Health Technology Assessment 2007; Vol 11: number 26
Executive Summary
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Hormonal therapies for early breast cancer: systematic review and economic evaluation
D Hind,1* S Ward,1 E De Nigris,1 E Simpson,1 C Carroll1 and L Wyld2
1 The School of Health and Related Research (ScHARR), University of Sheffield,
UK
2 Surgical Oncology, University of Sheffield, UK
* Corresponding author
Description of proposed service
Aromatase inhibitors (AIs) are proposed for the adjuvant treatment of oestrogen receptor-positive early breast cancer in postmenopausal women in three different indications: (1) instead of the current anti-oestrogen treatment, tamoxifen, for 5 years ('primary adjuvant'); (2) instead of tamoxifen for 2–3 years of an adjuvant programme, implemented opportunistically after a woman survives disease free for a period on tamoxifen ('unplanned switching strategy'), or planned from the time of surgery ('planned sequence strategy'); (3) for 3–5 years in women who are disease free following 5 years of tamoxifen: this is known as an 'extended adjuvant' strategy. The three AIs and their licensed indications are (1) anastrozole (primary adjuvant), (2) letrozole (primary adjuvant, extended adjuvant) and, (3) exemestane (unplanned switching).
Epidemiology and background
Around 23,000 postmenopausal women will be diagnosed with oestrogen receptor-positive early breast cancer every year. Treated with tamoxifen, disease will have recurred in about one-quarter after 5 years with recurrences continuing up to 20 years after surgery.
Objectives of the review
The objectives of this review were 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 with oestrogen receptor-positive early-stage breast cancer.
Methods
Fourteen electronic bibliographic databases and three trials registers were searched from May to June 2005. Three conference abstract databases were searched in December 2005. Studies evaluating the clinical effectiveness of AIs against 5 years' tamoxifen treatment were included and critically appraised on the adequacy of allocation concealment, randomisation, double blinding and intention-to-treat analysis. Critical appraisal and data extraction into standardised forms were performed independently, unblinded, by two researchers.
Three strategies for the proposed use of AIs were considered. First, primary adjuvant therapy, comparing AIs with tamoxifen in treatment of patients randomised at zero years after surgery. Second, unplanned switch therapy, patients randomised following 2–3 years of tamoxifen to either continue on tamoxifen for the remainder of the 5-year adjuvant treatment period or switch to an AI. Third, extended/sequential adjuvant therapy, patients randomised after 5 years of tamoxifen to receive 5 years of further treatment on an AI or placebo.
The three treatment strategies were considered separately within the economic analysis. Trials with strategies that randomised patients half-way through or at the end of the standard 5-year adjuvant treatment period with a strategy which randomised patients immediately after surgery were not compared directly.
The independent economic analysis used a state transition (Markov) approach to simulate the disease outcomes of patients up to a time horizon of 35 years post-surgery for early breast cancer. The primary outcome of interest was the cost per quality-adjusted life-year (QALY) gained, associated with AIs versus tamoxifen (or placebo, in the case of the extended adjuvant setting).
HRs from the trials were applied to the tamoxifen event rates to estimate event rates in the aromatase inhibitor arm.
Costs of health states were based on a review of published evidence to obtain the most recent and appropriate costs. Where published data were not identified, clinical opinion was sought. First-year costs and subsequent-year costs are assigned for each of the different health states modelled. Costs of managing adverse events are modelled.
The utility of the disease-free population was adjusted for age, based on data from Kind and Dolan. A literature review was undertaken in order to identify utility estimates for health states within the model. These were used as multipliers to adjust the age-related utility of the general population following an event. It is assumed that there is no disutility for patients on AIs or tamoxifen.
Results
Number and quality of studies and direction of evidence
Seven Phase III randomised controlled trials of varying methodological quality were found. Meta-analysis of studies was prohibited by the heterogeneity of trial designs. As most of the study populations had a relatively good prognosis and events are rare, hazard ratios (HRs) with 95% confidence intervals (CIs) and absolute risk reductions (ARRs) are presented.
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 (details academic-in-confidence). 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 (68 months' follow-up: HR 0.87, 95% CI 0.78 to 0.97; ARR 0.024) and letrozole (26 months' follow-up: HR 0.83, 95% CI 0.73 to 0.94; ARR 0.019), and with an exemestane switching strategy (31 months' follow-up: HR 0.68, 95% CI 0.56 to 0.82; ARR 0.035). Other trials did not report this outcome. Breast cancer recurrence (censoring death as an event) was significantly improved with primary adjuvant anastrozole (68 months' follow-up: HR 0.79, 95% CI 0.70 to 0.90; ARR 0.031) and letrozole (26 months' follow-up: HR 0.74, 95% CI 0.64 to 0.87; ARR 0.021), anastrozole switching (28 months' follow-up: HR 0.59, 95% CI 0.44 to 0.81; ARR 0.027): extended adjuvant anastrozole (60 months' follow-up: HR 0.64, 95% CI 0.41 to 0.99; ARR 0.042) or letrozole (30 months' follow-up: HR 0.58, 95% CI 0.45 to 0.76; ARR 0.024). 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 women of this age. 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.
Cost-effectiveness results
The cost-effectiveness results for anastrozole and letrozole, compared with tamoxifen in the primary adjuvant setting, were estimated to be £32,000 and £21,600 per QALY, respectively, based on an analysis over 35 years. There is, however, greater uncertainty around the results for letrozole, as the hazard ratio is based on an average follow-up of 26 months, compared with 68 months for anastrozole. There is currently no trial evidence for exemestane in this setting.
The cost-effectiveness results in the unplanned switching setting for anastrozole and exemestane, compared with tamoxifen, were estimated to be £23,200 and £19,200 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 was estimated to be £9800, based on an analysis over 35 years.
All these results were considered to be conservative. In the base case it was assumed that the benefits of AIs over tamoxifen or placebo seen during the therapy period were gradually lost during the following 10 years. In other words, the rate of recurrence for AIs after the trial period was assumed to be higher than that for tamoxifen between 5 and 15 years post-surgery, to the extent that by year 15 the number of patients in a disease-free state was the same in both arms. An alternative scenario, the 'benefits maintained' scenario, was tested in sensitivity analysis. In this scenario, it was assumed that following the treatment period the annual rate of recurrence in both arms would be the same. This reduced the cost-effectiveness ratio by over 50%, to around £10,000–12,000, £5000 and £3000 in the primary adjuvant, unplanned switching and extended adjuvant setting, respectively. The limited evidence to date of benefits after the therapy period suggested that the 'benefits maintained' scenario may be realistic.
One-way and probabilistic sensitivity analysis suggested that these results were generally robust to changes in the key model parameters. Understanding of the long-term treatment effects is, however, incomplete. The economic model considered costs and benefits over the lifetime of a patient, requiring extrapolation of these costs and benefits well beyond the timeframe of the reported trial outcomes to date. 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. The largest uncertainty in terms of adverse events relates to the future risk of fracture in the period following adjuvant therapy, as the treated population gets older
The results from the economic analyses within the industry submissions were generally lower than the results from the authors' model and were close to or below £12,000 in all three settings. The authors' analyses generally produced 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 economic model.
Conclusions
Clinical effectiveness
No individual study reported a difference in overall survival between any AI and tamoxifen (or placebo in the extended adjuvant setting). An unpublished meta-analysis of individual patient data from three trials did find a significant difference in overall survival when unplanned anastrozole switching strategy was compared with 5 years' tamoxifen. Compared with 5 years' tamoxifen, DFS (absence of disease recurrence or death from any cause) was significantly increased in the primary adjuvant setting (using anastrozole or letrozole) and the unplanned switching strategy (using anastrozole or exemestane). Breast cancer recurrence (censoring death as an event) was significantly improved with primary adjuvant anastrozole or letrozole, an anastrozole or exemestane unplanned switching strategy and an extended adjuvant anastrozole or letrozole strategy. There is no evidence that AIs confer any advantage in overall health-related quality of life. 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.
Cost-effectiveness
Three treatment strategies for AIs – primary adjuvant therapy, unplanned switch therapy and extended adjuvant therapy – were considered separately within the economic analysis. 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 and £32,000 in the primary adjuvant setting and around £20,000 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. 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. However, understanding of the long-term treatment effects oncost-effectiveness is incomplete.
Need for further research
Randomisation of populations at any point other than the start of treatment programmes should be strongly discouraged in future trials as it limits the utility of the resulting dataset. In the present case, this means randomising at the start of, not half way through or at the end of, the adjuvant period, because the objective is the same from successful surgery until relapse or death.
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.
Long-term follow-up data on major adverse events, including cholesterol levels, cardiovascular events and fracture rates, are awaited. Evidence to date suggests that the impact of these adverse events does not unduly impact on the cost-effectiveness ratios. The long-term implications for the costs and benefits of AIs and tamoxifen will need to be reviewed as and when new information becomes available.
Publication
Hind D, Ward S, De Nigris E, Simpson E, Carroll C, Wyld L. Hormonal therapies for early breast cancer: systematic review and economic evaluation. Health Technol Assess 2007;11(26).
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