Impact of a health alert and its implementation on flutamide prescriptions for women: an interrupted time series analysis.

BACKGROUND: Off-label drug use among ambulatory patients is often based on little or no scientific support. This paper reports the impact of a health warning about the risks of off-label flutamide use by women and the actions subsequently implemented by the public health service targeting such use. METHOD: The study was undertaken in a region in north-west Spain. We designed a segmented regression model of an interrupted time series, in which the dependent variable was the monthly value of defined daily doses of flutamide per 1000 inhabitants/day (DDD/TID), both total and stratified by sex. The following two data sources were used: flutamide prescriptions billed to the Spanish National Health Service; and flutamide deliveries made by wholesale drug distributors to pharmacies. The intervention assessed consisted of the issue of an official health warning and the actions subsequently taken to implement it. RESULTS: There was an immediate reduction of 49.33% in DDD/TID billed to the Spanish National Health Service in respect of women; the mean value of the population percentage of DDD/TID of flutamide billed in respect of women fell from 34.4% pre-intervention to 23.72% post-intervention. There was an immediate reduction of 19.92% (95%CI: 6.68-33.15%) in total DDD/TID invoiced. There were no significant changes in DDD/TID billed in respect of men or in flutamide use in the private medical sector. CONCLUSIONS: Off-label drug misuse is a reality among ambulatory patients, even after actions are implemented following a toxicity warning issued by the competent Health Authority.

Management of acne vulgaris with hormonal therapies in adult female patients.

Acne vulgaris is a very common condition affecting up of 93% of adolescents. Although rare, this disease may persist in adulthood. In adult women with acne (those older than 25 years old), this condition is particularly relevant because of the refractory to conventional therapies, which makes acne a challenge for dermatologists in this group of patients. In order to its potential risk for chronicity and the involvement of visible anatomical sites such as face and upper torso, acne has been associated with a wide spectrum of psychological and social dysfunction such as depression, anxiety, suicidal ideation, somatization, and social inhibition. In particular, adult women with acne have been shown to be adversely impacted by the effect of acne on their quality of life. For the last four decades, dermatologists have used hormonal therapies for the management of acne vulgaris in adult women, which are considered a rational choice given the severity and chronicity of this condition in this group of patients. The aim of this work is to review the hormonal drugs for management of acne.

A randomized phase IIb presurgical study of finasteride vs. low-dose flutamide vs. placebo in men with prostate cancer. Efficacy monitored by karyometry.

OBJECTIVE: Presurgical, window of opportunity trials have been proposed as a model to assess the activity of preventive and therapeutic interventions in a cost-effective manner in prostate cancer (CaP). The aim of the study was to explore karyometry as a method for monitoring the efficacy of intervention with preventive agents in patients with CaP. MATERIALS AND METHODS: The material used in this investigation was from the 2F study, i.e., an Italian prospective randomized phase IIb presurgical study of finasteride vs. low-dose flutamide vs. placebo in men with CaP. Image analysis was performed in 16 cases treated with finasteride, 24 with flutamide, and 20 with placebo. For all these cases, CaP and normal looking secretory epithelium were present in the pretreatment biopsies as well as the post-treatment ex-vivo biopsies obtained from the radical prostatectomy specimens. RESULTS: To establish a direction of nuclear change from normal to malignancy, i.e., the so-called line of progression, a discriminant function was derived with the normal looking epithelium in the pretreatment biopsies as one endpoint, and the CaP in the pretreatment biopsies as the other. The discriminant function was then applied to the post-treatment groups. The increase in relative nuclear area was the dominant feature. In the placebo group, 15 out of 20 CaP (75%) cases had a higher discriminant function score at the end of study, with a significant increase of the mean score by 90%. The flutamide treated CaP cases had increased discriminant function scores in 19 out of 24 cases (79%) and an increase of the mean score by 43%; the 5 cases with lower scores involved only minor reductions. In contrast, the finasteride treated CaP cases had increased discriminant function scores for 8 out of 16 cases (50%), but the increase in the mean score was by only 8%. CONCLUSION: This exploratory study establishes that karyometric monitoring can track the results of subtle nuclear changes induced by preventive interventions in men with CaP, thus allowing assessment of agent activity in a cost-effective manner.

Upfront androgen deprivation therapy with salvage radiation may improve biochemical outcomes in prostate cancer patients with post-prostatectomy rising PSA.

PURPOSE: The addition of androgen deprivation therapy (ADT) to definitive external beam radiation therapy (RT) improves outcomes in higher-risk prostate cancer patients. However, the benefit of ADT with salvage RT in post-prostatectomy patients is not clearly established. Our study compares biochemical outcomes in post-prostatectomy patients who received salvage RT with or without concurrent ADT. METHODS AND MATERIALS: Of nearly 2,000 post-prostatectomy patients, we reviewed the medical records of 191 patients who received salvage RT at the University of Pennsylvania between 1987 and 2007. Follow-up data were obtained by chart review and electronic polling of the institutional laboratory database and Social Security Death Index. Biochemical failure after salvage RT was defined as a prostate-specific antigen of 2.0 ng/mL above the post-RT nadir or the initiation of ADT after completion of salvage RT. RESULTS: One hundred twenty-nine patients received salvage RT alone, and 62 patients received combined ADT and salvage RT. Median follow-up was 5.4 years. Patients who received combined ADT and salvage RT were younger, had higher pathologic Gleason scores, and higher rates of seminal vesicle invasion, lymph node involvement, and pelvic nodal irradiation compared with patients who received salvage RT alone. Patients who received combined therapy had improved biochemical progression-free survival (bPFS) compared with patients who received RT alone (p = 0.048). For patients with pathologic Gleason scores ≤7, combined RT and ADT resulted in significantly improved bPFS compared to RT alone (p = 0.013). CONCLUSIONS: These results suggest that initiating ADT during salvage RT in the post-prostatectomy setting may improve bPFS compared with salvage RT alone. However, prospective randomized data are necessary to definitively determine whether hormonal manipulation should be used with salvage RT. Furthermore, the optimal nature and duration of ADT and the patient subgroups in which ADT could provide the most benefit remain open questions.

Eliciting patient preferences for hormonal therapy options in the treatment of metastatic prostate cancer.

Treatment choices for metastatic prostate cancer are complex and can involve men balancing survival versus quality of life. The present study aims to elicit patient preferences with respect to the attributes of treatments for metastatic prostate cancer through a discrete choice experiment (DCE) questionnaire. Men with recently diagnosed localized prostate cancer were asked to envisage that they had metastatic disease when completing a survey. As expected, men with prostate cancer placed considerable importance on gains in survival; however, avoiding side effects of treatment was also clearly important. Survival gains should be considered alongside side effects when discussing treatment options in metastatic disease.

Long-term hormone therapy and radiation is cost-effective for patients with locally advanced prostate carcinoma.

BACKGROUND: In Radiation Therapy Oncology Group (RTOG) trial 92-02, after men received neoadjuvant hormone cytoreduction and radiotherapy for locally advanced prostate carcinoma, they were randomized to receive either 2 years of long-term androgen-deprivation (LTAD) or no further treatment (short-term androgen-deprivation [STAD]). The specific objective of the current study was to determine whether LTAD was a cost-effective treatment for patients with locally advanced prostate carcinoma. METHODS: The cost-effectiveness of LTAD was tested using a Markov model that was designed using proprietary software. The analysis took a payor's perspective. Unit costs were obtained by estimation using a global Medicare fee schedule. Costs and outcomes were discounted by 3%. Distributions were sampled at random from the treatment utilities, transition probabilities, and costs using a second-order Monte Carlo simulation technique. RESULTS: The expected mean cost was 32,564 dollars for LTAD compared with 33,039 dollars for STAD after accounting for the additional cost of salvage treatment for men who were treated with STAD. The mean number of quality-adjusted life years (QALYs) for men who received LTAD was 4.13 QALYs compared with a mean of 3.68 QALYs for men who received STAD. The cost-effectiveness acceptability curve analysis showed a 91% probability that LTAD was cost-effective compared with STAD. Although overall survival was similar in the LTAD and STAD groups, the patients who received LTAD experienced gains in QALYs and had lower costs, because LTAD prevented biochemical failure and the necessitating salvage hormone therapy. CONCLUSIONS: The current analysis showed that LTAD was cost-effective for the entire population studied in RTOG trial 92-02.

Is combined androgen blockade with bicalutamide cost-effective compared with combined androgen blockade with flutamide?

OBJECTIVES: To determine the cost-effectiveness of combined androgen blockade (CAB) with bicalutamide versus CAB with flutamide in men with Stage D2 prostate cancer. Both bicalutamide and flutamide are commonly used in CAB for prostate cancer. Although the cost of bicalutamide is more than that of flutamide, it is important that the efficacy, quality of life, and side effects are also considered when determining whether CAB with bicalutamide is a cost-effective option. METHODS: A decision model was created to compare treatment strategies. Survival and side-effect information was based on a randomized trial that directly compared bicalutamide and flutamide. The costs and quality-of-life effects related to therapy were determined from published sources. RESULTS: The incremental cost per quality-adjusted life year gained for bicalutamide versus flutamide was 22,000 dollars and 16,000 dollars at 5 and 10 years, respectively. If a quality adjustment was not included, the incremental cost-effectiveness ratio for CAB with bicalutamide compared with CAB with flutamide was even more favorable (20,000 dollars/life year gained at 5 years). One-way sensitivity analysis demonstrated that the cost-effectiveness estimates were most sensitive to drug costs and survival (baseline survival was not significantly different between therapies). Multi-way uncertainty analysis revealed that the median value of the incremental cost-effectiveness ratio at 5 years was 13,637 dollars/quality-adjusted life year when all the parameters were varied over a clinically reasonable range. CONCLUSIONS: Bicalutamide is cost-effective compared with flutamide when used for androgen blockade as part of CAB for men with advanced prostate cancer.

An index of local sensitivity to nonignorable drop-out in longitudinal modelling.

In longitudinal studies with potentially nonignorable drop-out, one can assess the likely effect of the nonignorability in a sensitivity analysis. Troxel et al. proposed a general index of sensitivity to nonignorability, or ISNI, to measure sensitivity of key inferences in a neighbourhood of the ignorable, missing at random (MAR) model. They derived detailed formulas for ISNI in the special case of the generalized linear model with a potentially missing univariate outcome. In this paper, we extend the method to longitudinal modelling. We use a multivariate normal model for the outcomes and a regression model for the drop-out process, allowing missingness probabilities to depend on an unobserved response. The computation is straightforward, and merely involves estimating a mixed-effects model and a selection model for the drop-out, together with some simple arithmetic calculations. We illustrate the method with three examples.

Comparative study of the clinical efficacy of two dosing regimens of flutamide.

PURPOSE: We performed a randomized trial to compare the efficacy and toxicity of a new dose of flutamide (500 mg QD) with the currently recommended dose (250 mg q8h) in the treatment of advanced prostate cancer. The primary endpoints were percent of patients having normalization of prostate specific antigen (PSA), time to normalization, and percent change from baseline. Secondary endpoints were quality of life and toxicity. PATIENTS: Altogether, 440 men aged 46 to 94 years (mean 71 years) with confirmed stage M(1) disease, documented PSA rise >0.2 ng/mL, ECOG status 0 to 2, no second neoplasm, no liver function tests > or = 1.5-fold normal values, and no previous treatment for metastatic disease were entered in the trial. RESULTS: The PSA normalized by week 12 in 71% of the patients receiving 500-mg dose and 75% of those receiving the standard dose. The percent change in PSA was 89% and 96%, respectively. The treatment groups were not significantly different with respect to the incidence of adverse events: 71% v 68% in the 500-mg and 250-mg arms, respectively (P = 0.337). CONCLUSIONS: When combined with castration, 500 mg of flutamide appears to be equally effective in lowering serum PSA and is not significantly more toxic than conventional dosing. The use of 500 mg QD instead of the standard 250 mg q8h would result in a cost savings of 30%.

A quality assurance audit: phase III trial of maximal androgen deprivation in prostate cancer (TROG 96.01).

In 1997 the Trans-Tasman Radiation Oncology Group (TROG) performed a quality assurance (QA) audit of its phase III randomized clinical trial investigating the effectiveness of different durations of maximal androgen deprivation prior to and during definitive radiation therapy for locally advanced carcinoma of the prostate (TROG 96.01). The audit reviewed a total of 60 cases from 15 centres across Australia and New Zealand. In addition to verification of technical adherence to the protocol, the audit also incorporated a survey of centre planning techniques and a QA time/cost analysis. The present report builds on TROG's first technical audit conducted in 1996 for the phase III accelerated head and neck trial (TROG 91.01) and highlights the significant progress TROG has made in the interim period. The audit provides a strong validation of the results of the 96.01 trial, as well as valuable budgeting and treatment planning information for future trials. Overall improvements were detected in data quality and quantity, and in protocol compliance, with a reduction in the rate of unacceptable protocol violations from 10 to 4%. Audit design, staff education and increased data management resources were identified as the main contributing factors to these improvements. In addition, a budget estimate of $100 per patient has been proposed for conducting similar technical audits. The next major QA project to be undertaken by TROG during the period 1998-1999 is an intercentre dosimetry study. Trial funding and staff education have been targeted as the key major issues essential to the continued success and expansion of TROG's QA programme.

Salutary clinical response of prostate cancer to antiandrogen withdrawal: assessment of flutamide in an in vitro paradigm predictive of tumor growth enhancement.

Salutary clinical responses to withdrawal of flutamide have been widely reported, indicating the potential of this arylalkylamine antiandrogen to stimulate the growth of prostate cancer. Flutamide is known to inhibit cytochrome P450-mediated testosterone synthesis and metabolism. Our laboratory has shown that arylalkylamine potencies in three in vitro assays of P450 binding or function correspond to a propensity of the drugs to enhance tumor growth in vivo. Accordingly, we measured inhibition by flutamide of (a) histamine binding to cytochrome P450 in rat liver microsomes, as determined spectrally, (b) P450-mediated demethylation of aminopyrine, and (c) DNA synthesis in mouse spleen cells stimulated by concanavalin A, and we compared its potencies in these assays with those of other arylalkylamine pharmaceuticals. Flutamide inhibited histamine binding to P450 (Ki = 31 +/- 7 microM), aminopyrine demethylation (Ki = 39 +/- 2 microM), and mitogenesis (IC50 = 12 +/- 1 microM). In overall potency, it ranked with a group of eight drugs, including the antiestrogen tamoxifen, all linked with enhanced tumor growth. In the context of clinical observations that some patients with prostate cancer benefit from flutamide withdrawal, our findings underline concerns that many arylalkylamine drugs have the potential to stimulate the growth or development of malignancies, including prostate cancer. Tumor growth enhancement by flutamide and other arylalkylamines may result from drug perturbation and/or induction of histamine-binding P450 enzymes involved in the synthesis of steroid and eicosanoid mediators that regulate gene function and cell growth.

Treatment considerations for persons with metastatic prostate cancer: survival versus out-of-pocket costs.

OBJECTIVES: Treatment decisions for metastatic prostate cancer require the consideration of factors such as survival, quality of life, costs of care, and toxicities. In this study, we queried physicians who had extensive experience with prostate cancer about features of metastatic prostate cancer, patients' quality of life, and factors influencing their decision to prescribe flutamide. METHODS: Data were gathered through physician surveys and focus group discussions. Demographic information on the physicians and their patients was collected. Physicians made assessments of five health states related to metastatic prostate cancer, based on the time trade-off technique, and on the desirability of flutamide, based on average expected improvement in survival free of progressive disease, side effects, and drug cost. RESULTS: Physicians were internally consistent in their judgments of the factors most important to quality of life for individuals with metastatic prostate cancer. Physicians considered bone pain and weight loss/anorexia the most important factors. Physicians who cared for a higher proportion of older persons or Medicare recipients rated each scenario as less undesirable than did physicians with a lower proportion of these patients. Out-of-pocket cost was the major factor predicting whether a physician would prescribe flutamide. Physicians working for health maintenance organizations were more likely to prescribe flutamide but were more sensitive to out-of-pocket costs than were other physicians. CONCLUSIONS: Physicians-varied in their perceptions of quality of life for persons with metastatic prostate cancer and in their willingness to prescribe flutamide. These perceptions and prescribing preferences are strongly influenced by factors other than health status or specific health benefits. In deciding to prescribe flutamide, concerns over out-of-pocket expenditures loom large for most clinicians. It would be important to know the degree to which these concerns are shared by patients and whether prescribing preferences differ for Medicare managed-care patients who have pharmaceutical benefits.

Cost-effective models for flutamide for prostate carcinoma patients: are they helpful to policy makers?

BACKGROUND: More than 50,000 male patients received hormonal therapy for metastatic prostate carcinoma in 1995. Nonsteroidal antiandrogens, such as flutamide, when used in conjunction with castration, are effective in prolonging the time to progression of disease and survival. Only one-third of newly diagnosed patients with metastatic prostate carcinoma receive flutamide. Physicians may be reluctant to prescribe flutamide because of quality of life, toxicity, and cost considerations. METHODS: Physician focus groups evaluated quality of life factors for metastatic prostate cancer. RESULTS: Using quality of life estimates with the National Cancer Institute's (NCI) 0036 clinical trial results, our revised model of flutamide use predicted that, for minimal disease, survival increased by 4.33 quality adjusted months (QAMs) at an incremental cost of $25,000 per quality adjusted life year (QALY) saved and for severe disease, survival increased by 4.11 QAM at a cost of $18,000 per QALY saved. However, if quality of life estimates are used in conjunction with the Prostate Cancer Trialists' Collaborative Group (PCTCG) meta-analysis estimates, survival increased by 2.1 QAM at an incremental cost of $41,000 per QALY saved for persons with severe disease and increased by 2.6 QAM at an incremental cost of $53,700 per QALY saved for persons with minimal disease. CONCLUSIONS: Using NCI 0036 trial data, flutamide has an incremental cost-effectiveness more favorable than most therapies, while estimates based on the PCTCG found a less favorable outcome for the drug. Concerns about out-of-pocket expenditures and efficacy limit flutamide utilization; quality of life considerations are less cogent.

Estimating the cost effectiveness of total androgen blockade with flutamide in M1 prostate cancer.

OBJECTIVES: Although combined androgen blockade with flutamide plus medical or surgical castration is effective in metastatic prostate cancer, debate exists over whether it is cost effective. METHODS: Decision analysis model of hypothetical cohorts of 70-year-old men presenting with metastatic prostate cancer, using a societal perspective, calculated anticipated survival and incremental cost per life-year gained. Time to progression and survival rate were from the Intergroup 0036 trial. Costs were based on Medicare data and wholesale drug pricing. Flutamide was estimated to reduce the relative risk of progressive disease by 25% (range, 0 to 50%). Costs and survival benefits were discounted at a 5% annual rate. RESULTS: In our model for minimal disease, median survival increased from 42.3 to 49.4 months with flutamide and average survival by 5.2 months at an incremental cost of $25,300 per life-year gained. If the efficacy were as high as 50%, the benefit would be 12 months at a cost of $13,700 per life-year gained. At a 10% efficacy, the benefit would be 1.9 months at a cost of $60,900 per life-year gained. For severe disease, the model estimated the median survival increased from 29.5 to 34.3 months with flutamide and average survival by 4.0 months at an incremental cost of $20,000 per life-year gained. At worst-case 10% efficacy, the benefit decreased to 1.5 months at an incremental cost of $47,500 per life-year gained. Total costs for patients treated with an orchiectomy and flutamide compared to leuprolide alone were similar if severe disease was present and actually lowered costs if there was minimal disease. CONCLUSIONS: Flutamide has an incremental cost effectiveness more favorable than most accepted therapies. If drug costs are covered under health care reform, flutamide should be initiated and covered for all good performance status patients.

Advanced prostate cancer. The role of high priced hormone therapy.

OBJECTIVE: To compare the costs of the various options presently available in Australia for treatment of advanced prostatic carcinoma by androgen deprivation. DESIGN: Forty patients underwent a bilateral orchidectomy for prostatic carcinoma during the 1990/91 financial year at the Princess Alexandra Hospital, Brisbane. The Yale Cost Model, as adapted for use in Australian case-mix projects, was used to derive a diagnosis related group (DRG) cost for this procedure. This was compared with the projected cost that would be incurred in treating patients with the various medical alternatives. To enable comparison, expenses were calculated assuming a mean duration of survival of two years. RESULTS: The average cost of a bilateral orchidectomy was $2869. This compared to $11,253 for goserelin and $12,329 for cyproterone acetate when used alone in treating a single patient. Flutamide is presently only approved for combination therapy with a luteinising hormone-releasing hormone agonist, and when used with goserelin an average cost of $16,148 per patient was projected. CONCLUSIONS: Bilateral orchidectomy is clearly the cheapest means of hormone manipulation for prostatic carcinoma. Unless the costs of alternative therapies are drastically reduced in Australia, their use is difficult to justify in other than exceptional circumstances. We believe their use should be restricted presently to patients who would otherwise require a bilateral orchidectomy and have an anticipated survival of less than six months.