First-line allogeneic hematopoietic stem cell transplantation of HLA-matched sibling donors compared with first-line ciclosporin and/or antithymocyte or antilymphocyte globulin for acquired severe aplastic anemia.

BACKGROUND: Acquired severe aplastic anemia is a rare and potentially fatal disease, which is characterized by hypocellular bone marrow and pancytopenia. The major signs and symptoms are severe infections, bleeding, and exhaustion. First-line allogeneic hematopoietic stem cell transplantation (HSCT) of a human leukocyte antigen (HLA)-matched sibling donor (MSD) is a treatment for newly diagnosed patients with severe aplastic anemia. First-line treatment with ciclosporin and/or antithymocyte or antilymphocyte globulin (as first-line immunosuppressive therapy) is an alternative to MSD-HSCT and is indicated for patients where no MSD is found. OBJECTIVES: To evaluate the effectiveness and adverse events of first-line allogeneic hematopoietic stem cell transplantation of HLA-matched sibling donors compared to first-line immunosuppressive therapy including ciclosporin and/or antithymocyte or antilymphocyte globulin in patients with acquired severe aplastic anemia. SEARCH METHODS: We searched the electronic databases MEDLINE (Ovid), EMBASE (Ovid), and The Cochrane Library CENTRAL (Wiley) for published articles from 1946 to 22 April 2013. Further searches included trial registries, reference lists of recent reviews, and author contacts. SELECTION CRITERIA: The following prospective study designs were eligible for inclusion: randomized controlled trials (RCTs) and non-randomized controlled trials if the allocation of patients to treatment groups was consistent with 'Mendelian randomization'. We included participants with newly diagnosed severe aplastic anemia who received MSD-HSCT or immunosuppressive therapy without prior HSCT or immunosuppressive therapy, and with a minimum of five participants per treatment group. We did not apply limits on publication year or languages. DATA COLLECTION AND ANALYSIS: Two review authors abstracted the data on study and patient characteristics and assessed the risk of bias independently. We resolved differences by discussion or by appeal to a third review author. The primary outcome was overall mortality. Secondary outcomes were treatment-related mortality, graft failure, no response to first-line immunosuppressive therapy, graft-versus-host-disease (GVHD), relapse after initial successful treatment, secondary clonal and malignant disease, health-related quality of life, and performance score. MAIN RESULTS: We identified three trials that met the inclusion criteria. None of these trials was a RCT. 302 participants are included in this review. The three included studies were prospectively conducted and had features consistent with the principle of 'Mendelian randomization' as defined in the present review. All studies had a high risk of bias due to the study design. All studies were conducted more than 10 years ago and may not be applicable to the standard of care of today. Primary and secondary outcome data showed no statistically significant difference between treatment groups. We present results for first-line allogeneic hematopoietic stem cell transplantation of an HLA-matched sibling donor, which we denote as the MSD-HSCT group, versus first-line treatment with ciclosporin and/or antithymocyte or antilymphocyte globulin, which we denote as the immunosuppressive therapy group in the following section.The pooled hazard ratio for overall mortality for the MSD-HSCT group versus the immunosuppressive therapy group was 0.95 (95% confidence interval 0.43 to 2.12, P = 0.90, low quality evidence). Therefore, overall mortality was not statistically significantly different between the groups. Treatment-related mortality ranged from 20% to 42% for the MSD-HSCT group and was not reported for the immunosuppressive therapy group (very low quality evidence). The authors reported graft failure from 3% to 16% for the MSD-HSCT group and GVHD from 26% to 51% (both endpoints not applicable for the immunosuppressive therapy group, very low quality evidence). The authors did not report any data on response and relapse for the MSD-HSCT group. For the immunosuppressive therapy group, the studies reported no response from 15% (not time point stated) to 64% (three months) and relapse in one of eight responders after immunosuppressive therapy at 5.5 years (very low quality evidence). The authors reported secondary clonal disease or malignancies for the MSD-HSCT group versus the immunosuppressive therapy group in 1 of 34 versus 0 of 22 patients in one study and in 0 of 28 versus 4 of 86 patients in the other study (low quality evidence). None of the included studies addressed health-related quality of life. The percentage of the evaluated patients with a Karnofsky performance status score in the range of 71% to 100% was 92% in the MSD-HSCT group and 46% in the immunosuppressive therapy group. AUTHORS' CONCLUSIONS: There are insufficient and biased data that do not allow any conclusions to be made about the comparative effectiveness of first-line allogeneic hematopoietic stem cell transplantation of an HLA-matched sibling donor and first-line treatment with ciclosporin and/or antithymocyte or antilymphocyte globulin (as first-line immunosuppressive therapy). We are unable to make firm recommendations regarding the choice of intervention for treatment of acquired severe aplastic anemia.

Autologous hematopoietic stem cell transplantation following high dose chemotherapy for non-rhabdomyosarcoma soft tissue sarcomas.

BACKGROUND: Soft tissue sarcomas (STS) are a highly heterogeneous group of rare malignant solid tumors. Non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) comprise all STS except rhabdomyosarcoma. In patients with advanced local or metastatic disease, autologous hematopoietic stem cell transplantation (HSCT) applied after high-dose chemotherapy (HDCT) is a planned rescue therapy for HDCT-related severe hematologic toxicity. The rationale for this update is to determine whether any randomized controlled trials (RCTs) have been conducted and to clarify whether HDCT followed by autologous HSCT has a survival advantage. OBJECTIVES: To assess the effectiveness and safety of HDCT followed by autologous HSCT for all stages of non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) in children and adults. SEARCH METHODS: For this update we modified the search strategy to improve the precision and reduce the number of irrelevant hits. All studies included in the original review were considered for re-evaluation in the update. We searched the electronic databases CENTRAL (2012, Issue 11) in The Cochrane Library , MEDLINE and EMBASE (05 December 2012) from their inception using the newly developed search strategy. Online trials registers and reference lists of systematic reviews were searched. SELECTION CRITERIA: Terms representing STS and autologous HSCT were required in the title or abstract. In studies with aggregated data, participants with NRSTS and autologous HSCT had to constitute at least 80% of the data. Single-arm studies were included in addition to studies with a control arm because the number of comparative studies was expected to be very low. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted study data. Some studies identified in the original review were re-examined and found not to meet the inclusion criteria and were excluded in this update. For studies with no comparator group, we synthesized the results for studies reporting aggregate data and conducted a pooled analysis of individual participant data using the Kaplan-Meyer method. The primary outcomes were overall survival (OS) and treatment-related mortality (TRM). MAIN RESULTS: The selection process was carried out from the start of the search dates for the update. We included 57 studies, from 260 full text articles screened, reporting on 275 participants that were allocated to HDCT followed by autologous HSCT. All studies were not comparable due to various subtypes. We identified a single comparative study, an RCT comparing HDCT followed by autologous HSCT versus standard chemotherapy (SDCT). The overall survival (OS) at three years was 32.7% versus 49.4% with a hazard ratio (HR) of 1.26 (95% confidence interval (CI) 0.70 to 2.29, P value 0.44) and thus not significantly different between the treatment groups. In a subgroup of patients that had a complete response before treatment, OS was higher in both treatment groups and OS at three years was 42.8% versus 83.9% with a HR of 2.92 (95% CI 1.1 to 7.6, P value 0.028) and thus was statistically significantly better in the SDCT group. We did not identify any other comparative studies. We included six single-arm studies reporting aggregate data of cases; three reported the OS at two years as 20%, 48%, and 51.4%. One other study reported the OS at three years as 40% and one further study reported a median OS of 13 months (range 3 to 19 months). In two of the single-arm studies with aggregate data, subgroup analysis showed a better OS in patients with versus without a complete response before treatment. In a survival analysis of pooled individual data of 80 participants, OS at two years was estimated as 50.6% (95% CI 38.7 to 62.5) and at three years as 36.7% (95% CI 24.4 to 49.0). Data on TRM, secondary neoplasia and severe toxicity grade 3 to 4 after transplantation were sparse. The one included RCT had a low risk of bias and the remaining 56 studies had a high risk of bias. AUTHORS' CONCLUSIONS: A single RCT with a low risk of bias shows that OS after HDCT followed by autologous HSCT is not statistically significantly different from standard-dose chemotherapy. Therefore, HDCT followed by autologous HSCT for patients with NRSTS may not improve the survival of patients and should only be used within controlled trials if ever considered.

Autologous hematopoietic stem cell transplantation following high-dose chemotherapy for non-rhabdomyosarcoma soft tissue sarcomas.

BACKGROUND: Soft tissue sarcomas (STS) are a highly heterogeneous group of rare malignant solid tumors. Non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) comprise all STS except rhabdomyosarcoma. In patients with advanced local or metastatic disease, autologous hematopoietic stem cell transplantation (HSCT) applied after high-dose chemotherapy (HDCT) is a planned rescue therapy for HDCT-related severe hematologic toxicity. OBJECTIVES: To assess the effectiveness and safety of HDCT followed by autologous HSCT for all stages of soft tissue sarcomas in children and adults. SEARCH STRATEGY: We searched the electronic databases CENTRAL (The Cochrane Library 2010, Issue 2), MEDLINE and EMBASE (February 2010). Online trial registers, congress abstracts and reference lists of reviews were searched and expert panels and authors were contacted. SELECTION CRITERIA: Terms representing STS and autologous HSCT were required in the title, abstract or keywords. In studies with aggregated data, participants with NRSTS and autologous HSCT had to constitute at least 80% of the data. Comparative non-randomized studies were included because randomized controlled trials (RCTs) were not expected. Case series and case reports were considered for an additional descriptive analysis. DATA COLLECTION AND ANALYSIS: Study data were recorded by two review authors independently. For studies with no comparator group, we synthesised results for studies reporting aggregate data and conducted a pooled analysis of individual participant data using the Kaplan-Meyer method. The primary outcomes were overall survival (OS) and treatment-related mortality (TRM). MAIN RESULTS: We included 54 studies, from 467 full texts articles screened (11.5%), reporting on 177 participants that received HSCT and 69 participants that received standard care. Only one study reported comparative data. In the one comparative study, OS at two years after HSCT was estimated as statistically significantly higher (62.3%) compared with participants that received standard care (23.2%). In a single-arm study, the OS two years after HSCT was reported as 20%. In a pooled analysis of the individual data of 54 participants, OS at two years was estimated as 49% (95% CI 34% to 64%). Data on TRM, secondary neoplasia and severe toxicity grade 3 to 4 after transplantation were sparse. All 54 studies had a high risk of bias. AUTHORS' CONCLUSIONS: Due to a lack of comparative studies, it is unclear whether participants with NRSTS have improved survival from autologous HSCT following HDCT. Owing to this current gap in knowledge, at present HDCT and autologous HSCT for NRSTS should only be used within controlled trials.

Low-dose rate brachytherapy for men with localized prostate cancer.

BACKGROUND: Localized prostate cancer is a slow growing tumor for many years for the majority of affected men. Low-dose rate brachytherapy (LDR-BT) is short-distance radiotherapy using low-energy radioactive sources. LDR-BT has been recommended for men with low risk localized prostate cancer. OBJECTIVES: To assess the benefit and harm of LDR-BT compared to radical prostatectomy (RP), external beam radiotherapy (EBRT), and no primary therapy (NPT) in men with localized prostatic cancer. SEARCH STRATEGY: The Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (from 1950), and EMBASE (from 1980) were searched in June 2010 as well as online trials registers and reference lists of reviews. SELECTION CRITERIA: Randomized, controlled trials comparing LDR-BT versus RP, EBRT, and NPT in men with clinically localized prostate cancer. DATA COLLECTION AND ANALYSIS: Data on study methods, participants, treatment regimens, observation period and outcomes were recorded by two reviewers independently. MAIN RESULTS: We identified only one RCT (N = 200; mean follow up 68 months). This trial compared LDR-BT and RP. The risk of bias was deemed high. Primary outcomes (overall survival, cause-specific mortality, or metastatic-free survival) were not reported. Biochemical recurrence-free survival at 5 years follow up was not significantly different between LDR-BT (78/85 (91.8%)) and RP (81/89 (91.0%)); P = 0.875; relative risk 0.92 (95% CI: 0.35 to 2.42).For severe adverse events reported at 6 months follow up, results favored LDR-BT for urinary incontinence (LDR-BT 0/85 (0.0%) versus RP 16/89 (18.0%); P < 0.001; relative risk 0) and favored RP for urinary irritation (LDR-BT 68/85 (80.0%) versus RP 4/89 (4.5%); P < 0.001; relative risk 17.80, 95% CI 6.79 to 46.66). The occurrence of urinary stricture did not significantly differ between the treatment groups (LDR-BT 2/85 (2.4%) versus RP 6/89 (6.7%); P = 0.221; relative risk 0.35, 95% CI: 0.07 to 1.68). Long-term information was not available.We did not identify significant differences of mean scores between treatment groups for patient-reported outcomes function and bother as well as generic health-related quality of life. AUTHORS' CONCLUSIONS: Low-dose rate brachytherapy did not reduce biochemical recurrence-free survival versus radical prostatectomy at 5 years. For short-term severe adverse events, low-dose rate brachytherapy was significantly more favorable for urinary incontinence, but radical prostatectomy was significantly more favorable for urinary irritation. Evidence is based on one RCT with high risk of bias.

[Management of chronic heart failure - a systematic review of guidelines in the context of the DMP revision]. / Versorgung der chronischen Herzinsuffizienz - eine systematische Leitliniensynopse im Rahmen der geplanten DMP-Aktualisierung.

BACKGROUND: Disease Management Programmes (DMPs) are structured treatment programmes for chronic diseases. The DMP requirements are primarily derived from evidence-based guidelines. DMPs are regularly revised to ensure that they reflect current best practice and medical knowledge. The aim of this study was to assess the need for updating the German DMP module on heart failure by comparing it to relevant guidelines and identifying recommendations that should be revised. METHODS: We systematically searched for clinical guidelines on heart failure published in German, English or French, and extracted relevant guideline recommendations. All included guidelines were assessed for methodological quality. To identify revision needs in the DMP, we performed a synoptic analysis of the extracted guideline recommendations and DMP requirements. RESULTS: 27 guidelines were included. The extracted recommendations covered all aspects of the management of heart failure. The comparison of guideline recommendations with DMP requirements showed that, overall, guideline recommendations were more detailed than DMP requirements, and that the guidelines covered topics not included in the DMP module. CONCLUSIONS: The DMP module is largely consistent with current guidelines on heart failure. We did not identify any need for significant revision of the DMP requirements. However, some specific recommendations of the DMP module could benefit from revision.

First-line matched related donor hematopoietic stem cell transplantation compared to immunosuppressive therapy in acquired severe aplastic anemia.

INTRODUCTION: Acquired severe aplastic anemia (SAA) is a rare and progressive disease characterized by an immune-mediated functional impairment of hematopoietic stem cells. Transplantation of these cells is a first-line treatment option if HLA-matched related donors are available. First-line immunosuppressive therapy may be offered as alternative. The aim was to compare the outcome of these patients in controlled trials. METHODS: A systematic search was performed in the bibliographic databases MEDLINE, EMBASE, and The Cochrane Library. To show an overview of various outcomes by treatment group we conducted a meta-analysis on overall survival. We evaluated whether studies reported statistically significant factors for improved survival. RESULTS: 26 non-randomized controlled trials (7,955 patients enrolled from 1970 to 2001) were identified. We did not identify any RCTs. Risk of bias was high except in 4 studies. Young age and recent year of treatment were identified as factors for improved survival in the HSCT group. Advanced age, SAA without very severe aplastic anemia, and combination of anti-lymphocyte globulin with cyclosporine A were factors for improved survival in the IST group. In 19 studies (4,855 patients), summary statistics were sufficient to be included in meta-analysis. Considerable heterogeneity did not justify a pooled estimate. Adverse events were inconsistently reported and varied significantly across studies. CONCLUSIONS: Young age and recent year of treatment were identified as factors for improved survival in the transplant group. Advanced age, SAA without very severe aplastic anemia, and combination of anti-lymphocyte globulin with cyclosporine A were factors for improved survival in the immunosuppressive group. Considerable heterogeneity of non-randomized controlled studies did not justify a pooled estimate. Adverse events were inconsistently reported and varied significantly across studies.

High-dose chemotherapy followed by autologous stem cell transplantation for metastatic rhabdomyosarcoma--a systematic review.

INTRODUCTION: Patients with metastatic rhabdomyosarcoma (RMS) have a poor prognosis. The aim of this systematic review is to investigate whether high-dose chemotherapy (HDCT) followed by autologous hematopoietic stem cell transplantation (HSCT) in patients with metastatic RMS has additional benefit or harm compared to standard chemotherapy. METHODS: Systematic literature searches were performed in MEDLINE, EMBASE, and The Cochrane Library. All databases were searched from inception to February 2010. PubMed was searched in June 2010 for a last update. In addition to randomized and non-randomized controlled trials, case series and case reports were included to complement results from scant data. The primary outcome was overall survival. A meta-analysis was performed using the hazard ratio as primary effect measure, which was estimated from Cox proportional hazard models or from summary statistics of Kaplan Meier product-limit estimations. RESULTS: A total of 40 studies with 287 transplant patients with metastatic RMS (age range 0 to 32 years) were included in the assessment. We identified 3 non-randomized controlled trials. The 3-year overall survival ranged from 22% to 53% in the transplant groups vs. 18% to 55% in the control groups. Meta-analysis on overall survival in controlled trials showed no difference between treatments. Result of meta-analysis of pooled individual survival data of case series and case reports, and results from uncontrolled studies with aggregate data were in the range of those from controlled data. The risk of bias was high in all studies due to methodological flaws. CONCLUSIONS: HDCT followed by autologous HSCT in patients with RMS remains an experimental treatment. At present, it does not appear justifiable to use this treatment except in appropriately designed controlled trials.

Permanent interstitial low-dose-rate brachytherapy for patients with localised prostate cancer: a systematic review of randomised and nonrandomised controlled clinical trials.

CONTEXT: Prostate cancer (PCa) is the most common cancer in men. Permanent interstitial low-dose-rate brachytherapy (LDR-BT) is a short-distance radiation therapy in which low-energy radioactive sources are implanted permanently into the prostate. OBJECTIVE: To assess the effectiveness and safety of LDR-BT compared to treatment alternatives in men with localised PCa. EVIDENCE ACQUISITION: Bibliographic databases (Medline, Embase, and the Cochrane Library) were searched from inception until June 2010 for randomised and nonrandomised controlled trials comparing LDR-BT with radical prostatectomy (RP), external-beam radiation therapy (EBRT), or no primary therapy (NPT). Primary outcome was overall survival (OS). Secondary outcomes were disease-free survival (DFS), biochemical recurrence-free survival (bRFS), physician-reported severe adverse events (SAE), and patient-reported outcomes (PRO). EVIDENCE SYNTHESIS: A total of 31 studies, including 1 randomised controlled trial (RCT), were identified. Risk of bias was high for all 31 studies. OS was reported in one nonrandomised controlled study; however, these data were not interpretable because of strong residual confounding. DFS was not reported. Comparison of bRFS between treatment groups is not validated; thus, results were not interpretable. Physician-reported urogenital late toxicity grade 2 to 3 was more common in the LDR-BT group when compared to the EBRT group. With respect to PRO, better scores for sexual and urinary function as well as urinary incontinence were reported for LDR-BT compared to RP. Better scores for bowel function were reported for LDR-BT compared to EBRT. CONCLUSIONS: We found a low amount of evidence in studies that exclusively compared LDR-BT with other treatment modalities. LDR-BT may have some different physician-reported SAE and patient-reported outcomes. The current evidence is insufficient to allow a definitive conclusion about OS. Randomised trials focusing on long-term survival are needed to clarify the relevance of LDR-BT in patients with localised PCa.

Assessment of representativity of a study population - experience of the Kiel Obesity Prevention Study (KOPS).

OBJECTIVE: Exemplified by data of the Kiel Obesity Prevention Study (KOPS), different methods to control for response bias and to assess representativity were compared. METHODS: 4,997 cross-sectional data of 5- to 7-year-old German children (main cohort) were investigated between 1996 and 2001 within school entry examination. A subgroup responded to a questionnaire to socio-demographic and lifestyle factors (responders, n = 2,631). Representativity of the main cohort was tested in comparison to the total population. To control for response bias within the responders a non-response analysis as well as an analysis of missing values were performed. RESULTS: The comparison with the total population showed a higher prevalence of obese boys and girls from families of low socio-economic status (SES) within the main cohort. The responders were less frequently obese and overweight and more rarely belonged to low SES families when compared with non-responders. Analysis of missing values did not detect any further biases. According to an epidemiological assessment of differences the main cohort of KOPS is suggested to be representative for all 5- to 7-year-old children in Kiel, whereas the responders can be at best called 'relatively' representative. CONCLUSION: The analysis of non-response is the most sensitive method to detect group differences, but a comparison with the total population can also be used to control for biases. In addition representativity has to be proven not only for the main cohort but also for the subgroup of responders with which data analysis will be done.