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Background: Combined-modality treatment consisting of chemotherapy and consolidation radiotherapy is standard of care for patients with early-stage unfavourable Hodgkin lymphoma. However, the use of radiotherapy can have long-term sequelae, which is of particular concern, as Hodgkin lymphoma is frequently diagnosed in young adults with a median age of approximately 30 years. In the German Hodgkin Study Group HD17 trial, we investigated whether radiotherapy can be omitted without loss of efficacy in patients who have a complete metabolic response after receiving two cycles of escalated doses of etoposide, cyclophosphamide, and doxorubicin, and regular doses of bleomycin, vincristine, procarbazine, and prednisone (eBEACOPP) plus two cycles of doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD) chemotherapy (2 + 2). Methods: In this multicentre, open-label, randomised, phase 3 trial, patients (aged 18–60 years) with newly diagnosed early-stage unfavourable Hodgkin lymphoma (all histologies) and an Eastern Cooperative Oncology Group performance status of 2 or less were enrolled at 224 hospitals and private practices in Germany, Switzerland, Austria, and the Netherlands. Patients were randomly assigned (1:1) to receive either standard combined-modality treatment, consisting of the 2 + 2 regimen (eBEACOPP consisted of 1250 mg/m2 intravenous cyclophosphamide on day 1, 35 mg/m2 intravenous doxorubicin on day 1, 200 mg/m2 intravenous etoposide on days 1–3, 100 mg/m2 oral procarbazine on days 1–7, 40 mg/m2 oral prednisone on days 1–14, 1·4 mg/m2 intravenous vincristine on day 8 [maximum dose of 2 mg per cycle], and 10 mg/m2 intravenous bleomycin on day 8; ABVD consisted of 25 mg/m2 intravenous doxorubicin, 10 mg/m2 intravenous bleomycin, 6 mg/m2 intravenous vinblastine, and 375 mg/m2 intravenous dacarbazine, all given on days 1 and 15) followed by 30 Gy involved-field radiotherapy (standard combined-modality treatment group) or PET4-guided treatment, consisting of the 2 + 2 regimen followed by 30 Gy of involved-node radiotherapy only in patients with positive PET at the end of four cycles of chemotherapy (PET4; PET4-guided treatment group). Randomisation was done centrally and used the minimisation method and seven stratification factors (centre, age, sex, clinical symptoms, disease localisation, albumin concentration, and bulky disease), and patients and investigators were masked to treatment allocation until central review of the PET4 examination had been completed. With the final analysis presented here, the primary objective was to show non-inferiority of the PET4-guided strategy in a per-protocol analysis of the primary endpoint of progression-free survival. We defined non-inferiority as an absolute difference of 8% in the 5-year progression-free survival estimates between the two groups. Safety analyses were done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT01356680. Findings: Between Jan 13, 2012, and March 21, 2017, we enrolled and randomly assigned 1100 patients to the standard combined-modality treatment group (n=548) or to the PET4-guided treatment group (n=552); two patients in each group were found ineligible after randomisation. At a median follow-up of 46·2 months (IQR 32·7–61·2), 5-year progression-free survival was 97·3% (95% CI 94·5–98·7) in the standard combined-modality treatment group and 95·1% (92·0–97·0) in the PET4-guided treatment group (hazard ratio 0·523 [95% CI 0·226–1·211]). The between-group difference was 2·2% (95% CI −0·9 to 5·3) and excluded the non-inferiority margin of 8%. The most common grade 3 or 4 acute haematological adverse events were leucopenia (436 [83%] of 528 patients in the standard combined-modality treatment group vs 443 [84%] of 529 patients in the PET4-guided treatment group) and thrombocytopenia (139 [26%] vs 176 [33%]), and the most frequent acute non-haematological toxic effects were infection (32 [6%] vs 40 [8%]) and nausea or vomiting (38 [7%] vs 29 [6%]). The most common acute radiotherapy-associated adverse events were dysphagia (26 [6%] in the standard combined-modality treatment group vs three [2%] in the PET4-guided treatment group) and mucositis (nine [2%] vs none). 229 serious adverse events were reported by 161 (29%) of 546 patients in the combined-modality treatment group, and 235 serious adverse events were reported by 164 (30%) of 550 patients in the PET4-guided treatment group. One suspected unexpected serious adverse reaction (infection) leading to death was reported in the PET4-guided treatment group. Interpretation: PET4-negativity after treatment with 2 + 2 chemotherapy in patients with newly diagnosed early-stage unfavourable Hodgkin lymphoma allows omission of consolidation radiotherapy without a clinically relevant loss of efficacy. PET4-guided therapy could thereby reduce the proportion of patients at risk of the late effects of radiotherapy. Funding: Deutsche Krebshilfe.

Summary Background A high proportion of patients with relapsed classical Hodgkin's lymphoma achieve a response with the antibody-drug conjugate brentuximab vedotin, and the drug is well tolerated. We modified the escalated BEACOPP regimen (eBEACOPP; bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) and implemented brentuximab vedotin with the aim to reduce toxic effects while maintaining the protocol's efficacy. Methods We did an open-label, multicentre, randomised phase 2 study at 20 study sites in Germany. Adult patients (aged 18–60 years) with newly diagnosed, advanced, classical Hodgkin's lymphoma were randomly assigned (1:1) to treatment with six cycles of either BrECAPP (brentuximab vedotin 1·8 mg/kg on day 1, etoposide 200 mg/m 2 on days 2–4, doxorubicin 35 mg/m 2 on day 2, cyclophosphamide 1250 mg/m 2 on day 2, procarbazine 100 mg/m 2 on days 2–8, and prednisone 40 mg/m 2 on days 2–15) or BrECADD (brentuximab vedotin 1·8 mg/kg on day 1, etoposide 150 mg/m 2 on days 2–4, doxorubicin 40 mg/m 2 on day 2, cyclophosphamide 1250 mg/m 2 on day 2, dacarbazine 250 mg/m 2 on days 3–4, and dexamethasone 40 mg on days 2–5). Randomisation was done centrally by stratified minimisation, with study site and sex as stratification factors. The co-primary endpoints were complete response to chemotherapy and complete remission at the end of treatment, which were assessed by intention to treat. Patients who were found not to meet inclusion criteria after randomisation or without restaging data after two cycles of study treatment were excluded from the primary endpoint analysis. All patients who started study treatment were assessable for safety. This report presents the final analysis at a median follow-up of 17 months (IQR 13·2–21·5). The preplanned 2-year follow-up analysis is yet to be reported. This trial is registered with ClinicalTrials.gov, number NCT01569204. Findings Between Oct 26, 2012, and May 15, 2014, 104 patients were enrolled to the study (52 were assigned to each study arm). Two patients dropped out before the start of study treatment because of acute infection (n=1) and withdrawal of consent (n=1) and one patient was excluded because of intermediate-stage disease (all were assigned BrECAPP). 42 (86%, 95% CI 73–94) of 49 patients assigned BrECAPP achieved a complete response after chemotherapy and 46 (94%, 95% CI 83–99) had complete remission as their final treatment outcome. In the BrECADD group, 46 (88%, 95% CI 77–96) of 52 patients achieved both a complete response after chemotherapy and complete remission as their final treatment outcome. 58 serious adverse events were reported, 32 events in 21 of 50 patients who received BrECAPP and 26 events in 18 of 52 patients who received BrECADD. The most common grade 3–4 toxic effects were haematological adverse events (91 [89%] of 102 patients). Grade 3–4 organ toxic effects were reported in seven (17%) of 42 patients assigned BrECAPP and two (4%) of 46 allocated BrECADD. 16 (32%) of 50 patients assigned BrECAPP and 18 (35%) of 52 allocated BrECADD had grade 1–2 peripheral neuropathy, and one (2%) patient assigned BrECAPP developed grade 3 peripheral neuropathy; all but one case (allocated BrECAPP) resolved. No deaths were reported during the follow-up period. Interpretation Both eBEACOPP variants met the co-primary efficacy endpoints. Particularly, the BrECADD regimen was associated with a more favourable toxicity profile and was, therefore, selected to challenge standard eBEACOPP for the treatment of advanced classical Hodgkin's lymphoma in the phase 3 HD21 study by the German Hodgkin Study Group (NCT02661503), which aims to further reduce treatment-related morbidity. Funding Takeda Pharmaceuticals.

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.

Objective The improvement in Arterial Spin Labeling (ASL) perfusion quantification, especially for delayed bolus arrival times (BAT), with an acquisition redistribution scheme mitigating the T1 decay of the label in multi-TI ASL measurements is investigated. A multi inflow time (TI) 3D-GRASE sequence is presented which adapts the distribution of acquisitions accordingly, by keeping the scan time constant. Material and Methods The MR sequence increases the number of averages at long TIs and decreases their number at short TIs and thus compensating the T1 decay of the label. The improvement of perfusion quantification is evaluated in simulations as well as in-vivo in healthy volunteers and patients with prolonged BATs due to age or steno-occlusive disease. Results The improvement in perfusion quantification depends on BAT. At healthy BATs the differences are small, but become larger for longer BATs typically found in certain diseases. The relative error of perfusion is improved up to 30% at BATs > 1500 ms in comparison to the standard acquisition scheme. Conclusion This adapted acquisition scheme improves the perfusion measurement in comparison to standard multi-TI ASL implementations. It provides relevant benefit in clinical conditions that cause prolonged BATs and is therefore of high clinical relevance for neuroimaging of steno-occlusive diseases.

Hodgkin's disease (HD) is a fatal disorder with the unique histologic features of few dysplastic Hodgkin- and Reed-Sternberg (HRS) cells surrounded by an abundance of nonatypical bystander cells in primary biopsies. By using the first Hodgkin cell line L428 the cytokine receptor CD30 was discovered. CD30 proved to be an excellent target for the diagnoses of CD30+ malignancies and for monoclonal antibody therapy in patients with these malignancies because of its highly restricted expression in healthy individuals. Recently, a new anti-CD30-toxin-drug-conjugate consisting of an anti-CD30 monoclonal antibody bound to the nonimmunogenic toxin auristatin E with a newly designed linker was generated.

Background Treatment options for patients with nonbulky stage IA-IIA Hodgkin lymphoma include combined modality therapy (CMT) using doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) plus involved-field radiation therapy (IFRT), and chemotherapy with ABVD alone. There are no mature randomized data comparing ABVD with CMT using modern radiation techniques. Patients and methods Using German Hodgkin Study Group HD10/HD11 and NCIC Clinical Trials Group HD.6 databases, we identified 588 patients who met mutually inclusive eligibility criteria from the preferred arms of HD10 or 11 (n = 406) and HD.6 (n = 182). We evaluated time to progression (TTP), progression-free (PFS) and overall survival, including in three predefined exploratory subset analyses. Results With median follow-up of 91 (HD10/11) and 134 (HD.6) months, respective 8-year outcomes were for TTP, 93% versus 87% [hazard ratio (HR) 0.44, 95% confidence interval (CI) 0.24-0.78]; for PFS, 89% versus 86% (HR 0.71, 95% CI 0.42-1.18) and for overall survival, 95% versus 95% (HR 1.09, 95% CI 0.49-2.40). In the exploratory subset analysis including HD10 eligible patients who achieved complete response (CR) or unconfirmed complete response (CRu) after two cycles of ABVD, 8-year PFS was 87% (HD10) versus 95% (HD.6) (HR 2.8; 95% CI 0.64-12.5) and overall survival 96% versus 100%. In contrast, among those without CR/CRu after two cycles of ABVD, 8-year PFS was 88% versus 74% (HR 0.35; 95% CI 0.16-0.79) and overall survival 95% versus 91%, respectively (HR 0.42; 95% CI 0.12-1.44). Conclusions In patients with nonbulky stage IA-IIA Hodgkin lymphoma, CMT provides better disease control than ABVD alone, especially among those not achieving complete response after two cycles of ABVD. Within the follow-up duration evaluated, overall survivals were similar. Longer follow-up is required to understand the implications of radiation and chemotherapy-related late effects. Clinical trials The trials included in this analysis were registered at ClinicalTrials.gov: HD10 - NCT00265018, HD11 - NCT00264953, HD.6 - NCT00002561.

Background In early-stage Hodgkin's lymphoma (HL), treatment according to the early favorable or unfavorable subgroup is guided by staging definitions, which differ between various study groups worldwide. We analyzed risk factors used in different international staging systems and their impact on the outcome of early-stage HL patients. Patients and methods In 1173 early-stage HL patients treated homogenously within the German Hodgkin Study Group (GHSG) trials HD10 and HD11, the impact of three staging systems developed and used by the GHSG, the European Organization for Research and Treatment of Cancer (EORTC), and the National Comprehensive Cancer Network (NCCN) in discriminating risk groups for progression-free survival (PFS) and overall survival (OS) was assessed and the relevance of their single risk factors was investigated. Results All the three staging systems defined an unfavorable risk group out of early-stage patients of comparable size (56%, 55%, and 57%), having a significantly poorer PFS and OS as compared with the corresponding favorable group; 5-year differences between early favorable and early unfavorable in terms of PFS were 9.4% (HR 2.61, 95% CI 1.74–3.91), 6.7% (HR 2.10, 95% CI 1.41–3.13), and 8.6% (HR 2.14, 95% CI 1.45–3.16) with the GHSG, EORTC, and NCCN definition, respectively. Sensitivity was high for all systems (84%, 79%, and 83%); however, there was a low specificity with high rates of false-positive results (1-specificity 54%, 53%, and 55%, respectively). Models of high sensitivity included risk factors associated with large tumor burden and high tumor activity. Most risk factors for tumor-specific end points were also predictive of OS. Conclusions Differentiating between a favorable and an unfavorable risk group has significant impact on PFS and OS in early-stage HL patients in the modern treatment era. Risk-adapted treatment strategies using new risk factors with higher specificity are needed.

Background To evaluate long-term toxicity and efficacy of a combined modality strategy including extended-field radiotherapy (EF-RT) or involved-field radiotherapy (IF-RT), the German Hodgkin Study Group carried out a follow-up analysis in patients with early unfavorable Hodgkin's lymphoma (HL). Patients and methods One thousand two hundred and four patients were randomized to four cycles of chemotherapy followed by either 30 Gy EF- or 30 Gy IF-RT (HD8 trial); 532 patients in each treatment arm were eligible. Results At 10 years, no arm differences were revealed with respect to freedom from treatment failure (FFTF) (79.8% versus 79.7%), progression-free survival (79.8% versus 80.0%), and overall survival (86.4% versus 87.3%). Non-inferiority of IF-RT was demonstrated for the primary end point FFTF (95% confidence interval for hazard ratio 0.72–1.25). Elderly patients had a poorer outcome when treated with EF-RT. So far, 15.0% of patients in arm A and 12.2% in arm B died, mostly due to secondary malignancies (5.3% versus 3.4%) or HL (3.2% versus 3.4%). After EF-RT, there were more secondary malignancies overall (58 versus 45), especially acute myeloid leukemias (11 versus 4). Conclusion Radiotherapy intensity reduction to IF-RT does not result in poorer long-term outcome but is associated with less acute toxicity and might be associated with less secondary malignancies.

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.

Background: The reduction of treatment-related toxic effects is the main goal in the current trials of the German Hodgkin Study Group (GHSG). In this regard, the protection of the ovarian reserve in young women is very important. Therefore, the GHSG investigated the use of gonadotropin-releasing hormone-analogues (GnRH-a) and oral contraceptives (OC) in young women with advanced-stage Hodgkin lymphoma (HL). Patients and methods: Women (18–40 years) were randomly assigned either to receive daily OC or monthly GnRH-a during escalated combination therapy with bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPPesc). Hormonal levels were determined at baseline, during therapy, and at follow-up. Results: The study was closed prematurely after an interim analysis of 12 patients in arm A (OC) and 11 in arm B (GnRH-a), 9 and 10 are assessable for the primary end point. Women’s median age was 25 years in both arms. The anti-Mullerian hormone level after at least 12 months was reduced in all patients. For the entire study cohort, the respective ovarian follicle preservation rate was 0% (95% confidence interval 0% to 12%). Conclusion: We observed no protection of the ovarian reserve with hormonal co-treatment during BEACOPPesc. This result supports efforts of ongoing trials to reduce chemotherapy intensity and toxicity. Alternative strategies for the protection of fertility must be offered to young female HL patients before the start of BEACOPPesc therapy.

Purpose To evaluate the effect of radiotherapy on the severe pulmonary toxicity observed in the pilot study of BAGCOPP (bleomycin, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone, and gemcitabine) for advanced-stage Hodgkin's lymphoma. Methods and Materials Patients with Stage III or IV Hodgkin's lymphoma or Stage IIB with risk factors participated in this single-arm, multicenter pilot study. Results Twenty-seven patients were enrolled on the study before its premature closure as a result of the development of serious pulmonary toxicity in 8 patients. The pulmonary toxicity occurred either during or immediately after the BAGCOPP chemotherapy course. Pulmonary toxicity contributed to one early fatality but resolved in the other 7 patients after cessation of gemcitabine and bleomycin, allowing continuation of therapy. Fifteen patients received consolidative radiotherapy, including 4 who previously had pulmonary toxicity. There were no reported cases of radiation pneumonitis and no exacerbation of pulmonary symptoms in the 4 patients who had had previous pulmonary toxicity. Conclusions The severe pulmonary toxicity observed in this study has been attributed to an interaction between gemcitabine and bleomycin. Gemcitabine (when administered without bleomycin) remains of interest in Hodgkin's lymphoma and is being incorporated into a new German Hodgkin's Lymphoma Study Group protocol that also includes consolidative radiotherapy. This study supports the concept of the integration of radiotherapy in gemcitabine-containing regimens in Hodgkin's lymphoma if there is an interval of at least 4 weeks between the two modalities and with a schedule whereby radiotherapy follows the chemotherapy.

Patients with Hodgkin's lymphoma might have persistent fatigue even years after treatment. However, knowledge of the development of fatigue persisting long after completion of treatment is limited. Therefore, we did a detailed analysis of fatigue in our first-line clinical trials for early-stage favourable (HD13 trial), early-stage unfavourable (HD14 trial), and advanced-stage (HD15 trial) Hodgkin's lymphoma. Beyond the description of fatigue from diagnosis up to 5 years after treatment, we aimed to assess any effect of patient characteristics, disease characteristics, or treatment characteristics on persistent fatigue.In this longitudinal study, we included patients with early-stage favourable, early-stage unfavourable, and advanced-stage Hodgkin's lymphoma from the HD13, HD14, and HD15 trials, respectively, aged between 18 and 60 years. Eligible patients for these trials had newly diagnosed, histologically proven Hodgkin's lymphoma, an Eastern Cooperative Oncology Group performance status of 2 or lower, HIV negativity, and absence of comorbidity disallowing protocol treatment. We used the fatigue scale of the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaire to assess fatigue from diagnosis up to 5 years after the end of treatment. The primary outcomes of interest in this study were fatigue scores in the second and fifth year after end of treatment. We estimated the effect of different disease, patient, and treatment characteristics on fatigue with multiple regression analyses and identified fatigue trajectories with growth mixture models. The regression analyses and growth mixture models used robust and full information maximum likelihood estimates to account for missing data. The HD13, HD14, and HD15 trials are registered as international standard randomised controlled trials, ISRCTN63474366, ISRCTN04761296, and ISRCTN32443041, respectively.The HD13 trial enrolled patients with early-stage favourable disease from Jan 28, 2003, to Sept 30, 2009; the HD14 trial enrolled patients with early-stage unfavourable disease from Jan 28, 2003, to Dec 23, 2009; and the HD15 trial enrolled patients with advanced-stage disease from Jan 28, 2003, to April 18, 2008. 5306 patients were enrolled in these trials. We analysed 4215 patients with any valid fatigue assessment up to 5 years after the end of treatment. Patients with higher tumour burden at diagnosis had more fatigue at baseline (mean fatigue score in HD13: 30·8 [SD 28·0]; in HD14: 39·8 [29·4], and in HD15: 49·0 [30·2]). Fatigue scores (FA) in the second year after the end of treatment were 28·5 (24·7) in HD13, 28·8 (24·4) in HD14, and 30·7 (24·4) in HD15; in the fifth year after the end of treatment FA was 30·8 (26·0) in HD13, 27·1 (24·8) in HD14, and 28·2 (24·9) in HD15. Predictors of fatigue in the second and fifth year after end of treatment were baseline fatigue (p0·0001) and age as a continuous variable (p0·0001). In addition to preceding fatigue and age, patient sex and Hodgkin's lymphoma specific risk factors at baseline did not consistently and significantly improve the prognosis of fatigue in the first, second, and fifth year after end of treatment. There was no significant effect of treatment on fatigue scores in the second and fifth year after treatment.Our findings show a high incidence of severe acute and persistent fatigue in Hodgkin's lymphoma survivors, which is largely independent of tumour stage and treatment. Our results contribute to a better understanding of fatigue in patients with Hodgkin's lymphoma and Hodgkin's lymphoma survivors and could inform development of urgently needed intervention strategies.Deutsche Krebshilfe.

In 2007, patients who have Hodgkin's lymphoma, even in advanced stages, have a better than 85% chance of being cured of their disease if adequate therapy is given at the outset. Most ongoing or planned international studies tailor therapy according to the needs of the individual patient, also accounting for anatomic stage, tumor burden, age, gender, and biologic host factors that affect prognosis. With this approach it might be possible to use less aggressive treatment regimens for the lower-risk groups and limit the use of the more aggressive dose- and time-intensified/dense regimens for the higher-risk groups. With this individualized approach it might be possible to yield higher cure rates and simultaneously reduce the risk for late complications and mortality.

Treatment strategies of early stage Hodgkin lymphoma (HL) have changed during recent years. Until recently, extended field (EF) irradiation has been considered the standard treatment. However, due to the recognition of the high relapse rate and the fatal long-term effects, EF radiotherapy (radiation to initially involved and adjacent lymph node areas) is now being abandoned by most study groups. Instead, for favourable early stage disease, short duration chemotherapy for control of occult lesions is combined with involved field irradiation (IF-RT; restricted only to initially involved lymph node areas). Most groups and centres give four courses of adriamycin, bleomycin, vinblastine, dacarbazine (ABVD) followed by IF-RT [30–35 gray (Gy)][1]. Many of the ongoing and recently completed studies were developed in an attempt to reduce the long-term complications of treatment without increasing mortality from HL. These include studies that evaluate reduction of radiation dose or field size; combined modality treatment in an attempt to identify the optimal chemotherapy regimen; the optimal number of cycles of chemotherapy; and to determine the optimal radiation volume and dose when combined with chemotherapy. Table 1 summarizes the most prominent ongoing or recently terminated international trials [2, 3].

Background: The optimal treatment of elderly patients with Hodgkin’s lymphoma (HL) is still a matter of debate. Since many of these patients receive combined modality treatment, we evaluated the impact of different radiation field sizes, that is extended-field (EF) or involved-field (IF) technique when given after four cycles of chemotherapy. Patients and methods: In the multicenter HD8 study of the German Hodgkin Study Group, 1204 patients with early-stage unfavorable HL were randomized to receive four cycles of chemotherapy followed by either radiotherapy (RT) of 30 Gy EF + 10 Gy to bulky disease (arm A) or 30 Gy IF + 10 Gy to bulky disease (arm B). A total of 1064 patients were assessable for the analysis. Of these, 89 patients (8.4%) were 60 years or older. Results: Elderly patients had a poorer risk profile. Acute toxicity from RT was more pronounced in elderly patients receiving EF-RT compared with IF-RT [World Health Organization (WHO) grade 3/4: 26.5% versus 8.6%)]. Freedom from treatment failure (FFTF, 64% versus 87%) and overall survival (OS, 70% versus 94%) after 5 years was lower in elderly patients compared with younger patients. Importantly, elderly patients had poorer outcome when treated with EF-RT compared with IF-RT in terms of FFTF (58% versus 70%; P = 0.034) and OS (59% versus 81%; P = 0.008). Conclusion: Elderly patients with early-stage unfavorable HL generally have a poorer risk profile and outcome when compared with younger patients. Treatment with EF-RT instead of IF-RT after chemotherapy has a negative impact on survival of elderly patients and should be avoided.

Over the past decades, Hodgkin's lymphoma has become one of the most curable tumors in adults. This is mainly because of large clinical trials using risk-adapted, highly effective therapy modalities. For a long time, radiation therapy was the standard for treating patients with Hodgkin's lymphoma. Within the past 20 years, management has undergone a paradigm shift from the use of chemotherapy as an adjunct to radiation therapy in advanced-stage disease to combined therapy modalities with chemotherapy and involved-field irradiation in early stages and time- and dose-intensified effective drug regimens in advanced stages. Modern therapeutic strategies aim at reducing therapyassociated acute and late toxicities, while maintaining the highest tumor control. Founded in 1978, the German Hodgkin's Lymphoma Study Group has initiated numerous clinical trials contributing to the high cure rate in all stages of this lymphoma entity. This article gives an overview of the German Hodgkin's Lymphoma Study Group trials and a review of the current treatment strategies.

Background: Since there are no randomized studies, the treatment of choice for patients with early stage lymphocyte-predominant Hodgkin’s lymphoma (LPHL) remains unclear. We thus reviewed all LPHL cases registered in the database of the German Hodgkin Study Group (GHSG) and compared the different treatment approaches, such as extended field (EF), involved field (IF) radiation and combined modality (CM) treatment for LPHL stage IA patients. Patients and methods: One hundred and thirty-one patients with LPHL in clinical stage IA without risk factors were analyzed. Forty-five patients were treated with EF radiotherapy, 45 patients with IF radiation and 41 patients received CM treatment. The median follow-up was 78 months in the EF group, 40 months after CM and 17 months after IF, respectively. Results: A total of 129 patients achieved complete remission (CR and CRu): 98% after EF radiotherapy, 100% after IF radiation and 95% after CM. With a median follow-up of 43 months there were 5% relapses and only three patients died. Toxicity of treatment was generally mild with most events observed after CM. Conclusion: In terms of remission induction IF radiotherapy for stage IA LPHL patients is as effective as EF or CM treatment. However, longer follow-up is needed before final conclusion as the optimal therapy.

Background: Combination chemotherapy can cure patients with non-Hodgkin’s lymphoma (NHL), but those who suffer treatment failure or relapse still have a poor prognosis. High-dose chemotherapy (HDCT) with autologous stem cell transplantation (ASCT) can improve the outcome of these patients. We evaluated an intensified high-dose sequential chemotherapy program with a final myeloablative course. Patients and methods: Inclusion criteria were age 18 – 65 years, histologically proven primary progressive or relapsed aggressive NHL and eligibility for HDCT. The therapy consists of two cycles DHAP: dexamethasone 40 mg (day 1 – 4), high-dose cytarabine 2 g/m 2 12q (day 2), cisplatin 100 mg/m 2 (day 51); patients with partial (PR) or complete remission (CR) received cyclophosphamide 4 g/m 2 (day 37), followed by peripheral blood stem cell (PBSC) harvest; methotrexate 8 g/m 2 (day 1) plus vincristine 1.4 mg/m 2 (day 51); and etoposide 500 mg/m 2 (day 58 – 62). The final myeloblative course was BEAM: cytarabine 200 mg/m 2 12q (day 81 – 84), etoposide 150 mg/m 2 12q (day 81 – 84), melphalan 140 mg/m 2 (day 80), carmustin 300 mg/m 2 (day 80) followed by PBSCT. Results: Fifty-seven patients (median age 43 years, range 24 – 65) were enrolled: 23 (40%) patients were refractory to primary therapy and 34 (60%) patients had relapsed NHL. The response rate (RR) after 2 cycles of DHAP was 72% (9% CR, 63% PR) and at the final evaluation (100 days post transplantation) 43% (32% CR, 11% PR). Toxicity was tolerable. Median follow-up was 25 months (range 1 – 76 months). Freedom from second failure (FF2F) and overall survival (OS) at 2 years were 25% and 47% for all patients, respectively. FF2F at 2 years for patients with relapse and for patients refractory to primary therapy were 35% and 9% (P = 0.0006), respectively. OS at 2 years for patients with relapse and for patients refractory to primary therapy were 58% and 24% (P = 0.0044), respectively. Conclusions: We conclude that this regimen is feasible, tolerable and effective in patients with relapsed NHL. In contrast, the results in patients with progressive disease are unsatisfactory. This program is currently being modified by addition of rituximab for patients with relapsed aggressive NHL.

In contrast to younger patients, the prognosis of elderly patients with advanced Hodgkin's disease (HD) has not improved substantially over the last 20 years. We thus carried out a prospectively randomized study (HD9(elderly)) to compare the BEACOPP regimen in this setting against standard COPP-ABVD. Between February 1993 and 1998, 75 patients aged 66-75 years with newly diagnosed HD in advanced stages were recruited into the HD9 trial as a separate stratum (HD9(elderly)). Patients were assigned to eight alternating cycles of COPP and ABVD or eight cycles of BEACOPP in baseline doses. Radiotherapy was given to initial bulky or residual disease. In total, 68 of 75 registered patients were assessable: 26 were treated with COPP-ABVD and 42 with BEACOPP baseline. There were no significant differences between COPP-ABVD and BEACOPP in terms of complete remission (76%), overall survival (50%) and freedom from treatment failure (FFTF) (46%) at 5 years. At a median follow-up of 80 months, a total of 37 patients died: 14/26 patients (54%) treated with COPP-ABVD and 23/42 patients (55%) with BEACOPP. Two patients (8%) treated with COPP-ABVD and nine patients (21%) treated with BEACOPP died of acute toxicity. Hodgkin-specific FFTF at 5 years was 55% after COPP-ABVD and 74% after BEACOPP (P=0.13). Thus, there are no differences in survival between these regimens in elderly patients.

Purpose To guarantee the treatment quality of involved-field radiotherapy (IF-RT) of patients in the Hodgkin's disease (HD)10 and HD11 trials of the German Hodgkin Study Group, with 460 participating study centers, a quality assurance program was conducted. It was based on a central prospective radiation oncologic review of all patients' entire diagnostic imaging and clinical findings. An individual RT prescription was provided for every study patient. The purpose of the present investigation was to assess the feasibility of such a procedure and its impact on the final definition of disease extension and patient treatment. Methods and materials Between 1998 and 2002, 1371 patients were enrolled into the HD10 trial (early-stage disease) and 1570 patients into the HD11 trial (intermediate-stage disease). The HD10 trial tested four cycles of Adriamycin (doxorubicin), bleomycin, vinblastine, and dacarbazine (ABVD) against two cycles of ABVD followed by 20 Gy of IF-RT vs. 30 Gy of IF-RT (four study arms). The HD11 trial compared four cycles of ABVD with four cycles of BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) baseline followed by 20 Gy IF-RT vs. 30 Gy IF-RT in a four-arm design. All study centers were required to score disease involvement at a total of 34 possible anatomic sites on case report forms and send them, together with all diagnostic imaging, to the RT reference center in Cologne, Germany. Images were reviewed there by a panel of expert radiation oncologists and radiologists and compared with the case report form. Differences between the disease involvement documented by the participating center and the reference center were recorded. Subsequently, an individualized treatment proposal was compiled. Complete sets of documentation were submitted to the reference center for 89% of the patients in both HD10 and HD11. Results A considerable proportion of involved sites were incorrectly recorded on the corresponding case report form by the participating center. For patients with early-stage HD (HD10), there was a correction of disease involvement in 49% (593 of 1214 patients) and for patients with intermediate-stage HD (HD11) in 67% (936 of 1397 patients). Most discrepancies were seen in the lower mediastinum (23%), infraclavicular (17%), upper cervical (16%), supraclavicular (13%), and pulmonary hilar region (13%). This resulted in a change of disease stage in 41 of those 1,529 patients whose documented disease involvement had to be corrected (2.7%). Ninety-three patients had to be treated in a different protocol, because of changes in stage and risk factors. Owing to incorrect lymph node documentation of the participating centers, the RT treatment volume had to be enlarged in 891 (34%) and reduced in 82 (3%) of 2,611 patients. Conclusion A central prospective review of patient data and consecutive prescription of individual RT treatment volume is feasible within large multicenter trials for HD. Such a procedure has a significant impact on the correctness of stage definition, allocation to treatment groups, and extent of the IF treatment volume.

Purpose Deviations of radiation treatment portals and dose from prospective treatment plans are unfavorable prognostic factors for lymphoma patients. Therefore, an extensive radiotherapy quality assurance program is used in the ongoing German lymphoma studies. The introduction of teleradiotherapy offered the opportunity to optimize and simplify the workflow of these quality assurance programs. The purpose of this report was to evaluate the feasibility of teleradiotherapy and to describe our experiences with these innovative tools. Methods and materials During this pilot phase, five radiotherapy centers were equipped with the hardware and software that guarantees a rapid and high-quality transfer of imaging data, as well as real-time teleconferences. The workstation consists of standard PCs with Windows NT as the operating system and the commercial telemedicine software Hipax. Results As a first step, imaging communication between the radiotherapy reference centers in Cologne and Homburg/Saar was established. Subsequently, three additional radiotherapy departments (Universities of Berlin, Munster, and Munich) with large numbers of lymphoma patients were connected. Other study centers delivered digital imaging on mobile data carriers or via an Integrated Services Digital Network point-to-point connection. Communication units were completed for interactive teleconferences. A facility for central online documentation was installed. Telemedical functions were integrated into the ongoing radiotherapy quality assurance program. Since the introduction of a teleradiotherapeutic workstation in the radiotherapy reference center in Cologne in January 2001, the images of 10% ( n = 228 patients) of all reviewed cases of the ongoing Hodgkin's disease 10–12 trials were delivered digitally. The amount of digitally available imaging is continuously increasing. Conclusion The introduction of teleradiotherapy improved the dialog between the radiotherapy reference centers and study centers and thus contributed toward high radiotherapy quality for lymphoma patients in Germany.

The outcome of patients with all stages of Hodgkin's lymphoma has improved dramatically over the past few decades. This is mainly due to the use of risk-adapted therapies using intensive polychemotherapeutic regimens in combination with other modalities. Patients with early favourable or unfavourable (intermediate) stage disease receive two or four cycles of chemotherapy, respectively, followed by involved-field radiotherapy (20-30Gy). Advanced stage Hodgkin's lymphoma is treated more aggressively using six to eight cycles of chemotherapy but the effectiveness of consolidative radiotherapy for patients who show a complete response after chemotherapy alone is still unknown. The main challenge in the near future will be the development of strategies that decrease late morbidity and mortality but retain the same efficacy of current regimens. In this paper we review current diagnostic techniques and management strategies used to treat Hodgkin's lymphoma, and the range of new modalities being used to improve long-term outcome and patient quality of life.

For personal use. Only reproduce with permission from The Lancet. Classic Hodgkin’s lymphoma is characterised by Hodgkin and Reed-Sternberg cells and in most cases are derived from germinal-centre B cells. Despite progress in basic research showing the natural precursor cells of Hodgkin’s lymphoma, most key questions still remain unanswered. Among these are the basic transforming events, the involvement of oncogenic viruses, the mechanisms enabling Hodgkin and Reed Sternberg cells to resist apoptosis in the germinal centre, and the molecular causes of their characteristic phenotype. Beyond the disclosure of these issues, the detection of changes in gene expression, gene mutations, and chromosomal imbalances specific of Hodgkin’s lymphoma are central to recent research that may allow one a better understanding of the natural history of this type of lymphoma.

Although treatment regimens for Hodgkin's lymphoma have become more sophisticated, little is known about the prevalence of fatigue in long-term survivors. Therefore, we investigated the fatigue status of long-term survivors of Hodgkin's lymphoma and a control group using a pre-validated questionnaire. In 1995/1996, we contacted 1981 patients, who were enrolled in the German Hodgkin Studies HD 1-6. All patients were treated according to the treatment protocols HD1-3 (1981-1988) and HD 4-6 (1988-1993). The patients with a current status of complete remission were asked to complete a quality-of-life (QoL) questionnaire (European Organisation for Research and Treatment of Cancer Quality of Life Core 30 (EORTC QLQ C-30)) and a fatigue questionnaire (Multidimensional Fatigue Inventory (MFI)). The results were compared with the data from 935 controls, matched for age, gender and living area. Eight-hundred and eighteen questionnaires from the patients were available for analysis. The median time between the end of treatment and completing the questionnaire is 5.2 years. Fatigue levels of patients with Hodgkin's lymphoma are high, even years after treatment. Fatigue dimensions are significantly influenced by several clinical and non-clinical factors. Fatigue levels of Hodgkin's lymphoma patients are significantly higher than those of the control group. Further investigations are warranted to explore the effectiveness of treatment strategies for fatigue.

Background: Hodgkin’s disease (HD) is the most common non-AIDS-defining tumor diagnosed in HIVinfected patients. Antineoplastic treatment is difficult considering the underlying immunodeficiency caused by HIV itself and may increase the risk of opportunistic infections. The purpose of this study was to evaluate the efficacy and safety of the chemotherapeutic regimen bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisone (BEACOPP) in HIV-infected patients with HD (HIV-HD). Patients and methods: Twelve patients with HIV-HD were scheduled to receive six cycles of BEACOPP. Five patients received concomitant antiretroviral therapy. Two patients received additional radiotherapy. Restaging was carried out after three and six cycles of chemotherapy. CD4 counts and HIV RNA levels were regularly monitored during the course of chemotherapy. Results: Complete remission (CR) was achieved in all patients. Of 12 patients, eight patients received the intended six cycles of BEACOPP. Two patients died of opportunistic infections within the treatment period, one patient died of a relapse after 26 months. The other nine patients remain in CR for their individual follow-up period, median 49 months (range 13–108). The most commonly observed toxicity was bone marrow suppression with National Cancer Institute Common Toxicity Criteria (NCI-CTC) grade 3/4 leukopenia in 75% of all cases. The mean decline of CD4+ lymphocytes was 238 ± 230/µl, with a mean recovery of 272 ± 329/µl 6 months after the last cycle. Plasma levels of HIV RNA increased moderately or even declined under chemotherapy if highly active anti-retroviral therapy was given concomitantly with BEACOPP. Conclusions: The BEACOPP regimen is feasible and highly effective in HIV-HD patients. With respect to its overall moderate toxicity, BEACOPP is a safe regimen even in the immunocompromised patient.

An important variable affecting outcome in relapsed and refractory Hodgkin's disease (HD) is the potential of conventional salvage chemotherapy to reduce tumor volume before high-dose chemotherapy (HDCT) and autologous stem cell transplantation. Currently, the optimal salvage chemotherapy regimen for these patients is unclear. Since dexamethasone/cisplatin/cytarabine (DHAP) given at 3-4 week intervals has been shown to be very effective in patients with relapsed aggressive non-Hodgkin's lymphoma, we evaluated this regimen given at a median of 16-day intervals in patients with relapsed and refractory HD.Patients with relapsed or refractory HD were treated with two cycles of DHAP [dexamethasone 40 mg intravenously (i.v.) day 1-4, cisplatin 100 mg/m(2) i.v. as 24-h continuous infusion day 1, and cytarabine 2 g/m(2) i.v. 12q day 2]. Granulocyte colony-stimulating factor (G-CSF) was given at a dose of 5 micro g/kg from day 4 until day 13. Patients with partial remission (PR) or complete remission (CR) after two cycles of DHAP received sequential HDCT.The median age of the 102 patients included was 34 years (range 21-64 years). Forty-two percent of the patients had late relapse, 29% early relapse, 12% multiple relapse and 16% primary progressive/refractory disease. The response rate (RR) after two cycles of DHAP was 89% (21% CR, 68% PR). The RRs for patients with late, early, multiple and progressive HD were 91%, 93%, 92% and 65%, respectively. Using the chi-square test for independence, remission status (relapsed HD versus progressive HD) and stage at relapse (stage I/II versus stage III/IV) were significant factors for response to DHAP. WHO grade 4 leukocytopenia and thrombocytopenia were the main toxic- ities occurring in 43% (mean duration 1.1 days, range 0-6) and 48% (mean duration 1.4 days, range 0-11) of all courses, respectively. Neither severe infections nor treatment-related deaths occurred. Peripheral blood stem cells (PBSCs) were collected after the first cycle DHAP in eight patients. The hematopoietic progenitors showed a very rapid increase from day 10 with a synchronous and impressive peak on day 12. A mean of 6.1 x 10(6)/kg CD34(+) cells were collected per apheresis. As originally recommended in the protocol, PBSCs were routinely collected during sequential HDCT in the remaining patients.A brief tumor-reducing program with two cycles of DHAP given in short intervals supported by G-CSF is effective and well-tolerated in patients with relapsed and refractory HD. This regimen can be used to mobilize stem cells and select those patients with chemosensitive relapse who should subsequently be treated with HDCT.

During the past 40 years substantial progress has been made in the treatment of hematologic malignancies, particularly in some subgroups of patients. Today, cure is attainable for patients with Hodgkin's disease and a considerable proportion of patients with high-grade non-Hodgkin's lymphoma. Prognosis is improving in patients with acute promyelocytic leukemia and, to some extent, those with acute lymphoblastic and myeloid leukemias. However, the majority of patients who suffer from a hematologic malignancy live with incurable disease. In CLL, outside the setting of a clinical trial, it is advisable to postpone treatment until the manifestation of clinical symptoms. It is yet to be determined whether treatment strategies based on new prognostic parameters such as cytogenetics can change the course of disease. In indolent lymphomas, cure is not attainable for the vast majority of patients; the median survival of 9 to 10 years has remained unchanged for several decades. Nevertheless, there has been a dramatic change in therapeutic paradigms in the past few years. For the first time, with the use of new cytostatic drugs and recombinant monoclonal antibodies, it is possible to achieve molecular remissions. Whether this will translate into cure or prolonged survival is still to be determined. In Hodgkin's disease, which is curable when treated with radiotherapy, chemotherapy, or combined therapy, depending on the stage of disease, the focus of future studies must be on prevention of early relapse and on primary resistant disease, both of which present a very poor prognosis. Finally, regardless of underlying malignancy and prognosis, the preservation of quality of life is of major consideration in the setting of hematologic malignancies. Semin Oncol 29 (suppl 8):30-39. Copyright 2002, Elsevier Science (USA). All rights reserved.

Summary Background High-dose chemotherapy followed by transplantation of autologous haemopoietic stem cells (BEAMHSCT) is frequently used to treat patients with relapsed Hodgkin's disease. We aimed to compare this treatment with conventional aggressive chemotherapy without stem-cell transplantation (Dexa-BEAM). Methods 161 patients between 16 and 60 years of age with relapsed Hodgkin's disease were randomly assigned two cycles of Dexa-BEAM (dexamethasone and carmustine, etoposide, cytarabine, and melphalan) and either two further courses of Dexa-BEAM or high-dose BEAM and transplantation of haemopoietic stem cells. Only patients with chemosensitive disease (complete or partial remission after two courses of Dexa-BEAM) proceeded to further treatment. The primary endpoint was freedom from treatment failure for patients with chemosensitive disease. Analysis was per protocol. Findings 17 patients were excluded from the study after randomisation (ten given Dexa-BEAM and seven given BEAM-HSCT). Median follow-up was 39 months (IQR 3–78). Freedom from treatment failure at 3 years was significantly better for patients given BEAM-HSCT (55%) than for those on Dexa-BEAM (34%; difference −21%, 95% CI −39·87 to −2·13; p=0·019). Overall survival of patients given either treatment did not differ significantly. Interpretation High-dose BEAM and transplantation of haemopoietic stem cells improves freedom from treatment failure in patients with chemosensitive first relapse of Hodgkin's disease irrespective of length of initial remission.

Crosslinking of the transmembrane receptor CD95/Fas leads to activation of a signaling cascade resulting in apoptosis. c-FLIP is a recently described protein that potently inhibits Fas-mediated apoptosis and has been shown to be a key factor in germinal center B cell survival. Because Hodgkin and Reed-Sternberg cells in classical Hodgkin's disease (cHD) are also resistant to Fas-mediated apoptosis we studied the role of c-FLIP in classical HD. High levels of c-FLIP protein were identified in two Fas-resistant Hodgkin-derived cell lines. In contrast to other tumor cells, inhibition of protein synthesis by cycloheximide did not lead to down-regulation of c-FLIP protein in these HD cell lines. Furthermore, Fas-mediated apoptosis was only partially restored suggesting that normal regulation of c-FLIP was disrupted. The in vivo relevance of these findings was supported by demonstration of significant c-FLIP expression by immunohistochemistry in 18 of 19 evaluable cases of primary HD. Taken together, c-FLIP is constitutively expressed in HD and may therefore be a major mechanism responsible for Fas-resistance in HD.

Background: The bleomycin-etoposide-doxorubicin-cyclophosphamide-vincristine-procarbazine-prednisone (BEACOPP) regimen was developed to investigate the potential of moderate dose escalation of conventional polychemotherapy to improve the unsatisfactory treatment results in advanced-stage Hodgkin's lymphoma (HL). Following pilot studies, the randomised trial HD 9 demonstrated that BEACOPP (baseline dose) attained superior failure-free survival to COPP/ABVD, and that dose escalation made a further marked improvement. Toxicity was severe but manageable. Patients and methods: The current GHSG multicentre randomised trial HD 12 has a 2 × 2 factorial design in order to make two comparisons: (i) eight cycles of escalated BEACOPP (as in HD9) are compared with four escalated cycles followed by four at baseline dose; (ii) the use of additional local radiotherapy to initial bulky disease and residual disease after chemotherapy is compared with chemotherapy alone, except where radiotherapy Was prescribed by a central diagnostic panel. Eligible are patients aged 16-65 years with newly diagnosed HL of stage IIB with risk factors or stage III/IV. The EORTC multicentre trial 20012 randomises patients with HL stage III/IV to either eight cycles of ABVD or eight cycles of BEACOPP (four escalated + four baseline). ). Results: The first interim analysis (January 2001) of HD 12 with 221 evaluable patients indicated continuation of recruitment. Recruitment will end in 2002 and the final data analysis will appear in 2006. Conclusions: The BEACOPP regimen is highly effective, and moderate dose escalation makes a further worthwhile improvement in tumour control Current trials will measure BEACOPP against the international standard and show whether the amount of chemotherapy and/or radiotherapy can be reduced.

Background: Early adjustment of treatment may benefit the patient In order to guide treatment adjustment use of early response (ER) or early complete response (ECR), judged after the few initial cycles of chemotherapy, is common in pediatric and also adult Hodgkin's and non-Hodgkin's studies, Paradoxically, almost no data support this strategy. Patients and methods: The influence of ECR on outcome was evaluated in three series of advanced Hodgkin's disease (HD), leading to a series of questions. Results: The 1982 EORTC study assessed prospectively the time frame needed to reach an apparent complete response (CR) through repeated tumor measurements. In patients assessed at mid-treatment before the fifth cycle, both 15 year freedom from progression (FFP) and overall survival (OS) were superior in ECR patients compared with other patients continued on the same treatment (61% versus 37%; P

Depending on stage and risk factor profile, up to 95% of patients with Hodgkin’s disease (HD) at first presentation reach complete remission (CR; disappearance of all detectable clinical and radiographic evidence of disease) after standard treatment [1]. Depending on their initial treatment, those patients relapsing have different treatment options, including radiotherapy for localized disease in previously non-irradiated areas, conventional salvage chemotherapy, or high-dose chemotherapy (CT) followed by autologous stem cell transplantation (autoSCT) [2, 3]. Conventional CT is the treatment of choice for patients relapsing after initial radiotherapy for early stage HD. The survival of these patients is at least equal compared with advanced-stage patients initially treated with CT [4]. In contrast, patients with relapsed HD after primary CT generally have a poorer prognosis. The therapeutic options include salvage radiotherapy, salvage CT, and high-dose CT with autoSCT. More recently, new approaches such as sequential highdose CT, tandem high-dose CT, allogeneic (allo) SCT, or nonmyeloablative conditioning with allogeneic blood progenitor cell transplantation (‘mini-transplants’) have been investigated in relapsed HD [4–6]. Since more aggressive approaches are associated with increased toxicity, an accurate pretreatment prognostic assessment of patients is required to help selection of the most appropriate therapeutic regimen.

UNLABELLED Infertility after treatment of patients with Hodgkin's disease (HD) is considered as a side effect of alkylating agent containing chemotherapy regimens. To investigate whether gonadal failure is related primarily to the toxic effect of chemotherapy or rather to the disease itself, we investigated the fertility status before the onset of treatment. PATIENTS AND METHODS Semen quality and hormonal status were evaluated in 158 patients with first diagnosis of HD enrolled into trials of the German Hodgkin Lymphoma Study Group (GHSG). The median age of the patients was 28 years (range 16-52). Twenty patients (13%) were classified as early stage HD, 63 patients (40%) as intermediate stage, and 75 patients (47%)) as advanced stage according GHSG grading. Sixty-seven patients (42%) showed systemic symptoms. Semen analysis was performed according to WHO guidelines. Follicle-stimulating hormone (FSH) and luteinising hormone (LH) plasma levels were measured by specific double-antibody radio-immune-assay (RIA) methods. RESULTS Prior to treatment, severe damage of fertility, i.e.. azoospermia and oligoasthenoteratospermia (OAT-syndrome) was found in 13 (8%) and 20 patients (13%), respectively. Thirty-eight patients (24%) had single, i.e., oligo-(O), astheno-(A) or teratospermia-(T), and 40 patients (26%) showed combined damages, i.e., OA, OT or AT. In 47 patients (30%) a normal sperm count was found. Thus, III patients (70%) showed semen abnormalities before the onset of treatment. In a multivariate analysis elevated ESR (P < 0.003) and advanced stage of disease (P < 0.01) could be distinguished as prognostic factors for severe damage of fertility. No correlation was found between pre-therapeutic gonadotropine levels and fertility status. CONCLUSION Patients with HD have an increased risk for inadequate semen quality even prior to treatment. Infertility is more frequent in patients with elevated ESR and advanced stage of disease. This association demonstrates the predominant influence of the disease on fertility. Assuming HD is the major initial cause for infertility efforts should be made to identify new non-gonadal toxic chemotherapies to be able to regain fertility after effective therapy. Further investigations have to be performed to clarify mechanisms inducing fertility defects in patients with HD.

Summary Background The magnitude of chemotherapy dose escalation made possible by the use of recombinant haematopoietic growth factors has not been quantified in a randomized trial Patients and methods Patients with refractory or relapsing Hodgkin’s disease were randomized to receive the Dexa-BEAM regimen with escalating etoposide doses supported by placebo or granulocyte-macrophage colony-stimulating factor (GMCSF) Using an adaptive sampling method independently in both arms, the etoposide dose was escalated until the maximal tolerated dose for the first cycle was reached Results Thirty patients were randomized to GM-CSF and thirty to placebo The etoposide dose could be escalated considerably in both treatment arms Maximal etoposide dose for the first cycle was 1920 mg/m2 for patients receiving GM-CSF and 1160 mg/m2 for patients receiving placebo (P = 0 045 one-sided), corresponding to a 65% higher etoposide dose and a 13% higher dose intensity with GM-CSF Dose-limiting events were similar in both arms, consisting mainly of prolonged neutropenia and consecutive infections Treatment efficacy was not different in the two treatment groups Conclusions While GM-CSF permits a somewhat higher dose escalation than placebo, the increase in dose intensity provided by GM-CSF is small The use of CSF for interval reduction rather than dose escalation is the more effective strategy for dose intensification

To determine parameters of distinctive value in polycythemia rubra vera (PV) versus secondary polycythemias (SP), a clinicopathological study was performed on 199 patients. These presented with a borderline to marked elevation of the hemoglobin level (> 18 g/dl in men and > 16 g/dl in women). Evaluations of clinical features and bone marrow histopathology were carried out independently. According to the results derived from laboratory data and representative pretreatment trephine biopsies, three groups of patients emerged: group I presenting with the concordant clinical and morphological findings of early to manifest PV (136 patients), group II consisting of 55 patients with the congruent signs and symptoms of SP mostly caused by various chronic bronchopulmonal disorders, and finally eight patients (group III) with divergent findings. Between group I and II patients (PV versus SP), a number of clinical parameters proved to be significantly different. With the exception, of the red cell mass, platelet count, leukocyte alkaline phosphatase, LDH, spleen size, and the erythropoietin level had a significantly discriminating impact. Morphological features of distinctive value consisted of a set of specific lesions. Contrasting SP with an only borderline to slight increase in cellularity associated with a moderate enlargement of the erythroblastic islets, PV was always characterized by a significant increase in hematopoiesis, revealing a trilinear proliferation (panmyelosis). Megakaryopoiesis was strikingly different in PV as compared to SP by displaying clustering and a pleomorphous appearance. i.e., very small and giant megakaryocytes with staghorn-like nuclei were neighboring each other. Moreover, conspicuous alterations of the interstitial compartment were recognizable in SP. These consisted of deposits of cell debris in histiocytic reticular cells, iron-laden macrophages, and a plasmacytosis, implying an inflammatory reaction. These changes were only very rarely observed in PV, as opposed to a minimal to slight increase in reticulin fibers in about 12% of patients. In conclusion, a more elaborate evaluation of bone marrow features resulted in a set of diagnostic criteria with discriminating capacity that should be considered in prospective clinical trials.

Summary Background: Evidence is recently accumulating that the novel BEACOPP (bleomycin (B), etoposide (E), adriamycin (A), cyclophosphamide (C), vincristine (O), procarbazine (P), prednisone (P)) chemotherapy is a highly effective treatment for advanced stage Hodgkin's disease. Two dose variants of BEACOPP are currently tested in a phase III randomized multicenter trial of the GHSG. To enable more extensive testing of BEACOPP we characterized its practicability regarding schedule adherence, acute hematotoxicity and need for supportive treatment. Patients and methods: Data of 858 patients (6592 therapy cycles) from 184 participating institutions were evaluated. Planned total drug doses of the baseline variant (arm 1) were 80, 2400, 200, 5200,11.2, 5600 and 4480 mg/m 2 for B, E, A, C, O, P and P, respectively. Compared to arm 1, the doses of E, A and C in the dose-intensified variant (arm 2) were escalated by factor 2.0, 1.4, 1.92, respectively, using G-CSF assistance. Stepwise dose reductions were specified in case of dose-limiting toxicities. Both variants are given in eight three-weekly courses. Results: Median dose adherence (dose actually given relative to planned arm 1 dose) in arm 1 was 1.0 for all drugs. Relative dose escalation of E, A, and C actually maintained in arm 2 was 1.83, 1.37 and 1.77 (medians), respectively, and 70% of patients maintained elevated dose levels throughout the entire treatment. Dose-limiting toxicities occurred in 25% of cycles in arm 2, most frequently due to leukocytopenia and thrombocytopenia. Time courses of leukocytes in arm 2 showed more severe but not more prolonged leukocytopenia compared with arm 1. WHO grades 3-4 infections were documented in 2.1% (arm 1) and 3.1% (arm 2) of all cycles. Erythrocytes were transfused in 6% (arm 1) and 28% (arm 2), platelets in < 1% (arm 1) and 6% (arm 2) of all cycles. Conclusions: Both BEACOPP schemes are practicable in a large multicenter setting. Despite increased hematotoxicity, moderate dose escalation is safe for the majority of the patients with G-CSF assistance and standard supportive treatment.

We describe a case of Guillain-Barré syndrome (GBS) in a patient with non-Hodgkin's lymphoma (NHL). A 21-year-old woman with a newly diagnosed stage IV high-grade lymphoma (precursor T-cell NHL according to the R.E.A.L. Classification) developed flaccid quadriparesis and bilateral facial diplegia after three weeks of treatment with vincristine, daunorubicin, L-asparaginase and prednisolone. The clinical course and neurological examination were consistent with GBS. Despite treatment with intravenous immunoglobulins her neurological symptoms progressed. Plasmapheresis was therefore initiated followed by intravenous immunoglobulins. After partial remission of neurologic symptoms, induction chemotherapy with cyclophosphamide and cytarabine was continued without any further complication. Three months later, the lymphoma was in complete remission. GBS has been described in Hodgkin's disease and after bone marrow transplantation but is rare in NHL. In patients with NHL who develop neurological symptoms, drug toxicity and nervous system infiltration are the leading cause of neuropathology, but GBS should be considered in the differential diagnosis.

Classical Hodgkin's disease (HD) is associated with Epstein-Barr virus (EBV) infection. Although in developing countries EBV can be demonstrated in Hodgkin-Reed-Sternberg (H-RS) cells in up to 95% of HD cases, in industrialized countries only about 50% of HD cases are associated with EBV. An open question remains whether EBV in the EBV-negative cases has escaped detection by standard screening procedures due to deletions in the viral genome associated with integration of viral fragments into the host cell genome. We, among others, recently described this phenomenon in Burkitt's lymphoma cells. To investigate whether H-RS cells in latent membrane protein-1 (LMP-1)-negative HD cases harbor fragments of the EBV genome, we combined fluorescence in situ hybridization (FISH) using a set of six overlapping DNA probes spanning the whole EBV genome with immunophenotyping of fresh frozen lymphoma sections. Results in the eight cases analyzed were as follows: in three LMP-1-positive cases, FISH analysis yielded specific signals for each EBV DNA probe in H-RS cells, which had been identified by morphology and CD30 staining. In contrast, none of the EBV DNA probes hybridized to the H-RS cells in the five LMP-1-negative cases. Thus, there is no evidence for the presence of fragments of the viral genome integrated into the host cell genome in the LMP-1-negative cases. Furthermore, in the LMP-1-positive cases analyzed, no large deletions in the viral genome were detected. These results show that, in classical HD, LMP-1-negative cases do not harbor EBV DNA within the H-RS cells. Whether, in these cases, a still unknown virus contributes to the transformation and maintenance of the malignant phenotype remains to be established.

Triple antiretroviral treatment including protease inhibitors (PIs) delays the clinical progression of HIV infection and may thus reduce the risk of malnutrition. However fat redistribution (lipodystrophy) was recognized recently as a metabolic side effect of PIs. The study aimed to assess the effect of triple antiretroviral treatment on body composition and on the prevalence of malnutrition. Two cross-sectional studies 1 in 1996 (t96; n = 247) and 1 in 1997 (t97; n = 266) were conducted in HIV-infected outpatients. Among patients who participated in both studies 111 patients started a new antiretroviral treatment including a PI between t96 and t97 and were studied longitudinally. Total body water (TBW) intracellular water (ICW) extracellular water (ECW) and fat mass were estimated by monofrequency bioelectrical impedance analysis (BIA). Prevalence of malnutrition was reduced by 30--50% from t96 to t97 depending on the definition used. In the longitudinal study TBW and the ratio between ICW and ECW increased and fat mass decreased (P < 0.001). BIA indicated a greater increase in ICW in 23 (21%) patients with clinically apparent fat redistribution than in patients without this syndrome but estimates of fat mass changes were not significantly different. Triple antiretroviral treatment may protect HIV-infected patients against the development of malnutrition. Whole-body BIA data suggest an increase in appendicular body cell mass associated with improved antiretroviral treatment. However the method is unreliable in detecting fat redistribution and current prediction equations will need to be recalibrated for HIV-infected patients receiving highly active antiretroviral treatment. (authors)

Due to increasingly strained budgets in the German statutory health insurance system, new and expensive medical technologies have come under increased scrutiny. This also applies to stem cell transplantation (SCT), which is a highly costly treatment for certain types and stages of malignant diseases. In 1996, a large number of hospitals applied for licences to perform SCT, raising fears of deteriorating standards and a cost explosion, especially as new indications such as breast cancer emerged. To address this problem, the Concerted Action Stem Cell Transplantation (CASCT) was created. It consists of several scientific medical societies and the sickness funds. The steps taken by CASCT include binding standards for SCT and expert assessments of institutions wishing to perform SCT. This has successfully reduced the number of new hospitals performing SCT to 11 until June 1999. Recommended procedures for SCT were agreed with the sickness funds including experimental indications such as breast and lung cancer. A national registry for SCT has been set up which will publish data on a yearly basis. An important role of economic analyses for the evaluation of SCT has been agreed. CASCT is a development that extends elements of corporatist self-government found in the German ambulatory healthcare sector to the hospital sector. Its aim is to reconcile an expensive new medical modality with the requirements of quality assurance and cost control. Its long-term effects are as yet unclear and will require further investigation.

The history of successful therapy of Hodgkin’s disease was initiated at the beginning of this century with the first reports of effective X-ray treatments by Pusey and Senn (1, 2). Today, at the end of this century, over 70% of patients with Hodgkin’s disease will be cured using modern treatment strategies. Both megavoltage radiotherapy and combination chemotherapy are effective treatment modalities. Therefore the optimal choice of treatment depends on the knowledge of 1) prognostic factors influencing the individual treatment outcome, 2) results of the different treatment alternatives, and 3) the risk of acute and long-term complications incurred by these treatments. Historically, extended field (EF) or subtotal nodal irradiation (STNI) is the treatment of choice for patients with pathological stage I and II after staging laparotomy. The use of limited irradiation volumes (involved field) in clinically staged patients is inadequate with an excess in relapse rates of over 50%. Following the strategy of staging laparotomy and, if negative, EF-irradiation or STNI, overall survival is excellent with a rate over 90% at 10 years (3). Since the introduction of the MOPP-regimen by DeVita (4) and ABVD-regimen by Bonadonna (5), these chemotherapy protocols are standard therapies, for the advanced stages. However, 50% of patients with advanced stages failed in initial treatment programmes, and the prognosis of these treatment failures is very poor.

Effective reduction of HIV replication by protease inhibitor (PI) treatment was expected to reverse some of the weight loss associated with HIV infection. Body weight changes in undernourished HIV-infected patients starting PI treatment were compared to its virologic and immunologic effects. This was designed as a retrospective study using prospectively collected weight data; the setting was the HIV outpatient department of a university hospital. Among 223 consecutive HIV-positive patients starting treatment with PI February 1996 to September 1997, 63 undernourished patients were evaluable. The main outcome measures were weight trend, calculated by linear regression of a patient's weight versus time, and its change from a 4-14-wk baseline period to the first 14 wk, and 28 wk, after treatment. In our results, weight trend remained unchanged (baseline, +0.4 +/- 4.0 kg/100 d; 14 wk, +0.7 +/- 4.1 kg/100 d, and 28 wk, +1.0 +/- 3.4 kg/100 d, n.s.). Reduction of viremia and increase in CD4 cell count were unrelated to weight trends. Treatment with PI did not result in an improved weight trend. Altered body composition with PI treatment, as observed in other studies, does not seem to result in body weight changes. Drug side effects may have counteracted any positive effects. The metabolic and nutritional impact of effective antiviral treatment merits further study.

Recombinant immunotoxins (rITs) are highly specific anti-tumor agents composed of monoclonal antibody fragments or other specific carriers coupled to plant or bacterial toxins. A major problem in the purification of rITs is the low periplasmic yield in currently available expression systems. Thus, the aim of this study was the development of a new bacterial expression system for high-level production of rITs. We constructed a series of pET-based vectors for pelB-directed periplasmic secretion or cytoplasmic production under the control of the T7lac promoter. Expression in Escherichia coli BL21(DE3)pLysS allowed a tightly regulated isopropyl beta-d-thiogalactopyranoside (IPTG) induction of protein synthesis. An enterokinase-cleavable poly-histidine cluster was introduced into this setup for purification by affinity chromatography. A major modification resulted from the insertion of a specifically designed multiple cloning site. It contains only rare restriction enzyme recognition sites used for cloning of immunoglobulin variable region genes, as well as unique SfiI and NotI restriction sites for directed insertion of single-chain variable fragments (scFv) available from established bacteriophage systems. For this purpose, we deleted two naturally occurring internal SfiI consensus sites in a deletion mutant of Pseudomonas aeruginosa exotoxin A (ETA'). Each single structural element of the new vector (promoter, leader sequence, purification tag, scFv sequence, selectable marker, and toxin gene) was flanked by unique restriction sites allowing simple directional substitution. The fidelity of IPTG induction and high-level expression were demonstrated using an anti-CD30 scFv (Ki-4) fused to ETA'. These data confirm a bacterial vector system especially designed for efficient periplasmic expression of ETA'-based fusion toxins.

Two cases of opportunistic cerebral infections in HIV-negative cancer patients due to chemotherapy induced immunosuppression are reported. A 61-year-old patient with low grade lymphoma (immunocytoma as referred to the Kiel classification) developed stereotactical biopsy proven toxoplasmic encephalitis 6 months after initiation of fludarabine treatment. The lymphoma had been diagnosed 8 years earlier and had been treated with several different regimens. In the second case, a 55-year-old patient developed neurological symptoms while in complete remission from acute T-cell leukaemia. The patient had been treated with a multidrug chemotherapy regimen including radiotherapy of the brain and intrathecal chemotherapy. When toxoplasmic encephalitis was bioptically diagnosed the patient was on maintenance chemotherapy with methotrexate and mercaptopurine for 12 months. The patients' characteristics and outcome are reported and the potential pathogenesis is discussed.

Summary At present over 90% of early stage Hodgkin's disease patients will be cured. Both radiotherapy and combination chemotherapy are effective treatment modalities. However, the optimal choice of treatment or combinations of treatment is still debated. Recently, several trials reported excellent treatment results with combined modality in early stages of Hodgkin's disease. The use of chemotherapy regimen not including alkylating agents may avoid the risk of infertility and secondary malignancies and facilitates reduction of dose and field size of radiotherapy in early stages. In intermediate stages new chemotherapy regimen (i.e., BEACOPP) will offer the chance to reduce the fraction of patients with initial treatment failure, while reducing the extent of radiotherapy. With the introduction of the escalated BEACOPP regimen it was demonstrated that the prognosis of the advanced stages could be positively influenced by intensification of therapy. Future trials aim to answer: 1) which chemotherapy regimen in which quantity will be the best with respect to efficacy and longterm toxicity and 2) which dose and field size of radiotherapy is adequate within the combined modality approach.