Evaluation of goserelin effectiveness based on assessment of inflammatory cytokines and symptoms in uterine leiomyoma.

Background Uterine leiomyoma is a benign tumour of the uterine smooth muscles associated with an elevated level of inflammatory cytokines. Goserelin, a synthetic gonadotropin-releasing hormone analogue, suppresses the production of sex hormones and release of inflammatory cytokines in uterine leiomyoma cells. Objective The primary objective of this study was to find out the effectiveness of subcutaneous goserelin therapy on lowering serum levels of inflammatory cytokines and improving uterine leiomyoma-related symptoms in female patients diagnosed with uterine leiomyoma. The secondary objective was to assess the tolerability to goserelin therapy used in the management of this tumour. Setting Outpatient gynaecological clinic of the medical consultation department of Baghdad Teaching Hospital, Baghdad province, Iraq. Methods A single centre, prospective, longitudinal, cohort study was carried out on female patients diagnosed with uterine leiomyoma. Goserelin 3.6 mg subcutaneous injection was given in a consecutive monthly dose for the total time duration of three months. Serum levels of inflammatory cytokines, tumour necrosis factor-α and monocyte chemotactic protein-1 were detected before and after goserelin therapy in a consecutive monthly assessment. The study also assessed the improvement in uterine leiomyoma-related symptoms, including pelvic pain alongside the incidence of goserelin-related side effects during therapy schedules. Main Outcome Measures Assessment of serum levels of tumour necrosis factor-α and monocyte chemotactic protein-1 alongside uterine leiomyoma-related symptoms, including pelvic pain and goserelin-related side effects. Results There was a significant decrease in serum levels of tumour necrosis factor-α and monocyte chemotactic protein-1 compared to the baseline level over the 3-month duration of goserelin therapy (0.11 ± 0.02 vs. 0.74 ± 0.19) pg/mL; (0.07 ± 0.00 vs. 0.44 ± 0.18) pg/mL respectively. Patients showed a clinical improvement regarding uterine leiomyoma-related symptoms following each of the consecutive monthly doses of goserelin therapy (n = 11, 55%, P < 0.0001; n = 15, 75%, P < 0.0001; n = 18, 90%, P < 0.0001) respectively. This also includes a significant decrease in the intensity of leiomyoma-related pelvic pain before and after goserelin therapy (7.2 ± 1.43 vs. 3.05 ± 1.14, P < 0.0001). The majority of patients reported vaginal dryness (60%) as the main goserelin-related side effect. Conclusion Goserelin therapy reduces serum levels of inflammatory cytokines, tumour necrosis factor- α and monocyte chemotactic protein-1, improving leiomyoma-related symptoms with good tolerability in patients with uterine leiomyoma.

Long-term consequences of ovarian ablation for premenopausal breast cancer.

The TEXT and SOFT trials concluded that an aromatase inhibitor (AI) with ovarian ablation (OA) yields a higher 5-year disease-free survival than tamoxifen alone in premenopausal ER+ high-risk early breast cancer. However, the long-term health consequences and costs of OA, either by GnRH agonist or oophorectomy, have not been evaluated. The objective was to conduct a cost-effectiveness analysis comparing tamoxifen to OA with AI. Markov Monte Carlo simulation model estimated the costs and benefits of 3 endocrine strategies: (1) tamoxifen; (2) GnRH agonist with AI (GnRHa-AI); (3) bilateral salpingo-oophorectomy with AI (BSO-AI). Effectiveness was measured in life expectancy gain (years), and costs were averaged over a lifetime (USD 2015). Adverse events and deaths from each strategy were modeled in the United States population over a time horizon of 40 years. For women without prior chemotherapy (low-risk), tamoxifen alone was more effective (18.03 years) and less costly ($1566) than GnRHa-AI (17.66 years, $93,692) or BSO-AI (17.63 years, $25,892). For those with prior chemotherapy (high-risk), BSO-AI was more costly but more effective (16.78 years, $25,368) than tamoxifen alone (16.55 years, $1523) with an ICER of $102,290, while GnRHa-AI yielded an ICER of $443,376. The simulation estimated 787 and 577 deaths attributable to OA among 9320 high-risk women after BSO-AI and GnRHa-AI, respectively. There may be a role for ovarian ablation in premenopausal women with ER+ high-risk early breast cancer; however, this analysis raises concerns about the long-term health consequences of ovarian ablation and the potential effects on overall survival.

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.

Cost-utility analysis of adjuvant goserelin (Zoladex) and adjuvant chemotherapy in premenopausal women with breast cancer.

BACKGROUND: Increased health care costs have made it incumbent on health-care facilities and physicians to demonstrate both clinical and cost efficacy when recommending treatments. Though studies have examined the cost-effectiveness of adjuvant goserelin with radiotherapy for locally advanced prostate cancer, few have compared the cost-effectiveness of adjuvant goserelin to adjuvant chemotherapy alone in premenopausal breast cancer. METHODS: In this retrospective study at one hospital, the records of 152 patients with stage Ia to IIIa ER + breast cancer who received goserelin or chemotherapy were reviewed. Survival analysis was assessed by the Kaplan-Meier method. Patients were interviewed to evaluate their quality of life using the European Organization for Research and Treatment Quality of Life questionnaire (EORTC-QLQ-C30, version 4.0), and to obtain the utility value by the standard gamble (SG) and visual scale (VS) methods. Total medical cost was assessed from the (National Health Insurance) NHI payer's perspective. RESULTS: Survival at 11 years was significantly better in the groserelin group (P < 0.0012). The lifetime lost was lower in the goserelin group (42 months vs. 66 months). The quality adjusted survival (QAS) of patients who received goserelin was longer (122.5 ± 6.3 vs. 112.2 ± 6.7 months). Total expenses of goserelin were more than cyclophosphamide, methotrexate, 5-fluorouracil (CMF) or 5-fluorouracil, epirubicin, cyclophosphamide (FEC) chemotherapy regimes, but less than docetaxel, epirubicin (TE) or docetaxel, epirubicin, cyclophosphamide (TEC) regimes. The quality-adjusted life-year was higher in the goserelin group. CONCLUSIONS: Goserelin therapy results in better survival and higher utility-weighted life-years, and is more cost-effective than TC or TEC chemotherapy.

Evaluation of osteoporosis risk assessment in veterans receiving androgen-deprivation therapy.

OBJECTIVE: To identify whether veterans receiving androgen-deprivation therapy (ADT) are screened at any time by bone mass measurement. DESIGN: Cross-sectional study. SETTING: Veterans Administration Tennessee Valley Healthcare System (VA-TVHS). PATIENTS: All male veterans who received at least one dose of goserelin or leuprolide within the fiscal years October 1, 2005, through September 30, 2009. INTERVENTIONS: Data from patients' charts were extracted for demographic information (race, age, and weight prior to the initial injection); date of initiation of therapy; the use of calcium, vitamin D, bisphosphonate, or calcitonin therapy; and documented bone-mineral density testing. MAIN OUTCOME MEASURE: To determine whether veterans receiving ADT with goserelin or leuprolide for prostate cancer were screened at any time for BMD more or less than rates as documented in previous literature. RESULTS: 22.8% of veterans were screened for BMD, which was statistically significant when compared with results found in previous literature. CONCLUSION: Although rates of BMD testing were higher at VA-TVHS compared with previous literature, this rate is still low given the well-known risk of accelerated osteoporosis associated with ADT.

Results of the Zometa cost-utility model for the german healthcare system based on the results of the ABCSG-12 study.

BACKGROUND: The ABCSG-12 trial investigated the efficacy of gonadotropin-releasing hormone (GnRH)analogs in combination with tamoxifen or anastrozole + or - zoledronic acid (4 mg, q6m for 3 years) in 1,803 premenopausal women with hormone receptor-positive (HR+) breast cancer. After 48 months of follow-up, there was a 36% improvement in the disease-free survival (DFS) (recurrence-free survival 35%) using zoledronic acid. Based on these data, the costutility of zoledronic acid was calculated for the German healthcare system. MATERIALS AND METHODS: Costs of surveillance, adverse effects, recurrence, contralateral breast cancer, metastasis, and end-of-life care were determined based on the Einheitlicher Bewertungsmabetastab (EBM 2009) and the diagnosis-related groups (DRG) system. Utilities were surveyed with a questionnaire (n = 95). Estimation of the cost-utility was made by calculating the incremental costeffectiveness ratio (ICER) per quality-adjusted life year (QALY), using a Markov model. RESULTS: Including zoledronic acid as adjuvant therapy for 3 years resulted in total costs of euro 2,262. The use of zoledronic acid is dominant when clinical efficacy and quality of life are taken into consideration (- euro 45.83/QALY) (95% confidence interval (CI) - euro 1,838 to E 2,375; 0.02-0.41 QALY). The sensitivity analyses present with a probability of 90% that the cost per QALY gained are

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.

A cost-outcome analysis of long-term adjuvant goserelin in addition to radiotherapy for locally advanced prostate cancer.

To quantify the incremental costs and outcomes of using long-term adjuvant goserelin in addition to radiotherapy for locally advanced prostate cancer. The cost of radiotherapy for prostate cancer has been calculated using an activity-costing model. The total cost of administering adjuvant hormonal therapy for 3 years is based on local pharmacy charges plus typical physician billing fees and additional laboratory costs. Outcome data were obtained from the published EORTC 22,863 randomized trial comparing treatment of locally advanced prostate cancer with radiotherapy alone or in combination with 3 years of adjuvant goserelin. Using this information, the cost-effectiveness of adjuvant goserelin was calculated and expressed in terms of dollars per life-years (LY) gained. The total institutional costs of radiotherapy are $9000 Cdn. and the additional costs of providing adjuvant goserelin for 3 years are approximately $19,800 CDN. The improvement in outcome with the use of adjuvant goserelin was estimated to be 1.2 LY per patient treated, giving a cost-effectiveness ratio of $16,500 Cdn ($11,000 US) per LY from an institutional perspective. Our sensitivity analysis confirms the robustness of our findings since even in our "worst case" scenario the cost-effectiveness ratio was estimated to be $21,600 Can ($14,400 US) per LY gained. This figure is still below $50,000 US per LY gained which is the quoted current standard for cost-effectiveness. This analysis demonstrates that the use of long-term adjuvant goserelin for locally advanced prostate cancer provides substantial benefit at an acceptable cost.

[Hysteroscopic ablation of the endometrium in cases of dysfunctional uterine bleeding--advantage of preparations including zoladex]. / Khisteroskopska ablatsiia na endometriuma pri disfunktsionalni matochni kruvotechniia--predimstva na podgotovkata sus Zoladeks.

Hysteroscopic endometrial ablation (HEA) is a new alternative for patients with dysfunctional uterine bleeding (DUB), resistant to medical treatment. The relatively thin endometrium is a big advantage at the time of operation. In this article the results of an initial series of hysteroscopic operations (HEA) are given--as a whole and depending on preoperative treatment with GnRH-agonist. Seventeen patients with DUB underwent HEA. Six of them were pretreated with Goserelin acetate (Zoladex 3.6 mg, Astra Zeneca) two subcutaneous application at 28 days interval. The other 11 women were operated in the early postmenstrual period without medical pretreatment. Comparison was made between the two groups regarding preoperative endometrial thickness, operative time, operative complications, duration of hospital stay, change of the menstrual pattern after 6 and 12 months. Results showed 41.2% achievement of persistent amenorrhoea in patients as a whole (62.7% in the Zoladex group and 27.2% in the untreated group). Better results in the patients with Zoladex pretreatment (shorter operative time, higher incidence of amenorrhoea, patient's higher evaluation of the operation) can be explained with the reduced endometrial thickness at the time procedure. The authors consider the hysteroscopic roller-ball endometrial ablation as an upto-date cost-effective method for treatment of DUB. The method is quick, with very low incidence of complications, easy toleration, immediately recovery of the patient and the only possibility for women with high anaesthesiologic and operative risk. Two depot-doses of Zoladex before hysteroscopy lead to better intra- and postoperative results.

Estimating survival gain for economic evaluations with survival time as principal endpoint: a cost-effectiveness analysis of adding early hormonal therapy to radiotherapy in patients with locally advanced prostate cancer.

The problem of estimating expected outcomes for the economic evaluation of treatments for which the outcome of principal interest is (quality adjusted) survival time has so far not received sufficient attention in the literature. The best estimate of expected survival is mean survival time, but with censored survival data, the true survival time for all the subjects is not known, so the mean is not defined.A possible solution to this estimation problem is illustrated by a retrospective cost-effectiveness analysis of the addition of hormonal therapy to standard radiotherapy for patients with locally advanced prostate cancer. A recently proposed method is used to approach the problem caused by censored cost data, and the impact of uncertainty is assessed by bootstrap resampling techniques. Mean survival time is estimated by a restricted means analysis with the time point of restriction determined by statistical criteria. When average total costs and mean survival time is evaluated at this time point of restriction, the result is that the combined therapy (radiotherapy plus hormonal therapy) increases mean survival time by about 1 year, while reducing the costs per patient for the French health insurance system by 12 700 FF. The time point of restriction may also be determined by other criteria and mean survival time may be estimated by extrapolating the survival curves by means of various parametric survival distributions. We show that the exact results of the economic evaluation are decisively determined by the restriction time point chosen and the approach taken to estimate mean survival time.

Cost-effectiveness of the addition of early hormonal therapy in locally advanced prostate cancer: results decisively determined by the cut-off time-point chosen for the analysis.

We present a retrospective cost-effectiveness analysis using data from a randomised controlled trial (EORTC 22863) of the addition of early hormonal therapy with a luteinising hormone-releasing hormone (LHRH) analogue to radiotherapy in the treatment of patients with locally advanced prostate cancer. Data on the use of medical resources were extracted from the hospital charts of 90 patients recruited into the trial by one French hospital. Costs are assessed from the viewpoint of the French healthcare financing system and adjusted for censoring. Expected costs per patient of each treatment is related to the expected outcome, mean survival time, estimated by a restricted means analysis. The time point of restriction is determined by statistical criteria. In the base case analysis with a cut-off time point at 8.58 years, the combined therapy group (COMB) had a gain in mean survival time of 1.06 years (7.05 versus 5.99 years) and a reduction of average total costs of 12700 French francs (FF) (58300 FF versus 71000 FF). The analysis of uncertainty uses bootstrap techniques with 5000 replicates to examine the joint distribution of cost and survival outcomes. In 76% of the cases, COMB results in longer mean survival time and lower costs than the radiotherapy group (RT). In cases where COMB therapy raises costs (13% of the cases), it is rarely by more than 20000 FF per patient, no matter the size of the associated survival gain. It is thus highly likely that COMB should be considered a cost-effective option compared with RT for these patients. The exact result of the economic evaluation is decisively determined by the restriction time point selected for the determination of mean survival time, partly also because the average total costs of the two treatments develop entirely differently as a function of the survival time.

Goserelin (Zoladex) or orchiectomy in metastatic prostate cancer? A quality of life and cost-effectiveness analysis.

BACKGROUND: We have today two treatment alternatives (orchiectomy or LHRH-analogue) in metastatic prostate cancer offering the same expectations of survival. This study documents the quality of life (QoL) and cost-effectiveness of these alternatives. PATIENTS AND METHODS: 65 consecutive patients treated at the University Hospital of Tromsø (UHT), Norway, between 1994 and 1999 were registered. At evaluation, 45 patients (LHRH-analogue--15 patients, orchiectomy--30 patients) were alive and included in the QoL-study (EORTC QLQ C-30, QoL 15D). 45 patients were followed-up at the UHT and included in the cost-analysis. Costs were calculated for a 36-month interval and converted to British pounds (1 Pound = 13 NOK). A 5% d.r. was employed. RESULTS: The mean QoL (15D) was 76.4 (orchiectomy) and 72 (LHRH) (0-100 scale). Constipation, urinating problems, fatigue, pain and loss of sexual functioning were the dominant symptoms. The treatment costs per patient treated were 8,895 Pounds (orchiectomy) and 10,937 Pounds (LHRH-analogue). The crossover in cost was located at 25 months. A sensitivity analysis varying discount rate (0-10%), drug charges (25-50% off) and treatment time (12-18 months) did not alter the conclusion. CONCLUSION: Orchiectomy is the treatment of choice when life expectancy is more than two years.

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.

A cost effectiveness analysis of goserelin compared with danazol as endometrial thinning agents.

OBJECTIVE: To analyse the cost, effectiveness and cost effectiveness of two endometrial thinning agents prior to laser ablation for dysfunctional uterine bleeding: danazol and goserelin. SETTING: A district general hospital. DESIGN: A retrospective cost effectiveness analysis, from the perspective of the health service, based on data from an open, randomised, parallel group comparative study of 160 pre-menopausal women with dysfunctional uterine bleeding. METHODS: Within the trial, length of operation and duration of hospital stay was recorded for each woman. Resource use due to complications of surgery and adverse drug events was evaluated by one of the authors (R.G.). Additional surgery after completion of the study was collected using a postal questionnaire which was distributed to every woman who had undergone surgery. Resource use was costed using detailed unit costs from a specific NHS trust and from published sources. A cost effectiveness analysis was undertaken relating differential cost to differential rates of amenorrhoea at women's last point of follow up. RESULTS: Information on amenorrhoea was available from 138 women, of whom 111 had completed the questionnaire to indicate longer term follow up. Women who did not complete the clinical trial were not included in this economic evaluation. On average, women randomised to goserelin spent less time in theatre and on the ward. Based on longer term follow up, rates of retreatment were similar in the two groups. The mean (SD) health service cost of women in the goserelin group was pound sterling 323.84 (pound sterling 309.94), compared with pound sterling 243.45 (pound sterling 265.23) in the danazol group; median (range) costs were pound sterling 220.29 (pound sterling 191-pound sterling 2127) and pound sterling 159.76 (pound sterling 140-pound sterling 1426) in the two groups, respectively. These costs were significantly higher for goserelin (P = 0.0001). The goserelin group also had a higher rate of amenorrhoea (38.8% vs 28.6%, P = 0.23). Based on mean differences in cost, the incremental cost of goserelin per additional woman with amenorrhoea was pound sterling 788; based on median differences in cost the ratio was pound sterling 590. CONCLUSIONS: The shorter duration in theatre and stay in hospital provided a modest offset of the higher acquisition cost of goserelin, but the overall cost of management remained significantly higher than managing women with danazol. The rates of amenorrhoea indicated that goserelin was more effective at 24 weeks and approximately two years after surgery, although statistical significance was only achieved at 24 weeks. The economic impact of women withdrawn from treatment was not considered, but sensitivity analysis indicates that these women may have had a large effect on the overall result of this study. Purchasers will need to decide whether the additional cost of management with goserelin is justified by the increased rates of amenorrhoea and the reduced withdrawals from treatment.

GnRH analogue in everyday gynecology: is it possible to rationalize its use?

BACKGROUND: The study was an audit of patients who attended the Menstrual Disorders Clinic at Glasgow Royal Infirmary over a five year period, and received gonadotrophin-releasing hormone analog (GnRHa). We aimed to identify the clinical indications for the use of GnRHa, and the effect of the latter in terms of symptom resolution and ultimate outcome. We aim to use this information to formulate a strategy for the use of GnRHa by targeting this expensive therapy to those situations where maximum benefit will be achieved. METHODS: A retrospective case review analysis of 201 patients. RESULTS: Thirty-eight percent of women presented with pelvic pain, 33% with disordered menstruation and 26% with premenstrual symptomatology. Overall, 74% of patients reported a beneficial effect of GnRHa. In the non-cyclical pelvic pain group, those patients with adhesions constituted a much greater proportion of those who did not derive benefit from GnRHa than those who did (43% vs. 16%; p<0.05; data not shown). In those patients with disordered menses, there was no difference between the diagnosis in those who did or did not derive benefit from GnRHa. Also with the exception of endometrial preparation prior to ablation and in the correction of anemia, the ultimate outcome was no different in the two groups. Of the patients with premenstrual symptomatology, the greatest proportion of those deriving benefit from GnRHa (41%) ultimately had an operative resolution. CONCLUSIONS: Our results enable us to use GnRHa as a first line in those clinical situations where maximum benefit will be achieved, either in terms of symptom resolution or as a tool to identify the most appropriate therapeutic option. We can therefore rationalize our prescribing both to the benefit of the patient and to our budget.

Relative effectiveness and cost-effectiveness of methods of androgen suppression in the treatment of advanced prostate cancer.

OBJECTIVES: With 184,500 new cases and 39,200 deaths anticipated in 1998, prostate cancer is second only to lung cancer in cancer mortality for men. This report is a systematic review of the evidence from randomized controlled trials on the relative effectiveness of alternative strategies for androgen suppression as treatment of advanced prostate cancer. Three key issues are addressed: (1) the relative effectiveness of the available methods for monotherapy (orchiectomy, luteinizing hormone-releasing hormone [LHRH] agonists, and antiandrogens), (2) the effectiveness of combined androgen blockade compared to monotherapy, and (3) the effectiveness of immediate androgen suppression compared to androgen suppression deferred until clinical progression. Outcomes of interest are overall, cancer-specific, and progression-free survival; time to treatment failure; adverse effects; and quality of life. Two supplementary analyses were conducted for each key question: (1) meta-analysis of overall survival at 2 years (questions 1 and 2) and 5 years (questions 2 and 3), and (2) cost-effectiveness analysis. SEARCH STRATEGY: The MEDLINE, CANCERLIT, and EMBASE databases were searched from 1966 to March 1998, and Current Contents to August 24, 1998, for the terms: leuprolide (Lupron); goserelin (Zoladex); buserelin (Suprefact); flutamide (Eulexin); nilutamide (Anandron, Nilandron); bicalutamide (Casodex); cyproterone acetate (Androcur); diethylstilbestrol (DES); and orchiectomy (castration, orchidectomy). The search was then limited to human studies indexed under the MeSH term "prostatic neoplasms" and by the UK Cochrane Center search strategy for randomized controlled trials. Total yield was 1,477 references. SELECTION CRITERIA: We Reports of efficacy outcomes were limited to randomized controlled trials. Phase II studies that reported on withdrawals from therapy and all studies reporting on quality of life were also included. DATA COLLECTION AND ANALYSIS: The systematic review used a prospectively designed protocol conducted by two independent reviewers, with disagreements resolved by consensus. The meta-analysis combined data on overall survival using a random effects model. The cost-effectiveness analysis used a decision analysis model of advanced prostate cancer with health states and transitions derived from the literature and estimates of effectiveness derived from the meta-analysis. The cost-effectiveness analysis is conducted from a societal perspective, consistent with the guidelines of the U.S. Public Health Service Panel on Cost-Effectiveness in Health and Medicine. MAIN RESULTS: Survival after treatment with an LHRH agonist is equivalent to survival after orchiectomy. The available LHRH agonists are equally effective, and no LHRH agonist is superior to the other when adverse effects are considered. Survival may be somewhat lower with use of a nonsteroidal antiandrogen. There is no statistically significant difference in survival at 2 years between patients treated with combined androgen blockade or monotherapy. Meta-analysis of the limited data available shows a statistically significant difference in survival at 5 years that favors combined androgen blockade. However, the magnitude of this difference is of questionable clinical significance. For the subgroup of patients with good prognosis, there is no statistically significant difference in survival. Adverse effects leading to withdrawal from therapy occurred more often with combined androgen blockade. No evidence is yet available from randomized controlled trials of androgen suppression initiated at prostate-specific antigen (PSA) rise after definitive therapy for clinically localized disease. For patients who are newly diagnosed with locally advanced or asymptomatic metastatic disease, the evidence is insufficient to determine whether primary androgen suppression initiated at diagnosis improves outcomes. (ABSTRACT TRUNCATED)

Quality of life assessment in a cross-cultural context: use of the Rotterdam Symptom Checklist in a multinational randomised trial comparing CMF and Zoladex (Goserlin) treatment in early breast cancer.

AIM: The aim of the study is to investigate quality of life (QoL) in the context of a multinational trial. The questions addressed are: is the Rotterdam Symptom Checklist (RSCL) 1) feasible and 2) reliable in cross cultural research, 3) is earlier validation confirmed in a multinational trial and 4) are there systematic differences in QoL across cultures? PATIENTS AND METHODS: Patients with histologically confirmed stage II, node positive breast cancer, were randomised in a multinational trial (the 'ZEBRA-study') comparing standard chemotherapy (CMF) or temporary ovarian ablation by treatment with a LHRH analogue (Zoladex, Goserlin). Patients originating from 13 countries completed a QoL questionnaire at baseline and three months after the start of treatment. RESULTS: 1) The questionnaire was completed by 689 patients at the first and 544 at the second measurement (response 78% and 68% respectively). The proportion of missing data was < 2.5% for 87.8% and 92.7% of the items at the respective time points. 2) Reliabilities of the physical and psychological distress scale were ranging from 0.68 to 0.90 across cultures. Reliability of the activity scale ranged from 0.42 to 0.89. 3) The structure at baseline was in agreement with the two factor structure proposed earlier. 4) Cross-cultural comparison indicated a systematic difference in QoL across cultures (P = 0.0028-< 0.0001) as well as a difference in change across cultures. CONCLUSIONS: QoL assessment using the RSCL proved feasible in the context of multinational clinical trials. Psychometric qualities were satisfactory. Systematic differences in QoL were found between cultures. This finding implies that in multinational clinical trials, treatment comparisons with respect to QoL should carefully account for a differential impact of cultures on the results.

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.