Stefan Lange

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.

Randomized Controlled Trials on PET: A Systematic Review of Topics, Design, and Quality

Randomized controlled trials (RCTs) add important information to diagnostic accuracy studies in the evaluation of PET and PET/CT. We evaluated how many RCTs on PET existed, which clinical topics they addressed, and what their design and quality were. Methods: We searched MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials (Clinical Trials) up to August 2010. We also searched in ClinicalTrials.gov and the International Clinical Trials Registry Platform for ongoing RCTs up to March 2011. Titles and abstracts and full texts were screened independently by 2 reviewers. Study characteristics were extracted with standard extraction sheets for ongoing and published RCTs, and risk of bias was assessed for published ones. Results: We identified 54 RCTs, 12 of which were published. The main topics in published studies were non–small cell lung cancer and colorectal cancer; only 3 were conducted in nononcologic fields (this trend was similar in ongoing studies, in which the most common topic was Hodgkin disease). The main indications in the oncologic PET studies were staging in published studies and restaging (mostly including an early assessment of treatment response) in ongoing ones. All except 1 of the published studies applied a marker-based strategy design, whereas about 43% (18/42) of ongoing studies use a more efficient design (Enrichment Design or Marker by Treatment Interaction Design). Conclusion: A relatively high number of ongoing RCTs of PET in several oncologic fields are expected to produce robust results over the next few years. For nononcologic topics, further high-quality studies are still needed to ascertain the benefit of this technique for patients. As funding is usually difficult in nondrug topics, alternative concepts of funding, which should also involve the manufacturers of diagnostic devices, but also more efficient study designs, should be applied to bridge the evidence gap on PET in the near future.

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.

Local difference measures between complex networks for dynamical system model evaluation.

A faithful modeling of real-world dynamical systems necessitates model evaluation. A recent promising methodological approach to this problem has been based on complex networks, which in turn have proven useful for the characterization of dynamical systems. In this context, we introduce three local network difference measures and demonstrate their capabilities in the field of climate modeling, where these measures facilitate a spatially explicit model evaluation. Building on a recent study by Feldhoff et al. [1] we comparatively analyze statistical and dynamical regional climate simulations of the South American monsoon system. Three types of climate networks representing different aspects of rainfall dynamics are constructed from the modeled precipitation space-time series. Specifically, we define simple graphs based on positive as well as negative rank correlations between rainfall anomaly time series at different locations, and such based on spatial synchronizations of extreme rain events. An evaluation against respective networks built from daily satellite data provided by the Tropical Rainfall Measuring Mission 3B42 V7 reveals far greater differences in model performance between network types for a fixed but arbitrary climate model than between climate models for a fixed but arbitrary network type. We identify two sources of uncertainty in this respect. Firstly, climate variability limits fidelity, particularly in the case of the extreme event network; and secondly, larger geographical link lengths render link misplacements more likely, most notably in the case of the anticorrelation network; both contributions are quantified using suitable ensembles of surrogate networks. Our model evaluation approach is applicable to any multidimensional dynamical system and especially our simple graph difference measures are highly versatile as the graphs to be compared may be constructed in whatever way required. Generalizations to directed as well as edge- and node-weighted graphs are discussed.

The Role of End-of-Life Issues in the Design and Reporting of Cancer Clinical Trials: A Structured Literature Review

Background Randomized controlled trials (RCTs) are important sources of information on the benefits and harms patients may expect from treatment options. The aim of this structured literature review by the German Institute for Quality and Efficiency in Health Care was to explore whether and how the end-of-life (EoL) situation of patients with advanced cancer is considered in RCTs investigating anti-cancer treatments. Methods Our journal pool comprised 19 medical journals, namely five preselected key general medical journals as well as 14 specialist journals (mainly cancer) identified via a scoping search. We systematically searched these journals in MEDLINE to identify RCTs investigating anti-cancer treatments for the following four cancer types: glioblastoma, lung cancer (stage IIIb-IV), malignant melanoma (stage IV), and pancreatic cancer (search via OVID; November 2012). We selected a representative sample of 100 publications, that is, the 25 most recent publications for each cancer type. EoL was defined as a life expectancy of ≤ two years. We assessed the information provided on (1) the descriptions of the terminal stage of the disease, (2) the therapeutic goal (i.e. the intended therapeutic benefit of the intervention studied), (3) the study endpoints assessed, (4) the authors’ concluding appraisal of the intervention’s effects, and (5) the terminology referring to the patients’ EoL situation. Results Median survival was ≤ one year for each of the four cancer types. Descriptions of the terminal stage of the disease were ambiguous or lacking in 29/100 publications. One or more therapeutic goals were mentioned in 51/100 publications; these goals were patient-relevant in 38 publications (survival alone: 30/38; health-related quality of life (HRQoL) or HRQoL and survival: 6/38; symptom control or symptom control and survival: 2/38). Primary endpoints included survival (50%), surrogates (44%), and safety (3%). Patient-reported outcomes (PROs) were assessed in 36/100 RCTs. The implications of treatment-related harms for the patients were discussed in 22/100 appraisals. Terminology referring to the patients’ EoL situation (e.g. “terminal”) was scarce, whereas terms suggesting control of the disease (e.g. “cancer control“) were common. Conclusions The EoL situation of patients with advanced cancer should be more carefully considered in clinical trials. Although the investigation and robust reporting of PROs is a prerequisite for informed decision-making in healthcare, they are rarely defined as endpoints and HRQoL is rarely mentioned as a therapeutic goal. Suggestions for improving standards for study design and reporting are presented.

The Range and Scientific Value of Randomized Trials

BACKGROUND The randomized, controlled trial (RCT) is the gold standard of scientific evidence for the attribution of clinical effects (benefits and harms) to medical interventions. Many different designs for RCTs have been developed in order to counter legitimate critical objections and to better adapt the trials to the continually changing challenges that face clinical research. METHODS The diversity and adaptability of randomized trial designs are presented and discussed on the basis of a selective literature review and specific illustrative examples. RESULTS A wide range of RCT designs enables adaptation to special research tasks and clinical framework conditions. These include (among others) crossover trials, n=1 trials, factorial RCT designs, and cluster-randomized trials. In addition, adaptive designs such as modern platform trials and pragmatic RCTs with simplified clinical questions and less severely restricted patient groups make broad recruitment of patients possible even in routine clinical practice. CONCLUSION Only the randomized allocation of subjects to the treatment and control groups, which is the defining property of RCTs, can adequately ensure that traits of the subjects which might disturb or bias a comparison of two or more medical interventions, will be evenly distributed across groups, regardless of whether these traits are known or unknown. The methodological variants and further elaborations of the RCT that are discussed here will help protect patients by enabling the assessment of the benefits and harms of medical methods and products on the basis of robust evidence even in the present era of rapid innovation.

Evidence-Based Assessment of PET in Germany

TO THE EDITOR: The article by Weber (1) offers some interesting interpretations of how PET is currently being assessed not only in Germany by the Institute for Quality and Efficiency in Health Care (IQWiG) but also in other countries. However, the author made an incorrect statement about IQWiG that needs to be clarified. IQWiG does not “typically give grants to small companies specialized in preparing systematic reviews.” IQWiG has actually established a diligent process of selecting and commissioning external partners who have profound expertise both in evidence-based methodology and in the clinical field concerned. In most cases, IQWiG’s external experts are based or have previously worked at highly reputed universities. This can be easily checked on our Web site. However, the full range of expertise involved in IQWiG reports is not presented on the Web site, as some external experts prefer not to be named. In addition, we would like to note that every report on PET published by IQWiG was prepared in collaboration with at least one experienced clinician.

Maßzahlen für Krankheitshäufigkeiten

Was konnen wir aus Aussagen wie „Die meisten Menschen mit Nierensteinen trinken weniger als 1 Liter Flussigkeit pro Tag“ oder „Die meisten Autounfalle geschehen innerhalb eines Umkreises von 10 km des Wohnortes des Unfallopfers“ lernen? Die Antwort lautet: Nichts!

Inconsistent conclusions on QoL outcomes from the same clinical trial

Letter to the editor on the article by Kripp et al. ‘‘Quality of life of older adult patients receiving docetaxel-based chemotherapy triplets for esophagogastric adenocarcinoma: a randomized study of the Arbeitsgemeinschaft Internistische Onkologie (AIO),’’ Gastric Cancer (2014) 17:181–187. There is a lack of quality-of-life (QoL) data from cancer trials [1, 2]. Therefore, the article by Kripp et al. [3] is to be welcomed. However, we have some queries and would like to see the following issues addressed by the authors:

The Role of PET and PET-CT Scanning in Assessing Response to Neoadjuvant Therapy in Esophageal Carcinoma A Systematic Review

BACKGROUND The response to neoadjuvant (radio-)chemotherapy for esophageal carcinoma is often assessed with the aid of positron-emission tomography (PET), either alone or in combination with computed tomography (PET-CT). In this review, we discuss the diagnostic validity and clinical benefit of these imaging techniques. METHODS We systematically searched the Medline, Embase, and Cochrane Library databases for randomized controlled trials (RCTs) and controlled clinical trials (CCTs) comparing PET-CT with conventional techniques such as endosonography and CT. We then determined the diagnostic validity of these methods on the basis of information from published systematic reviews, updated with further information from more recent primary studies. RESULTS We did not find any RCTs that addressed the question of the patient-relevant benefit of PET-CT. We found 20 studies of diagnostic methods, carried out on a total of 854 patients, of whom 82.2% were male. These studies had a high potential for bias. In two of them, PET-CT was directly compared with endosonography or CT. Estimates of sensitivity and specificity varied widely across studies. 54% of all patients (median value across studies) had no histopathological response to therapy at the end of treatment. Taking a reduction of the standard uptake value (SUV) by at least 35% as a threshold criterion, we found that the median negative predictive value of PET across all studies was 86.5. CONCLUSION There is no robust evidence for a patient-relevant benefit of PET and PET-CT in patients with esophageal carcinoma. PET could potentially be used to distinguish treatment responders from non-responders after the first cycle of treatment. RCTs with patient-relevant endpoints will be needed in order to determine whether this is useful.