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Pneumococcal vaccine for asthma.

BACKGROUND: Infection with Streptococcus pneumoniae is an important cause of pneumonia and other serious illnesses, particularly amongst those with certain high-risk medical conditions such as asthma. Although pneumococcal vaccine is routinely advocated for people with asthma, there is uncertainty about the evidence base that underpins this recommendation. OBJECTIVES: To determine the efficacy of pneumococcal vaccine in reducing mortality or morbidity from pneumococcal disease in asthmatics. SEARCH STRATEGY: Randomised controlled trials were identified using the Cochrane Airways Group's register derived from MEDLINE, EMBASE, and CINAHL electronic databases and hand searched respiratory journals and meeting abstracts. SELECTION CRITERIA: Randomised controlled trials, with or without blinding, in which pneumococcal vaccine has been compared with placebo or no treatment in people with clinician diagnosed asthma. DATA COLLECTION AND ANALYSIS: Two reviewers independently reviewed all abstracts and full papers of all articles of potential relevance were retrieved. Methodological quality was rated using the Cochrane approach and the Jadad rating scale. Data extraction was performed by one reviewer and checked independently by a second. We planned to perform quantitative analyses of outcomes on an intention-to-treat basis, where possible. MAIN RESULTS: Of the three papers retrieved, only one satisfied the inclusion criteria and the methodological quality of this study was low (unblinded and inadequate allocation concealment). None of the data could be aggregated in a meta-analysis. Comparisons in a sub-set of 30 asthmatic children prone to recurrent episodes of otitis media, showed that pneumococcal vaccination decreased the incidence of acute asthma exacerbations from 10 to 7 (per child per year). REVIEWER'S CONCLUSIONS: This review found very limited evidence to support the routine use of pneumococcal vaccine in people with asthma. A randomised trial of vaccine efficacy in children and adults with asthma is needed.

Asthma↗

A systematic review of protein and energy supplementation for hip fracture aftercare in older people.

OBJECTIVES: To evaluate whether protein and energy supplementation influences recovery after hip fracture. DESIGN: Systematic review of randomised and quasi-randomised trials in people aged 65 y and over. DATA SOURCES: We searched seven electronic databases from 1966 to April 2002, four journals and reference lists of relevant articles. We contacted trial investigators and experts for details of other trials. MAIN OUTCOME MEASURES: Mortality, complications and unfavourable outcome (mortality or survivors with complications) were the primary outcomes. We also sought data on length of hospital stay, functional status after hip fracture, quality of life and compliance with supplementation. RESULTS: In total, 12 randomised trials involving 898 participants were included. Nine trials evaluated protein and energy supplementation (five oral and four nasogastric feeding), and a further three trials tested oral protein supplementation. Potential biases resulting from inadequate allocation concealment and lack of assessor blinding and intention-to-treat analysis, as well as the limited outcome data, mean that the results must be interpreted with caution. Pooled data from eight of the nine trials evaluating protein and energy supplements showed no evidence for an effect on mortality (relative risk 0.92, 95% CI 0.56-1.50). Limited data from only three trials showed that oral protein and energy supplements may reduce unfavourable outcome (relative risk 0.52, 95% CI 0.32-0.84). CONCLUSION: Based on limited evidence, oral protein and energy supplementation after hip fracture may reduce unfavourable outcome. Further evidence from good-quality randomised trials is required to inform clinical practice.

Aged↗

Treatment of congestive heart failure a neuroendocrine disorder.

The understanding of heart failure is no longer based on a supply and demand model of pump failure. Rather, heart failure is seen as a complex pathophysiological process with activation of various neuroendocrine systems. The goals of treatment have changed towards modifying these counterproductive neuroendocrine systems and slowing myocardial maladaptation. Angiotensin converting enzyme inhibitors are the only licensed drugs in veterinary practice that have a direct effect on neurohormones in heart failure. The range of drug options in human medicine is greater and some of these drugs are also increasingly being used in veterinary cardiology practice. This review describes the neuroendocrine systems involved in heart failure and discusses the range of drugs available in human and veterinary medicine. In doing so, it concentrates on the evidence available from good quality randomised trials in both the veterinary field and, where relevant, the human medical field.

Adrenergic beta-Antagonists↗

Clinicians' attitudes to recruitment to randomised trials in cancer care: a qualitative study.

OBJECTIVES: To explore attitudes to and problems experienced with recruitment into randomised trials in cancer care. METHODS: In-depth semi-structured interviews with a purposive sample of 20 hospital clinicians in the South West of England identified from 192 participants in a larger postal survey. Interviews were recorded on audiotape and fully transcribed. Data were analysed by comparing transcripts and describing emergent themes. RESULTS: Clinicians do not always find it easy to identify key randomised trials in their area of interest. Even when they identify those trials in which they would like to participate, they are not always able to recruit patients. Although recruitment can be hindered by the time and administration involved and the resources needed, the attitudes of clinicians to research in general, the design of randomised trials, clinicians' concerns regarding individual patients and patients' preferences for different treatments also present major barriers. Other factors of concern include the imposition of strict eligibility criteria and the expense and complexity of monitoring and follow-up. CONCLUSION: Barriers to recruitment depend on the clinicians' individual situations and on a complex combination of factors. Action is needed to promote awareness of randomised trials under way, to ensure that trials address issues of importance, are acceptable to patients and clinicians, and that practical support is provided for participating centres.

Attitude of Health Personnel↗

Tanacetum parthenium and Salix alba (Mig-RL) combination in migraine prophylaxis: a prospective, open-label study.

BACKGROUND: Tanacetum parthenium (feverfew) has been used traditionally to treat migraine, and although its mechanism of action is not fully understood, serotonin 5-HT receptor blocking effects have been suggested. T. parthenium and Salix alba (white willow) either alone or in combination (Mig-RL) were recently shown to inhibit binding to 5-HT(2A/2C) receptors; T. parthenium failed to recognise 5-HT(1D) receptors, whereas S. alba or the combination did. It was hypothesised that S. alba in combination with T. parthenium may provide superior migraine prophylactic activity compared with T. parthenium alone. METHODS: A prospective, open-label study was performed in 12 patients diagnosed with migraine without aura. Twelve weeks' treatment with T. parthenium 300 mg plus S. alba 300 mg (Mig-RL) twice daily was administered to determine the effects of therapy on migraine attack frequency (primary efficacy criterion), intensity and duration (secondary efficacy criteria), and quality of life, together with tolerability for patients. RESULTS: Attack frequency was reduced by 57.2% at 6 weeks (p < 0.029) and by 61.7% at 12 weeks (p < 0.025) in nine of ten patients, with 70% patients having a reduction of at least 50%. Attack intensity was reduced by 38.7% at 6 weeks (p < 0.005) and by 62.6% at 12 weeks (p < 0.004) in ten of ten patients, with 70% of patients having a reduction of at least 50%. Attack duration decreased by 67.2% at 6 weeks (p < 0.001) and by 76.2% at 12 weeks (p < 0.001) in ten of ten patients. Two patients were excluded for reasons unrelated to treatment. Self-assessed general health, physical performance, memory and anxiety also improved by the end of the study. Mig-RL treatment was well tolerated and no adverse events occurred. CONCLUSION: The remarkable efficacy of Mig-RL in not only reducing the frequency of migraine attacks but also their pain intensity and duration in this trial warrants further investigation of this therapy in a double-blind, randomised, placebo-controlled investigation involving a larger patient population.

Adult↗

[The different meanings of the word stratification].

In clinical research, stratification has three different meanings. In its first meaning, it describes the natural distribution of patients into subgroups, for instance patients may be stratified by stage. In its second meaning, stratification controls the random allocation of the treatments in a clinical trial, for instance the randomisation can be stratified on stage. Lastly, in its third meaning, stratification of a trial analysis consists into taking into account patients' characteristics in the analysis. This three meanings will be illustrated with a basic example.

Humans↗

Calcitonin for metastatic bone pain.

BACKGROUND: Pain is the most frequent symptom experienced by cancer patients, its intensity dependent on the site of the tumour. Tumours that compromise bone or nervous structures due to the bone destruction process are the most painful. There are several treatments to deal with pain (and other symptoms) caused by bone metastases. The hormone, calcitonin, has the potential to relieve pain, and also retain bone density, thus reducing the risk of fractures. This review is an update of a previously published review in The Cochrane Library (Issue 3, 2003) on this topic. OBJECTIVES: To assess the effectiveness of calcitonin in controlling metastatic bone pain and reducing bone complications (hypercalcemia, fractures and nerve compression) in patients with bone metastases. SEARCH STRATEGY: Electronic searches were performed in MEDLINE (1966 to 2005), EMBASE (1974 to 2005), the Cochrane Central Register of Controlled Trials (Issue 2, 2005), specialised registers of the Cochrane Cancer Network and of the Cochrane Pain, Palliative and Supportive Care Group. Registers of clinical trials in progress were also searched. SELECTION CRITERIA: Studies were included if they were randomised, double-blind clinical trials of patients with metastatic bone pain, treated with calcitonin, where the major outcome measure was pain, assessed at four weeks or longer. DATA COLLECTION AND ANALYSIS: Study selection and data extraction were performed by two independent review authors. Only two studies (90 patients) were eligible for inclusion in the review and therefore meta-analysis of the data was not possible. Intention-to-treat analysis was performed by imputing all missing values as adverse outcomes. MAIN RESULTS: Of the two small studies included in the review, one study showed a non-significant effect of calcitonin in the number of patients with total pain reduction (RR 2.50; CI 95%, 0.55 to 11.41). The second study provided no evidence that calcitonin reduced analgesia consumption (RR 1.05; CI 95%, 0.90 to 1.21) in patients with painful bone metastases. There was no evidence that calcitonin was effective in controlling complications due to bone metastases; for improving quality of life; or patients' survival. Although not statistically significant, a greater number of adverse effects were observed in the groups given calcitonin in the two included studies (RR 3.35, CI 95%, 0.72 to 15.66). AUTHORS' CONCLUSIONS: The limited evidence currently available does not support the use of calcitonin to control pain from bone metastases. Since the last version of this review, none of the new relevant studies have provided additional information on this treatment, in contrast to other therapeutic approaches that should be considered.

Bone Neoplasms↗

Interventions for intermittent exotropia.

BACKGROUND: The clinical management of intermittent exotropia has been discussed frequently in the literature, but there is a lack of clarity regarding the indications for intervention, the most effective type and if there is a time point at which it should be carried out. OBJECTIVES: The objective of this review was to analyse the effects of various surgical and non-surgical treatments in randomised trials of people with intermittent exotropia, to report intervention criteria and determine the significance of factors such as age with respect to outcome. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials - CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) on The Cochrane Library (2006, Issue 1), MEDLINE (1966 to March 2006), EMBASE (1980 to March 2006) National Research Register (2006, Issue 1), PubMed (searched on 13 March 2006; last 90 days) and LILACS (Latin American and Caribbean Literature on Health Sciences) (1966 to 2002). We manually searched the British Orthoptic Journal, proceedings of the European Strabismological Association (ESA), International Strabismological Association (ISA) and American Academy of Paediatric Ophthalmology and Strabismus meeting (AAPOS). We contacted researchers who are active in the field for information about further published or unpublished studies. There were no language restrictions in the manual or electronic searches. SELECTION CRITERIA: We included randomised controlled trials of any surgical or non-surgical treatment for intermittent exotropia. DATA COLLECTION AND ANALYSIS: Each review author independently assessed study abstracts identified from the database and manual searches. Author analysis was then compared and full papers for appropriate studies were obtained. MAIN RESULTS: We found one randomised trial that was eligible for inclusion. This trial showed that unilateral surgery was more effective than bilateral surgery for correcting basic intermittent exotropia. AUTHORS' CONCLUSIONS: The available literature consists mainly of retrospective case reviews which are difficult to reliably interpret and analyse. The one randomised trial included found unilateral surgery more effective than bilateral for basic intermittent exotropia but there remains a need for more carefully planned clinical trials to be undertaken to improve the evidence base for the management of this condition.

Exotropia↗

Screening for prostate cancer.

BACKGROUND: Any form of screening aims to reduce mortality and increase a person's quality of life. Screening for prostate cancer has generated considerable debate within the medical community, as demonstrated by the varying recommendations made by medical organizations and governed by national policies. Much of this debate is due to the limited availability of high quality research and the influence of false-positive or false-negative results generated by use of the diagnostic techniques such as the digital rectal examination (DRE) and prostate specific antigen (PSA) blood test. OBJECTIVES: To determine whether screening for prostate cancer reduces prostate cancer mortality and has an impact on quality of life. SEARCH STRATEGY: Electronic databases (PROSTATE register, CENTRAL the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, CANCERLIT and the NHS EED) were searched electronically in addition to hand searching of specific journals and bibliographies in an effort to identify both published and unpublished trials. SELECTION CRITERIA: All randomised controlled trials of screening versus no screening or routine care for prostate cancer were eligible for inclusion in this review. DATA COLLECTION AND ANALYSIS: The search identified 99 potentially relevant articles that were selected for full text review. From these 99 citations, two randomised controlled trials were identified as meeting the review's inclusion criteria. Data from the trials were independently extracted by two authors. MAIN RESULTS: Two randomised controlled trials with a total of 55,512 participants were included; however, both trials had methodological weaknesses. Re-analysis using intention-to-screen and meta-analysis of results from the two randomised controlled trials indicated no statistically significant difference in prostate cancer mortality between men randomised for prostate cancer screening and controls (RR 1.01, 95% CI: 0.80-1.29). Neither study assessed the effect of prostate cancer screening on quality of life, all-cause mortality or cost effectiveness. AUTHORS' CONCLUSIONS: Given that only two randomised controlled trials were included, and the high risk of bias of both trials, there is insufficient evidence to either support or refute the routine use of mass, selective or opportunistic screening compared to no screening for reducing prostate cancer mortality. Currently, no robust evidence from randomised controlled trials is available regarding the impact of screening on quality of life, harms of screening, or its economic value. Results from two ongoing large scale multicentre randomised controlled trials that will be available in the next several years are required to make evidence-based decisions regarding prostate cancer screening.

Humans↗

Effects of cognitive behavioural group training (CBGT) in adult patients with poorly controlled insulin-dependent (type 1) diabetes: a pilot study.

A substantial group of patients with type 1 diabetes has difficulty adhering to the treatment regimen, and as a consequence is at increased risk of developing microvascular complications. Cognitive behavioural interventions may help these patients to cope more effectively with their diabetes. We developed a 4 weeks cognitive behavioural group training (CBGT) for patients with type 1 (insulin-dependent) diabetes in persistent poor glycaemic control, to help them overcome negative beliefs and attitudes towards diabetes and improve their self-care behaviours. Feasibility and efficacy of CBGT were tested in a non-randomised prospective study in 24 poorly-controlled type 1 diabetes patients (mean age 35.2+/-11.1years; 15 female; mean HbA(1c) 9.3% (+/-1.2)), with assessments at 3 and 6 months follow-up. The programme was delivered in small groups (n=6-8), by a team of a diabetes nurse specialist and a psychologist. Primary outcome measures were glycosylated haemoglobin (HbA(1c)), diabetes-related emotional distress (PAID) and psychological well-being (WBQ-12). Changes in diabetes self-care activities (DSCI) were documented, along with perceived barriers in diabetes questionniare (BDQ) and fear of hypoglycaemia survey (HFS). Data were analysed using repeated measures analysis of variance. The CBGT proved to be feasible in this selected group of patients and was well appreciated. Following CBGT, mean HbA(1c) dropped by 0.8% at 6 months from baseline, while emotional well-being was preserved. It is concluded that CBGT is a promising intervention that deserves further evaluation in randomised controlled trials.

Adult↗

Identifying outcome reporting bias in randomised trials on PubMed: review of publications and survey of authors.

OBJECTIVE: To examine the extent and nature of outcome reporting bias in a broad cohort of published randomised trials. DESIGN: Retrospective review of publications and follow up survey of authors. Cohort All journal articles of randomised trials indexed in PubMed whose primary publication appeared in December 2000. MAIN OUTCOME MEASURES: Prevalence of incompletely reported outcomes per trial; reasons for not reporting outcomes; association between completeness of reporting and statistical significance. RESULTS: 519 trials with 553 publications and 10,557 outcomes were identified. Survey responders (response rate 69%) provided information on unreported outcomes but were often unreliable--for 32% of those who denied the existence of such outcomes there was evidence to the contrary in their publications. On average, over 20% of the outcomes measured in a parallel group trial were incompletely reported. Within a trial, such outcomes had a higher odds of being statistically non-significant compared with fully reported outcomes (odds ratio 2.0 (95% confidence interval 1.6 to 2.7) for efficacy outcomes; 1.9 (1.1 to 3.5) for harm outcomes). The most commonly reported reasons for omitting efficacy outcomes included space constraints, lack of clinical importance, and lack of statistical significance. CONCLUSIONS: Incomplete reporting of outcomes within published articles of randomised trials is common and is associated with statistical non-significance. The medical literature therefore represents a selective and biased subset of study outcomes, and trial protocols should be made publicly available.

Bias↗

Who defaults after treatment for gonorrhoea? Randomised controlled study of effect of an educational leaflet.

A study of patients with gonorrhoea showed that those who defaulted most from follow up were male, heterosexual, and had multiple sexual partners. A prospective, blind, randomised controlled trial showed that a leaflet giving information about gonorrhoea had a positive effect on follow up attendance by women, but no appreciable effect on rates of defaulting overall. This has implications for the initial treatment schedules.

Adolescent↗

Consent and equipoise, the crucial ethical issues in randomised clinical trials.

Randomised clinical trials are widely accepted as the gold standard of clinical research. They seem to be the only means of conclusively establishing a relationship between an intervention and an observed outcome. However, randomisation by definition rules out individual choice of a treatment option. The justification of randomising is that the different options are in equipoise, and therefore no patient is at a disadvantage in the trial. There is concern whether equipoise, in a strict sense, is at all possible. This would require that there is no evidence as to the comparative efficacy of the treatments to be tested. This condition is in contrast to an honest null hypothesis. Several suggestions have been made to solve the tension of the equipoise requirement and are discussed in this paper. The second important condition for randomised clinical trials is to obtain informed consent from the patient. Valid consent requires that it is given voluntarily by a competent person who is adequately informed.

Austria↗

Cimetidine and chlorpheniramine in the treatment of psoriasis.

We examined the efficacy of cimetidine and chlorpheniramine alone and in combination in the treatment of psoriasis under the conditions of a randomised controlled double-blind study. Analysis of data from 52 patients revealed that none of the treatment regimes showed a demonstrable beneficial effect on the course of the psoriasis.

Chlorpheniramine↗

Therapeutic benefit of bisphosphonates in the management of prostate cancer-related bone disease.

A diversity of bone pathology is present in men with prostate cancer. Androgen deprivation therapy (ADT) can cause significant and progressive osteopoenia and osteoporosis. Bone is also the primary site for metastases leading to associated pain, skeletal fractures and hypercalcaemia. Bisphosphonate therapy decreases bone resorption, which may prevent or reverse loss of bone mineral density. Both pamidronate and zoledronic acid have proven efficacy in preventing ADT-induced bone loss. In a randomised, placebo-controlled trial, in men with hormone-refractory prostate cancer, there was a decreased incidence of skeletal- related adverse events in men receiving zoledronic acid. So far, randomised trials have failed to show improved pain control. Formalised guidelines are needed to help clinicians decide which patients should be treated with bisphosphonates, when to initiate therapy and for what duration.

Androgens↗

[Calcium antagonists in cardiovascular disease. Clinical evidence from morbidity and mortality trials].

Calcium antagonists, particularly the newer, longer-acting agents, are clearly effective in reducing elevated blood pressure with minimal to modest adverse effect profiles, and are therefore used extensively. The goal of antihypertensive therapy, however, is not simply to reduce blood pressure, but also to reduce vascular injury due to hypertension. Prospective controlled clinical trials evaluating cardiovascular morbidity and mortality are needed to test calcium antagonists in patients with hypertension. This review summarises the design and, in some cases, the results of 7 trials (5 of them still ongoing) that have provided insight into the effects of moderate- to long-acting calcium antagonists on mortality and target-organ damage in patients with hypertension. The Systolic Hypertension in Europe (Syst-Eur) trial studied 4695 elderly patients with isolated systolic hypertension, and demonstrated significant reductions in stroke and all fatal and nonfatal cardiac end-points in patients randomised to nitrendipine versus placebo. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) compares the effects of standard diuretic treatment with 3 alternatives (amlodipine, lisinopril, and doxazosin) on the incidence of fatal coronary artery disease and nonfatal myocardial infarction in more than 42,000 hypertensive patients with additional cardiovascular risk factors. The Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) compares the effects of amlodipine +/- perindopril with atenolol +/- bendrofluazide on fatal coronary artery disease and nonfatal myocardial infarction in 18,000 high risk patients. The Controlled ONset Verapamil INvestigation of Cardiovascular End-points (CONVINCE) study is assessing the incidence of fatal or nonfatal myocardial infarction and stroke, and cardiovascular disease-related death in patients on controlled-onset extended-release verapamil compared with a standard regimen of hydrochlorothiazide or atenolol. The Nordic Diltiazem Study (NORDIL) also compares a calcium antagonist (diltiazem) with conventional antihypertensive drug treatment (diuretics or beta-blockers) with add-on therapy as needed, in preventing cardiovascular mortality or morbidity. The Prospective Randomized Evaluation of the Vascular Effects of Norvasc Trial (PREVENT) tests a similar hypothesis, examining the effects of amlodipine on atherosclerotic lesions. The African-American Study of Kidney Disease (AASK) trial is evaluating the effects of amlodipine in hypertensive patients with renal disease. These important clinical trials of different classes of antihypertensive agents are critical for optimising the treatment of hypertensive patients in order to prevent coronary artery disease and other vascular diseases in this new millennium. Importantly, these randomised trials are free of the major problems of observational studies, i.e., confounding by indication, and should fully address the concerns raised by observational studies and small, under-powered, randomised trials that calcium antagonists may have adverse effects on myocardial infarction, bleeding and cancer. To date, these trials in progress have provided no evidence to support these concerns.

Aged↗

[Interactions between radiation and hormonal therapy in breast cancer: simultaneous or sequential treatment].

BACKGROUND: Combining radiation and hormone therapy (administration of selective estrogen receptor modulators) has become common clinical practice in recent years for receptor positive breast cancer. Little is known about a possible interaction of both treatment modalities if they are given simultaneously. Tamoxifen (antiestrogen molecule, triphenylethylene derivative) may theoretically render cancer cells less responsive to radiotherapy arresting hormone-receptor-positive cells in G0/G1 phase and increase the risk of breast and lung fibrosis stimulating the secretion of transforming growth factor beta in human fibroblasts. PURPOSE: This article reviews the published data to assess the impact of sequencing of hormonal and radiation therapy on outcomes in breast cancer. METHODS: Computerised searches for publications debating the sequencing of hormonal therapy relative to radiation therapy were done using MEDLINE data. RESULTS: Results of tamoxifen experiments with cell culture regarding radioprotection of tumour clonogens are conflicting. In contrast to in vitro results, in animal studies no protective effect of tamoxifen was observed. In one in vitro study, letrozole (non-steroid selective aromatase inhibitor) had a radiosensitizing effect on breast-cancer lines. No randomised clinical trials to date have studied sequencing of tamoxifen or other selective estrogen receptor modulators and radiotherapy. Results from retrospective clinical studies which included treatment arms with and without tamoxifen showed reduction in tumour recurrence with tamoxifen. Some of these studies have noted increased risk of lung and breast fibrosis with tamoxifen with radiotherapy. Results of three articles examined the effect of tamoxifen sequence showed no adverse effect on local control or survival in sequential versus concurrent tamoxifen and radiation patients. One of the three studies also assessed the risk of complications with respect to the timing of tamoxifen with radiotherapy. There was no difference in the rates of complications between the two groups. The association of radiation and selective aromatase inhibitors or aromatase inactivators has not been addressed in clinical studies. CONCLUSIONS: Combined application of tamoxifen and radiotherapy improves survival and local control in breast cancer. Available clinical studies do not indicate that the simultaneous application of tamoxifen and radiotherapy is disadvantageous, as was suggested by some of the in vitro studies. The risk of subcutaneous breast and lung fibrosis might be slightly increased if tamoxifen is given simultaneously with radiotherapy. Both treatment modalities should be started early after surgery. There is no sufficient evidence to withhold tamoxifen administration during irradiation of breast cancer. The issue of optimal sequencing of hormonal and radiotherapy should be addressed in randomised clinical trials.

Animals↗