Frank Peinemann

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.

Single-center trials tend to provide larger treatment effects than multicenter trials: a systematic review

OBJECTIVES To assess whether the reported trial characteristics are associated with treatment effects on all-cause mortality within critical care medicine. STUDY DESIGN AND SETTING We identified all eligible randomized controlled trials (RCTs) from Cochrane Reviews on patients with sepsis, septic shock, and cardiogenic shock. Risk of bias was judged on 12 trial characteristics, including the differentiation between single-center and multicenter trials. Hierarchical random-effects models quantified the impact of the risk of bias items on the reported effect estimates of mortality. RESULTS Twelve meta-analyses that involved 82 RCTs were selected and judged. Single-center trials estimated a significant larger treatment effect compared with multicenter trials (ratio of odds ratios, 0.64; 95% confidence interval: 0.47, 0.87). Treatment effect tended to be overestimated with selective reporting of preplanned end points. Biases in different trial characteristics are unlikely to operate independently and may have modified these associations. CONCLUSION The results of this study highlight a substantial difference in treatment effect estimates between single-center and multicenter trials. Therefore, we recommend that results from single-center trials should be cautiously used for decision making.

Using multiple types of studies in systematic reviews of health care interventions--a systematic review.

Background A systematic review may evaluate different aspects of a health care intervention. To accommodate the evaluation of various research questions, the inclusion of more than one study design may be necessary. One aim of this study is to find and describe articles on methodological issues concerning the incorporation of multiple types of study designs in systematic reviews on health care interventions. Another aim is to evaluate methods studies that have assessed whether reported effects differ by study types. Methods and Findings We searched PubMed, the Cochrane Database of Systematic Reviews, and the Cochrane Methodology Register on 31 March 2012 and identified 42 articles that reported on the integration of single or multiple study designs in systematic reviews. We summarized the contents of the articles qualitatively and assessed theoretical and empirical evidence. We found that many examples of reviews incorporating multiple types of studies exist and that every study design can serve a specific purpose. The clinical questions of a systematic review determine the types of design that are necessary or sufficient to provide the best possible answers. In a second independent search, we identified 49 studies, 31 systematic reviews and 18 trials that compared the effect sizes between randomized and nonrandomized controlled trials, which were statistically different in 35%, and not different in 53%. Twelve percent of studies reported both, different and non-different effect sizes. Conclusions Different study designs addressing the same question yielded varying results, with differences in about half of all examples. The risk of presenting uncertain results without knowing for sure the direction and magnitude of the effect holds true for both nonrandomized and randomized controlled trials. The integration of multiple study designs in systematic reviews is required if patients should be informed on the many facets of patient relevant issues of health care interventions.

Utilisation of preventative health check-ups in the UK: findings from individual-level repeated cross-sectional data from 1992 to 2008

Objectives To analyse and compare the determinants of screening uptake for different National Health Service (NHS) health check-ups in the UK. Design Individual-level analysis of repeated cross-sectional surveys with balanced panel data. Setting The UK. Participants Individuals taking part in the British Household Panel Survey (BHPS), 1992–2008. Outcome measure Uptake of NHS health check-ups for cervical cancer screening, breast cancer screening, blood pressure checks, cholesterol tests, dental screening and eyesight tests. Methods Dynamic panel data models (random effects panel probit with initial conditions). Results Having had a health check-up 1 year before, and previously in accordance with the recommended schedule, was associated with higher uptake of health check-ups. Individuals who visited a general practitioner (GP) had a significantly higher uptake in 5 of the 6 health check-ups. Uptake was highest in the recommended age group for breast and cervical cancer screening. For all health check-ups, age had a non-linear relationship. Lower self-rated health status was associated with increased uptake of blood pressure checks and cholesterol tests; smoking was associated with decreased uptake of 4 health check-ups. The effects of socioeconomic variables differed for the different health check-ups. Ethnicity did not have a significant influence on any health check-up. Permanent household income had an influence only on eyesight tests and dental screening. Conclusions Common determinants for having health check-ups are age, screening history and a GP visit. Policy interventions to increase uptake should consider the central role of the GP in promoting screening examinations and in preserving a high level of uptake. Possible economic barriers to access for prevention exist for dental screening and eyesight tests, and could be a target for policy intervention. Trial registration This observational study was not registered.

Unrelated donor stem cell transplantation in acquired severe aplastic anemia: a systematic review

Acquired severe aplastic anemia is a rare disease characterized by an immune-mediated functional impairment of hematopoietic stem cells. Transplantation of these cells from unrelated donors is a treatment option frequently offered to patients after failed immunosuppressive therapy. This systematic review indicates that unrelated donor hematopoietic stem cell transplantation in patients with acquired severe aplastic anemia after failure of immunosuppressive therapy is a valid treatment option. Acquired severe aplastic anemia is a rare disease characterized by an immune-mediated functional impairment of hematopoietic stem cells. Transplantation of these cells from unrelated donors is a treatment option frequently offered to patients after failed immunosuppressive therapy. The aim was to investigate the outcome of these patients treated with unrelated donor transplants. Systematic literature searches were performed in MEDLINE, EMBASE, and The Cochrane Library. All databases were searched from inception to June 2009. Only full-text publications and studies including at least 10 patients were considered. The primary outcome was 5-year overall survival from the day of transplantation and the secondary outcomes were graft failure and graft-versus-host disease. A meta-analysis of survival estimates was conducted and heterogeneity was investigated. A total of 18 studies, one controlled trial and 17 case series were identified. The overall survival at five years and the corresponding confidence interval was stated in 8 studies and ranged from 28% to 94%. A meta-analysis revealed considerable heterogeneity between the studies that could not be explained and was also present in subgroups of the studies. The proportion of acute graft failure was 45% in one study using only umbilical cord blood, and it was reported to be 0–26% in 15 studies using mainly bone marrow as stem cell source after different follow-up periods. Acute GVHD grade II–IV was reported for 8–86% and extensive chronic GVHD for 0–38% of the evaluated patients in 16 studies. Recipient age, human leukocyte antigen match, performance status, year of transplantation, and conditioning with serotherapy were identified as significant factors for improved survival. Unrelated donor hematopoietic stem cell transplantation in patients with acquired severe aplastic anemia after failure to immunosuppressive therapy is a treatment option. A stable physical condition of the patients before receiving the transplant (for example, performance and age) may be associated with a better survival. Detailed HLA-matching facilitated by DNA-based typing, among other factors, may have contributed to recent improvements on survival after unrelated donor HSCT as a second-line treatment.

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.

Cervical cancer screening service utilisation in UK

This study investigates empirically how past screening behaviour, individual and household characteristics affect the current uptake of cervical cancer screening in UK. For the conceptual framework, we use a modified Grossman model which is extended for non-economic factors. A dynamic version of a random effects panel probit model with initial conditions is estimated on the balanced sub-sample of the data. The analysis sample is restricted to women of age 16 and older and grouped into different age categories with respect to the NHS Cervical Screening Programme (NHSCSP). As dataset a balanced panel data of 857 women with 11,998 observations from the British Household Panel Study (BHPS) for the period from 1992 to 2008 is used for the analysis. Results suggest show that previous screening uptake, age, partner status, employment status and a previous GP visit have a significant influence on the likelihood of the uptake of cervical cancer screening.

Breast and cervical cancer screening in Great Britain: Dynamic interrelated processes

No previous analysis has investigated the determinants of screening uptake for breast and cervical cancer screening for possible spillover effects from one type of screening examination to the other type of screening examination with a dynamic bivariate panel probit model. For our analysis, we used a dynamic random effects bivariate panel probit model with initial conditions (Wooldridge-type estimator) and dependent variables were the participation of breast and cervical cancer screening in the recent year. The balanced panel sample consisted of 844 women from the British Household Panel Survey (BHPS) from the time period 1992 to 2008. Our analysis showed the high relevance of past screening behaviour and the importance of state dependency for the same and the other type of cancer screening examinations even after controlling for covariates and unobserved heterogeneity. The uptake for breast and cervical cancer screening was higher when the same screening examination was done one or three years earlier. This result is in accordance with the medical screening programmes in Great Britain. With regard to breast and cervical cancer screening positive spillover effects existed between screening examinations in the third order lags. Women with a previous visit to a general practitioner and individuals in the recommended age groups had a higher uptake for breast and cervical cancer screening. Other socioeconomic and health related variables had non-uniform results in both screening examinations. Promoting the uptake of one female prevention activity could also enhance the uptake of the other prevention activity.

Stem cell transplantation of matched sibling donors compared with immunosuppressive therapy for acquired severe aplastic anaemia: a Cochrane systematic review

Objectives Acquired severe aplastic anaemia is a rare and potentially fatal disease. The aim of this Cochrane review was to evaluate the effectiveness and adverse events of first-line allogeneic haematopoietic stem cell transplantation of human leucocyte antigen (HLA)-matched sibling donors compared with first-line immunosuppressive therapy. Setting Specialised stem cell transplantations units in primary care hospitals. Participants We included 302 participants with newly diagnosed acquired severe aplastic anaemia. The age ranged from early childhood to young adulthood. We excluded studies on participants with secondary aplastic anaemia. Interventions We included allogeneic haematopoietic stem cell transplantation as the test intervention harvested from any source of matched sibling donor and serving as a first-line therapy. We included immunosuppressive therapy as comparator with either antithymocyte/antilymphocyte globulin or ciclosporin or a combination of the two. Primary and secondary outcome measures planned and finally measured The primary outcome was overall mortality. Secondary outcomes were treatment-related mortality, graft failure, graft-versus-host disease, no response to immunosuppressive therapy, relapse after initial successful treatment, secondary clonal disease or malignancies, health-related quality of life and performance scores. Results We identified three prospective non-randomised controlled trials with a study design that was consistent with the principle of ‘Mendelian randomisation’ in allocating patients to treatment groups. All studies had a high risk of bias due to the study design and were conducted more than 15 years. The pooled HR for overall mortality for the donor group versus the no donor group was 0.95 (95% CI 0.43 to 2.12, p=0.90). Conclusions There are insufficient and biased data that do not allow any firm conclusions to be made about the comparative effectiveness of first-line allogeneic haematopoietic stem cell transplantation of HLA-matched sibling donors and first-line immunosuppressive therapy of patients with acquired severe aplastic anaemia.