Comparative Healthcare Research Outcomes of Novel Surgery in prostate cancer (IP4-CHRONOS): A prospective, multi-centre therapeutic phase II parallel Randomised Control Trial.

INTRODUCTION: Focal therapy (FT) targets individual areas of cancer within the prostate, providing oncological control with minimal side-effects. Early evidence demonstrates encouraging short-medium-term outcomes. With no randomized controlled trials (RCT) comparing FT to radical therapies, Comparative Healthcare Research Outcomes of Novel Surgery in prostate cancer (CHRONOS) will compare the cancer control of these two strategies. PATIENTS AND METHODS: CHRONOS is a parallel phase II RCT for patients with clinically significant non-metastatic prostate cancer, dependent upon clinician/patient decision, patients will enrol into either CHRONOS-A or CHRONOS-B. CHRONOS-A will randomize patients to either radical treatment or FT. CHRONOS-B is a multi-arm, multistage RCT comparing focal therapy alone to FT with neoadjuvant agents that might improve the current focal therapy outcomes. An internal pilot will determine the feasibility of, and compliance to, randomization. The proposed definitive study plans to recruit and randomize 1190 patients into CHRONOS-A and 1260 patients into CHRONOS-B. RESULTS: Primary outcome in CHRONOS-A is progression-free survival (transition to salvage local or systemic therapy, development of metastases or prostate-cancer-related mortality) and in CHRONOS-B is failure-free survival (includes the above definition and recurrence of clinically significant prostate cancer after initial FT). Secondary outcomes include adverse events, health economics and functional outcomes measured using validated questionnaires. CHRONOS is powered to assess non-inferiority of FT compared to radical therapy in CHRONOS-A, and superiority of neoadjuvant agents with FT in CHRONOS-B. CONCLUSION: CHRONOS will assess the oncological outcomes after FT compared to radical therapy and whether neoadjuvant treatments improve cancer control following one FT session.

Patterns of Bicalutamide Use in Prostate Cancer Treatment: A U.S. Real-World Analysis Using the SEER-Medicare Database.

INTRODUCTION: Bicalutamide (BIC), a non-steroidal anti-androgen, is FDA-indicated for use in combination with a luteinizing hormone-releasing hormone (LHRH) analog for treatment of Stage D2 metastatic carcinoma of the prostate. Lack of consensus exists regarding the clinical benefit of BIC use, either alone or combined use of BIC with an LHRH analog or antagonist (combined androgen blockade or CAB), versus treatment with androgen deprivation therapy (ADT) alone. METHODS: The SEER-Medicare database was used to identify prostate cancer patients aged ≥ 66 years diagnosed between 2007 and 2011 and who filled at least one prescription for BIC. Duration of BIC treatment was assessed in relation to ADT use; either alone (monotherapy), as part of CAB only, and as part of CAB followed by monotherapy. Additionally, we assessed use of BIC during or outside a potential testosterone flare prevention period (initiation within 2 months of an LHRH agonist). RESULTS: A total of 7521 prostate cancer patients who filled a prescription for BIC were identified. Eighteen percent of the cohort used BIC alone, over half the patients (54%) used BIC as part of CAB and 27% used BIC as part of CAB followed by monotherapy. Among men treated with BIC as part of CAB, 58% received BIC only within the potential flare period. CONCLUSIONS: Although there is no FDA indication for BIC use as monotherapy, > 44% of patients in this study used BIC alone or as part of CAB followed by monotherapy. Further research is necessary to understand the outcomes of BIC utilization in these settings, particularly compared with newer second-generation anti-androgens. FUNDING: Medivation LLC, a Pfizer company, and Astellas, Pharma, Inc.

Characterization of a novel KCNQ1 mutation for type 1 long QT syndrome and assessment of the therapeutic potential of a novel IKs activator using patient-specific induced pluripotent stem cell-derived cardiomyocytes.

INTRODUCTION: Type 1 long QT syndrome (LQT1) is a common type of cardiac channelopathy associated with loss-of-function mutations of KCNQ1. Currently there is a lack of drugs that target the defected slowly activating delayed rectifier potassium channel (IKs). With LQT1 patient-specific human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (hiPSC-CMs), we tested the effects of a selective IKs activator ML277 on reversing the disease phenotypes. METHODS: A LQT1 family with a novel heterozygous exon 7 deletion in the KCNQ1 gene was identified. Dermal fibroblasts from the proband and her healthy father were reprogrammed to hiPSCs and subsequently differentiated into hiPSC-CMs. RESULTS: Compared with the control, LQT1 patient hiPSC-CMs showed reduced levels of wild type KCNQ1 mRNA accompanied by multiple exon skipping mRNAs and a ~50% reduction of the full length Kv7.1 protein. Patient hiPSC-CMs showed reduced IKs current (tail current density at 30 mV: 0.33±0.02 vs. 0.92±0.21, P<0.05) and prolonged action potential duration (APD) (APD 50 and APD90: 603.9±39.2 vs. 319.3±13.8 ms, P<0.005; and 671.0±41.1 vs. 372.9±14.2 ms, P<0.005). ML277, a small molecule recently identified to selectively activate KV7.1, reversed the decreased IKs and partially restored APDs in patient hiPSC-CMs. CONCLUSIONS: From a LQT1 patient carrying a novel heterozygous exon7 deletion mutation of KCNQ1, we generated hiPSC-CMs that faithfully recapitulated the LQT1 phenotypes that are likely associated with haploinsufficiency and trafficking defect of KCNQ1/Kv7.1. The small molecule ML277 restored IKs function in hiPSC-CMs and could have therapeutic value for LQT1 patients.

Japan Cancer of the Prostate Risk Assessment for combined androgen blockade including bicalutamide: clinical application and validation.

OBJECTIVES: The Japan Cancer of the Prostate Risk Assessment was developed as a risk stratification instrument for patients undergoing primary androgen deprivation therapy. However, there have been no studies to validate the accuracy of the Japan Cancer of the Prostate Risk Assessment in predicting clinical outcomes. We examined whether the clinical outcomes of patients treated with combined androgen blockade could be stratified using the Japan Cancer of the Prostate Risk Assessment. METHODS: A total of 319 patients with prostate cancer treated with luteinizing hormone-releasing hormone agonist plus bicalutamide were included in this analysis. Progression-free survival, cause-specific survival and overall survival were compared among patients divided according to the prostate-specific antigen level at diagnosis, Gleason score on biopsy specimens, tumor-nodes-metastasis classification and Japan Cancer of the Prostate Risk Assessment score. RESULTS: The median age of the patients was 75 years, and the median prostate-specific antigen at diagnosis was 25.4 ng/mL. A total of 102 patients (32.0%) had lymph node and/or distant metastases. On univariate analysis, the factors adopted in the Japan Cancer of the Prostate Risk Assessment points were significant predictors of progression-free survival. On multivariate analysis, clinical T stage and M stage were significant predictors of progression-free survival. The probabilities of progression-free survival and cause-specific survival were significantly different among the groups categorized according to the Japan Cancer of the Prostate Risk Assessment risk strata. The probability of overall survival in the low-risk group was higher than in the other groups. CONCLUSIONS: The progression-free survival, cause-specific survival and overall survival of prostate cancer patients treated by combined androgen blockade with bicalutamide were stratified by the Japan Cancer of the Prostate Risk Assessment. The Japan Cancer of the Prostate Risk Assessment score is clinically useful as a predictor of the prognosis of prostate cancer treated with combined androgen blockade.

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.

Combined androgen blockade for prostate cancer: review of efficacy, safety and cost-effectiveness.

A standard treatment for advanced prostate cancer is androgen deprivation by surgical or medical castration. In theory, however, combined androgen blockade (CAB) with an antiandrogen plus castration should be more effective because castration alone does not completely eliminate androgens in the prostate. Therefore, a number of randomized clinical trials (RCT) were conducted in the 1990s to investigate the efficacy of CAB with an antiandrogen (nilutamide or flutamide) plus castration; however, there were both positive and negative results for the efficacy of CAB. The lack of data on safety, quality of life (QOL) and cost-effectiveness has been a hindrance to the adoption of CAB for the treatment of prostate cancer. Nevertheless, discussion on CAB for the treatment of prostate cancer has continued for over 20 years, which suggests that there remains some hope for this regimen. In the 2000s, clinical research on CAB with the antiandrogen bicalutamide commenced. CAB using this new antiandrogen was found to prolong overall survival (OS) in patients with prostate cancer, with favorable safety profiles and cost-effectiveness, without deteriorating QOL. In this article, we discuss the feasibility of CAB with bicalutamide for the treatment of prostate cancer by reviewing the theoretical background of CAB and then the results of RCT conducted in the 1990s when the usefulness of CAB was assessed.

[Impact of new therapeutic products for the treatment of chronic obstructive pulmonary disease and asthma in primary care in Madrid between 1996 and 2005]. / Impacto de las novedades terapéuticas para el tratamiento de la enfermedad pulmonar obstructiva crónica y el asma en atención primaria de Madrid, entre 1996 y 2005.

OBJECTIVES: To analyze the trend of use of new drugs for the treatment of chronic obstructive pulmonary disease in primary care of Madrid (Spain) between 1996 and 2005, and to evaluate its impact in terms of supply, use and costs. METHODS: Drug utilization study of new products of the R03 group (Anatomical Therapeutic Chemical Classificaction System: drugs for obstructive airway diseases) prescribed by doctors of primary care of Madrid, during 1996 and 2005. Information on drug utilization and cost was obtained from the prescription database. Date was expressed in daily doses defined by 1,000 inhabitants and day. RESULTS: The supply experiences few quantitative variations although of great qualitative interest, when disappearing drugs without therapeutic utility and commercializing 6 therapeutic new products. In 2005, the use of the 6 new products generates 28.03% of the total of the consumption and 79% of the costs. The new drugs of greater impact are salmeterol/fluticasone and tiotropio. CONCLUSIONS: The supply of medicines qualitatively improves when disappearing drugs without therapeutic utility. The consumption of therapeutic new products has a great impact on the total consumption of the R03 group and, mainly, in the costs by its elevated price, in spite of contributing only limited therapeutic advantages. The new drugs have been gotten up at great speed to the prescription.

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.

A class of repeated measures concordance correlation coefficients.

The repeated measures concordance correlation coefficient was proposed for measuring agreement between two raters or two methods of measuring a response in the presence of repeated measurements (King et al., 2007). This paper proposes a class of repeated measures concordance correlation coefficients that are appropriate for both continuous and categorical data. We illustrate the methodology with examples comparing (1) 1-hour vs. 2-hour blood draws for measuring cortisol in an asthma clinical trial, (2) two measurements of percentage body fat, from skinfold calipers and dual energy x-ray absorptiometry, and (3) two binary measures of quality of health from an asthma clinical trial.

Economic impact of asthma therapy with fluticasone propionate, montelukast, or zafirlukast in a managed care population.

STUDY OBJECTIVE: To compare asthma-related health care expenditures among patients newly prescribed fluticasone propionate 44 or 110 microg, montelukast 5 or 10 mg, or zafirlukast 20 mg. DESIGN: Retrospective cohort analysis of medical and pharmacy claims. SETTING: University-affiliated health outcomes research center. PATIENTS: Seven hundred eighty-one patients (aged > or = 4 yrs) with asthma treated with controller therapy for 9 months (postindex period), with no claim for an inhaled corticosteroid or leukotriene modifier in the previous 9 months (preindex period). INTERVENTION: Asthma-related medical and pharmacy data from insurance claims of four managed care plans (two Northeastern, one Midwestern, and one Western) were tabulated over the pre- and postindex periods. MEASUREMENTS AND MAIN RESULTS: Numbers of patients identified were 284 beginning fluticasone propionate; 302, montelukast; and 195, zafirlukast. Fluticasone propionate treatment was associated with significantly (p<0.001) lower risk-adjusted asthma-related charges compared with montelukast and zafirlukast treatment: $528, $967, and $1359, respectively In this cohort, fluticasone propionate also was associated with fewer hospitalizations, less need for additional controller agents, and longer maintenance on the index drug compared with montelukast and zafirlukast. CONCLUSIONS: Based on these real-world data, as well as established national and international asthma guidelines, consideration should be given to inhaled corticosteroid therapy, particularly fluticasone propionate, for first-line, long-term effective management of asthma.

Cost-efficacy analysis of fluticasone propionate versus zafirlukast in patients with persistent asthma.

OBJECTIVE: To compare the relative value of an inhaled corticosteroid, fluticasone propionate 88 microg twice daily, versus an oral leukotriene receptor antagonist, zafirlukast 20 mg twice daily, in patients with persistent asthma currently receiving short acting beta2-agonists alone. STUDY DESIGN: A cost-efficacy analysis using resource utilisation and clinical data obtained prospectively from a multicentre, randomised, double-blind, double-dummy, placebo-controlled 12-week clinical trial conducted in the US. PERSPECTIVE: Third-party payor. PATIENTS AND METHODS: A total of 451 corticosteroid-naive patients with persistent asthma were treated with either fluticasone propionate 88 microg twice daily or zafirlukast 20 mg twice daily. All patients were given salbutamol (albuterol) to be used as rescue medication. Data were examined using intent-to-treat analysis. RESULTS: Mean daily per person cost-efficacy ratios using improvement in forced expiratory volume in 1 second (FEV1) [> or = 12% increase from baseline] were $US 3.47 for fluticasone propionate compared with $US 7.81 for zafirlukast (1999 values). The mean daily per person cost-efficacy ratios for symptom-free days obtained were $US 5.51 for fluticasone propionate compared with $US 14.98 for zafirlukast. These cost-efficacy ratios remained in favour of fluticasone propionate after a robust sensitivity analysis. CONCLUSIONS: Treatment with fluticasone propionate 88 kg twice daily was the most cost effective treatment compared with zafirlukast 20 mg twice daily in this 12-week clinical trial. This analysis supports the use of fluticasone propionate 88 microg twice daily as first-line treatment in patients with persistent asthma previously treated with short-acting beta2-agonist alone.

Asthma outcome changes associated with use of the leukotriene-receptor antagonist zafirlukast.

A new class of asthma drugs modifying the leukotriene pathway was introduced in 1996. The authors investigated outcome changes associated with use of the leukotriene-receptor antagonist zafirlukast. The study group included patients with asthma (12-64 yr), most with mild-to-moderate, persistent asthma, who had at least two zafirlukast prescriptions within 90 days after the start of zafirlukast treatment. Zafirlukast treatment was associated with reductions in occurrence of outpatient visits, emergency department visits, inpatient stays, and prescriptions for short-acting beta-adrenergic agonists in the next six months (all P < .05). A 12-month pre- and post-zafirlukast treatment comparison in a smaller group of patients and a classification of patients into three mutually exclusive outcome groups (increase, decrease, or no change in outcome events) verified the majority of the findings. A cost analysis from a third-party perspective indicated that costs of zafirlukast treatment were more than offset by cost savings associated with the reductions in outcome events.

A risk-benefit assessment of antileukotrienes in asthma.

The antileukotriene drugs are the first new therapeutic agents approved for the treatment of asthma in more than 20 years. The currently available compounds are orally active and either prevent the cysteinyl leukotrienes from binding to and activating the cysLT-1 receptor in the lung (leukotriene receptor antagonists) or inhibit leukotriene synthesis (leukotriene synthesis inhibitors). Studies performed in individuals without asthma and patients with asthma reveal that antileukotrienes prevent the bronchoconstriction produced by exercise, cold-air, allergen, aspirin (acetylsalicylic acid) and sulphur dioxide. Except for the setting of aspirin sensitivity where the antileukotrienes are nearly uniformly effective, individual responses to them are variable with complete protection in some, no protection in others and a modest degree of protection in the majority. The antileukotrienes bronchodilate the airways of patients with baseline bronchoconstriction, although usually not as well as beta-agonists. When given for weeks to months they rapidly improve pulmonary function and symptoms in patients with mild-to-moderate asthma, and probably in patients with more severe asthma as well, and these improvements persist for the duration of treatment. Here too, their beneficial effects are variable and not predictable based on clinical criteria. Recent studies suggest they can reduce asthma-induced airway inflammation and are equal or more effective than sodium cromoglycate, but equal or less effective than low-to-moderate dosages of inhaled corticosteroids. Initial experience with the antileukotrienes reveals limited toxicity and what appears to be a favourable therapeutic-to-toxic ratio. However, exposure of more patients with differing characteristics for longer periods of time is needed to substantiate this initial impression. The exact role of the antileukotrienes in the treatment of asthma remains to be determined, as does the relative potency of the various agents.

Zafirlukast. A review of its pharmacology and therapeutic potential in the management of asthma.

Zafirlukast is a competitive and selective leukotriene receptor antagonist indicated for the prophylaxis and treatment of chronic asthma. The rationale for the development of leukotriene antagonists was based on in vitro and in vivo data demonstrating the extensive role of the cysteinyl leukotrienes C4 (LTC4), D4 (LTD4) and E4 (LTE4) in the pathogenesis of asthma. Initial data have demonstrated an improvement in pulmonary function and symptom control and a reduction in the use of short-acting inhaled beta 2-adrenoceptor agonist therapy in patients with mild to moderate asthma treated with oral zafirlukast at the recommended dosage of 20 mg twice daily. Available data also suggest that zafirlukast may significantly reduce the incidence of asthma exacerbations. Data on the comparative efficacy of zafirlukast and existing antiasthma medications are limited. Results from 2 double-blind randomised studies comparing zafirlukast 20 mg twice daily with sodium cromoglycate aerosol or dry powder inhalation reported similar efficacy for both drugs. In a comparison with inhaled beclomethasone dipropionate (0.2 to 0.25 mg twice daily), improvements in morning peak expiratory flow rate, forced expiratory volume in 1 second and daytime symptom score were significantly less with zafirlukast 20 mg twice daily for 6 weeks. However, available data suggest that patient compliance and patient preference may be greater with oral zafirlukast 20 mg twice daily than with twice-daily inhaled corticosteroid therapy. Confounding results from 2 studies preclude any clear conclusions regarding the potential steroid-sparing effect of zafirlukast at the recommended dosage of 20 mg twice daily. Furthermore, Churg-Strauss syndrome has been reported in 6 patients who were being withdrawn from oral corticosteroid therapy while receiving treatment with oral zafirlukast. It is, therefore, recommended that zafirlukast-treated patients who require a reduction in their oral corticosteroid therapy are closely monitored. Zafirlukast is generally well tolerated. Reports of elevated liver enzymes in patients receiving high dosages of zafirlukast (80 mg twice daily) preclude the use of dosages exceeding 40 mg twice daily. Careful monitoring is necessary in zafirlukast-treated patients receiving concomitant therapy with drugs such as warfarin, terfenadine and erythromycin because of the potential for drug interactions. Thus, zafirlukast is a potentially useful addition to current antiasthma therapies in patients with mild to moderate asthma. Because zafirlukast is administered orally, it may be particularly beneficial in patients poorly compliant with asthma therapy as a result of poor inhaler technique. Further investigation of the efficacy of zafirlukast is expected to more clearly define its position in the management of asthma.

Effectiveness of the leukotriene receptor antagonist zafirlukast for mild-to-moderate asthma. A randomized, double-blind, placebo-controlled trial.

BACKGROUND: The increasing costs of managing asthma are due in part to the introduction of new medications, such as leukotriene receptor antagonists. These antagonists interfere with the action of leukotrienes, which are implicated in bronchoconstriction and the formation of airway edema in patients with asthma. Leukotriene receptor antagonists must be shown to be clinically and economically effective for their clinical use to be justified. OBJECTIVE: To assess the clinical and economic effectiveness of zafirlukast, a leukotriene receptor antagonist, in patients with mild-to-moderate asthma who might benefit from regular anti-inflammatory therapy. DESIGN: Randomized, double-blind, multicenter, placebo-controlled trial. SETTING: 28 outpatient clinics. PATIENTS: 146 patients with mild-to-moderate asthma who were 12 years of age or older, had not smoked cigarettes in the previous 6 months, had a smoking history of less than 10 pack-years, had an FEV1 at least 55% of the predicted value with no upper limit, had demonstrated bronchial hyperresponsiveness, and were symptomatic during the 7-day run-in period. All patients were seen every 2 to 3 weeks for 13 weeks. INTERVENTION: 103 patients received zafirlukast (20 mg twice daily), and 43 patients received placebo (twice daily). All patients received inhaled beta-agonists as needed. MEASUREMENTS: Data were obtained from medical examinations, patient questionnaires, and daily diaries. The clinical effectiveness outcomes were days per month without asthma symptoms, limitation of activity, use of beta-agonists, sleep disturbance, and episodes of asthma (the latter was a composite measure made up of the first four outcomes plus the occurrence of adverse events). The economic effectiveness outcomes were frequency and type of unscheduled health care contacts, use of beta-agonist inhalers, consumption of nonasthma medications, and days of absence from work or school. RESULTS: The zafirlukast group had 89% more days without symptoms (adjusted rates, 7.0 compared with 3.7 days per month; P = 0.03), 89% more days without use of beta-agonists (adjusted rates, 11.3 compared with 6.0 days per month; P = 0.001), and 98% more days without episodes of asthma (adjusted rates, 10.1 compared with 5.1 days per month; P = 0.003). They also had 55% (95% CI, 19% to 74%) fewer health care contacts (18.5 compared with 40.7 per 100 per month; P = 0.007) and 55% (CI, 3% to 79%) fewer days of absence from work or school (15.6 compared with 35.0 per 100 per month; P = 0.04). They used 17% fewer canisters of inhaled beta-agonists (P = 0.17) and 19% less nonasthma medication (P < 0.2). CONCLUSIONS: A daily regimen of zafirlukast added to as-needed inhaled beta-agonists is more effective than beta-agonists alone in treating mild-to-moderate asthma. The clinical and economic effectiveness of zafirlukast, a potential alternative to inhaled corticosteroids, provides further impetus to use regular "preventive" therapy in patients with mild-to-moderate asthma.