[Validity of Recommendations for Secondary Prevention of Colon Cancer]. / Validität der Empfehlungen zur Sekundärprävention von Dickdarmkrebs.

BACKGROUND: Prevention programmes should only be recommended if they achieve what they promise to achieve. Therefore, we checked the variation and validity of recommendations for screening for colorectal cancer of nine organisations. METHODS: We analysed the information concerning recommended screening age, guaiac faecal occult blood test (gFOBT), faecal immunological test (FIT), faecal DNA test, sigmoidoscopy, colonoscopy, double-contrast examination/double-contrast barium enema, and virtual colonoscopy/CT colonography in the following three steps: 1) we gathered the references quoted by the nine organisations; 2) references were categorised according to mortality, incidence and sensitivity/specificity; 3) the validity of references that reported reduced mortality attributed to screening were evaluated. RESULTS: Evidence of occult faecal blood was the only screening method recommended by all nine organisations. Colonoscopy was recommended by seven organisations. Fifteen of the 33 references used endpoints other than mortality to justify screening. One publication was a meta-analysis. Eleven of 17 publications evaluated the gFOBT, three evaluated sigmoidoscopy, one FIT, one coloscopy, and one general diagnosis of the intestine. On average, two of nine validity criteria were completely fulfilled, five only partially, and two were not fulfilled. In two publications, none of the validity criteria were completely met. CONCLUSION: Analysis of screening for colorectal cancer revealed that nine organisations had different goals and different recommendations. Scrupulous and thorough evaluation of the scientific studies in relation to mortality, upon which these recommendations are based, revealed numerous shortcomings and therefore could not sufficiently substantiate the international recommendations for screening for colorectal cancer. It would be useful to establish a consensus about which data have to be collected to provide a reliable basis for health-care decisions.

[Clinical economics: a concept to optimize healthcare services]. / Klinische Ökonomik: Ein Konzept zur Optimierung der Gesundheitsversorgung.

Clinical economics strives to support healthcare decisions by economic considerations. Making economic decisions does not mean saving costs but rather comparing the gained added value with the burden which has to be accepted. The necessary rules are offered in various disciplines, such as economy, epidemiology and ethics. Medical doctors have recognized these rules but are not applying them in daily clinical practice. This lacking orientation leads to preventable errors. Examples of these errors are shown for diagnosis, screening, prognosis and therapy. As these errors can be prevented by application of clinical economic principles the possible consequences for optimization of healthcare are discussed.

[Clinical ecomomics: a pleading for complementing the medical curriculum and specialty training]. / Klinische Ökonomik--Ein Plädoyer für die Ergänzung der medizinischen Lehre und Spezialisierung.

Clinical economics requires an understanding of clinical relationships just like health economy requires an understanding of economic relationships. Hitherto we have ensured that economists can differentiate symptoms from diagnoses and diagnostics from screening at the interface between medicine and economy. However, we overlooked the fact that physicians should be able to understand the principles of marginal benefit and medical ethics, as well as the differences among efficacy, effectiveness, and benefit, to be able to make sound decisions. To make up for this neglected demand, we present our definition of clinical economics, identify the potential conflicts between medical professionalism and commercialized medicine, describe the importance - but also the limits - of scientific evidence, explain the difference between 'prioritization' and strict rationing, and attempt to justify the fact that the necessary changes in the provision of healthcare will probably only be achieved if we instill this new way of thinking in medical students during their medical education. Complementing the medical curriculum with clinical economics would achieve this goal.

[Methods of health economic evaluation for health services research]. / Methoden der gesundheitsökonomischen Evaluation in der Versorgungsforschung.

On August 30, 2010, the German Network for Health Services Research [Deutsches Netzwerk Versorgungsforschung e. V. (DNVF e. V.)] approved the Memorandum III "Methods for Health Services Research", supported by the member societies mentioned as authors and published in this Journal [Gesundheitswesen 2010; 72: 739-748]. The present paper focuses on methodological issues of economic evaluation of health care technologies. It complements the Memorandum III "Methods for Health Services Research", part 2. First, general methodological principles of the economic evaluations of health care technologies are outlined. In order to adequately reflect costs and outcomes of health care interventions in the routine health care, data from different sources are required (e. g., comparative efficacy or effectiveness studies, registers, administrative data, etc.). Therefore, various data sources, which might be used for economic evaluations, are presented, and their strengths and limitations are stated. Finally, the need for methodological advancement with regard to data collection and analysis and issues pertaining to communication and dissemination of results of health economic evaluations are discussed.

[Validity of clinical trials: are there differences between conventional and complementary alternative medicine?]. / Studienvalidität: Gibt es Unterschiede zwischen Schul- und Komplementärmedizin?

So far there has been no consensus on the criteria which confirm the validity of scientific contributions in conventional medicine (CM) and complementary/ alternative medicine (CAM). An interdisciplinary group of experts from various disciplines within each of the areas of medicine held six well-documented sessions in an effort to reach a consensus. The group agreed that the methods to confirm the validity of clinical trials are identical in CM and CAM. There are differences in research strategies and there may also be differences in interpreting the results, depending on the concept of medicine.

[The development of a questionnaire for the assessment of integrated health-care programmes from the patients' perspective (BIGPAT)]. / Die Entwicklung eines Fragebogens zur Beurteilung integrierter Gesundheitsversorgungsprogramme durch die Patienten (BiGPAT)*

AIMS: The aim of the study is the development of a questionnaire for the assessment of health care from the patients' perspective. METHODS: In the framework of a bottom-up approach, 8 focus groups of patients with diabetes or cardiovascular diseases from two different regions have been conducted. Results of the focus groups have been analysed by means of qualitative content analysis. On the basis of the results of the qualitative content analysis, a pool of 125 questions has been developed which constitute the starting point of a stepwise process for the selection of 44 items for a field test questionnaire. The field test questionnaire has been completed by 195 patients from three regions. The dimensional structure and the psychometric properties of the questionnaire have been analysed by means of exploratory and confirmatory factor analyses and by means of item-response-theory (IRT) models. RESULTS: The final questionnaire consists of 18 items belonging to the five dimensions "physician treatment", "treatment equity", "consultation by pharmacists", "preventive care" and "waiting times". The results of the confirmatory factor analysis reveal a good fit of the five factor model. Results of IRT analyses confirm that all subscales have at least an ordinal scale level. The reliability of the five subscales ranges between 0.70 and 0.91. CONCLUSIONS: A questionnaire for the assessment of health care from the patients' perspective has been developed. The new instrument can be applied in the evaluation of interventions for the improvement of the organisational aspects of health care for patients with chronic conditions.

[Lay assessment of health care services using therapy for rectal cancer as an example]. / Vergleichende bewertung von gesundheitsleistungen durch laien am beispiel der therapie des rektumkarzinoms.

AIM: Multimodal treatment strategies make the assessment of health care services very difficult even for experts and almost impossible for lay persons. The aim of this project was to present complex data from scientific publications in a simplified way so that all essential information is preserved, but still assessable by lay persons and to compare their assessments with the recommendations of experts. METHODS: Using the surgical treatment of rectal cancer with or without preoperative radiation as an example, the aims of treatment as well as the "outcomes" (actually intended study endpoints) and "outputs" (surrogate parameters) were defined, identified and presented graphically for five key studies of neoadjuvant treatment. RESULTS: German lay persons (n = 59) favoured in the majority of the cases (93 %) surgical treatment without preoperative radiation. Lay persons assessed the results in a similar manner to other groups (physicians, health care workers, and health care politicians) and lay persons of other cultural backgrounds. Altogether, the participants (n = 152) favoured surgical treatment without preoperative therapy in 86 % of the cases (653 of 760). This lay assessment did not correlate with the assessments and recommendations of the scientific societies responsible for the guidelines. CONCLUSIONS: Complex scientific results can be prepared in such a way that their assessment by lay persons is feasible. Lay persons orientate their assessment according to the outcomes, while the recommendations of the guidelines are more directed by the outputs. These different viewpoints should be taken more into consideration for the development of guidelines than they are now.

Targeted therapy for advanced renal cell carcinoma.

BACKGROUND: Advanced renal cell carcinoma has been resistant to drug therapy of different types and new types of drug therapy are needed. Targeted agents inhibit known molecular pathways involved in cellular proliferation and neoangiogenesis, the induction by the tumour of host microvascular networks. Angiogenesis is of special interest in the clear cell histologic subtype of renal cancer because of its vascularity and constitutively activated hypoxia-inducible path in the majority of tumours. OBJECTIVES: 1) To provide a systematic review of studies testing targeted agents.2) To identify the type and degree of clinical benefit, if any, of targeted agents over the prior standard of care, particularly any impact on overall survival. SEARCH STRATEGY: 1) Electronic search of CENTRAL, MEDLINE and EMBASE databases.2) Hand search of international cancer meeting abstract and other sources specified in the protocol. SELECTION CRITERIA: Randomized controlled studies of targeted agents in patients with advanced renal cell cancer reporting major remission rate or overall survival by allocation. Progression-free survival (PFS) was adopted as an additional outcome because PFS was a commonly chosen primary outcome, and because several pivotal studies allowed crossover from the control to the investigational arm after closure to accrual thereby making overall survival a problematic endpoint. DATA COLLECTION AND ANALYSIS: Nineteen fully eligible studies tested ten different targeted agents (Table 04). One additional study was excluded because no outcome data by allocation have been reported (Hutson 2007). For purposes of comparison, the studies were divided into three groups: Group 1 studies compared different doses of the same agents; Group 2 studies examined the impact of targeted agents in patients who had received prior cytokine or other systemic therapy; and Group 3 studies tested targeted agents in systemically naive patients, either against standard interferon-alfa or against another control therapy. Meta-analysis was not utilized because there were very few situations where the same agents had been tested in the same group in more than one study. MAIN RESULTS: In systemically untreated patients in studies using subcutaneous interferon-alfa as control therapy, the major findings were: 1) An improvement in overall survival has been demonstrated only with the use of weekly intravenous temsirolimus in patients with unselected renal cancer histology and adverse prognostic features (median survival 10.9 months versus 7.3 months for temsirolimus or interferon-alfa respectively, HR 0.73, P = 0.008 log rank, Hudes 2007). However, the chance of major remission was low and not improved with temsirolimus. 2) In patients with mostly good or intermediate prognostic risk with clear cell renal cancer, oral sunitinib improves the chance of major remission, the probability of symptomatic improvement, and freedom from disease progression (Motzer 2007); in a similar setting, the addition of biweekly intravenous bevacizumab to interferon-alfa also improved the chance of major remission and prolonged progression-free survival (Escudier 2007b); overall survival had not changed at the time of interim reporting of either study. In patients with clear cell renal cancers who had failed prior cytokine therapy, oral sorafenib gives a better quality of life than placebo as well as improved chance of being free of disease progression; overall survival may have improved but is hard to evaluate because of crossover of placebo-assigned patients after the study closed to accrual (Escudier 2007a). AUTHORS' CONCLUSIONS: Based on less than a decade of experience, some targeted agents with specified molecular targets have demonstrated clinically useful benefits over the previous standard of care for patients with advanced renal cancer. Much more research is required to fully establish the role of targeted agents in this condition.

[Evidence level Ia--is the gold standard of scientific evidence as attractive as its reputation?]. / Evidence Level I a--Ist die Königin der wissenschaftlichen Evidenz so attraktiv wie ihr Ruf?

Here we raise the question as to whether the highest standard of valid statements, the meta-analysis, really earns its reputation and needs no further testing. For that purpose we formulated the hypothesis that the evaluation of clinical studies and meta-analyses is largely based on subjective criteria, which have hitherto not been sufficiently standardised. To support this hypothesis, we present scientific evidence on three topics: 1) Studies included in meta-analyses do not always meet the quality demands for inclusion in a meta-analysis. 2) The comprehensive results of a meta-analysis, which is read by scientists, do not always correspond with the summary in the same meta-analysis, which is read by politicians and decision makers in the health-care system. 3) Every scientist who does not want to relinquish his/her autonomy will decide for him- / herself whether new scientific data (external evidence) is sufficiently valid and convincing to change his/her previous conviction (internal evidence) should this not coincide with the new data. This process is always subjective and individual. We believe we can prove with sufficiently valid methods that even meta-analyses require testing, which can only be guaranteed by the scientific community itself. This guarantee must be reliable, i. e., pseudoevidence must be avoided because society will otherwise lose trust in the achievements of the scientific community and orient itself towards other statements, which may be subject to less methodically stringent proof.

[Significance of outcomes research for health insurance]. / Die Bedeutung der Ergebnisforschung für die Krankenversicherung.

Innovation is an important stimulus of the economy and the healthcare system. Two components may inhibit innovations, an increased risk of the developers to market their innovations and an increased risk of the public to increase the costs due to uncontrolled use of innovations. New information can contribute to controlling both risks. We use the term "outcomes research" to describe the new working field that generates this information. The need for outcomes research is described. To differentiate clinical research from outcomes research, we demonstrate that these two fields of research pursue different goals, use different methods, and finally generate different types of results.

Emergency ultrasound-based algorithms for diagnosing blunt abdominal trauma.

BACKGROUND: Ultrasonography is regarded as the tool of choice for early diagnostic investigations in patients with suspected blunt abdominal trauma. Although its sensitivity is too low for definite exclusion of abdominal organ injury, proponents of ultrasound argue that ultrasound-based clinical pathways enhance the speed of primary trauma assessment, reduce the number of computed tomography scans and cut costs. OBJECTIVES: To assess the efficiency and effectiveness of trauma algorithms that include ultrasound examinations in patients with suspected blunt abdominal trauma. SEARCH STRATEGY: We searched MEDLINE, EMBASE, CENTRAL, CCMED, publishers' databases, controlled trials registers and the Internet. Bibliographies of identified articles and congress abstracts were handsearched. Trials were obtained from the Cochrane Injuries Group's trials register. Authors were contacted for further information and individual patient data. PARTICIPANTS: patients with blunt torso, abdominal or multiple trauma undergoing diagnostic investigations for abdominal organ injury. INTERVENTIONS: diagnostic algorithms comprising emergency ultrasonography (US). CONTROLS: diagnostic algorithms without US ultrasound examinations (e.g. primary computed tomography [CT] or diagnostic peritoneal lavage [DPL]). OUTCOME MEASURES: mortality, use of CT and DPL, cost-effectiveness, laparotomy and negative laparotomy rates, delayed diagnoses, and quality of life. STUDIES: randomised controlled trials (RCTs) and quasi-randomised trials (qRCTs). DATA COLLECTION AND ANALYSIS: Two reviewers independently selected trials for inclusion, assessed methodological quality and extracted data. Where possible, data were pooled and relative risks (RRs), risk differences (RDs) and weighted mean differences, each with 95% confidence intervals (CIs), were calculated by fixed- or random-effects modelling, as appropriate. MAIN RESULTS: We identified two RCTs with US in the experimental arm and another with US in the control group. We also considered two qRCTs. Overall, trials were of moderate methodological quality. Few authors responded to our written inquiries seeking to resolve controversial issues and to obtain individual patient data. We were able to pool data from two trials comprising 1037 patients for primary endpoint analysis (i.e. mortality). The relative risk in favour of the no-US arm was 1.4 (95% CI 0.94 to 2.08). Because of a lack of details, the meaning of this observation remains unclear. There was a marginal benefit with US-based pathways in reducing CT scans (random-effects RD -0.46; 95% CI -1.00 to 0.13), offset by trials of higher methodological rigour. No differences were observed in DPL and laparotomy rates. AUTHORS' CONCLUSIONS: There is insufficient evidence from RCTs to justify promotion of ultrasound-based clinical pathways in diagnosing patients with suspected blunt abdominal trauma.

Immunotherapy for advanced renal cell cancer.

BACKGROUND: The course of advanced renal cell carcinoma is extremely variable, ranging from spontaneous remission to disease progression refractory to chemotherapy. Immunotherapy has held promise of improved outcomes based on uncontrolled studies and randomized controlled trials generally limited by small size and low power. OBJECTIVES: To evaluate immunotherapy for advanced renal cell carcinoma by comparing: (1) high dose interleukin-2 to other options and (2) interferon-alfa to other options. The primary outcome of interest was overall survival at one year, with remission as the main secondary outcome of interest. SEARCH STRATEGY: A systematic search of the CENTRAL, MEDLINE, and EMBASE databases was conducted for the period 1966 through end of December 2003. Handsearches were made of the proceedings of the periodic meetings of the American Urologic Association, the American Society of Clinical Oncology, ECCO - the European Cancer Conference, and the European Society of Medical Oncology for the period 1995 to June 2004. SELECTION CRITERIA: Randomized controlled trials that selected (or stratified) patients with advanced renal cell carcinoma, utilized an immunotherapeutic agent in at least one study arm, and reported remission or survival by allocation. Fifty-three identified studies involving 6117 patients were eligible and all but one reported remission; 32 of these studies reported the one-year survival outcome. DATA COLLECTION AND ANALYSIS: Two reviewers independently abstracted each article by following a prospectively designed protocol. Dichotomous outcomes for treatment remission (partial plus complete) and for deaths at one year were used for the main comparisons. Survival hazard ratios were also used for studies of interferon-alfa versus controls, and for two randomized studies of the value of initial nephrectomy prior to interferon-alfa in fit patients with metastases detected at the time of diagnosis. MAIN RESULTS: Combined data for a variety of immunotherapies gave an overall chance of partial or complete remission of only 12.9% (99 study arms), compared to 2.5% in 10 non-immunotherapy control arms, and 4.3% in two placebo arms. Twenty-eight percent of these remissions were designated as complete (data from 45 studies). Median survival averaged 13.3 months (range by arm, 6 to 27+ months). The difference in remission rate between arms was poorly correlated with the difference in median survival so that remission rate is not a good surrogate or intermediate outcome for survival for advanced renal cancer. We were unable to identify any published randomized study of high-dose interleukin-2 versus a non-immunotherapy control, or of high-dose interleukin-2 versus interferon-alfa reporting survival. It has been established that reduced dose interleukin-2 given by intravenous bolus or by subcutaneous injection provides equivalent survival to high dose interleukin-2 with less toxicity. Results from four studies (644 patients) indicate that interferon-alfa is superior to controls (OR for death at one year = 0.56, 95% confidence interval 0.40 to 0.77). Using the method of Parmar 1998, the pooled overall hazard ratio for death was 0.74 (95% confidence interval 0.63 to 0.88). The weighted average median improvement in survival was 3.8 months. T he optimal dose and duration of interferon-alfa remains to be elucidated. The addition of a variety of enhancers, including lower dose intravenous or subcutaneous interleukin-2, has failed to improve survival compared to interferon-alfa alone. Two recent randomized studies have examined the role of initial nephrectomy prior to interferon-alfa therapy in highly selected fit patients with metastases at diagnosis and minimal symptoms: despite minimal improvement in the chance of remission, both studies of up-front nephrectomy improved median survival by 4.8 months over interferon-alfa alone. Recent studies have been examining anti-angiogenesis agents. A landmark study of bevacizumab, an anti-vascular endothelial growth factor antibody, was associated with significant prolongation of the time to progression of disease when given at high dose compared to low-dose or placebo therapy though frequency of remissions or survival were not improved. AUTHORS' CONCLUSIONS: interferon-alfa provides a modest survival benefit compared to other commonly used treatments and should be considered for the control arm of future studies of systemic agents. In fit patients with metastases at diagnosis and minimal symptoms, nephrectomy followed by interferon-alfa gives the best survival strategy for fully validated therapies. The need for more effective specific therapy for this condition is apparent.

[Evidence-based medicine in orthopedics - a sensible or unnecessary addition to clinical routine? Part 1: the diagnostics tool]. / Evidence-Based Medicine in der Orthopädie - Sinnvolle Ergänzung oder überflüssiger Ballast in der klinischen Arbeit? Teil 1: Das Modul "Diagnostik"

AIM: The methods of evidence based medicine (EBM) are recommended to solve problems in day-to-day routine. Aim of this article is to demonstrate the practicability of this procedure for the diagnostic module. METHODS: Within a teaching session in our department 20 participants guided by an extern al EBM teacher validated the results of an article according to the EBM criteria concerning the module "diagnosis". We demonstrate what EBM can contribute to solve day-to-day clinical problems and discuss the six formal steps for the implementation of EBM into day-to-day practice. 1) To transform the clinical problem into an answerable 4-part question. 2) To answer this question based on your internal evidence. 3) To search for external evidence to answer this question. 4) To critically appraise the evidence found with respect to its validity, importance and applicability. 5) To integrate the appraised external evidence into your existing internal evidence in order to come to a new decision if the additional new external evidence is convincing. 6) To assess the benefit which was gained for the patient. RESULTS: Statistical tests to evaluate the relevance and validity of the chosen article were performed. The following data were determined: sensitivity, specifity, pretest probability, posttest probability, likelihood ratio, positive predictive value, negative predictive value. CONCLUSION: In conclusion we show that EBM can help to solve day-to-day clinical problems, because the structured analysis of concrete questions can lead to a validation of the literature.

[Evidence-based medicine in orthopaedics - a sensible or unnecessary addition to clinical routine? Part 2: the therapy tool]. / Evidence-Based Medicine in der Orthopädie - Sinnvolle Ergänzung oder überflüssiger Ballast in der klinischen Arbeit ? Teil 2: Das Modul "Therapie"

AIM: In the second part of our project to implement evidence-based medicine into day-to-day clinical practice the module therapy is presented. METHODS: Within a teaching session in our department 20 participants guided by an extern al EBM teacher validated the results of an article according to the EBM criteria concerning the module therapy. To work with this module formal procedures are necessary, too. RESULTS: Statistical tests to evaluate the relevance and validity of the chosen article were performed. The following data were determined: relative risk reduction, absolute risk reduction, number needed to treat. CONCLUSION: In conclusion we can show, that EBM can help to solve day-to-day clinical problems, because the structured analysis concerning valid answers to concrete clinical problems is possible.

[Evidence-based medicine and anaesthesiology--six steps towards implementation into clinical practice]. / Evidence-based Medicine und Anästhesiologie--Sechs Schritte zur Umsetzung in die Praxis.

Whenever evidence-based medicine (EbM) is mentioned among physicians, it evokes many different and contradictory reactions. On the one hand a lot of physicians have heard of this concept, but may hardly associate anything with it. On the other hand most of the physicians seem to be skeptical rather than in favour of evidence-based medicine. They seem to be concerned about restrictions in daily clinical decision-making or negative implications for the relationship between patient and physician. In this article we would like to deal with the question whether evidence-based medicine is useful for clinicians and which chances are provided for both the physicians and the patients by using it. First, the methodology and aims of evidence-based medicine are introduced. Second, by using an example of clinical anaesthesiology, we discuss the six formal steps for implementing this method. Third, important points which help to assess clinical studies are mentioned. In conclusion we would like to point out that evidence-based medicine is no entirely new concept of medicine but aims to highlight a solid and conscientious scientific basis of clinical decision-making. Thus, evidence-based medicine may act as a methodological strategy helping to clear the proceedings of decision-making and improve the provision of medical care to patients. Furthermore, it may guarantee a rapid transfer of knowledge from outcome-related research to patient care.