Horst Müller

Dose Intensity of Chemotherapy in Patients With Relapsed Hodgkin's Lymphoma

PURPOSE High-dose chemotherapy (HDCT) followed by autologous stem-cell transplantation (PBSCT) has become the standard treatment for patients with relapsed Hodgkins lymphoma (HL). The intensity of treatment needed is unclear. This European intergroup study evaluated the impact of sequential high-dose chemotherapy (SHDCT) before myeloablative therapy. PATIENTS AND METHODS Patients with histologically confirmed, relapsed HL were treated with two cycles of dexamethasone, cytarabine, and cisplatin, and those without disease progression were randomly assigned. In the standard arm (A), patients received myeloablative therapy with carmustine, BEAM (carmustine, etoposide, cytarabine, and melphalan) followed by PBSCT. Patients in the experimental arm (B) also received sequential cyclophosphamide, methotrexate, and etoposide in high-doses before BEAM. Freedom from treatment failure (FFTF) was the primary end point. Remission rates, overall survival (OS), and toxicity of treatment were secondary end points. RESULTS From a total of 284 patients included, 241 responding patients were randomly assigned after two cycles of dexamethasone, cytarabine, and cisplatinum. Patients treated in arm B had longer treatment duration and experienced more toxicity and protocol violations (P < .05). Mortality was similar in both arms (20% and 18%). With a median observation time of 42 months, there was no significant difference in terms of FFTF (P = .56) and OS (P = .82) between arms. FFTF at 3 years was 62% (95% CI, 56% to 68%) and OS was 80% (95% CI, 75% to 85%). Patients with stage IV, early relapse, multiple relapse, anemia, or B symptoms had a higher risk of recurrence (P < .001). CONCLUSION Compared with conventional high-dose chemotherapy, additional SHDCT is associated with more adverse effects and does not improve the prognosis of patients with relapsed HL.

Hodgkin's Lymphoma in Adolescents Treated With Adult Protocols: A Report From the German Hodgkin Study Group

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

Long-Term Follow-Up of Contemporary Treatment in Early-Stage Hodgkin Lymphoma: Updated Analyses of the German Hodgkin Study Group HD7, HD8, HD10, and HD11 Trials

Purpose Combined-modality treatment is widely considered the standard of care in early-stage Hodgkin lymphoma (HL), and treatment intensity has been reduced over the last years. Long-term follow-up is important to judge both efficacy and safety of the different therapies used. Patients and Methods We analyzed updated follow-up data on 4,276 patients treated within the German Hodgkin Study Group trials HD7 and HD10 for early-stage favorable HL and HD8 and HD11 for early-stage unfavorable HL between 1993 and 2003. Results In HD7 (N = 627; median follow-up, 120 months), combined-modality treatment was superior to extended-field radiotherapy (RT), with 15-year progression-free survival (PFS) of 73% versus 52% (hazard ratio [HR], 0.5; 95% CI, 0.3 to 0.6; P < .001), without differences in overall survival (OS). In HD10 (N = 1,190; median follow-up, 98 months), noninferiority of two cycles of doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD) plus 20 Gy involved-field (IF)-RT to more intensive four cycles of ABVD plus 30 Gy IF-RT was confirmed with 10-year PFS of 87% each (HR, 1.0; 95%, 0.6 to 1.5) and OS of 94% each (HR, 0.9; 95% CI, 0.5 to 1.6), respectively. In both trials, no differences in second neoplasias were observed. In HD8 (N = 1,064; median follow-up, 153 months), noninferiority of involved-field RT to extended-field RT regarding PFS was confirmed (HR, 1.0; 95% CI, 0.8 to 1.2). In HD11 (N = 1,395; median follow-up, 106 months), superiority of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone at baseline over ABVD was not observed. After BEACOPPbaseline, 20 Gy IF-RT was noninferior to 30 Gy (10-year PFS, 84% v 84%; HR, 1.0; 95% CI, 0.7 to 1.5). In contrast, PFS was inferior in ABVD-treated patients receiving 20 Gy instead of 30 Gy IF-RT (10-year PFS, 76% v 84%; HR, 1.5; 95% CI, 1.0 to 2.1). No differences in OS or second neoplasias were observed in in both trials. Conclusion Long-term follow-up data of the four randomized trials largely support the current risk-adapted therapeutic strategies in early-stage HL. Nevertheless, continued follow-up is necessary to assess the long-term safety of currently applied therapeutic strategies.

Risk factors and a prognostic score for survival after autologous stem-cell transplantation for relapsed or refractory Hodgkin lymphoma

Background Novel agents are changing the treatment of relapsed or refractory Hodgkin lymphoma (HL). Nevertheless, high-dose chemotherapy and autologous stem-cell transplantation (ASCT) are considered standard of care in eligible patients. To identify patients who could benefit most from novel therapeutic approaches, we investigated a comprehensive set of risk factors (RFs) for survival after ASCT. Methods In this multinational prognostic multivariable modeling study, 23 potential RFs were retrospectively evaluated in HL patients from nine prospective trials with multivariable Cox proportional hazards regression analyses (part I). The resulting prognostic score was then validated in an independent clinical sample (part II). Results In part I, we identified 656 patients treated for relapsed/refractory HL between 1993 and 2013 with a median follow-up of 60 months after ASCT. The majority of potential RFs had significant impact on progression-free survival (PFS) with hazard ratios (HR) ranging from 1.39 to 2.22. The multivariable analysis identified stage IV disease, time to relapse ≤3 months, ECOG performance status ≥1, bulk ≥5 cm and inadequate response to salvage chemotherapy [<partial remission by computed tomography (CT)] as significant and non-redundant RFs for PFS. A risk score composed of these equally weighed RFs was significantly prognostic for PFS (HR = 1.67 for each additional RF; P < 0.0001). Validation in an independent sample of 389 patients treated in different clinical settings with evaluation of response to salvage therapy by functional imaging instead of CT confirmed the excellent discrimination of risk groups and significant prognostication of PFS and overall survival (OS) after ASCT (HR = 1.70 and HR = 1.63, respectively; P < 0.0001). Conclusions Based on this large study (n = 1045), precise and valid risk prognostication in HL patients undergoing ASCT can be achieved with five easily available clinical RFs. The proposed prognostic score hence allows reliable stratification of patients for innovative therapeutic approaches in clinical practice and future trials. Registered trials GHSG HD10 NCT00265018, HD11 NCT00264953, HD12 NCT00265031, HD13 ISRCTN63474366, HD14 ISRCTN04761296, HD15 ISRCTN32443041 and HDR2 NCT00025636.

Prognostic relevance of DHAP dose-density in relapsed Hodgkin lymphoma: an analysis of the German Hodgkin-Study Group

Abstract Only 50% of patients with relapsed Hodgkin lymphoma (HL) can be cured with intensive induction chemotherapy, followed by high-dose chemotherapy (HDCT) and autologous stem cell transplant (ASCT). Based on the results of the HDR2 trial two courses of DHAP and subsequent HDCT/ASCT are the current standard of care in relapsed HL. In order to assess the prognostic relevance of DHAP dose density, we performed a retrospective multivariate analysis of the HDR2 trial (N = 266). In addition to four risk factors (early or multiple relapse, stage IV disease or anemia at relapse, and grade IV hematotoxicity during the first cycle of DHAP) a delayed start of the second cycle of DHAP > day 22 predicted a significantly poorer progression-free survival (PFS, p = 0.0356) and overall survival (OS, p = 0.0025). In conclusion, our analysis strongly suggests that dose density of DHAP has a relevant impact on the outcome of relapsed HL patients.

The Effect of Specialized Cancer Treatment Centers on Treatment Efficacy in Hodgkin's Lymphoma

BACKGROUND The presumed benefits of centralization and minimum case numbers often guide health-policy decisions, but these benefits remain inadequately documented, particularly in oncology. In this study, we aim to measure the effect of the type of treatment center and/or the number of patients treated in it on the outcome of patients with Hodgkins lymphoma. METHODS From 1988 to 2002, 8121 patients with newly diagnosed Hodgkins lymphoma were treated in Germany in multicenter randomized and controlled trials (RCTs) of the German Hodgkin Study Group (GHSG). Center-related effects on progression-free survival (PFS) were assessed univariately with Kaplan-Meier plots and log-rank tests, as well as with a multivariate Cox regression model. RESULTS The 500 participating centers in Germany included 52 university hospitals, 304 non-university hospitals, and 144 medical practices specializing in hematology and oncology. No significant differences in PFS were found between patients from centers with high or low case numbers (5-year-PFS: 78.7% and 78.6% for centers with fewer than 50 and more than 50 patients, respectively) or from different types of centers [5-year-PFS: university hospital, 77.7%; non-university hospital, 79.4%; practice, 79.8%]. Even after statistical controls for the effect of other known and unknown prognostic factors and validation in further datasets, no center effects were found. CONCLUSIONS The type of center and the minimum number of patients treated in a center have no impact on the treatment outcome of patients with Hodgkins lymphoma in Germany. In all GHSG centers, regardless of type, the quality standards for successful treatment are apparently met on all levels of patient care.

Construct Validity of the Questionnaire on Experience with Skin Complaints (Short Form)

Abstract. Introduction: Feelings of stigmatization can strongly influence quality of life in individuals with chronic skin diseases. The Short-Form of the Questionnaire on Experience with Skin Complaints (SF-QES) differentiates four factors of stigmatization: self-esteem and retreat, experienced refusal, concealment, and composure. The current study aimed to investigate the construct validity of the SF-QES. Method: The analysis was based on the complete SF-QES records of a clinical psoriasis trial, which yielded 1,005 records at baseline, 1,010 records at the end of therapy, and 885 and 827 records, respectively, at two follow-ups. Factor analyses and corresponding structural equation models (SEMs) using robust maximum likelihood estimation (RML) were applied. Additionally, the responsiveness of the scales to judgments of treatment success and two different interventions were compared. Results: The factor analyses provided results that widely agreed with the supposed four factors. SEM, however, showed mod...

Application of the German SF-36 in hospitals: overestimations in the psycho-social scales.

The well-known SF-36 is the most widely used generic instrument to quantify health-related quality of life (Ware 2000; Ware et al. 1993). Although it was originally developed for epidemiological research, it is increasingly applied in in-patient settings. However, results from in-patients who are requested to fi ll out the SF-36 at the end of their hospital stay show high non-response rates for the items of three scales (Zwingmann et al. 1998). Since some of the terms in the German SF-36 (Bullinger & Kirchberger 1998) such as “at home” or “at work” do not make sense in a hospital setting, this is hardly surprising. To eliminate this problem we developed a slightly modifi ed version of the SF-36. The psychometric evaluation of this modifi ed SF-36 yielded favorable results (Müller et al. 2001). However, we also observed a small but statistically signifi cant response shift bias yielding higher SF-36 scores in the hospital environment. It was not established whether this is unique to the original SF-36 or whether the modifi ed instrument version is equally sensitive to this response shift bias. The present paper examines this issue.

Metabolic Tumour Volume for Response Prediction in Advanced-Stage Hodgkin Lymphoma

18F-FDG PET/CT for staging Hodgkin lymphoma may allow for accurate and reliable assessment of the metabolic tumor volume (MTV) as a baseline risk factor. Our aim was to analyze the prognostic impact of MTV measurements obtained by different means in advanced-stage Hodgkin lymphoma patients treated within the German Hodgkin Study Group HD18 trial. Methods: Within HD18, 310 patients underwent 18F-FDG PET/CT scanning for staging, which was available to the central review panel for quantitative analysis. We calculated the MTV by 4 different thresholding methods and performed receiver-operating-characteristic analysis to evaluate the potential for prediction of early response determined by PET after 2 cycles (PET-2) of dose-escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (eBEACOPP). Logistic regression was used to evaluate its prognostic value concerning progression-free survival and overall survival. Results: All of the different MTV calculations predicted PET-2 response to a moderate and comparable degree (area under the curve, 0.62–0.63; P = 0.01–0.06). With none of the measuring methods did the receiver-operating-characteristic curves point to any unique cutoffs; rather, a wide range of possible cutoffs was indicated. None of the MTV measurements was prognostic for progression-free survival (hazard ratio, 1.2–1.5; P = 0.15–0.52) or overall survival (hazard ratio, 1.0–1.5; P = 0.95–0.27). Conclusion: Baseline MTV as determined by different means is a predictive factor for early response to eBEACOPP after 2 cycles. However, value as a prognostic factor after a highly effective PET-2–adapted treatment strategy could not be observed.

Hodgkin Lymphoma has a seasonal pattern of incidence and mortality that depends on latitude

Seasonal variations in incidence and mortality after a Hodgkin lymphoma (HL) diagnosis have been previously described with partly conflicting results. The goal of this analysis is to provide a comprehensive analysis of these seasonal variations. In total, 41,405 HL cases diagnosed between 1973 and 2012 in the 18 Surveillance, Epidemiology, and End Results registries were included. Cosinor analysis and Cox proportional-hazards models were employed to analyze seasonality of incidence and mortality, respectively. HL shows a sinusoid seasonal incidence pattern (p < 0.001). Estimated incidence in March is 15.4% [95%-CI: 10.8-20.0] higher than in September. This sinusoid pattern is more pronounced at higher latitudes (p = 0.023). The risk of dying within the first three years after a HL diagnosis in winter is significantly increased compared to a HL diagnosis in summer at higher latitudes (HR = 1.082 [95%-CI: 1.009-1.161], p = 0.027). Furthermore, increasing northern latitude increases the additional mortality risk conferred by a diagnosis in winter (pinteraction0.033). The seasonality patterns presented here provide epidemiological evidence that Vitamin D might play a protective role in HL. Further evidence on the direct association between Vitamin D levels and the clinical course of HL needs to be collected to advance the understanding of the role of Vitamin D in HL.