There is currently no consensus regarding the optimal timing for androgen suppression therapy in patients with prostate cancer that have undergone local therapy with curative intent but are proven to have node-positive disease without signs of distant metastases at the time of local therapy. The objective of this systematic review was to determine the benefits and harms of early (at the time of local therapy) versus deferred (at the time of clinical disease progression) androgen suppression therapy for patients with node-positive prostate cancer after local therapy.
The protocol was registered prospectively (CRD42011001221; http://www.crd.york.ac.uk/PROSPERO). We searched the MEDLINE, EMBASE, and CENTRAL databases, as well as reference lists, the abstracts of three major conferences, and three trial registers, to identify randomized controlled trials (search update 04/08/2012). Two authors independently screened the identified articles, assessed trial quality, and extracted data.
Four studies including 398 patients were identified for inclusion. Early androgen suppression therapy lead to a significant decrease in overall mortality (HR 0.62, 95% CI 0.46-0.84), cancer-specific mortality (HR 0.34, 95% CI 0.18-0.64), and clinical progression at 3 or 9 years (RR 0.29, 95% CI 0.16-0.52 at 3 years and RR 0.49, 95% CI 0.36-0.67 at 9 years). One study showed an increase of adverse effects with early androgen suppression therapy. All trials had substantial methodological limitations.
The data available suggest an improvement in survival and delayed disease progression but increased adverse events for patients with node-positive prostate cancer after local therapy treated with early androgen suppression therapy versus deferred androgen suppression therapy. However, quality of data is low. Randomized controlled trials with blinding of outcome assessment, planned to determine the timing of androgen suppression therapy in node-positive prostate cancer using modern diagnostic imaging modalities, biochemical testing, and standardized follow-up schedules should be conducted to confirm these findings.
Prostatic neoplasms; Lymphatic metastasis; Lymph node excision; Androgen suppression therapy; Systematic review; Meta-analysis
Overweight and obesity pose a big challenge to pregnancy as they are associated with adverse maternal and perinatal outcome. Evidence of lifestyle intervention resulting in improved pregnancy outcome is conflicting. Hence the objective of this study is to determine the efficacy of antenatal dietary, activity, behaviour or lifestyle interventions in overweight and obese pregnant women to improve maternal and perinatal outcomes.
A systematic review and meta-analyses of randomised and non-randomised clinical trials following prior registration (CRD420111122 http://www.crd.york.ac.uk/PROSPERO) and PRISMA guidelines was employed. A search of the Cochrane Library, EMBASE, MEDLINE, CINAHL, Maternity and Infant care and eight other databases for studies published prior to January 2012 was undertaken. Electronic literature searches, study selection, methodology and quality appraisal were performed independently by two authors. Methodological quality of the studies was assessed according to Cochrane risk of bias tool. All appropriate randomised and non-randomised clinical trials were included while exclusions consisted of interventions in pregnant women who were not overweight or obese, had pre-existing diabetes or polycystic ovarian syndrome, and systematic reviews. Maternal outcome measures, including maternal gestational weight gain, gestational diabetes and Caesarean section, were documented. Fetal outcomes, including large for gestational age and macrosomia (birth weight > 4 kg), were also documented.
Thirteen randomised and six non-randomised clinical trials were identified and included in the meta-analysis. The evidence suggests antenatal dietary and lifestyle intervention in obese pregnant women reduces maternal pregnancy weight gain (10 randomised clinical trials; n = 1228; -2.21 kg (95% confidence interval -2.86 kg to -1.59 kg)) and a trend towards a reduction in the prevalence of gestational diabetes (six randomised clinical trials; n = 1,011; odds ratio 0.80 (95% confidence interval 0.58 to 1.10)). There were no clear differences reported for other outcomes such as Caesarean delivery, large for gestational age, birth weight or macrosomia. All available studies were assessed to be of low to medium quality.
Antenatal lifestyle intervention is associated with restricted gestational weight gain and a trend towards a reduced prevalence of gestational diabetes in the overweight and obese population. These findings need to be interpreted with caution as the available studies were of poor to medium quality.
What is the best management approach for gynecomastia?
In most patients, surgical correction usually leads to immediate cosmetic and symptomatic improvement and is considered the best approach. In men who are being treated with antiandrogen therapies, pharmacological intervention with tamoxifen is the most effective approach, followed by radiotherapy.
Pitfalls to avoid when treating gynecomastia
Failure to detect the very rare male breast cancerOverly aggressive early intervention or evaluationAppropriate medical interventionWhen to refer to specialist treatment
gynecomastia; testosterone; estrogen
Androgen ablation is the mainstay treatment for advanced prostate cancer (PC). Researchers proposed that maximum androgen blockade (MAB) therapy with antiandrogen agent in combination with castration might result in a better outcome among patients with advanced PC. In the last two decades, numerous trials and pooled data analyses were conducted to optimize the role of MAB in the treatment of metastatic PC. Non-steroidal antiandrogens administered as part of MAB proved to have a small (3%) survival benefit, however, the magnitude of this difference is of questionable clinical significance. Available evidence suggests that MAB should not be routinely offered to patients with metastatic PC, however, it should remain a reasonable option when discussing management. The standard first line treatment should be a monotherapy, consisting of orchiectomy or LHRH agonist. MAB still has a role as a short-term therapy (2-4 weeks). The ongoing large sample population based prospective studies may add new dimensions in the use of MAB in treatment of the prostate cancer in future.
Advanced prostate cancer; maximum androgen blockade; total androgen blockade
The benefits of aspirin as an anti-platelet agent are well established; however, there has been much debate about the lack of uniformity in the efficacy of aspirin to inhibit platelet function. In some patients, aspirin fails to inhibit platelets even where compliance has been verified, a phenomenon which has been termed “aspirin resistance”. These patients may in turn be at a higher risk of future vascular events. The proportion of “resistant” patients identified depends on the type of platelet function test. Therefore, the aim of this systematic review is to determine which, if any, platelet function test has utility in terms of identifying patients with a high risk of vascular events. The review has been registered with PROSPERO (CRD42012002151).
Relevant studies will be sought from bibliographic databases. Trials registers will be searched for ongoing studies. Reference lists will be checked and subject experts contacted. There will be no date or language restrictions. Standard reviewing methodology to minimise bias will be employed. Any prospective studies in patients on aspirin therapy and assessing platelet function in relation to relevant clinical outcomes will be included, as will studies reporting prognostic models. Risk of bias assessment will be based on the Quality Assessment of Diagnostic Accuracy Studies guidelines, and suitable criteria for assessing quality of prognostic studies. Data on test accuracy measures, relative risks, odds or hazard ratios will be extracted and meta-analysed, where possible, using a random-effects model to account for between-study heterogeneity. Where appropriate, the causes of heterogeneity will be explored through meta-regression and sub-group or sensitivity analyses. If platelet function testing is demonstrated to have diagnostic/predictive utility in a specific population, the potential for a cost-effectiveness analysis will be considered and, if possible, an economic model constructed. This will be supported by a systematic review of existing economic evaluation studies.
The results of the review could indicate if platelet function test(s) could lead to a reliable prediction of the risk of clinically important events in a defined population, and thus support investigations into adjustments to therapy in order to compensate for a predicted poor response to standard aspirin.
Aspirin resistance; Cardiovascular disease; Cerebrovascular disease; Diabetes; Diagnosis; Meta-analysis; Platelet function test; Prediction; Prognosis; Test accuracy
A key priority in developing policies for providing affordable cancer care is measuring the value for money of new therapies using cost-effectiveness analyses (CEAs). For CEA to be useful it should focus on relevant outcomes and include thorough investigation of uncertainty. Randomized controlled trials (RCTs) of five years of aromatase inhibitors (AI) versus five years of tamoxifen in the treatment of post-menopausal women with early stage breast cancer, show benefit of AI in terms of disease free survival (DFS) but not overall survival (OS) and indicate higher risk of fracture with AI. Policy-relevant CEA of AI versus tamoxifen should focus on OS and include analysis of uncertainty over key assumptions.
We conducted a systematic review of published CEAs comparing an AI to tamoxifen. We searched Ovid MEDLINE, EMBASE, PsychINFO, and the Cochrane Database of Systematic Reviews without language restrictions. We selected CEAs with outcomes expressed as cost per life year or cost per quality adjusted life year (QALY). We assessed quality using the Neumann checklist. Using structured forms two abstractors collected descriptive information, sources of data, baseline assumptions on effectiveness and adverse events, and recorded approaches to assessing parameter uncertainty, methodological uncertainty, and structural uncertainty.
We identified 1,622 citations and 18 studies met inclusion criteria. All CE estimates assumed a survival benefit for aromatase inhibitors. Twelve studies performed sensitivity analysis on the risk of adverse events and 7 assumed no additional mortality risk with any adverse event. Sub-group analysis was limited; 6 studies examined older women, 2 examined women with low recurrence risk, and 1 examined women with multiple comorbidities.
Published CEAs comparing AIs to tamoxifen assumed an OS benefit though none has been shown in RCTs, leading to an overestimate of the cost-effectiveness of AIs. Results of these CEA analyses may be suboptimal for guiding policy.
Bicalutamide is approved as an adjuvant to primary treatments (radical prostatectomy or radiotherapy) or as monotherapy in men with locally advanced, nonmetastatic prostate cancer (pca). However, this treatment induces gynecomastia in most patients, which often results in treatment discontinuation. Optimal therapy for these breast events is not known so far. We undertook a meta-analysis to assess the efficacy of various treatment options for bicalutamide-induced gynecomastia.
The medline, cancerlit, and Cochrane library databases were searched and the Google search engine was used to identify prospective and retrospective controlled studies published in English from January 2000 to December 2010 comparing prophylactic or curative treatment options with a control group (no treatment) for pca patients who developed bicalutamide-induced gynecomastia. Radiotherapy-induced cardiotoxicity was also evaluated.
The search identified nine controlled trials with a total patient population of 1573. Pooled results from prophylactic trials showed a significant reduction of gynecomastia in pca patients treated with prophylactic tamoxifen 20 mg daily (odds ratio: 0.06; 95% confidence interval: 0.05 to 0.09; p = 0.09), and pooled results from treatment trials showed a significant response of gynecomastia to definitive radiotherapy (odds ratio: 0.06; 95% confidence interval: 0.01 to 0.24; p < 0.0001). Aromatase inhibitors and weekly tamoxifen were not found to be effective as prophylactic and curative options. For the radiotherapy, skin-to-heart distance was found to be an important risk factor for cardiotoxicity (p = 0.006). A funnel plot of the meta-analysis showed significant heterogeneity (Egger test p < 0.00001) because of low sample size.
Our meta-analysis suggests using prophylactic tamoxifen 20 mg daily as the first-line preventive measure and radiotherapy as the first-line treatment option for bicalutamide-induced gynecomastia. Aromatase inhibitors and weekly tamoxifen are not recommended.
Meta-analysis; bicalutamide-induced gynecomastia; prostate cancer
Following publication of the PRISMA statement, the UK Centre for Reviews and Dissemination (CRD) at the University of York in England began to develop an international prospective register of systematic reviews with health-related outcomes. The objectives were to reduce unplanned duplication of reviews and provide transparency in the review process, with the aim of minimizing reporting bias.
An international advisory group was formed and a consultation undertaken to establish the key items necessary for inclusion in the register and to gather views on various aspects of functionality. This article describes the development of the register, now called PROSPERO, and the process of registration.
PROSPERO offers free registration and free public access to a unique prospective register of systematic reviews across all areas of health from all around the world. The dedicated web-based interface is electronically searchable and available to all prospective registrants. At the moment, inclusion in PROSPERO is restricted to systematic reviews of the effects of interventions and strategies to prevent, diagnose, treat, and monitor health conditions, for which there is a health-related outcome.
Ideally, registration should take place before the researchers have started formal screening against inclusion criteria but reviews are eligible as long as they have not progressed beyond the point of completing data extraction.
The required dataset captures the key attributes of review design as well as the administrative details necessary for registration.
Submitted registration forms are checked against the scope for inclusion in PROSPERO and for clarity of content before being made publicly available on the register, rejected, or returned to the applicant for clarification.
The public records include an audit trail of major changes to planned methods, details of when the review has been completed, and links to resulting publications when provided by the authors.
There has been international support and an enthusiastic response to the principle of prospective registration of protocols for systematic reviews and to the development of PROSPERO.
In October 2011, PROSPERO contained 200 records of systematic reviews being undertaken in 26 countries around the world on a diverse range of interventions.
Systematic review protocol; register; PROSPERO
Exemestane, a steroidal aromatase inhibitor, is licensed for postmenopausal patients with estrogen receptor (ER)-positive breast cancer as second-line therapy in metastatic disease following antiestrogen failure and as part of sequential adjuvant therapy following initial tamoxifen. This study is a systematic literature review, evaluating exemestane in different clinical settings. The Ovid Medline (1948–2012), Embase (1980–2012), and Web of Science (1899–2012) databases were searched. Forty-two relevant articles covering randomized controlled trials were reviewed for efficacy and safety, and three for adherence. With regard to efficacy in metastatic disease, exemestane is superior to megestrol acetate after progression on tamoxifen. There is evidence for noninferiority to fulvestrant (following a prior aromatase inhibitor) and to nonsteroidal aromatase inhibitors in the first-line setting. Combined use with everolimus is shown to be more efficacious than exemestane alone following previous aromatase inhibitor use. In the adjuvant setting, a switch to exemestane after 2–3 years of tamoxifen is superior to 5 years of tamoxifen. Exemestane is noninferior to 5 years of tamoxifen as upfront therapy, and may have a role as an extended adjuvant therapy. Used as neoadjuvant therapy, increased breast conservation is achievable. As chemoprevention, exemestane significantly reduces the incidence of breast cancer in “at-risk” postmenopausal women. Exemestane is associated with myalgias and arthralgias, as well as reduced bone mineral density and increased risk of fracture, which do not appear to persist at follow-up, with subsequent return to pretreatment values. Compared with tamoxifen, there is a reduced incidence of endometrial changes, thromboembolic events, and hot flashes. Limited evidence shows nonadherence in 23%–32% of patients. Evidence is growing in support of exemestane in all clinical settings. It is generally more efficacious and has a better safety profile than tamoxifen. How it compares with the nonsteroidal aromatase inhibitors remains to be established. Further studies are required on adherence to ensure that maximum benefit is obtained.
breast cancer; exemestane; review; adherence; metastatic; adjuvant
Adrenal androgens show a dual and apparently opposite effect on the growth of oestrogen-responsive breast cancer: they stimulate growth on their own, but counteract the growth-stimulatory effect of oestrogens. Focusing on the inhibitory action we have studied the effects of 5-en-androstene-3 beta,17 beta-diol (ADIOL) on the growth of oestrogen-responsive MCF-7 breast cancer cells in the presence of oestrogens (oestradiol and diethylstilboestrol), antiestrogens (tamoxifen) and antiandrogens (hydroxyflutamide). The inhibition of oestrogen-stimulated growth, attained with nanomolar concentrations of ADIOL, was not modified by increasing concentrations of diethylstilboestrol up to 100 nM. This inhibition was counteracted by antiandrogens, which were unable to block the ADIOL stimulatory effect in steroid-free medium. On the other hand, in the presence of tamoxifen ADIOL showed an additive antiproliferative activity also in steroid-free medium, rather than the usual stimulatory effect. These results suggest that ADIOL stimulates breast cancer cell growth via oestrogen receptors, but inhibits oestrogen-stimulated growth via androgen receptors.
The 21-gene Recurrence Score assay (RS) is prognostic for women with node-negative, estrogen receptor (ER)-positive breast cancer (BC) treated with tamoxifen. A low RS predicts little benefit of chemotherapy. For node-positive BC, we investigated whether RS was prognostic in women treated with tamoxifen alone and whether it identified those who might not benefit from anthracycline-based chemotherapy, despite higher recurrence risks.
The phase III trial S8814 for postmenopausal women with node-positive, ER-positive BC showed that CAF chemotherapy prior to tamoxifen (CAF-T) added survival benefit to tamoxifen alone. Optional tumor banking yielded specimens for RS determination by RT-PCR. We evaluated the effect of RS on disease-free survival (DFS) by treatment group (tamoxifen versus CAF-T) using Cox regression adjusting for number of positive nodes.
There were 367 specimens (40% of parent trial) with sufficient RNA (tamoxifen, 148; CAF-T, 219). The RS was prognostic in the tamoxifen arm (p=0.006). There was no CAF benefit in the low RS group (logrank p=0.97; HR=1.02, 95% CI (0.54,1.93)), but major DFS improvement for the high RS subset (logrank p=.03; HR=0.59, 95% CI (0.35, 1.01)), adjusting for number of positive nodes. The RS-by-treatment interaction was significant in the first 5 years (p=0.029), with no additional prediction beyond 5 years (p=0.58), though the cumulative benefit remained at 10 years. Results were similar for overall survival and BC-specific survival.
In this retrospective analysis, the RS is prognostic for tamoxifen-treated patients with positive nodes and predicts significant CAF benefit in tumors with a high RS. A low RS identifies women who may not benefit from anthracycline-based chemotherapy despite positive nodes.
Exemestane is a third-generation aromatase inhibitor, which has proven to be a useful drug in the treatment of early stage breast cancer. Several clinical trials have been performed or are currently underway using exemestane as adjuvant therapy in postmenopausal women, which will be the indication reviewed here. A relative reduction in risk of breast cancer recurrence or death of 24% has been shown with exemestane compared with tamoxifen when given after 2 to 3 years of tamoxifen. This corresponded to a 3.3% absolute reduction in recurrence or death at the end of 5 years, for a number needed to treat of 30. The main use of exemestane in the adjuvant setting is as an alternative to tamoxifen, and toxicities are discussed in relation to tamoxifen toxicities. In general, patients receiving exemestane experience less hot flashes and more arthralgias in comparison to tamoxifen, while there is also a reduction in venous thromboembolic events and vaginal bleeding. Patients on exemestane as a group do not appear to have a significantly changed quality of life in comparison to tamoxifen, while having a statistically significant benefit in preventing breast cancer recurrence.
breast cancer; exemestane; adjuvant
Low levels of 25-OH vitamin D are associated with respiratory tract infection (RTI). However, results from randomized controlled trials are inconclusive. Therefore, we performed a systematic review and meta-analysis to assess the preventive effect of vitamin D supplementation on RTI.
Randomized, controlled trials of vitamin D for prevention of RTI were used for the analysis. The risks of within-trial and publication bias were assessed. Odds ratios of RTI were pooled using a random-effects model. Heterogeneity was assessed using Cochran's Q and I2. Meta-regressions and subgroup analyses were used to assess the influence of various factors on trial outcome. The pre-defined review protocol was registered at the PROSPERO international prospective register of systematic reviews, registration number CRD42013003530.
Of 1137 citations retrieved, 11 placebo-controlled studies of 5660 patients were included in the meta-analysis. Overall, vitamin D showed a protective effect against RTI (OR, 0.64; 95% CI, 0.49 to 0.84). There was significant heterogeneity among studies (Cohran's Q p<0.0001, I2 = 72%). The protective effect was larger in studies using once-daily dosing compared to bolus doses (OR = 0.51 vs OR = 0.86, p = 0.01). There was some evidence that results may have been influenced by publication bias.
Results indicate that vitamin D has a protective effect against RTI, and dosing once-daily seems most effective. Due to heterogeneity of included studies and possible publication bias in the field, these results should be interpreted with caution.
The evidence that higher levels of physical activity and/or lower levels of physical inactivity are associated with beneficial health-related outcomes stems mainly from observational studies. Findings from these studies often differ from randomised controlled trials and systematic reviews currently demonstrate mixed results, due partly to heterogeneity in physical activity interventions, methodologies used and populations studied. As a result, translation into clinical practice has been difficult. It is therefore essential that an overview is carried out to compare and contrast systematic reviews, and to identify those physical activity interventions that are the most effective in preventing and/or treating major chronic disease. This protocol has been registered on PROSPERO 2013: CRD42013003523.
We will carry out an overview of Cochrane systematic reviews. We will search the Cochrane Database of Systematic Reviews for systematic reviews of randomised controlled trials that have a primary focus on disease-related outcomes. We will restrict reviews to those in selected major chronic diseases. Two authors will independently screen search outputs, select studies, extract data and assess the quality of included reviews using the assessment of multiple systematic reviews tool; all discrepancies will be resolved by discussing and reaching a consensus, or by arbitration with a third author. The data extraction form will summarise key information from each review, including details of the population(s) (for example, disease condition), the context (for example, prevention, treatment or management), the participants, the intervention(s), the comparison(s) and the outcomes. The primary outcomes of interest are the prevention of chronic disease and/or improved outcomes, in the treatment or management of chronic disease. These outcomes will be summarised and presented for individual chronic diseases (for example, any change in blood pressure in hypertension or glucose control in diabetes). Secondary outcomes of interest are to describe the structure and delivery of physical activity interventions across chronic disease conditions and adverse events associated with physical activity.
We anticipate that our results could inform researchers, guideline groups and policymakers of the most efficacious physical activity interventions in preventing and/or managing major chronic disease.
Physical activity; Inactivity; Exercise; Adherence; Non-communicable disease; Management; Systematic overview
Tamoxifen has been implicated as a risk factor for venous thrombosis in advanced breast cancer although the evidence for increased arterial or venous thrombosis with tamoxifen in early breast cancer is less clear. The effect of tamoxifen on haemostasis, and thereby possible thromboembolic risk, was investigated in normal women enrolled in a placebo controlled trial of tamoxifen as a chemopreventative agent for breast cancer. There was an initial reduction in fibrinogen levels in all women on tamoxifen over the first year of follow-up and a marginal reduction in antithrombin III and Protein S in postmenopausal women at 6 months. There were no changes in cross linked fibrinogen degradation products or Protein C for pre or post-menopausal women. There was no increase in the incidence of thromboembolic events on tamoxifen. This study demonstrates that tamoxifen has only marginal effects on factors involved in haemostasis reported to affect the incidence of arterial or venous thromboembolic disease. The follow-up time is relatively short (maximum 36 months) and careful long term follow-up is necessary to detect clinically significant morbidity.
The third-generation aromatase inhibitors (AIs) letrozole, anastrozole, and exemestane are replacing tamoxifen as adjuvant therapy in most postmenopausal women with early breast cancer. Although AIs have demonstrated superior efficacy and better overall safety compared with tamoxifen in randomized controlled trials, they may not provide the cardioprotective effects of tamoxifen, and bone loss may be a concern with their long-term adjuvant use. Patients require regular bone mineral density monitoring, and prophylactic bisphosphonates are being evaluated to determine whether they may protect long-term bone health. AIs decrease the risks of thromboembolic and cerebrovascular events compared with tamoxifen, and the overall rate of cardiovascular events in patients treated with AIs is within the range seen in age-matched, non-breast-cancer populations. AIs are also associated with a lower incidence of endometrial cancer and fewer vaginal bleeding/discharge events than tamoxifen. Compared with tamoxifen, the incidence of hot flashes is lower with anastrozole and letrozole but may be higher with exemestane. Generally, adverse events with AIs are predictable and manageable, whereas tamoxifen may be associated with life-threatening events in a minority of patients. Overall, the benefits of AIs over tamoxifen are achieved without compromising overall quality of life.
Adjuvant therapy; Aromatase inhibitors; Early breast cancer; Letrozole; Safety
The Study of Tamoxifen and Raloxifene (STAR) demonstrated that raloxifene was as effective as tamoxifen in reducing the risk of invasive breast cancer (IBC) in postmenopausal women and had lower risks of thromboembolic events, endometrial cancer, and cataracts but had a nonstatistically significant higher risk of noninvasive breast cancer. There is a need to summarize the risks and benefits of these agents.
Patients and Methods
Baseline incidence rates of IBC and other health outcomes, absent raloxifene and tamoxifen, were estimated from breast cancer chemoprevention trials; the Surveillance, Epidemiology and End Results Program; and the Women's Health Initiative. Effects of raloxifene and tamoxifen were estimated from STAR and the Breast Cancer Prevention Trial. We assigned weights to health outcomes to calculate the net benefit from raloxifene compared with placebo and tamoxifen compared with placebo.
Risks and benefits of treatment with raloxifene or tamoxifen depend on age, race, breast cancer risk, and history of hysterectomy. Over a 5-year period, postmenopausal women with an intact uterus had a better benefit/risk index for raloxifene than for tamoxifen. For postmenopausal women without a uterus, the benefit/risk ratio was similar. The benefits and risks of raloxifene and tamoxifen are described in tables that can help identify groups of women for whom the benefits outweigh the risks.
We developed a benefit/risk index to quantify benefits from chemoprevention with tamoxifen or raloxifene. This index can complement clinical evaluation in deciding whether to initiate chemoprevention and in comparing the benefits and risks of raloxifene versus tamoxifen.
Retirement represents a major transitional life stage in middle to older age. Changes in physical activity typically accompany this transition, which has significant consequences for health and well-being. The aim of this systematic review was to evaluate the evidence for the effect of interventions to promote physical activity in adults aged 55 to 70 years, focusing on studies that reported long-term effectiveness. This systematic review adheres to a registered protocol (PROSPERO CRD42011001459).
Randomized controlled trials of interventions to promote physical activity behavior with a mean/median sample age of 55 to 70 years, published between 2000 and 2010, were identified. Only trials reporting the long-term effect (≥ 12 months) on objective or self-reported physical activity behavior were included. Trials reporting physiological proxy measures of physical activity were excluded. Meta-analyses were conducted when trials provided sufficient data and sensitivity analyses were conducted to identify potential confounding effects of trials of poor methodological quality or with attrition rates ≥ 30%.
Of 17,859 publications identified, 32 were included which reported on 21 individual trials. The majority of interventions were multimodal and provided physical activity and lifestyle counselling. Interventions to promote physical activity were effective at 12 months (standardized mean difference (SMD) = 1.08, 95% confidence interval (CI) = 0.16 to 1.99, pedometer step-count, approximating to an increase of 2,197 steps per day; SMD = 0.19, 95% CI = 0.10 to 0.28, self-reported physical activity duration outcome), but not at 24 months based on a small subset of trials. There was no evidence for a relationship between intervention effectiveness and mode of delivery or number of intervention contacts; however, interventions which involved individually tailoring with personalized activity goals or provision of information about local opportunities in the environment may be more effective.
Interventions in adults aged 55 to 70 years led to long term improvements in physical activity at 12 months; however, maintenance beyond this is unclear. Identified physical activity improvements are likely to have substantial health benefits in reducing the risk of age-related illnesses. These findings have important implications for community-based public health interventions in and around the retirement transition.
Physical activity; intervention; aging; systematic review; meta-analysis
OBJECTIVE--To determine any cardiac or vascular morbidity associated with long term treatment with tamoxifen given after mastectomy for primary breast cancer. DESIGN--Cohort study using linkage between database of a randomised trial and statistics of Scottish hospital inpatients to identify episodes of cardiac and vascular morbidity. SETTING--NHS hospitals in Scotland. SUBJECTS--1312 women who had undergone mastectomy for breast cancer and who were randomised either to a treatment group to receive adjuvant tamoxifen or to a control group to be given tamoxifen only on first relapse of disease. Maximum duration of tamoxifen treatment was 14 years. Total woman years of follow up were 9943. MAIN OUTCOME MEASURES--Randomised and observational comparisons of risk (expressed as hazard ratios) of myocardial infarction, other cardiac event, cerebrovascular disease, or thromboembolic event according to treatment allocated and between nonusers, former users, and current users of tamoxifen. RESULTS--Use of tamoxifen was associated with lower rates of myocardial infarction. Hazard ratio for women in control group was 1.92 (95% confidence interval 0.99 to 3.73) compared with women allocated to adjuvant treatment. The association was stronger for current use: hazard ratio for non-users was 3.49 (1.52 to 8.03) compared with current users. Current users of tamoxifen, however, had higher rates of thromboembolic events:hazard ratio for non-users was 0.40 (0.18 to 0.90) compared with current users. CONCLUSIONS--Our results provide further evidence that tamoxifen reduces the risk of myocardial infarction. Thromboembolic events should be carefully monitored in trials of tamoxifen, particularly those of prophylactic treatment, in which tamoxifen is given to healthy women.
Prophylactic breast bud radiotherapy is used to prevent gynaecomastia and mastalgia in patients with prostate cancer who are being treated with antiandrogen and oestrogen therapy. Here a case is presented of a patient who developed soft-tissue sarcoma of the breast subsequent to breast bud radiotherapy prior to bicalutamide hormone treatment. Bicalutamide is often prescribed for younger men in the adjuvant setting or as monotherapy for locally advanced disease. The data regarding the efficacy of prophylactic breast bud radiotherapy is reviewed, and it is proposed that alternative therapies should be considered such as tamoxifen.
The third-generation aromatase inhibitors (AIs) anastrozole, exemestane and letrozole have largely replaced tamoxifen as the preferred treatment for hormone receptor – positive breast cancer in postmenopausal women. Approximately 185,000 new cases of invasive breast cancer are diagnosed yearly, and at least half of these women are both postmenopausal and eligible for adjuvant therapy with AIs. In addition, AIs are currently being tested as primary prevention therapy in large randomised trials involving tens of thousands of women at increased risk for breast cancer. Given the volume of use, internists will increasingly see postmenopausal women who are taking or considering treatment with AIs. Physicians need to be able to: (i) briefly discuss the pros and cons of using a selective estrogen receptor modulator such as tamoxifen or raloxifene vs. an AI for risk reduction and (ii) recognise and manage AI-associated adverse events. The primary purpose of this review is to help internists with these two tasks.
Review CriteriaExpert opinion based on review of literature on relevant clinical trials.Message for the ClinicBoth tamoxifen and AIs are effective for the adjuvant and neoadjuvant treatment of postmenopausal breast cancer; the optimal choice of drug is dependent on the characteristics of the patient and tumour. Adverse events with both drug classes are manageable. Adverse events associated with tamoxifen include increased risk of uterine cancers and thromboembolic events vs. an increased incidence of vaginal dryness, loss of libido, musculoskeletal pain and bone mineral density loss with AIs. Promising studies of AIs in the breast cancer prevention setting are ongoing.
Gynecomastia is the most bothersome side effect in men taking antiandrogens. It is exceptionally severe and distressing physically and mentally as in the reported case. A man, aged 63, with a history of a well-treated macroprolactinoma, was referred in 2004 for gynecomastia that appeared after treatment by microsurgery, radiotherapy and flutamide for a lesion suspected to be prostate cancer. Clinical examination was normal except for huge enlargement of the breasts. Mammography and breasts MRI did not show any tumor. There was not any metastasis of the supposed prostate cancer and prostatic acid phosphates were within normal ranges. Hormonal exploration showed subclinical hypogonadism [testosterone: 7.4 ng/ml (n: 3-9), FSH: 14.9 mu/ml (n: 0.7-11) and LH: 9.7 mu/ml (n: 0.8-7.6)]. Testes ultrasounds were normal. Radiological and hormonal adrenal explorations were normal [Cortisol: 76 ng/ml (n: 50-250), DHEA-S: 59 μg/ml (n: 50-560), E2:40.2 pg/ml (n < 50)]. Body scan was normal too. The discussed etiologies were post radiation subclinical hypogonadism, and treatment with anti androgens. After flutamide withdraw, there was not any sign of prostate cancer recurrence, and gynecomastia decreased significantly, but did not disappear probably because of fibrosis.
Aging; antiandrogens; gynecomastia; prostate cancer
QUESTION I frequently see adolescent boys in my practice with transient gynecomastia. My management includes reassuring the boys and their families; however, I also understand that specific medication, alcohol, and drugs can cause gynecomastia. How common is this phenomenon, and what medications can induce gynecomastia?
ANSWER While gynecomastia is a physiologic phenomenon in most newborns and adolescents, it is important to consider pathologic conditions and medications that can cause breast enlargement. Antibiotics, antiulcer drugs, growth hormones, and chemotherapy have been reported to induce gynecomastia. Adolescents who use anabolic steroids, or who abuse alcohol, marijuana, heroin, or amphetamines, should be alerted to the fact that gynecomastia might develop. Treatment of drug-induced gynecomastia includes discontinuation of the offending drug. Very rarely is surgical intervention required.
Tamoxifen reduces the risk of developing breast cancer but also affects the risks of certain vascular and neoplastic events. Our purpose was to estimate the effects of tamoxifen on potentially life-threatening vascular and neoplastic outcomes.
Random effects meta-analysis of published randomized controlled trials.
Participants in all trials in which a treatment arm that included tamoxifen was compared to a similar control arm. Breast cancer risk reduction and treatment trials were included.
Tamoxifen at variable dose and duration.
MEASUREMENTS AND MAIN RESULTS
Thirty-two trials (52,929 patients) reported one or more outcomes of interest. Tamoxifen was associated with significantly increased risks of endometrial cancer (relative risk [RR] 2.70; 95% CI, 1.94 to 3.75), gastrointestinal cancers (RR 1.31; 95% CI, 1.01 to 1.69), strokes (RR 1.49; 95% CI, 1.16 to 1.90), and pulmonary emboli (RR 1.88; 95% CI, 1.77 to 3.01). Tamoxifen had no effect on secondary malignancies other than endometrial and gastrointestinal cancers (RR 0.96; 95% CI, 0.81 to 1.13). In contrast, tamoxifen significantly decreased myocardial infarction deaths (RR 0.62; 95% CI, 0.41 to 0.93) and was associated with a statistically insignificant decrease in myocardial infarction incidence (RR 0.90; 95% CI, 0.66 to 1.23). Postmenopausal women had greater risk increases for neoplastic outcomes.
This meta-analysis of randomized trials found tamoxifen use to be significantly associated with several neoplastic and vascular outcomes. Consideration of tamoxifen use requires balance of potential benefits and risks.
tamoxifen; adverse events; selective estrogen receptor modulators; chemoprevention
A literature review of recently published trials, reviews, and practice guidelines outlining the surgical and adjuvant management of early breast cancer in older women is presented.
Women aged ≥65 are generally underrepresented in early breast cancer studies. Therefore, the optimal management of this group of women remains less certain.
A literature review of recently published trials, reviews, and practice guidelines outlining the surgical and adjuvant management of early breast cancer in older women was performed.
Surgery remains as the cornerstone treatment for early breast cancer in the elderly. Adjuvant radiation is generally considered if the projected lifespan is >5 years. Hormone receptor–positive disease is best treated with adjuvant endocrine treatment; aromatase inhibitors and tamoxifen are both options. Evidence for the use of adjuvant chemotherapy and trastuzumab for high-risk disease in the elderly is more limited. Polychemotherapy is still preferred in fit older women. Certain toxicities from systemic treatments can be more pronounced and should be carefully managed. Treatment with systemic agents should be individualized, with consideration of patient preference, performance status, comorbidities, and projected lifespan. Molecular tumor signatures may help better select patients for treatment in the future.
Age in itself should not be an absolute contraindication to any breast cancer therapy. Comprehensive, multidisciplinary assessment of elderly patients is imperative in evaluating eligibility for beneficial therapies.
Breast neoplasms; Aged; Geriatrics; General surgery; Adjuvant chemotherapy; Adjuvant radiation