Cost effectiveness of letrozole in the treatment of advanced breast cancer in postmenopausal women in the UK

OBJECTIVE: To simulate the treatment of postmenopausal women with advanced breast cancer from second-line hormone therapy to death, and to generate estimates of the cost and effectiveness of letrozole and megestrol in order to determine the incremental cost effectiveness of letrozole, expressed as cost per life-years gained. DESIGN: A decision-analytic model, using Markov process techniques, was designed to evaluate the lifetime clinical and economic consequences of treatment with letrozole compared with standard care with megestrol. The model was based on clinical trial results showing a clear advantage of letrozole in terms of time to progression and duration of response. SETTING: The setting of the study was that of the UK healthcare system in 1996. PATIENTS AND PARTICIPANTS: A hypothetical cohort of patients, identical to the patients recruited for the AR/BC2 clinical trial, who were postmenopausal women with advanced breast cancer who had previously failed to respond to first-line or adjuvant anti-estrogen therapy. INTERVENTIONS: The dosages of medications were 2.5 and 160 mg/day for letrozole and megestrol, respectively. The analysis covered the period from treatment initiation until death (lifetime model). Effectiveness was expressed as survival and time without progression, and the model also included all relevant economic measures. MAIN OUTCOME MEASURES AND RESULTS: Based on the model, the average survival time of the letrozole group was 2.1 years (25.3 months) versus 1.9 years (21.5 months) for the megestrol group, a gain in survival of 2.4 months (10.5%). The average time without progression, cumulatively calculated over the different treatment options, amounted to 20.2 months for letrozole and 17.8 months for megestrol, an increase of 13.7% for the former patients. The total average cost per patient for the treatment of advanced breast cancer starting from second-line hormone therapy until death was higher in the letrozole group at 7547 Pounds versus 6820 Pounds for the megestrol group (discounted at an annual rate of 5%), leading to an incremental cost-effectiveness ratio of 3588 Pounds per life-year gained (1996 values). CONCLUSIONS: Based on the assumptions used in this model, letrozole offers a suitable alternative to megestrol in the treatment of second-line hormone therapy.     

Cost effectiveness of letrozole versus anastrozole in postmenopausal women with HR+ early-stage breast cancer

Abstract

Background:

The Breast International Group (BIG) 1-98 and Arimidex, Tamoxifen Alone or in Combination (ATAC) trials demonstrated that, in postmenopausal women with hormone receptor positive (HR+) early-stage breast cancer, 5 years of initial adjuvant endocrine therapy with letrozole or anastrozole is superior to tamoxifen. With expected generic availability of anastrozole in July 2010 and letrozole in June 2011, there may be financial pressures prior to letrozole's generic availability to start treatment-naïve patients on anastrozole vs. letrozole or to switch patients already receiving letrozole to anastrozole.     

Absolute bioavailability of letrozole in healthy postmenopausal women

Letrozole is a new non-steroidal inhibitor of the aromatase enzyme system. It is currently under development for the treatment of postmenopausal women with advanced breast cancer. Absolute bioavailability of letrozole when given orally as one 2·5 mg film-coated tablet in comparison to the same dose given intravenously as a bolus injection was studied in 12 healthy postmenopausal women. Letrozole absolute systemic bioavailability after p.o. administration was 99·9±16·3%. Elimination of letrozole was slow. Total-body clearance of letrozole from plasma after i.v. administration was low (2.21 L h⁻¹). The calculated distribution volume at steady state (1.87 L kg⁻¹) suggests a rather high tissue distribution. Biotransformation of letrozole is the main elimination mechanism with the glucuronide conjugate of the secondary alcohol metabolite being the predominant species found in urine. The two study treatments were tolerated equally well. © 1997 John Wiley & Sons, Ltd.     

Cost effectiveness of pregabalin in the treatment of fibromyalgia from a UK perspective

Abstract

Background:

Fibromyalgia is a chronic condition associated with widespread pain, sleep disturbance and disability. Disease related costs are high and effective treatment options few.     

Population pharmacokinetic analysis of letrozole in Japanese postmenopausal women

Purpose  

Letrozole is an orally active aromatase inhibitor for the treatment of breast cancer. The objectives of this study were to examine the pharmacokinetic profile of letrozole in Japanese subjects and to identify factors that influence variability in the pharmacokinetics of letrozole using population pharmacokinetic (PPK) analysis.     

A stochastic economic evaluation of letrozole versus tamoxifen as a first-line hormonal therapy: for advanced breast cancer in postmenopausal patients

BACKGROUND: Letrozole is a third-generation aromatase inhibitor that is a feasible alternative to tamoxifen as a first-line hormonal therapy for patients with advanced breast cancer. OBJECTIVE: This paper presents the results of an economic evaluation comparing letrozole and tamoxifen as first-line hormonal therapies in postmenopausal women diagnosed with advanced breast cancer. PERSPECTIVE: UK National Health Service. DESIGN: A decision model (Markov process) was built describing possible patient pathways from the point of diagnosis to death. The model was populated using patient-specific clinical trial data, data from the existing literature, and expert opinion. Stochastic analyses of the model were undertaken, whereby the majority of the input parameters were described as probability distributions to represent the uncertainty about their true value. Costs were presented in year 2000 values. RESULTS: The baseline results showed that letrozole is a cost-effective alternative to tamoxifen with a mean incremental cost per life-year gained of pound 2342, whilst the incremental cost increases to just over pound 10,000 at the 95th percentile of the cost-effectiveness range (2000 values). CONCLUSIONS: The results of the economic analysis indicate that letrozole is a cost-effective alternative first-line therapy compared with tamoxifen for postmenopausal women with advanced breast cancer, achieving additional life-years with a modest increase in costs.     

他莫昔芬与来曲唑治疗绝经后激素受体阳性乳腺癌的疗效与安全性

目的分析他莫昔芬与来曲唑治疗绝经后激素受体阳性乳腺癌的疗效与安全性。方法选取2016年1月～2018年1月我院收治的乳腺癌患者98例,根据随机数字表抽取法分为对照组和观察组,各49例,对照组给予他莫昔芬治疗,观察组给予来曲唑治疗,观察对比两组患者治疗前及治疗后第6、12个月的雌二醇(E2)水平,治疗12个月后的临床疗效,不良反应发生情况。结果治疗前,两组E2水平比较,差异无统计学意义(P 0.05);治疗第6、12个月后,两组患者E2水平均显著下降,且观察组E2水平显著低于对照组,差异有统计学意义(P 0.05);相较之对照组,观察组的临床总有效率明显更高,不良反应发生率明显更低,差异有统计学意义(P 0.05)。结论来曲唑治疗绝经后激素受体阳性乳腺癌的不良反应较少,临床疗效显著,值得合理推广应用。     

Cost effectiveness of multi-therapy treatment strategies in the prevention of vertebral fractures in postmenopausal women with osteoporosis.

OBJECTIVE: The aim of this study was to evaluate the cost effectiveness of multi-therapy treatment strategies in the prevention of vertebral fractures in postmenopausal women with osteoporosis. DESIGN: A retrospective, incremental cost-effectiveness analysis was conducted from a societal perspective. It compared 9 treatment strategies over 3 years and incorporated the willingness of patients to initiate and continue each therapy. MAIN OUTCOME MEASURES AND RESULTS: Four nondominated strategies formed the efficient frontier in the following order: (i) calcium-->no therapy; (ii) ovarian hormone therapy (OHT)-->calcium-->no therapy [166 Canadian dollars ($Can)]; (iii) OHT-->etidronate-->calcium-->no therapy ($Can2331); and (iv) OHT-->alendronate-->calcium-->no therapy ($Can40,965). The figures in parentheses are the incremental costs per vertebral fracture averted to move to that strategy from the previous strategy for patients who had undergone a hysterectomy. CONCLUSIONS: We identified 4 efficient multi-therapy strategies for the treatment of vertebral osteoporosis in postmenopausal women, 2 of which were consistent with the practice guidelines of the Osteoporosis Society of Canada. Decision-makers may select from among these efficient strategies on the basis of incremental cost effectiveness.     

Pharmacoeconomic aspects of adjuvant anastrozole or tamoxifen in breast cancer: a Slovenian perspective

New treatment approaches that include the use of aromatase inhibitors in adjuvant breast cancer management are associated with higher efficacy and increased drug costs. Our aim was to calculate the difference in total costs of care associated with two therapeutic options, anastrozole and tamoxifen, from the perspective of a healthcare provider. The cost of care and a decision tree analysis were used in this assessment. The efficacy of both drugs in terms of relapse rate was obtained from an ATAC (Arimidex, Tamoxifen Alone or in Combination) trial after the median observational time of 68 months. The total sum of all direct healthcare costs over a 60-month period was 14,438 and 8,009 Euros per person in the anastrozole and tamoxifen arm, respectively. Despite higher total costs of care associated with anastrozole, the drug cost ratio of anastrozole/tamoxifen=8.1/1 converted to a ratio of only 1.75/1 in favor of tamoxifen when costs of recurrence and adverse events were included. The total costs of care, including disease recurrences and adverse event management obtained in our analysis were similar to total costs of care values for other surveys, which lead us to believe that anastrozole is also a cost-effective alternative to tamoxifen in Slovenia.     

来曲唑片在中国健康绝经期女性志愿者人体生物等效性及安全性研究(英文)

来曲唑是一种口服芳香酶抑制剂,用于治疗绝经期女性乳腺癌。一项单剂量、随机、开放、双向交叉研究比较了2种2.5mg的来曲唑片剂在空腹状态下的中国健康绝经期女性志愿者的人体生物等效性和安全性。在给药前以及给药后0.25、0.50、0.75、1.00、1.25、1.50、2.00、2.50、3.00、3.50、4.00、6.00、8.00、12.00、24.00、48.00、72.00、96.00、144.00、192.00和240.00小时采集血样。采用LC-MS/MS法测定来曲唑的血浆浓度。安全性的评估包括监测不良事件、生命体征及临床生物学数据等。共入选了30位中国健康绝经期女性受试者,由于1位受试者发生了严重不良事件,生物等效性研究仅包括了29位受试者的数据。lnCmax,AUC0–t,AUC0–∞的90%CIs分别为99.55%–115.17%,97.35%–103.50%,97.29%–103.96%,这些数值均满足生物等效的标准。1位受试者(3.3%)服用参比制剂发生了严重不良事件,10位受试者(33.3%)发生了13例次的轻度不良事件(4位受试者服用受试制剂发生4例次轻度不良事件,6位受试者服用参比制剂发生9例次轻度不良事件)。来曲唑单剂量2.5mg的受试制剂和参比制剂在中国健康绝经期女性受试者人体生物等效,两种药物在中国健康绝经期女性受试者中耐受性良好。中国临床试验注册号:ChiCTR-TRC-11001457。     

Cost effectiveness of the German screen-and-treat strategy for postmenopausal osteoporosis

BACKGROUND: The German osteology umbrella organization, Dachverband Osteologie (DVO), has published a new guideline for the secondary prevention of osteoporotic fractures. According to the guideline, women are screened using dual x-ray absorptiometry (DXA). Those with an absolute 10-year fracture risk > or =30% are treated with bisphosphonates such as alendronate or risedronate for 4 years or with teriparatide for 18 months. OBJECTIVE: To determine the cost effectiveness of the screen-and-treat strategy versus no intervention in women of the general population aged 50-90 years in Germany. METHODS: Cost-utility and budget-impact analyses were performed from the perspective of the statutory health insurance (SHI). A Markov model with a 1-year cycle length simulated costs and benefits (QALYs), discounted at 3%, over a lifetime horizon. The number of women correctly diagnosed by pre-tests and DXA as having a 10-year fracture risk of > or =30% was estimated for different age groups (50-60, 60-70, 70-80 and 80-90 years). Incremental cost-effectiveness ratios (ICERs) were calculated; all costs are presented in euro, year 2006 values. Robustness of the results was tested by a probabilistic Monte Carlo simulation. RESULTS: Alendronate was the most cost-effective drug in all age groups; the ICERs were euro 3849, euro 16 589, euro 6600 and euro 2337 per QALY for 50-, 60-, 70- and 80-year-old women, respectively, followed by risedronate. Teriparatide was dominated in every age group. Implementing the screen-and-treat strategy would result in annual costs of euro 175 million for alendronate (euro 181 million for risedronate) or 0.14% of the SHI annual budget. Results were robust in the sensitivity analysis. CONCLUSION: While the screen-and-treat strategy would result in a substantial cost increase for the SHI, the use of alendronate within such a strategy appears cost effective when compared with many generally accepted medical interventions.     

来曲唑一线治疗绝经后妇女晚期乳腺癌

目的：研究来曲唑一线治疗绝经后妇女晚期乳腺癌的临床疗效和不良反应。方法：采用多中心协作开放临床试验，入组患者共32例，口服来曲唑2.5mg,qd，共服4－6周，疗前2周内及治疗6周后的3d内检测血中雌二醇（E2）水平，同时评价疗效和不良反应。结果：入组32例均可评价疗效，CR1例，PR14例，有效率为46.9%。其中，绝经时间＜5年与≥5年者的有效率分别33.3%及55.0%；ER与PR均阳性、ER或PR阳性、受体未测者的有效率分别为75.0%(3/4),66.7%(4/6)与36.4%(8/22)；表明绝经时间长的患者疗效优于绝经时间短者；ER与PR均阳性的疗效好，而受体未测者疗效较差的原因可能是这部分患者中有一部分为受体阴性；另外，皮肤、淋巴结与软组织转移的疗效亦优于实质器官转移的疗效。疗后对E2的平均有效抑制率为66.7%。主要不良反应为乏力、头晕。结论：来曲唑作为一线药物对绝经后晚期乳腺癌疗效肯定，不良反应轻微，值得临床推广应用。     

Cost effectiveness of memantine in Alzheimer's disease: an analysis based on a probabilistic Markov model from a UK perspective

BACKGROUND: Clinical trials with memantine, an uncompetitive moderate-affinity NMDA antagonist, have shown improved clinical outcomes, increased independence and a trend towards delayed institutionalisation in patients with moderately severe-to-severe Alzheimer's disease. In a randomised double-blind, placebo-controlled, 28-week study conducted in the US, reductions in resource utilisation and total healthcare costs were noted with memantine relative to placebo. While these findings suggest that, compared with placebo, memantine provides cost savings, further analyses may help to quantify potential economic gains over a longer treatment period. OBJECTIVE: To evaluate the cost effectiveness of memantine therapy compared with no pharmacological treatment in patients with moderately severe-to-severe Alzheimer's disease over a 2-year period. METHODS: A Markov model was constructed to simulate patient progression through a series of health states related to severity, dependency (determined by patient scores on the Alzheimer's Disease Cooperative Study-Activities of Daily Living [ADCS-ADL] inventory and residential status ('institutionalisation') with a time horizon of 2 years (each 6-month Markov cycle was repeated four times). Transition probabilities from one health state to another 6 months later were mainly derived from a 28-week, randomised, double-blind, placebo-controlled clinical trial. Inputs related to epidemiological and cost data were derived from a UK longitudinal epidemiological study, while data on quality-adjusted life-years (QALYs) were derived from a Danish longitudinal study. To ensure conservative estimates from the model, the base case analysis assumed drug effectiveness was limited to 12 months. Monte Carlo simulations were performed for each state parameter following definition of a priori distributions for the main variables of the model. Sensitivity analyses included worst case scenario in which memantine was effective for 6 months and one-way sensitivity analyses on key parameters. Finally, a subgroup analysis was performed to determine which patients were most likely to benefit from memantine. Informal care was not included in this model as the costs were considered from National Health Service and Personal Social Services perspective.RESULTS: The base case analysis found that, compared with no treatment, memantine was associated with lower costs and greater clinical effectiveness in terms of years of independence, years in the community and QALYs. Sensitivity analyses supported these findings. For each category of Alzheimer's disease patient examined, treatment with memantine was a cost-effective strategy. The greatest economic gain of memantine treatment was in independent patients with a Mini-Mental State Examination score of > or =10. CONCLUSION: This model suggests that memantine treatment is cost effective and provides cost savings compared with no pharmacological treatment. These benefits appear to result from prolonged patient independence and delayed institutionalisation for moderately severe and severe Alzheimer's disease patients on memantine compared with no pharmacological treatment.     

Tamoxifen plus chemotherapy versus tamoxifen alone as adjuvant therapies for node-positive postmenopausal women with early breast cancer: a stochastic economic evaluation

BACKGROUND: There remains uncertainty around the appropriate choice of adjuvant therapies to offer postmenopausal women with node-positive early breast cancer. OBJECTIVE AND STUDY DESIGN: To present the results derived from a discrete event simulation (DES) model that compared tamoxifen plus chemotherapy versus tamoxifen alone in node-positive postmenopausal women diagnosed with early breast cancer. METHODS: The data populating the model were mainly derived from the existing literature, which was analysed to specify probability distributions describing the uncertainty around the true value of each input parameter. The specified probability distributions facilitated the stochastic analysis of the decision model, whereby distributions of the model's outputs [aggregate costs and quality-adjusted life years (QALYs)] were estimated. RESULTS: The baseline results show that the addition of chemotherapy to tamoxifen in this patient group is relatively cost effective (under pound 4000 per additional QALY), but the distribution of the incremental cost-effectiveness ratio shows a wide range, including 10% of observations in which tamoxifen dominates tamoxifen plus chemotherapy. CONCLUSIONS: The results demonstrate the intuitive nature of stochastic evaluations of healthcare technologies, which may ease decision-makers' interpretation of cost-effectiveness results.     

Assessing the risk of bone fracture among postmenopausal women who are receiving adjuvant hormonal therapy for breast cancer

ABSTRACT

Objective: To understand better the true impact of wide­spread adoption of adjuvant aromatase inhibitor (AI) therapy on postmenopausal breast cancer patients’ risk of bone fracture.

Methods: Data from three different studies were used to estimate the relative risk of bone fracture for each of the following groups of women (i.e., versus a control group of healthy postmenopausal women): (a) healthy postmenopausal women receiving tamoxifen; (b) post­menopausal women who had received treatment for early breast cancer; (c) postmenopausal breast cancer patients on adjuvant tamoxifen therapy; (d) postmenopausal breast cancer patients on adjuvant anastrozole therapy. The results of these analyses were then used to estimate the likely incidence of clinical fracture among such popula­tions in ‘real-life’ clinical practice.

Results: Breast cancer survivors were calculated to be at increased risk of clinical bone fracture (i.e., RR 1.15 vs. control group over 5 years). Breast cancer patients initiated on adjuvant anastrozole were also calculated to be at increased risk of bone fracture (RR = 1.36 vs. control group over 5 years), while the calculated risk of fracture among tamoxifen-treated breast cancer patients was similar to that observed in the control population (RR = 0.91).

Conclusion: Breast cancer patients are at increased risk of clinical bone fracture (compared with the general postmenopausal population) and adjuvant anastrozole therapy slightly adds to this risk. Importantly, however, the absolute risk of bone fracture appears to remain low in each of the evaluated patient populations, suggesting that fear of fracture should not prevent the initiation of adjuvant aromatase inhibitor therapy.     

Cost effectiveness of trastuzumab in the adjuvant treatment of early breast cancer: a lifetime model

BACKGROUND: Recent randomised trials have demonstrated a statistically significant effect of trastuzumab on disease-free survival when used as adjuvant therapy for human epidermal growth factor receptor 2 protein (HER2)-positive resectable early stage breast cancer, with a treatment course lasting either 9 or 52 weeks. However, the cost effectiveness of adjuvant trastuzumab with respect to mortality remains uncertain, especially in an Australian setting. OBJECTIVE: To estimate the cost effectiveness of trastuzumab in Australia, in a cohort of 50-year-old patients with HER2-positive breast cancer over a lifetime, using (i) disease-free survival and cardiotoxicity data from recent randomised trials; (ii) information on long-term survival of patients with treated primary breast cancer; and (iii) costs of treating local and distant relapses and disease from causes other than breast cancer. METHODS: A Markov model consisting of four health states (remission, loco-regional recurrence, metastatic disease and death) was developed. Transition probabilities corresponded to patterns of relapse and metastases seen in recent trials. The model was run until age 100 years to allow calculation of average survival. Outcome measures were life-years and QALYs (calculated using utility weights reported in the literature).The model was calibrated to reflect literature evidence that the risk of breast cancer recurrence following primary treatment diminishes progressively to zero after about 20 years. It was assumed that the morbidity benefit of trastuzumab observed in trials would be present for 5 years but would then diminish progressively to zero after 8 years. Costs (year 2005 values) and benefits were discounted at 3% per annum. RESULTS: For every 1000 patients treated with a 52-week course of trastuzumab, there were 136 fewer breast cancer deaths (relative risk reduction 28%). The incremental cost-effectiveness ratios (ICERs) were Australian dollars ($ A)13 730 per year of life saved (YOLS) and $ A22 793 per QALY. The net incremental cost was $ A56.3 million ($ A414 012/cancer death avoided). Cost effectiveness declined (ICER = $ A27 734/QALY) in older patients (age 65 years at treatment initiation).The ICER was driven mainly by the drug acquisition costs, the assumption of the duration of benefit and the discount rate. Cost offsets from reduced costs of treating recurrent or metastatic breast cancer during follow-up were present but these factors were of less importance according to sensitivity analyses. The 9-week treatment schedule approached economic dominance (ICER = $ A1700/QALY) because of decreased costs, improved relative risk for prevention of metastases and more cancer deaths avoided (196). CONCLUSION: The results suggest that trastuzumab as adjuvant therapy for early breast cancer may be cost effective when given over either 52 or 9 weeks at current acquisition costs in Australia. However, the overall budget impact of the 52-week course is significant, and the 9-week course appears economically attractive.     

来曲唑治疗绝经后妇女晚期乳腺癌临床研究

目的：研究来曲唑治疗绝经后妇女晚期乳腺癌的临床疗效和不良反应。方法：采用多中心随机对照方法。101例和31例分别口服来曲唑2.5mg,qd与氨鲁米特（AG）250mg,tid-qid及泼尼松10mg,qd。连服4－6周,疗前2周内及治疗4周后的3d内检测血中雌二醇（E2）水平,同时评价疗效和不良反应。结果：来曲唑组和AG组分别有98例和29例可评价疗效和不良反应。有效率分别为27．6％和20．7％,绝经时间长者疗效明显优于绝经时间短者,雌激素受体（ER）阳性疗效较阴性好,软组织和骨转移的疗效亦明显优于肝转移的疗效。疗后对E2的平均有效抑制率分别为57％和54％。来曲唑组乏力、头晕等不良反应显著低于AG组。结论：来曲唑对E2的抑制作用和对绝经后晚期乳腺癌疗效肯定,不良反应轻微,值得临床推广应用。     

Cost effectiveness and cost utility of adjuvant interferon alpha in cutaneous melanoma: a review

Although interferon alpha (IFN) has been approved since 1995 in the US as adjuvant therapy for high-risk melanoma patients, its cost effectiveness and economic value have only been recently addressed. There are very few papers that address the overall cost and cost components of treating melanoma patients, all of them focusing on the US. These studies showed the large cost of treatment of stage III and IV patients (around $US40,000-60,000 [1997/8 values]). Chemotherapy and adjuvant immunomodulators comprised a large part of this cost. Cost-effectiveness studies performed for the US, Spain and Italy have been largely based on the results of the pivotal Eastern Cooperative Oncology Group (ECOG) 1684 trial using high-dose (10-20 Megaunits [MU]/m(2)) IFN in mainly stage III patients. Incremental cost-effectiveness ratios for adjuvant IFN versus observation from these studies fall in the range of $US13,000-40,000 per life-year gained (1998 values), depending on the time horizon, discount rate and cost of IFN, with an extrapolated life-gain over lifetime ranging between 1.9 and 3 years. Only one study, the French Cooperative Melanoma Group trial in stage IIA/B patients, used low-dose (3 MU(2)) IFN and yielded a quite favourable incremental cost effectiveness ratio (cost per life-year gained) ranging from $US12,954 over 5 years (survival gain 3 months) to $US1,544 over a lifetime (extrapolated survival gain 2.6 years) [1995 values]. Although these results could be seen as supporting the more widespread use of adjuvant IFN in melanoma, it should be stressed that they were based on the only two positive clinical trials out of a total of ten. Moreover, the impact on survival was lost in both positive trials at > or = 8 years' follow-up and thus the costs assessments are likely to be overly optimistic. The eight negative high-dose (HDI) and low-dose (LDI) IFN trials have failed to show an impact on survival (HDI: ECOG 1690 and North Central Cancer Treatment Group [NCCTG]; LDI: ECOG 1690, WHO-16, UK Coordinating Committee on Cancer Research [UKCCRC] and Austrian, Scottish and European Organisation for Research and Treatment of Cancer trials). Mature results from more recent trials are pending. A definitive appraisal of the cost effectiveness of IFN in melanoma patients will have to await these results and their economic analyses.