review of luteinizing hormone-releasing hormone agonists

Technology Report

Issue 44 December 2003

Review of Luteinizing Hormone-Releasing Hormone Agonists in Non-adjuvant Therapy for Advanced Prostate Cancer

i

Publications can be requested from:

CCOHTA

600-865 Carling Avenue Ottawa, Ontario, Canada K1S 5S8

Tel. (613) 226-2553 Fax. (613) 226-5392

Email: [email protected]

or download from CCOHTA’s web site: http://www.ccohta.ca

Cite as: Iskedjian M, Hemels M, Einarson TR, Vicente C, Iscoe N, Fleshner N. Review of luteinizing hormone-releasing hormone agonists in non-adjuvant therapy for advanced prostate cancer. Ottawa: Canadian Coordinating Office for Health Technology Assessment; 2003. Technology report no 44. Reproduction of this document for non-commercial purposes is permitted provided appropriate credit is given to CCOHTA. CCOHTA is a non-profit organization funded by the federal, provincial and territorial governments. Legal Deposit - 2003 National Library of Canada ISBN: 1-894978-04-8 (print) ISBN: 1-894978-03-X (electronic version) Publications Mail Agreement Number: 40026386

ii

Canadian Coordinating Office for Health Technology Assessment

Review of Luteinizing Hormone-Releasing

Hormone Agonists in Non-adjuvant Therapy for Advanced Prostate Cancer

Michael Iskedjian MSc1 Michiel Hemels MSc MSc1

Thomas R. Einarson PhD1 Colin Vicente BSc12

Neill Iscoe MD2

Neil Fleshner MD2

December 2003

1 PharmaIdeas Research and Consulting Inc., Oakville, Ontario, Canada 2 Sunnybrook and Women’s College Health Science Centre, Toronto, Ontario, Canada, at the time this study was

performed.

iii

Reviewers These individuals kindly provided comments on this report.

External Reviewers Abbott Laboratories Ltd. St. Laurent, Quebec Aventis Pharma Laval, Quebec

Laurence Klotz, MD FRCSCProfessor of Surgery University of Toronto Chief, Division of Urology Sunnybrook and Women's College Health Sciences Centre Toronto, Ontario

Michael A.S. Jewett, MD FRCSC FACS Professor, Department of Surgery (Urology) University of Toronto Toronto, Ontario

Chris Morash, MD FRCSC Head, Urology Section Division of Surgical Oncology Ottawa Regional Cancer Centre Ottawa, Ontario

Lawrence Joseph, PhD Associate Professor Department of Epidemiology and Biostatistics McGill University Montreal, Quebec

CCOHTA Scientific Advisory Panel Reviewers Gina Bravo, PhD Professor, Department of Community Health Sciences Faculty of Medicine University of Sherbrooke Sherbrooke, Quebec

Kenneth Marshall, BA MSc MD FRCPC FCFP Professor of Family Medicine (Retired) University of Western Ontario London, Ontario

This report is a review of existing public literature, studies, materials and other information and documentation (collectively the “source documentation”) which are available to CCOHTA. The accuracy of the contents of the source documentation on which this report is based is not warranted, assured or represented in any way by CCOHTA and CCOHTA does not assume responsibility for the quality, propriety, inaccuracies or reasonableness of any statements, information or conclusions contained in the source documentation. CCOHTA takes sole responsibility for the final form and content of this report. The statements and conclusions in this report are those of CCOHTA and not of its Panel members or reviewers.

i

Authorship

PharmIdeas Research and Consulting Inc. was commissioned by the Canadian Coordinating Office for Health Technology Assessment (CCOHTA) to produce this report. The authors from PharmIdeas and two clinical expert consultants on this project are listed below. Michael Iskedjian participated in design and supervision of the project, review of the literature, data analysis and interpretation, design of the model and report writing and revision. Michiel Hemels undertook the literature review, meta-analysis of the data, model design and resource utilization and valuation. Thomas R. Einarson undertook design and supervision of the project, data analysis and interpretation, design of the model and report writing and revision. Colin Vicente undertook data acquisition and analysis, revision of model design, revision of resource utilization and valuation; and assisted in report writing and revision. Neill Iscoe undertook data analysis and interpretation; and assisted in report review and revision. Neil Fleshner undertook data analysis and interpretation; and assisted in report review and revision. Acknowledgements We thank H. Bennett for editorial and analytical assistance, B. Garrido for statistical and analytical assistance and B. Maturi for technical assistance (all from PharmIdeas). From CCOHTA, M. Boucher and V. Skukla are acknowledged for their assistance in the analysis and data presentation; and B. Brady is acknowledged for his comments on the economics parts of the report. Conflicts of Interest The authors decared no conflicts of interest. Laurence Klotz (external reviewer) declared the following regarding the manufacturers of luteinizing hormone-releasing hormone agonists: for Aventis [manufacturer of buserelin (Suprefact®)], was a member of the advisory board; for Abbott [manufacturer of leuprolide (Lupron®)], received research funds; and for Astra Zeneca [manufacturer of goserelin (Zoladex®)], was a member of the speakers’ bureau, was a member of the advisory board and received research funds.

ii

REPORT IN BRIEF December 2003 LHRH Agonists as Non-adjuvant Treatment for Prostate Cancer

Technology Name Luteinizing hormone-releasing hormone (LHRH) agonists (LAs)

Disease/Condition Prostate cancer is the most commonly diagnosed cancer in Canadian men. Some types of prostate cancer advance rapidly while others progress over many years.

Technology Description LAs are synthetic proteins that are structurally similar to human LHRH. LHRH, which is secreted by the hypothalamus, indirectly stimulates the production of testosterone, mainly in the testes and adrenal glands. Testosterone stimulates the growth of normal and malignant prostate tissue. LAs reduce the production of testosterone and thus suppress prostate tumour growth.

The Issue LAs offer a reversible, more psychologically acceptable therapy than orchiectomy (surgical removal of the testes). Traditionally, LAs have been used in advanced prostate cancer. Given the cost of LAs, there is a need to assess their clinical value as a non-adjuvant therapy in advanced prostate cancer.

Assessment Objectives To review the clinical evidence for the use of LAs compared to antiandrogens (AA), diethylstilbestrol (DES), orchiectomy or combination pharmacotherapy (i.e. LA plus AA) in non-adjuvant treatment of patients with advanced prostate cancer. Adjuvant therapy with non-drug interventions such as surgery and radiotherapy were not considered.

Methods The literature from1980 to the end of 2000 was searched for randomized controlled trials that included patients with metastatic or locally advanced prostate cancer. Two reviewers independently selected 16 relevant studies (14 metastatic, two locally advanced) from a total of 334. The interventions were LAs [buserelin (Suprefact®), goserelin (Zoladex®) or leuprolide (Lupron®)] compared to orchiectomy, pharmacotherapy or combination pharmacotherapy.

Conclusions For locally advanced prostate cancer: • No statistically significant differences in

objective response rates, overall survival rates or progression-free survival rates are found between LAs and LAs plus AA combination.

• Findings are based on two studies and should be interpreted with caution.

• There is insufficient evidence to make other comparisons.

For metastatic prostate cancer: • There is a possible advantage in objective

response rates when LAs are compared with estrogen therapy, but no overall or progression-free survival advantage is found.

• The combination therapy of LAs with AAs has a potential survival benefit over monotherapy. This advantage varies in magnitude and is not identified for all treatment periods or for all LAs.

These results are based on limited evidence and should be interpreted with caution.

This summary is based on a comprehensive health technology assessment available from CCOHTA’s web site (www.ccohta.ca): Iskedjian M, Hemels M, Einarson TR, Vicente C, Iscoe N, Fleshner N. Review of luteinizing hormone-releasing hormone agonists in non-adjuvant therapy for advanced prostate cancer.

Canadian Coordinating Office for Health Technology Assessment (CCOHTA) 600-865 Carling Avenue, Ottawa, ON, Canada K1S 5S8 Tel: 613-226-2553 Fax: 613-226-5392 www.ccohta.ca

CCOHTA is an independent, not-for-profit health assessment organization funded by the federal, provincial and territorial governments

3

EXECUTIVE SUMMARY The Issue Prostate cancer is the most commonly diagnosed cancer in Canadian men. By 2016, as many as 35,200 new cases are expected to be diagnosed annually in Canada. A Canadian male has a one in eight change of being diagnosed with prostate cancer and a one in 28 chance of dying from the disease. How prostate cancer is treated depends on factors such as patient characteristics and the biological potential (stage and grade) of the tumour. Options for managing prostate cancer include orchiectomy, radiotherapy, hormonal therapy and chemotherapy, as well as a combination of these interventions. Pharmacological options for treament include antiandrogens (AAs) and estrogens in the form of diethystilbestrol (DES). Luteinizing hormone-releasing hormone (LHRH) agonists (LAs) are also used to manage advanced prostate cancer. The LAs approved for use in Canada are buserelin (Superfact®), goserelin (Zoladex®) and leuprolide (Lupron®). Tradionally, these agents have been used in advanced prostate cancer. However, there is a trend in using them in earlier stages of the disease, even though they are associated with significant costs. Objectives To review the clinical evidence on the use of the LAs compared to AAs, DES, orchiectomy or combination pharmacotherapy (i.e. LA plus AA) in non-adjuvant treatment of patients with advanced prostate cancer. For this report, two stages of the disease were considered: locally advanced prostate cancer and metastatic prostate cancer. Neo-adjuvant and adjuvant therapy with surgery or radiotherapy were not considered. Methods A systematic review of the available clinical evidence was performed. The literature from 1980 to the end of 2000 was searched for randomized controlled trials that included patients with metastic or locally advanced prostate cancer. The review compared LAs to AAs, DES, combination pharmacotheraphy (i.e., LA plus AA) and orchiectomy in treating patients with advanced prostate cancer. The efficacy of prostate cancer therapies was determined by qualitative and quantitative reviews of all randomized controlled trials that compared LAs with placebo or other LAs as identified by the literature: • estrogens with DES as a prototype • antiandrogens (AAs) • combination therapy (LAs plus AAs) • surgical orchiectomy (the only non-pharmacological option, included in this study as a

historical standard comparator.) The clinical outcomes examined in this report included objective response – stratified as overall best response measured at three, six and 12 months – and overall survival and progression-free survival, which were measured yearly.

iv

Results Of the 334 studies of advanced prostate cancer identified, two (276 patients) for locally advanced prostate cancer and 14 (2,000 patients) for metastatic prostate cancer were included in the review. For locally advanced prostate cancer, the two trials compared an LA (goserelin) to a combination of LA and AA (goserelin and flutamide). A meta-analysis of the objective response rates and overall survival rates showed no statistically significant differences between the two treatments. Progression-free survival was reported in one study. For metastatic prostate cancer, no statistically significant differences were observed in the best objective responses for LA versus orchiectomy or for LA versus DES. Two studies compared LA versus LA plus AA. One showed a small but statistically significant difference in favour of the combination therapy. There were no statistically significant differences in survival rates between LA and orchiectomy for metastatic prostate cancer. Most studies comparing survival rates between LA and DES did not show a statistically significant difference, except for year 3 in one study that compared buserelin to DES-orchiectomy. No statistically significant differences were observed in progression-free survival for LA versus orchiectomy; LA versus DES; and LA versus LA plus chemotherapy. The LA plus AA combination seemed to be associated with better progression-free outcomes in overall survival rates than LA monotherapy. An economic evaluation of LAs was not undertaken, given the lack of clinical data. Some components of an economic evaluation are presented in Appendix 4 to be used, as needed, in future economic analyses. Conclusions In the treatment of locally advanced prostate cancer, it was impossible to compare LA to treatment modalities other than the LA plus AA combination. No statistically significant differences in objective response rates, overall survival rates, or progression-free survival rates were found for this comparison. However, evidence was limited to two studies, including one of small sample size. Accordingly, our findings should be interpreted with caution. There is a need for more research in this area. For metastatic prostate cancer, the body of evidence was larger, but still limited. Statistically significant results were observed for a limited number of outcomes and comparisons. Although a possible advantage of LA was identified in the objective response rates, when compared to DES therapy, no overall or progression-free survival advantage was found. The only treatment strategy with a potential advantage over LA monotherapy was combination therapy with AA. This included a possible survival benefit. Such an advantage, however, was not identified for all periods and for all LAs. In addition, the magnitude of reported differences varied. Accordingly, our findings regarding metastatic disease should be interpreted with caution. The objective of this report was to review the clinical evidence on LA-based pharmacotherapy in advanced prostate cancer. The evidence used for this review was published between 1980 and 2000. Recent evidence suggests that there is a shift towards using LAs as adjuvant therapy, i.e. in combination with radiotherapy or surgery. However such an assessment was beyond the scope of this review.

v

TABLE OF CONTENTS EXECUTIVE SUMMARY........................................................................................................ iv

ABBREVIATIONS ................................................................................................................... vii

1 Introduction..............................................................................................................................1 1.1 Background Information..................................................................................................1

1.1.1 Pathology and epidemiology................................................................................ 1 1.1.2 Natural history of prostate cancer ........................................................................ 2 1.1.3 Staging ................................................................................................................. 2

1.2 Current Clinical Practice..................................................................................................2 1.2.1 Treatment options ................................................................................................ 2 1.2.2 Treatment of advanced and metastatic disease .................................................... 4 1.2.3 Economic burden ................................................................................................. 6

2 OBJECTIVES ........................................................................................................................8

3 CLINICAL REVIEW............................................................................................................8 3.1 Methods............................................................................................................................8

3.1.1 Literature search................................................................................................... 8 3.1.2 Inclusion and exclusion criteria............................................................................ 8 3.1.3 Method ................................................................................................................. 9

3.2 Results............................................................................................................................13 3.2.1 Quantity and quality of research available......................................................... 13 3.2.2 Assessment of studies ........................................................................................ 13 3.2.3 Clinical outcomes............................................................................................... 21

4 DISCUSSION .......................................................................................................................34 4.1 Review of Clinical Evidence .........................................................................................34 4.2 Other Review Studies ....................................................................................................37 4.3 Economic Component....................................................................................................38

5 CONCLUSIONS ..................................................................................................................39

6 REFERENCES.....................................................................................................................40 Appendix 1: Criteria for Acceptance of Studies and Inclusion of Data ........................................50 Appendix 2: Log of Rejected Studies and Reasons for Rejection .................................................52Appendix 3: Data Extraction Forms ..............................................................................................54 Appendix 4: Components of an Economic Evaluation..................................................................55

vi

ABBREVIATIONS AA antiandrogen ADR adverse drug reaction AE adverse event ARR absolute risk reduction AUA American Urological Association BPG British Prostate Group BPGC British Prostate Group criteria CEA cost-effectiveness analysis CI confidence interval CT computerized tomography CTA cytotoxic agents DES diethylstilbestrol DHT dihydrotestosterone DRE digital rectal examination EORTC European Organisation for Research and Treatment of Cancer FSH follicular stimulating hormone ITT intent-to-treat LA luteinizing hormone-releasing hormone agonist LH luteinizing hormone LHRH luteinizing hormone-releasing hormone MAB maximal androgen blockade MRI magnetic resonance imaging NPCP National Prostate Cancer Project OCCP Ontario Case Costing Project ODB Ontario Drugs Benefit OSB Ontario Schedule of Benefits for Physician Services OSLF Ontario Schedule of Benefits for Laboratory Services and Fees PSA prostate specific antigen QALY quality-adjusted life year RCT randomized controlled trial TRUS transrectal ultrasonography US United States

vii

1 INTRODUCTION

1.1 Background Information 1.1.1 Pathology and epidemiology

The prostate gland, located in the pelvis below the bladder and anterior to the rectum, comprises one anterior lobe, one posterior lobe, one median lobe and two lateral lobes.1 Its growth depends on stimulation by androgens. Luteinizing hormone-releasing hormone (LHRH, luliberin), which is secreted by the hypothalamus, stimulates the pituitary gland to secrete luteinizing hormone (LH, lutropin). In response to LH, interstitial (Leydig) cells in the testes produce testosterone, which is converted to dihydrotestosterone (DHT) in prostate cells. About 95% of testosterone is produced by the testes and 5% by the adrenal glands.1 The most frequent malignant condition of the prostate gland is adenocarcinoma. Other primary neoplasms occurring in this gland are rare, so the terms “prostate cancer” and “carcinoma of the prostate” are understood to be synonymous with adenocarcinoma of the prostate. Some tumours advance rapidly by local extension or metastasis, while others may progress over many years.2 When prostate cancer progresses, it may invade structures adjacent to the prostate or it may spread to distant organs through the lymphatic system or the bloodstream.2 Late in the course of the disease, bladder outlet obstruction, urethral obstruction, hematuria and pyuria may occur. Metastases to the pelvis, ribs and vertebral bodies may cause bone pain. Prostate cancer is the most commonly diagnosed cancer in Canadian men.3 A Canadian male has a one in eight risk of being diagnosed with prostate cancer and a one in 28 chance of dying from the disease.3 As many as 35,200 new cases are expected to be diagnosed in Canada in 2016.4 In 2003, the incidence of prostate cancer is estimated to be 18,800, which represents 13.4% of all new cancer cases. The incidence of death from prostate cancer is estimated to be 4,200, representing 6.2% of all cancer-related deaths in Canada (Table 1).3 The numbers of new cases and deaths, which are an important measure of the cancer burden, can be used to plan patient services and health care facilities to meet increasing demand.

Table 1: Estimates of incidence of prostate cancer and prostate cancer related deaths

in Canadian males for 2003 and as a percentage of estimated overall cancer rates3

2003 Estimates for Prostate Cancer New Cases

Deaths Deaths to Cases Ratio

Incidence of all cancers 139,000 67,400 0.48 Incidence of prostate cancer 18,800 4,200 0.22 Prostate cancer as a percentage of all cancer cases 13.4% 6.2% Distribution by age group 60 to 69 years 6,200 530 70 to 79 years 6,700 1,500 80 plus years 3,200 2,100 Average annual percentage change in age-standardized incidence (1991 to 1998) and mortality (1991 to 1999) rates

(-1.5%)

(-1.9%)

1

1.1.2 Natural history of prostate cancer

The evaluation of the effect of intervention must be based on the course that the disease would follow if it is allowed to proceed without interference. Some prostate cancers tend to become more widespread with a consequential increase in morbidity and mortality as localized disease becomes metastatic.2 The death rate from localized prostate cancer (clinical stages T1 and T2) in the first five years post-diagnosis is low. Death is usually a result of comorbidities.2,5 Hence, a more accurate assessment of these patients’ survival rate would occur at 10 and 15 years post-diagnosis. In most patients who have undergone surgery or radiotherapy, progression of disease, i.e., evidence of tumour as indicated by a rise in serum prostate specific antigen (PSA), becomes apparent by five years.2 Progression is often asymptomatic and found only through surveillance examinations.2 The few patients who experience progression-free survival beyond 10 years require frequent assessment.2

1.1.3 Staging

Several staging systems for prostate cancer have been described. The two most often used are the Jewett-Whittmore (also known as the ABCD) system and the American Joint Committee (TNM) system.2 Table 2 provides a comparison of the two systems. Patients in stages M1 or D2 have bone metastases established through bone scan, computerized tomography (CT) or magnetic resonance imaging (MRI). Stages M0, D1 or C (i.e. locally advanced prostate cancer) include patients with non-metastatic advanced prostate cancer who could be node-positive (T1-4N1M0) or not (T3-T4 N0M0). Both systems have been modified because of the need to accommodate evolving concepts of prostate cancer. Staging of the local extent of prostate cancer is achieved by digital rectal examination (DRE), serum PSA, serum acid phosphatase, transrectal ultrasonography (TRUS), CT scan and MRI.2,6 CT scan, MRI and radioisotopic bone scan are used to stage distant metastases.2

1.2 Current Clinical Practice 1.2.1 Treatment options

Treatment options for prostate cancer depend on patient characteristics such as age, functional level, medical status and the biologic potential, i.e. the stage and grade of the tumour.2,7 Options for management of localized prostate cancer include radical prostatectomy, radiotherapy, hormonal therapy, chemotherapy and surveillance.2,5,8 Patients most likely to benefit from radical prostatectomy have a relatively long life expectancy (10 years or more), have a low profile of surgical risk factors and are willing to undergo surgery.2,5 The potential advantages are removal of the cancer and “cure,” provided the tumour is confined to the prostate. Potential harm includes urinary incontinence and erectile dysfunction.2,5 If the cancer is not eradicated, disease progression may occur.

2

Table 2: Clinical and operational definition of advanced and metastatic prostate cancer

Categories of Advanced

Prostate Cancer

TNM*

Stage Jewett-

Whitmore†

Stage

Definition

A. Metastatic M1 D2 Patients with bone metastases established through bone scan, CT or MRI

B. Non-metastatic advanced

M0 D1, C and others

High risk, advanced: • Node positive

T1-4N1M0 Detected by imaging, needle biopsy, open biopsy, open orchiectomy

• Not node positive

T3-T4 N0M0 High volume tumour (adjuvant or primary Tx)

Invasion of capsule, no metastases

• Not node positive

T1-2N0Mx Low volume tumour, high risk (Adjuvant Tx)

Nodes are not clinical, not pathologically involved or not detected Gleason score ≥8 PSA level >30

• Miscellaneous (Salvage Tx) Surgery; rising PSA Radiotherapy; rising PSA

CT=computed tomography; MRI=magnetic resonance imaging; PSA=prostate specific antigen; *TNM=tumor, nodes and metastases9; †Jewett-Whitmore10

Watson et al.11 address the role of androgen deprivation (or neoadjuvant therapy) before radical prostatectomy. Their article reviews six randomized clinical trials of patients in clinical stages from T1 to T3. Patients are treated with a combination of LHRH agonist (LA) and antiandrogen (AA) (dosages were not stated in most trials) for approximately three to 12 months before prostatectomy. Most patients reach their PSA nadir by eight months. The disadvantages of neoadjuvant hormonal therapy include increased costs, temporary adverse events and periprostatic fibrous reactions.11 Patients who are most likely to benefit from radiotherapy have a relatively long life expectancy, no significant risk factors for radiation toxicity and a preference for this treatment.2,8 The advantages of radiotherapy include the potential for cure and increased tolerability for most patients. Disadvantages include radiation cystitis, proctitis, erectile dysfunction, fatigue and diarrhea.2,8 Persistence and progression of disease may occur. Patients with a shorter life expectancy or a low-grade tumour are most likely to benefit from surveillance.2 The benefits of surveillance for low- or intermediate-grade, localized prostate cancer include a lack of treatment-related morbidity with marginal compromise of disease-specific survival at five to 10 years of follow-up.2 Progression of the disease is more likely to occur.

3

1.2.2 Treatment of advanced and metastatic disease

a) Androgen withdrawal therapy The standard approach of hormonal suppression thereapy for metastatic prostate cancer is irreversible bilateral orchiectomy, i.e., surgical castration. This is associated with such psychological trauma that it has led to an an increase in the use of pharmacological castration.12 The advantages of surgical orchiectomy over hormone therapy includes rapid response, the avoidance of patient non-compliance and low acquisition cost (the cost is lower than the two-year cost for hormonal pharmacotherapy).13 Serious adverse events (AEs) from surgical orchiectomy include a loss of libido (100%), impotence (100%) and mild to severe hot flashes (57%).14,15 By suppressing the release of LH from the pituitary gland, several classes of drugs induce levels of testosterone similar to those achieved with castration. The estrogen diethylstilbestrol (DES) suppresses the hypothalamic release of LHRH and increases the levels of testosterone-binding globulin.12 The complications associated with DES therapy include salt and water retention, gynecomastia and breast tenderness, nausea, thromboembolic events, loss of libido, impotence and an increased incidence of cardiovascular disease.13 Although the acquisition cost of DES is relatively low, it is rarely used due to the improved safety profiles of newer drugs.16 A newer class of medications – LAs, including buserelin (Suprefact®), goserelin (Zoladex®, leuprolide (Lupron®) and triptorelin (Trelstar Depot® in the US) – produce an initial rise in the levels of LH and testosterone (flare) followed by a fall.12,17 This “flare” phenomenon, a disadvantage of using these drugs alone, can be prevented by administering cyproterone acetate or DES one week before LA therapy.12 LA therapy is more acceptable to patients when compared with surgical orchiectomy because of the reversible mechanism of castration and for psychological reasons.18 The LAs exert their antitumour activity via chemical castration and they act on tumour cells by blocking the LA receptors.19 LAs are associated with hot flashes, atrophy of reproductive organs, loss of libido, gynecomastia and impotence. The main disadvantages of LA therapy include a higher cost and the necessity for periodic injections.13,20 Non-steroidal AAs, which include cyproterone (an older agent) and newer agents such as flutamide, nilutamide and bicalutamide, have no direct gonadotropic or progestational effects and most studies do not support the use of these agents alone.12 Recent data, however, suggest that higher dose bicalutamide monotherapy may be equivalent to surgical castration in non-metastatic cancer.12 Most experience with these drugs has been in combination therapy with LAs, although there are a few studies of monotherapy in advanced cancer.18 AAs (e.g. flutamide) produce an incomplete androgen blockade and thus are not approved in the US for monotherapy. These should be used with LAs or orchiectomy.20 The main disadvantage of AA therapy is its relatively high cost.13 Major adverse effects include gynecomastia, severe diarrhea, flushing and liver function abnormalities.13 Steroidal (mixed) AAs (megestrol plus cyproterone acetate) inhibit the secretion of gonadotropin and the production of testosterone. The combination of low-dose cyproterone acetate and mini-doses of DES achieves potent androgen ablation at one third the cost of LAs.12 Cyproterone acetate therapy is reversible with serum testosterone levels returning to normal after therapy is

4

withdrawn.13 Megestrol loses some of its activity after four to six months of use.13 Also, with megestrol, the serum levels of testosterone, LH and follicle stimulating hormone (FSH) rise but do not return to normal levels.13 The antiandrogenic properties of megestrol acetate are limited.13 Seidenfeld et al. performed a meta-analysis to compare LAs to orchiectomy or DES and to compare AAs with any of these three alternatives.21 All studies included in the meta-analysis were randomized controlled trials (RCTs). The patient population was composed of men with advanced prostate cancer, including regional or disseminated metastases and, according to the authors, minimally advanced disease, “stage C [T3 or T4, N0 or M0].” Most patients had metastatic disease that was staged as D2 or M1. The outcomes of interest were overall cancer-specific and progression-free survival, time to treatment failure, incidence of AEs and quality of life. Seidenfeld et al identified 24 suitable RCTs that randomized 6,600 patients to different monotherapies. A total of 1,539 patients who received LAs in 12 trials were included in the meta-analysis. The LAs included leuprolide, goserelin and buserelin. Of the nine trials that compared an LA to orchiectomy or DES, none found a significant difference in survival rates.21 Four of five trials comparing LAs to orchiectomy or DES found no significant differences in progression-related outcomes. One trial favoured the control arm (p<0.05), which consisted of DES or orchiectomy. There were no significant differences in time to treatment failure in trials that compared an LA to orchiectomy or DES. There was no difference in overall survival among the LAs, although the confidence intervals (CI) were wider for leuprolide [hazard ratio 1.09 (CI95%: 0.21 to 5.84)] and buserelin [1.13 (0.53 to 2.40)] than for goserelin [1.12 (0.89 to 1.39)]. Evidence from eight trials involving 2,717 patients suggested that non-steroidal AAs were associated with lower overall survival. Withdrawals due to adverse effects occurred less often among patients treated with an LA (0% to 4%) than among patients treated with AAs (4% to 10%). b) Combination therapy Among the endogenous androgens, 60% can be removed by orchiectomy or LAs, but 40% of the DHT that is made in the prostatic tissue from adrenal precursors is left free and continues to stimulate prostate cancer growth after castration.22 All double-blind randomized and prospective clinical trials in advanced prostate cancer have shown that combination therapy using a non-steroidal AA in association with a LA or orchiectomy leads to a significantly better response than either LA or a non-steroidal compound alone. The benefits observed in this maximal androgen blockade (MAB) probably result from the blockage of the androgens of adrenal origin by the AAs.22 Intermittent combined androgen blocking is being studied in phase III trials of metastatic prostate cancer for its ability to increase the quality of life and survival of men with advanced prostate cancer while decreasing the cost of therapy.19 Cost is an issue with combination therapy, especially in LA-AA combinations, as two expensive agents are used together.13 Studies that indicate a benefit from the combination of orchiectomy and the use of an AA are encouraging, as this could avoid the use of more costly LAs.13

5

1.2.3 Economic burden

The economic burden of prostate cancer in Canada is predicted to increase rapidly as baby boomers approach their 50s and 60s.23 Statistics Canada estimates that the population of men over age 40 will increase from 5.7 million in 1995 to 9.0 million in 2016. The estimate for potential years of life lost due to prostate cancer was 32,000 for Canada in 1999, representing 3.5% of potential years of life lost due to all cancers.3 There are no available data on the costs of prostate cancer in Canada.23 A study by Denmeade et al. estimated the cost for treatment of localized prostate cancer in the United States to be US$10,000 to US$25,000 per patient; and the cost for treatment of advanced disease to be US$30,000 to US$100,000 per patient.24 Total drug costs to the Ontario Drug Benefit (ODB) program for prostate cancer treatments in men over 64 years of age increased 70-fold from $0.2 million in 1985 to more than $15 million in 1992. During this period, overall drug costs to the ODB program sustained a three-fold increase from $212 million to $646 million.25 According to IMS data, in 1984, 78% of cytotoxic agents (CTAs) were sold through hospitals and total sales reached $1.1 million. By 2000, sales had increased over 200-fold to $238.4 million, with approximately equal amounts being sold through hospitals and through drugstores.26 LAs form 29% of the total cost of pharmacological treatment for prostate cancer ($69 million out of $238 million) and account for 37% of the increase each year. Overall CTA prescription volume rose 14-fold from about 50,000 in 1980 to 689,000 in 2000, of which 11.3% were for LAs. a) Published economic evaluations Three studies assessing the cost-effectiveness of LAs in prostate cancer were retrieved. Alloul et al. performed a meta-analysis and an economic evaluation of depot formulations of LAs in advanced prostatic carcinoma.27 They performed a cost-minimization analysis after noting no statistically significant differences among LAs on the two endpoints of survival and progression-free survival. The results of the cost-minimization analysis were sensitive to variations in the dosing interval and in the time horizon.27 The authors reported that buserelin remained the most economical alternative, even when the parameters were varied.27,28 The Alloul et al. paper was criticized due to the limitations inherent in its analysis.29-31 According to reviewers, many methodological principles of meta-analysis were violated, including a lack of a statistical test for homogeneity and the lack of a blinded independent review of the articles to ascertain comparability and quality of the evidence extracted.29 Oh et al. re-analyzed the original data and demonstrated that the conclusions could change based on the definitions of the time horizon and the dosing interval of LAs.29 Einarson and Yannicelli further criticized the approach taken by Alloul et al., by identifying flaws in costing methods and noting a bias favouring buserelin, the drug manufactured by the sponsor of the study.30 A study by Nygard et al. prospectively evaluated over 36 months the costs and the outcomes of two cohorts of Norwegian patients who received either LAs or orchiectomy.32 They concluded that orchiectomy was the treatment of choice, with an incremental cost of over £2,000 (or approximately C$5,000). The high cost of orchiectomy found in their study (£8,895) differed from the low cost derived in our costing approach in Appendix 4.

6

Another study by Bayoumi et al. evaluated the cost-effectiveness of androgen suppression therapies in advanced prostate cancer from a societal perspective.33 The analysis was based on a Markov model with one-month cycles and six treatment options, the same four as in our models (Appendix 4 Figures 2 and 3) and an AA monotherapy arm and an arm with the combination of AAs and orchiectomy. The time horizon was 20 years and locally advanced disease was included. In the Bayoumi study,33 DES was found to be the least expensive and the least effective strategy with a cost of US$3,600 per 4.6 QALYs. Orchiectomy had an incremental cost-effectiveness ratio of US$7,500/QALY relative to DES. Orchiectomy costs amounted to US$7,000. All other options were dominated by orchiectomy. In sensitivity analyses based on the 95% CI for outcomes derived from a meta-analysis, the combination of LAs plus AAs always yielded incremental cost-effectiveness ratios of more than US$100,000/QALY compared with orchiectomy. In sensitivity analyses, varying the utility for orchiectomy from 0.92 to 0.83 resulted in incremental cost-effectiveness ratios for LAs of less than US$50,000/QALY. They concluded that in men “who accept it,” orchiectomy was the most cost-effective option. The cost of orchiectomy was higher in the Nygard and Bayoumi studies when compared with those derived in Appendix 4. The costs of LAs and AAs, however, were also higher in those studies when compared with derived costs.

7

2 OBJECTIVES The objective of this research project is to review the clinical evidence available on the use of LAs, compared to AAs, DES, orchiectomy or combination pharmacotherapy (i.e. LA plus AA) in the non-adjuvant therapy of patients with advanced prostate cancer.The review entails a qualitative and quantitative review of the level I clinical evidence of LAs in the treatment of advanced prostate cancer divided into two stages: locally advanced prostate cancer and metastatic prostate cancer.The LAs approved for use in Canada are buserelin (Suprefact®), goserelin (Zoladex®) and leuprolide (Lupron®). Neo-adjuvant and adjuvant therapy with surgery were not considered for this review. 3 CLINICAL REVIEW

3.1 Methods 3.1.1 Literature search

A comprehensive literature search was undertaken to identify all published papers on the treatment of advanced prostate cancer with the drugs included in the analysis. MEDLINE®, EMBASE®, HealthSTAR, CANCERLIT® and Cochrane were searched for studies published from 1980 to the end of 2000. Key words used in the search were Prostate cancer and: LA / buserelin / goserelin / leuprorelin / leuprolide / antiandrogens / flutamide / nilutamide / bicalutamide / orchiectomy / orchidectomy / hormones / DES / diethylstilbestrol. References from review papers, meta-analyses and retrieved articles were also used to find additional articles to be included in the meta-analysis. Abstracts, posters and presentations at scientific meetings and symposia were excluded. The drugs of interest were buserelin, goserelin and leuprorelin-leuprolide, which are all available in Canada. The comparators, which were established after review of the literature and discussions with clinicians (NF and NI), included DES, orchiectomy, AAs and the combination of a LA with an AA. Radiotherapy and radiotherapy in combination with one of the listed treatment options were excluded.

3.1.2 Inclusion and exclusion criteria

a) Types of trials All reports describing prospective, randomized controlled trials of both parallel and crossover design, regardless of language, were identified. An inclusion-exclusion form (Appendix 1) was created and the defined criteria were applied to potential studies. To be accepted, articles had to meet all inclusion criteria. Any articles containing exclusion critieria were rejected from the meta-analysis.

8

b) Types of participants The eligibility criteria for trial participants were:

• patients with metastatic prostate cancer (for definitions, see Table 2) • patients with locally advanced prostate cancer (for definitions, see Table 2).

Evaluation of the effect of active intervention must have taken into account the course and stage of the disease.2 Although patients with the two forms of disease are often grouped together in randomized trials, their clinical presentations differ and they have different life expectancies. Therefore, the efficacy of treatments should be assessed separately. Consequently, we performed two analyses, i.e. one for patients with metastatic prostate cancer and another for patients with locally advanced disease. c) Types of interventions We accepted all RCTs that evaluated, in at least one treatment arm, the efficacy of buserelin, goserelin or leuprolide in patients who were diagnosed with advanced prostate cancer as defined by any standard scale. Treatment comparators included pharmacotherapy alone or in combination with other pharmacological options and orchiectomy, a non-pharmacological option. Orchiectomy was included as the historical standard to which pharmacotherapies were compared. d) Types of outcome measures The clinical outcomes examined in this review of the evidence were:

• objective response • overall survival • progression-free survival.

For assessing the benefit of interventions, we followed the American Urological Association’s (AUA) prostate cancer clinical guidelines,2 which considered these outcomes to be the most important to the patient. Success rates (sum of complete, partial and stable objective response rates) and failure rates (progressive objective response rate) were measured at the most commonly used assessment periods as reported in RCTs, i.e. three, six and 12 months. We also assessed the overall best objective response rate. Overall survival and progression-free survival data were determined at intervals commonly measured in RCTs, i.e. one, two, three, four and five years. Table 3 lists the definitions of the outcomes objective response, overall survival and progression-free survival. The National Prostatic Cancer Project (NPCP)34 and the British Prostate Group (BPG)35 criteria are the most commonly used to evaluate response rates in RCTs of advanced prostate cancer.

3.1.3 Method

a) Selection process Two reviewers (MH and MI) independently reviewed citations and discarded irrelevant ones, based on the titles or abstracts. Reports considered irrelevant included case reports, review articles and studies unrelated to the use of LAs for the treatment of prostate cancer.

9

Table 3: Definitions of objective response measures in LA treatment

Objective Scale Objective Measures

Objective Category Definition of Category

National Prostatic Cancer Project (NPCP) Criteria34

Objective complete response Objective partial regression Objectively stable Objective progression

All of the following: -Tumor masses, if present, disappeared and no new lesions appeared -Elevated acid phosphatase, if present, returned to normal -Osteoblastic lesions, if present, disappeared -Osteolytic lesions, if present, recalcified -If hepatomegaly is a significant indicator, there must be a complete return in liver size to normal, and normalization of all pre-treatment abnormalities of liver function, including bilirubin mg%, and serum glutamic oxalacetic transaminase (SGOT) -No significant cancer related deterioration in weight (>10%), symptoms and performance status All of the following: -At least one tumor mass, if present, was reduced by =50% in cross-sectional area -Elevated acid phosphatase, if present returned to normal -Osteoblastic lesions, if present, did not progress -Osteolytic lesions, if present, underwent recalcification in one or more, but not necessarily in all. -If hepatomegaly is a significant indicator, there must be at least a 30% reduction in liver size and at least a 30% improvement of all pre-treatment abnormalities of liver function, including bilirubin mg% and SGOT. -There may be no increase in any other lesion and no new areas of malignant disease may appear -No significant cancer related deterioration in weight (>10%), symptoms or performance status All of the following: -No new lesions occurred and no measurable lesions increased more than 25% in cross-sectional area -Elevated acid phosphatase, if present, decreased, though need not have returned to normal -Osteoblastic lesions, if present, remained stable -Osteolytic lesions, if present, did not appear to worsen -Hepatomegaly, if present, did not worsen by more than a 30% increase in liver measurements and hepatic abnormalities did not worsen, including bilirubin mg% and SGOT. -No significant cancer related deterioration in weight (>10%), symptoms or performance status Any of the following: -Significant cancer related deterioration of weight (>10%), symptoms, or performance status -Appearance of new areas of malignant disease -Increase in any previously measurable lesion by >25% in cross-sectional area -Development of recurring anemia secondary to prostate cancer -Development of uretral obstruction

British Prostate Group (BPG) Criteria35

Complete objective response Partial objective regression Stable response

-No tumor palpable (T0) and -No evidence of distant metastases Any of the following: -Reduction in primary tumour by one or more T category -Reduction in primary tumour area by 50% -Return to normal serum acid phosphatase (if elevated) -Reduction in size of soft tissue metastases by 50% -Recalcification of any osteolytic lesions if present (Regression in primary tumuor but other evidence of progression = objective progression) -No change in T or M category (There must be documented progression of disease before this response)

10

Objective Scale Objective Measures

Objective Category Definition of Category

EORTC Genito- Urinary Group criteria36

Objective progression Complete remission Partial remission No change Progression

Any of the following: -Increase in primary tumour by one or more T category -Increase in tumour area by 50% -Increase in serum acid phosphatase on two or more occasions -Increase in size of soft tissue metastases by 50% -New bony lesions on scan or x-ray All of the following: -Absence of any clinically detectable soft tissue tumour mass -Return of an elevated acid phosphatase to normal -The recalcification of all osteolytic lesions if present -No evidence of progression of osteoblastic lesions, if any are present -There may be no increase in any other lesion and no new areas of malignant disease may appear -No significant deterioration in weight (>10%), symptoms or performance status (one score level) -If hepatomegaly is a significant indicator, there must be a reduction in liver size and at least a 30% improvement of all pretreatment abnormalities of liver function Any of the following: -A significant decrease in size in at least 50% of all soft tissue lesions while the remainder are static; in the case of accurately measurable lesions, such a decrease is defined as a reduction by 50% of the product of the two largest tumour diameters; for lesions that do not lend themselves to accurate measurement, the reduction should be at least three-fourths of the estimated volume -Return of an elevated acid phosphatase to normal -The recalcification of some osteolytic lesions if present -There may be no increase in any other lesion and no new areas of malignant disease may appear -No significant deterioration in weight (>10%), symptoms or performance status (one score level) -If hepatomegaly is a significant indication, there must be a reduction in liver size and at least a 30% improvement of all pretreatment abnormalities of liver function All of the following: -No new lesions appear and no lesion increases in size; decreases in lesion size, if any, are insufficient to indicate a partial remission -No significant deterioration in weight, symptoms or performance status Any of the following: -The primary lesion must increase by >50% of the sum of the products of the two maximum perpendicular diameters -Bone metastases: new hot spots on the bone scan which persists at a subsequent scan and show x-ray changes; patients should not be taken off study if existing bone lesions increase in size -New palpable lymph node metastases -New pulmonary metastases on chest x-ray -NB. Subjective deterioration in a patient’s general condition alone is not an indication of progression and patients should continue on treatment. If the clinician wishes to withdraw the patient from the trial, then discussion with the study coordinator is essential before the treatment is changed and reasons for the withdrawal notified on a summary sheet to the data center. -Survival: All patients will be followed to death

11

b) Selection of relevant studies Potentially relevant studies were retrieved. Two reviewers (MH and MI) examined selected articles to determine whether they met the inclusion criteria. Discrepancies were settled through consensus, with unresolved disputes adjudicated by a third reviewer (TRE). c) Quality assessment The quality of the included studies was assessed using the Jadad scale, which assesses the appropriateness of randomization, double-blinding, withdrawals and dropouts.37 The concealment of allocation to treatment was also judged. Two reviewers (MH and MI) assessed the quality of the studies independently. For this review, Jadad scores of ≤2 were considered to be of low quality, scores between 3 to 4 of moderate quality and a score of 5 high quality. d) Data extraction The same two reviewers extracted data from those studies included in the meta-analysis. Discrepancies in data extraction were resolved in the same manner as for article identification. e) Data analysis We used a meta-analytic approach to quantify the clinical outcomes data in the published literature.38 Results were produced for time points that included objective responses at six and 12 months; and overall and progression-free survival rates at one, two, three, four and five years where such data were available. Analyses were based on intent-to-treat (ITT) results. If these were unavailable, the analysis was based on evaluable subjects. We tested the data in each analysis to identify the presence of heterogeneity among the effects being examined and to verify the combination of results. A chi-square test was used to detect statistical differences among rates derived from different studies. As recommended, statistical heterogeneity was defined as a significance level of 10% to account for the test’s low power.39 We also used a random effects model that incorporates any differences into the analysis, thereby adjusting for the heterogeneity of those rates derived from primary research studies. This approach reduced the impact of between-study differences. We calculated absolute risk reduction (ARR) between drugs when results were reported in head-to-head trials. ARR calculations were based on proportions of responders in each group, using the ITT sample size. Head-to-head trials were also contrasted with respect to scores (i.e. objective response rates, survival and progression-free survival) at each interval using a random effects model. The following direct treatment comparators were included (if data were available): Individual LAs, as appropriate, versus alternative therapies including:

• estrogens (DES) • orchiectomy • antiandrogens (AAs) • combination therapy (LAs plus AAs).

12

To calculate the ARR between RCTs, we used the CIA statistical package version 2.0.0 from Altman et al.40 We also calculated 95% CIs for each value.41,42 When the statistical combination of ARRs was possible, we used EasyMA99 to obtain a common risk difference (CRD). This was downloaded from http://www.spc.univ-lyon1.fr/~mcu/easyma/download.htm.

3.2 Results 3.2.1 Quantity and quality of research available

A total of 334 studies of metastatic or locally advanced prostate cancer were identified. After reading the abstracts, we identified 100 articles on locally advanced prostate cancer and 107 on metastatic disease. Of these studies, 98 on locally advanced disease and 93 on metastatic disease were excluded from the analysis. A description of the flow of documents is presented in Figure 1. We were unable to retrieve level I evidence on AAs monotherapy. As a result, AAs were excluded from the analysis. Appendix 2 lists the rejected studies and the reasons for exclusion. As a result, only two studies (2%) were eligible for the meta-analysis of locally advanced prostate cancer with 14 studies (13%) for metastatic prostate cancer. Tables 4 and 5 describe the accepted trials. An overview of the data availability in the included studies is presented in Table 6.

3.2.2 Assessment of studies

a) Locally advanced prostate cancer LA versus LA plus AAs Data were available from two studies, namely, one by Jurinic et al.43 and the other by Tyrrell et al.44-46 Quality assessment revealed that the first study was of low quality, while the second was of moderate quality. Jurinic et al.43 compared goserelin with a combination of goserelin and flutamide in patients with locally advanced prostate cancer. Of the 29 patients diagnosed with locally advanced prostate cancer who entered into the study, 14 were randomized to receive goserelin and 15 to receive goserelin plus flutamide (Table 7). For the objective response outcome, all patients who were intended to be treated could be evaluated throughout the trial. Objective response was measured after six months. No significant difference was observed between goserelin and goserelin plus flutamide groups in objective response [ARR with 95% CI: 7% (-17%; 28%)]. Survival and progression-free survival rates for up to 50 months were available for the 13 patients taking goserelin and the 15 patients on combination therapy (Table 8). No significant difference was observed between goserelin and goserelin plus flutamide groups in the overall survival rates at year 1 [ARR: - 8% (95% CI: -30%; 18%)], year 2 [ARR: -15% (95% CI: -40%; 12%)], year 3 [ARR: - 8% (95% CI: -35%;19%)] and year 4 [ARR: 13% (95% CI: -15%; 45%)]. Similar results were obtained for progression-free survival rates, except in the second year for which a statistically significant difference was observed. ARR with 95% CI for the progression-free survival rate between goserelin and goserelin plus flutamide groups at years 1, 2, 3 and 4 were 7% (-16%, 30%), 27% (1%, 54%), 19% (-7%, 49%) and 11% (-16%, 42%) respectively.

13

Figure 1: Search flowchart

Databases searched: MEDLINE, EMBASE, CANCERLIT,

IPA, Cochrane 1980-2000

Keywords: Euprolide, leuproelin, buserelin, goserelin (and) Prostate cancer (and) clinical trial

33+ Studies

Preselection through reading abstracts Exclusion because: inappropriate research design, comparator, disease condition,

patient population, outcome measurement Considered:

Metastatic: 107, Advanced: 100

Selection through reading articles

Rejected: 191 Included: 16 Total metastatic: 14 Total advanced: 2

Exclusion Mestatic Total excluded: 93

Exclusion Advanced Total excluded: 98

Leuprorelin Metastatic: 3 Advanced: 0

Goserelin Metastatic: 7 Advanced: 2

Buserelin Metastatic: 4 Advanced: 0 Reason for exclusion:

1. Inappropriate research design: 25 2. Inappropriate comparator: 22 3. Inappropriate disease condition: 1 4. Inappropriate patient population: 17 5. Data not extractable/state:18 6. Duplicate data/article: 11

Reason for exclusion: 1. Inappropriate research design: 15 2. Inappropriate comparator: 16 3. Inappropriate disease condition: 1 4. Inappropriate patient population: 405. Data not extractable/state : 17 6. Duplicate data/article: 10

LHRH agonists

14

14

Table 4: Randomized controlled trials in locally advanced prostate cancer

Author Study design Stage Drug and Dosage Age Mean (range)

Goserelin 3.6 mg/28 days 68 (55 to 75) Jurinic et al. 199143

Randomized C, D1

Goserelin 3.6 mg/28 days plus flutamide 250 mg PO tid

67 (54 to 75)

Goserelin 3.6 mg/28 days 73 (50 to 90) Tyrell et al.44-46 Randomized C, D1

Goserelin 3.6 mg/28 days plus flutamide 250 mg PO tid

73 (47 to 91)

PO=per oral; tid=three times per day. Tyrrell et al.44-46 also compared goserelin with a combination of goserelin and flutamide in patients with locally advanced prostate cancer. In this study, 247 patients diagnosed with locally advanced prostate cancer were randomized to receive either goserelin (n=120) or goserelin plus flutamide (n=127, Table 2). Based on the ITT data, no significant difference was observed between goserelin and goserelin plus flutamide groups in the best objective response rates at six months [ARR with 95% CI: 2% (-6%, 10%)]. Also, no significant difference was observed between goserelin and goserelin plus flutamide groups in the overall survival rate for the different assessment periods except in the third year; year 1 [ARR: 0.2% (-8%, 8%)], year 2 [ARR: 0.1% (-10%, 10%)], year 3 [ARR: 32% (20%, 44%)], year 4 [ARR: 0.4% (-12%, 15%)] and year 5 [ARR: 2% (-10%, 15%)]. Progression-free survival rates were not reported for patients with locally advanced prostate cancer separately, but overall progression-free survival rates were available for all types of patients with prostate cancer (including M0 and M1). It was possible to combine the objective response rates (at six months) and the overall survival rates (for the first four years) that were presented in the Jurinic et al. and Tyrell et al. trials. Meta-analytic objective response rates failed to show a statistically significant difference [common ARR: 1% with 95% CI: (-6%, 8%)] between goserelin monotherapy and goserelin plus flutamide combination therapy (Table 9). Statistical heterogeneity was not identified when either the fixed effect or random effects model was used. Similar results were obtained when the overall survival rates were meta-analyzed (Table 10). The common ARR of pooled goserelin versus goserelin plus flutamide data did not reach statistical significance during any of the assessment periods. Statistical heterogeneity was not identified. b) Metastatic prostate cancer Most of the metastatic prostate cancer trials used the NPCP34 criteria, followed by the BPG criteria,35 to evaluate the objective response rates and progression-free survival rates. The European Organisation for Research and Treatment of Cancer (EORTC) genito-urinary group’s criteria were also used to evaluate objective response,36 but none of the trials that met the criteria for inclusion used the EORTC criteria.

15

Table 5: Randomized controlled trials in metastatic prostate cancer

First Author Study Design

Drug Dosage Response Criteria

Leuprolide Study Group,47 1984

Leuprorelin 1 mg/day SC NPCP†

Randomized open

DES 3 mg/day PO Sharifi,48 1985 Leuprolide 1 mg/day SC NPCP†

Randomized controlled trial DES 3 mg/day PO

Navratil,49 1987 Buserelin 0.5 mg/day SC NPCP†

Randomized double-blind Buserelin plus

antiandrogen 0.5 mg/day SC + 300 mg/day

Klioze,50 1988 Randomized Buserelin 1.5 mg SC for 7 days, then 0.2 mg SC, and 1.2 mg IN

NPCP†

Huben,51 1988 Buserelin 1.5 mg SC for 7 days, then 0.2 mg SC, and 1.2 mg IN

NPCP†

Randomized

Orchiectomy-DES 3 mg/day PO Crawford,52 McLeod53 Leuprolide plus

placebo 1 mg/day SC NPCP†

Randomized double-blind

Leuprolide plus nilutamide

1 mg/day SC+ 750 mg/day

Turkes,54 1990 Goserelin 3.6 mg/28 days BPGC*

Orchiectomy

Phase III Randomized Multicentre DES plus

Orchiectomy 3 mg/day PO

The Zoladex Prostate Study Group55,56

Goserelin, 3.6 mg/28 days NPCP†

Randomized

Orchiectomy Citrin,57 1991 Goserelin 3.6 mg/day SC NPCP†

Randomized Multicenter DES 3 mg/day PO

Jurinic,43 1991 Goserelin 3.6 mg/28 days BPGC*

Randomized

Goserelin plus flutamide

3.6 mg + 250 mg PO TID

Kaisary,58 1991 Goserelin 3.6 mg/28 days BPGC* (minor modifications)

Randomized

Orchiectomy Tyrrel,44-46l1991 Goserelin 3.6 mg/28 days Criteria listed

in article

Randomized

Goserelin plus flutamide

3.6 mg + 250 mg PO TID

Bruun,59 1996 Buserelin 1.5 mg/day SC NPCP†

Estrogens 160 mg/month, after 3 months 80 mg/month

Randomized open phase III

Orchiectomy Fontana,60 1998 Goserelin 3.6 mg/28 days Criteria listed

in article

Randomized

Goserelin plus mitomycin C

3.6 mg/28 days + 14 mg/m2 IV/month

DES=diethylstilbestrol; IN=intranasal; IV=intravenous; PO=per oral; SC=subcutaneous; TID=three times per day; *BPGC=British Prostate Group Criteria;35 †NPCP=National Prostatic Cancer Project;34 ‡EORTC genito-urinary group’s criteria36

16

Table 6: Data availability listed by study for objective response, survival, progression-free survival Stage Author Best

Objective Response

Objective Response (months)

Overall Survival (years) Progression-free Survival (years)

Observation period

3 6 12 1 2 3 4 5 1 2 3 4 5

Locally advanced prostate cancer

Jurinic43 - - X - X X X X - X X X X -

Tyrrell44-46 - - X - X X X X X - - - - -Metastatic prostate cancer

Leuprolide Study Group47 X - - - X X - - - - - - - -

Sharifi48 - - X X - - - - - - - - - - Navratil49 X - - - - - - - - X - - - - Klioze50 X - - - X X X - - X X - - - Huben51 - - - - X X - - - X X - - - Crawford,52 McLeod53 X - - - X X X X - X X X X - Turkes54 - X - - - - - - - - - - - -

17 Citrin57 X - - - X X - - - X X - - - Jurinic43 - - X - X X X X - X X X - - Kaisary58 X - - - X X X - - - - - - - Tyrrell45,46 - - X - X X X X X - - - - - The Zoladex Prostate Study

Group55,56 X - - - X X X X X - - - - -

Bruun59 - - X X X - - - - - - - - - Fontana60 - - - - - - - - - X X X X -

-=no data available; X=data available

17

Table 7: Studies included in clinical review of LAs reporting objective response rates for locally advanced prostate cancer

Clinical Outcome§

ITT (%) Study

(year and location)

Design* QualityScore

Modified Quality Score†

Comparators (dose, duration,

route, continuous or intermittent)

Participants‡

(age, stage of PC, co-morbidities

where available)

Total Number

Randomized and

Evaluable

Responders Failure

Response Criteria

Adverse Event Rate

(% ITT)

Jurinic43 (1991, Europe)

Randomized, comparative, open label

2 5 Goserelin 3.6 mg/ 28 day depot SC Goserelin 3.6 mg/ 28 day depot SC and flutamide 250 mg PO TID Mean duration: goserelin 28.5 months (4 to 48); goserelin and flutamide 33 months (11 to 48)

Goserelin: age (mean) 68, range 55 to 75. Goserelin and flutamide: age (mean) 67, range 54 to 75, stage C

Total: 29 and 29. Goserelin: 14 and 14. Goserelin and flutamide: 15 and 15

Goserelin: 13 (93%). Goserelin and flutamide: 15 (100%)


BPGC (six months)


Tyrell44-46 (1991, Europe and South Africa)


3 7 Goserelin 3.6 mg/ 28 day depot SC Goserelin 3.6 mg/ 28 day depot SC and flutamide 250 mg PO TID Median duration for all was two years

Goserelin: age (mean) 72.6, range 50 to 90. Goserelin and flutamide: age (mean) 72.2, range 47 to 91, stage M0




Criteria listed in article (six months)

Total local and metastatic. Goserelin: 18 (6%). Goserelin and flutamide: 69 (24%)

18

DES=diethylstilbestrol; IN=intranasal; SC=subcutaneous; NA=not available; PO=per oral; TID=three times per day; NR=not reported. *For design, specify random allocation, parallel group or cross over, single- or double-blinding, open label. †Modified quality scoring system that includes the Jadad system plus confounders, instrument, power and representativeness. The total possible number of points with this approach is nine as opposed to five with the Jadad scale. ‡For age, specify mean or median and range. §For objective response, specify response criteria.

18

Table 8: Survival data included in clinical review of LHRH agonists for locally advanced prostate cancer

Study (year and location)

Design* Total Number(randomized and

evaluable)

Overall Survival Progression-free Survival

LA versus LA plus AA Jurinic43 (1991, Europe)



Goserelin n=13: 1 year 92%, 2 years 85%, 3 years 85%, 4 years 85%

Goserelin and flutamide n=15: 1 year 100%, 2 years 100%, 3 years 92%, 4 years 70%






Goserelin n=119: 1 year 90%, 2 years 77%, 3 years 64%, 4 years 56%, 5 years 50%

Goserelin and flutamide n=127: 1 year 90%, 2 years 77%, 3 years 68%, 4 years 56%, 5 years 48%

Goserelin NR

Goserelin and flutamide NR

19 *For design, specify random allocation, parallel group or cross over, single- or double-blinding, open label. AA=antiandrogen; LA=LHRH agonist; DES=diethylstilbestrol; NR=not reported.

Table 9: Meta-analytic objective response rates at six months in locally advanced prostate cancer

Study Pooled ARR 95% CI

Heterogeneity

Chi square (Q Cochran)

p Value

Fixed effect 1%

(-6%, 8%) 0.4829, df: 1

0.49 Jurinic43 (1991, Europe) and Tyrell44-46 Random effects

1% (-6%, 8%) 0.1454, df: 1

0.7

ARR=absolute risk reduction; CI=confidence interval; df=degree of freedom.

19

Table 10: Meta-analytic survival rates at years 1, 2, 3 and 4 in patients with locally advanced prostate cancer

Study Year 1 Homogeneity Pooled ARR

(95% CI) (p value)

Year 2 Pooled ARR

(95% CI)

Homogeneity (p value)

Year 3 Pooled ARR

(95% CI)


Year 4 Pooled ARR

(95% CI)


Jurinic43 and Tyrell44-46

Fixed effect -0.6%

(-8%, 6%)

0.2237, df: 1 (0.64)

Fixed effect -2%

(-12%, 7%)

0.9902, df: 1 (0.32)

Fixed effect -4%

(-15%, 6%)

0.1329, df: 1 (0.72)

Fixed effect 2%

(-8%, 14%)

1.0683, df: 1 (0.3)

Randomeffects

0.2237, df: 1

-0.6% (-8%, 6%)

(0.64)

Random effects -2%

(-12%, 7%)

0.9902, df: 1 (0.32)

Random effects -4%

(-15%, 6%)

0.1329, df: 1 (0.72)

Random effects

3% (-9%, 16%)

1.0, df: 1 (0.32)

ARR=absolute risk reduction; CI=confidence interval; df=degree of freedom. 20

20

3.2.3 Clinical outcomes

a) Best objective response LA versus orchiectomy Two studies compared LA (goserelin) treatment with orchiectomy for 641 patients using the best objective response rate as an outcome (Table 11) (Kaisary 1991,58 Zoladex Prostate Study Group).55,56 One study was of moderate quality and one was of low quality. Goserelin showed no advantage over orchiectomy in the meta-analysis of ITT data [ARR with 95% CI: 2% (-5%, 9%)], using both for fixed and random effects models. No significant heterogeneity was observed among the pooled studies (p = 0.42) (Table 12). In one study (Klioze et al., 198850) comparing buserelin and orchiectomy and DES, no significant difference was observed between buserelin and orchiectomy [ARR with 95% CI: -16% (-43%; 1%)]. There were no studies that compared other LA and orchiectomy by using the best objective response as the main endpoint. LA versus estrogens or estrogen analogues Two studies of moderate quality (scores of 3), one comparing goserelin with DES and another comparing leuprolide with DES, used best objective response rate as an outcome (Citrin et al. 1991,57 Leuprolide Study Group 198447). No significant difference was observed between goserelin and DES [ARR with 95% CI: 3% (-2%; 19%)] and between leuprolide and DES [ARR with 95% CI: 0.8% (-9%; 11%)]. In one study (Klioze et al.198850) comparing buserelin to either orchiectomy or DES, no significant difference was observed between buserelin and the comparator groups [ARR, with 95% CI: 2% (-16%; 18%)]. LA monotherapy versus combination of LA plus AA Two studies of high quality (Jadad scores of 5) compared LA monotherapy with LA plus AA combination therapy, using the best objective response rate as an outcome. In one study, a small but statistically significant difference in favour of combination therapy was observed between luprolide monotherapy and luprolide plus flutamide therapy, when ITT data on the objective response rate were compared [ARR: - 9% (-16%, -1%] (McLeod et al.53). In another study comparing buserelin monotherapy to burerelin plus nilutamide, no significant difference was observed between the two treatment groups [ARR: 7% (-18%, 34%)] (Navaratil et al.49). b) Objective response measured at three months LA versus orchiectomy One study (Turkes et al., 198754) of moderate quality (scores of 3) comparing goserelin and orchiectomy reported the objective response rate at three months. Analysis on an ITT basis showed a non-statistically significant difference between the two treatment options [ARR: -0.4% (95% CI: -17%; 8%)]. LA versus DES One study of low quality comparing leuprolide and DES reported objective response data at three, six and 12 months (Sharifi et al., 198548). Analysis on an ITT basis at three months showed no statistically significant difference between leuprolide and DES [ARR: 14% (-15%; 48%)].

21

Table 11: Studies included in clinical review of LAs reporting objective response rates for metastatic prostate cancer

Clinical Outcome§

ITT (%) Study (year and location)

Design* Quality Score

(Jadad)


Comparators (dose, duration, route, continuous or intermittent)

Participants‡

(age, stage of PC, comorbidities where available)

Total Number Randomized and Evaluable

Responders Failure

Response Criteria

Adverse Event Rate

(% ITT) LA versus orchiectomy Kaisary58 (1991, UK, Ireland)

Randomized and comparative open label

2 5 Goserelin 3.6 mg/ 28 day depot SC. Mean duration: goserelin 65.8 weeks, orchiectomy 59.6 weeks

Goserelin: age (mean) 71.8, range 49 to 86. Orchiectomy: age (mean) 72.5 range 55 to 89. Stage D2.

Total 358 and 292. Goserelin 176 and 148. Orchiectomy 182 and 144.

Goserelin 89 (50%). Orchiectomy 94 (52%).

Goserelin 11 (6%). Orchiectomy6 (3%).

BPGC (best objective response)

Goserelin NR. Orchiectomy NR.

Zoladex Prostate Study group55,56 (1995, US) Final esults by Vogelzang et al.55

Randomized and comparative open label

3 7 Goserelin 3.6 mg/ 28 day depot SC (minimum duration 4 years for all patients)

Goserelin: age (mean) 69, range 44 to 95. Orchiectomy: age (mean) 69, range 46 to 92. Stage D2.




NPCP (best objective response)


Turkes54 (1987, UK)

Randomized and comparative, open label

3 6 Goserelin 3.6 mg/ 28 day depot SC (duration until withdrawal)

Goserelin: age (mean) 73, range 55 to 90. Orchiectomy: age (mean) 72, range 49 to 86. Stage D2.




BPGC (at 12 weeks)


22


Goserelin 58 (45%). Orchiectomy53 (47%).


BPGC (at 24 weeks)


LA versus DES Bruun59 (1995, Denmark)

Randomized comparative, open label

3 6 Buserelin 1.5 mg/ day SC for 7 days, then 1.2 mg IN. Estrogens 160 mg/month, after 3 months 80 mg/month. Orchiectomy (duration NR)

Buserelin: age (median) 71.7, range 47 to 91. Estrogens: age (median), range 46 to 92. Stage T2,3,4, Nx, M1.

Total 140 and 106. Buserelin 72 and 56. Estrogens 22 and 16. Orchiectomy 46 and 34.

Buserelin 37 (51%). Estrogens 9 (41%). Orchiectomy 26 (56%).


NPCP (6 months)

Buserelin 5 (7%). Estrogen NR. Orchiectomy NR.

22

Clinical Outcome§



(Jadad)



Participants‡



Responders Failure

Response Criteria

Adverse Event Rate

(% ITT) Total 140 and

78. Buserelin

Buserelin 72 and 40. Estrogens 22 and 12. Orchiectomy 46 and 26.

25 (35%). Estrogens 6 (27%). Orchiectomy 13 (28%).


NPCP (12 months)

Buserelin 5 (7%). Estrogen NR. Orchiectomy NR.

Citrin57 (1991, US)


3 5 Goserelin 3.6 mg/ 28 day depot SC. DES 3 mg/day PO. Median duration: goserelin 95 weeks (27 to 168 weeks); DES 92 weeks (6 to 148 weeks).

Goserelin: age (mean) 70, range 54 to 87. DES: age (mean) 68, range 54 to 83. Stage D2.

Total 67 and 61. Goserelin 48 and 45. DES 19 and 16.

Goserelin 42 (88%). DES 16 (84%).

Goserelin 3 (6%). DES 0 (0%).


Goserelin NR. DES NR.

Leuprolide Study Group47 (1984, Canada and US)


3 6 Leuprolide 1 mg/day depot SC. DES 3 mg/day PO. Median duration: leuprolide 72 weeks (5 to 114); DES 73 weeks (2 to 114).

Leuprolide: age (mean) 69, range 46 to 87. DES: age (mean) 71, range 43 to 96. Stage D2.

Total 186 and 186. Leuprolide 92 and 92. DES 94 and 94.

Leuprolide 79 (86%). DES 80 (85%).

Leuprolide 10 (11%). DES 2 (2%).


Leuprolide 3 (3%). DES 12 (13%).

Sharifi48 (1985, US)


2 4 Leuprolide1 mg/day depot SC. DES 3 mg/day PO. (mean duration NR)

Leuprolide : age (mean) NR, range NR (>50). DES: Age (mean) NR Range NR (>50) Stage D2

Total 25 and 21, 17, 14. Leuprolide 12 and 11, 10. DES 13 and 10, 4.

Leuprolide 10 (83%), 10 (83%), 7 (58%). DES 9 (69%), 7 (54%), 2 (15%).

Leuprolide 1 (8%), 1 (8%), 3 (25%). DES 1 (8%), 1 (8%), 2 (15%).

NPCP (3, 6, 12 months)

Leuprolide 12 (100%). DES 13 (100%).

23

23

Clinical Outcome§



(Jadad)



Participants‡



Responders Failure

Response Criteria

Adverse Event Rate

(% ITT) LA versus DES / orchiectomy Klioze50 (1988, USA║)


2 4 Buserelin 1.5 mg/d SC for 7 days, then either 0.8 mg/day SC or 1.2 mg/day IN. DES 1 mg TID

Stage D2 Total 167 and 160. Buserelin 105 and 90. DES 41 and 32. Orchiectomy 14 and 13.

Buserelin 66 (62.8%). DES 25 (61.0%). Orchiectomy 11 (78.6%).

Buserelin 24 (22.9%). DES 7 (17.1%). Orchiectomy 2 (14.3%).


Beserelin 18 (17.1%). DES 27 (65.9%). Orchiectomy 0 (0%).

Huben51 (1988, US)


2 4 Buserelin 1.5 mg/d SC for 7 days, then either 0.2 mg/day SC or 1.2 mg/day IN. DES 1 mg TID PO. Methotrexate (MTX) 40 mg/m2 IV on day 1, 60 mg/m2 on day 8 and every 14 days thereafter, plus DES 1 mg TID PO or orchiectomy.

Age (mean) NR. Stage D2.

Total 265 and 211. Buserelin 111 and 91. DES-orchiectomy: 56 and 47. MTX+DES-orchiectomy 98 and 73.

Buserelin NR. DES-orchiectomy NR MTX+DES-orchiectomy NR.

Buserelin NR. DES-orchiectomy NR MTX+DES-orchiectomy NR.

NR BuserelinNR. DES-orchiectomy NR. MTX+DES-orchiectomy NR.

LA versus LA plus AA Navratil49 (1987, France)

Randomized, comparative, double-blind

5 7 Buserelin0.5mg/day SC. Buserelin 0.5 mg/day SC and 300 mg/day nilutamide. Duration NR.

Buserelin age (median) 75, range NR. Buserelin and AA: age (median) 72, range NR. Stage D2.

Total 49 and 38. Buserelin 26 and 22. Buserelin and AA 23 and 16.

Buserelin: 12 (46%). Buserelin and AA 9 (39%).

Buserelin: 8 (31%). Buserelin and AA 4 (17%).


Buserelin 13 (50%). Buserelin and AA 17 (74%).

24

24

Clinical Outcome§



(Jadad)



Participants‡



Responders Failure

Response Criteria

Adverse Event Rate

(% ITT) Jurinic43 (1991, Europe)


2 5 Goserelin 3.6 mg/ 28 day depot SC. Goserelin 3.6 mg/ 28 day depot SC and flutamide 250 mg PO TID. Mean duration goserelin 28.5 months (4 to 48) goserelin flutamide 33 months (11 to 48).

Goserelin: age (mean) 68, range 55 to 75. Goserelin and flutamide age (mean) 67, range 54 to 75. Stage D2.

Totall 22 and 22. Goserelin: 11 and 11. Goserelin and flutamide: 11 and 11.

Goserelin 10 (91%). Goserelin and flutamide 11 (100%).

Goserelin 1 (9%) Goserelin and flutamide: 0 (0%).

BPGC (6 months)




3 7 Goserelin 3.6 mg/ 28 day depot SC Goserelin 3.6 mg/ 28 day depot SC and flutamide 250 mg PO TID. Median duration for all was 2 years.

Goserelin: age (mean) 72.6, range NR. Goserelin and flutamide: age (mean) 72.2, range NR. Stage D2.

Total 300 and 289. Goserelin 151 and 146. Goserelin and flutamide 149 and 143.

Goserelin 134 (89%). Goserelin and fllutamide 134 (90%).


Criteria listed in article (6 months).

Total local and metastatic: Goserelin 18 (6%). Goserelin and flutamide 69 (24%).

McLeod53 (1990, US)

Randomized, comparative, double-blind

5 8 Leuprolide 1 mg/day SC. Leuprolide 1 mg/day SC and flutamide 750 mg/day PO. Duration NR.

Leuprolide: age (mean) 68, range 48 to 98. Leuprolide and flutamide: age (mean) 69, range 44 to 86. Stage D2.

Total 603 and 549. Leuprolide 300 and 269. Leuprolide and flutamide 303 and 280.

Leuprolide 95 (32%). Leuprolide and flutamide 122 (40%).

Leuprolide NR. Leuprolide and flutamide NR.


Leuprolide NR. Leuprolide and flutamide

25

25

Clinical Outcome§



(Jadad)



Participants‡



Responders Failure

Response Criteria

Adverse Event Rate

(% ITT) LA versus LA + mitomycin C Fontana60 (1998, Italy)


3 5 Goserelin 3.6 mg/ 28 day depot SC. Goserelin 3.6 mg/ 28 day depot SC and mitomycin C 14 mg/m2 IV/42 days. Median duration for all 47 months

Goserelin: age (mean) 69.3, SD±8.1, range NR. Goserelin and mitomycin C: age (mean) 68.9, SD± 9.3, range NR. Stage D2

Total 63 and 55. Goserelin 30 and 27. Goserelin and mitomycin C 33 and 28.

Goserelin NR. Goserelin and mitomycin C NR.

Goserelin NR. Goserelin and mitomycin C NR.

Criteria listed in article

Goserelin 5 AEs in 3 (10 %) patients. Goserelin and mitomycin C 37 AEs in 19 (58%) patients.

DES=diethylstilbestrol, IN=intranasal, SC=subcutaneous, NA=not available, PO=per oral, TID=three times per day, NR=not reported. *For design, specify random allocation, parallel group or cross over, single- or double-blinding, open label. †Modified quality scoring system includes Jadad system plus confounders, instrument, power, and representativeness. Total possible number of points with this approach is 9, as opposed to 5 with Jadad scale. ‡For age, specify mean or median and range. §For objective response, specify response criteria. 26

║In this trial, patients received either buserelin, DES or orchiectomy (not DES and orchiectomy in combination). ¶For this trial, patients received either DES or bilateral orchiectomy; buserelin; or methotrexate plus DES or orchiectomy.

26

Table 12: Meta-analytic best objective response rates in metastatic prostate cancer comparing goserelin versus orchiectomy

Study Pooled ARR 95% CI Heterogeneity

Chi Square (Q Cochran)

p Value

Fixed effect model

2%

(-5%; 9%)

0.6605, df: 1

0.42

Kaisary et al58 Zoladex Prostate Study Group55,56

Random effects model

2%

(-5%; 9%)

0.6605, df: 1

0.42

ARR=absolute risk reduction, CI=confidence interval, df=degree of freedom. c) Objective response measured at six months LA versus orchiectomy Turkes et al.54 also reported an objective response rate at six months comparing goserelin (ITT: 45%); and orchiectomy (ITT: 47%); Analysis on an ITT basis showed a non-statistically significant difference between the two options [ARR: -2% (95% CI: -15%; 10%)]. A comparison between another LA and orchiectomy was conducted by Bruun et al.59 This investigator compared buserelin (ITT: 51%); with orchiectomy (ITT: 56%). No statistically significant differences between the two approaches were observed, based on an ITT analysis [ARR: 5% (95% CI: -12%; 23%)]. LA versus DES Two studies, one of moderate quality (scores of 3) comparing buserelin and estrogens and another of low quality (scores of 2) comparing leuprolide and DES, reported six months objective response rate data. Based on the ITT data, no statistically significant difference was observed between buserelin and estrogen [ARR with 95% CI: 10% (-10%; 34%)] (Bruun study59). ITT analysis of the objective response rate at six months in the second study, however, showed a statistically significant difference between leuprolide and DES [ARR with 95% CI: 30% (2%, 66%)] (Sharifi et al., 198548). LA versus combination LA plus AA One study (Tyrell et al.44-46) of moderate quality (scores of 3) and another (Jurinic et al.43) of low quality (scores of 2) comparing goserelin monotherapy with goserelin plus flutamide reported objective response rate results at six months. Pooled analysis of the results of these two studies, on an ITT basis, (n=322) showed no significant difference between the two groups [ARR with 95% CI: -2% (-8%, 5%)]. No statistically significant heterogeneity was observed in the pooled analysis (p = 0.77) (Table 13).

27

Table 13: Meta-analytic objective response rates measured at six months in metastatic prostate cancer comparing goserelin versus goserelin plus flutamide

Study Pooled ARR

95% CI

Heterogeneity

Chi Square Cochran Q Test

p Value

Fixed effect model -2%

(-8%; 5%)

0.0884, df: 1

0.77

Jurinic et al,431991 Tyrell et al,44-46 1991

Random effects model -2%

(-8%; 5%)

0.0844, df: 1

0.77

ARR=absolute risk reduction, CI=confidence interval, df=degree of freedom. d) Objective response measured at 12 months LA versus DES Two studies reported 12 months’ results on the objective response rate. One was of low quality (scores of 2, Sharifi et al.48) and the other was of moderate quality (scores of 3, Bruun et al.59). The study by Bruun et al.59 compared buserelin with DES. The objective response rates (ITT) for buserelin was 35% (25/72); and for DES, 27% (6/22). A non-statistically significant ARR of 7% (-11%, 31%) was calculated for this comparison. Sharifi et al.48 reported objective response rates comparing leuprolide with DES. The ITT analysis (n=46) showed that leuprolide has a significant advantage over DES [ARR with 95% CI: 43% (18%; 81%)]. LA versus Orchiectomy Bruun et al.59 compared buserelin with orchiectomy. Objective response rates (ITT) for buserelin was 35% (25/72) and for orchiectomy 28% (13/46). e) Overall survival The individual results per randomized trial reporting survival rates are shown in Table 14. LA versus orchiectomy Three studies compared overall survival rates between LAs and orchiectomy (Table 15). In the two studies on Goserelin, Kaisary et al.58 reported overall survival rates for years 1, 2, and 3 and the Zoladex Prostate Study Group55,56 reported overall survival rates over five years. Meta-analysis of data from the first three years was performed using a random effects model to calculate the risk difference between goserelin and orchiectomy. No statistically significant difference was observed between goserelin and orchiectomy at year 1 [ARR: -8% (95% CI: -23%; 7%)], year 2 [ARR: 2% (95% CI: -6%; 9%)] and year 3 [ARR: 1% (95% CI: -21%; 23%)]. No significant difference was observed between goserelin and orchiectomy in the Zoladex Prostate Study Group55,56 at year 4 [ARR: -2% (95% CI: -15%; 10%)] and year 5 [ARR: -0.3% (95 % CI: -13%; 12%)]. Bruun et al.59 reported overall survival rates for year 1 in a study comparing buserelin and orchiectomy. No significant difference was observed between the two treatments [ARR: 14% (95% CI: -6%; 33%)].

28

Table 14: Survival data included in clinical review of LAs for metastatic prostate cancer


Design* Overall Survival Progression-free Survival

LA versus orchiectomy Kaisary58 (1991, UK, Ireland)


Goserelin n=148: 1 year 77%, 2 years 54%, 3 years 39%

Orchiectomy n=144: 1 year 77%, 2 years 52%, 3 years 27%

Goserelin NR Orchiectomy NR

Zoladex Prostate Study group55,56 (1995, US)



Orchiectomy n=97: 1 year 96%, 2 years 64%, 3 years 48%, 4 years 33%, 5 years 28%

Goserelin NR Orchiectomy NR

Turkes54 (1987, UK) Randomized, comparative, open label

Goserelin NR Orchiectomy NR Goserelin NR Orchiectomy NR

LA versus DES Bruun59 (1995, Denmark)


Buserelin n=40: 1 year 87%

Estrogen n=12: 1 year 74%. Orchiectomy n=26: 1 year 72%

Buserelin NR

Estrogen NR

Citrin57 (1991, US) Randomized, comparative, open label

Goserelin n=48: 1 year 89%, 2 year 63%

DES n=19: 1 year 84%, 2 years 68%

Goserelin n=48: 1 year 58%, 2 years 33%

DES n=19: 1 year 42%, 2 years 37%

Leuprolide Study Group47 (1984, Canada and US)


Leuprolide n=92: 1 year 87%, 2 years 54%

DES n=94: 1 year 78%, 2 years 52%

Leuprolide NR

DES NR

Sharifi48 (1985, US) Randomized, comparative, open label

Leuprolide NR

DES NR

Leuprolide NR

DES NR

LA versus DES plus orchiectomy Klioze50 (1988, US)† Randomized,

comparative, open label

Buserelin 1 year 82%, 2 years 66%, 3 years 43%

DES or orchiectomy 1 year 87%, 2 years 74%, 3 years 57.5%

Buserelin 1 year 53%, 2 years 24%

DES or orchiectomy 1 year 68%, 2 years 37%

29

29



Huben51 (1988, US)† Randomized, comparative, open label


DES-orchiectomy 1 year 85%, 2 years 78%

MTX+DES-orchiectomy 1 year 85%, 2 years 70%


DES-orchiectomy: 1 year 68%, 2 years 40%

MTX plus DES-orchiectomy 1 year 78%, 2 years 53%

LA versus LA plus AA Navratil49 (1987, France) Randomized,

comparative, double-blind

Buserelin NR

Buserelin and AA NR Buserelin n=22: 1 year 48%

Buserelin and AA n=16: 1 year 63%

Jurinic43 (1991, Europe) Randomized, comparative, open label



Goserelin n=11: 1 year 80%, 2 years 48%, 3 years 8%

Goserelin and flutamide n=11: 1 year 100%, 2 years 61%, 3 years 48%




Goserelin and flutamide n=149: 1 year 79%, 2 years 53%, 3 years 40%, 4 years 30%, 5 years 27%

Goserelin NR Goserelin and flutamide NR

McLeod53 (1990, US) Randomized, comparative, double-blind

Leuprolide 1 year 85%, 2 years 58%, 3 years 36%, 4 years 27%

Leuprolide and flutamide 1 year 91%, 2 years 65%, 3 years 48%, 4 years 38%

Leuprolide 1 year 53%, 2 years 34%, 3 years 30%, 4 years 26%

Leuprolide and flutamide: 1 year 63%, 2 years 42%, 3 years 37%, 4 years 33%

LA versus LA plus mitomycin C Fontana60 (1998, Italy) Randomized,

comparative, open-label

Goserelin NR

Goserelin and mitomycin C NR


Goserelin and mitomycin C n=33: 1 year 66%, 2 years 50%, 3 years 34%, 4 years 25%

30

DES=diethylstilbestrol; NR=not reported. *For design, specify random allocation, parallel group or cross over, single- or double-blinding, open label. †In this study, patients received buserelin, DES or orchiectomy (not DES and orchiectomy in combination).

30

Table 15: Meta-analytic survival rates at years 1, 2 and 3 in metastatic prostate cancer patients treated with goserelin compared to orchiectomy

Treatment N (n) Year 1

Rate (95% CI)


Year 2 Rate

(95% CI)


Year 3 Rate

(95% CI)


Goserelin 2 (246) 0.875(0.674 to 1.0)

28.16 (<0.01) 0.538 (0.421 to 0.656)

3.65 (0.056)

0.386 (0.325 to 0.447)

0.05 (0.821)

Orchiectomy 2 (241) 0.867 (0.683 to 1.0)

21.61 (<0.01) 0.577 (0.461 to 0.693)

0.341 (0.065)

0.375 (0.166 to 0.584)

11.57 (<0.01)

OR (LA versus orchiectomy)

1.05(0.62 to 1.76)

0.33 (0.563) 0.86 (0.60 to 1.22)

0.001 (0.955)

1.14 (0.79 to 1.64)

6.60 (0.010)

CI=confidence interval, N=number of studies, n=number of patients, OR=odds ratio for goserelin-orchiectomy.

Table 16: Meta-analytic survival rates at years 1, 2, 3 and 4 in metastatic prostate cancer patients treated with goserelin compared to goserelin plus flutamide

31 Study Pooled ARRYear 1

(95% CI)

Heterogeneity Chi Square

(Q Cochran test) (p value)

Pooled ARR Year 2

(95% CI)


(Q Cochran test)(p value)

Pooled ARR Year 3

(95% CI)


(Q Cochran test)(p value)

Pooled ARR Year 4

(95% CI)


(Q Cochran test) (p value)

Jurinic et al.,43 1991

Fixed effect 5%

(-2%, 13%)

0.9805, df: 1 (0.32)

Fixed effect 1.7%

(-10%, 11%)

7.1606, df: 1 (0.0075)

Fixed effect 0.7%

(-10%, 11%)

0.0013, df: 1 (0.97)

Fixed effect -2%

(-12%, 8%)

1.8582, df: 1 (0.17)

Tyrell et al.,44-46 1991

Random effects 5%

(-2%, 13%)

0.9805, df: 1 (0.32)

Random effects -15%

(-60%, 29%)

1.0, df: 1 (0.32)

Random effects 0.7%

(-10%, 11%)

0.0013, df: 1 (0.97)

Random effects -8%

(-31%, 16%)

1.0000, df: 1 (0.32)

AA=antiandrogens, CI=confidence interval, LA=LHRH agonists, N=number of studies, n=number of patients, OR=odds ratio for LA or LA plus AA.

31

LA versus DES Bruun et al.59 reported overall survival rates for year 1 in a study comparing buserelin and estrogens. No significant difference was observed between the two treatments [ARR: 12% (95% CI: -13%; 31%)]. Citrin et al.57 reported overall survival rates over two years in a study comparing goserelin and DES. No significant difference was observed between goserelin and DES at year 1 [(ARR: 5% (95% CI: -17%; 21%)] and year 2 [(ARR: -6% (95 % CI: -16%; 31%)] survival rates. The Leuprolide Study Group47 reported overall survival rates over two years comparing leuprolide and DES. No significant difference was observed between leuprolide and DES at year 1 [(ARR: 9% (95% CI: -2%; 20%)] and year 2 [(ARR: 2% (95% CI: -12%; 16%)] survival rates. Klioze et al.50 compared buserelin and DES-orchiectomy, with the overall survival rates being reported over three years. No significant difference was observed between buserelin and DES-orchiectomy for the first two years [year 1 ARR: -5% (95% CI: -18%; 5%) and year 2 ARR: -9% (95% CI: -24%; 5%)]. Statistical significance in favour of DES-orchiectomy was observed after three years of treatment [ARR: -15% (95% CI: -32%; -0.2%)]. Huben et al.51 reported overall survival rates over two years in a study comparing buserelin and DES-orchiectomy. No significant difference was observed between buserelin and DES-orchiectomy at year 1 [ARR: -3% (95% CI: -16%; 8%)] and year 2 [ARR: -7% (95% CI: -22%; 5%)]. Sharifi et al.48 reported no overall survival rates. LA versus combination LA plus AA In the study by Jurinic et al.43 the overall survival rates were reported over four years. Tyrrell et al.44-46 reported overall survival rates over five years in a comparison of goserelin monotherapy versus goserelin plus flutamide therapy. Meta-analysis of the one-, two-, three- and four-year data from these studies was performed to calculate the common risk difference between the two interventions. No statistically significant differences were identified between goserelin monotherapy and combination therapy with flutamide [pooled ARR with the 95% CI for year 1: 5% (-2%, 13%); year 2: 0.2% (-10%, 10%); year 3: 0.7% (-10%, 11%); and year 4: -2% (-12%, 8%)]. Table 16 presents fixed and random effects results. Statistical heterogeneity was observed for year 2. Tyrrell et al.44-46 reported overall survival at year 5 and showed a borderline statistically significant difference between goserelin monotherapy and goserelin plus flutamide therapy after five years of treatment [ARR: -10% (95% CI: -19%; -0.4%)].

In the study by Crawford et al.53,61-63 comparing leuprolide monotherapy to leuprolide plus flutamide combination therapy, the overall survival rates were reported over four years. The leuprolide plus flutamide combination showed a statistically significant difference compared with leuprolide monotherapy at year 1 [ARR: -6% (95% CI: -11%, -1%)], year 3 [ARR: -12% (95% CI: -20%, -4%)] and year 4 [ARR: 95% CI: -11% (-18%, -4%)]. There was no statistically significant difference at year 2 [ARR: -7% (95% CI: -15%, 1%)]. Navratil et al.49 and Fontana60 reported no overall survival data.

32

f) Progression-free survival LA versus orchiectomy Kaisary et al.,58 The Zoladex Prostate Study group55,56 and Turkes et al.54 reported no progression-free survival rates. LA versus DES Citrin et al.57 reported progression-free survival rates over two years. No statistically significant difference was observed between goserelin and DES at year 1 [ARR: 18% (95% CI: -4%; 44%)] and at year 2 [ARR: 95% CI: -4% (-26%, 22%)]. Klioze et al.50 compared buserelin and DES-orchiectomy. The progression-free survival rates were reported over two years. No statistically significant difference was observed between buserelin and DES-orchiectomy at 1 year [ARR with 95% CI: -14% (-30%, 0.5%)] and year 2 [ARR with 95% CI: -13% (-27%, 3%)]. Huben et al.51 reported progression-free survival rates over two years. Buserelin was found to be less effective than DES-orchiectomy in avoiding progression of the disease after the first year of treatment [ARR with 95% CI: -16% (-32%, -2%)]. No statistically significant difference was observed between the two groups after two years of treatment [ARR: -12% (95% CI: -27%, 3%)]. Sharifi et al.,48 Bruun et al.59 and Leuprolide Study Group47 reported no progression-free survival rates. LA versus combination LA plus AA In the Navratil et al.49 study, no statistically significant difference was observed between buserelin monotherapy and buserelin plus AA therapy in progression-free survival rates at year 1 [ARR: -12% (95% CI: -43%; 15%)]. In the study by Jurinic et al.,43 statistically significant differences between goserelin monotherapy and goserelin plus flutamide therapy were observed at year 1 [ARR: -18% (95% CI: -47%; -11%)] and year 3 [ARR: - 36% (95% CI: -74%; -9%)]. No statistically significant difference was observed at year 2 [ARR: -18% (95% CI: -57%; 14%)]. In their study, Crawford et al.53,61-63 compared leuprolide monotherapy to leuprolide plus flutamide therapy. The progression-free survival rates were reported over four years. Statistically significant differences were observed at year 1 [ARR: -10% (95% CI: -18%; -2%)], year 2 [ARR: - 8% (95% CI: -16%; -0.3%)] and year 4 [ARR: -7% (95% CI: -14%; -0.1%)]. No statistically significant difference was observed at year 3 [ARR: -7% (95% CI: -14%; 1%)]. Navratil et al.49 and Tyrrell et al.44-46 reported no overall survival data. LA versus LA plus chemotherapy Fontana et al.60 reported progression-free survival rates over four years. No significant difference was observed between goserelin monotherapy and goserelin plus mitomycin C therapy at year 1 [ARR: 7% (95% CI: -14%; 29%)], year 2 [ARR: -8% (95% CI: -32%; 14%)], year 3 [ARR: 95% CI: -7% (-29%, 14%)] and year 4 [ARR: 2% (95% CI: -23%; 19%)].

33

4 DISCUSSION

4.1 Review of Clinical Evidence Despite a large volume of literature on the topic, we were able to include only a small number of RCTs. One reason was that several trials included both metastatic and locally advanced cancers. In those studies, data were combined; there was no differentiation in the outcome assessment between the two patient subgroups (Table 17). As a result, we could not extract useful data. In addition, studies that included treatment with concurrent or post-radiotherapy were excluded, as the focus was on pharmacological treatments alone or in combination with other pharmaco-logical options. Meta-analytic results were only available for a few studies, so we were unable to identify differences between the treatments for most outcomes. The response assessment scales (mainly the BPG35 and the NPCP34 criteria) used to evaluate the objective response rates varied across the studies. Their equivalence has been controversial.64,65 Furthermore, the trials included in our analysis were not published over a long period. Consequently, the researchers in the trials may have used different testing procedures that may have contributed to differences in stage migration. For example, because of PSA testing, we can now detect advanced prostate cancer in its earlier stages. Patients in earlier trials who were diagnosed with advanced prostate cancer could have been of a later stage of metastatic disease and consequently, had different life expectancies. Also, the method used for detecting stage and diagnosis at the time that some studies were performed could not differentiate between early stage and late stage metastatic prostate cancer. This could have been the source of statistical heterogeneity with pooled estimates. Such heterogeneity, however, was only identified for a limited number of comparisons. In addition, because there was a lack of evidence for intermittent combined androgen blockade, there was no meaningful result. Intermittent therapy is being studied in phase III trials of metastatic prostate cancer. Further research may provide evidence about possible outcomes and the cost advantages of intermittent therapy. Another limitation is the fact that a small number of confounding factors were identified. This may affect our results. For example, in the study by Bruun et al.,59 cyproterone was started five days before the treatment with buserelin and continued for 28 days to avoid possible tumour exacerbation. It is difficult to assess to what extent this initial therapy may have contributed to the outcomes evaluated at six and 12 months. In our analysis, we considered any potential effect from this initial approach to be negligible. In the study by Klioze et al.,50 which evaluated buserelin, all subjects on the comparator intervention were either assigned to DES or to orchiectomy, based on whether patients were healthy enough to receive DES. In our review, all outcomes associated with the comparator intervention were analyzed as DES, since it was impossible to extract specific numbers for separate treatments.

34

Table 17: List of studies on mixed patient groups with advanced prostate cancer

Author Study Design Stage of Disease Drug and Dosage Mean Age Median Age Boccardo et al.66,67 Randomized D Goserelin 3.6 mg/28 days NA 74 (49 to 86) Goserelin 3.6 mg plus flutamide

250 mg PO TID NA 73 (48 to 88)

Di Silverio et al.68 Randomized Advanced withbone metastases

Goserelin 3.6 mg/28 days 71 NA

Multicentre Goserelin 3.6 mg/28 days plus cyproterone acetate +200 mg/day PO

71 NA

Fourcade et al.69 DB RCT, placebo controlled

Advanced with M1 and M0

Goserelin 3.6 mg/28 days plus placebo

74.4 (54 to 95)

NA

Multicentre Goserelin 3.6 mg/28 days plus flutamide 750 mg/day PO

73.5 (51 to 90)

NA

Schulze et al.70 Randomized Advanced Goserelin 3.6 mg/28 days 71.8 (51 to 84)

NA

Multicenter Orchiectomy 70.3 NA (52 to 85)

Goserelin 3.6 mg plus flutamide 50 mg PO TID

70.2 (51 to 85)

NA

Orchiectomy Plus flutamide 250 mg PO TID

72.7 (57 to 85)

NA

Waymont et al.71 Randomized Advanced andmetastatic

Goserelin 3.6 mg/28 days NA 72.4 (45 to 87)

Phase III DES 3 mg/day PO NA 72.6 (52 to 93) Akaza et al.72 Randomized B, C, D Leuprolide 3.75 mg/28 days, NA NA Leuprolide 7.5 mg/28 days NA NA Rizzo et al.73 Leuprolide 3.75 mg SC/28 days NA 68.5 (52 to 86)

Randomized Phase II Leuprolide 7.5 mg NA 67 (52 to 86)

35

C, D1, D2

Leuprolide 15 mg NA 71.5 (52 to 86) Leuprolide 30 mg NA 61

35

Author Study Design Stage of Disease Drug and Dosage Mean Age Median Age Ferrari et al.74 Buserelin 1.5 mg SC for 7 days,

then 1.2 mg IN 71.6 NA

Randomized M1, D1, D2

Buserelin as above plus 750 mg flutamide

68.7 NA

Thorpe et al.75 Goserelin 3.6 mg/28 days 70 (47 to 88)

NA

Cyproteroneacetate;

100 mg TID 72 (39 to 88)

NA

Randomized prospective

C, D1, D2

Combination 7-day cyproterone acetate pretreatment, rest depot goserelin

71 (46 to 87)

NA

Wechsel et al.76 Leuprolide 3.75 mg SC/28 days 70.3 NA

Phase II multicenter trial 1:2 randomized, 9 months

C, D1, D2

Leuprolide 11.25 mg/3 months 74.4 NA

Parmar et al.77 Leuprolide 0.1 mg/day slow release 72.3 (51 to 87)

NA

Open randomized

Advanced with bone metastases

Orchiectomy 75.8(60 to 84)

NA

36

DES=diethylstilbestrol; IN=intranasal; IV=intravenous; NA=not available PO=per oral; SC=subcutaneous; TID=three times per day

36

The use of large databases based on information about patients over time is preferable for the examination of ADR rates and severity. Furthermore, there is a need for more disease-specific categorization in trials regarding new drugs and standard therapy and for more high-quality RCTs.

4.2 Other Review Studies Four quantitative reviews evaluating LAs in advanced prostate cancer were identified.21,27,78,79 The Prostate Cancer Trialists’ Collaborative Group performed a meta-analysis of RCTs on maximum androgen blockade (MAB).79 The trials included in that meta-analysis compared conventional castration (surgical or medical) with MAB (castration plus prolonged use of an AA). The comparison of interest in the meta-analysis was that between LA and the combination of LA plus AA. The authors found no significant difference (p=0.09) between the death rates in the LA group (50.1%) versus LA plus AA group (48.1%).79 Although we found no difference in survival rates between the two treatment strategies for locally advanced disease, we did identify some differences for metastatic cancer. Seidenfeld et al.21 compared LAs to orchiectomy or DES and compared AAs with any of the three alternatives. Their outcomes of interest were cancer-specific and progression-free survival, time to treatment failure, adverse effects and quality of life. They reported that of the nine trials that compared an LA to orchiectomy or DES, none found a significant difference in survival rates.21 Four of the five trials comparing LAs to orchiectomy or DES found no significant differences in progression-related outcomes. One trial favoured the DES and orchiectomy control arm (p<0.05). There were no significant differences in time to treatment failure in trials that compared an LA to orchiectomy or DES. Furthermore, the authors reported that there was no difference in overall survival among the LAs, although the 95% CIs were wider for leuprolide [hazard ratio: 1.09 (95% CI, 0.21 to 5.84)] and buserelin [1.13 (0.53 to 2.40)] than for goserelin [1.12 (0.89 to 1.39)]. De Voogt et al. pooled data on the efficacy of buserelin in 1,522 patients with stage D1 and D2 prostate cancer. The authors concluded that as it seemed to give equivalent results to orchiectomy in terms of progression-free and overall survival (no significance of data was reported), buserelin may be regarded as standard therapy for patients with advanced prostatic cancer.78 Alloul et al.27 claimed in their study that buserelin was the most cost-effective treatment alternative.27,28 The critical errors identified in that study rendered its conclusions invalid. LAs are associated with hot flashes, atrophy of reproductive organs, loss of libido, gynecomastia and impotence.13,19,20 This meta-analysis, however, does not report rates of adverse drug reactions (ADRs), because no serious ADRs could be identified for the LAs. The clinical experts on this project agreed that differences between drugs in this respect are minimal. The estrogens are the only class in which serious ADRs are apparent. Complications associated with DES therapy include salt and water retention, gynecomastia, breast tenderness, nausea, thromboembolic events, loss of libido, impotence and an increased incidence of cardiovascular disease.13 Due to the improved toxicity profiles of newer drugs, DES is rarely used.16 In addition

37

to the usual side effects of androgen withdrawal therapy, DES causes a significant increase in the risk of cardiovascular events (including myocardial infarction), cerebrovascular events and pulmonary emboli.16

4.3 Economic Component An economic evaluation was planned for this project, but because of insufficient clinical data, the results are unavailable. Appendix 4 contains components of an evaluation that could be used in a future economic analysis. Appendix 4 describes a potential economic model and some of the costs associated with the treatment of locally advanced and metastatic prostate cancer. Probabilities for the transitions between health states would need to be derived for the model.

38

5 CONCLUSIONS In the treatment of locally advanced prostate cancer, it was impossible to compare LA to treatment modalities other than the LA plus AA combination. No statistically significant differences in objective response rates, overall survival rates, or progression-free survival rates were found for this comparison. However, evidence was limited to two studies, including one of small sample size. Accordingly, our findings should be interpreted with caution. There is a need for more research in this area. For metastatic prostate cancer, the body of evidence was larger, but still limited. Statistically significant results were observed for a limited number of outcomes and comparisons. Although a possible advantage of LA was identified in the objective response rates, when compared to DES therapy, no overall or progression-free survival advantage was found. The only treatment strategy with a potential advantage over LA monotherapy was combination therapy with AA. This included a possible survival benefit. Such an advantage, however, was not identified for all periods and for all LAs. In addition, the magnitude of reported differences varied. Accordingly, our findings regarding metastatic disease should be interpreted with caution. The objective of this report was to review the clinical evidence on LA-based pharmacotherapy in advanced prostate cancer. The evidence used for this review was published between 1980 and 2000. Recent evidence suggests that there is a shift towards using LAs as adjuvant therapy, i.e. in combination with radiotherapy or surgery. However such an assessment was beyond the scope of this review.

39

6 REFERENCES 1. Cersosimo RJ, Carr D. Prostate cancer: current and evolving strategies. Am J Health Syst Pharm

1996;53(4):381-96.

2. Middleton RG, Thompson IM, Austenfeld MS, Cooner WH, Correa RJ, Gibbons RP, et al. Prostate Cancer Clinical Guidelines Panel Summary report on the management of clinically localized prostate cancer. The American Urological Association. J Urol 1995;154(6):2144-8.

3. National Cancer Institute of Canada, Canadian Cancer Society. Canadian cancer statistics 2003. Toronto: The Society; 2003. Available: http://www.cancer.ca/vgn/images/portal/cit_776/61/38/56158640niw_stats_en.pdf.

4. Levy IG, Iscoe NA, Klotz LH. Prostate cancer: 1. The descriptive epidemiology in Canada. CMAJ 1998;159(5):509-13.

5. Goldenberg SL, Ramsey EW, Jewett MA. Prostate cancer: 6. Surgical treatment of localized disease. CMAJ 1998;159(10):1265-71.

6. Meyer F, Fradet Y. Prostate cancer: 4. Screening. CMAJ 1998;159(8):968-72.

7. Nam RK, Jewett MA, Krahn MD. Prostate cancer: 2. Natural history. CMAJ 1998;159(6):685-91.

8. Warde P, Catton C, Gospodarowicz MK. Prostate cancer: 7. Radiation therapy for localized disease. CMAJ 1998;159(11):1381-8.

9. American Joint Committee on Cancer. Manual for staging of cancer. 4th ed. Philadelphia: J.B. Lippincott Company; 1992.

10. Prout GR. Proceedings: Diagnosis and staging of prostatic carcinoma. Cancer 1973;32(5):1096-103.

11. Watson R, Soloway MS. Is there a role for induction androgen deprivation prior to radical prostatectomy? Hematol Oncol Clin North Am 1996;10(3):627-41.

12. Gleave ME, Bruchovsky N, Moore MJ, Venner P. Prostate cancer: 9. Treatment of advanced disease. CMAJ 1999;160(2):225-32.

13. Gudziak MR, Smith AY. Hormonal therapy for stage D cancer of the prostate. West J Med 1994;160(4):351-9.

14. Denis L, Smith PH, De Moura JL, Newling DW, Bono A, Keuppens F, et al. Orchidectomy vs. Zoladex plus flutamide in patients with metastatic prostate cancer. The EORTC GU Group. Eur Urol 1990;18 Suppl 3:34-40.

15. Iversen P, Christensen MG, Friis E, Hornbol P, Hvidt V, Iversen HG, et al. A phase III trial of zoladex and flutamide versus orchiectomy in the treatment of patients with advanced carcinoma of the prostate. Cancer 1990;66(5 Suppl):1058-66.

16. Taub M, Begas A, Love N. Advanced prostate cancer. Endocrine therapies and palliative measures. Postgrad Med 1996;100(3):139-40, 143-6, 152.

17. Iversen P, Tveter K, Varenhorst E. Randomised study of Casodex 50 MG monotherapy vs orchidectomy in the treatment of metastatic prostate cancer. The Scandinavian Casodex Cooperative Group. Scand J Urol Nephrol 1996;30(2):93-8.

40

18. Kirby RS. Recent advances in the medical management of prostate cancer. Br J Clin Pract 1996;50(2):88-93.

19. Altwein JE. The combination of LH-RH analogues with other treatment modalities in prostate cancer. Recent Results Cancer Res 2000;153:71-81.

20. McLeod DG, Crawford ED, DeAntoni EP. Combined androgen blockade: the gold standard for metastatic prostate cancer. Eur Urol 1997;32 Suppl 3:70-7.

21. Seidenfeld J, Samson DJ, Hasselblad V, Aronson N, Albertsen PC, Bennett CL, et al. Single-therapy androgen suppression in men with advanced prostate cancer: a systematic review and meta-analysis. Ann Intern Med 2000;132(7):566-77.

22. Labrie F, Belanger A, Simard J, Labrie C, Dupont A. Combination therapy for prostate cancer. Endocrine and biologic basis of its choice as new standard first-line therapy. Cancer 1993;71(3 Suppl):1059-67.

23. Grover SA, Zowall H, Coupal L, Krahn MD. Prostate cancer: 12. The economic burden. CMAJ 1999;160(5):685-90.

24. Denmeade SR, Isaacs JT. Prostate cancer: where are we and where are we going? Br J Urol 1997;79 Suppl 1:2-7.

25. To T, Iscoe N, Klotz L, Naylor CD. Orchidectomy and hormonal therapy of prostate cancer. Can J Urol 1995;2(1):109-15.

26. Iskedjian M, Einarson TR. Impact of leuteinizing hormone releasing hormone agonists on the cytostatic drug market in Canada 1985-2000. Pharmacoepidemiol Drug Saf 2001;10 (Suppl 1):S136-S137.

27. Alloul K, Sauriol L, Lafortune L. Meta-analysis and economic evaluation of LH-RH agonists' depot formulations in advanced prostatic carcinoma. Can J Urol 1998;5(3):585-94.

28. Alloul K. Reply by author, Re: Meta-analysis and economic evaluation of LH-RH agonists' depot formulations in advanced prostatic carcinoma. Can J Urol 1998;5(5):668.

29. Oh PI, Manzi P, Parison D. Re: Meta-analysis and economic evaluation of LH-RH agonists' depot formulations in advanced prostatic carcinoma. Can J Urol 1998;5(5):664.

30. Einarson TR, Yannicelli D. Re: Meta-analysis and economic evaluation of LH-RH agonists' depot formulations in advanced prostatic carcinoma. Can J Urol 1998;5(5):666.

31. Goel V. Reply by editor, Re: Meta-analysis and economic evaluation of LH-RH agonists' depot formulations in advanced prostatic carcinoma. Can J Urol 1998;5(5):671.

32. Nygard R, Norum J, Due J. Goserelin (Zoladex) or orchiectomy in metastatic prostate cancer? A quality of life and cost-effectiveness analysis. Anticancer Res 2001;21(1B):781-8.

33. Bayoumi AM, Brown AD, Garber AM. Cost-effectiveness of androgen suppression therapies in advanced prostate cancer. J Natl Cancer Inst 2000;92(21):1731-9.

34. Murphy GP, Slack NH. Response criteria for the prostate of the USA National Prostatic Cancer Project. Prostate 1980;1(3):375-82.

35. Chisholm CD, editor. Urology [Tutorials in postgraduate medicine]. London: Heinemann Medical Books; 1980.

41

36. Schroeder FH. Treatment response criteria for prostatic cancer. Prostate 1984;5(2):181-91.

37. Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 1996;17(1):1-12.

38. Einarson TR, Leeder JS, Koren G. A method for meta-analysis of epidemiological studies. Drug Intell Clin Pharm 1988;22(10):813-24.

39. Petitti DB. Approaches to heterogeneity in meta-analysis. Stat Med 2001;20(23):3625-33.

40. Altman DG, Machin D, Bryant TN, Gardner MJ, editors. Statistics with confidence: confidence intervals and statistical guidelines. 2nd ed. [London]: BMJ Books; 2000.

41. Altman DG. Confidence intervals for the number needed to treat. BMJ 1998;317(7168):1309-12.

42. Barrowman NJ. Missing the point (estimate)? Confidence intervals for the number needed to treat. CMAJ 2002;166(13):1676-7.

43. Jurinic CD, Horlbeck R, Klippel KF. Combined treatment (goserelin plus flutamide) versus monotherapy (goserelin alone) in advanced prostate cancer: a randomized study. Semin Oncol 1991;18(5 Suppl 6):21-5.

44. Tyrrell CJ, Altwein JE, Klippel F, Varenhorst E, Lunglmayr G, Boccardo F, et al. Multicenter randomized trial comparing Zoladex with Zoladex plus flutamide in the treatment of advanced prostate cancer. Survival update. International Prostate Cancer Study Group. Cancer 1993;72(12 Suppl):3878-9.

45. Tyrrell CJ, Altwein JE, Klippel F, Jurincic-Winkler C, Varenhorst E, Lunglmayr G, et al. Comparison of an LH-RH analogue (Goeserelin acetate, 'Zoladex') with combined androgen blockade in advanced prostate cancer: final survival results of an international multicentre randomized-trial. International Prostate Cancer Study Group. Eur Urol 2000;37(2):205-11.

46. Tyrrell CJ, Altwein JE, Klippel F, Varenhorst E, Lunglmayr G, Boccardo F, et al. A multicenter randomized trial comparing the luteinizing hormone-releasing hormone analogue goserelin acetate alone and with flutamide in the treatment of advanced prostate cancer. The International Prostate Cancer Study Group. J Urol 1991;146(5):1321-6.

47. Leuprolide versus diethylstilbestrol for metastatic prostate cancer. The Leuprolide Study Group. N Engl J Med 1984;311(20):1281-6.

48. Sharifi R, Lee M, Ojeda L, Ray P, Stobnicki M, Guinan P. Comparison of leuprolide and diethylstilbestrol for stage D2 adenocarcinoma of prostate. Urology 1985;26(2):117-24.

49. Navratil H. Double-blind study of Anandron versus placebo in stage D2 prostate cancer patients receiving buserelin. Results on 49 cases from a multicentre study. Prog Clin Biol Res 1987;243A:401-10.

50. Klioze SS, Miller MF, Spiro TP. A randomized, comparative study of buserelin with DES/orchiectomy in the treatment of stage D2 prostatic cancer patients. Am J Clin Oncol 1988;11 Suppl 2:S176-82.

51. Huben RP, Murphy GP. A comparison of diethylstilbestrol or orchiectomy with buserelin and with methotrexate plus diethylstilbestrol or orchiectomy in newly diagnosed patients with clinical stage D2 cancer of the prostate. Cancer 1988;62(9):1881-7.

52. Crawford ED, Goodman P, Blumenstein B. Combined androgen blockade: leuprolide and flutamide versus leuprolide and placebo. Semin Urol 1990;8(3):154-8.

42

53. McLeod DG, Benson RC, Jr., Eisenberger MA, Crawford ED, Blumenstein BA, Spicer D, et al. The use of flutamide in hormone-refractory metastatic prostate cancer. Cancer 1993;72(12 Suppl):3870-3.

54. Turkes AO, Peeling WB, Griffiths K. Treatment of patients with advanced cancer of the prostate: phase III trial, zoladex against castration; a study of the British Prostate Group. J Steroid Biochem 1987;27(1-3):543-9.

55. Vogelzang NJ, Chodak GW, Soloway MS, Block NL, Schellhammer PF, Smith JA, et al. Goserelin versus orchiectomy in the treatment of advanced prostate cancer: final results of a randomized trial. Zoladex Prostate Study Group. Urology 1995;46(2):220-6.

56. Soloway MS, Chodak G, Vogelzang NJ, Block NL, Schellhammer PF, Smith JA, et al. Zoladex versus orchiectomy in treatment of advanced prostate cancer: a randomized trial. Zoladex Prostate Study Group. Urology 1991;37(1):46-51.

57. Citrin DL, Resnick MI, Guinan P, al Bussam N, Scott M, Gau TC, et al. A comparison of Zoladex and DES in the treatment of advanced prostate cancer: results of a randomized, multicenter trial. Prostate 1991;18(2):139-46.

58. Kaisary AV, Tyrrell CJ, Peeling WB, Griffiths K. Comparison of LHRH analogue (Zoladex) with orchiectomy in patients with metastatic prostatic carcinoma. Br J Urol 1991;67(5):502-8.

59. Bruun E, Frimodt-Moller C. The effect of Buserelin versus conventional antiandrogenic treatment in patients with T2-4NXM1 prostatic cancer. A prospective, randomized multicentre phase III trial. The "Danish Buserelin Study Group". Scand J Urol Nephrol 1996;30(4):291-7.

60. Fontana D, Bertetto O, Fasolis G, Berruti A, Tarabuzzi R, Pagani G, et al. Randomized comparison of goserelin acetate versus mitomycin C plus goserelin acetate in previously untreated prostate cancer patients with bone metastases. Tumori 1998;84(1):39-44.

61. Crawford ED. Combination studies with leuprolide. Eur Urol 1990;18 Suppl 3:30-3.

62. Crawford ED, Blumenstein BA, Goodman PJ, Davis MA, Eisenberger MA, McLeod DG, et al. Leuprolide with and without flutamide in advanced prostate cancer. Cancer 1990;66(5 Suppl):1039-44.

63. Crawford ED, Eisenberger MA, McLeod DG, Spaulding JT, Benson R, Dorr FA, et al. A controlled trial of leuprolide with and without flutamide in prostatic carcinoma. N Engl J Med 1989;321(7):419-24.

64. Citrin DL, Elson P, DeWys WD. Treatment of metastatic prostate cancer. An analysis of response criteria in patients with measurable soft tissue disease. Cancer 1984;54(1):13-7.

65. Emtage LA, Perren TJ, Stuart NS, Arkell DG, Wallace DM, Hughes MA, et al. Phase II study of Zoladex depot in advanced prostatic cancer with special reference to criteria of response and survival. Br J Urol 1987;60(5):436-42.

66. Boccardo F, Decensi A, Guarneri D, Rubagotti A, Oneto F, Martorana G, et al. Zoladex with or without flutamide in the treatment of locally advanced or metastatic prostate cancer: interim analysis of an ongoing PONCAP study. Italian Prostatic Cancer Project (PONCAP). Eur Urol 1990;18 Suppl 3:48-53.

67. Boccardo F, Pace M, Rubagotti A, Guarneri D, Decensi A, Oneto F, et al. Goserelin acetate with or without flutamide in the treatment of patients with locally advanced or metastatic prostate cancer. The Italian Prostatic Cancer Project (PONCAP) Study Group. Eur J Cancer 1993;29A(8):1088-93.

68. Di Silverio F, Serio M, D'Eramo G, Sciarra F. Zoladex vs. Zoladex plus cyproterone acetate in the treatment of advanced prostatic cancer: a multicenter Italian study. Eur Urol 1990;18 Suppl 3:54-61.

43

69. Fourcade RO, Cariou G, Coloby P, Colombel P, Coulange C, Grise P, et al. Total androgen blockade with Zoladex plus flutamide vs. Zoladex alone in advanced prostatic carcinoma: interim report of a multicenter, double-blind, placebo-controlled study. Eur Urol 1990;18 Suppl 3:45-7.

70. Schulze H, Kaldenhoff H, Senge T. Evaluation of total versus partial androgen blockade in the treatment of advanced prostatic cancer. Urol Int 1988;43(4):193-7.

71. Waymont B, Lynch TH, Dunn JA, Emtage LA, Arkell DG, Wallace DM, et al. Phase III randomised study of zoladex versus stilboestrol in the treatment of advanced prostate cancer. Br J Urol 1992;69(6):614-20.

72. Akaza H, Aso Y, Koiso K, Fuse H, Isurugi K, Okada K, et al. Leuprorelin acetate depot: results of a multicentre Japanese trial. TAP-144-SR Study Group. J Int Med Res 1990;18 Suppl 1:90-102.

73. Rizzo M, Mazzei T, Mini E, Bartoletti R, Periti P. Leuprorelin acetate depot in advanced prostatic cancer: a phase II multicentre trial. J Int Med Res 1990;18 Suppl 1:114-25.

74. Ferrari P, Castagnetti G, Ferrari G, Pollastri CA, Tavoni F, Dotti A. Combination treatment in M1 prostate cancer. Cancer 1993;72(12 Suppl):3880-5.

75. Thorpe SC, Azmatullah S, Fellows GJ, Gingell JC, O'Boyle PJ. A prospective, randomised study to compare goserelin acetate (Zoladex) versus cyproterone acetate (Cyprostat) versus a combination of the two in the treatment of metastatic prostatic carcinoma. Eur Urol 1996;29(1):47-54.

76. Wechsel HW, Zerbib M, Pagano F, Coptcoat MJ. Randomized open labelled comparative study of the efficacy, safety and tolerability of leuprorelin acetate 1M and 3M depot in patients with advanced prostatic cancer. Eur Urol 1996;30 Suppl 1:7-14.

77. Parmar H, Phillips RH, Lightman SL, Edwards L, Allen L, Schally AV. Randomised controlled study of orchidectomy vs long-acting D-Trp-6-LHRH microcapsules in advanced prostatic carcinoma. Lancet 1985;2(8466):1201-5.

78. de Voogt HJ, Adenauer H, Widdra WG. The use of the LHRH-analogue Buserelin in the treatment of prostatic cancer. A 10-year review on 1522 patients treated in 119 centres on 4 continents. Scand J Urol Nephrol Suppl 1991;138:131-6.

79. Maximum androgen blockade in advanced prostate cancer: an overview of 22 randomised trials with 3283 deaths in 5710 patients. Prostate Cancer Trialists' Collaborative Group. Lancet 1995;346(8970):265-9.

80. Bischoff W. 3.75 and 7.5 mg leuprorelin acetate depot in the treatment of advanced prostatic cancer: preliminary report. German Leuprorelin Study Group. J Int Med Res 1990;18 Suppl 1:103-13.

81. Crook JM, Szumacher E, Malone S, Huan S, Segal R. Intermittent androgen suppression in the management of prostate cancer. Urology 1999;53(3):530-4.

82. Kienle E, Lubben G. Efficacy and safety of leuprorelin acetate depot for prostate cancer. The German Leuprorelin Study Group. Urol Int 1996;56 Suppl 1:23-30.

83. Navratil H. Preliminary clinical evaluation of leuprorelin acetate depot injection in France, in the management of prostatic cancer. J Int Med Res 1990;18 Suppl 1:69-73.

84. O' Brien A, Hibberd M. Clinical efficacy and safety of a new leuprorelin acetate depot formulation in patients with advanced prostatic cancer. J Int Med Res 1990;18 Suppl 1:57-68.

85. Soloway MS. Efficacy of buserelin in advanced prostate cancer and comparison with historical controls. Am J Clin Oncol 1988;11 Suppl 1:S29-S32.

44

86. Waxman J, Sandow J, Abel P, Barton C, Keane P, Williams G. Three-monthly GnRH agonist (buserelin) for prostatic cancer. Br J Urol 1990;65(1):43-5.

87. Jorgensen T, Tveter KJ, Jorgensen LH. Total androgen suppression: experience from the Scandinavian Prostatic Cancer Group Study No. 2. Eur Urol 1993;24(4):466-70.

88. Williams G, Asopa R, Abel PD, Smith C. Pituitary adrenal and gonadal endocrine suppression for the primary treatment of prostate cancer. Br J Urol 1990;65(5):504-8.

89. Khan MS, O'Brien A. An evaluation of pharmacokinetics and pharmacodynamics of leuprorelin acetate 3M-depot in patients with advanced and metastatic carcinoma of the prostate. Urol Int 1998;60(1):33-40.

90. Presant CA, Soloway MS, Klioze SS, Yakabow A, Presant SN, Mendez RG, et al. Buserelin treatment of advanced prostatic carcinoma. Long-term follow-up of antitumor responses and improved quality of life. Cancer 1987;59(10):1713-6.

91. Van Cangh PJ, Opsomer RJ. Treatment of advanced carcinoma of the prostate with a depot luteinizing hormone-releasing hormone analogue (ICI-118630). J Urol 1987;137(1):61-4.

92. Frohmuller HG, Theiss M, Manseck A, Wirth MP. Survival and quality of life of patients with stage D1 (T1-3 pN1-2 M0) prostate cancer. Radical prostatectomy plus androgen deprivation versus androgen deprivation alone. Eur Urol 1995;27(3):202-6.

93. Metz R, Namer M, Adenis L, Audhuy B, Bugat R, Colombel P, et al. Zoladex as primary therapy in advanced prostatic cancer. A French cooperative trial. Am J Clin Oncol 1988;11 Suppl 2:S112-S114.

94. de Voogt HJ, Klijn JG, Studer U, Schroder F, Sylvester R, De Pauw M. Orchidectomy versus Buserelin in combination with cyproterone acetate, for 2 weeks or continuously, in the treatment of metastatic prostatic cancer. Preliminary results of EORTC-trial 30843. J Steroid Biochem Mol Biol 1990;37(6):965-9.

95. Dupont A, Cusan L, Gomez JL, Koutsilieris M, Suburu R, Emond J, et al. Combination therapy with flutamide and the LHRH agonist [D-Trp6, des-Gly-NH(2)10]LHRH ethylamide in stage C prostatic carcinoma. Br J Urol 1993;72(5 Pt 1):629-34.

96. Iversen P. Zoladex plus flutamide vs. orchidectomy for advanced prostatic cancer. Danish Prostatic Cancer Group (DAPROCA). Eur Urol 1990;18 Suppl 3:41-4.

97. Iversen P, Suciu S, Sylvester R, Christensen I, Denis L. Zoladex and flutamide versus orchiectomy in the treatment of advanced prostatic cancer. A combined analysis of two European studies, EORTC 30853 and DAPROCA 86. Cancer 1990;66(5 Suppl):1067-73.

98. Keuppens F, Denis L, Smith P, Carvalho AP, Newling D, Bond A, et al. Zoladex and flutamide versus bilateral orchiectomy. A randomized phase III EORTC 30853 study. The EORTC GU Group. Cancer 1990;66(5 Suppl):1045-57.

99. Corn BW, Winter K, Pilepich MV. Does androgen suppression enhance the efficacy of postoperative irradiation? A secondary analysis of RTOG 85-31. Radiation Therapy Oncology Group. Urology 1999;54(3):495-502.

100. Rosendahl I, Kiebert GM, Curran D, Cole BF, Weeks JC, Denis LJ, et al. Quality-adjusted survival (Q-TWiST) analysis of EORTC trial 30853: comparing goserelin acetate and flutamide with bilateral orchiectomy in patients with metastatic prostate cancer. European Organization for Research and Treatment of Cancer. Prostate 1999;38(2):100-9.

45

101. Sarosdy MF, Schellhammer PF, Soloway MS, Vogelzang NJ, Crawford ED, Presti J, et al. Endocrine effects, efficacy and tolerability of a 10.8-mg depot formulation of goserelin acetate administered every 13 weeks to patients with advanced prostate cancer. BJU Int 1999;83(7):801-6.

102. Boccardo F, Rubagotti A, Barichello M, Battaglia M, Carmignani G, Comeri G, et al. Bicalutamide monotherapy versus flutamide plus goserelin in prostate cancer patients: results of an Italian Prostate Cancer Project study. J Clin Oncol 1999;17(7):2027-38.

103. Lee M, Browneller R, Wu Z, Jung A, Ratanawong C, Sharifi R. Therapeutic effects of leuprorelin microspheres in prostate cancer. Adv Drug Deliv Rev 1997;28(1):121-38.

104. Prezioso D, Lotti T, Montironi R, Polito M. Leuprorelin 1-month depot as neoadjuvant therapy for prostate cancer. Takeda NHT Italian Group. Urol Int 1998;60 Suppl 2:11-7.

105. Schellhammer P, Sharifi R, Block N, Soloway M, Venner P, Patterson AL, et al. A controlled trial of bicalutamide versus flutamide, each in combination with luteinizing hormone-releasing hormone analogue therapy, in patients with advanced prostate cancer. Casodex Combination Study Group. Urology 1995;45(5):745-52.

106. Sarosdy MF, Schellhammer PF, Sharifi R, Block NL, Soloway MS, Venner PM, et al. Comparison of goserelin and leuprolide in combined androgen blockade therapy. Urology 1998;52(1):82-8.

107. Veronesi A, Lo RG, Dal B, V, Foladore S, Belmonte P, Ciaccio B, et al. Buserelin treatment of advanced prostatic carcinoma: prognostic factor analysis. Eur Urol 1992;21(4):274-9.

108. Akaza H, Usami M, Koiso K, Kotake T, Aso Y, Niijima T. Long-term clinical study on luteinising hormone-releasing hormone agonist depot formulation in the treatment of stage D prostatic cancer. The TAP-144-SR Study Group. Jpn J Clin Oncol 1992;22(3):177-84.

109. Labrie F, Dupont A, Cusan L, Gomez J, Diamond P, Koutsilieris M, et al. Downstaging of localized prostate cancer by neoadjuvant therapy with flutamide and lupron: the first controlled and randomized trial. Clin Invest Med 1993;16(6):499-509.

110. Garnick MB. Leuprolide versus diethylstilbestrol for previously untreated stage D2 prostate cancer. Results of a prospectively randomized trial. Urology 1986;27(1 Suppl):21-8.

111. Bono AV, DiSilverio F, Robustelli della CG, Benvenuti C, Brausi M, Ferrari P, et al. Complete androgen blockade versus chemical castration in advanced prostatic cancer: analysis of an Italian multicentre study. Italian Leuprorelin Group. Urol Int 1998;60 Suppl 1:18-24.

112. Sharifi R, Soloway M. Clinical study of leuprolide depot formulation in the treatment of advanced prostate cancer.The Leuprolide Study Group. J Urol 1990;143(1):68-71.

113. Akaza H, Homma Y, Okada K, Yokoyama M, Moriyama N, Usami M, et al. Early results of LH-RH agonist treatment with or without chlormadinone acetate for hormone therapy of naive localized or locally advanced prostate cancer: a prospective and randomized study. The Prostate Cancer Study Group. Jpn J Clin Oncol 2000;30(3):131-6.

114. Koutsilieris M, Tolis G. Long-term follow-up of patients with advanced prostatic carcinoma treated with either buserelin (HOE 766) or orchiectomy: classification of variables associated with disease outcome. Prostate 1985;7(1):31-9.

115. Koutsilieris M, Faure N, Tolis G, Laroche B, Robert G, Ackman CF. Objective response and disease outcome in 59 patients with stage D2 prostatic cancer treated with either Buserelin or orchiectomy. Disease aggressivity and its association with response and outcome. Urology 1986;27(3):221-8.

46

116. Schroeder FH, Lock TM, Chadha DR, Debruyne FM, Karthaus HF, de Jong FH, et al. Metastatic cancer of the prostate managed with buserelin versus buserelin plus cyproterone acetate. J Urol 1987;137(5):912-8.

117. Debruyne FM, Karthaus HF, Schroder FH, de Voogt HJ, de Jong FH, Klijn JG. Results of a Dutch Phase II trial with the LHRH agonist buserelin in patients with metastatic prostatic cancer. Prog Clin Biol Res 1985;185A:251-70.

118. Debruyne FM. Results of a Dutch trial with the LHRH agonist buserelin in patients with metastatic prostatic cancer and results of EORTC studies in prostatic cancer. Am J Clin Oncol 1988;11 Suppl 1:S33-5.

119. Crawford ED, Allen JA. Treatment of newly diagnosed state D2 prostate cancer with leuprolide and flutamide or leuprolide alone, phase III, intergroup study 0036. J Steroid Biochem Mol Biol 1990;37(6):961-3.

120. Smith JA, Glode LM, Wettlaufer JN, Stein BS, Glass AG, Max DT, et al. Clinical effects of gonadotropin-releasing hormone analogue in metastatic carcinoma of prostate. Urology 1985;25(2):106-14.

121. Sharifi R, Bruskewitz RC, Gittleman MC, Graham SD, Hudson PB, Stein B. Leuprolide acetate 22.5 mg 12-week depot formulation in the treatment of patients with advanced prostate cancer. Clin Ther 1996;18(4):647-57.

122. Dijkman GA, Debruyne FM, Fernandez dM, Plasman JW, Hoefakker JW, Idema JG, et al. A phase III randomized trial comparing the efficacy and safety of the 3-monthly 10.8-mg depot of Zoladex with the monthly 3.6-mg depot in patients with advanced prostate cancer. Dutch South East Cooperative Urological Group. Eur Urol 1994;26 Suppl 1:1-2.

123. Winfield H, Trachtenberg J. A comparison of a powerful luteinizing hormone releasing hormone analogue agonist and estrogen in the treatment of advanced prostatic cancer. J Urol 1984;131(6):1107-9.

124. Fornara P, Jocham D. Clinical study results of the new formulation leuprorelin acetate three-month depot for the treatment of advanced prostate carcinoma. Urol Int 1996;56 Suppl 1:18-22.

125. Kirby R, Robertson C, Turkes A, Griffiths K, Denis LJ, Boyle P, et al. Finasteride in association with either flutamide or goserelin as combination hormonal therapy in patients with stage M1 carcinoma of the prostate gland. International Prostate Health Council (IPHC) Trial Study Group. Prostate 1999;40(2):105-14.

126. Chodak GW, Vogelzang NJ, Caplan RJ, Soloway M, Smith JA. Independent prognostic factors in patients with metastatic (stage D2) prostate cancer. The Zoladex Study Group. JAMA 1991;265(5):618-21.

127. Emtage LA, Trethowan C, Hilton C, Kelly K, Blackledge GR. Interim report of a randomized trial comparing Zoladex 3.6 mg depot with diethylstilbestrol 3 mg/day in advanced prostate cancer. The West Midlands Urology Research Group. Am J Clin Oncol 1988;11 Suppl 2:S173-5.

128. Murphy GP, Greco JM, Chin JL, Huben RP, Scott M, deHaan HA. Zoladex (ICI 118,630): clinical trial of new luteinizing hormone-releasing hormone analog in metastatic prostatic carcinoma. Urology 1987;29(2):185-90.

129. Debruyne FM, Dijkman GA, Lee DC, Witjes WP, del Moral F, Karthaus HF, et al. A new long acting formulation of the luteinizing hormone-releasing hormone analogue goserelin: results of studies in prostate cancer. J Urol 1996;155(4):1352-4.

130. Debruyne FM, Witjes WP, Schulman CC, Van Cangh PJ, Oosterhof GO. A multicentre trial of combined neoadjuvant androgen blockade with Zoladex and flutamide prior to radical prostatectomy in prostate cancer. The European Study Group on Neoadjuvant Treatment. Eur Urol 1994;26 Suppl 1:4.

47

131. Fowler JE, Gottesman JE, Reid CF, Andriole GL, Soloway MS. Safety and efficacy of an implantable leuprolide delivery system in patients with advanced prostate cancer. J Urol 2000;164(3 Pt 1):730-4.

132. Dawson NA, Figg WD, Cooper MR, Sartor O, Bergan RC, Senderowicz AM, et al. Phase II trial of suramin, leuprolide, and flutamide in previously untreated metastatic prostate cancer. J Clin Oncol 1997;15(4):1470-7.

133. Jocham D. Leuprorelin three-month depot in the treatment of advanced and metastatic prostate cancer: long-term follow-up results. Urol Int 1998;60 Suppl 2:18-24.

134. Dijkman GA, Debruyne FM, Fernandez dM, Plasman JW, Hoefakker JW, Idema JG, et al. A randomised trial comparing the safety and efficacy of the Zoladex 10.8-mg depot, administered every 12 weeks, to that of the Zoladex 3.6-mg depot, administered every 4 weeks, in patients with advanced prostate cancer. The Dutch South East Cooperative Urological Group. Eur Urol 1995;27(1):43-6.

135. Fernandez del Moral P, Dijkman GA, Debruyne FM, Witjes WP, Kolvenbag GJ. Three-month depot of goserelin acetate: clinical efficacy and endocrine profile. Dutch South East Cooperative Urological Group. Urology 1996;48(6):894-900.

136. Presant CA, Soloway MS, Klioze SS, Kosola JW, Yakabow AL, Mendez RG, et al. Buserelin as primary therapy in advanced prostatic carcinoma. Cancer 1985;56(10):2416-9.

137. Lunglmayr G. A multicenter trial comparing the luteinizing hormone releasing hormone analog Zoladex, with Zoladex plus flutamide in the treatment of advanced prostate cancer. The International Prostate Cancer Study Group. Eur Urol 1990;18 Suppl 3:28-9.

138. Moffat LE. Comparison of Zoladex, diethylstilbestrol and cyproterone acetate treatment in advanced prostate cancer. Eur Urol 1990;18 Suppl 3:26-7.

139. Giraud B. Interim report of a large French multicentre study of efficacy and safety of 3.75 mg leuprorelin depot in metastatic prostatic cancer. J Int Med Res 1990;18 Suppl 1:84-9.

140. Waxman J, Sandow J, Thomas H, James N, Williams G. A pharmacological evaluation of a new 3-month depot preparation of buserelin for prostatic cancer. Cancer Chemother Pharmacol 1989;25(3):219-20.

141. Ferrari P, Castagnetti G, Ferrari G, Baisi B, Dotti A. Combination treatment versus LHRH alone in advanced prostatic cancer. Urol Int 1996;56 Suppl 1:13-7.

142. Waxman JH, Sandow J, Man A, Barnett MJ, Hendry WF, Besser GM, et al. The first clinical use of depot buserelin for advanced prostatic carcinoma. Cancer Chemother Pharmacol 1986;18(2):174-5.

143. Tyrrell CJ, Denis L, Newling D, Soloway M, Channer K, Cockshott ID. Casodex 10-200 mg daily, used as monotherapy for the treatment of patients with advanced prostate cancer. An overview of the efficacy, tolerability and pharmacokinetics from three phase II dose-ranging studies. Casodex Study Group. Eur Urol 1998;33(1):39-53.

144. Bales GT, Chodak GW. A controlled trial of bicalutamide versus castration in patients with advanced prostate cancer. Urology 1996;47(1A Suppl):38-43.

145. Brisset JM, Boccon-Gibod L, Botto H, Camey M, Cariou G, Duclos JM, et al. Anandron (RU 23908) associated to surgical castration in previously untreated stage D prostate cancer: a multicenter comparative study of two doses of the drug and of a placebo. Prog Clin Biol Res 1987;243A:411-22.

146. Beland G, Elhilali M, Fradet Y, Laroche B, Ramsey EW, Venner PM, et al. Total androgen blockade vs orchiectomy in stage D2 prostate cancer. Prog Clin Biol Res 1987;243A:391-400.

48

147. Kaisary AV, Tyrrell CJ, Beacock C, Lunglmayr G, Debruyne F. A randomised comparison of monotherapy with Casodex 50 mg daily and castration in the treatment of metastatic prostate carcinoma. Casodex Study Group. Eur Urol 1995;28(3):215-22.

148. Denis LJ, Carnelro de Moura JL, Bono A, Sylvester R, Whelan P, Newling D, et al. Goserelin acetate and flutamide versus bilateral orchiectomy: a phase III EORTC trial (30853). EORTC GU Group and EORTC Data Center. Urology 1993;42(2):119-29.

149. Rajfer J, Handelsman DJ, Crum A, Steiner B, Peterson M, Swerdloff RS. Comparison of the efficacy of subcutaneous and nasal spray buserelin treatment in suppression of testicular steroidogenesis in men with prostate cancer. Fertil Steril 1986;46(1):104-10.

150. Hoogendijk E, de Voogt HJ. Treatment of advanced prostatic cancer with anti-androgens alone and a combination of anti-androgen with anti-prolactin--a pilot study. Urol Res 1986;14(3):129-31.

151. Blackledge GR. High-dose bicalutamide monotherapy for the treatment of prostate cancer. Urology 1996;47(1A Suppl):44-7.

152. Chapman GB, Elstein AS, Kuzel TM, Sharifi R, Nadler RB, Andrews A, et al. Prostate cancer patients' utilities for health states: how it looks depends on where you stand. Med Decis Making 1998;18(3):278-86.

153. Kattan MW, Cowen ME, Miles BJ. A decision analysis for treatment of clinically localized prostate cancer. J Gen Intern Med 1997;12(5):299-305.

154. CPS: compendium of pharmaceuticals and specialties. 36th ed. Ottawa: Canadian Pharmacists Association; 2001.

155. Canadian Coordinating Office for Health Technology Assessment. Guidelines for economic evaluation of pharmaceuticals: Canada. 2nd ed. Ottawa: The Office; 1997. Available: http://www.ccohta.ca/entry_e.html.

156. Coyle D, Buxton MJ, O'Brien BJ. Stratified cost-effectiveness analysis: a framework for establishing efficient limited use criteria. Health Econ 2003;12(5):421-7.

157. Goel V, Williams JI, Anderson GM, Blackstien-Hirsch P, Fooks C, Naylor CD, et al. Patterns of health care in Ontario: the ICES practice atlas. 2nd ed. Ottawa: Canadian Medical Association [for] the Institute for Clinical Evaluative Sciences in Ontario; 1996.

158. To T, Iscoe N, Klotz L, Naylor CD. Patterns of use of specific drugs in the elderly: prostate cancer. In: Naylor CD, Anderson GM, Goel V, editors. Patterns of health care in Ontario. Ottawa: Canadian Medical Association [for] the Institute for Clinical Evaluative Sciences in Ontario; 1994. p.314-7.

49

Appendix 1: Criteria for Acceptance of Studies and Inclusion of Data

Inclusion Criteria* Yes No NA

a. Primary research report b. Randomized controlled trial (RCT) b-1. Double-blind study b-2 Single-blinded b-3. Open-label c. One or more appropriate comparators c-1. Goserelin (Zoladex®) c-2. Buserelin (Suprefact®) c-3. Leuprolide (Lupron®) c-4. Estrogens c-5. DES c-6. Flutamide or nilutamide c-7. Orchiectomy d. Stage of disease d-1. Local extension beyond capsule (C1 to C2, D1 or T3a to T4b)

d-2. Metastatic (D2 or N1 to M1c) e. Combination of stages in study population e-1.Outcomes separate by stage f. Adult population g. Results available g-1. Patient number g-2. Survival time g-3. Progression-free survival time g-4. Objective response g-5. Subjective response * For inclusion, questions a,b, c, d, f, g, g-1 and at least one of b-1 to b-3, one of c-1 to c-7, one of d-1 or d-2, one of g-1 to g-5 should be answered ‘yes.”

Exclusion criteria

Nonpalpable (A1 to B0 or T1a to T1c)

Palpable or visible, confined to capsule (B1 or T2a to T2c)

INCLUDE: YES: NO:

50

Summary of articles and response criteria applied

Stage Author Response criteria Jurinic43 BPGC* Locally advanced prostate

cancer Tyrrell44-46 Criteria listed in article Bruun59 NPCP† Citrin57 NPCP† Jurinic43 BPGC* Kaisary58 BPGC* (with minor

modifications) Leuprolide Study Group47 NPCP† Sharifi48 NPCP† Klioze50 NPCP† The Zoladex Prostate Study Group55,56

NPCP†

Tyrrell44-46 Criteria listed in article Huben51 NPCP† Fontana60 Criteria listed in article Navratil49 NPCP† Turkes54 BPGC*

Metastatic prostate cancer

Crawford,52 McLeod53 NPCP† *BPGC=British Prostate Group Criteria35; †NPCP=National Prostatic Cancer Project34

51

Appendix 2: Log of Rejected Studies and Reasons for Rejection

State of Prostate Cancer (studies)

Reason for Rejection (studies rejected)

Author (reference)

Inappropriate research design (15)

Bischoff,80 Crook,81 Kienle and Lubben,82 Navratil,83 O'Brien,84 Soloway,85 Soloway et al.,56 Waxman,86 Jorgensen,87 Williams,88 Khan ,89 Presant,90 van Cangh,91 Frohmuller,92 Metz93

Inappropriate comparator (16)

De Voogt,94 Dupont,95 Iversen,96 Iversen,15 Iversen,97 Keuppens,98 Corn,99 Rosendahl,100 Sarosdy,101 Boccardo102 Lee,103 Prezioso,104 Schellhammer,105 Sarosdy,106 Veronesi,107 Akaza108

Inappropriate disease condition (1)

Labrie109

Inappropriate patient population (39)

Bruun,59 Citrin,57 Citrin,64 EORTC,14 Di Silverio,68 Fourcade,69 Kaisary,58 Leuprolide Study Group,47 Schulze,70 Sharifi,48 Waymont,71 Akaza,72 Rizzo,73 Ferrari,74 Garnick,110 Klioze,50 Soloway,56 Vogelzang,55 Thorpe,75 Bono,111 Huben,51 Wechsel,76 Fontana,60 Turkes,54 Sharifi,112 Crawford,52,61,63 Parmar,77 Akaza,113 Koutsilieris and Tois,114 Koutsilieris,115 Schroeder,116 DeBruyne,117,118 Crawford,119 Smith,120 Sharifi,121

Inappropriate outcome measures: Data not extractable or not stated (17)

Boccardo,66,67 Dijkman,122 Winfield,123 Fornara,124 Kirby,125 Chodak,126 Emtage,127 Murphy,128 DeBruyne,129 DeBruyne,130 Fowler,131 Dawson,132 Jocham,133 Dijkman,134 Fernandez del Moral,135 Presant,136

Locally advanced (98)

Inappropriate outcome measures: Duplicate data or article (10)

Lunglmayr,137 Moffat,138 Giraud,139 Waxman,140 McLeod,53 Ferrari,141 Crawford,62 Crawford,63 Crawford,61 Waxman,142

Metastatic disease (93)

Inappropriate research design (25)

Bischoff,80 Crook,81 Kienle and Lubben,82 Navratil,83 O'Brien,84 Soloway,85 Soloway,56 Waxman,86 Jorgensen,87 Bono,111 Williams,88 Koutsilieris and Tois,114 Sharifi,112 Khan,89 Presant,90 van Cangh,91 Frohmuller,92 Koutsilieris,115 Metz,93 Smith,120 Tyrrell,143 Bales,144 Brisset,145 Beland,146 Navratil49

52

State of Prostate Cancer (studies)

Reason for Rejection (studies rejected)

Author (reference)

Inappropriate comparator (21)

Corn,99 De Voogt,94 Dupont,95 Iversen,96 Iversen,15 Iversen,97 Keuppens,98 Rosendahl,100 Sarosdy,101 Boccardo,102 Lee,103 Prezioso,104 Schellhammer,105 Sarosdy,106 Veronesi,107 Sharifi,121 Brisset,145 Beland,146 Kaisary,147 Iversen,17 Denis,14,148

Inappropriate disease condition (1)

Labrie109

Inappropriate patient population (17)

Boccardo66,67 Di Silverio,68 Fourcade,69 Schulze,70 Waymont,71 Akaza,72 Rizzo,73 Ferrari,74 Thorpe,75 Wechsel,76 Parmar,77 Akaza,113 Presant,136 Schroeder,116 DeBruyne,117,118 Akaza108

Inappropriate outcome measures: Data not extractable or not stated (18)

Dijkman,122 Rajfer,149 Winfield,123 Fornara,124 Kirby,125 Chodak,126 Emtage,127 Murphy,128 DeBruyne,129 DeBruyne,130 Fowler,131 Dawson,132 Jocham,133 Dijkman,134 Fernandez del Moral,135 Crawford,119 Hoogendijk,150 Blackledge,151

Inappropriate outcome measures: Duplicate data or article (11)

Lunglmayr,137 Moffat,138 Giraud,139 Waxman,140 McLeod,53 Ferrari,141 Crawford,62 Crawford,63 Crawford,61 Waxman,142 Garnick110

53

Appendix 3: Data Extraction Forms Data extraction form for objective response

Clinical outcome§

ITT (%) Clinical outcome§

Evaluable (%) Study

Year and Location

Design*

QualityScore


Comparators (dose, duration,

route, continuous or intermittent)

Participants‡

(age, stage of PC,

comorbidities where

available)

Total Number

Randomized and

Evaluable

Responders Failure Responders Failure

Response Criteria

Adverse Event Rate

(% ITT)

Comparators

Data extraction form for survival data

54



Comparators

54

Appendix 4: Components of an Economic Evaluation Objectives One objective of this research project was to develop economic models, collect data on costs and outcomes and, perform an economic evaluation of LAs versus alternative therapies. An economic evaluation was not undertaken, however, because there was insufficient clinical data. As a result, only the models and the costing and utility data are presented there. The models, which have been tested with costs and outcomes data inputs, would be operational if appropriate clinical data were available. The purpose of including this economic information is to facilitate a future economic analysis of LAs. Another alternative would be to perform limited analyses based on hypothetical, but plausible, assumptions, such as clinical equivalence among the LAs. Methods Patient population: Models were developed to analyze the costs and consequences of administering LAs to two advanced prostate cancer populations: metastatic prostate cancer patients and locally advanced prostate cancer patients. Analytic approach: Prostate cancer management was modelled by means of Markov decision analytic modelling, with four treatment arms, using Data (TreeAge) software version 3.5. Two Markov models were developed for the economic evaluation of LAs versus alternative therapies: one model for locally advanced prostate cancer patients and another for metastatic prostate cancer patients. The models included treatment arms that would capture the costs and consequences of prostate cancer management. Two types of analyses were proposed: a cost-effectiveness analysis and a cost-utility analysis. Markov models: This type of decision analysis allows alternative treatments to be varied and patients to move from one disease state to the next, until they reach the absorbing state (i.e., death). Patients can move in only one direction through the health states (i.e., no remission) toward the absorbing state. The time spent in each health state depends on derived probabilities. Two models were constructed, one for each patient subgroup. 1. Locally advanced prostate cancer

The structure (decision tree) for the locally advanced prostate cancer model is shown in Figure 2 of Appendix 4. It has four possible health states:

• stable • local progression • metastatic disease • death (the absorbing state).

All patients enter the first health state “stable” (i.e. non-progression of disease). From this state, there are four possible health states that a patient can enter. They may remain in the

55

”stable” state, they may move to ”local progression,” they may move to “metastatic disease” or they may move to “death.” Similarly, patients who are in the health state of “local progression” may remain in that state, they may move to ”metastatic disease” or they may move to “death.” Finally, patients who are in the “metastatic disease” health state may remain in that state or move to “death.” If the model were run over a long enough period, all patients would reach the “death” state.

2. Metastatic prostate cancer

The structure (decision tree) for the metastatic prostate cancer model is shown in Figure 3 of Appendix 4. It has three possible health states: • stable • metastatic progression • death (the absorbing state).

All patients enter the first health state “stable” (i.e. non-progression of disease). From this state, there are three possible health states that a patient can enter. They may remain in the “stable” health state, they may move to ”metastatic progression” or they may move to “death.” Similarly, patients who are in the health state of “metastatic progression” may remain there, or they may move directly to “death.” If the model were run over a long enough period of time, all patients would reach the “death” state. Treatment arms: In both models, there are four treatment arms: LA therapy, estrogen therapy, surgical procedure (i.e. orchiectomy) and combination therapy (i.e. LA plus AA). In the base case analysis, the patient in the LA therapy arm should incur the costs and consequences that reflect those of a specific LA evaluated. Another approach would be to apply the averages of all LA therapies, once their clinical equivalence is established or assumed based on evidence from the published literature. Costs and consequences for each LA (i.e. goserelin, buserelin and leuprolide) would be derived individually and then combined to determine an average cost or consequence figure for LA therapy in the “average” analysis. The estrogen therapy arm can be represented by diethylstilbestrol (DES) as the prototype. Orchiectomy, which represents the surgical treatment of the disease, is considered to be “the standard by which the effectiveness of other therapies for prostate cancer is judged.”16 The costs and consequences for the combination therapy arm could be derived by applying each combination of LA and AA separately, including the least expensive and the most expensive.

56

Outcome variables: Outcomes include all appropriate clinical outcomes relevant in the model. Success rates may be defined in terms of: • overall survival • progression-free survival time. Due to the lack of evidence in the published literature, transition probabilities (between the health states) were not estimated. For the cost-effectiveness analysis, the suggested outcome measures would be the number of expected life-years (ELY) and progression-free ELYs. • In the former case, where effectiveness is measured in terms of patients’ overall survival rate,

ELYs are awarded at the end of each six-month cycle (i.e. 0.5 ELY over each six-month cycle for survival) for patients who remained alive, regardless of whether they remained stable. Patients who entered the death state would receive a transition award of zero.

• In the latter case, where effectiveness is measured in terms of the overall progression-free

survival rate, ELYs are awarded at the end of each six-month cycle (i.e. 0.5 ELY over each six-month cycle) for patients who remained alive and stable. Patients who experienced disease progression or entered the death state would receive a transition award of zero.

For the cost-effectiveness analysis, patients who stay alive would be awarded with utilities, which vary according to the health state. Utility value for health states: Utilities for prostate cancer have been reported in a study by Chapman et al.152 and in another study by Kattan et al.153 In the Chapman study, a comparison of two time-trade-off (TTO) techniques was undertaken to compare personal and impersonal versions of a questionnaire for evaluating a set of three hypothetical health states (A, B, C) associated with prostate cancer. Each health state comprised five aspects of quality of life: pain; mood; sexual function; bladder and bowel function; and fatigue and energy. Each aspect was assigned one of three possible levels: high, moderate or low, where state A represented little effect on the aspects, state B represented a moderate effect and state C represented a marked effect. Combinations of these levels were used to form three clinically realistic health state descriptions. Patients were then asked to assess the utility of each health state by identifying the number of years of perfect health that would be as attractive as 10 years in the health state under discussion. Separate scores were reported for localized disease and metastatic cancer patients. Mean TTO scores for states A, B and C were 0.78, 0.57 and 0.27 for those with localized disease and 0.76, 0.64 and 0.29 for those with metastatic cancer. By assuming that health state B most closely represented metastatic patients who remained stable, a value of 0.64 could be used for the utility of a metastatic patient remaining stable and a value of 0.29 could be used for the utility for a metastatic patient with progressing disease. In the study by Kattan et al.,153 utility values were obtained by interviewing 31 male patients who were not diagnosed with prostate cancer, to assess how much of their remaining life expectancy they would give up to live in a particular health state. The utility was calculated by dividing the number of “healthy” years by the years of remaining life expectancy. The utility

57

reported for the health state of metastatic cancer was 0.42, which approximates the midpoint (0.46) between states B and C for metastatic cancer patients in the Chapman152 study. Perspective: The primary analysis was to be performed from the perspective of a public health care payer, such as a ministry of health, with all direct medical costs of care included. A societal perspective would include direct costs to the patients and their families; and the indirect costs of lost time or productivity due to the disease or toxicity of treatment options. Resource use: To identify resource use, available sources, such as the literature and expert opinion, were used with priority given to “hard data,” i.e. peer-reviewed publications of scientifically valid and relevant studies. Resource consumption included: • acquisition cost of drugs (LAs, other hormonal therapy anti-cancer drugs) • physician visits (oncologists, surgeons) • hospitalization costs for orchiectomy • diagnostics and laboratory tests for monitoring • costs associated with the treatment of adverse events resulting from therapy. The resource use associated with each of the four treatment options are described: 1. Treatment with LAs was represented by the administration of a fixed-dose depot injection of

each drug at predefined intervals, i.e. buserelin 9.45 mg every 90 days, goserelin 3.6 mg every 28 days and leuprolide 22.5 mg every 90 days.154 These regimens were confirmed by the clinical experts. Discussion with clinical experts revealed that patients would visit the urologist for prescription renewal every six months during the stable phase of the disease and that consultations would increase to once every three months when the patient entered the progressive phase. At each consultation, a PSA test would be performed, but monitoring of therapy was not routinely undertaken in a clinical setting.

2. A literature review indicated that DES 3 mg daily was the most used single estrogen for the

treatment of advanced prostate cancer. The clinical experts confirmed this observation. In this treatment arm, the patient would visit the urologist for prescription renewal every six months during the stable phase of the disease and consultations would increase to once every three months when the patient entered the progressive phase of the disease. At each consultation, a PSA test would be performed. Adverse events (i.e. cardiovascular events) could be incorporated into the model, as they could affect costs.

3. The resource use associated with an orchiectomy includes surgery using a local and general

anesthetic, the anesthesiologist’s fee and the surgical assistant’s fee.

58

4. Resource use and costs for the combination therapy arm were derived by combining the costs of the specific combination of LA plus AA. AA treatment was represented by the average oral administration of nilutamide 300 mg daily, flutamide 750 mg daily, bicalutamide 50 mg daily and cyproterone acetate 300 mg daily.154 These regimens were confirmed by the clinical experts. In discussion with clinical experts, it was determined that patients would visit the urologist for prescription renewal every six months during the stable phase of the disease and that consultations would increase to once every three months when the patient entered the progressive phase. At each consultation, a PSA test would be performed.

Costs: For costing purposes, the perspective of the Ontario Ministry of Health was used as a proxy for the Canadian health care system. Standard lists used for cost determination included: • the Ontario Drug Benefit (ODB) program formulary for deriving the costs of medications • the Ontario Schedule of Benefits for Physician Services (OSB) for deriving the costs

associated with surgical procedures and physician consultations • the Ontario Schedule of Benefits for Laboratory Services and Fees (OSLF) for deriving costs

associated with laboratory testing • the Ontario Case Costing Project (OCCP) for deriving hospitalization costs. Appendix 4 Table 18 shows the units for the drug therapies and for drug administration. Appendix 4 Table 19 shows the unit costs of other direct medical resources, including surgical costs; physician fees; and testing and measurement costs. Appendix 4 Table 20 shows the resource use and total cost of the drug therapies for six months. All monetary amounts are in Canadian dollars unless indicated otherwise. Time horizon: The time horizon in each model depends on the time that it took all patients to enter the death state. This in turn depends on natural disease progression and the effects of the treatments, which would be reflected in the resulting transitional probabilities between defined health states. Discount rate: As recommended in the CCOHTA Economic Guidelines, outcomes and costs should be discounted at a 5% rate;155 and rates of 0% and 3% should be used in sensitivity analysis. Handing uncertainty and variation: The uncertainty of key parameters could be addressed using deterministic sensitivity analyses; or preferably, probabilistic analysis. Heterogeneity in the populations could be addressed through stratified analysis.156 Key sensitivities could include: • costs and probabilities (associated with treatment effects) associated with using the specific

LAs and combination therapies individually (this could include the most common combinations, i.e. goserelin plus flutamide and leuprolide plus nilutamide)

• changes to the utility values associated with each health state

59

• intermittent use of LAs either as monotherapy or in combination with AAs (it could be assumed that patients are “on” and “off” treatment for six months at a time, with “off” periods following “on” periods for the whole time horizon)

• the discard of AAs and estrogens. The evidence for the efficacy of AAs is limited; there are serious adverse cardiovascular events associated with DES and clinicians have largely switched to LAs for the treatment of prostate cancer. Evidence from the ODB shows a decrease in DES utilization from 100% of the claims in 1985 to 10% in 1992. Further evidence demonstrates a concurrent increase in the use of LAs.25,157,158 This sensitivity analysis provides a clearer picture of the comparison between what is becoming standard treatment in pharmacological castration (i.e. LAs), a variant of it (i.e. combination of LAs plus AAs), and surgical castration.

60

Appendix 4 Figure 2: Structure of Markov decision tree for locally advanced prostate cancer

61

61

Appendix 4 Figure 3: Structure of Markov decision tree for metastic prostate cancer

62

62

Appendix 4 Table 18: Direct medical costs and resources for drug therapy*

Drug Therapy** Unit Price Unit LAs

$670.00 6.3 mg implant kit $990.00 9.45 mg implant kit $46.88 1 mg/mL injection Sol-5.5 mL pack

Buserelin $62.80 1mg/mL Nas Sp-10 mL pack

$381.75 3.6 mg depot injection Goserelin $1,087.99 10.8 mg depot injection

$304.50 3.75 mg injection kit $387.97 7.5 mg injection kit $913.50 11.25 mg injection kit

$1,071.00 22.5 mg injection kit

Leuprolide

$1,428.00 30 mg injection kit Nonsteroidal antiandrogens Bicalutamide $6.44 50 mg tab Flutamide $1.35 250 mg tab

$1.70 50 mg tab Nilutamide $2.00 100 mg tab

Antiandrogen Cyproterone acetate $1.51 50 mg tab Estrogens

$0.26 0.5 mg tab Estrogen diethylstilbiesterol

$0.23 1 mg tab

Drug administration costs*** Subcutaneous injection With visit

$2.27 Injection (G372)

$5. 20 Injection (G373) Sole reason first injection additional injection $2.27 Injection (G372) Implantation of hormone pellets


Basic fee-per-visit premium


*All costs reported in 2003 Canadian dollars. **Source: Ontario Drug Benefit Formulary: Comparative Drug Index (January 30, 2003). ***Source: Ontario Schedule of Benefits for Physician Services under the Health Insurance Act (July 1, 2003) . Nas Sp=nasal spray; mg=milligram; mL=millilitre.

63

Appendix 4 Table 19: Direct medical resources other than drug costs*

Parameter Unit Cost Source Surgical costs (orchiectomy)

Surgical fee: unilateral $167.30 OSB (S589) Anesthesiologist fee: unilateral $ 46.60 OSB (S589) Surgical assistant fee: unilateral $ 30.30 OSB (S589)

Hospital cost: general ward $612.00/day OCCP 1997 Physician fees

GP (consult) $54.75 OSB (A005) Urology (consult) $55.95 OSB (A355) Urology (special surgical consult) $112.35 OSB (A935) Urology (partial assessment) $19.50 OSB (A354)

Testing and measurement costs Chest X-ray OSB (X090)

Technical component $15.15 Professional component $5.65 Full blood count $7.76 OSLF (L393) Prostate-specific antigen $7.00 QLBM (2351)

*All costs reported in 2003 Canadian dollars. GP=general practitioner; OSB=Ontario Schedule of Benefits for Physician Services under Health Insurance Act (July 1, 2003); OSLF=Ontario Schedule of Benefits for Laboratory Services and Fees (April 1, 2001); OCCP=Ontario Case Costing Project; QLBM=Québec Laboratoires de biologie médicale, 2003-2004 edition.

64

Appendix 4 Table 20: Cost of buserelin, goserelin, leuprolide, antiandrogen and estrogen utilization for the treatment of locally advanced and

metastatic prostate cancer for a six-month cycle*

Drug Dose (mg) Cost/dose

($/mg)†Interval between

Doses (days) Doses /

Six-Month Cycle

Cost of Drug/

Six-Month Cycle

LAs Buserelin 9.45 $990.00 90 2 $1,980‡

3.6 $381.75 28 6.5 $2,481‡Goserelin 10.8 $1,087.99 90 2 $2,176

Leuprolide 22.5 $1,071.00 90 2 $2,142

AAs§

Cyproterone acetate

100 $3.02 0.33 540 $1,631‡

Flutamide 250 $1.35 0.33 540 $729‡

Bicalutamide 50 $6.44 1 180 $1,159 Nilutamide 100 $2.00 0.33 540 $1,080

Estrogens 3 $0.69 1 180 $124 *All costs reported in 2003 Canadian dollars. This is an average representation for illustration purposes. †Based on unit prices presented in Appendix 4 Table 18. ‡Least and most expensive alternatives to be used in potential pharmacoeconomic analyses. §For the cost of combination LA plus AA, add respective cost of each treatment. LAs=LHRH agonists; AA=antiandrogens.

65

review of luteinizing hormone-releasing hormone agonists

Documents