Areas Of Clinical Uncertainty Research Articles

When randomized trials and observational data disagree: The case of preoperative versus postoperative chemoradiotherapy for esophageal cancer

We read with interest the recent study by Wojcieszynski and colleagues, who used the Surveillance, Epidemiology, and End Results (SEER) database to assess “whether the sequencing of chemoradiotherapy (CRT) has an effect on survival and cardiopulmonary mortality” for esophageal cancer.1 Although chemotherapy data are not available in SEER, the authors use the delivery of radiotherapy (RT) as a surrogate for CRT, assuming that RT is “almost always administered concurrently with chemotherapy.”1 The findings are striking: the use of preoperative RT was associated with a 10% improvement in 5-year survival compared with postoperative RT (P < .0001). The sequencing of CRT relative to surgery is an area of clinical uncertainty, with arguments supporting both approaches. One advantage of neoadjuvant CRT is that RT volumes are usually smaller; conversely, with the adjuvant approach, some patients may avoid CRT if their surgical staging indicates very early stage disease. The authors indicate that no randomized controlled trials (RCTs) are available to address this issue; but indeed there is at least 1, and the differences in results are quite informative. That trial randomized 238 patients who were undergoing surgery for locally advanced thoracic squamous cell esophageal carcinoma to preoperative CRT, postoperative CRT, or surgery alone. There were no differences in survival between the preoperative and postoperative arms, and both were superior to surgery.2 Although there are some differences between the baseline populations in the 2 studies, we are faced with a situation in which RCT data conflict with the results from a population-based study. Conceivably, the 2 studies may differ because of a lack of generalizability of the RCT, but it is more likely that the differences arise because randomization can control for both measured and unmeasured confounders, whereas an observational study cannot control for the latter. One unmeasured confounder that threatens the validity of the SEER study is comorbidity. In some situations, controlling for comorbidity can reverse the results of an observational study: for example, SEER data indicate that postoperative RT for N2 nonsmall cell lung cancer improves overall survival,3 whereas the more robust SEER-Medicare data (controlling for comorbidity) indicate a trend toward harm.4 Furthermore, radiation dose is not available in SEER, and some patients in the postoperative cohort in the study by Wojcieszynski et al actually may have received RT for palliation of early recurrence. The optimal timing CRT for esophageal cancer remains uncertain, and an ongoing RCT is comparing quality-of-life outcomes with the 2 approaches.5 We encourage additional RCTs to further examine survival outcomes between the 2 groups. David A. Palma, MD, MSc, PhD1George B. Rodrigues, MD, MSc1Richard Malthaner, MD, MSc2 1Department of Radiation Oncology, London Health Sciences Center, London, Ontario, Canada 2Department of Thoracic Surgery, London Health Sciences Center, London, Ontario, Canada

Uncertainty in Transfusion Practice for Acute Upper Gastrointestinal Bleeding (AUGIB): Implications for Clinical Trial Design

Introduction Transfusion of red blood cells (RBCs) is a cornerstone for managing AUGIB. There has been a paradigm shift over the last decade in critical care and surgery with several studies associating RBC transfusion with adverse patient outcomes. Most relevant to decision making are recent data suggesting an association between early RBC transfusion in AUGIB and the risk of re-bleeding. Methods In preparation for a proposed UK multi-centre, cluster randomised trial of restrictive versus liberal blood transfusion strategies in patients presenting with AUGIB we sought to determine: (1) the key area of clinical uncertainty in RBC transfusion practice for AUGIB; (2) the proportion of admissions likely to be eligible for trial entry; (3) estimates of the intra-cluster correlation co-efficient to inform sample size calculations for a cluster randomised phase III trial. Data was analysed from 6,750 admissions with AUGIB from the 2007 UK national audit of AUGIB and applied to potential recruiting centres for the proposed trial. Results The key area of clinical uncertainty whether to transfuse patients presenting with a haemoglobin (Hb) concentration between 8.1 and 10 g/dl; in this range 51% (604/1190) of patients received transfusion and 49% (588/1190) did not and a similar degree of uncertainty persisted when patients were stratified by the absence/presence of haemodynamic shock. The Hb range 8.1-10 g/dl, together with other eligibility criteria, was used to estimate recruitment for the proposed trial. Centres meeting cluster eligibility criteria have an average 41 admissions with AUGIB/month. Under a range of clinical scenarios anywhere between 26.4% to 44.8% of new admissions with AUGIB will meet trial eligibility criteria. Intra-cluster correlation co-efficient (ICC) range between 0.007-0.015; assuming an ICC of 0.01 and 30 centres for a phase III trial, 44 patients per centre would be required to detect a 5% reduction in re-bleeding from 15% to 10%, across 30 centres with 90% power and 5% significance by use of a restrictive transfusion practice. Conclusion Cluster randomised trials are useful designs for pragmatic trials measuring the effectiveness of an intervention in routine clinical practice. They have unique challenges in design, conduct and analysis. Detailed observational data from the UK national audit of AUGIB has enabled key methodological components to be addressed for a cluster-randomised trial of restrictive versus liberal transfusion practice in AUGIB.

Contemporary treatment principles for early rheumatoid arthritis: a consensus statement

RA has a substantial impact on both patients and healthcare systems. Our objective is to advance the understanding of modern management principles in light of recent evidence concerning the condition's diagnosis and treatment. A group of practicing UK rheumatologists formulated contemporary management principles and clinical practice recommendations concerning both diagnosis and treatment. Areas of clinical uncertainty were documented, leading to research recommendations. A fundamental concept governing treatment of RA is minimization of cumulative inflammation, referred to as the inflammation-time area under the curve (AUC). To achieve this, four core principles of management were identified: (i) detect and refer patients early, even if the diagnosis is uncertain: patients should be referred at the first suspicion of persistent inflammatory polyarthritis and rheumatology departments should provide rapid access to a diagnostic and prognostic service; (ii) treat RA immediately: optimizing outcomes with conventional DMARDs and biologics requires that effective treatment be started early-ideally within 3 months of symptom onset; (iii) tight control of inflammation in RA improves outcome: frequent assessments and an objective protocol should be used to make treatment changes that maintain low-disease activity/remission at an agreed target; (iv) consider the risk-benefit ratio and tailor treatment to each patient: differing patient, disease and drug characteristics require long-term monitoring of risks and benefits with adaptations of treatments to suit individual circumstances. These principles focus on effective control of the inflammatory process in RA, but optimal uptake may require changes in service provision to accommodate appropriate care pathways.

When medicine fails: evaluating website quality for interpretation of uncertain diagnoses

To date there has been little agreement on standardised methods for conducting health website quality assessments. One useful approach would be to identify the information consumers are more likely to use in personal health assessments or self care, relative to traditional provider-based information. Ranking of such information might serve to better identify associated benefits or dangers for healthcare consumers. In areas of clinical uncertainty, for example, greater risk (or potential reward) might be attributed to websites where consumers might be more likely to avoid their provider's opinion about such information. For illustration purposes, in this exploratory study we examine web-based content within a longstanding area of uncertainty for consumers, the diagnosis and treatment of rheumatism. More refined analysis of web-based resources in such a specified, hierarchical domain can provide important clues related to the strategies of healthcare consumers.

Who decides about prostate cancer treatment? A qualitative study.

Shared decision-making between patients and health professionals has been promoted as ethically and clinically desirable. Patients vary in their willingness to participate in decision-making, while clinicians identify practical barriers to greater participation, such as time and communication skills. A paternalistic approach to treatment decisions remains common even in an area of clinical uncertainty. The willingness of patients to participate in decision-making varies over time during the course of an illness but patients may not be given the opportunity to revisit clinical decisions with their specialists after the initial consultation. To gain an in depth understanding of the perspectives of men recently diagnosed with localized prostate cancer, and to explore the value of decision-making models in the setting of NHS practice. The study design was a qualitative analysis of semi-structured interviews. Nineteen men recently diagnosed with localized prostate cancer were included from patients attending a British District General Hospital. The interviews suggested that the respondents' treatment plans were mostly decided on their behalf by their clinicians. Whilst initially accepting this paternalistic approach, the interviewees over time wished to revisit the decisions. Patients' barriers to shared decision-making included fear of appearing disrespectful to their doctors and of taking responsibility for the outcome of treatment. The structure of patient follow-up did not afford the men an opportunity to discussion treatment decisions further. The paternalistic decision-making model remains the chosen approach in this situation. The patients' willingness to become actively involved in choosing their care varies over time. Barriers to shared decision-making can be identified both in the nature of the doctor-patient relationship and the structure of the clinical follow-up.

Understanding our mistakes: a primer on errors in clinical reasoning

Clinical reasoning allows physicians to move from areas of clinical uncertainty to points where the medical literature offers guidance, and is equally important in deducing whether the results of clinical trials are applicable to an individual patient. However, studies in the field of cognitive psychology indicate that the reasoning skills of clinicians are imperfect. Moreover, clinicians may be aware of their mistakes but often do not understand the cognitive processes underlying their errors. Greater understanding of the reasoning process has the potential to improve patient care but independent study of clinical reasoning can be difficult, as the literature is complex and unfamiliar to most physicians. This article provides an introduction to diagnostic reasoning and highlights some of the cognitive factors that lead to errors in clinical problem solving. Clinical scenarios are used to illustrate key points and place the material in a readily accessible framework.

Cultural basis for differences between US and French clinical recommendations for women at increased risk of breast and ovarian cancer

Two recent consensus statements, one from the USA1 and one from France,2 made recommendations about clinical management of women with an inherited predisposition to breast cancer and ovarian cancer due primarily to the presence of BRCA1 or BRCA2 susceptibility-conferring alleles. The groups formulating these statements had the difficult task of making recommendations despite inadequate or equivocal evidence on risk reduction strategies. The two sets of recommendations are similar for the most part, but they diverge in some areas of clinical uncertainty (panel).

Can meta-analysis help uncertainty in surgery for otitis media in children

While otitis media is perhaps the most common disease of childhood that receives medical attention, there is little agreement concerning the efficacy of the medical and surgical therapies employed to try to alleviate its symptoms or hasten its natural resolution. Because various surgeries including adenoidectomy, myringotomy, and insertion of tympanostomy tubes are frequently involved in the treatment of otitis media with effusion (OME), it is likely the most expensive condition being managed in national terms. In an attempt to elucidate the most appropriate management of this condition, a meta-analysis was attempted to the 12 randomized control trials of surgical treatments for OME in children, published between 1966 and 1990. Heterogeneity both in the populations and comparisons studied and in the outcomes presented made meta-analysis an inappropriate method for clarifying this area of clinical uncertainty. Important elements in the design of randomized control trials that should be included in future studies of treatment for OME are therefore discussed.