The impact of the introduction of generic aromatase inhibitors on adherence to hormonal therapy over the full course of 5-year treatment for breast cancer.

BACKGROUND: High out-of-pocket costs (OOPCs) often are found to be inversely associated with adherence to medical treatment. The introduction of generic aromatase inhibitors (GAIs) significantly reduced the OOPCs of patients. The objective of the current study was to explore the impact of the introduction of GAIs on adjuvant hormone therapy (AHT) adherence over the full course of breast cancer treatment. METHODS: Women aged ≥65 years who were diagnosed with hormone receptor-positive breast cancer from 2007 through mid-2009 were identified from the Surveillance, Epidemiology, and End Results (SEER)-Medicare-linked database. Multivariate logistic regression was used to estimate the likelihood of AHT initiation and an interrupted time series model was used to predict the association between the introduction of GAIs and AHT adherence. The model was stratified further using Medicare low-income subsidy (LIS) status. RESULTS: A total of 10,905 women were included, approximately 62.8% of whom initiated AHT within the first year of their breast cancer diagnosis. Adjusted adherence among LIS beneficiaries was 11.4% higher than among non-LIS beneficiaries (P < .001). Non-LIS beneficiaries had an overall decreasing trend of adherence (-0.035; P < .001) prior to the introduction of GAIs. They experienced a 3.4% increase in the slope 6 months after the first GAI, anastrozole, entered the market, and an additional 0.8% increase in the slope 6 months after letrozole and exemestane were introduced (P < .001). Adherence change among LIS patients was small and statistically insignificant. CONCLUSIONS: With the introduction of GAIs, the decrease trend of adherence to therapy atteunated over the course of treatment. Although the successful implementation of the Medicare LIS program minimized the OOPCs for financially vulnerable patients, policymakers should be cautious not to introduce disparities for those who may be of low income but ineligible for such a program.

Cost-effectiveness analysis of endocrine therapy alone versus partial-breast irradiation alone versus combined treatment for low-risk hormone-positive early-stage breast cancer in women aged 70 years or older.

PURPOSE: We performed a cost-effectiveness analysis of three strategies for the adjuvant treatment of early breast cancer in women age 70 years or older: an aromatase inhibitor (AI-alone) for 5 years, a 5-fraction course of accelerated partial-breast irradiation using intensity-modulated radiation therapy (APBI-alone), or their combination. METHODS: We constructed a patient-level Markov microsimulation from the societal perspective. Effectiveness data (local recurrence, distant metastases, survival), and toxicity data were obtained from randomized trials when possible. Costs of side effects were included. Costs were adjusted to 2019 US dollars and extracted from Medicare reimbursement data. Quality-adjusted life-years (QALY) were calculated using utilities extracted from the literature. RESULTS: The strategy of AI-alone ($12,637) was cheaper than both APBI-alone ($13,799) and combination therapy ($18,012) in the base case. All approaches resulted in similar QALY outcomes (AI-alone 7.775; APBI-alone 7.768; combination 7.807). In the base case, AI-alone was the cost-effective strategy and dominated APBI-alone, while combined therapy was not cost-effective when compared to AI-alone ($171,451/QALY) or APBI-alone ($107,932/QALY). In probabilistic sensitivity analyses, AI-alone was cost-effective at $100,000/QALY in 50% of trials, APBI-alone in 28% and the combination in 22%. Scenario analysis demonstrated that APBI-alone was more effective than AI-alone when AI compliance was lower than 26% at 5 years. CONCLUSIONS: Based on a Markov microsimulation analysis, both AI-alone and APBI-alone are appropriate options for patients 70 years or older with early breast cancer with small cost differences noted. A prospective trial comparing the approaches is warranted.

Cost-effectiveness analysis of extended adjuvant endocrine therapy in the treatment of post-menopausal women with hormone receptor positive breast cancer.

Five years of Tamoxifen (Standard TAM) is a common treatment option for early-stage, hormone receptor positive (HR+) breast cancer (BC). Extending Standard TAM by 5 additional years (Extended TAM) can improve survival and BC recurrences. In postmenopausal women, the use of extended aromatase inhibitors (Extended AI) after Standard TAM is an alternative to Extended TAM. This study examines the cost-effectiveness (CE) of extending Standard TAM with Extended TAM vs. Extended AI in postmenopausal HR+ early-stage BC patients. Three treatments were assessed: (1) Standard TAM; (2) Extended TAM; (3) Extended AI through a Markov model using a Canadian health system perspective, lifetime time-horizon, quality adjusted life years (QALYs), and a 5 % discount rate for future costs and utilities. Incremental cost-effectiveness ratios (ICERs) were calculated, and the impact of parameter uncertainty was assessed through probabilistic sensitivity analyses (SA) using conventional CE thresholds. The estimated total per person costs in 2012 Canadian dollars [$1.00 CAD = $0.99 US 2012] were the least for Extended TAM ($8,623 CAD) and most for Extended AI ($9,432 CAD). Extended AI was the most effective regimen, while Standard TAM was the least. Extended AI was cost-effective at conventional thresholds vs. Extended TAM (ICER: $3,402 CAD/QALY) which was robust to the SA. This study suggests that Extended AI and Extended TAM result in improved QALYs and lower healthcare costs vs Standard TAM. Extended AI results in the greatest improvement in QALYs and is the most cost-effective treatment alternative despite its higher drug costs.

Cost-effectiveness of full coverage of aromatase inhibitors for Medicare beneficiaries with early breast cancer.

BACKGROUND: Rates of nonadherence to aromatase inhibitors (AIs) among Medicare beneficiaries with hormone receptor-positive early breast cancer are high. Out-of-pocket drug costs appear to be an important contributor to this and may be addressed by eliminating copayments and other forms of patient cost sharing. The authors estimated the incremental cost-effectiveness of providing Medicare beneficiaries with full prescription coverage for AIs compared with usual prescription coverage under the Medicare Part D program. METHODS: A Markov state-transition model was developed to simulate AI use and disease progression in a hypothetical cohort of postmenopausal Medicare beneficiaries with hormone receptor-positive early breast cancer. The analysis was conducted from the societal perspective and considered a lifetime horizon. The main outcome was an incremental cost-effectiveness ratio, which was measured as the cost per quality-adjusted life-year (QALY) gained. RESULTS: For patients receiving usual prescription coverage, average quality-adjusted survival was 11.35 QALYs, and lifetime costs were $83,002. For patients receiving full prescription coverage, average quality-adjusted survival was 11.38 QALYs, and lifetime costs were $82,728. Compared with usual prescription coverage, full prescription coverage would result in greater quality-adjusted survival (0.03 QALYs) and less resource use ($275) per beneficiary. From the perspective of Medicare, full prescription coverage was cost-effective (incremental cost-effectiveness ratio, $15,128 per QALY gained) but not cost saving. CONCLUSIONS: Providing full prescription coverage for AIs to Medicare beneficiaries with hormone receptor-positive early breast cancer would both improve health outcomes and save money from the societal perspective.

Predictors of non-adherence to aromatase inhibitors among commercially insured women with breast cancer.

The purpose of this study is to investigate 1-year adherence rates to aromatase inhibitors (AI) and to determine risk factors for non-adherence among commercially insured post-menopausal breast cancer patients. A retrospective cohort of 13,593 commercially insured breast cancer patients with a prescription claim for an AI therapy (exemestane, anastrozole, and letrozole) in 2006 were identified using the MarketScan Commercial Claims and Encounters Database. Adherence was calculated by the medication possession ratio (MPR) for a 1-year period following the initial claim in 2006. The main outcome variable was non-adherence (<80% MPR) to AI therapy. Multivariate logistic regression was used to determine predictors of non-adherence. Over a 1-year period, 23% of patients were non-adherent with their AI therapy. AI non-adherence was associated with younger age, out-of-pocket costs ≥$30 per AI prescription, as well as with measures during the 12-month period prior to the initial 2006 AI claim of lower patient out-of-pocket total pharmacy costs, no mastectomy, and higher Charlson Comorbidity Index. Non-adherence to AI is a common occurrence. A number of factors were identified that influence patience non-adherence. These factors can be used to identifying patients at increased risk for non-adherence to better target and intervene to support medication taking behaviors.

Cost-effectiveness of ribociclib as initial treatment for premenopausal women with advanced breast cancer in Singapore.

BACKGROUND: CDK4/6 inhibitors have shown promising results for treating advanced breast cancer (ABC) and are routinely used in Singapore. In view of their high costs, it is important to assess their relative value compared to existing standards of care in the local setting. AIMS: This study evaluates the cost-effectiveness of adding ribociclib to goserelin and a nonsteroidal aromatase inhibitor or tamoxifen as initial therapy for premenopausal women with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) ABC in Singapore. METHODS: A partitioned survival model with four health states (progression-free on first-line treatment, progression-free on second-line treatment, progressed disease, and death) was developed from a healthcare system perspective over a 10-year time horizon. Key clinical inputs were derived from the MONALEESA-7 trial, and survival curves were extrapolated beyond the trial period. Health state utilities were derived from the literature and direct medical costs were obtained from local public healthcare institutions. A discount rate of 3% was applied to both costs and outcomes. One-way deterministic and probabilistic sensitivity analyses were conducted to explore uncertainties. RESULTS: The base-case analysis resulted in an incremental cost-effectiveness ratio (ICER) of SGD197, 667 per quality-adjusted life-year. Sensitivity analyses showed that the ICER was sensitive to the survival parametric distribution, ribociclib price, time horizon, and utility weights used. Even when these were varied, ICERs remained high and not cost-effective in the local context. CONCLUSION: At its current price, adding ribociclib to endocrine therapy is unlikely to be cost-effective in Singapore for HR+, HER2- ABC. Results from this study are useful to inform future funding decisions for CDK4/6 inhibitors alongside other factors including clinical effectiveness, safety, and budget impact considerations.

Conflict of interest in economic analyses of aromatase inhibitors in breast cancer: a systematic review.

To determine whether authors conducting economic analyses of aromatase inhibitors in breast cancer are less likely to reach unfavorable conclusions if the economic study is sponsored by the manufacturer of the drug. Articles reporting the economic analyses of aromatase inhibitors in breast cancer were selected from PubMed in May 2009. Information was collected on the types of analysis, the qualitative conclusion, the quantitative results, and the funding sources. Fisher's exact test was conducted to compare the frequency of unfavorable conclusions based on study sponsorship. Thirty-two eligible articles were identified. Twenty-six were funded by pharmaceutical companies, and 4 were funded by non-pharmaceutical companies. Two studies did not report a funding source. Twenty-one studies evaluated aromatase inhibitors in the adjuvant setting, while 11 studies examined their use in advanced breast cancer. Twenty-two studies evaluated one type aromatase inhibitor, while 10 compared multiple types of aromatase inhibitors. Only one of the 26 (4%) pharmaceutical company-sponsored studies reported unfavorable cost-effectiveness of an aromatase inhibitor, which was a competitor's product, whereas two of four (50%) non-pharmaceutical company-sponsored studies concluded aromatase inhibitors are not cost-effective in certain clinical scenarios (P < 0.05). Seven pharmaceutical company-sponsored studies conducted a comparison among several aromatase inhibitors; all 7 studies reported favorable conclusions for the sponsoring company's products. The majority of economic analyses of aromatase inhibitors in breast cancer are sponsored by pharmaceuticals. Economic evaluations of aromatase inhibitors in breast cancer that are funded by a pharmaceutical company are less likely to reach unfavorable conclusions about the sponsor's product.

Discussion about switch strategy in the adjuvant hormonal therapy of breast cancer: psychological aspects of physician-patient communication.

BACKGROUND: A survey of oncologists was conducted in Italy to evaluate the potential problems of physician-patient discussion about hormonal switch in the adjuvant therapy of breast cancer. MATERIALS AND METHODS: A questionnaire, including both closed and open-ended questions, was administered to 70 oncologists. Fifty-one of them returned completely filled questionnaires. RESULTS: Forty-seven percent of the physicians reported difficulties in proposing the hormonal switch, and 60% stated that they found it difficult to make the therapeutic change acceptable to patients. The oncologist's barriers to propose the switch were related mostly to scientific and economic issues, such as the lack of certain advantages of aromatase inhibitors over tamoxifen (28%), their costs (14%) and their side-effects (34%). On the other hand, according to physicians, the patient's barriers to accept the therapeutic change were mainly due to psychological-relational factors, in particular the anxiety produced by the change (40%) and the bad patient-physician communication experienced in the past (26%). CONCLUSIONS: Patient-physician communication difficulties about switch strategy in the adjuvant hormonal treatment of breast cancer are, at least in part, related to psychological and relational factors. It is likely that training programs, improving doctor's communication skills, can overcome these problems.

Exemestane: a review of its use in postmenopausal women with breast cancer.

Exemestane (Aromasin) is an orally active steroidal irreversible inactivator of the aromatase enzyme indicated as an adjuvant treatment in postmenopausal women with estrogen receptor-positive early-stage breast cancer following 2-3 years of adjuvant treatment with tamoxifen, and for the treatment of advanced breast cancer in postmenopausal women whose disease has progressed following tamoxifen or other antiestrogen therapy. Exemestane is effective for the treatment of postmenopausal women with early-stage or advanced breast cancer. In early-stage disease, switching to exemestane for 2-3 years after 2-3 years of adjuvant tamoxifen treatment was more effective in prolonging disease-free survival than continuing tamoxifen therapy, although it was not associated with an overall survival benefit, except in those with estrogen receptor-positive or unknown receptor status disease when nodal status, hormone replacement therapy (HRT) and chemotherapy use were adjusted for. Moreover, preliminary data suggest that the efficacy of exemestane is generally no different to that of tamoxifen in the primary adjuvant treatment of early-stage breast cancer, although exemestane may be better in prolonging the time to distant recurrence. In advanced disease, exemestane showed equivalent efficacy to megestrol in patients with disease refractory to tamoxifen and an efficacy not significantly different from that of fulvestrant in those refractory to a nonsteroidal aromatase inhibitor. Available data, some of which are limited, suggest exemestane is also effective in the first-line hormonal treatment of advanced breast cancer in postmenopausal women. Exemestane is generally well tolerated, although the potential bone fracture risk of the drug requires further investigation. Results from directly comparative trials indicating the efficacy, tolerability and bone fracture risk of exemestane relative to third-generation aromatase inhibitors and other agents in both early-stage and advanced disease, as well as the optimal sequence of endocrine therapies, are awaited with interest. In the meantime, switching to exemestane should be considered in postmenopausal women who have received 2-3 years of adjuvant tamoxifen treatment for early-stage breast cancer, and is an emerging treatment option for postmenopausal women with advanced breast cancer refractory to one or more antiestrogen therapies.

Letrozole combined with norethisterone acetate compared with norethisterone acetate alone in the treatment of pain symptoms caused by endometriosis.

BACKGROUND: The available data on effectiveness of aromatase inhibitors in treating pain symptoms related to endometriosis is limited. We compared the efficacy and tolerability of the aromatase inhibitor letrozole combined with norethisterone acetate versus norethisterone acetate alone in treating pain symptoms. METHODS: This prospective, open-label, non-randomized trial included 82 women with pain symptoms caused by rectovaginal endometriosis. Patients received either a combination of letrozole and norethisterone acetate (group L) or norethisterone acetate alone (group N) for 6 months. Changes in pain symptoms during treatment and in the 12 months of follow-up were evaluated. Side effects of each treatment protocol were recorded. RESULTS: Intensity of chronic pelvic pain and deep dyspareunia significantly decreased during treatment (P < 0.001 versus baseline by 3 months) in both study groups. At both 3- and 6-month assessment, the intensity of chronic pelvic pain (P < 0.001, P = 0.002, respectively) and deep dyspareunia (P < 0.001, P = 0.005, respectively) was significantly lower in group L than group N. At completion of treatment, 63.4% of women in group N were satisfied with treatment compared with 56.1% in group L (P = 0.49). Pain symptoms recurred after the completion of treatment; at 6-month follow-up no difference was observed in the intensity of pain symptoms between the groups. Adverse effects were more frequent in group L than in group N (P = 0.02). CONCLUSIONS: The combination drug regimen was more effective in reducing pain and deep dyspareunia than norethisterone acetate; however, letrozole caused a higher incidence of adverse effects, cost more and did not improve patients' satisfaction or influence recurrence of pain.

The economic consequences of breast cancer adjuvant hormonal treatments.

RATIONALE: Adjuvant hormone therapy (HT) based on tamoxifen (TX) or aromatase inhibitors (AIs) has become the standard of care for treating hormone receptor -positive (HR+) breast cancer (BC) over the past 20 years. Based on clinical trial results, AI use is recommended by the American Society of Clinical Oncology for treatment of postmenopausal women with HR+ breast cancer. AIs, however, are significantly more expensive than TX, raising concerns about access and use of effective treatment among women of lower socio-economic status. OBJECTIVES: To examine the relationship between adjuvant HT modality and experience of financial hardship among a cohort of older BC survivors. Also, to examine the extent to which financial concerns affect the probability of switching between adjuvant HT modalities. DESIGN: Population-based, prospective survey study. PARTICIPANTS: Elderly (65+) women who had an incident BC surgery in 2003 and who reported receiving adjuvant HT during the first 12 months post-surgery. METHODS: Multivariate regression models. RESULTS: Use of AIs was associated with a significantly higher probability of financial hardship. Women who had taken only an AI were more likely to experience financial difficulty than women who took only TX (OR = 1.4; 95% CI: 1.1-1.7), but women who switched between TX and AI were not more likely to experience financial difficulty. Breast cancer survivors with no drug coverage (OR = 4.5; 95% CI: 3.3-5.9) or partial drug coverage (OR = 3.6; 95% CI: 2.8-4.5) were more likely to experience financial difficulty compared to those with full coverage. Lack of drug coverage was also the main factor associated with the likelihood that BC survivors did not switch adjuvant HT modalities. CONCLUSIONS: Adjuvant HTs have important economic consequences for BC survivors. These consequences are ameliorated by full, but not partial, drug coverage.

Radiation Therapy Without Hormone Therapy for Women Age 70 or Above with Low-Risk Early Breast Cancer: A Microsimulation.

PURPOSE: Hormone therapy without radiation therapy is considered appropriate for women age 70 or above with low-risk, hormone-positive breast cancer after partial mastectomy. However, some patients may prefer radiation without hormone therapy, for which there is minimal modern data. We modeled the comparative efficacy of aromatase inhibition alone without radiation versus radiation alone without hormone therapy. METHODS AND MATERIALS: We constructed a patient-level Markov model and compared 5 years of anastrozole to a 15-fraction course of radiation without boost or anastrozole. The relative effectiveness between treatments was based on the National Surgical Adjuvant Breast and Bowel Project B-21 trial, which was further adjusted such that the endocrine-alone arm matched the Cancer and Leukemia Group B 9343 and PRIME II trials. Common or severe side effects were considered. Eight survival metrics were assessed and validated against clinical trial data. The cost-efficacy of each strategy was considered using the quality-adjusted life year and incremental cost-effectiveness ratio (ICER). RESULTS: The model's predicted outcomes matched those demonstrated by modern trials. Aromatase inhibitors were superior in preventing contralateral cancers, with a small impact on the risk of distant metastatic disease. Radiation was superior in preventing ipsilateral breast tumor recurrence with a small impact on regional failure. No clinically significant differences were seen in the other 4 oncologic endpoints. Differences in quality-adjusted life years were small, but radiation therapy was $3809 more expensive over the average lifetime. The ICER suggested anastrozole was cost-effective in 62% of probabilistic simulations. However, the ICER was unstable owing to a denominator that approached zero. CONCLUSIONS: Women age 70 or above with low-risk early breast cancer who are reluctant or unable to pursue adjuvant aromatase inhibition can safely pursue adjuvant radiation alone with limited differences in outcome and a modest increase in costs.

HR+/HER2- Metastatic Breast Cancer: Epidemiology, Prescription Patterns, Healthcare Resource Utilisation and Costs from a Large Italian Real-World Database.

BACKGROUND AND OBJECTIVE: Breast cancer is the second leading cause of cancer death worldwide. The economic burden of breast cancer is crucial for the sustainability of healthcare systems. The objective of this study was to estimate the burden of HR+/HER2- metastatic breast cancer (MBC) in Italy, in terms of incidence, prescription patterns, healthcare resource utilisation and costs for the National Health System (NHS). METHODS: A cohort study based on healthcare administrative data (ReS database), covering > 10 million Italians, was performed. Incident cases of HR+/HER2- MBC were identified among adult women in 2013. The cohort was followed-up for 2 years to describe healthcare utilisation and integrated costs (pharmaceuticals, hospitalisations and outpatient services) for NHS. Prescription patterns were described as first-line choice and therapeutic changes. Specific therapeutic changes were used as proxies of disease progression. A survival analysis was performed to estimate the time from diagnosis to first disease progression. RESULTS: Of 5174,723 women, 355 cases of de novo HR+/HER2- MBC were selected (incidence: 6.9 per 100,000). During the 1st follow-up year, they generated an average cost of €7543, whereas €4834 in the 2nd year. The 85.9% received a monotherapy, while the 14.1% received a combination therapy. The most used monotherapy was nonsteroidal-aromatase-inhibitors (45.9%), while the most prescribed combination was tamoxifen + luteinizing hormone releasing hormone (LHRH) analogues (6.2%). Therapeutic changes occurred in 45.4% of patients, especially from chemotherapy to nonsteroidal-aromatase-inhibitors, after an average of 276.8 days from the first treatment. Disease progression was identified in 22.5% of patients occurring after a mean 13 ± 6 months from diagnosis. CONCLUSIONS: This detailed picture of HR+/HER2- MBC, based on real-world data, could be helpful in health technology assessment and expenditure forecasts of future therapeutic strategies for this condition in Italy.

CDK4/6 inhibition in low burden and extensive metastatic breast cancer: summary of an ESMO Open-Cancer Horizons pro and con discussion.

In December 2017, ESMO Open-Cancer Horizons convened a round-table discussion on the background and latest data regarding cyclin-dependent kinase (CDK)4/6 inhibitors with endocrine therapy (ET) in the treatment of endocrine-sensitive breast cancer (BC). A review on this discussion was published in summer 2018 (https://esmoopen.bmj.com/content/3/5/e000368).Endocrine-sensitive BC with non-visceral disease and limited spread of the metastases.Endocrine-sensitive BC with non-life-threatening visceral involvement. Several open questions were identified, which led to a second ESMO Open discussion on CDK4/6 inhibitors, taking place in December 2018 and covered in this article. The panel discussed two important clinical scenarios and the pro and cons of a treatment approach with CDK4/6 inhibitors for each scenario:Endocrine-sensitive BC with non-visceral disease and limited spread of the metastases.Endocrine-sensitive BC with non-life-threatening visceral involvement. Regarding scenario 1, the panel agreed that CDK4/6 inhibitors should be recommended in first-line therapy for most patients if cost and practicality allow. However, the use of single-agent ET with an aromatase inhibitor in the first-line treatment of these patients is still a possibility for a small group of patients with very limited disease, such as one or two bone lesions or limited lymph node involvement. Regarding scenario 2, chemotherapy is the first approach for patients with endocrine-sensitive metastatic BC with life-threatening visceral involvement because of the need for a faster response. The therapeutic approaches for patients with non-life-threatening visceral involvement are still under debate. Nevertheless, CDK4/6 inhibitors are currently the treatment of choice for most patients with a close follow-up of tumour response. A treatment algorithm has been suggested at the round table.

Aromatase inhibitors in early hormone receptor-positive breast cancer : what is the optimal initiation time for the maximum benefit?

Breast cancer is common, affecting one in nine women worldwide. As stipulated by the St Gallen consensus guidelines, hormone therapy is an integral part of treatment for hormone-responsive disease. Previously, this has been with tamoxifen; however, as a result of a number of recent studies, aromatase inhibitors are now competing for use as first-line agents. In addition, there is as yet no firm consensus as to when and how these drugs should be used within the adjuvant setting. This article reviews the use of aromatase inhibitors in early stage hormone-positive breast cancer. It describes the evidence from the studies involving the aromatase inhibitors in an upfront, switch and extended setting. It further discusses the mathematical models proposed to determine the optimum timing of initiation. In light of the ongoing research into predictive biomarkers, this review then concentrates on whether future focus should be on more individualized treatment strategies than the optimum timing of aromatase inhibitors.

Methodological issues in evaluating cost effectiveness of adjuvant aromatase inhibitors in early breast cancer: a need for improved modelling to aid decision making.

The optimal adjuvant hormonal strategy in post-menopausal women with early breast cancer is a subject of ongoing debate. Aromatase inhibitors (AIs) have been successfully evaluated in clinical trials that have compared them with a standard treatment of 5 years of tamoxifen. However, several options are available in terms of treatment schedule and selected drug. Systematic reviews of clinical trials and health economic evaluations attempt to contribute to the debate. The objective of this paper is to provide a critical review of existing health economic evaluations with a focus on those parameters and assumptions with the largest impact on final outcomes.A wide range of different inputs and assumptions exist, which make a comparison of results difficult, if not impossible. In particular, the modelling of recurrence rates over longer time horizons than those observed in clinical trials, a cornerstone of health economic modelling, is subject to quite different approaches. The practice of indirect comparison of different AIs without sufficiently acknowledging population differences is also bothersome. A list of key features (related to time horizon, clinical data input, patient subtypes, budget impact and model calibration) that an ideal model should have in order to better assist decision makers in this field is proposed.

Experience with exemestane in the treatment of early and advanced breast cancer.

BACKGROUND: Exemestane represents the only steroidal third-generation aromatase inactivator implemented for breast cancer therapy. OBJECTIVE: Present clinical and translational data defining the role of exemestane as an aromatase inhibitor. METHODS: Literature search including PubMed and ISI Web of Science. RESULTS/CONCLUSION: Exemestane potently inhibits in vivo aromatization resembling anastrozole and letrozole. Randomized trials have revealed superiority for exemestane compared to conventional therapy in metastatic breast cancer. In addition sequential treatment with tamoxifen (for 2 - 3 years) followed by exemestane (for 3 - 2 years) has revealed superiority with respect not only to relapse-free but also borderline improvement in overall survival in adjuvant therapy. Several studies now confirm lack of cross-resistance between non-steroidal aromatase inhibitors and exemestane, which could be due to exemestane's low androgen-agonistic activity through its 17-hydro metabolite.

Economic Evaluation of Letrozole for Early Breast Cancer in a Health Resource-Limited Setting.

OBJECTIVE: Long-term aromatase inhibitor (AI) therapy is expected to improve the health outcomes with high health resource consumption in early breast cancer. The aim of the study was to assess the cost-effectiveness of letrozole for postmenopausal women with estrogen receptor positive early breast cancer in a health resource-limited setting. METHODS: A Markov model was developed to project the lifetime outcomes based on the clinical course of early breast cancer. The clinical and utility data were derived from reported results. Costs were estimated from the perspective of Chinese health care. The quality-adjusted life-year (QALY) and incremental cost-effective ratio (ICER) were measured. Probabilistic sensitivity and one-way analyses were conducted. RESULTS: Compared to 5 years of tamoxifen therapy, 5 years of AI treatment with letrozole improved the QALYs (10.44 versus 10.84) and increased the lifetime costs (CNY ¥13,613 versus CNY ¥28,797), resulting in an ICER of CNY ¥38,092 /QALY. The ICER of 5 years of letrozole versus 2-3 years of tamoxifen and then letrozole was CNY ¥68,233 /QALY. Sensitivity analyses showed that the age of initiating adjuvant endocrine therapy was the most influential parameter. CONCLUSIONS: In health resource-limited settings, adjuvant endocrine therapy with letrozole is a cost-effective strategy compared to tamoxifen in women with early breast cancer.

Aromatase inhibitors--socioeconomical issues.

With costs of health care in general and for cancer therapy in particular escalating due to implementation of novel compounds, there is an increasing focus on therapy costs in most countries. A common way of assessing therapeutic utility versus cost is by assessing cost per additional life year gained or cost per additional quality-adjusted life year (QALY) gained with a novel therapy. While endocrine therapy in general is associated with low costs, the fact that aromatase inhibitors are administered over several years to each patient in the adjuvant setting, together with the substantial number of postmenopausal breast cancer patients that are candidates for adjuvant treatment with aromatase inhibitors, advocates critical examination of cost-utilities related to implementation of such therapy in the adjuvant setting. While cost-utility estimates for treatment with aromatase inhibitors in the adjuvant setting look favorable, the estimates are sensitive to variations with respect to long-term benefits but also side effects. For patient groups with a low-risk of relapse but also patients with a limited life expectancy due to high age, cost-utility estimates may exceed the upper limits generally proposed for costs per quality-adjusted life year gained.

Hormonal therapies for early breast cancer: systematic review and economic evaluation.

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.