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PubMed2006

Immunotherapy for IgM anti-myelin-associated glycoprotein paraprotein-associated peripheral neuropathies.

BACKGROUND: Serum monoclonal anti-myelin associated glycoprotein antibodies may be pathogenic in some people with IgM paraprotein and demyelinating neuropathy. Immunotherapies aimed at reducing the level of these antibodies might be expected to be beneficial. OBJECTIVES: To examine the efficacy of any form of immunotherapy in reducing disability and impairment resulting from IgM anti-myelin associated glycoprotein paraprotein-associated demyelinating peripheral neuropathy. SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group Register (March 2005), MEDLINE (January 1966 to March 2005) and EMBASE (January 1980 to March 2005) for controlled trials. We also checked bibliographies and contacted authors and experts in the field. SELECTION CRITERIA: We included randomised or quasi-randomised controlled trials of participants of any age treated with any type of immunotherapy for anti-myelin-associated glycoprotein antibody associated demyelinating peripheral neuropathy with monoclonal gammopathy of undetermined significance of any severity. Our primary outcome measure was change in the Neuropathy Impairment Scale or Modified Rankin Scale at six months after randomisationSecondary outcome measures were: Neuropathy Impairment Scale or the Modified Rankin Score at 12 months after randomisation; ten-metre walk time, subjective clinical scores and electrophysiological parameters at six and 12 months after randomisation; IgM paraprotein levels and anti-myelin associated glycoprotein antibody titres at six months after randomisation and adverse effects of treatments. DATA COLLECTION AND ANALYSIS: We identified eight possible trials. Of these, five randomised controlled trials were included after discussion between the authors. One author extracted and the other checked the data. No missing data could be obtained from trial authors. MAIN RESULTS: The five eligible trials (97 participants) tested intravenous immunoglobulin, interferon-alpha or plasma exchange. Only two, of intravenous immunoglobulin, had comparable interventions and outcomes but both were short-term. There were no significant benefits of the treatments used in the outcomes predefined for this review, but not all the predefined outcomes were used in every included trial. Intravenous immunoglobulin showed benefits in terms of improvement in Modified Rankin Scale at two weeks and 10-metre walk time at four weeks. Serious adverse effects of intravenous immunoglobulin are known to occur from observational studies but none were encountered in these trials. AUTHORS' CONCLUSIONS: There is inadequate reliable evidence from trials of immunotherapies in anti-myelin associated glycoprotein paraproteinaemic neuropathy to recommend any particular immunotherapy treatment. Intravenous immunoglobulin is relatively safe and may produce some short-term benefit. Large well-designed randomised trials of at least six to 12 months duration are required to assess existing or novel therapies.

Demyelinating Diseases↗
PubMed2004

Hyperbaric oxygen therapy for chronic wounds.

BACKGROUND: Chronic wounds are common and present a health problem with significant effect on quality of life. The wide range of therapeutic strategies for such wounds reflects the various pathologies that may cause tissue breakdown, including poor blood supply resulting in inadequate oxygenation of the wound bed. Hyperbaric oxygen therapy (HBOT) has been suggested to improve oxygen supply to wounds and therefore improve their healing. OBJECTIVES: To assess the benefits and harms of adjunctive HBOT for treating chronic ulcers of the lower limb (diabetic foot ulcers, venous and arterial ulcers and pressure ulcers). SEARCH STRATEGY: We searched the Cochrane Wounds Group Specialised Trial Register (searched 6 February 2003), CENTRAL (The Cochrane Library Issue 1, 2003), Medline (1966 - 2003), EMBASE (1974 - 2003), DORCTHIM (1996 - 2003), and reference lists of articles. Relevant journals were handsearched and researchers in the field were contacted. SELECTION CRITERIA: Randomised studies comparing the effect on chronic wound healing of therapeutic regimens which include HBOT with those that exclude HBOT (with or without sham therapy). DATA COLLECTION AND ANALYSIS: Three reviewers independently evaluated the quality of the relevant trials using the validated Oxford-Scale (Jadad 1996) and extracted the data from the included trials. MAIN RESULTS: Five trials contributed to this review. Diabetic foot ulcer (4 trials, 147 patients): Pooled data of three trials with 118 patients showed a reduction in the risk of major amputation when adjunctive HBOT was used, compared to the alternative therapy (RR 0.31, 95% CI 0.13 to 0.71). Sensitivity analysis for the allocation of dropouts did not significantly alter that result. This analysis predicts that we would need to treat 4 individuals with HBOT in order to prevent 1 amputation in the short term (NNT 4, 95% CI 3 to 11). There was no statistically significant difference in minor amputation rate (pooled data of two trials with 48 patients). Healing rates were reported in one trial (Abidia 2003) which showed a significant improvement in the chance of healing 1 year after therapy (RR for failure to heal with sham 2.3, 95%CI 1.1 to 4.7, P=0.03), although no effect was determined immediately post HBOT, nor at 6 months. Further, the beneficial effect after 1 year was sensitive to allocation of dropouts. Venous ulcer: (1 trial, 16 patients): This trial reported data at six weeks (wound size reduction) and 18 weeks (wound size reduction and healing rate) and suggested a significant benefit of HBOT in terms of reduction in ulcer area only at 6 weeks (WMD 33%, 95%CI 19% to 47%, P<0.00001). Arterial and pressure ulcers: No trials that satisfied inclusion criteria were located. REVIEWERS' CONCLUSIONS: In people with foot ulcers due to diabetes, HBOT significantly reduced the risk of major amputation and may improve the chance of healing at 1 year. The application of HBOT to these patients may be justified where HBOT facilities are available, however economic evaluations should be undertaken. In view of the modest number of patients, methodological shortcomings and poor reporting, this result should be interpreted cautiously however, and an appropriately powered trial of high methodological rigour is justified to verify this finding and further define those patients who can be expected to derive most benefit from HBOT. Regarding the effect of HBOT on chronic wounds associated with other pathologies, any benefit from HBOT will need to be examined in further, rigorous randomised trials. The routine management of such wounds with HBOT is not justified by the evidence in this review.

Amputation, Surgical↗
PubMed1998

Continuous infusional chemotherapy for early breast cancer: the Royal Marsden Hospital experience.

5-FU is a cycle-specific S-phase-dependent drug with a short half life of 10-20 min. There is therefore a rationale for its use in long-term continuous infusional therapy, with doses of up to 300 mg/m2 per day proving feasible for prolonged periods. The schedule is active in patients with heavily pre-treated breast cancer, with responses in up to 53% (overall 29%). At the Royal Marsden Hospital we have evaluated infusional 5-FU 200 mg/m2 per day for up to 6 months in combination with 3-weekly bolus epirubicin (E) 60 mg/m2 and cisplatin (C) 60 mg/m2 (infusional ECF) as pre-operative/neo-adjuvant treatment in 123 patients with operable breast cancer greater than 3 cm (median 6 cm), initially in a phase II study of 50 patients and subsequently as part of a randomised phase III trial. One hundred and eighteen (96%) have achieved objective tumour responses, with 67 (57%) achieving CR. The 5-year actuarial survival rate is 78% and the local recurrence rate without associated metastatic disease 12%. The pathological complete remission (CR) rate was 16%, with a further 5% having residual DCIS only. Pathological CR but not clinical CR is an independent predictor for disease-fee survival. The Royal Marsden is now conducting two multicentre randomised trials of infusional ECF: (i) versus conventional AC (adriamycin cyclophosphamide) as pre-operative/neo-adjuvant chemotherapy, with 376 patients so far randomised towards a target of 400; and (ii), more recently, a similar adjuvant trial versus conventional FEC (5-FU, epirubicin, cyclophosphamide), with 168 patients so far randomised. These trials will determine whether encouraging phase II activity with continuous infusional chemotherapy translates eventually into real survival benefit for patients with early breast cancer.

Breast Neoplasms↗
PubMedDate not supplied

Modulating the design of clinical trials to address the question of mechanisms of disease.

The evaluation of causation of a disease is judgemental. It should be based on an overview of how far the observed association satisfies several criteria, including its strength, dose response, temporal sequence, independence, consistency, presence of a plausible mechanism, predictive power, and reversibility. Whilst the results of randomised controlled trials are frequently incorrectly considered as proof (or otherwise) of causation, what they do allow is an evaluation of the reversibility of disease. Whilst reversibility is one of the criteria which allows causation to be judged and randomised trials are reasonably considered as the 'gold standard' study design, they do not necessarily shed light on mechanisms of disease, particularly in the context of chronic degenerative disorders such as those underpinned by the atherosclerotic process.

Humans↗
PubMed1998

Can unequal be more fair? Ethics, subject allocation, and randomised clinical trials.

Randomised clinical trials provide the most valid means of establishing the efficacy of clinical therapeutics. Ethical standards dictate that patients and clinicians should not consent to randomisation unless there is uncertainty about whether any of the treatment options is superior to the others ("equipoise"). However, true equipoise is rarely present; most randomised trials, therefore, present challenging ethical dilemmas. Minimising the tension between science and ethics is an obligation of investigators and clinicians. This article briefly reviews several techniques for addressing this issue and suggests that unbalanced randomisation, a technique rarely employed in current clinical trial practice, may be useful for enhancing the ethical design of human experimentation.

Attitude to Health↗
PubMed1996

The role of induction androgen deprivation prior to radical prostatectomy.

In patients with localised prostate cancer and a life expectancy of at least 10 years, radical prostatectomy is increasingly being performed. Pre-operative clinical staging of prostate cancer is, however, inaccurate with around 10-20% of clinical T1, 10-30% of clinical T2a, and 30-60% of clinical T2b cases having tumour at the surgical margin. There is no documented best treatment for patients with a positive surgical margin. Options include close observation, adjuvant radiation therapy or androgen deprivation. The role of induction androgen deprivation has, therefore, evolved in an attempt to improve upon the cure rate for radical prostatectomy, and in this review results from clinical trials are discussed. In the largest United States randomised trial in patients with stage T2b prostate cancer, pre-operative androgen deprivation resulted in a significantly lower rate of positive surgical margins, normalisation of prostate-specific antigen and a decrease in the size of the prostate. Sufficient follow-up is required from all of the completed prospective randomised trials before pre-operative androgen deprivation can be justified in all T2b patients.

Androgen Antagonists↗
PubMed2004

Quantifying adverse drug events : are systematic reviews the answer?

Quantifying adverse drug events (ADEs) is critical to clinicians, consumers and policy makers. Most ADE information comes from large clinical trials. Systematic reviews have become a popular tool in quantifying the efficacy of different therapeutic interventions and ADE data collected in randomised trials may be helpful in quantifying the risk associated with a specific pharmacological agent. However, clinicians who are interested in conducting systematic reviews of ADEs may face many challenges. These challenges are geared towards two main areas: poor quality of ADE reporting in randomised trials and poor indexing of ADEs in medical databases. In this review, we will discuss these challenges in detail using some examples from the literature. Where possible, we also discuss strategies that may overcome these problems. More rigourous standards of reporting ADEs in randomised trials, as well as better indexing of ADE terminology in medical databases, could one day make systematic reviews of ADEs a powerful tool for practising clinicians.

Adverse Drug Reaction Reporting Systems↗
PubMed1998

Methodological considerations in the design of the WHO Antenatal Care Randomised Controlled Trial.

We discuss methodological issues arising in a recent evaluation trial of a new antenatal care programme, as sponsored by the Special Programme of Research, Development and Research Training in Human Reproduction, and WHO's Division of Reproductive Health (Technical Support). The randomisation unit for the trial is the antenatal care clinic, with 53 clinics located in four countries randomly allocated to provide either the new programme or the traditional programme currently in use. Approximately 24,000 women presenting for antenatal care over an average period of 18 months will have been recruited.

Argentina↗
PubMed2004

Antibiotic prophylaxis to reduce respiratory tract infections and mortality in adults receiving intensive care.

BACKGROUND: Pneumonia is an important cause of mortality in intensive care units. The incidence of pneumonia in such patients ranges between 7% and 40%, and the crude mortality from ventilator associated pneumonia may exceed 50%. Although not all deaths in patients with this form of pneumonia are directly attributable to pneumonia, it has been shown to contribute to mortality in intensive care units independently of other factors that are also strongly associated with such deaths. OBJECTIVES: The objective of this review was to assess the effects of antibiotics for preventing respiratory tract infections and overall mortality in adults receiving intensive care. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (issue 3, 2003), which contains the Acute Respiratory Infections (ARI) Group specialised trials register; MEDLINE (January 1966 to September 2003); EMBASE (January 1990 to September 2003); proceedings of scientific meetings and reference lists of articles from January 1984 to December 2002. We also contacted investigators in the field. SELECTION CRITERIA: Randomised trials of antibiotic prophylaxis for respiratory tract infections and deaths among adult intensive care unit patients. DATA COLLECTION AND ANALYSIS: At least two reviewers independently extracted data and assessed trial quality. MAIN RESULTS: Overall 36 trials involving 6922 people were included. There was variation in the antibiotics used, patient characteristics and risk of respiratory tract infections and mortality in the control groups. In 17 trials (involving 4295 patients) that tested a combination of topical and systemic antibiotic, the average rates of respiratory tract infections and deaths in the control group were 36% and 29% respectively. There was a significant reduction of both respiratory tract infections (odds ratio 0.35, 95% confidence interval 0.29 to 0.41) and total mortality (odds ratio 0.78, 95% confidence interval 0.68 to 0.89) in the treated group. On average 5 patients needed to be treated to prevent one infection and 21 patients to prevent one death. In 17 trials (involving 2664 patients) that tested topical antimicrobials alone (or comparing topical plus systemic versus systemic alone) the rates of respiratory tract infections and deaths in the control groups were 30% and 26% respectively. There was a significant reduction of respiratory tract infections (odds ratio 0.52, 95% confidence interval 0.43 to 0.63) but not in total mortality (odds ratio 0.97, 95% confidence interval 0.81 to 1.16) in the treated group. REVIEWER'S CONCLUSIONS: A combination of topical and systemic prophylactic antibiotics reduces respiratory tract infections and overall mortality in adult patients receiving intensive care. A treatment based on the use of topical prophylaxis alone reduces respiratory infections but not mortality. The risk of occurrence of resistance as a negative consequence of antibiotic use was appropriately explored only in the most recent trial by de Jonge which did not show any such effect.

Adult↗
PubMed2000

Oestrogen and progestogen hormone replacement therapy for peri-menopausal and post-menopausal women: weight and body fat distribution.

BACKGROUND: Hormone replacement therapy (HRT) is commonly prescribed to treat menopausal symptoms and to prevent post-menopausal bone loss. However, many women are concerned about hormonal replacement therapy because they believe that such treatment will result in weight gain. The effect of HRT on weight and body fat distribution has not yet been examined in systematic reviews. It is an important topic since many women decline oestrogen therapy due to their concerns about resultant weight gain, and thus forego its potential therapeutic benefits. OBJECTIVES: To evaluate the effect of unopposed oestrogen or combined oestrogen and progestogen hormone replacement therapy (HRT) upon the weight and body fat distribution of perimenopausal and postmenopausal women. SEARCH STRATEGY: The search strategy of the Menstrual Disorders and Subfertility Group was used for the identification of randomised controlled trials (RCTs). Computerised searches of MEDLINE, EMBASE, Current Contents, Biological Abstracts and CINAHL were performed. Attempts were made to identify trials from citation lists of review articles and relevant papers already obtained. In most cases, first authors of each eligible trial were contacted for additional information. All those trials that had been located as at August 1998 were examined for eligibility. SELECTION CRITERIA: All randomised, placebo or no treatment controlled trials that detailed the effect of HRT on weight or body fat distribution, including studies where HRT was combined with other therapy such as diet, supplements or exercise. Studies were eligible for consideration even though the main focus of the trial may have been on another aspect of HRT. Previous HRT use should have ceased at least one month (in the case of patches, cream or gel) or three months (for oral preparations or subcutaneous pellets) before commencement of the study. DATA COLLECTION AND ANALYSIS: Twenty two RCTs were identified that fulfilled the inclusion criteria for this review. The results of one trial were not available in a form that allowed it to be included in the meta-analysis; however, it has been included in the text of the review for discussion. Twenty four RCTs are awaiting assessment pending additional information from first authors. Two reviewers extracted the data independently, and the weighted mean differences for continuous outcomes were estimated from the data. Results for unopposed oestrogen and combined oestrogen were analysed separately, and the effect of each treatment regimen on body weight, BMI, waist-hip ratio, fat mass and skinfold measurement was examined where available. The effect of differing dosage levels on these parameters was also examined. MAIN RESULTS: Outcomes were evaluated separately for unopposed oestrogen and oestrogen/progestogen regimens. Statistical analysis was performed using the weighted mean difference for continuous outcomes as recommended by the Cochrane Menstrual Disorders and Subfertility Group. No statistically significant difference was found in mean weight gain between those using unopposed oestrogen and non-HRT users (0.66 kg, 95% CI -0.62, 1.93). No significant difference was found in mean weight gain between those using oestrogen/progestogen therapy and non-HRT users (-0.47 kg, 95% CI -1.63, 0.69). Insufficient data exist to enable meta-analysis of the effect of unopposed oestrogen on BMI. The reviewers found no statistically significant difference in mean BMI increase between those using oestrogen/progestogen and non-HRT users (-0.50, 95% CI -1.06, 0.06). Insufficient data exist to enable meta-analysis of the effect of HRT on waist-hip ratio, fat mass or skinfold thickness. REVIEWER'S CONCLUSIONS: There is evidence of no effect of unopposed oestrogen or combined oestrogen on body weight, indicating that these regimens do not cause extra weight gain in addition to that normally gained at menopause. (ABSTRACT TRUNCATED)

Body Mass Index↗
PubMed1999

Randomised controlled trials of ursodeoxycholic-acid therapy for primary biliary cirrhosis: a meta-analysis.

BACKGROUND: Ursodeoxycholic acid (UDCA) is the only approved treatment for primary biliary cirrhosis, but its effect on disease progression and survival is uncertain. The aim of this study was to clarify the efficacy of UDCA in primary biliary cirrhosis. METHODS: A systematic review, including the use of meta-analysis, was done for the randomised and switch-over phases of trials comparing UDCA with placebo, obtained from Medline and Embase databases, and from manual searches derived from review articles and abstracts of major international meetings. All trials had more than a mean of 6 months' follow-up and only included patients with primary biliary cirrhosis (PBC) according to established diagnostic criteria. FINDINGS: 17 relevant articles were identified: 11 randomised controlled trials, including 1272 patients, and six reports of the switch-over phases. UCDA had a favourable effect on liver biochemistry in most of the studies but not on symptoms or the progression of histological stage; two studies did not assess survival, liver transplantation, or complications of liver disease. Meta-analysis showed no difference between UDCA and placebo in the incidence of death (odds ratio 1.21, 95% CI 0.71-2.04), liver related death (0.72, 0.22-2.32), liver transplantation (1.27, 0.78-2.07), death or liver transplantation (1.26, 0.87-1.82), and in the development of complications of liver disease (1.11, 0.64-1.92). With the primary end point defined by the authors (a combined end point in three studies, and death or liver transplantation in the others) an odds ratio of 1.53 (0.97-2.42) was obtained. Assessment of the switch-over phases, during which there was a longer follow-up, did not change the results of the meta-analysis. INTERPRETATION: Published randomised controlled trials of UDCA do not show evidence of therapeutic benefit in PBC and its use as standard therapy needs to be re-examined.

Evidence-Based Medicine↗
PubMed2006

Alternative clinical end points in rectal cancer--are we getting closer?

BACKGROUND: In rectal cancer a high risk of local recurrence has been reported for patients treated by surgery alone. It is also recognised that 20%-40% of rectal cancer patients continue to develop distant metastases and die, even when a very low risk of local recurrence has been achieved with the use of preoperative radiotherapy and total mesorectal excision (TME). Hence, the current design of randomised trials in rectal cancer continues to use the standard end points of local control and survival. This strategy is time-consuming. The recently published EORTC 22921 trial, which compared radiotherapy with chemoradiotherapy and tested the role of postoperative adjuvant chemotherapy, has taken 14 years from planning to results. The aim of this review was to use the evidence from both phase II and phase III trials to provide a comprehensive survey of alternative clinical trial end points in rectal cancer, where preoperative chemoradiation has now become the standard treatment. We describe their strengths and weaknesses. Some are clearly defined, easy to assess and can be obtained early, because surgical resection usually takes place within 6-8 weeks of the completion of treatment. Some pathological response end points reflect biological activity, although their effect on survival has yet to be validated in randomised controlled trials. We will propose measurement and analytical techniques for minimising bias and intra- and inter-observer variability of the non-validated end points in the hope of basing these judgements on as firm a ground as possible. METHODS: A literature search identified both randomised and non-randomised trials of preoperative radiation therapy (RT) and chemoradiation therapy (CRT) in rectal cancer from 1993 to 2005. The aim was to find those studies that documented potential alternative end points. RESULTS: Pathological parameters have been used as early end points to compare studies of preoperative radiotherapy or chemoradiation. In the light of the German CAO/ARO/AIO-94 study, which demonstrated an improved therapeutic ratio for preoperative treatment, enthusiasm for preoperative chemoradiation in the management of rectal cancer is increasing. Current evidence cannot indicate whether the degree of response to chemoradiation (e.g. complete pathological response; downsizing the primary tumour; sterilizing the regional nodes; tumour regression grades or residual cell density) or the achievement of a curative resection (CRM/R0 resection) is the best early clinical end point. Problems with these end points include lack of structured measurement and analysis techniques to control for intra- and inter-observer variation and lack of validation as surrogates for long-term clinical end points such as local control and survival. However, retrospective studies in rectal cancer have confirmed a strong association between the presence of microscopic tumour cells within 1 mm of the CRM and increased risks of both local recurrence and distant metastases. Further end points of current clinical relevance for which adequate methodologies for assessment are lacking include sphincter sparing end points, and assessment of long-term toxicities, ano-rectal function and their specific impact on quality of life. Recommendations are made as to the most appropriate information, which should be documented in future trials. CONCLUSIONS: Pathological complete response following preoperative chemoradiation does not reliably predict late outcome. There are other events not mediated through this end point and there are also unintended effects (often an excess of non-cancer related deaths). Disease-free survival currently remains the best (because it is relatively quick) primary end point in designing randomised phase III studies of preoperative chemoradiation in rectal cancer, although it is necessary to control for postoperative adjuvant chemotherapy. However, the CRM status can substantially account for effects on disease-free and overall survival after chemoradiation, radiation or surgery alone. Hopefully, randomised controlled trials, which utilise these alternative clinical end points, will in future determine the precise percentages of the effect of different chemoradiation schedules on disease-free and overall survival.

Biomarkers, Tumor↗
PubMedDate not supplied

[Hypothermia as a neuroprotective agent].

Hypothermia has long been employed for therapeutic purposes but its use has been limited because of the potential life-threatening side-effects. In late eighties a neuroprotective effect of bold hypothermia was demonstrated and this implied that the method could be used more safely. It has then been shown in a lot of animal experiments that post-ischaemic mild hypothermia significantly limits damage to the brain caused by cardiac arrest. Similar results have been obtained for local brain ischaemia and for experimental head trauma. Molecular basis for this neuroprotection with mild hypothermia has been found to be complex, involving attenuation of the excitotoxic effects of glutamate and diminishing the synthesis of free radicals. In the last decade some clinical series and multicenter randomised trials have shown that mild hypothermia is safe and effective in global brain ischaemia due to cardiac arrest. Clinical data suggest also its effectiveness in ischaemic stroke though no multicenter randomised study has been published to date. At present there are conflicting results of clinical trials concerning brain injuries. Although some authors have reported up to 38% improvement in the outcome, a recently published multicenter randomised trial has failed to demonstrate any practical benefit of mild hypothermia after acute brain injury. There is however virtually no data in the literature on mild hypothermia in spinal cord injury.

Brain↗
PubMed1995

Support for trials of promising medications through the Pharmaceutical Benefits Scheme. A proposal for a new authority category.

I propose a new authority category for the Pharmaceutical Benefits Scheme (PBS)--authority to prescribe only within a controlled trial. This would benefit both the PBS and the pharmaceutical companies, but the main winners would be the Australian population, who would obtain better value for money spent by the PBS. Drugs which show promise, but for which conclusive evidence of advantage over standard therapy is lacking, or drugs for new indications, could be prescribed within a randomised trial. PBS support would fund a substantial portion of the trial costs. This proposal would greatly boost local and international investment in Australian medical research.

Australia↗
PubMed1998

[Roaming through methodology. X. The testing of diagnostic procedures].

In this era of evidence-based medicine, diagnostic tests cannot escape close scrutiny of their effectiveness. Sensitivity and specificity have up till now played a central role in the evaluation of diagnostic tests. These terms are not without their shortcomings when it comes to the characterisation of a test's true worth for patients. Randomised clinical trials are increasingly used for evaluation of medical tests and outlining of strategy. The indirect relationship between test results and health outcome creates additional challenges for designers of such trials.

Diagnostic Techniques and Procedures↗
PubMed2006

[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↗
PubMed2001

[Hormonal supplements for postmenopausal women: no evidence of protection against cardiovascular disease].

Atherothrombotic cardiovascular disease is a leading cause of death in women, especially in the postmenopause. It is controversial whether postmenopausal hormone replacement therapy is protective with regard to cardiovascular disease. On the one hand, observational studies consistently show that the risk of cardiovascular disease is 35 to 50% lower among users of hormonal replacement than among non-users. In addition, hormonal replacement is associated with an improvement of the lipid profile and several other potentially beneficial effects. On the other hand, two recent placebo-controlled randomised trials did not find evidence in favour of cardiovascular protection by hormonal replacement. This discrepancy may be explained by insufficient adjustment for lifestyle factors in observational studies and insufficient consideration of methodological flaws in experimental studies, both of which lead to an overestimation of the protective effect of hormonal replacement. Hormonal replacement may affect the pathophysiology of atherothrombosis in several ways, both positive and negative. Progress in this field requires the isolation of the positive effects.

Aged↗