Reinduction therapy with everolimus in combination with dexamethasone, high-dose cytarabin and cisplatinum in patients with relapsed or refractory classical Hodgkin lymphoma: an experimental phase I/II multicentre trial of the German Hodgkin Study Group (GHSG HD-R3i).

Reinduction chemotherapy followed by high-dose chemotherapy and autologous stem cell transplant (HDCT + ASCT) is second-line standard of care for transplant-eligible patients with relapsed/refractory classical Hodgkin lymphoma (r/r cHL) but has a high failure rate. Because response to reinduction is predictive of the outcome after HDCT + ASCT, we aimed to improve the standard dexamethasone, high-dose cytarabine and cisplatinum (DHAP) reinduction regimen by addition of the oral mammalian target of rapamycin inhibitor everolimus (everDHAP). Transplant-eligible patients aged 18-60 years with histologically confirmed r/r cHL were included in this experimental phase I/II trial. Everolimus (10 mg/day, determined in phase-I-part) was administered on day 0-13 of each DHAP cycle. From July 2014 to March 2018, 50 patients were recruited to the phase II everDHAP group; two were not evaluable, three discontinued due to toxicity. Randomization to a placebo group stopped in October 2015 due to poor recruitment after nine patients. The primary end-point of computed tomography (CT)-based complete remission (CR) after two cycles of everDHAP was expected to be ≥40%. With a CT-based CR rate of 27% (n = 12/45) after two cycles of everDHAP the trial did not meet the primary end-point. Adding everolimus to DHAP is thus feasible; however, the everDHAP regimen failed to show an improved efficacy.

Pooled RT-qPCR testing for SARS-CoV-2 surveillance in schools - a cluster randomised trial.

BACKGROUND: The extent to which children and adolescents contribute to SARS-CoV-2 transmission remains not fully understood. Novel high-capacity testing methods may provide real-time epidemiological data in educational settings helping to establish a rational approach to prevent and minimize SARS-CoV-2 transmission. We investigated whether pooling of samples for SARS-CoV-2 detection by RT-qPCR is a sensitive and feasible high-capacity diagnostic strategy for surveillance of SARS-CoV-2 infections in schools. METHODS: In this study, students and school staff of 14 educational facilities in Germany were tested sequentially between November 9 and December 23, 2020, two or three times per week for at least three consecutive weeks. Participants were randomized for evaluation of two different age adjusted swab sampling methods (oropharyngeal swabs or buccal swabs compared to saliva swabs using a 'lolli method'). Swabs were collected and pooled for SARS-CoV-2 RT-qPCR. Individuals of positive pooled tests were retested by RT-qPCR the same or the following day. Positive individuals were quarantined while the SARS-CoV-2 negative individuals remained in class with continued pooled RT-qPCR surveillance. The study is registered with the German Clinical Trials register (registration number: DRKS00023911). FINDINGS: 5,537 individuals were eligible and 3970 participants were enroled and included in the analysis. In students, a total of 21,978 swabs were taken and combined in 2218 pooled RT-qPCR tests. We detected 41 positive pooled tests (1·8%) leading to 36 SARS-CoV-2 cases among students which could be identified by individual re-testing. The cumulative 3-week incidence for primary schools was 564/100,000 (6/1064, additionally 1 infection detected in week 4) and 1249/100,000 (29/2322) for secondary schools. In secondary schools, there was no difference in the number of SARS-CoV-2 positive students identified from pooled oropharyngeal swabs compared to those identified from pooled saliva samples (lolli method) (14 vs. 15 cases; 1·3% vs. 1·3%; OR 1.1; 95%-CI 0·5-2·5). A single secondary school accounted for 17 of 36 cases (47%) indicating a high burden of asymptomatic prevalent SARS-CoV-2 cases in the respective school and community. INTERPRETATION: In educational settings, SARS-CoV-2 screening by RT-qPCR-based pooled testing with easily obtainable saliva samples is a feasible method to detect incident cases and observe transmission dynamics. FUNDING: Federal Ministry of education and research (BMBF; Project B-FAST in "NaFoUniMedCovid19"; registration number: 01KX2021).

Whole-slide image analysis of the tumor microenvironment identifies low B-cell content as a predictor of adverse outcome in patients with advanced-stage classical Hodgkin lymphoma treated with BEACOPP.

A subset of patients with advanced-stage classical Hodgkin Lymphoma (cHL) relapse or progress following standard treatment. Given their dismal prognosis, identifying this group of patients upfront represents an important medical need. While prior research has identified characteristics of the tumor microenvironment, which are associated with cHL outcomes, biomarkers that are developed and validated in this high-risk group are still missing. Here, we applied whole-slide image analysis (WSI), a quantitative, large-scale assessment of tumor composition that utilizes conventional histopathology slides. We conducted WSI on a study cohort with pre-treatment biopsies of 340 advanced-stage cHL patients enrolled in the HD12 and HD15 trials of the German Hodgkin Study Group (GHSG), and tested our results in in a validation cohort of 147 advanced-stage cHL patients within the GHSG HD18 trial. All patients were treated with BEACOPP-based regimens. By quantifying T cells, B cells, Hodgkin-Reed-Sternberg-cells and macrophages with WSI, 80% of all cells in the tumor tissue were identified. Crucially, low B cell count was associated with significantly reduced progression-free survival (PFS) and overall survival (OS), while T cell-, macrophage- and Hodgkin-Reed-Sternberg-cell content was not associated with the risk of progression or relapse in the study cohort. We further validated low B cell content as a prognostic factor of PFS and OS in the validation cohort and demonstrate good inter-observer agreement of WSI. WSI may represent a key tool for risk stratification of advanced-stage cHL that can easily be added to the standard diagnostic histopathology work-up.

[Glaucoma Drainage Devices - Evaluation of Surgical Modifications to Avoid Postoperative Complications]. / Glaukomdrainageimplantate ­ Evaluation chirurgischer Modifikationen zur Vermeidung postoperativer Komplikationen.

BACKGROUND: In glaucoma therapy, there are many treatment options, such as glaucoma drainage devices (GDI). The aim of this study is to compare postoperative outcomes after using different surgical techniques. MATERIAL AND METHODS: 269 eyes of 250 patients who received a GDI at the ophthalmological center at the university hospital in Cologne between February 2010 and September 2016 were included in this study. The patients' baseline parameters were collected: age, sex, intraocular pressure, visual acuity, glaucoma medication, diagnosis, operated eye (right or left), number of previous eye surgeries (including laser therapy), duration-of-stay at the hospital as well as all glaucoma complications and complication-related reoperations. RESULTS: The mean individual pressure reduction was 39, 42 and 46% after 6, 12 and 24 months respectively, while the use of medication was reduced by 38, 42 and 50%. The success rates after 1 to 5 years was 75, 60, 57, 50 and 37% with a median survival of 48 months. 86 eyes (32%) experienced early complications and 156 eyes (56%) experienced late complications. 52% of the eyes (n = 139) had to be re-operated. The technique of creating a track to enter the anterior chamber had statistically significant influence on the early postoperative hypotony (p < 0,001). Fibrin glue had no influence on early hypotony. In the univariate analysis of early postoperative hypertension requiring paracentesis, the implant type (p = 0,009), tracking-technique with a paracentesis knife or a 22-gauge needle (p = 0,004), the occlusion method (p = 0,001) and the application of viscoelastics (p = 0,001) were statistically significant parameters. If GDI were implanted as a second implant, significantly more conjunctival erosion was recorded (p = 0.040). CONCLUSION: The use of a 22-gauge needle entering the anterior chamber reduces the hypotony risk when compared to fibrin glue. That risk is not increased by adding venting slits. When implanting GDI as a second implant, the higher risk of conjunctival erosion should be considered.

Symptomatic osteonecrosis as a treatment complication in Hodgkin lymphoma: an analysis of the German Hodgkin Study Group (GHSG).

The majority of patients with Hodgkin Lymphoma (HL) can be cured with stage and risk adapted treatment today. Therefore, current research focuses on reducing long-term sequelae of treatment. Osteonecrosis (ON) is a severe long-term complication of HL treatment which has so far not been systematically evaluated. Hence, we investigated incidence, risk factors and timing of symptomatic ON in HL patients. Further endpoints included localization, intervention and outcome of ON. We included all qualified HL patients of the randomized German Hodgkin Study Group trials HD10-15 and HD18, recruited between 05/1998 and 07/2014 and aged from 16 to 60 years. Among 11 330 patients, 66 developed symptomatic ON after first-line treatment, 83.3% within three years. The incidence of symptomatic ON was 0.2% in early-stage HL and 1.0% in advanced-stage HL. Logistic regression revealed the total cumulative corticosteroid dose to be a strong risk factor interacting with younger age. Male sex additionally increased the risk of symptomatic ON. The prognostic value of the corresponding logistic regression model was rather high (AUC = 0.78). Other tested potential risk factors including obesity, IPS and radiotherapy did not further increase the risk of ON. Further development of current treatment protocols should aim to reduce the cumulative corticosteroid dose.

Anatomical investigations on intraosseous access in stillborns - Comparison of different devices and techniques.

AIM: Intraosseous (IO)-access plays an alternative route during resuscitation. Our study was performed to investigate the successful rate of IO-access in preterm and term stillborns using different devices and techniques. METHODS: The cadavers used were legal donations. 16 stillborns, median: 29.2 weeks (IQR 27.2-38.4) were investigated. Two different needles (a: Butterfly needle, 21G, Venofix® Fa.Braun; b: Arrow®EZ-IO®15G, Teleflex, Dublin, Ireland) were used. Needles were inserted i: manually, using a Butterfly needle; ii: manually, using EZ-IO® needle or iii: using a battery-powered semi-automatic drill (Arrow®EZ-IO®). Spectral-CT's were performed. The diameter of the corticalis was determined from the CT-images. Successful hit rates with 95% confidence intervals (CI) and odds ratios between the three methods were estimated using a generalised linear mixed model (GLMM). RESULTS: Estimated success rate was 61.1% (95%CI:39.7%-78.9%) for the Butterfly needle, 43.0% (95%CI:23.4%-65.0%) for hand-twisted EZ-IO® screwing and 39.7% (95%CI:24.1-57.7%) for the semi-automatic drill (Arrow®EZ-IO®), all referring to an average diameter of the corticalis of 1.2 mm. The odds of a correct position were 2.4 times higher (95%CI:0.8-7.6) when using the Butterfly needle than with the drill. In contrast, the odds of correct positioning when inserting the needle by hand were not significantly different from using the drill (odds ratio 1.1, 95%CI: 0.4-3.3). Neither of these effects nor the diameter of the corticalis with an odds ratio near one were significant in the model. Median diameter of the bone marrow cavity was 4.0 mm [IQR 3.3-4.7]. CONCLUSION: Intraosseous access for premature and neonatal infants could be best achieved by using a manually twisted Butterfly needle.

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 Hodgkin Study Group.

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 (BEACOPPescalated) 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 BEACOPPescalated and centrally assessed by an expert panel. Patients with a positive PET after 2 cycles of BEACOPPescalated chemotherapy (PET-2) were randomly assigned (1:1) to receive six additional courses of either BEACOPPescalated (BEACOPPescalated group) or BEACOPPescalated plus rituximab (R-BEACOPPescalated group). PET-2 was assessed using a 5-point scale with 18FDG uptake higher than the mediastinal blood pool (corresponding to Deauville scale 3) defined as positive. BEACOPPescalated was given as previously described; rituximab was given intravenously at a dose of 375 mg/m2 (maximum total dose 700 mg), the first administration starting 24 h before starting the fourth cycle of BEACOPPescalated (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 BEACOPPescalated group (n=220) or the R-BEACOPPescalated 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 BEACOPPescalated group and 93·0% (89·4-96·6) for those in the R-BEACOPPescalated 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 BEACOPPescalated group vs 211 [96%] of 220 patients in the R-BEACOPPescalated 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 BEACOPPescalated group and ten (5%) of 220 in the R-BEACOPPescalated group died; fatal treatment-related toxic effects occurred in one (<1%) patient in the BEACOPPescalated group and three (1%) in the R-BEACOPPescalated group, all of them due to infection. INTERPRETATION: The addition of rituximab to BEACOPPescalated 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.

Impact of centralized diagnostic review on quality of initial staging in Hodgkin lymphoma: experience of the German Hodgkin Study Group.

Accurate clinical staging is crucial for adequate risk-adapted treatment in Hodgkin lymphoma (HL) to prevent patients from under- or over-treatment. Within the latest German Hodgkin Study Group trial generation, diagnostic findings such as histopathology, computerized tomography imaging and clinical risk factors were re-evaluated by expert panels. Here, we retrospectively analysed 5965 patients and identified 399 in who major discordant findings changed their first-line treatment allocation. Histopathology review did not confirm the initial diagnosis of HL in 87 patients. Treatment allocation was revised in 312 of the remaining 5878 patients: 176 were assigned to a higher and 128 to a lower risk group, respectively; the correct treatment group remained unclear in 8 patients. Cases of revised treatment allocation accounted for 9·8%, 6·0%, 0·8%, and 14·8% of patients initially assigned to the HD13, HD14, HD15 trials and stage IA lymphocyte-predominant HL project, respectively. Most revisions were due to wrong application of clinical stage (20·5% of 312 patients with revised treatment group), histological subtype (9·0%) or the risk factors ≥3 involved areas (46·8%) or large mediastinal mass (9·3%). In conclusion, centralized review by experienced experts changed risk-adapted first-line treatment in a relevant proportion of HL patients. Quality control measures clearly improve the accuracy of treatment and should be implemented in clinical practice.

Impact of Bleomycin and Vincristine Dose Reductions in Patients With Advanced Hodgkin Lymphoma Treated With BEACOPP: An Analysis of the German Hodgkin Study Group HD12 and HD15 Trials.

PURPOSE: The role of bleomycin and vincristine in the treatment of patients with advanced Hodgkin lymphoma (HL) is unclear, and the impact of dose reductions of these drugs on outcome and tolerability has not been systematically assessed. Because both drugs can cause significant toxicity and are frequently discontinued, we performed an analysis of patients with HL treated with BEACOPP (bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, and prednisone) in the German Hodgkin Study Group HD12 and HD15 trials. PATIENTS AND METHODS: Characteristics and outcome of patients were analyzed with respect to discontinuation of bleomycin and/or vincristine. RESULTS: With 3,309 patients with HL analyzed, bleomycin was discontinued in 17.6% and vincristine in 32.6%. A total of 157 patients (4.7%) received ≤ four cycles of bleomycin, and 218 (6.6%) received ≤ three cycles of vincristine; these were compared with patients receiving > four cycles of bleomycin or > three cycles of vincristine, respectively. After a median follow-up of 59 and 67 months for progression-free survival (PFS) and overall survival (OS), respectively, there was no significant difference in PFS or OS in patients receiving ≤ or > four cycles of bleomycin (5-year PFS difference, 1.7%; 95% CI, -4.2% to 7.6%; 5-year OS difference, 1.5%; 95% CI, -2.6% to 5.5%). Similarly, there was no significant difference in patients receiving ≤ or > three cycles of vincristine (5-year PFS difference, -1.3%; 95% CI, -5.6% to 3.1%; 5-year OS difference, -0.1%; 95% CI, -3.1% to 2.9%). CONCLUSION: Bleomycin and vincristine discontinuation because of drug-specific adverse effects does not affect the efficacy of treatment in this setting.

Relapse analysis of irradiated patients within the HD15 trial of the German Hodgkin Study Group.

PURPOSE: To determine, in the setting of advanced-stage of Hodgkin lymphoma (HL), whether relapses occur in the irradiated planning target volume and whether the definition of local radiation therapy (RT) used by the German Hodgkin Study Group (GHSG) is adequate, because there is no harmonization of field and volume definitions among the large cooperative groups in the treatment of advanced-stage HL. METHODS AND MATERIALS: All patients with residual disease of ≥ 2.5 cm after multiagent chemotherapy (CTX) were evaluated using additional positron emission tomography (PET), and those with a PET-positive result were irradiated with 30 Gy to the site of residual disease. We re-evaluated all sites of disease before and after CTX, as well as the PET-positive residual tumor that was treated in all relapsed patients. Documentation of radiation therapy (RT), treatment planning procedures, and portal images were carefully analyzed and compared with the centrally recommended RT prescription. The irradiated sites were compared with sites of relapse using follow-up computed tomography scans. RESULTS: A total of 2126 patients were enrolled, and 225 patients (11%) received RT. Radiation therapy documents of 152 irradiated patients (68%) were analyzed, with 28 irradiated patients (11%) relapsing subsequently. Eleven patients (39%) had an in-field relapse, 7 patients (25%) relapsed outside the irradiated volume, and an additional 10 patients (36%) showed mixed in- and out-field relapses. Of 123 patients, 20 (16%) with adequately performed RT relapsed, compared with 7 of 29 patients (24%) with inadequate RT. CONCLUSIONS: The frequency and pattern of relapses suggest that local RT to PET-positive residual disease is sufficient for patients in advanced-stage HL. Insufficient safety margins of local RT may contribute to in-field relapses.

Assessment of tumor size reduction improves outcome prediction of positron emission tomography/computed tomography after chemotherapy in advanced-stage Hodgkin lymphoma.

PURPOSE: Positron emission tomography (PET) after chemotherapy can guide consolidating radiotherapy in advanced-stage Hodgkin lymphoma (HL). This analysis aims to improve outcome prediction by integrating additional criteria derived by computed tomography (CT). PATIENTS AND METHODS: The analysis set consisted of 739 patients with residues≥2.5 cm after chemotherapy from a total of 2,126 patients treated in the HD15 trial (HD15 for advanced stage Hodgkin's disease: Quality assurance protocol for reduction of toxicity and the prognostic relevance of fluorodeoxyglucose-positron-emission tomography [FDG-PET] in the first-line treatment of advanced-stage Hodgkin's disease) performed by the German Hodgkin Study Group. A central panel performed image analysis and interpretation of CT scans before and after chemotherapy as well as PET scans after chemotherapy. Prognosis was evaluated by using progression-free survival (PFS); groups were compared with the log-rank test. Potential prognostic factors were investigated by using receiver operating characteristic analysis and logistic regression. RESULTS: In all, 548 (74%) of 739 patients had PET-negative residues after chemotherapy; these patients did not receive additional radiotherapy and showed a 4-year PFS of 91.5%. The 191 PET-positive patients (26%) receiving additional radiotherapy had a 4-year PFS of 86.1% (P=.022). CT alone did not allow further separation of patients in partial remission by risk of recurrence (P=.9). In the subgroup of the 54 PET-positive patients with a relative reduction of less than 40%, the risk of progression or relapse within the first year was 23.1% compared with 5.3% for patients with a larger reduction (difference, 17.9%; 95% CI, 5.8% to 30%). CONCLUSION: Patients with HL who have PET-positive residual disease after chemotherapy and poor tumor shrinkage are at high risk of progression or relapse.

Therapy-related acute myeloid leukemia and myelodysplastic syndromes in patients with Hodgkin lymphoma: a report from the German Hodgkin Study Group.

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).

Effect of initial treatment strategy on survival of patients with advanced-stage Hodgkin's lymphoma: a systematic review and network meta-analysis.

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 (BEACOPPescalated), 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 BEACOPPbaseline, BEACOPPescalated, 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 BEACOPPescalated (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 BEACOPPescalated is 7% (95% CrI 3-10)-ie, a 5 year survival of 95%. Reconstructed individual survival data showed that, at 5 years, BEACOPPescalated has a 10% (95% CI 3-15) advantage over ABVD in overall survival. INTERPRETATION: Six cycles of BEACOPPescalated 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.

Reduced-intensity chemotherapy and PET-guided radiotherapy in patients with advanced stage Hodgkin's lymphoma (HD15 trial): a randomised, open-label, phase 3 non-inferiority trial.

BACKGROUND: The intensity of chemotherapy and need for additional radiotherapy in patients with advanced stage Hodgkin's lymphoma has been unclear. We did a prospective randomised clinical trial comparing two reduced-intensity chemotherapy variants with our previous standard regimen. Chemotherapy was followed by PET-guided radiotherapy. METHODS: In this parallel group, open-label, multicentre, non-inferiority trial (HD15), 2182 patients with newly diagnosed advanced stage Hodgkin's lymphoma aged 18-60 years were randomly assigned to receive either eight cycles of BEACOPP(escalated) (8×B(esc) group), six cycles of BEACOPP(escalated) (6×B(esc) group), or eight cycles of BEACOPP(14) (8×B(14) group). Randomisation (1:1:1) was done centrally by stratified minimisation. Non-inferiority of the primary endpoint, freedom from treatment failure, was assessed using repeated CIs for the hazard ratio (HR) according to the intention-to-treat principle. Patients with a persistent mass after chemotherapy measuring 2·5 cm or larger and positive on PET scan received additional radiotherapy with 30 Gy; the negative predictive value for tumour recurrence of PET at 12 months was an independent endpoint. This trial is registered with Current Controlled Trials, number ISRCTN32443041. FINDINGS: Of the 2182 patients enrolled in the study, 2126 patients were included in the intention-to-treat analysis set, 705 in the 8×B(esc) group, 711 in the 6×B(esc) group, and 710 in the 8×B(14) group. Freedom from treatment failure was sequentially non-inferior for the 6×B(esc) and 8×B(14) groups as compared with 8×B(esc). 5-year freedom from treatment failure rates were 84·4% (97·5% CI 81·0-87·7) for the 8×B(esc) group, 89·3% (86·5-92·1) for 6×B(esc) group, and 85·4% (82·1-88·7) for the 8×B(14) group (97·5% CI for difference between 6×B(esc) and 8×B(esc) was 0·5-9·3). Overall survival in the three groups was 91·9%, 95·3%, and 94·5% respectively, and was significantly better with 6×B(esc) than with 8×B(esc) (97·5% CI 0·2-6·5). The 8×B(esc) group showed a higher mortality (7·5%) than the 6×B(esc) (4·6%) and 8×B(14) (5·2%) groups, mainly due to differences in treatment-related events (2·1%, 0·8%, and 0·8%, respectively) and secondary malignancies (1·8%, 0·7%, and 1·1%, respectively). The negative predictive value for PET at 12 months was 94·1% (95% CI 92·1-96·1); and 225 (11%) of 2126 patients received additional radiotherapy. INTERPRETATION: Treatment with six cycles of BEACOPP(escalated) followed by PET-guided radiotherapy was more effective in terms of freedom from treatment failure and less toxic than eight cycles of the same chemotherapy regimen. Thus, six cycles of BEACOPP(escalated) should be the treatment of choice for advanced stage Hodgkin's lymphoma. PET done after chemotherapy can guide the need for additional radiotherapy in this setting. FUNDING: Deutsche Krebshilfe and the Swiss Federal Government.

Eight cycles of escalated-dose BEACOPP compared with four cycles of escalated-dose BEACOPP followed by four cycles of baseline-dose BEACOPP with or without radiotherapy in patients with advanced-stage hodgkin's lymphoma: final analysis of the HD12 trial of the German Hodgkin Study Group.

PURPOSE: Eight cycles of BEACOPP(escalated) (escalated dose of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) followed by radiotherapy (RT) to initial bulk or residual tumor mass is the German Hodgkin Study Group standard of care for advanced-stage Hodgkin's lymphoma (HL). However, treatment-related toxicity is a concern, and the role of RT in this setting is unclear. The HD12 study thus aimed to reduce toxicity while maintaining efficacy. PATIENTS AND METHODS: In this prospectively randomized multicenter trial, eight cycles of BEACOPP(escalated) was compared with four cycles of BEACOPP(escalated) followed by four cycles of the baseline dose of BEACOPP (BEACOPP(baseline); 4 + 4), and RT with no RT in the case of initial bulk or residual disease. The study was designed to exclude a difference in 5-year freedom from treatment failure (FFTF) rate of 6%. RESULTS: Between January 1999 and January 2003, 1,670 patients age 16 to 65 years were enrolled onto the HD12 study. At 5 years, FFTF was 86.4% in the BEACOPP(escalated) arm and 84.8% in the 4 + 4 arm (difference, -1.6%; 95% CI, -5.2% to 1.9%), and overall survival was 92% versus 90.3% (difference, -1.7%; 95% CI, -4.6% to 1.1%). Deaths related to acute toxicity of chemotherapy were observed in 2.9% of patients (BEACOPP(escalated), n = 19; 4 + 4, n = 27). FFTF was inferior without RT (90.4% v 87%; difference, -3.4%; 95% CI, -6.6% to -0.1%), particularly in patients who had residual disease after chemotherapy (difference, -5.8%; 95% CI, -10.7% to -1.0%), but not in patients with bulk in complete response after chemotherapy (difference, -1.1%; 95% CI, -6.2% to 4%). CONCLUSION: The reduction of BEACOPP to the 4 + 4 regimen did not substantially reduce severe toxicity but might decrease efficacy. Our results do not support the omission of consolidation RT for patients with residual disease. Alternative strategies for improving the risk-to-benefit ratio for patients with advanced HL are needed.

Lymphocyte-depleted classical Hodgkin's lymphoma: a comprehensive analysis from the German Hodgkin study group.

PURPOSE: To investigate the clinical characteristics and treatment outcome of patients with lymphocyte-depleted classical Hodgkin's lymphoma (LDCHL) compared with other histologic subtypes of Hodgkin's lymphoma (HL). PATIENTS AND METHODS: From a total of 12,155 evaluable patients with biopsy-proven HL treated within the German Hodgkin Study Group trials HD4 to HD15, 10,019 patients underwent central expert pathology review. Eighty-four patients with LDCHL (< 1%) were identified and confirmed. The median follow-up time was 67 months. RESULTS: Patients with LDCHL, compared with patients with other histologic subtypes, presented more often with advanced disease (74% v 42%, respectively; P < .001) and "B" symptoms (76% v 41%, respectively; P < .001). Other risk factors were also more frequent in patients with LDCHL. Complete remission or unconfirmed complete remission was achieved in 82% of patients with LDCHL compared with 93% of patients with other HL subtypes (P < .001), and more patients with LDCHL had progressive disease. At 5 years, progression-free survival (PFS) and overall survival (OS) were significantly lower in patients with LDCHL compared with patients with other HL subtypes (PFS, 71% v 85%, respectively; P < .001; OS, 83% v 92%, respectively; P = .0018). However, when analyzing the subgroup of patients who underwent treatment with intensified or dose-dense bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone, patients with LDCHL (n = 39) had similar outcomes when compared with patients with other subtypes of HL (n = 3,564; P = .61). CONCLUSION: LDCHL has a different pattern from other HL subtypes with more clinical risk factors at initial diagnosis and significantly poorer prognosis. Patients with LDCHL should be treated with modern dose-intense treatment strategies.

Epoetin alfa in patients with advanced-stage Hodgkin's lymphoma: results of the randomized placebo-controlled GHSG HD15EPO trial.

PURPOSE: To determine whether epoetin alfa reduces anemia-related fatigue, improves other aspects of health-related patient-recorded outcomes (PROs), reduces the number of RBC transfusions, and has an impact on freedom from treatment failure (FFTF) and overall survival (OS) in patients with advanced-stage Hodgkin's lymphoma (HL). PATIENTS AND METHODS: The prospectively randomized HD15EPO study performed by the German Hodgkin Study Group investigated epoetin alfa administered at doses of 40,000 U weekly during and after chemotherapy (six to eight cycles of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone [BEACOPP]) in a double-blind, placebo-controlled setting. The study accrued 1,379 patients, of whom 1,328 were assessable for safety, 1,303 were assessable for clinical outcome, and 930 were assessable for PROs. RESULTS: PROs were not different in patients receiving placebo or epoetin alfa, both after the end of chemotherapy and 6 months thereafter. There was no difference between patients treated with epoetin alfa or placebo with respect to FFTF and OS. There were also no differences in the numbers of deaths, progressions, relapses, and thromboembolic events. The median number of RBC transfusions was reduced from four per patient in the placebo group to two per patient in the epoetin alfa group (P < .001), with 27.4% of patients needing no RBC transfusion in the placebo group compared with 36.7% of patients in the epoetin alfa group (P < .001). CONCLUSION: Epoetin alfa administered at 40,000 U weekly parallel to BEACOPP chemotherapy was safe in patients with advanced-stage HL and reduced the number of RBC transfusions but had no impact on fatigue and other PRO domains.

Hodgkin's lymphoma in adolescents treated with adult protocols: a report from the German Hodgkin study group.

PURPOSE The standard of care for adolescent patients with Hodgkin's lymphoma (HL) is undefined, particularly the choice between pediatric and adult protocols. Thus, we compared risk factors and outcome of adolescents and young adults treated within study protocols of the German Hodgkin Study Group (GHSG). PATIENTS AND METHODS Three thousand seven hundred eighty-five patients treated within the GHSG studies HD4 to HD9 were analyzed; 557 patients were adolescents age 15 to 20 years, and 3,228 patients were young adults age 21 to 45 years. Results Large mediastinal mass and involvement of three or more lymph node areas were more frequent in adolescents (P < .001). The incidence of other risk factors did not differ significantly between age groups. With a median observation time of 81 months for freedom from treatment failure (FFTF) and 85 months for overall survival (OS), log-rank test showed no significant differences between age groups regarding FFTF (P = .305) and a superior OS (P = .008) for adolescents. Six-year estimates for FFTF and OS were 80% and 94%, respectively, for adolescents and 80% and 91%, respectively, for young adults. After adjustment for other predictive factors, Cox regression analysis revealed age as a significant predictor for OS (P = .004), with a higher mortality risk for young adults. Secondary malignancies were more common in young adults (P = .037). CONCLUSION Outcome of adolescent and young adult patients treated within GHSG study protocols is comparable. These data suggest that adult treatment protocols exhibit a safe and effective treatment option for adolescent patients with HL. However, longer follow-up, including assessment of late toxicity, is necessary for final conclusions.

Health-related quality of life during the first year after severe brain trauma with and without polytrauma.

OBJECTIVE: The increasing number of patients surviving severe traumatic brain injury (sTBI) but with significant sensorimotor and neuropsychological deficits is a challenge to rehabilitation medicine. So far, most research initiatives have focused on mortality rates, physiological or economic parameters to estimate therapeutic effects of rehabilitation strategies. Investigations on health-related quality of life (HRQoL) after TBI with and without concomitant polytrauma are rare compared to other disorders. DESIGN/PATIENTS: A prospective study was conducted to investigate HRQoL using the SF-36 questionnaire in 49 patients with sTBI (Glasgow Coma Scale < 9 for more than 24 hours) with and without concomitant polytrauma 6 and 12 months after injury. RESULTS: The SF-36 score profiles 6 and 12 months after trauma were similar. Scores 12 months after trauma, however, were higher in 7/8 dimensions indicating an improvement over time. Similar observations were made for physical and mental sum scores. There was no difference in the SF-36 scoring pattern between the patients with isolated TBI and the patients with concomitant polytrauma, except for physical functioning after 12 months. CONCLUSION: While there is significant overall improvement of HRQoL over time, sTBI appears to bear major influence on post-traumatic HRQoL and outcome.