First-line Treatment with Ribociclib plus Endocrine Therapy for Premenopausal Women with Hormone-receptor-positive Advanced Breast Cancer: A Cost-effectiveness Analysis.

BACKGROUND: We conducted a cost-effectiveness analysis incorporating recent phase III clinical trial (MONALEESA-7) data to evaluate the cost-effectiveness of ribociclib (RIB) as a first-line treatment for premenopausal women with hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC) from the United States healthcare payer perspective. In addition, because RIB has not been marketed in China, we identified the range of drug costs for which RIB could be considered cost effective from a Chinese healthcare system perspective. PATIENTS AND METHODS: A Markov model was developed to evaluate the cost-effectiveness of adding RIB to endocrine therapy over a lifetime. The clinical outcomes and utility data were obtained from published literature. Costs data were obtained from United States and Chinese official websites, and we determined the potential price for RIB in China based on its price in the United States. The main outcomes of this study were the incremental cost-effectiveness ratio (ICER) and quality-adjusted life-years (QALYs). RESULTS: The model projected that mean outcome was better with RIB and endocrine combined (3.83366 QALYs) than with endocrine therapy alone (2.71203 QALYs). In the United States, RIB and endocrine therapy cost an additional $604,960.06, resulting in an ICER of $539,357.95/QALY compared with endocrine monotherapy. Subgroup analyses indicated that, in China, the projected mean outcomes were better for RIB and endocrine therapy (6.37 QALYs) than for endocrine monotherapy (2.71 QALYs). The corresponding incremental costs were $224,731.88943. Thus, the ICER comparing RIB and endocrine therapy with endocrine therapy alone represented a $61,454.96/QALY gain. CONCLUSION: Additional use of RIB is estimated to not be cost effective as a first-line treatment for premenopausal women with HR-positive, HER2-negative ABC in the United States. A value-based price for the cost of RIB is less than $31.74/200 mg for China.

Effect of simultaneously started clomiphene citrate and gonadotropins in antagonist regimes, on cumulative live births, fresh-cycle live births and cost of stimulation in IVF cycles.

AIM: The aim of the study was to compare simultaneously started clomiphene citrate (CC) and gonadotropins (Gn) with gonadotropins alone in conventional antagonist regimes with respect to fresh-cycle live births, cumulative live births and cost of ovarian stimulation per started cycle. METHODS: This was a single-center prospective cohort study conducted over 1 year. Women undergoing autologous in vitro fertilization (IVF) treatment in antagonist protocols and who consented to participate in the study were divided into two cohorts. The CC cohort (n = 86) received 50 mg CC for 5 days and individualized Gn daily until the hCG trigger, both starting from day 2 and antagonist daily from day 8 of menstrual cycle. The Gn-only cohort (n = 349) received individualized Gn from day 2 and the antagonist from day 7 of menstrual cycle. IVF outcomes and cost of stimulation were compared between two cohorts across expected ovarian response categories. RESULTS: The CC cohort used a mean lower dose of Gn (1741.38 ± 604.46 vs 1980.54 ± 686.42; MD = -239.16; 95%CI = -348.03 to -189.24; P = 0.003) over fewer days (8.54 ± 1.86 vs 9.25 ± 1.97; MD =-0.71;95% CI = -1.17 to -0.25; P = 0.0026) to achieve similar retrieved oocytes, (9.19 ± 5.92 vs 9.36 ± 6.96; MD = -0.17; 95%CI -1.77 to + 1.43; P = 0.83), positive bhCG rates (40% vs 29.6%, MD = 10.4%; OR = 1.65, 95%CI = 0.95-2.86; P = 0.078) and live births in fresh cycles (32.31% vs 21.30%; MD = 11.01%; OR = 1.76; 95%CI = 0.97-3.19; P = 0.06) and cumulative live births per initiated cycle (30.23% vs 20.34%; MD = 9.89%; OR = 1.697; 95%CI = 0.99-2.88; P = 0.0501). The dose lowering achieved a 28-40% reduction in the cost of stimulation, which was most noticeable in the hyper-responder category for both hMG cycles, (Rs.11 602.3 ± 3365.9 vs 19615 ± 2677.1; MD = -8012.7; %age reduction: 40.8%; P = 0.0007) and recombinant FSH cycles (Rs. 22 459.6 ± 6255.3 vs 33 022.1 ± 9891.2; MD: -10 562; %age reduction: -32%; P = 0.0001). CONCLUSION: CC started simultaneously with Gn in antagonist regimes helps lower the cost of stimulation without affecting IVF outcomes.

Cost-effectiveness of fulvestrant 250 mg versus 500 mg in postmenopausal women with estrogen receptor-positive metastatic breast cancer and disease progression after antiestrogen therapy.

PURPOSE: To determine the cost-effectiveness of fulvestrant 250 mg compared to 500 mg in postmenopausal women with estrogen receptor-positive metastatic breast cancer and disease progression after antiestrogen therapy. METHODS: A Markov model was constructed to find the incremental cost-effectiveness of fulvestrant 250 mg monthly when compared with the 500 mg monthly in patients with progression after antiestrogen therapy. The model duration was 24 months. Clinical efficacy data inputs were derived from a phase III clinical trial demonstrating a statistically significant increase in progression-free survival in patients receiving 500 mg versus 250 mg. Cost data utilized were all relevant Ambulatory Payment Classification payment rates from the 2011 Medicare Outpatient Prospective Payment System. A Monte Carlo simulation was performed to test the model at various willingness to pay thresholds. RESULTS: The incremental cost-effectiveness ratio as determined by the Markov model was US$10,972 per month of progression-free survival for the 500 mg dose compared with the 250 mg dose. Using a Monte Carlo simulation, it was found that 500 mg monthly was cost-effective at and above the willingness to pay threshold of US$15,000 per month. A series of one-way sensitivity analyses showed this result is robust to geographical practice variations in costs of drug administration and physician examination. CONCLUSION: From a third party payer perspective, the value of fulvestrant 500 mg monthly is dependent on the willingness to pay threshold. Despite a labeling change for fulvestrant in September 2010, fulvestrant 250 mg monthly appears to be a viable option in the target population.

Effect of food intake on the oral absorption of poorly water-soluble drugs: in vitro assessment of drug dissolution and permeation assay system.

The aim of the present work was to establish appropriate conditions for the dissolution/permeation system (D/P system) to estimate the effect of food intake on oral drug absorption. The D/P system is an in vitro assay system to evaluate the drug dissolution and permeation processes after oral administration. Caco-2 monolayer was used as a model membrane of the intestinal epithelium. In this study, two types of simulated intestinal fluid reflecting the fasted and the fed state conditions of the human gastrointestinal tract were used. Drugs were applied to the D/P system as a powder, then, permeated amounts of drugs into the basal side were monitored. A sigmoidal correlation was obtained between in vivo oral absorption (% absorbed of dose) and in vitro permeated amount (% of dose/2 h) under both states. From the D/P system, the estimated absorption of albendazole in both states was found to correspond well with in vivo observation. Moreover, the D/P system could estimate the effect of self-emulsifying formulation on the oral absorption of danazol, quantitatively. In conclusion, the D/P system was proved to be a useful assay system not only for the oral absorption of drugs, but also for the food effect on the absorption.

A randomised controlled trial of microwave endometrial ablation without endometrial preparation in the outpatient setting: patient acceptability, treatment outcome and costs.

OBJECTIVE: To compare outpatient microwave endometrial ablation (MEA) in the postmenstrual phase to standard MEA treatment after drug preparation in a day case theatre environment. DESIGN: A randomised controlled trial. SETTING: A large United Kingdom teaching hospital. POPULATION: Two hundred and ten women complaining of excessive menstrual loss. METHODS: Two hundred and ten women with excessive menstrual loss were randomised. Ninety-seven women were treated as outpatients in the immediate post-menstrual phase and 100 were treated in an operating theatre after hormonal preparation. All procedures were commenced under local anaesthesia with or without conscious sedation. Analysis was by modified intention to treat. MAIN OUTCOME MEASURES: Primary outcome measures were satisfaction with treatment (measured at one year) and acceptability of treatment (measured at two weeks). Secondary outcome measures were menstrual outcome and financial cost. RESULTS: Significantly more women found treatment post-menses acceptable; 86 (89.5%) versus 76 (76.0%) [difference in proportions 13.6%, 95% CI (3.0%, 23.9%)]. Similar numbers in each arm were totally or generally satisfied with the treatment, 86 (92.5%) versus 84 (88.4%) [difference in proportions 4.1%, 95% CI (-4.7%, 12.9%)] while amenorrhoea rates at one year were comparable, 52 (55.9%) versus 60 (61.9%). [difference in proportions -5.9%, 95% CI (-19.8%, 7.6%)]. The mean health service costs were 124 pounds (95% CI 86-194 pounds) lower for the patients in the post-menses group. CONCLUSION: MEA performed under local anaesthesia (with or without conscious sedation) in the post-menstrual phase achieves high levels of satisfaction is very acceptable to patients and results in significantly reduced health service costs. Importantly menstrual outcomes are not affected by omission of drug preparation. There is now good evidence to support the use of MEA, without drug endometrial preparation, in the outpatient setting.

Stimulated intrauterine insemination: efficient, cost-effective, safe?

A retrospective report of pregnancy and birth rates achieved in 1010 cycles of stimulated intrauterine insemination (SIUI). Over the years there has been an increasing emphasis on safety, particularly towards reducing the number of high order multiple pregnancies. SIUI is a complex form of assisted conception and requires a high level of clinical judgement to maintain an optimal balance between maximising pregnancy and birth rates and minimising complications, of which the most serious is multiple pregnancy. Extrapolating from these results, it is concluded that a well managed SIUI programme that selects patients appropriately, monitors them intensively and has in place effective strategies to manage over-responders safely, should be able to deliver at least a 15% live birth rate per cycle started with only a 5% cycle cancellation rate. Although SIUI birth rates are lower than IVF rates, the much lower cost of SIUI means that this treatment can be more cost-effective than IVF. However SIUI remains more risky than IVF and, despite careful management, high order multiple pregnancy rates will occasionally occur. It is estimated that the rate of unavoidable high order multiple pregnancies (triplets and above) is 4 per 1000 cycles started.

An open and randomized study comparing the efficacy of standard danazol and modified triptorelin regimens for postoperative disease management of moderate to severe endometriosis.

OBJECTIVE: To compare the efficacy of danazol and triptorelin (Decapeptyl CR, Ferring, Kiel, Germany) in the management of moderate and severe endometriosis in terms of symptom control and revised American Fertility Society (AFS) score reduction, and to evaluate the hormonal profile of patients treated with triptorelin every 6 weeks. DESIGN: Open and randomized trial. SETTING: Kwong Wah Hospital, a large public hospital in an urban location (Hong Kong). PATIENT(S): Forty patients after their first conservative operation for endometriosis, with surgical confirmation of revised AFS stage III or IV endometriosis. INTERVENTION(S): Postoperative 6 months' therapy of danazol or triptorelin every 6 weeks, postmedical therapy second-look laparoscopy. MAIN OUTCOME MEASURE(S): Symptom control and patients' tolerance during medical therapy, posttherapy revised AFS score, hormonal profile during triptorelin therapy. RESULT(S): Pain control was similar between danazol and triptorelin therapy. There was less breakthrough bleeding with triptorelin. More patients failed to complete the whole course of danazol because of its side effects. The revised AFS score at second-look laparoscopy did not show a significant difference between the two medications. Adequate pituitary suppression was observed with injection of triptorelin every 6 weeks. CONCLUSION(S): Lengthening of triptorelin administration intervals from 4 weeks to 6 weeks is effective in maintaining a hypoestrogenic state. Patients were more compliant with triptorelin than danazol. Thus, triptorelin injection every 6 weeks is more cost-effective than conventional regimens.

Assessment of estrogenic activity in some common essential oil constituents.

Estrogenic responses have not only been associated with endocrine function, but also with cognitive function. Several studies have indicated that estrogen replacement therapy has favourable effects on cognition, and may have potential in the prevention and treatment of Alzheimer's disease. Thus, ligands for the estrogen receptor, that have a better efficacy and adverse-effect profile than drugs currently available, require investigation. This study was undertaken to investigate the potential estrogenic activity of a number of essential oil constituents. Initially, estrogenic activity was determined by a sensitive and specific bioassay using recombinant yeast cells expressing the human estrogen receptor. At high concentrations, estrogenic activity was detected for citral (geranial and neral), geraniol, nerol and trans-anethole, while eugenol showed anti-estrogenic activity. Molecular graphics studies were undertaken to identify the possible mechanisms for the interaction of geranial, neral, geraniol, nerol and eugenol with the ligand-binding domain of the estrogen alpha-receptor, using the computer program HyperChem. Citral, geraniol, nerol and eugenol were also able to displace [(3)H]17beta-estradiol from isolated alpha- and beta-human estrogen receptors, but none of these compounds showed estrogenic or anti-estrogenic activity in the estrogen-responsive human cell line Ishikawa Var I at levels below their cytotoxic concentrations, and none showed activity in a yeast screen for androgenic and anti-androgenic activity. The potential in-vivo estrogenic effects of citral and geraniol were examined in ovariectomized mice, but neither compound showed any ability to stimulate the characteristic estrogenic responses of uterine hypertrophy or acute increase in uterine vascular permeability. These results show that very high concentrations of some commonly used essential oil constituents appear to have the potential to interact with estrogen receptors, although the biological significance of this is uncertain.

Assessment of maintenance therapy with reduced doses of PTH(1-34) in combination with a raloxifene analogue (LY117018) following anabolic therapy in the ovariectomized rat.

This experiment was designed to evaluate the ability of a raloxifene analogue (RA), LY117018, with or without reduced dosing of human parathyroid hormone (hPTH)(1-34) to maintain gains in bone mass after a fully anabolic treatment regimen given to aging osteopenic rats. Six-month-old rats were ovariectomized (ovx) or sham-operated (sham). After 1 month, ovx rats were treated with an anabolic regimen consisting of subcutaneous hPTH(1-34) 80 microg/kg/day and oral raloxifene 3 mg/kg/day, each given 5 days/week for 3 months. Thereafter, the treated ovx rats went on to an 8 week maintenance phase of treatment with either RA alone at the same dose, hPTH(1-34) at a reduced dosing interval (twice a week), or a combination of the two. Bone mineral density (BMD) was measured ex vivo at four skeletal sites, lumbar spine (L2-4), proximal hemipelvis, whole femur, and tibia, by dual-energy X-ray densitometry. All four sites showed a similar pattern of response. After the 3 month anabolic phase, the sham group had significantly higher BMD values than ovx rats at all skeletal sites (p < or = 0.002). The ovx rats treated with PTH + RA during the anabolic phase of the protocol had significantly higher BMD than the sham group in the femur, tibia, and spine (p < or = 0.02) and higher but not significantly different values in the pelvis. Following the 2 month maintenance phase, comparisons were made with the PTH-RA group at the end of the anabolic phase. Decrements in BMD were seen in all three maintenance therapy groups, but they were not statistically significant in the RA plus reduced PTH dose group. However, reduced hPTH(1-34) dosing and RA alone resulted in significant reductions of bone mass measurements at several skeletal sites during the maintenance phase. We conclude that the raloxifene analogue LY117018 may be useful in maintaining bone mass in aging ovx rats following anabolic therapy with hPTH(1-34) and raloxifene analogue, but that this strategy only allows for dose reduction of hPTH(1-34) rather than its discontinuation.