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Doxorubicin, bleomycin, vinblastine sulfate, and dacarbazine (ABVD) is associated with severe toxicity in older patients, particularly from bleomycin-induced lung toxicity (BLT). Therefore, using bleomycin has been questioned in older Hodgkin lymphoma (HL) patients, especially in early-stage HL. We therefore analyzed feasibility, toxicity, and efficacy of ABVD or AVD in 287 older early-stage favorable HL patients. We included patients ≥60 years of age in the German Hodgkin Study Group HD10 and HD13 trials randomized to either 2 cycles of ABVD (2×ABVD; n = 137) or AVD (2×AVD; n = 82), each followed by involved-field radiotherapy (IF-RT), with patients randomized to 4×ABVD+IF-RT (n = 68). Patients' median age was 65 years (range, 60-75) with comparable patient and disease characteristics. Grade III-IV adverse event rates were similar in patients receiving 2×AVD and 2×ABVD (40% and 39%, respectively), but considerably higher in patients receiving 4×ABVD (65%). Similarly, BLT was rare in patients receiving 2×ABVD/AVD, but occurred in 7/69 (10%) of patients randomized to 4×ABVD, with 3 lethal events. In conclusion, no effects of bleomycin on toxicity rates were detectable in older patients receiving 2 cycles of chemotherapy. However, we found a high risk of severe toxicity of bleomycin in older HL patients receiving more than 2 cycles of ABVD. These trials are registered at www.clinicaltrials.gov and www.isrctn.com as #NCT00265018 (HD10) and #ISRCTN63474366 (HD13).

Purpose The optimal treatment of stage IA nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is not well defined. Thus, we performed an analysis using the database of the German Hodgkin Study Group. Patients and Methods The long-term outcome of 256 patients with stage IA NLPHL was evaluated. Patients had received combined-modality treatment (CMT; n = 72), extended-field radiotherapy (EF-RT; n = 49), involved-field radiotherapy (IF-RT; n = 108), or four weekly standard doses of rituximab (n = 27) within German Hodgkin Study Group clinical trial protocols between 1988 and 2009. Results The median age at NLPHL diagnosis was 39 years (range, 16 to 75 years). Most patients were male (76%). The whole patient group had a median follow-up of 91 months (CMT: 95 months; EF-RT: 110 months; IF-RT: 87 months; rituximab: 49 months). At 8 years, progression-free survival and overall survival rates were 88.5% and 98.6% for CMT, 84.3% and 95.7% for EF-RT, and 91.9% and 99.0% for IF-RT, respectively. Patients treated with rituximab had 4-year progression-free and overall survival rates of 81.0% and 100%, respectively. A second malignancy during the course of follow-up was diagnosed in 17 (6.6%) of 256 patients. A total of 12 deaths occurred. However, only one patient died from NLPHL. Conclusion Tumor control in this analysis was equivalent with CMT, EF-RT, and IF-RT. Therefore, IF-RT, which is associated with the lowest risk for the development of toxic effects, should be considered as standard of care for patients with stage IA NLPHL. Rituximab alone is associated with an increased risk of relapse in this patient population.

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.

Classical Hodgkin lymphoma (cHL) is characterized by a paucity of neoplastic Hodgkin/Reed Sternberg (HRS) cells within a complex cellular milieu that is rendered immunologically incapable of reacting against CD30(+) HRS cells due to a plethora of immune escape mechanisms initiated by the neoplastic cells. Accounting for 25% of all lymphomas and nearly 95% of all Hodgkin lymphomas, patients with cHL are typically young adults. Besides traditional prognostic factors, such as the International Prognostic Index (IPI), newer imaging and ancillary biomarkers (CD68, Galectin-1 and plasma microRNA) have shown promise. Furthermore, the evolution of gene expression profiling (GEP) in recent years has enabled the development of several practically feasible GEP-based predictors with prognostic relevance. This review discusses the current status of clinical prognostication in cHL, the critical role of histological evaluation in light of several mimicking entities, and the relevance of tissue as well as serum biomarkers pertaining to immune escape mechanisms and recent GEP studies.

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.

Purpose Older patients with Hodgkin lymphoma (HL) account for approximately 20% of all HL patients. ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) chemotherapy is regarded as standard of care in these patients. However, little is known on feasibility and efficacy of ABVD in this age group. Patients and Methods We analyzed the feasibility and efficacy of four cycles of ABVD in older patients age 60 to 75 years with early-stage HL who were treated within the German Hodgkin Study Group (GHSG) HD10 and HD11 trials; results were compared with those of younger patients treated within these trials. Results In total, 1,299 patients received four cycles of ABVD, and 117 of those patients were older than age 60 years (median, 65 years). In 14% of older patients, treatment was not administered according to protocol, mainly because of excessive toxicity. The mean delay of treatment was twice as high in the older patients (2.2 v 1.2 weeks). Fifty-nine percent of older patients achieved a relative dose-intensity of at least 80% compared with 85% of younger patients. Major toxicity (WHO grade 3 and 4), including leucopenia, nausea, infection, and others, was documented in 68% of older patients with a treatment-related mortality of 5%. Complete response was achieved in 89% of older patients, 3% had progressive disease, and 11% relapsed. At a median observation time of 92 months, 28% of the patients had died, and the 5-year progression-free survival estimate was 75% (95% CI, 66% to 82%). Conclusion In patients age ≥ 60 years with HL, four cycles of ABVD is associated with substantial dose reduction, treatment delay, toxicity, and treatment-related mortality.

CME Learning Objectives Discuss whether and how genetic variations influence clinical outcomes of Hodgkin lymphoma patients. Evaluate evidence that proximal IL10 promoter gene variations are associated with clinical courses of Hodgkin lymphoma patients. Compare host genetic variations from different cytokine/cytokine receptor gene variations. Background. Hodgkin lymphoma (HL) is a lymphoid malignancy characterized by the production of various cytokines possibly involved in immune deregulation. Interleukin-10 (IL-10) serum levels have been associated with clinical outcome in patients with HL. Because host genetic variations are known to alter the expression and function of cytokines and their receptors, we investigated whether genetic variations influence clinical outcome of patients with HL. Methods. A total of 301 patients with HL who were treated within randomized trials by the German Hodgkin Study Group were included in this exploratory retrospective study. Gene variations of IL-10 (IL-10-597AC, rs1800872; IL-10-824CT, rs1800871; IL-10-1087AG, rs1800896; IL-10-3538AT, rs1800890; IL-10-6208CG, rs10494879; IL-10-6752AT, rs6676671; IL-10-7400InDel), IL-13 (IL-13-1069CT, rs1800925; IL-13Q144R, rs20541), and IL-4R (IL-4RI75V, rs1805010; IL-4RQ576R, rs1801275) were genotyped. Results. Inferior freedom from treatment failure (FFTF) was found in patients harboring the IL-10-597AA, IL-10-824TT, or the IL-10-1087AA genotype. In contrast, the IL-10-1087G-824C-597C haplotype present in about 48% of analyzed HL patients is nominally significant for a better FFTF in a Cox-Regression model accounting for stage and treatment. No associations were observed between the other IL-10 gene variations, IL-13-1069CT, IL-13Q144R, IL-4RI75V, IL-4RQ576R and the clinical outcome of patients with HL. Conclusions. Our study provides further evidence that proximal IL-10 promoter gene variations are associated with clinical course of patients with HL. However, treatment success and survival rates are already at a very high rate, supporting the need to design studies focusing on identification of predictors to reduce the side effects of therapy.

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.

GS-1101 (CAL-101) is an oral PI3Kδ-specific inhibitor that has shown preclinical and clinical activity in non-Hodgkin lymphoma and chronic lymphocytic leukemia. To investigate the potential role of PI3Kδ in Hodgkin lymphoma (HL), we screened 5 HL cell lines and primary samples from patients with HL for PI3Kδ isoform expression and constitutive PI3K pathway activation. Inhibition of PI3Kδ by GS-1101 resulted in the inhibition of Akt phosphorylation. Cocultures with stroma cells induced Akt activation in HL cells, and this effect was blocked by GS-1101. Conversely, production of the stroma-stimulating chemokine, CCL5, by HL cells was reduced by GS-1101. GS-1101 also induced dose-dependent apoptosis of HL cells at 48 hours. Reductions in cell viability and apoptosis were enhanced when combining GS-1101 with the mTOR inhibitor everolimus. Our findings suggest that excessive PI3Kδ activity is characteristic in HL and support clinical evaluation of GS-1101, alone and in combination, as targeted therapy for HL.

Purpose In patients with early unfavorable Hodgkin's lymphoma (HL), combined modality treatment with four cycles of ABVD (adriamycin, bleomycin, vinblastine, and dacarbazine) and 30 Gy involved-field radiotherapy (IFRT) results in long-term tumor control of approximately 80%. We aimed to improve these results using more intensive chemotherapy. Patients and Methods Patients with newly diagnosed early unfavorable HL were randomly assigned to either four cycles of ABVD or an intensified treatment consisting of two cycles of escalated BEACOPP (bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, and prednisone) followed by two cycles of ABVD (2 + 2). Chemotherapy was followed by 30 Gy IFRT in both arms. The primary end point was freedom from treatment failure (FFTF); secondary end points included progression-free survival (PFS) and treatment-related toxicity. Results With a total of 1,528 qualified patients included, the 2 + 2 regimen demonstrated superior FFTF compared with four cycles of ABVD (P < .001; hazard ratio, 0.44; 95% CI, 0.30 to 0.66), with a difference of 7.2% at 5 years (95% CI, 3.8 to 10.5). The difference in 5-year PFS was 6.2% (95% CI, 3.0% to 9.5%). There was more acute toxicity associated with 2 + 2 than with ABVD, but there were no overall differences in treatment-related mortality or secondary malignancies. Conclusion Intensified chemotherapy with two cycles of BEACOPP escalated followed by two cycles of ABVD followed by IFRT significantly improves tumor control in patients with early unfavorable HL.

Purpose Eight cycles of BEACOPPescalated (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 BEACOPPescalated was compared with four cycles of BEACOPPescalated followed by four cycles of the baseline dose of BEACOPP (BEACOPPbaseline; 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 BEACOPPescalated 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 (BEACOPPescalated, 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.

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 Combined-modality treatment consisting of four to six cycles of chemotherapy followed by involved-field radiotherapy (IFRT) is the standard of care for patients with early unfavorable Hodgkin's lymphoma (HL). It is unclear whether treatment results can be improved with more intensive chemotherapy and which radiation dose needs to be applied. Patients and Methods Patients age 16 to 75 years with newly diagnosed early unfavorable HL were randomly assigned in a 2 × 2 factorial design to one of the following treatment arms: four cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) + 30 Gy of IFRT; four cycles of ABVD + 20 Gy of IFRT; four cycles of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPPbaseline) + 30 Gy of IFRT; or four cycles of BEACOPPbaseline + 20 Gy of IFRT. Results With a total of 1,395 patients included, the freedom from treatment failure (FFTF) at 5 years was 85.0%, overall survival was 94.5%, and progression-free survival was 86.0%. BEACOPPbaseline was more effective than ABVD when followed by 20 Gy of IFRT (5-year FFTF difference, 5.7%; 95% CI, 0.1% to 11.3%). However, there was no difference between BEACOPPbaseline and ABVD when followed by 30 Gy of IFRT (5-year FFTF difference, 1.6%; 95% CI, −3.6% to 6.9%). Similar results were observed for the radiotherapy question; after four cycles of BEACOPPbaseline, 20 Gy was not inferior to 30 Gy (5-year FFTF difference, −0.8%; 95% CI, −5.8% to 4.2%), whereas inferiority of 20 Gy cannot be excluded after four cycles of ABVD (5-year FFTF difference, −4.7%; 95% CI, −10.3% to 0.8%). Treatment-related toxicity occurred more often in the arms with more intensive therapy. Conclusion Moderate dose escalation using BEACOPPbaseline did not significantly improve outcome in early unfavorable HL. Four cycles of ABVD should be followed by 30 Gy of IFRT.

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.

Purpose The HD9 trial of the German Hodgkin Study Group compared two different doses (baseline and escalated) of the bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) chemotherapy regimen in 1,196 patients with advanced-stage Hodgkin's lymphoma (HL). The previous analysis with 5 years median follow-up had indicated improved tumor control with BEACOPP escalated. Since the long-term safety and efficacy of this regimen has been debated, we report the 10-year follow-up. Patients and Methods Patients received one of three chemotherapy regimens: eight cycles of cyclophosphamide, vincristine, procarbazine, and prednisone (COPP) alternating with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD); eight cycles of BEACOPP baseline; or eight cycles of BEACOPP escalated. Results Median follow-up was 111 months. At 10 years, freedom from treatment failure (FFTF) was 64%, 70%, and 82% with OS rates of 75%, 80%, and 86% for patients treated with COPP/ABVD (arm A), BEACOPP baseline (arm B), and BEACOPP escalated (arm C), respectively (P < .001). BEACOPP escalated was significantly better than BEACOPP baseline in terms of FFTF (P < .0001) and OS (P = .0053). A total of 74 second malignancies (6.2%) were documented, including acute myeloid leukemia (0.4%, 1.5%, and 3.0%), non-Hodgkin's lymphoma (2.7%, 1.7%, and 1.0%), and solid tumors (2.7%, 3.4%, and 1.9%). The corresponding overall secondary malignancy rates were 5.7%, 6.6%, and 6.0%, respectively. Conclusion The 10-year follow-up of the HD9 trial demonstrates a stabilized significant improvement in long-term FFTF and OS for BEACOPP escalated in advanced-stage HL. These results challenge ABVD as standard of care for this patient population.

Cerebral aneurysms result from a congenital or evolved weakness of stabilizing parts of the vessel wall and potentially lead to rupture and a life-threatening bleeding. Current medical research concentrates on the integration of blood flow simulation results for risk assessment of cerebral aneurysms. Scalar flow characteristics close to the aneurysm surface, such as wall shear stress, form an important part of the simulation results. Aneurysms exhibit variable surface shapes with only few landmarks. Therefore, the exploration and mental correlation of different surface regions is a difficult task. In this paper, we present an approach for the intuitive and interactive overview visualization of near wall flow data that is mapped onto the surface of a 3D model of a cerebral aneurysm. We combine a multi-perspective 2D projection map with a standard 3D visualization and present techniques to facilitate the correlation between a 3D model and a related 2D map. An informal evaluation with 4 experienced radiologists has shown that the map-based overview actually improves the surface exploration. Furthermore, different color schemes were discussed and, as a result, an appropriate color scheme for the visual analysis of the wall shear stress is presented.

Our understanding of the biology of Hodgkin's lymphoma has improved, in particular the genetic and phenotypic characteristics of malignant cells and the signaling pathways involved in the pathogenesis of this disease. While newer regimens have improved the cure rates of patients with Hodgkin's lymphoma, some are associated with severe acute and long-term toxicities. This comprehensive Review discusses combined modality regimens for treating early-stage disease, approaches used for treating advanced disease and other novel regimens. Significant advances in the biology and treatment of Hodgkin lymphoma (HL) have been accomplished over the past decades. In a landmark study, DeVita and colleagues showed that half of patients with advanced-stage HL experienced long-term disease-free survival following treatment with a four-drug chemotherapy regimen. Subsequent reports and randomized clinical trials conducted over the past 40 years have defined prognostic categories and refined the treatment options for patients with early-stage and advanced-stage HL. New treatment concepts and regimens have continued to increase the cure rate of HL, while other analyses have documented the acute and long-term morbid and potentially fatal side effects of HL therapy. Increased knowledge of HL biology has been gained, in particular, much has been learnt about the genetic and phenotypic characteristics of malignant cells and the varied oncogenic signaling pathways involved in HL. Continued translational research is needed to improve the long-term survival and to lessen the toxicities associated with therapy. Furthermore, continued clinical-trial involvement by oncologists and patients is imperative to further advance the field of HL.

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare subtype of Hodgkin lymphoma that differs from classic Hodgkin lymphoma (cHL) with respect to histologic and clinical presentation. Because the prognosis of NLPHL in early unfavorable and advanced stages is similar to that of cHL, treatment is similar. In contrast, early favorable-stage NLPHL has a better prognosis than cHL. Thus, NLPHL in early favorable stages might be treated with reduced-intensity programs without compromising cure rates. Because involved-field radiotherapy alone seems to be as effective as extended-field radiotherapy or combined modalities, it has been adopted by the German Hodgkin Study Group and the European Organisation for Research and Treatment of Cancer as the treatment of choice for stage IA NLPHL. Now that efficacy of the monoclonal antibody rituximab has been shown in relapsed NLPHL, its use in the first-line treatment of NLPHL is under investigation.

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.

Purpose To investigate whether combined-modality treatment (CMT) with two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) followed by extended-field radiotherapy (EF-RT) is superior to EF-RT alone in patients with early favorable Hodgkin's lymphoma (HL). Patients and Methods Between 1993 and 1998, 650 patients with newly diagnosed, histology-proven HL in clinical stages IA to IIB without risk factors were enrolled onto this multicenter study and randomly assigned to receive 30 Gy EF-RT plus 10 Gy to the involved field (arm A) or two cycles of ABVD followed by the same radiotherapy (arm B). Results At a median observation time of 87 months, there was no difference between treatment arms in terms of complete response rate (arm A, 95%; arm B, 94%) and overall survival (at 7 years: arm A, 92%; arm B, 94%; P = .43). However, freedom from treatment failure was significantly different, with 7-year rates of 67% in arm A (95% CI, 61% to 73%) and 88% in arm B (95% CI, 84% to 92%; P ≤ .0001). This was due mainly to significantly more relapses after EF-RT only (arm A, 22%; arm B, 3%). No patient treated with CMT experienced relapse before year 3. Relapses were treated mainly with bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone, or with the combination cyclophosphamide, vincristine, procarbazine, and prednisone/ABVD; treatment of relapse was significantly more successful in arm A than in arm B (P = .017). In total, there were 39 second malignancies, with 21 in arm A and 18 in arm B, respectively. The incidence was approximately 0.8% per year during years 2 to 9 and was highest in older patients (P < .0001) and those with “B” symptoms (P = .012). Conclusion CMT consisting of two cycles of ABVD plus EF-RT is more effective than EF-RT alone.

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.

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.

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.

Mittels prospektiv-randomisierter klinischer Studien der Deutschen Hodgkin Studiengruppe (DHSG) konnten in den letzten 40 Jahren systematisch Verbesserungen im Bereich von Strahlen- und Polychemotherapie umgesetzt werden. So entwickelte sich das Hodgkin-Lymphom von einer unheilbaren malignen Erkrankung zu derjenigen Malignitat mit der besten Prognose in der Erwachsenenonkologie. Neben den Verbesserungen der Therapieergebnisse konnten auch diagnostische Standards weiter entwickelt werden. Wesentliches Strukturmerkmal der DHSG ist die multidisziplinare Zusammenarbeit von internistischer Onkologie, Strahlentherapie, diagnostischer Radiologie, Nuklearmedizin und Biostatistik. In 5 aufeinander folgenden Studiengenerationen zur Primartherapie des Hodgkin-Lymphoms konnte durch intensive Kooperation verschiedener Fachbereiche auch ein Beitrag zur Qualitatssicherung geleistet werden.

Das maligne Hodgkin-Lymphom (HL) ist durch die fortschreitende Entwicklung der Behandlungsintensitat eine heilbare Erkrankung geworden. Allerdings kann dieses aggressive Vorgehen, das haufig Strahlen- und Chemotherapie kombiniert, u. a. sekundare Neoplasien zur Folge haben. Die Deutsche Hodgkin-Lymphom Studiengruppe fuhrte 3 Studiengenerationen mit 5411 Patienten in allen Stadien des HL durch. Insgesamt konnten 127 Patienten mit soliden Tumoren identifiziert werden (kumulatives Risiko 2%, mediane Nachbeobachtung 72 Monate), unter denen vor allem Bronchialkarzinome (23,6%) und kolorektale Adenokarzinome (20,5%) am haufigsten waren. Eine sekundare akute myeloische Leukamie trat bei 36 Patienten auf, weitere 10 zeigten ein myelodysplastisches Syndrom (kumulatives Risiko 1%, mediane Nachbeobachtung 55 Monate). Bei 52 Patienten entwickelte sich ein Non-Hodgkin-Lymphom (NHL; kumulatives Risiko 0,9%, mediane Nachbeobachtung 46 Monate). Insgesamt entwickelte sich bei 3,9% der HL-Patienten nach einer erfolgreichen Chemo- und/oder Radiotherapie eine Sekundarneoplasie. Die NHL konnen besondere Schwierigkeiten in der Abgrenzung zum initialen HL bieten, weshalb bei jedem fraglichen Rezidiv eine vollstandige histomorphologische Abklarung erfolgen muss.

Purpose Several scores have described sex as a prognostic factor in patients with Hodgkin's lymphoma (HL). However, little is known how sex-specific factors influence treatment outcome. We systematically investigated sex differences with regard to pretreatment characteristics and therapy-related variables, and examined their influence on the outcome of HL patients. Patients and Methods This analysis comprises 4,626 HL patients of all prognostic risk groups who were enrolled onto the multicenter studies HD4 to HD9 of the German Hodgkin Study Group. At 5.5 years, 2,050 female and 2,576 male patients were analyzed. Results Male and female patients had similar prognostic factors. There was more acute chemotherapy-related hematotoxicity in women, especially more severe leucopenia (WHO grade 3/4, 69.9% female and 55.2% male; P < .0001). Importantly, this did not translate into more infections. Female patients had similar response rates but fewer relapses and deaths, leading to a significantly better freedom from treatment failure (FFTF; at 66 months, 81% female [95% CI, 79% to 82%] and 74% male [95% CI, 72% to 76%]). Severe leucopenia during chemotherapy was strongly associated with better FFTF, both for males and females. In addition, when only those patients who developed severe leucopenia within the first two cycles of chemotherapy were included, the factor maintained its protective role. Conclusion The protective role of severe leucopenia suggests the testing of a more individualized therapy. In future trials, this therapy may be tailored in a response-adapted manner depending on the individual toxicity profile within the first cycles.

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.

According to the WHO classification, Hodgkin's lymphoma (HL) is subdivided into a classical variant and a nodular lymphocyte predominant variant which are characterized by the presence of Hodgkin's and Reed-Sternberg (H-RS) cells or lymphocytic and histiocytic (L&H) cells, respectively. This article reviews genetic characteristics and transcriptional changes of H-RS and L&H cells, including recent knowledge about transforming mechanisms and signaling pathways that contribute to the antiapoptotic phenotype displayed by H-RS and L&H cells. We also discuss major cellular and molecular mediators contributing to the establishment and maintenance of a reactive background in HL-affected tissues. We believe that an in-depth understanding of the pathogenesis of HL will eventually lead to the development of novel biologically based therapeutic strategies in the near future.

Die Prognose fur Patienten mit Hodgkin-Lymphom hat sich in den letzten 30 Jahren erheblich verbessert. In Abhangigkeit von dem Stadium bei Erstdiagnose konnen mittlerweile Heilungsraten von uber 80% erzielt werden. Moderne Therapiestrategien sollen insbesondere das Auftreten von therapiebedingten Spatfolgen bei gleichzeitiger Beibehaltung der guten Tumorkontrolle verringern. Offene Fragen in den fortgeschrittenen Stadien betreffen die optimale Zyklusanzahl bei einer effektiven Chemotherapie und die Notwendigkeit einer zusatzlichen Bestrahlung. Der Stellenwert der PET bezuglich der Unterscheidung zwischen residualen narbigen Veranderungen und aktivem Lymphomgewebe nach intensiver Chemotherapie wird in der aktuellen Studie (HD15) untersucht.

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.

Initial staging of Hodgkin's disease is crucial to determine the location and extent of disease, and is the hallmark for the choice of treatment. At present, the established radiological technique for staging Hodgkin's disease is computed tomography (CT). Modern multidetector row CT scanners allow fast imaging from the scull base to the groins during a single breath hold with a spatial resolution of approximately 1 mm. Both, nodal and extranodal involvement of Hodgkin's disease can be diagnosed with CT. Magnetic resonance (MR) imaging is another useful cross-sectional imaging modality for staging Hodgkin's disease. The development of fast MR imaging techniques has considerably reduced imaging time without compromising the quality of MR images. As a consequence, MR imaging is now considered to be as diagnostic as CT for staging Hodgkin's disease. The excellent soft-tissue contrast and the lack of exposure to ionizing radiation are the main advantages of MR imaging. For the detection of extranodal Hodgkin's disease, MR imaging is superior to assess involvement of the brain, the spinal cord and bone marrow; while CT allows excellent evaluation of lung disease. Common major problems in staging Hodgkin's disease are still the detection of nodal involvement in normal sized lymph nodes and residual tumor masses after therapy. In the future, newly developed lymphotropic contrast agents for MR imaging might be helpful to answer these questions.

Introduction: Lymphocyte predominant Hodgkin's lymphoma (LPHL) differs in histological and clinical presentation from classical Hodgkin's lymphoma (cHL). Treatment of LPHL patients using standard Hodgkin's lymphoma (HL) protocols leads to complete remission (CR) in more than 95% of patients. However, differences in terms of relapse rates, survival and freedom from treatment failure (FFTF) between LPHL and cHL patients were suggested by a recent intergroup analysis. To obtain a more comprehensive picture, we reviewed all LPHL-cases registered in the GHSG database and compared patient characteristics and treatment outcome with cHL patients. Patients and methods: We retrospectively analyzed 8298 HL patients treated within the GHSG trials (HD4–HD12): 394 LPHL patients and 7904 cHL patients. From 394 LPHL patients 63% were in early stage, 16% in intermediate and 21% in advanced stage of disease. Of the 7904 cHL patients analyzed, 22% were in early, 39% in intermediate and 39% in advanced stages. About 9% of LPHL patients had B symptoms compared to 40% in cHL patients. Results: About 91% LPHL vs. 86% cHL patients in early stages, 86% vs. 83% in intermediate and 79% vs. 75% in advanced stages reached CR/CRu. Additional analysis for LPHL IA patients showed 98% CR/CRu after extended field, 100% after involved field (IF) and 98% CR/CRu after combined modality treatment. About 0.3% LPHL patients developed progressive disease (PD) compared to 3.7% cHL patients. The relapse rate of LPHL patients was very similar to cHL (8.1% vs. 7.9%). There were 2.5% secondary malignancies in LPHL and 3.7% in cHL patients. About 4.3% LPHL patients and 8.8% cHL patients died. The FFTF rates for LPHL and cHL patients at a median observation of 41 or 48 months were 92% and 84%, respectively. The OS for LPHL and cHL patients was 96% and 92%, respectively. Conclusion: The cHL patients present more frequently with advanced stages and B symptoms compared to LPHL patients. There was no difference in treatment outcome in terms of CR/CRu, PD and mortality between LPHL and HL. Surprisingly, there were also no differences in patients with relapse.

The Sixth International Symposium on Hodgkin's disease was held in Cologne, Germany, between September 18 and 21, 2004, organized by the German Hodgkin Study Group (GHSG) and chaired by Volker Diehl. Since 1987 the international symposia were held at regular intervals in Cologne with the aim to facilitate international cooperation and to bring together new scientific and clinical results reached in the field of Hodgkin's disease. The expanding number of participants from about 300 attendees at the first symposium to almost 800 from 48 countries at the Sixth International Symposium indicates the increasing importance of this meeting. For the second time a patient seminar with more than 350 attendees has been organized. This sixth meeting was going to be unique, since the GHSG celebrated its 25th anniversary and honored Volker Diehl, the group's founder in recognition of his work during more than 25 yr. The symposium was held at the University of Cologne's main building, creating a special, scientific and familiar atmosphere. Throughout the symposia carried out by the GHSG, preclinical and clinical several topics have always been of basic interest and have provided a basis for discussion and scientific exchange.

A workshop, sponsored by the Rockefellar Foundation, was held between 9 to 16 July, 2003 to devise strategies to reduce mortality and improve quality of life of long-term survivors of Hodgkin's disease. Participants were selected for their clinical and research background on late effects after Hodgkin's disease therapy. Experts from both developed and developing nations were represented in the workshop, and efforts were made to ensure that the proposed strategies would be globally applicable whenever possible. The types of late complications, magnitude of the problem, contributing risk factors, methodology to assess the risk, and challenges faced by developing countries were presented. The main areas of late effects of Hodgkin's disease discussed were as follows: second malignancy, cardiac disease, infection, pulmonary dysfunction, endocrine abnormalities, and quality of life. This report summarizes the findings of the workshop, recommendations, and proposed research priorities in each of the above areas.

Hodgkin's Lymphoma (HL) has developed to one of the best curable human cancers and overall about 80% of patients experience long-term disease free survival. Therefore, current treatment strategies aim at further improving treatment outcome, thereby trying to by minimize therapy-induced complications, such as infertility, cardiopulmonary toxicity, and secondary malignancies. Ongoing trials investigate a reduction of chemotherapy in terms of dose or cycles given, and the application of lower radiation doses and smaller radiation fields. For patients with a specific high-risk profile, new approaches with more intense drug combinations are currently being investigated. Moreover, the advent of effective salvage high-dose therapy for relapsed disease and a better understanding of prognostic factors have further improved the management of HL. Here, we summarize current strategies of the German Hodgkin Study Group (GHSG) in diagnostics and treatment of primary and relapsed HL, together with recent approaches for specific subgroups of HL patients.

Patients with primary progressive or refractory Hodgkin's disease (HD) or aggressive non-Hodgkin's lymphoma (NHL) have a particularly poor prognosis. Here we report the results of autologous tandem transplantation in these patients. Patients aged 18-55 years with primary progressive or refractory relapsed HD and aggressive NHL were included. Patients received high-dose etoposide (2000 mg/m(2)) followed by peripheral blood stem cell harvest (PBSC). The first high-dose chemotherapy (TMC) consisted of thiotepa (750 mg/m(2)), mitoxantrone (40 mg/m(2)), and carboplatin (990 mg/m(2)). Patients with no change (NC), partial remission (PR), or complete remission (CR) after TMC then received BEAM with carmustine (300 mg/m(2)), etoposide (1200 mg/m(2)), cytarabine (1600 mg/m(2)), and melphalan (140 mg/m(2)). Patients with bulky disease (5 cm) or residual lymphoma received involved field radiotherapy. Twenty-five patients were included (HD=10, NHL=15, median age 34 years). Two patients with HD achieved a CR and five patients a PR [response rate (RR) 70%]. Three patients (30%) experienced treatment failure including two deaths due to peritransplant complications. Five patients with aggressive NHL were in CR and two patients in PR (RR 46%). Of the eight patients (56%) with treatment failure, three had progressive disease and five died from peritransplant complications. Freedom from treatment failure (FFTF) and overall survival (OS) for all patients after 12 months was 28% and 40%, respectively. Tandem HDCT followed by autologous stem cell transplantation (ASCT) offers a chance of cure in these poor prognostic patients, but is associated with risks.

Patients with early stage favorable Hodgkin's disease who relapse after extended field radiotherapy have satisfactory results. We retrospectively analysed patients with relapsed HD after initial radiation therapy alone to determine treatment outcome and prognostic factors. Nine-hundred and forty five patients in localized stages without risk factors received either 40 Gy extended field RT or 30 Gy EF RT followed by an additional 10 Gy to involved lymph node regions. 107 patients relapsed and received salvage therapy. Characteristics of the 107 patients at relapse were as follows: median age was 34 years (range 18--75) with relapse occuring at a median of 19 months (range 4--98 months), 31% were female. The majority of patients (93%) were treated with conventional chemotherapy. Sixty-nine percent were treated with COPP/ABVD like regimens, 21% with BEACOPP, and 3% received various other regimens. Seven percent were treated with radiotherapy alone. Complete remission was achieved in 87% of all salvaged patients. The median follow-up after relapse was 45 months. FF2F (freedom from second treatment failure) and OS (overall survival) were 81% and 89%, respectively. In multivariate analysis age was the major prognostic factor for FF2F and OS (p0.0001, for both). Further independent prognostic factors were B symptoms (p=0.05) and salvage chemotherapy (p=0.03) for FF2F, and B symptoms (p=0.03) and extranodal involvement (p=0.02) for OS. The long-term outcome of patients relapsing after EF RT is excellent. Age, B symptoms, extranodal involvement and salvage chemotherapy were identified as prognostic factors for second relapse and survival.

Patients have previously been described who showed clinical signs and symptoms suggesting essential thrombocythemia (ET), but later transformed to polycythemia vera (PV). From a series of 344 patients with a sustained borderline to moderate erythrocytosis, 44 failed to conform initially with the diagnostic criteria of the WHO for PV, because of their low hemoglobin level. Twenty-three patients of this group presented with a thrombocytosis exceeding 600 × 109/l and therefore suggested ET, but later developed full-blown PV. For comparison we investigated also 164 patients with manifest PV, 90 patients with ET and 22 patients with reactive thrombocytosis (Th). The histopathology of initial PV was evaluated by stepwise discriminant analysis of 17 standardized features. Quantity and left shifting of erythro- and granulopoiesis, giant forms and naked nuclei of megakaryocytes, cellularity and reticulin fibers proved to exert a significant relevance concerning differentiation from true ET and Th. In conclusion, initial PV with thrombocytosis is characterized by a special pattern of BM histopathology. Therefore, so-called masked PV in patients with ET or simultaneous PVR-1 gene expression and endogeneous erythroid colony growth in ET patients are probably in keeping with initial PV mimicking ET.

The aim of the present study was to evaluate the feasibility and efficacy of the intensified induction chemotherapy regimen ACOMED for patients with aggressive non-Hodgkin's lymphoma (NHL). Untreated adult patients with aggressive NHL, presenting with Ann Arbour stage II-IV disease or stage I with bulky disease, and with at least one of the following risk factors: age > 60 years, advanced disease, elevated serum lactate dehydrogenase level, Eastern Cooperative Oncology Group (ECOG) performance status >or= 2, presence of extranodal sites of disease and bulky disease, were treated with the ACOMED regimen consisting of 4-6 cycles of adriamycin 25 mg/m(2) i.v. on days 4-5, cyclophosphamide 250 mg/m(2) i.v. on days 1-5, vincristine 2 mg i.v. absolute on day 1, methotrexate 500 mg/m(2) i.v. on day 1 with leucovorin-rescue after 24 h 30 mg/m(2) i.v. and 3 x 15 mg p.o., etoposide 100 mg/m(2) i.v. on days 3-5, dexamethasone 10 mg/m(2) p.o. on days 1-5 and granulocyte colony-stimulating factor support, repeated on day 21. Twenty-two patients were treated within this study at a single center. After 4-6 cycles of ACOMED followed by additional involved field radiotherapy in 18 patients, the complete and overall response rates were 86% (19 of 22 patients) and 95% (21 of 22 patients), respectively. After a median observation time of 10 years and 2 months, 16/22 (73%) patients are alive in continuous complete response without evidence of any late toxicities. ACOMED followed by involved field radiation presents a highly effective regimen for remission induction and long-term survival in patients with aggressive NHL, and merits further investigation.

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.

Infradiaphragmatic Hodgkin lymphoma (IDH) accounts for 4-13% of cases of stage I-II Hodgkin lymphoma (HD). It has been associated with distinct pre-treatment characteristics and outcomes when compared with supradiaphragmatic HD (SDH). The comparison of IDH vs SDH can only be made in early and intermediate stages (I-II), such a comparison is not possible for advanced stages (III-IV). This study retrospectively compared two groups of 1013 patients with stage I-II SDH and 101 patients with IDH (10%). These two sub-groups of patients were treated in 1988-1993 in 2 prospective randomized clinical trials in Germany for early and intermediate stages of Hodgkin lymphoma. IDH-patients were older (median 39 vs 31 years; p < 0.001), predominantly male (73% vs 52%; p < 0.001) and more often had involvement of 3 lymph node areas (LNA) (80% vs 55%; p < 0.001). Histology in IDH was more likely to be mixed cellularity (46.5% vs 23.6%, p < 0.001) or lymphocyte predominant (20 vs 10%, p = 0.003) and less likely nodular sclerosis (25% vs 63%, p < 0.001). In early-stage unfavorable disease, IDH was associated with a higher treatment failure rate (unadjusted hazard ratio 2, 95% CI, 1.3-3.4; p = 0.003). After controlling for age, sex, stage, histology, B-symptoms and involvement of 3 LNA, the adjusted hazard ratio was 1.25 (95% CI, 0.65-2.4; p = 0.51) so that IDH was no longer associated with a statistically significant treatment failure rate. Poorer outcomes with IDH as compared to SDH are attributable to its association with known adverse prognostic risk factors, but IDH, in itself, is not an independent adverse prognostic factor for treatment failure or survival.