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The Cochrane Database of Systematic... Feb 2014Polycystic ovary syndrome (PCOS) is the most common cause of infrequent periods (oligomenorrhoea) and absence of periods (amenorrhoea). It affects about 4% to 8% of... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Polycystic ovary syndrome (PCOS) is the most common cause of infrequent periods (oligomenorrhoea) and absence of periods (amenorrhoea). It affects about 4% to 8% of women worldwide and often leads to anovulatory subfertility. Aromatase inhibitors (AIs) are a novel class of drugs that were introduced for ovulation induction in 2001. Over the last ten years clinical trials have reached differing conclusions as to whether the AI letrozole is at least as effective as the first-line treatment clomiphene citrate (CC).
OBJECTIVES
To evaluate the effectiveness and safety of aromatase inhibitors for subfertile women with anovulatory PCOS.
SEARCH METHODS
We searched the following sources from inception to 24/10/2013 to identify relevant randomised controlled trials (RCTs): the Menstrual Disorders and Subfertility Group Specialised Register, the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, PsycINFO, Pubmed, LILACS, Web of Knowledge, the World Health Organisation (WHO) clinical trials register and Clinicaltrials.gov. Furthermore, we manually searched the references of relevant articles.The search was not restricted by language or publication status.
SELECTION CRITERIA
We included all RCTs of aromatase inhibitors used alone or with other medical therapies for ovulation induction in women of reproductive age with anovulatory PCOS.
DATA COLLECTION AND ANALYSIS
Two review authors independently selected trials, extracted the data and assessed trial quality. Studies were pooled where appropriate using a fixed effect model to calculate pooled odds ratios (ORs) and 95% confidence intervals (CIs) for most outcomes and risk differences (RDs) for ovarian hyperstimulation syndrome (OHSS). The primary outcomes were live birth and OHSS. Secondary outcomes were pregnancy, miscarriage and multiple pregnancy. The quality of the evidence for each comparison was assessed using GRADE methods.
MAIN RESULTS
We included 26 RCTs (5560 women). In all studies the aromatase inhibitor was letrozole. Live birth (12 RCTs) One RCT compared letrozole with placebo in women who were clomiphene resistant and the results were inconclusive (OR 3.17, 95% CI 0.12 to 83.17, n=36)Nine RCTs compared letrozole with clomiphene citrate (with or without adjuncts) followed by timed intercourse. The birth rate was higher in the letrozole group (OR 1.63, 95% CI 1.31 to 2.03, n=1783, I²=3%)Two RCTs compared letrozole with laparoscopic ovarian drilling. There was no evidence of a difference between the groups in live birth rate (OR 1.19, 95% CI 0.76 to 1.86, n=407, I²=0%) OHSS (16 RCTs) There was no evidence of a difference in OHSS rates when letrozole was compared with placebo (one RCT, n=36), clomiphene citrate (with or without adjuncts) followed by timed intercourse (nine RCTs, n=2179), clomiphene citrate (with or without adjuncts) followed by intrauterine insemination (IUI) (two RCTs, n=1494), laparoscopic ovarian drilling (one RCT, n=260) or anastrozole (one RCT, n=220). Events were absent or very rare, and no study had more than 2 cases of OHSS. Clinical pregnancy (25 RCTs) One RCT compared letrozole versus placebo in women who were clomiphene resistant and the results were inconclusive (OR 3.17, 95% CI 0.12 to 83.17, n=36)Fourteen RCTs compared letrozole versus clomiphene citrate (with or without adjuncts) followed by timed intercourse. The pregnancy rate was higher in the letrozole group (OR 1.32, 95% CI 1.09 to 1.60, n=2066, I²=25%)Three RCTs compared letrozole versus clomiphene citrate (with or without adjuncts) followed by IUI. The pregnancy rate was higher in the letrozole group (OR 1.71, 95% CI 1.30 to 2.25, n=1597)Three RCTs compared letrozole versus laparoscopic ovarian drilling. There was no evidence of a difference in the clinical pregnancy rate (OR 1.14, 95% CI 0.80 to 1.65, n=553, I²=0%)Two RCTs compared letrozole versus anastrozole, one RCT compared a five day versus a 10 day administration protocol for letrozole and another RCT compared 5 mg of letrozole versus 7.5 mg of letrozole. There was no evidence of a difference in the clinical pregnancy rate in these comparisons.The quality of the evidence was rated as low for live birth and pregnancy outcomes. The reasons for downgrading the evidence were poor reporting of study methods, possible publication bias and the tendency for studies that reported live birth to report higher clinical pregnancy rates in the letrozole group than studies that failed to report live birth (suggesting that results might be somewhat less favourable to letrozole if all studies reported live birth).
AUTHORS' CONCLUSIONS
Letrozole appears to improve live birth and pregnancy rates in subfertile women with anovulatory PCOS, compared to clomiphene citrate. The quality of this evidence is low and findings should be regarded with some caution. There appears to be no difference in effectiveness between letrozole and laparoscopic ovarian drilling, though there were few relevant studies. OHSS was a very rare event, with no occurrences in most studies.
Topics: Anastrozole; Aromatase Inhibitors; Birth Rate; Clomiphene; Coitus; Female; Fertility Agents, Female; Humans; Infertility, Female; Letrozole; Nitriles; Ovary; Ovulation Induction; Polycystic Ovary Syndrome; Pregnancy; Pregnancy Outcome; Randomized Controlled Trials as Topic; Triazoles
PubMed: 24563180
DOI: 10.1002/14651858.CD010287.pub2 -
BMC Medicine Aug 2012Tamoxifen has emerged as a potential management option for gynecomastia and breast pain due to non-steroidal antiandrogens, and it is considered an alternative to... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Tamoxifen has emerged as a potential management option for gynecomastia and breast pain due to non-steroidal antiandrogens, and it is considered an alternative to surgery or radiotherapy. The objective of this systematic review was to assess the benefits and harms of tamoxifen, in comparison to other treatment options, for either the prophylaxis or treatment of breast events induced by non-steroidal antiandrogens in prostate cancer patients.
METHODS
We searched CENTRAL, MEDLINE, EMBASE, reference lists, the abstracts of three major conferences and three trial registers to identify ongoing randomized controlled trials (RCTs). Two authors independently screened the articles identified, assessed the trial quality and extracted data. The protocol was prospectively registered (CRD42011001320; http://www.crd.york.ac.uk/PROSPERO).
RESULTS
Four studies were identified. Tamoxifen significantly reduced the risk of suffering from gynecomastia (risk ratio 9RR0 0.10, 95% CI 0.05 to 0.22) or breast pain (RR 0.06, 95% CI 0.02 to 0.17) at six months compared to untreated controls. Tamoxifen also showed a significant benefit for the prevention of gynecomastia (RR 0.22, 95% CI 0.08 to 0.58) and breast pain (RR 0.25, 95% CI 0.10 to 0.64) when compared to anastrozole after a median of 12 months. One study showed a significant benefit of tamoxifen for the prevention of gynecomastia (RR 0.24, 95% CI 0.09 to 0.65) and breast pain (RR 0.20, 95% CI 0.06 to 0.65) when compared with radiotherapy at six months. Radiotherapy increased the risk of suffering from nipple erythema and skin irritation, but there were no significant differences for any other adverse events (all P>0.05).
CONCLUSIONS
The currently available evidence suggests good efficacy of tamoxifen for the prevention and treatment of breast events induced by non-steroidal antiandrogens. The impact of tamoxifen therapy on long-term adverse events, disease progression and survival remains unclear. Further large, well-designed RCTs, including long-term follow-ups, are warranted. Also, the optimal dose needs to be clarified.
Topics: Androgen Antagonists; Gynecomastia; Humans; Male; Mastodynia; Prostatic Neoplasms; Randomized Controlled Trials as Topic; Tamoxifen; Treatment Outcome
PubMed: 22925442
DOI: 10.1186/1741-7015-10-96 -
Human Reproduction Update 2012The effectiveness of aromatase inhibitors (AIs) in the treatment of anovulatory polycystic ovary syndrome (PCOS) remains unclear. The objective was to determine whether... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
The effectiveness of aromatase inhibitors (AIs) in the treatment of anovulatory polycystic ovary syndrome (PCOS) remains unclear. The objective was to determine whether AIs are effective in improving fertility outcomes in women with PCOS.
METHODS
Databases were searched until July 2011. Inclusion criteria were women with PCOS, who are infertile, receiving any type, dose and frequency of AI compared with placebo, no other treatment or other infertility treatment. Outcomes were rates of: ovulation, pregnancy, live birth, multiple pregnancies, miscarriage and adverse events, as well as quality of life and cost effectiveness. Data were extracted and risk of bias was assessed. A random-effects model was used for the meta-analyses, using odds ratios (ORs) and rate ratios (RRs).
RESULTS
The search returned 4981 articles, 78 articles addressed AIs and 13 randomized controlled trials (RCTs) met the inclusion criteria. No RCTs compared AIs versus placebo or no treatment, in therapy naïve women with PCOS. Meta-analyses of six RCTs comparing letrozole with clompihene citrate (CC) demonstrated that letrozole improved the ovulation rate per patient [OR 2.90 (95% confidence interval (CI) 1.72, 4.88), I(2) = 0%, P < 0.0001]; however, there was no statistical difference for the ovulation rate per cycle or the pregnancy, live birth, multiple pregnancy or miscarriage rates. Letrozole also did not improve pregnancy or live birth rates compared with placebo or with CC plus metoformin in women with CC-resistant PCOS. Results of comparisons of letrozole and anastrozole in women with CC-resistant PCOS were conflicting in terms of ovulation and pregnancy rates.
CONCLUSIONS
In the absence of supportive high-quality evidence, AIs should not be recommended as the first-line pharmacological therapy for infertility in women with PCOS, and further research is needed.
Topics: Anastrozole; Aromatase Inhibitors; Female; Humans; Infertility, Female; Letrozole; Live Birth; Nitriles; Ovulation; Polycystic Ovary Syndrome; Pregnancy; Pregnancy Rate; Pregnancy, Multiple; Randomized Controlled Trials as Topic; Triazoles
PubMed: 22431566
DOI: 10.1093/humupd/dms003 -
Value in Health : the Journal of the... Jan 2012The purpose of this systematic review is primarily to identify published cost-effectiveness analyses and cost-utility analyses of endocrine therapies for the treatment... (Review)
Review
OBJECTIVES
The purpose of this systematic review is primarily to identify published cost-effectiveness analyses and cost-utility analyses of endocrine therapies for the treatment of early breast cancer. A secondary objective is to identify whether differences in seven modeling characteristics are related to differences in outcome of these cost-effectiveness and cost-utility analyses.
METHODS
A systematic literature review was conducted to identify peer-reviewed full economic evaluations of endocrine treatments of early breast cancer published in the English language between 2000 and December 2010. Information from these publications was abstracted regarding outcome, quality, and modeling methods.
RESULTS
We identified 20 economic evaluations comprising 5 different endocrine therapeutic strategies, which are all assessed more then once. The incremental cost-effectiveness ratios (ICERs) of the reported outcomes varied widely for identical therapies. For anastrazole compared to tamoxifen, incremental life-years gained even ranged from 0.16 to 0.550 with an ICER ranging from €3,958 to €75,331. Incremental quality-adjusted life-years (QALYs) gained ranged from 0.092 to 0.378 with a cost per QALY gained varying from €3,696 to €120,265. These large differences in outcome were related to different modeling methods, with differences in time horizon and use of a carryover effect as most prominent causes.
CONCLUSION
Despite similar comparators and logical differences due to transferability issues, the outcomes of the included studies varied widely. To increase comparability and transparency of pharmacoeconomic evaluations, standardization of modeling methods for different therapeutic groups/diseases and the availability of a detailed and complete description of the model used in the evaluation is advocated. Recommendations for standardization in modeling treatment strategies in early breast cancer are presented.
Topics: Anastrozole; Antineoplastic Agents, Hormonal; Breast Neoplasms; Cost-Benefit Analysis; Female; Humans; Models, Economic; Neoplasm Recurrence, Local; Nitriles; Quality-Adjusted Life Years; Tamoxifen; Time Factors; Triazoles
PubMed: 22264977
DOI: 10.1016/j.jval.2011.08.003 -
Health Technology Assessment... 2011Breast cancer is the uncontrolled, abnormal growth of malignant breast tissue affecting predominantly women. Metastatic breast cancer (mBC) is an advanced stage of the... (Review)
Review
Lapatinib and trastuzumab in combination with an aromatase inhibitor for the first-line treatment of metastatic hormone receptor-positive breast cancer which over-expresses human epidermal growth factor 2 (HER2): a systematic review and economic analysis.
BACKGROUND
Breast cancer is the uncontrolled, abnormal growth of malignant breast tissue affecting predominantly women. Metastatic breast cancer (mBC) is an advanced stage of the disease when the disease has spread beyond the original organ. Hormone receptor status and human epidermal growth factor 2 (HER2) status are two predictive factors that are taken into consideration when estimating the prognosis of patients with breast cancer.
OBJECTIVES
To review the clinical effectiveness and cost-effectiveness evidence base for lapatinib (LAP) in combination with an aromatase inhibitor (AI) and trastuzumab (TRA) in combination with an AI for the first-line treatment of patients who have hormone receptor-positive (HR+)/human epidermal growth factor 2-positive (HER2+) mBC.
DATA SOURCES
Relevant electronic databases and websites, including MEDLINE, EMBASE and the Cochrane Library, were searched until May 2010. Further data were derived from the manufacturers' submissions for LAP + AI and TRA + AI.
REVIEW METHODS
A systematic review of the clinical effectiveness and cost-effectiveness of LAP + AI and TRA + AI was undertaken. As it was deemed inappropriate to compare LAP + AI with TRA + AI, two separate assessments of cost-effectiveness versus AIs alone were undertaken.
RESULTS
Three trials were included in the systematic review [the patient populations of the efficacy and safety of lapatinib combined with letrozole (EGF30008) trial, the efficacy and safety of trastuzumab combined with anastrozole (TAnDEM) trial and the efficacy and safety of letrozole combined with trastuzumab (eLEcTRA) trial]. As a result of differences in the exclusion criteria and because one trial was halted prematurely, comparisons across trials were believed to be inappropriate and meta-analysis was not possible. Individually, however, the findings from the trials all suggest that LAP + AI or TRA + AI results in improved progression-free survival and/or time to progression when compared with AIs alone. The trials do not show a statistically significant benefit in terms of overall survival. Two separate economic analyses were conducted based on the completed trials; neither LAP + AI nor TRA + AI was found to be cost-effective when compared with AI monotherapy.
LIMITATIONS
Because of differences in the EGF30008 and the TAnDEM trials, the Assessment Group believes the indirect comparisons analyses conducted by the manufacturers are inappropriate and, for the same reason, chooses not to compare LAP + AI with TRA + AI in an economic evaluation.
CONCLUSIONS
LAP + AI and TRA + AI appear to be clinically more effective than AI monotherapy, but neither is cost-effective compared with AIs alone. It was not possible to compare LAP + AI with TRA + AI. Future research should include research into treating mBC in the HR+/HER2+ population who are not TRA (or LAP) naive and into comparing the clinical effectiveness of AIs as monotherapy in patients with HER2+ and human epidermal growth factor 2-negative breast cancer.
FUNDING
The National Institute for Health Research Technology Assessment programme.
Topics: Anastrozole; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Clinical Trials as Topic; Cost-Benefit Analysis; Disease-Free Survival; Female; Humans; Lapatinib; Letrozole; Nitriles; Quinazolines; Receptor, ErbB-2; Trastuzumab; Triazoles
PubMed: 22152751
DOI: 10.3310/hta15420 -
Reproductive Biology and Endocrinology... Jun 2011This systematic review aims to assess the efficacy of aromatase inhibitors (AIs) in treating pain symptoms caused by endometriosis. A comprehensive literature search was... (Review)
Review
This systematic review aims to assess the efficacy of aromatase inhibitors (AIs) in treating pain symptoms caused by endometriosis. A comprehensive literature search was conducted to identify all the published studies evaluating the efficacy of type II nonsteroidal aromatase inhibitors (anastrozole and letrozole) in treating endometriosis-related pain symptoms. The MEDLINE, EMBASE, PubMed, and SCOPUS databases and the Cochrane System Reviews were searched up to October 2010. This review comprises of the results of 10 publications fitting the inclusion criteria; these studies included a total of 251 women. Five studies were prospective non-comparative, four were randomized controlled trials (RCTs) and one was a prospective patient preference trial. Seven studies examined the efficacy of AIs in improving endometriosis-related pain symptoms, whilst three RCTs investigated the use of AIs as post-operative therapy in preventing the recurrence of pain symptoms after surgery for endometriosis. All the observational studies demonstrated that AIs combined with either progestogens or oral contraceptive pill reduce the severity of pain symptoms and improve quality of life. One patient preference study demonstrated that letrozole combined with norethisterone acetate is more effective in reducing pain and deep dyspareunia than norethisterone acetate alone. However, letrozole causes a higher incidence of adverse effects and does not improve patients' satisfaction or influence recurrence of symptoms after discontinuation of treatment. A RCT showed that combining letrozole with norethisterone acetate causes a lower incidence of adverse effects and lower discontinuation rate than combining letrozole with triptorelin. Two RCTs demonstrated that, after surgical treatment of endometriosis, the administration of AIs combined with gonadotropin releasing hormone analogue for 6 months reduces the risk of endometriosis recurrence when compared with gonadotropin releasing hormone analogue alone. In conclusion, AIs effectively reduce the severity of endometriosis-related pain symptoms. Since endometriosis is a chronic disease, future investigations should clarify whether the long-term administration of AIs is superior to currently available endocrine therapies in terms of improvement of pain, adverse effects and patient satisfaction.
Topics: Anastrozole; Aromatase Inhibitors; Clinical Trials as Topic; Endometriosis; Female; Humans; Letrozole; Nitriles; Pain, Postoperative; Pelvic Pain; Triazoles
PubMed: 21693038
DOI: 10.1186/1477-7827-9-89 -
Breast Cancer Research and Treatment Aug 2010To undertake a systematic review of three first-line treatments (letrozole, anastrozole and exemestane) for hormone sensitive advanced or metastatic breast cancer (MBC)... (Review)
Review
To undertake a systematic review of three first-line treatments (letrozole, anastrozole and exemestane) for hormone sensitive advanced or metastatic breast cancer (MBC) in post-menopausal women. We searched six databases from inception up to January 2009 for relevant trials regardless of language or publication status. Randomised controlled clinical trials assessing the safety and efficacy of first-line AIs for post-menopausal women with hormone receptor-positive (HR+, i.e. ER+ and/or PgR+) with or without ErbB2 (HER2)-positive MBC, who have not received prior therapy for advanced or metastatic disease were included. Where meta-analysis using direct or indirect comparisons was considered unsuitable for some or all of the data, we employed a narrative synthesis method. Four studies (25 papers) met the inclusion criteria. From the available evidence, it was possible to directly compare the three AIs with tamoxifen. In addition, by using a network meta-analysis it was possible to compare the three AIs with each other. Based on direct evidence, letrozole seemed to be significantly better than tamoxifen in terms of time-to-progression (TTP) (HR = 0.70 (95% CI: 0.60, 0.82)), objective response rate (RR = 0.65 (95% CI: 0.52, 0.82)) and quality-adjusted time without symptoms or toxicity (Q-Twist difference = 1.5; P < 0.001). Exemestane seemed significantly superior to tamoxifen in terms of objective response rate (RR = 0.68 (95% CI: 0.53, 0.89)). Anastrozole seemed significantly superior to tamoxifen in terms of TTP in one trial (HR = 1.42 (95% CI: 1.15, NR)), but not in the other (HR = 1.01 (95% CI: 0.87, NR)). In terms of adverse events, no significant differences were found between letrozole and tamoxifen. Tamoxifen was associated with significantly more serious adverse events in comparison with exemestane (OR = 0.61 (95% CI: 0.38, 0.97)); while exemestane was associated with significantly more arthralgia in comparison with tamoxifen (OR = 2.33 (95% CI: 1.07, 5.11)). Anastrozole was associated with significantly more total adverse events (OR = 1.04 (95% CI: 1.00, 1.09)) and hot flushes (OR = 1.39 (95% CI: 1.03, 1.89)) in comparison with tamoxifen in one trial; however, the other trial showed no significant differences in adverse events between anastrozole and tamoxifen. The indirect comparison of AIs with each other in women with post-menopausal, hormone sensitive advanced or MBC showed that letrozole and exemestane were better in terms of objective response rate than anastrozole; while the more clinically relevant outcomes overall survival (OS) and progression-free survival (PFS) showed no significant differences between AIs. OS and PFS showed no significant differences between AIs and hence based on these results a class effect for all AIs is possible. However, these results are based on indirect comparisons and a network analysis for which the basic assumptions of homogeneity, similarity and consistency were not fulfilled. Therefore, despite the fact that these are the best available data, the results need to be interpreted with appropriate caution. Head-to-head comparisons between letrozole, anastrozole and exemestane in the first-line MBC setting are warranted.
Topics: Anastrozole; Androstadienes; Antineoplastic Agents; Aromatase Inhibitors; Breast Neoplasms; Female; Humans; Letrozole; Nitriles; Postmenopause; Randomized Controlled Trials as Topic; Triazoles
PubMed: 20535542
DOI: 10.1007/s10549-010-0974-0 -
The Cochrane Database of Systematic... Oct 2009Endocrine therapy removes the influence of oestrogen on breast cancer cells and so hormonal treatments such as tamoxifen, megestrol acetate and medroxyprogesterone... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Endocrine therapy removes the influence of oestrogen on breast cancer cells and so hormonal treatments such as tamoxifen, megestrol acetate and medroxyprogesterone acetate have been in use for many years for advanced breast cancer. Aromatase inhibitors (AIs) inhibit oestrogen synthesis in the peripheral tissues and have a similar tumour-regressing effect to other endocrine treatments. Aminoglutethimide was the first AI in clinical use and now the third generation AIs, anastrozole, exemestane and letrozole, are in current use. Randomised trial evidence on response rates and side effects of these drugs is still limited.
OBJECTIVES
To compare AIs to other endocrine therapy in the treatment of advanced breast cancer in postmenopausal women.
SEARCH STRATEGY
For this update, the Cochrane Breast Cancer Group Specialised Register and the Cochrane Central Register of Controlled Trials (CENTRAL) and relevant conference proceedings were searched (to 30 June 2008).
SELECTION CRITERIA
Randomised controlled trials in postmenopausal women comparing the effects of any AI versus other endocrine therapy, no endocrine therapy, or a different AI in the treatment of advanced (metastatic) breast cancer. Non-English language publications, comparisons of the same AI at different doses, AIs used as neoadjuvant treatment, or outcomes not related to tumour response were excluded.
DATA COLLECTION AND ANALYSIS
Data from published trials were extracted independently by two review authors and cross-checked by a third. Hazard ratios (HR) were derived for analysis of time-to-event outcomes (overall and progression-free survival). Odds ratios (OR) were derived for objective response, clinical benefit, and toxicity.
MAIN RESULTS
Thirty-seven trials were identified, 31 of which were included in the main analysis of any AI versus any other treatment (11,403 women). No trials were excluded due to inadequate allocation concealment. The pooled estimate showed a significant survival benefit for treatment with an AI over other endocrine therapies (HR 0.90, 95% CI 0.84 to 0.97). A subgroup analysis of the three commonly prescribed AIs (anastrozole, exemestane, letrozole) also showed a similar survival benefit (HR 0.88, 95% CI 0.80 to 0.96). There were very limited data to compare one AI with a different AI, but these suggested an advantage for letrozole over anastrozole.AIs have a different toxicity profile to other endocrine therapies. For those currently prescribed, and for all AIs combined, they had similar levels of hot flushes and arthralgia; increased risks of rash, nausea, diarrhoea and vomiting; but a 71% decreased risk of vaginal bleeding and 47% decrease in thromboembolic events compared with other endocrine therapies.
AUTHORS' CONCLUSIONS
In women with advanced (metastatic) breast cancer, aromatase inhibitors including those in current clinical use show a survival benefit when compared to other endocrine therapy.
Topics: Antineoplastic Agents, Hormonal; Aromatase Inhibitors; Breast Neoplasms; Female; Humans; Neoplasms, Hormone-Dependent; Postmenopause; Randomized Controlled Trials as Topic
PubMed: 19821307
DOI: 10.1002/14651858.CD003370.pub3 -
Health Technology Assessment... Jul 2007To establish the clinical and cost-effectiveness of aromatase inhibitors (AIs) anastrozole, letrozole and exemestane compared with tamoxifen in the adjuvant treatment of... (Review)
Review
OBJECTIVES
To establish the clinical and cost-effectiveness of aromatase inhibitors (AIs) anastrozole, letrozole and exemestane compared with tamoxifen in the adjuvant treatment of early oestrogen receptor-positive breast cancer in postmenopausal women.
DATA SOURCES
Major electronic databases and three trials registers were searched from May to June 2005. Three conference abstract databases were searched in December 2005. Industry submissions.
REVIEW METHODS
Studies evaluating the clinical effectiveness of AIs against 5 years' tamoxifen treatment were included and critically appraised. The review of the health economics of AIs in early breast cancer in comparison with standard therapies included a review of existing economic evaluations of the relevant therapies, a critique of each of the economic evaluations submitted to the National Institute for Health and Clinical Excellence (NICE) by pharmaceutical manufacturers and a detailed explanation of the methodologies and results of the authors' economic model. The three treatment strategies (primary adjuvant therapy, unplanned switch therapy and extended adjuvant therapy) were considered separately within the authors' economic analysis.
RESULTS
A meta-analysis of three trials found a significant difference in overall survival when an unplanned anastrozole switching strategy was compared with 5 years' tamoxifen. Significant improvements in overall survival are yet to be demonstrated in other strategies. Compared with 5 years' tamoxifen, disease-free survival (disease recurrence or death from any cause) was significantly improved in the primary adjuvant setting with anastrozole and letrozole, and with an exemestane switching strategy. Other trials did not report this outcome. Breast cancer recurrence (censoring death as an event) was significantly improved with primary adjuvant anastrozole and letrozole, anastrozole switching, extended adjuvant anastrozole or letrozole. The AIs and tamoxifen have different side-effect profiles, with tamoxifen responsible for small but statistically significant increases in endometrial cancer and, sometimes, thromboembolic events and stroke. AIs show a trend towards increases in osteoporosis, the statistical significance of which increases with follow-up time. The absence of tamoxifen treatment also increases the risk of hypercholesterolaemia and cardiac events in postmenopausal women. There was no significant difference in overall health-related quality of life between standard treatment and either primary adjuvant anastrozole and extended adjuvant letrozole strategies. The cost-effectiveness results for AIs compared with tamoxifen in the primary adjuvant setting, are estimated to be between 21,000 pounds and 32,000 pounds per quality-adjusted life-year (QALY) based on an analysis over 35 years. There is currently no trial evidence for exemestane in this setting. The cost-effectiveness results for anastrozole and exemestane, compared with tamoxifen in the unplanned switching setting, are estimated to be 23,200 pounds and 19,200 pounds per QALY, respectively, based on an analysis over 35 years. There is currently no trial evidence for letrozole in this setting. In the extended adjuvant setting, the cost per QALY for letrozole compared with placebo is estimated to be 9800 pounds, based on an analysis over 35 years. All these results are considered to be conservative. In the base case it is assumed that the benefits of AIs over tamoxifen or placebo seen during the therapy period are gradually lost during the following 10 years. An alternative scenario, the 'benefits maintained' scenario, is tested in sensitivity analysis. Here it is assumed that following the treatment period the annual rate of recurrence in both arms is the same. This reduces the cost-effectiveness ratio by over 50%, to around 10,000-12,000 pounds, 5000 pounds and 3000 pounds in the primary adjuvant, unplanned switching and extended adjuvant setting, respectively. The limited evidence to date of benefits after the therapy period suggests that the 'benefits maintained' scenario may be realistic. The results from the economic analyses within the industry submissions are generally lower than the results from the authors' model and are close to or below 12,000 pounds in all three settings. The authors' analyses generally produce a lower estimate of QALY gain for the aromatase inhibitors, due to the more conservative assumption regarding benefits, along with differences in the utility values used in the their analysis.
CONCLUSIONS
On the basis of the current data and within their licensed indications, AIs can be considered clinically effective compared with standard tamoxifen treatment. However, their long-term effects, in terms of both benefits and harms, remain unclear. Under the conservative assumption that benefits gained by AIs during the treatment period are gradually lost over the following 10 years, the cost per QALY for AIs compared with tamoxifen is estimated to be between 21,000 pounds and 32,000 pounds in the primary adjuvant setting and around 20,000 pounds in the unplanned switch setting. The cost per QALY for AIs compared with placebo in the extended adjuvant setting is estimated to be around 10,000 pounds. Under the less conservative assumption that rates of recurrence are the same in both arms after the therapy period is complete, the incremental cost-effectiveness ratios are typically at least 50% lower, suggesting that AIs are likely to be considered cost-effective in all three settings. Understanding of the long-term treatment effects on cost-effectiveness is, however, incomplete. Data on the impact of AIs on survival are awaited from the majority of the trials to confirm whether or not the benefits seen in disease-free survival and recurrence rates are translated into overall survival benefit in the medium to long-term.
Topics: Anastrozole; Androstadienes; Antineoplastic Agents, Hormonal; Aromatase Inhibitors; Breast Neoplasms; Chemotherapy, Adjuvant; Cost-Benefit Analysis; Drug Administration Schedule; Female; Humans; Letrozole; Neoplasm Recurrence, Local; Nitriles; Quality-Adjusted Life Years; Survival Analysis; Tamoxifen; Time Factors; Triazoles
PubMed: 17610808
DOI: 10.3310/hta11260 -
The Cochrane Database of Systematic... Jan 2007Hormonal treatments for advanced or metastatic breast cancer, such as tamoxifen and the progestins megestrol acetate and medroxyprogesterone acetate, have been in use... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Hormonal treatments for advanced or metastatic breast cancer, such as tamoxifen and the progestins megestrol acetate and medroxyprogesterone acetate, have been in use for many years. Aromatase inhibitors (AIs) are a class of compounds that systemically inhibit oestrogen synthesis in the peripheral tissues. Aminoglutethimide was the first AI in clinical use (first generation) and had a similar tumour-regressing effect to other endocrine treatments, which showed the potential of this alternative type of therapy. Other AIs have since been developed and the third generation AIs anastrozole, exemestane and letrozole are in current use. Randomised evidence on response rates and side effects of these drugs is still limited.
OBJECTIVES
To compare aromatase inhibitors to other endocrine therapy in the treatment of advanced breast cancer in postmenopausal women.
SEARCH STRATEGY
The Cochrane Breast Cancer Group Specialised Register was searched on 3 December 2004 using the codes for "advanced" and "endocrine therapy". Details of the search strategy applied to create the Register and the procedure used to code references are described in the Cochrane Breast Cancer Group module on The Cochrane Library. The search was updated to 30 September 2005 and additional publications were included. Experts were consulted to determine that no relevant studies had been excluded.
SELECTION CRITERIA
Randomised trials comparing the effects of any aromatase inhibitor versus other endocrine therapy, no endocrine therapy or a different aromatase inhibitor in the treatment of advanced (metastatic) breast cancer.
DATA COLLECTION AND ANALYSIS
Data from published trials were extracted by two independent review authors. A third independent author then carried out a further cross check for accuracy and consistency. Hazard ratios (HR) were derived for analysis of time-to-event outcomes (overall and progression-free). Odds ratios (OR) were derived for objective response and clinical benefit (both analysed as dichotomous variables). Toxicity data were extracted where present and treatments were compared using odds ratios. All but one of the studies included data on one or more of the following outcomes: overall survival, progression-free survival, clinical benefit and objective response.
MAIN RESULTS
Thirty studies were identified, twenty five of which were included in the main analysis of any AI versus any other treatment (9416 women). The pooled estimate showed a significant survival benefit for treatment with an AI over other endocrine therapies (HR 0.89, 95%CI 0.82 to 0.96). A subgroup analysis of the three commonly prescribed AIs (anastrozole, exemestane, letrozole) also showed a similar survival benefit (HR 0.88, 95%CI 0.80 to 0.96). The results for progression-free survival, clinical benefit and objective response were not statistically significant and there was statistically significant heterogeneity across types of AI. There were very limited data to compare one AI with a different AI, but these suggested an advantage for letrozole over anastrozole. All the trials of AIs used exclusively as first-line therapy were against tamoxifen. There was an advantage to treatment with AIs in terms of progression-free survival (HR 0.78, 95% CI 0.70 to 0.86) and clinical benefit (OR 0.70, 95% CI 0.51 to 0.97) but not overall survival or objective response. There was considerable heterogeneity across studies when considering clinical benefit (P = 0.001). Use of an AI as second-line therapy showed a significant benefit in terms of overall survival (HR 0.80, 95% CI 0.66 to 0.96) but not for progression-free survival (HR 1.08, 95% CI 0.89 to 1.31), clinical benefit (OR 1.00, 95% CI 0.87 to 1.14) or objective response (OR 0.96, 95% CI 0.81 to 1.14). This is difficult to interpret due to the extreme heterogeneity across AIs for progression-free survival but not the other endpoints.AIs have a different toxicity profile to other endocrine therapies. For all AIs combined, they had similar levels of hot flushes (especially when compared to tamoxifen) and arthralgia, increased risks of nausea, diarrhoea and vomiting, but a decreased risk of vaginal bleeding and thromboembolic events compared with other endocrine therapies. A similar pattern of risks and benefits was still seen when analyses were limited to the currently most-prescribed third generation AIs.
AUTHORS' CONCLUSIONS
In women with advanced (metastatic) breast cancer, aromatase inhibitors including those in current clinical use show a survival benefit when compared to other endocrine therapy.
Topics: Antineoplastic Agents, Hormonal; Aromatase Inhibitors; Breast Neoplasms; Female; Humans; Neoplasms, Hormone-Dependent; Randomized Controlled Trials as Topic
PubMed: 17253488
DOI: 10.1002/14651858.CD003370.pub2