BEACOPP in the treatment of patients with advanced stage hodgkin s lymphoma 10 years of follow up of the ghsg hd9 study
    Journal of Clinical Oncology, 2009
    Co-Authors: Andreas Engert, Jeremy Franklin, Michael Pfreundschuh, Bernd Dorken, Andreas Lohri, Wolfdieter Ludwig, Peter Paul Koch, Mathias Hanel, Martin Wilhelm
    Abstract:

    Purpose The HD9 trial of the German Hodgkin Study Group compared two different doses (baseline and escalated) of the bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) chemotherapy regimen in 1,196 patients with advanced-stage Hodgkin's lymphoma (HL). The previous analysis with 5 years median follow-up had indicated improved tumor control with BEACOPP escalated. Since the long-term safety and efficacy of this regimen has been debated, we report the 10-year follow-up. Patients and Methods Patients received one of three chemotherapy regimens: eight cycles of cyclophosphamide, vincristine, procarbazine, and prednisone (COPP) alternating with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD); eight cycles of BEACOPP baseline; or eight cycles of BEACOPP escalated. Results Median follow-up was 111 months. At 10 years, freedom from treatment failure (FFTF) was 64%, 70%, and 82% with OS rates of 75%, 80%, and 86% for patients treated with COPP/ABVD (...

  • Ten-year results of a German Hodgkin Study Group randomized trial of standard and increased dose BEACOPP chemotherapy for advanced Hodgkin lymphoma (HD9)
    Journal of Clinical Oncology, 2007
    Co-Authors: Jeremy Franklin, Beate Pfistner, A. Engert
    Abstract:

    LBA8015 Background: The HD9 trial was designed to compare standard and dose escalated versions of a novel chemotherapy BEACOPP in advanced Hodgkin lymphoma. The previous analysis in 2004 showed improved tumor control and overall survival due to dose escalation. The present 10 year analysis in March 2007 aimed to update and confirm these results and to monitor late effects. Methods: Patients aged 16–65 years with untreated Hodgkin lymphoma stage IIB/IIIA and risk factors or stage IIIB/IV were randomized to (A) 4 double cycles COPP/ABVD, (B) 8 cycles standard-dose BEACOPP or (C) 8 cycles increased-dose BEACOPP (doxorubicin, cyclophosphamide and etoposide at 140%, 192% and 200% of standard doses, respectively), each followed by irradiation of initial bulky and residual disease. Accrual of at least 900 patients was planned so as to detect a 9–10% improvement in the primary endpoint, freedom from treatment failure (FFTF), with a power of 80% (alpha=5%). Results: 1196 of 1201 eligible, randomized patients were ...

  • ten year results of a german hodgkin study group randomized trial of standard and increased dose BEACOPP chemotherapy for advanced hodgkin lymphoma hd9
    Journal of Clinical Oncology, 2007
    Co-Authors: Volker Diehl, Jeremy Franklin, Beate Pfistner, A. Engert
    Abstract:

    LBA8015 Background: The HD9 trial was designed to compare standard and dose escalated versions of a novel chemotherapy BEACOPP in advanced Hodgkin lymphoma. The previous analysis in 2004 showed imp...

  • mortality during treatment of patients with advanced hodgkin s lymphoma undergoing dose escalated BEACOPP chemotherapy an analysis of the german hodgkin study group ghsg
    Blood, 2005
    Co-Authors: Michael Fuchs, Jeremy Franklin, Beate Pfistner, Andreas Josting, Beate Klimm, Andreas Engert
    Abstract:

    Introduction: Due to substantial clinical progress over the past decades, the outcome of patients with Hodgkin’s Lymphoma (HL) has improved with a long-term disease free survival of nearly 80%. Even patients with advanced-stage HL show a five year freedom from treatment failure (FFTF) of 87% and overall survival (OS) of 91% when treated with 8 cycles of BEACOPP escalated (bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbacine, prednisone). However, BEACOPP escalated has been associated with some acute and long-term treatment related mortality (TRM). We thus analysed the incidence, clinical features and risk factors for TRM of patients treated with BEACOPP escalated in the HD12 multicenter trial of the GHSG performed between 1998 and 2002. The HD12 was conducted for advanced HL patients (Stage IIB with large mediastinal mass and/or extranodal involvement, stage III/IV). All patients received 8 cycles of chemotherapy either 8x BEACOPP escalated (Arm A/B) or 4xBEACOPP escalated + 4xBEACOPP baseline (Arm C/D) +/− 30Gy radiation on bulk and residual tumor. Results: In this study, 43 patients (3.1%) from a total of 1392 included died from TRM. 5 patients were excluded from this analysis because of various reasons (change of fist-line therapy due to toxicity, TRM in BEACOPP baseline ) 38 patients were eligible for this analysis. 30 patients (79%) had infectious complications, 6 (16%) cardiac events such as arrhythmia or heart failure, 1 patient died due to bleomycin-related toxicity and 1 case remained unclear. 25 patients (66%) were older than 50 years in contrast to the whole HD12 study population with only 17% of patients being older than 50. There was no statistical difference between those cases with treatment related mortality and the whole study population in terms of other clinical risk factors such as gender, B-symptoms, extranodal involvement, stage of disease, large mediastinal mass or elevated ESR. There was also no difference between the 4 study arms. Most events occurred during the first 4 courses of BEACOPP escalated (79%) with the majority during the first cycle (n = 12; 32%). 23/26 (89%) of patients who died during cycles 2 – 8 had prior WHO grade III/IV leucopenia or infection. Conclusion: Patient age and toxicity in previous cycles are the most obvious risk factors for TRM in patients with advanced HL undergoing BEACOPP escalated chemotherapy. In the HD12 study, the use of G-CSF was mandatory and most patients received their treatment on an outpatient basis. Thus, possible measures to reduce toxicity with this treatment include the prophylactic use of antibiotics as well as treating those with risk factors at least for the first course as inpatients.

  • BEACOPP chemotherapy for advanced hodgkin s disease results of further analyses of the hd9 and hd12 trials of the german hodgkin study group ghsg
    Blood, 2004
    Co-Authors: C. Brillant, Jeremy Franklin, Richard Greil, R. Hermann, A. Engert, Beate Pfistner
    Abstract:

    Background: The BEACOPP regimen has proved to be superior to the conventional drug combination COPP/ABVD in the HD9 trial. In the HD12 trial, the GHSG aimed to confirm these results but at the same time attempted to reduce acute and late toxicity. Objectives: HD 9: In the recent analysis of HD9, we aim to demonstrate the benefits of BEACOPP and of dose increase after longer follow-up. In particular, we reassess the occurrence of second malignancies and the impact on OS. HD12: The HD12 trial (closed in 1/2003) aimed at de-escalating chemotherapy by comparing 8 courses of escalated BEACOPP (8 esc.BEA) with 4 escalated and 4 baseline courses of BEACOPP (4+4BEA), with or without consolidatory radiation to initial bulky and residual disease. Methods: HD9: In 1993-98, 1201 eligible patients (aged 16-65, in stages IIB and IIIA with risk factors and stages IIIB and IV) were randomised to (A) 4 double cycles COPP/ABVD, (B) 8 cycles baseline BEACOPP or (C) 8 cycles esc.BEACOPP, followed by radiation of initial bulky or residual disease. HD12: In 1999-2002, 1396 eligible patients aged 16-65 with HL in stage IIB (large mediastinal mass and/or E-lesions) or stage III-IV were randomised according to a factorial design between: (A) 8 esc.BEA + RT, (B) 8 esc.BEA no RT, (C) 4+4BEA+ RT, (D) 4+4BEA no RT. An expert panel evaluated all cases immediately after chemotherapy and, where appropriate, recommended additional radiotherapy independent of randomisation. Results: HD9: In the recent update of this trial (7/2004) with a median follow-up of 82 months, the estimated FFTF and OS rates were: arm A 67% and 79%, arm B 75% and 84%, arm C 85% and 90% (p Conclusions: The results of the updated HD9 analysis convincingly demonstrate, despite an increased second leukemia rate, superior overall survival due to dose escalation of BEACOPP. Up to now the interim analysis of the HD12 trial shows no statistical difference between 8 cycles of escalated BEACOPP and 4 escalated and 4 baseline BEACOPP cycles. With a larger cohort of patients the excellent efficacy of the escalated BEACOPP regime for FFTF and OS seems to be confirmed in the HD12 trial.

Ina Monsef - One of the best experts on this subject based on the ideXlab platform.

  • comparison of first line chemotherapy including escalated BEACOPP versus chemotherapy including abvd for people with early unfavourable or advanced stage hodgkin lymphoma
    Cochrane Database of Systematic Reviews, 2017
    Co-Authors: Nicole Skoetz, Andreas Engert, C. Brillant, Ina Monsef, Andrea Will, Bastian Von Tresckow
    Abstract:

    Background There are two different international standards for the treatment of early unfavourable and advanced stage Hodgkin lymphoma (HL): chemotherapy with escalated BEACOPP (bleomycin/etoposide/doxorubicin/cyclophosphamide/vincristine/procarbazine/prednisone) regimen and chemotherapy with ABVD (doxorubicin/bleomycin/vinblastine/dacarbazine) regimen. Objectives To determine the advantages and disadvantages of chemotherapy including escalated BEACOPP compared to chemotherapy including ABVD in the treatment of early unfavourable or advanced stage HL as first-line treatment. Search methods We searched for randomised controlled trials in MEDLINE, CENTRAL and conference proceedings (January 1985 to July 2013 and for the update to March 2017) and Embase (1985 to November 2008). Moreover we searched trial registries (March 2017; www.controlled-trials.com, www.clinicaltrialsregister.eu/ctr-search/search, clinicaltrials.gov, www.eortc.be, www.ghsg.org, www.ctc.usyd.edu.au, www.trialscentral.org/index.html) Selection criteria We included randomised controlled trials examining chemotherapy including at least two cycles of escalated BEACOPP regimens compared with chemotherapy including at least four cycles of ABVD regimens as first-line treatment for patients with early unfavourable stage or advanced stage HL. Data collection and analysis The effect measures we used were hazard ratios (HRs) for overall survival (OS), progression-free survival (PFS) and freedom from first progression. We used risk ratios (RRs) relative risks to analyse harms: treatment-related mortality, secondary malignancies (including myeloid dysplastic syndrome (MDS) or acute myeloid leukaemia (AML)), infertility and adverse events. Quality of life was not reported in any trial, therefore not analysed. Two review authors independently extracted data and assessed quality of trials. Main results 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. Authors' conclusions 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.

  • comparison of chemotherapy including escalated BEACOPP versus chemotherapy including abvd for patients with early unfavourable or advanced stage hodgkin lymphoma
    Cochrane Database of Systematic Reviews, 2011
    Co-Authors: Andreas Engert, C. Brillant, Nicole Skoetz, Kathrin Bauer, Ina Monsef
    Abstract:

    Background There are two different international standards for the treatment of early unfavourable and advanced stage Hodgkin lymphoma (HL): chemotherapy with escalated BEACOPP (bleomycin/etoposide/doxorubicin/cyclophosphamide/vincristine/procarbazine/prednisone) regimen and chemotherapy with ABVD (doxorubicin/bleomycin/vinblastine/dacarbazine) regimen. Objectives To provide an evidence-based answer regarding the advantages and disadvantages of chemotherapy including escalated BEACOPP compared to chemotherapy including ABVD. Search methods We searched for randomised controlled trials in MEDLINE, CENTRAL and conference proceedings (January 1985 to November 2010) and EMBASE (1985 to November 2008). Selection criteria We included randomised controlled trials examining chemotherapy including at least two cycles of escalated BEACOPP regimens compared to chemotherapy including at least four cycles of ABVD regimens as first-line treatment for patients with early unfavourable stage or advanced stage HL. Data collection and analysis Effect measures used were hazard ratios (HR) for overall survival (OS), progression-free survival (PFS) and freedom from first progression. Relative risks were used to analyse complete response rate, treatment-related mortality and adverse events. Two independent review authors extracted data and assessed quality of trials. Main results A total of 790 records were screened. Five eligible trials (four published, one ongoing), were identified. These trials included only adult patients (16 to 60 years of age). Four trials with 2868 patients were included in the meta-analyses: the HD9 and HD14 trials from Germany, the HD2000 and GSM-HD trials from Italy. All trials reported results for PFS and OS. PFS was statistically significantly longer for escalated BEACOPP: HR was 0.53 (95% confidence interval (CI) 0.44 to 0.64, I2 = 0%). There was no statistically significant difference in OS between the comparators: HR was 0.80 (95% CI 0.59 to 1.09, I2 = 0%). Three trials reported adverse events: the escalated BEACOPP regimens caused statistically significantly more haematological toxicities WHO grade III or IV (anaemia P < 0.00001, neutropenia P = 0.007, thrombocytopenia P < 0.00001), infections (P < 0.00001)) and occurrence of myeloid dysplastic syndrome (MDS) or acute myeloid leukemia (AML) (P = 0.05). There were no differences between both regimens for secondary malignancies, treatment-related mortality or infertility. Authors' conclusions This meta-analysis showed that adult patients between 16 and 60 years of age with early unfavourable or advanced stage HL benefited from chemotherapy including escalated BEACOPP regarding PFS, but there was no significant difference in OS. Longer follow-up and the inclusion of the EORTC 20012 trial will lead to a more definitive answer with respect to OS.

  • Escalated BEACOPP Versus ABVD-Like Chemotherapy for Hodgkin Lymphoma Patients: a Cochrane Review.
    Blood, 2009
    Co-Authors: C. Brillant, Nicole Skoetz, Kathrin Bauer, Ina Monsef, Christine Herbst, Andreas Engert
    Abstract:

    Abstract 3705 Poster Board III-641 Introduction The main challenge in treating Hodgkin lymphoma (HL) is to find the optimal treatment with the best efficacy and least toxicity. So far there are two different international standards for the treatment of intermediate and advanced stage HL: chemotherapy with ABVD regime and chemotherapy with escalated BEACOPP regime. This review aims to clarify advantages and disadvantages of both treatments. Methods MEDLINE, CENTRAL and EMBASE were systematically searched for randomised controlled trials from 1985 to 2008. Trials comparing treatment with at least 2 cycles escalated BEACOPP versus chemotherapy with at least 4 cycles of ABVD within patients in intermediate or advanced stages HL were included. Trials without any published results will be excluded from the meta-analysis. Trial selection, quality assessment and data extraction were done independently by two review authors. Time-to-event outcome were analyzed with hazard ratios (HR) and 95% confidence interval (CI) in a fixed effects model. Results A total of 683 references were screened. Four eligible trials with 1970 patients were identified and included in the main analysis: the HD9 and HD14 trials from Germany, the HD2000 and GSM-HD trials from Italy. The escalated BEACOPP regime was more toxic during treatment than ABVD. Progression free survival (PFS) was statistically significantly longer for escalated BEACOPP: HR was 0.53 (95% CI [0.42, 0.67], I2=0%). In the main analysis of overall survival (OS), escalated BEACOPP was statistically significantly better than ABVD: HR was 0.70 (95% CI [0.50, 0.98], I2=0%). However, this result is not robust. In the OS-analysis restricted to advanced stage trials, the HR was 0.93 (95% CI [0.52, 1.04], I2=0%). Due to the high weight of the HD9 trial (57%), the OS-results are strongly influenced by this trial. In a sensitivity OS analysis without the HD9 trial the HR was 0.83 (95% CI [0.50, 1.38]). Only one trial (HD9) had a follow-up of over 5 years; the median of the other trials was approx. 3 years. Conclusions This meta-analysis showed a better PFS and suggests a benefit in OS for escalated BEACOPP in comparison to ABVD-like regimen. However, many trials had a short follow-up. Longer follow-up and the inclusion of the ongoing EORTC 20012 trial should allow a more definitive answer concerning OS. Disclosures: No relevant conflicts of interest to declare.

Peter Borchmann - One of the best experts on this subject based on the ideXlab platform.

  • Ther apy-r elated acute myeloid leukemia and myelodysplastic syndr omes in patients with Hodgkin lymphoma: a r epor t fr om the Ger man Hodgkin Study Gr oup Key Points
    2020
    Co-Authors: Bastian Von Tresckow, Peter Borchmann, Michael Fuchs, Beate Klimm, Andreas Engert Halbsguth, Volker Diehl, Stephanie Sasse, Achim Rothe, Boris Böll, Dennis A Eichenauer
    Abstract:

    Therapy-related acute myeloid leukemia and myelodysplastic syndromes (t-AML/MDS) represent severe late effects in patients treated for Hodgkin lymphoma (HL). Because more recent data are scarce, we retrospectively analyzed incidence, outcome, and risk factors for the development of t-AML/MDS after HL. A total of 11 952 patients treated for newly diagnosed HL within German Hodgkin Study Group trials between 1993 and 2009 were considered. At a median follow-up of 72 months, t-AML/MDS was diagnosed in 106/11 952 patients (0.9%). Median time from HL treatment to t-AML/MDS was 31 months. The median age of patients with t-AML/MDS was higher than in the whole patient group (43 vs 34 years, P < .0001). Patients who received 4 or more cycles of BEACOPP escalated had an increased risk to develop t-AML/MDS when compared with patients treated with less than 4 cycles of BEACOPP escalated or no BEACOPP chemotherapy (1.7% vs 0.7% vs 0.3%, P < .0001). The median overall survival (OS) for all t-AML/MDS patients was 7.2 months. However, t-AML/ MDS patients proceeding to allogeneic stem cell transplantation had a significantly better outcome with a median OS not reached after a median follow-up of 41 months (P < .001)

  • pet guided treatment in patients with advanced stage hodgkin s lymphoma hd18 final results of an open label international randomised phase 3 trial by the german hodgkin study group
    The Lancet, 2017
    Co-Authors: Peter Borchmann, Andreas Lohri, Richard Greil, Jana Markova, Julia Meissner, Dennis A Eichenauer, Helen Goergen, Carsten Kobe, Josee M Zijlstra, Michaela Feuringbuske
    Abstract:

    Summary Background The intensive polychemotherapy regimen eBEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone in escalated doses) is very active in patients with advanced-stage Hodgkin's lymphoma, albeit at the expense of severe toxicities. Individual patients might be cured with less burdensome therapy. We investigated whether metabolic response determined by PET after two cycles of standard regimen eBEACOPP (PET-2) would allow adaption of treatment intensity, increasing it for PET-2-positive patients and reducing it for PET-2-negative patients. Methods In this open-label, randomised, parallel-group phase 3 trial, we recruited patients aged 18–60 years with newly diagnosed, advanced-stage Hodgkin's lymphoma in 301 hospitals and private practices in Germany, Switzerland, Austria, the Netherlands, and the Czech Republic. After central review of PET-2, patients were assigned (1:1) to one of two parallel treatment groups on the basis of their PET-2 result. Patients with positive PET-2 were randomised to receive six additional cycles of either standard eBEACOPP (8 × eBEACOPP in total) or eBEACOPP with rituximab (8 × R-eBEACOPP). Those with negative PET-2 were randomised between standard treatment with six additional cycles of eBEACOPP (8 × eBEACOPP) or experimental treatment with two additional cycles (4 × eBEACOPP). A protocol amendment in June, 2011, introduced a reduction of standard therapy to 6 × eBEACOPP; after this point, patients with positive PET-2 were no longer randomised and were all assigned to receive 6 × eBEACOPP and patients with negative PET-2 were randomly assigned to 6 × eBEACOPP (standard) or 4 × eBEACOPP (experimental). Randomisation was done centrally using the minimisation method including a random component, stratified according to centre, age ( vs ≥45 years), stage (IIB, IIIA vs IIIB, IV), international prognostic score (0–2 vs 3–7), and sex. eBEACOPP was given as previously described; rituximab was given intravenously at a dose of 375 mg/m 2 (maximum total dose 700 mg). The primary objectives were to show superiority of the experimental treatment in the PET-2-positive cohort, and to show non-inferiority of the experimental treatment in the PET-2-negative cohort in terms of the primary endpoint, progression-free survival. We defined non-inferiority as an absolute difference of 6% in the 5-year progression-free survival estimates. Primary analyses in the PET-2-negative cohort were per protocol; all other analyses were by intention to treat. This trial was registered with ClinicalTrials.gov, number NCT00515554. Findings Between May 14, 2008, and July 18, 2014, we recruited 2101 patients, of whom 137 were found ineligible before randomisation and a further 19 were found ineligible after randomisation. Among 434 randomised patients (217 per arm) with positive PET-2, 5-year progression-free survival was 89·7% (95% CI 85·4–94·0) with eBEACOPP and 88·1% (83·5–92·7) with R-eBEACOPP (log-rank p=0·46). Patients with negative PET-2 randomly assigned to either 8 × eBEACOPP or 6 × eBEACOPP (n=504) or 4 × eBEACOPP (n=501) had 5-year progression-free survival of 90·8% (95% CI 87·9–93·7) and 92·2% (89·4–95·0), respectively (difference 1·4%, 95% CI −2·7 to 5·4). 4 × eBEACOPP was associated with fewer severe infections (40 [8%] of 498 vs 75 [15%] of 502) and organ toxicities (38 [8%] of 498 vs 91 [18%] of 502) than were 8 × eBEACOPP or 6 × eBEACOPP in PET-2-negative patients. Ten treatment-related deaths occurred: four in the PET-2-positive cohort (one [ Interpretation The favourable outcome of patients treated with eBEACOPP could not be improved by adding rituximab after positive PET-2. PET-2 negativity allows reduction to only four cycles of eBEACOPP without loss of tumour control. PET-2-guided eBEACOPP provides outstanding efficacy for all patients and increases overall survival by reducing treatment-related risks for patients with negative PET-2. We recommend this PET-2-guided treatment strategy for patients with advanced-stage Hodgkin's lymphoma. Funding Deutsche Krebshilfe, Swiss State Secretariat for Education and Research, and Roche Pharma AG.

  • progression free survival of early interim pet positive patients with advanced stage hodgkin s lymphoma treated with BEACOPPescalated alone or in combination with rituximab hd18 an open label international randomised phase 3 study by the german hodgk
    Lancet Oncology, 2017
    Co-Authors: Peter Borchmann, Heinz Haverkamp, Andreas Lohri, Ulrich Mey, Stefanie Kreissl, Richard Greil, Jana Markova, Michaela Feuringbuske, Julia Meissner, Ulrich Duhrsen
    Abstract:

    Summary Background Advanced stage Hodgkin's lymphoma represents a heterogeneous group of patients with different risk profiles. Data suggests that interim PET assessment during chemotherapy is superior to baseline international prognostic scoring in terms of predicting long-term treatment outcome in patients with Hodgkin's lymphoma. We therefore hypothesised that early interim PET-imaging after two courses of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) might be suitable for guiding treatment in patients with advanced stage Hodgkin's lymphoma. We aimed to assess whether intensifying standard chemotherapy (BEACOPP escalated ) by adding rituximab would improve progression-free survival in patients with positive PET after two courses of chemotherapy. Methods In this open-label, international, randomised, phase 3 study, we recruited patients aged 18–60 years with newly diagnosed, advanced stage Hodgkin's lymphoma from 160 hospitals and 77 private practices in Germany, Switzerland, Austria, the Netherlands, and the Czech Republic. Interim PET-imaging was done after two cycles of BEACOPP escalated and centrally assessed by an expert panel. Patients with a positive PET after 2 cycles of BEACOPP escalated chemotherapy (PET-2) were randomly assigned (1:1) to receive six additional courses of either BEACOPP escalated (BEACOPP escalated group) or BEACOPP escalated plus rituximab (R-BEACOPP escalated group). PET-2 was assessed using a 5-point scale with 18 FDG uptake higher than the mediastinal blood pool (corresponding to Deauville scale 3) defined as positive. BEACOPP escalated was given as previously described; rituximab was given intravenously at a dose of 375 mg/m 2 (maximum total dose 700 mg), the first administration starting 24 h before starting the fourth cycle of BEACOPP escalated (day 0 and day 3 in cycle 4, day 1 in cycles 5–8). Randomisation was done centrally and used the minimisation method including a random component, stratified according to centre, age, stage, international prognostic score, and sex. The primary efficacy endpoint was 5 year progression-free survival, analysed in the intention-to-treat population. We are reporting this second planned interim analysis as the final report of the trial. The trial is registered with ClinicalTrials.gov, number NCT00515554. Findings Between May 14, 2008, and May 31, 2011, we enrolled 1100 patients. 440 patients had a positive PET-2 and were randomly assigned to either the BEACOPP escalated group (n=220) or the R-BEACOPP escalated group (n=220). With a median follow-up of 33 months (IQR 25–42) for progression-free survival, estimated 3 year progression-free survival was 91·4% (95% CI 87·0–95·7) for patients in the BEACOPP escalated group and 93·0% (89·4–96·6) for those in the R-BEACOPP escalated group (difference 1·6%, 95% CI −4·0 to 7·3; log rank p=0·99). Common grade 3–4 adverse events were leucopenia (207 [95%] of 218 patients in the BEACOPP escalated group vs 211 [96%] of 220 patients in the R-BEACOPP escalated group), and severe infections (51 [23%] vs 43 [20%] patients). Based on a futility analysis, the independent data monitoring committee recommended publication of this second planned interim analysis as the final result. Six (3%) of 219 patients in the BEACOPP escalated group and ten (5%) of 220 in the R-BEACOPP escalated group died; fatal treatment-related toxic effects occurred in one ( escalated group and three (1%) in the R-BEACOPP escalated group, all of them due to infection. Interpretation The addition of rituximab to BEACOPP escalated did not improve the progression-free survival of PET-2 positive patients with advanced stage Hodgkin's lymphoma. However, progression-free survival for PET-2 positive patients was much better than expected, exceeding even the outcome of PET-2-unselected patients in the previous HD15 trial. Thus, PET-2 cannot identify patients at high-risk for treatment failure in the context of the very effective German Hodgkin Study Group standard treatment for advanced stage Hodgkin's lymphoma. Funding Deutsche Krebshilfe; Swiss State Secretariat for Education, Research and Innovation (SERI); and Roche Pharma.

  • targeted BEACOPP variants in patients with newly diagnosed advanced stage classical hodgkin lymphoma interim results of a randomized phase ii study
    Blood, 2013
    Co-Authors: Peter Borchmann, Heinz Haverkamp, Stefanie Kreissl, Julia Meissner, Dennis A Eichenauer, Michael Fuchs, Johannes C Hellmuth, Annette Pluetschow, Martin Soekler, Stephan Mathas
    Abstract:

    Rationale BEACOPPescalated (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) has substantially improved the outcome for patients with advanced stage Hodgkin Lymphoma (HL) achieving an overall survival of 95% at five years. Although this certainly is the most important endpoint for these mainly young patients, there still is concern about the toxicities of this intensified chemotherapy regimen. Brentuximab vedotin (BV) is an anti-CD30 directed antibody-drug conjugate that has shown very promising single-agent activity and good tolerability in HL. We aimed at improving the toxicity profile of BEACOPPescalated while maintaining its efficacy by introducing BV (targeted BEACOPP). Methods Two modified BEACOPP regimens were developed. In a more conservative variant (BrECAPP: BV, etoposide, cyclophosphamide, doxorubicin, procarbazine, prednisone), we replaced vincristine by BV and omitted bleomycin. In the more experimental variant (BrECADD: BV, etoposide, cyclophosphamide, doxorubicin, dacarbazine, dexamethasone) we additionally replaced procarbazine by dacarbazine to reduce gonadal toxicity, reduced the dose of etoposide to decrease risk of second acute myeloid leukemia while slightly increasing the dose of doxorubicin to maintain efficacy, and introduced dexamethasone (day 1-4) substituting for prednisone (day 1-14) to avoid immunosuppressive steroid treatment during neutropenia (please see [table 1][1]). Both regimens are administered q21d for 6 cycles. This is an ongoing randomized phase II study with the combined primary endpoint being the PET-based complete response rate after chemotherapy and the complete remission rate at final restaging including early follow-up. Here we report on the first 48 patients (planned n=100). View this table: Table 1 BrECADD and BEACOPP regimen Results The study started in October 2012. 48 patients have been enrolled by June 2013 and are included in this analysis. Median age is 29 years (range 19-60 years), 60% are male, and 83% have Ann-Arbor stage III or IV disease. 14 patients have been staged after 6 cycles of chemotherapy, 6 in the BrECAPP and 8 in the BrECADD arm. Four of these patients have not reached a complete response. The 95% confidence interval for the number of treatment successes is 42% to 92% and contains both the margin for failure (65%) as well as the margin for success (85%). Regarding feasibility, 6 of 15 patients (60%) with 6 cycles of chemotherapy required no dose reductions of etoposide, cyclophosphamide or doxorubicin during the entire treatment period (corresponding number for 6 cycles of BEACOPPescalated in the HD15 study: 50%). Hematological toxicity grade 3 or 4 of the targeted BEACOPP variants was documented in 26 of 32 patients (81%) with at least 1 cycle of chemotherapy documented (corresponding number for 4-6 cycles of BEACOPPescalated in the GHSG HD15 study: 91.7%), and grade 3 or 4 organ toxicity in 1 patient (3%, GHSG HD15 study: 14.1%). Four patients reported symptoms of peripheral sensory neuropathy so far (grade 1 n=2; grade 2 n=2). BV was not given in the 6th cycle in two of these patients. Conclusion These ongoing phase II trial results indicate that anti-CD30 targeted BEACOPP variants may be well feasible without compromising the efficacy associated with BEACOPPescalated. Enrollment is ongoing and updated results will be presented. Disclosures: Borchmann: Takeda: Honoraria, Research Funding. Off Label Use: Brentuximab vedotin first line Treatment of Hodgkin´s Lymphoma. Diehl: Takeda: Membership on an entity’s Board of Directors or advisory committees. Engert: Takeda: Consultancy. [1]: #T1

  • targeted BEACOPP variants in patients with newly diagnosed advanced stage classical hodgkin lymphoma final analysis of a randomized phase ii study
    Blood, 2013
    Co-Authors: Peter Borchmann, Heinz Haverkamp, Stefanie Kreissl, Julia Meissner, Dennis A Eichenauer, Michael Fuchs, Johannes C Hellmuth, Annette Pluetschow, Martin Soekler, Stephan Mathas
    Abstract:

    Rationale BEACOPPescalated (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) has substantially improved the outcome for patients with advanced stage Hodgkin Lymphoma (HL) achieving an overall survival of 95% at five years. Although this certainly is the most important endpoint for these mainly young patients, there still is concern about the toxicities of this intensified chemotherapy regimen. Brentuximab vedotin (BV) is an anti-CD30 directed antibody-drug conjugate that has shown very promising single-agent activity and good tolerability in HL. We aimed at improving the toxicity profile of BEACOPPescalated while maintaining its efficacy by introducing BV (targeted BEACOPP). Methods Two modified BEACOPP regimens were developed. In a more conservative variant (BrECAPP: BV, etoposide, cyclophosphamide, doxorubicin, procarbazine, prednisone), we replaced vincristine by BV and omitted bleomycin. In the more experimental variant (BrECADD: BV, etoposide, cyclophosphamide, doxorubicin, dacarbazine, dexamethasone) we additionally replaced procarbazine by dacarbazine to reduce gonadal toxicity, reduced the dose of etoposide to decrease risk of second acute myeloid leukemia while slightly increasing the dose of doxorubicin to maintain efficacy, and introduced dexamethasone (day 1-4) substituting for prednisone (day 1-14) to avoid immunosuppressive steroid treatment during neutropenia (please see [table 1][1]). Both regimens are administered q21d for 6 cycles. This is an ongoing randomized phase II study with the combined primary endpoint being the PET-based complete response rate after chemotherapy and the complete remission rate at final restaging including early follow-up. Here we report on the first 48 patients (planned n=100). View this table: Table 1 BrECADD and BEACOPP regimen Results The study started in October 2012. 48 patients have been enrolled by June 2013 and are included in this analysis. Median age is 29 years (range 19-60 years), 60% are male, and 83% have Ann-Arbor stage III or IV disease. 14 patients have been staged after 6 cycles of chemotherapy, 6 in the BrECAPP and 8 in the BrECADD arm. Four of these patients have not reached a complete response. The 95% confidence interval for the number of treatment successes is 42% to 92% and contains both the margin for failure (65%) as well as the margin for success (85%). Regarding feasibility, 6 of 15 patients (60%) with 6 cycles of chemotherapy required no dose reductions of etoposide, cyclophosphamide or doxorubicin during the entire treatment period (corresponding number for 6 cycles of BEACOPPescalated in the HD15 study: 50%). Hematological toxicity grade 3 or 4 of the targeted BEACOPP variants was documented in 26 of 32 patients (81%) with at least 1 cycle of chemotherapy documented (corresponding number for 4-6 cycles of BEACOPPescalated in the GHSG HD15 study: 91.7%), and grade 3 or 4 organ toxicity in 1 patient (3%, GHSG HD15 study: 14.1%). Four patients reported symptoms of peripheral sensory neuropathy so far (grade 1 n=2; grade 2 n=2). BV was not given in the 6th cycle in two of these patients. Conclusion These ongoing phase II trial results indicate that anti-CD30 targeted BEACOPP variants may be well feasible without compromising the efficacy associated with BEACOPPescalated. Enrollment is ongoing and updated results will be presented. Disclosures: Borchmann: Takeda: Honoraria, Research Funding. Off Label Use: Brentuximab vedotin first line Treatment of Hodgkin´s Lymphoma. Diehl: Takeda: Membership on an entity’s Board of Directors or advisory committees. Engert: Takeda: Consultancy. [1]: #T1