Initial Flare Symptoms Resulting from Use of LHRH Agonist in Metastatic Prostate Cancer: Systematic Review and Economic Evaluation

Yeesha Poon

A thesis submitted in conformity with the requirements for the degree of Master of Science in Health Technology Assessment & Management Health Policy, Management and Evaluation University of Toronto

Initial Flare Symptoms Resulting from Use of LHRH Agonists in Metastatic Prostate Cancer: Systematic Review and Economic Evaluation

Yeesha Poon

Master of Science in Health Technology Assessment and Management

Health Policy, Management and Evaluation

University of Toronto

2009

ABSTRACT

Background

LHRH agonists decrease tumour size/activity by suppressing testosterone in prostate

cancer; however, initial injection causes testosterone surge that triggers flare

symptoms. Anti-androgen given with agonist may reduce/avoid flare symptoms.

When LHRH antagonist/blocker is introduced, testosterone suppression is immediate,

but there is uncertainty about significance of flare symptoms without anti-androgen.

Objective

Systematic review compared significance of flare symptoms avoided and cost utility analysis using modelling comparing incremental value of blocker (degarelix) OR agonist (goserelin)+anti-androgen (bicalutamide) VERSUS agonist alone in prostate cancer patients.

ii Outcome

Incremental cost/QALY of bone pain as flare symptom between treatments

Results

Thirteen studies were reviewed. There was no standard definition for flare symptoms or data on LHRH antagonist versus other treatments on flare. From societal perspective, goserelin+bicalutamide was dominated over goserelin alone and similarly, from public perspective, goserelin+bicalutamide had favourable cost effectiveness profile against goserelin.

Conclusion

With bone pain as clinical endpoint, LHRH agonist+anti-androgen had favourable cost-effectiveness profile compared to goserelin.

iii ACKNOWLEDGMENTS

I would like to thank my supervisor Dr. Eric Nauenberg and my committee member, Dr. Muhammad Mamdani in providing assistance in numerous ways in getting this thesis completed.

I would also like to thank Dr. Wendy Ungar for providing directions for the thesis when needed.

I would like to thank Rumona Dickson for her advice and help with the systematic review.

I am grateful to the librarian, Klaus Boisen, who helped develop the search strategies and completed the literature searches.

I am indebted to my fellow student Dinsie Williams for acting as the second reviewer of articles for the systematic review and for providing inputs for the thesis when needed.

iv TABLE OF CONTENTS

ABSTRACT...... ii ACKNOWLEDGMENTS ...... iv TABLE OF CONTENTS...... v LIST OF TABLES...... vi LIST OF FIGURES ...... viii LIST OF APPENDICES...... ix EXECUTIVE SUMMARY ...... x Issue ...... x Objectives ...... xi Health Services Impact ...... xiv Conclusion ...... xiv Chapter 1...... 1 INTRODUCTION ...... 3 1.1 Background...... 3 1.2 Current Clinical Practice...... 3 1.2.1 Risk Stratification of Prostate Cancer...... 5 1.2.2 Androgen Deprivation Therapy ...... 6 1.2.3 LHRH Agonists ...... 7 1.2.3 Issues with LHRH Agonists – Testosterone Surge...... 7 1.3 Overview of New Technology...... 8 Chapter 2...... 10 SYSTEMATIC REVIEW...... 10 2.1 The Issue ...... 10 2.2 Objectives ...... 10 2.3 Methods...... 11 2.3.1 Literature search strategy...... 12 2.3.2 Selection criteria and method...... 13 2.3.3 Data extraction...... 15 2.3.4 Strategy for quality assessment...... 15 2.4 Results...... 15 2.4.1 Quantity of research available ...... 15 2.4.2 Quality of included studies ...... 17 2.4.3 Data analyses and synthesis...... 17 a) Primary Endpoint - Clinical Flare...... 17 Disease Flare...... 18 b) Secondary Endpoint - Testosterone Surge...... 21 2.5 Summary...... 22 Chapter 3...... 23 ECONOMIC ANALYSIS – 3-MONTH HORIZON ...... 23 3.1 Review of Economic Studies: Methods...... 23 3.2 The Issue ...... 23 3.3 Primary Economic Evaluation: Methods...... 24 3.3.1 Types of economic evaluation ...... 24 3.3.2 Target population...... 24 3.3.3 Comparators...... 24 3.3.4 Perspective ...... 25 3.3.5 Time horizon...... 26

v 5.3.6 Modelling...... 26 3.3.7 Valuing outcomes ...... 26 3.3.8 Utilities...... 26 3.3.9 Resource use and costs...... 28 3.3.10 Discount rate ...... 33 3.3.11 Variability and uncertainty ...... 33 3.3.12 Summary of model assumptions...... 33 3.4 Primary Economic Evaluation: Results ...... 33 3.4.1 Results – Societal Perspective ...... 33 3.4.2 Sensitivity Analyses – Societal Perspective ...... 42 3.4.3 Results – Public Perspective ...... 45 3.4.4 Sensitivity Analyses – Public Perspective ...... 47 3.5 Conclusion ...... 49 Chapter 4...... 52 ECONOMIC ANALYSIS – 1 YEAR HORIZON...... 52 4.1 Societal Perspective ...... 52 4.1.2 Results – Societal Perspective ...... 58 4.1.2 Univariate Sensitivity Analysis– Societal Perspective ...... 59 4.2 Public Perspective...... 61 4.2.2 Results – Public Perspective ...... 64 4.2.2 Univariate Sensitivity Analysis– Public Perspective...... 64 4.3 Conclusion ...... 67 Chapter 5...... 69 HEALTH SYSTEM IMPACT ISSUES ...... 69 DISCLOSURE...... 71 REFERENCES ...... 72

vi LIST OF TABLES

Table 1: Nova Scotia Cancer Care Staging (Wood et al, 2005) ...... 3 Table 2: Alberta Cancer Board & BC Cancer Agency - Risk Stratification of Prostate Cancer (Alberta Cancer Board, 2007; B.C. Cancer Agency, 2008) ...... 4 Table 3: Marketed LHRH Agonists...... 6 Table 4: Study and Patient Characteristics with Clinical Flare ...... 17 Table 5: Annual Utility ...... 26 Table 6: Healthcare Resource Use Associated with Drug Administration and Management of Patients Receiving Degarelix or Goserelin...... 27 Table 7: Number of Healthcare Resource Use Associated with Drug Administration and Management of Patients Receiving Degarelix or Goserelin...... 28 Table 8: Unit Costs (OHIP Listed Services)...... 28 Table 9: Drug Costs (Ontario Drug Benefit Formulary List, 2009) ...... 30 Table 10: Indirect Costs Non-Retirees and Patient (Retirees) Costs ...... 31 Table 11: Degarelix Societal Costs (With Bone Pain)...... 33 Table 12: Degarelix Societal Costs (Without Bone Pain) ...... 34 Table 13: Total Degarelix Societal Cost (With and Without Bone Pain)...... 35 Table 14: Goserelin Societal Costs (With Bone Pain)...... 35 Table 15: Goserelin Societal Costs (Without Bone Pain)...... 36 Table 16: Total Goserelin Societal Costs (With and Without Bone Pain) ...... 37 Table 17: Goserelin + Bicalutamide Societal Costs (With Bone Pain) ...... 37 Table 18: Goserelin + Bicalutamide Societal Costs (Without Bone Pain) ...... 38 Table 19: Total Goserelin + Bicalutamide Societal Costs (With and Without Bone Pain) ...... 39 Table 20: Incremental Cost per QALY...... 40 Table 21: Univariate Analysis ...... 41 Table 22: Univariate Analysis on Incremental Cost per QALY...... 41 Table 23: Multivariants on Incremental Cost per QALY for Degarelix versus Goserelin...... 42 Table 24: Incremental Cost per QALY – Best Case Scenario...... 43 Table 25: Multivariants on Incremental Cost per QALY for Degarelix versus Goserelin...... 43 Table 26: Incremental Cost per QALY – Worst Case Scenario ...... 44 Table 27: Direct Costs (with Bone Pain) ...... 44 Table 28: Direct Costs (without Bone Pain)...... 45 Table 29: Adjusted Public Costs...... 45 Table 30: Incremental Cost per QALY...... 46 Table 31: Univariate Analysis on Incremental Cost per QALY...... 46 Table 32: Multivariants on Incremental Cost per QALY for Degarelix versus Goserelin...... 47 Table 33: Incremental Cost per QALY – Best Case Scenario...... 48 Table 34: Multivariants on Incremental Cost per QALY for Degarelix versus Goserelin...... 48 Table 35: Incremental Cost per QALY – Worst Case Scenario ...... 48 Table 36: Costs of Medications ...... 51 Table 37: Degarelix Direct and Indirect Costs with Bone Pain...... 52 Table 38: Degarelix Direct and Indirect Costs without Bone Pain...... 53 Table 39: Goserelin Direct and Indirect Costs with Bone Pain...... 54 Table 40: Goserelin Direct and Indirect Costs without Bone Pain...... 54 Table 41: Total Goserelin Public Costs (With and Without Bone Pain) ...... 55 Table 42: Goserelin + Bicalutamide Direct and Indirect Costs with Bone Pain ...... 55

vii Table 43: Goserelin + Bicalutamide Direct and Indirect Costs without Bone Pain ....56 Table 44: Total Goserelin + Bicalutamide Societal Costs (With and Without Bone Pain) ...... 57 Table 45: Societal Perspective - Incremental Cost per QALY ...... 57 Table 46: Univariate Sensitivity Analysis - Variants ...... 58 Table 47: Univariate Sensitivity Analysis – Incremental Cost/QALY...... 58 Table 48: Multivariants on Incremental Cost per QALY for Degarelix versus Goserelin – Best Case Scenario ...... 59 Table 49: Incremental Cost per QALY – Best Case Scenario...... 59 Table 50: Multivariants on Incremental Cost per QALY for Degarelix versus Goserelin – Worst Case Scenario ...... 59 Table 51: Incremental Cost per QALY – Worst Case Scenario ...... 60 Table 52: Costs of Medications ...... 60 Table 53: Degarelix Direct Costs with Bone Pain...... 61 Table 54: Degarelix Direct Costs without Bone Pain...... 61 Table 55: Total Degarelix Public Costs (With and Without Bone Pain)...... 61 Table 56: Goserelin Direct Costs with Bone Pain ...... 61 Table 57: Goserelin Direct Costs without Bone Pain ...... 62 Table 58: Total Goserelin Public Costs (With and Without Bone Pain) ...... 62 Table 59: Goserelin + Bicalutamide Direct Costs with Bone Pain...... 62 Table 60: Goserelin + Bicalutamide Direct Costs without Bone Pain...... 62 Table 61: Total Goserelin + Bicalutamide Public Costs (With and Without Bone Pain) ...... 63 Table 62: Incremental Cost per QALY...... 63 Table 63: Univariate Sensitivity Analysis - Variants ...... 64 Table 64: Univariate Sensitivity Analysis – Incremental Cost/QALY...... 64 Table 65: Multivariate sensitivity analysis on Incremental Cost per QALY for Degarelix versus Goserelin – Best Case Scenario ...... 65 Table 66: Incremental Cost per QALY – Best Case Scenario...... 65 Table 67: Multivariate sensitivity analysis on Incremental Cost per QALY for Degarelix versus Goserelin – Worst Case Scenario ...... 65 Table 68: Incremental Cost per QALY – Worst Case Scenario ...... 65

viii

LIST OF FIGURES

Figure 1: Clinical Trials Search Results ...... 14 Figure 2: Decision Tree for Bone Pain ...... 24 Figure 3: Drugs for Cancer Pain Management (Cancer Care Nova Scotia, 2005)...... 28 Figure 4: Univariate Sensitivity Analysis (Societal Perspective)...... 41 Figure 5: Univariate Sensitivity Analysis (Public Perspective)...... 46 Figure 6: Univariate Sensitivity Analysis (Societal Perspective)...... 57 Figure 7: Univariate Sensitivity Analysis (Public Perspective)...... 63

ix LIST OF APPENDICES

APPENDIX 1 Cancer Care Nova Scotia Treatment Algorithm for Prostate Cancer .75 APPENDIX 2: Literature Search for Flare Symptoms...... 76 APPENDIX 3: Included and Excluded Studies...... 99 APPENDIX 4: Data Extraction Form...... 103 APPENDIX 5: Quality Assessment Forms...... 104 APPENDIX 6: Study Characteristics of Included Studies ...... 110 APPENDIX 7: Patient Characteristics of Included Studies...... 111 APPENDIX 8: Indirect Comparison...... 113 APPENDIX 9: Studies that Evaluated Testosterone Flare and Testosterone Levels 117 APPENDIX 10: Graphical Representations of Testosterone Surge Odds Ratios...... 118 APPENDIX 11: Literature Search on Economic evaluation of agonist versus agonist + anti-androgen in prostate cancer ...... 120 APPENDIX 12: Literature Search Testosterone and Tumour Growth in Prostate Cancer...... 122

x EXECUTIVE SUMMARY

Issue

In Canada, prostate cancer is the most prevalent cancer among men. These patients represent approximately 127,200 cases or 0.8% of the Canadian male population (Canadian Cancer Society, 2008). The incidence of prostate cancer is about 0.09% to 0.13% per year of the total Canadian population (Levy, 1995; Canadian Cancer Society, 2008).

In healthy males, testosterone is the major androgen for prostate development and growth (Hsing, 2001); however, in prostate cancer, testosterone can be responsible for fuelling the growth of cancerous prostatic cells (Msaouel et al, 2007).

The most common treatment for metastatic hormone dependent prostate cancer is androgen deprivation therapy i.e., luteinizing hormone releasing hormone (LHRH) agonists (e.g., goserelin). The main purpose of hormonal treatment using LHRH agonists is to decrease tumour size and activity by suppressing testosterone or the action of testosterone; however, initial injection of LHRH agonists can cause temporary increase of testosterone level, also known as testosterone surge.

Due to the potential growth of tumours from testosterone surge, flare symptoms include worsening bone pain, flank pain, uropathological obstruction, lymphedema, neurological symptoms and spinal cord compression, and possibly, death (Waxman, 1988; Trachtenberg, 1983).

Mahler discussed that flare symptoms can be prevented by initially combining the use of anti-androgen (e.g., bicalutamide) with LHRH agonists (Mahler, 1993).

A new drug class called LHRH antagonist, specifically degarelix is soon to be introduced in Canada for the treatment of prostate cancer. One purported advantage is the lack of initial testosterone surge that is associated with LHRH agonists. Testosterone surge can last up to 4 weeks (Thompson, 2001). The LHRH antagonist may replace the initial requirement of anti-androgen combined with LHRH agonist. The level of testosterone suppressed by LHRH antagonist has been suggested to be faster than and is equal to the combination use of anti-androgen and LHRH agonist

xi (Trachtenberg et al, 2002). Nevertheless, there is uncertainty about the relative benefit in preventing flare symptoms with a LHRH antagonist compared to a LHRH agonist alone or a LHRH agonist plus an anti-androgen. Therefore, a systematic review and a cost utility analysis were conducted.

Objectives This study investigated the clinical significance of flare symptoms and explored the cost utility of LHRH antagonist (degarelix) vs LHRH agonist (goserelin) ± anti- androgen (bicalutamide) for the treatment of flare symptoms in metastatic hormone dependent prostate cancer patients.

To achieve this objective, the following research questions were asked:

To systematically review the clinical impact between patients who start therapy on either intervention [a LHRH antagonist (degarelix), LHRH agonist (e.g., goserelin, leuprolide, triptorelin, buserelin) + anti-androgen (e.g., bicalutamide, flutamide)] versus a LHRH agonist alone in terms of flare symptoms.

To perform a cost utility analysis using LHRH antagonist alone compared to using LHRH agonist plus anti-androgen or using LHRH agonist alone to reduce the risk or severity of a clinical flare.

Methods:

a) Systematic Review

A systematic review in all prostate cancer patients was conducted to determine the clinical significance of flare symptoms including uretheral obstruction, bone pain, death, from treatment initiated with LHRH agonist alone, LHRH agonist + anti- androgen or LHRH antagonist alone. It was necessary to broaden the search beyond metastatic prostate cancer due to paucity of studies available.

Only randomized controlled trials between 1980 to March 2009 were included in the review. All search strategies were developed by a librarian.

xii b) Cost Utility Analysis

From the results of the systematic review, available data was extracted in order to model the incremental cost utility associated with the three treatment comparisons. The results were presented as incremental cost per quality adjusted life-year (QALY).

The systematic review did not find data on the use of LHRH antagonist versus LHRH agonist alone or LHRH agonist + anti-androgen in terms of flare symptoms. Therefore, a cost-utility analysis was conducted using bone pain as flare symptom (as identified in the systematic review). The analysis compared LHRH agonist to LHRH agonist + anti-androgen OR LHRH antagonist to determine the incremental QALY gained from societal and public payer perspectives over a 3-month and one-year time horizons. It was assumed that the risk of having flare symptoms is the same for LHRH antagonist as it is for LHRH agonist + anti-androgen, since the intent of adding anti- androgen with the initial injection of LHRH agonist is to avoid testosterone surge; hence, reducing the risk of getting clinical flare symptoms.

All the costs were derived from the Ontario Drug Benefit formularies and from OHIP (Ontario Health Insurance Plan).

Results: a) Systematic Review

Testosterone surge: The systematic review found a statistically significantly lower testosterone surge with a LHRH antagonist compared to the use of LHRH agonist + anti-androgen or LHRH agonist alone.

Flare symptoms: Different flare symptoms were evaluated in studies including bone pain, disease flare, death resulting from flare and overall pain; however, there was no standard definition of flare symptoms in any of the studies. Although in all situations, there was a reduction in the odds of getting flare symptoms associated with the use of LHRH agonist + anti-androgen versus LHRH agonist alone, only bone pain measured specifically as a flare symptom was significantly less common (29% versus 63%, respectively; p=0.05) (Kuhn et al, 1989).

xiii There was no data that evaluated flare symptoms between a LHRH antagonist versus LHRH agonist alone or versus a LHRH agonist + anti-androgen.

There were many limitations to this systematic review, including the lack of quality randomized controlled trials, the limited number of trials, lack of direct comparison between the degarelix (LHRH antagonist) and LHRH agonist or LHRH agonist + anti-androgen for flare symptoms.

b) Cost Utility Analysis

Bone pain was used as a proxy for flare symptoms in the cost utility analysis. Due to the low quality of the randomized controlled trials, bone pain from the Kuhn study was the only study that used a scale i.e., visual analog scale to specifically measure bone pain as a flare symptom. The other studies evaluated symptoms such as death, overall pain and disease flare as adverse drug reactions only. Therefore, from the available studies, the Kuhn study that evaluated bone pain was the most credible.

From a societal perspective, goserelin (LHRH agonist) + bicalutamide (anti- androgen) had a disfavourable cost-effectiveness profile in relation to goserelin (i.e., goserelin + bicalutamide was dominant over goserelin alone on both QALY and costs meaning less QALY and costs more). Furthermore, when degarelix (LHRH antagonist) was compared to goserelin (LHRH agonist), the incremental cost per QALY was $1,013.

From a public payer perspective, degarelix (LHRH antagonist) resulted in an incremental cost of $18,697 per QALY when compared to goserelin (LHRH agonist) alone. Finally, when goserelin (LHRH agonist) was compared to goserelin + bicalutamide (LHRH agonist + anti-androgen), goserelin resulted in an incremental cost of $9,119 per QALY in relation to goserlein + bicalutamide (i.e., dominant in both costs and QALY).

Univariate and multivariate sensitivity analyses were conducted. Iit was found that the costs of degarelix and goserelin and the utility values were the main drivers in the uncertainties of the analysis.

xiv From the sensitivity analyses, degarelix could go from a favourable cost effectiveness profile relative to goserelin to an incremental cost per QALY of over $45,000 to even $2,000,000 in the scenarios tested from a societal perspective.

Health Services Impact

When policy makers decide on coverage of degarelix or other new drugs, they should consider the timeliness of review of drugs for listing on the formulary. Shortening the time between public and private payer coverage will enhance equal access to patients irrespective of their type of insurance.

In terms of health equity, two types of equities were identified: vertical equity (preferential treatment for those with greater health needs) and horizontal equity (equal treatment for equivalent needs). With horizontal equity, it is difficult to determinine which patients have the same “needs” or same degree of sickness and who should decide, especially when discussing same type of cancer or even different types of cancers.

Regarding vertical equity, how do you make a system “fair” between patients in a healthy state, patients who are mildly ill or severely ill, patients whose prognosis differ with prostate cancer and the lifespan that is related to other disease? Should patients who are sicker be given preferential treatments? When examining degarelix from a societal perspective, what is its incremental value for patients with prostate cancer compared to other disease states? These questions will need to be posed in the future.

Conclusion

Although there were many limitations to the study, including the lack of quality randomized controlled trials, the limited number of trials, lack of direct comparison between the degarelix (LHRH antagonist) and LHRH agonist or LHRH agonist + anti-androgen for flare symptoms, the available data provided some information about the new treatment, degarelix, that could help decision makers with reimbursement listing.

xv Given the available data, it appeared that goserelin + bicalutmide had a favourable cost per QALY compared to goserelin alone both from a societal perspective and public payer perspective.

xvi 1

Chapter 1 Prostate Cancer Background

INTRODUCTION

1.1 Background

Prostate cancer is the most prevalent cancer among Canadian men. These patients represent approximately 127,200 cases or 0.8% of the Canadian male population per year (Canadian Cancer Society, 2008). The incidence of prostate cancer is about 0.09% to 0.13% per year of the total Canadian population (Levy, 1995; Canadian Cancer Society, 2008).

Prostate cancer is mainly a disease of older men. It is diagnosed most frequently in men between 60 and 69 years of age, followed by ages 70 to 79 (Canadian Cancer Society, 2008). These are the age groups that treatments would be reimbursed by the provincial drug plans.

1.2 Current Clinical Practice

The treatment tree for prostate cancer is presented in Appendix 1 (Cancer Care Nova Scotia, 2006). This clinical pathway map provides guidance to physicians to treat different risk stratified patients.

In normal developing pubescent males, testosterone is the main circulating androgen. It plays an essential role in prostate development and growth (Crawford, 2009); however, in males with prostate cancer, the presence of testosterone “fuels” the growth of cancerous prostatic cells. Therefore, the aim of treatment for prostate cancer is to “remove” testosterone from the body so that the growth and spread of the tumour can be slowed or stopped (Thompson, 2001).

After prostate cancer is diagnosed, staging of the disease is done to determine treatment options and patient’s prognosis. Staging determines whether the disease is localized, locally advanced, or metastatic (advanced) (National Cancer Institute, 2008).

Stage I

Stage I cancer is found in the prostate only. It cannot be felt during a digital rectal exam and is not visible by imaging. Stage I prostate cancer may also be called stage A1 prostate cancer as defined by the Jewett staging system (National Cancer Institute, 2005; National Cancer Institute, 2009). Some studies cite the Jewett staging system.

Stage II

In stage II, the cancer has not spread outside the prostate. Stage II prostate cancer may also be referred to as stage A2, stage B1, or stage B2 prostate cancer.

Stage III

In stage III, the cancer has spread beyond the outer layer of the prostate to nearby tissues. Cancer may be found in the seminal vesicles. Stage III prostate cancer may also be called stage C prostate cancer.

Stage IV

In stage IV, cancer has metastasized to lymph nodes near or far from the prostate, or to other parts of the body, such as the bladder, rectum, bones, liver, or lungs. Metastatic prostate cancer often spreads to the bones. Stage IV prostate cancer may also be called stage D1 or stage D2 prostate cancer.

To be more specific, staging is based on TNM subgroups (as defined in the next section).

Table 1: Nova Scotia Cancer Care Staging (Wood et al, 2005)

The treatment modalities between Canadian provinces are very similar. A minor difference is the risk stratification of prostate cancer patients between low risk and

3 intermediate risk. For example, the Alberta Cancer Board considers low risk patients to have clinical staging between T1 – T2b, whereas the Nova Scotia Cancer Board considers low risk patients to be between T1 – T2a. Patients with T2b fall under intermediate risk patients from Nova Scotia’s guideline. The difference between T2a and T2b is that T2a tumours involve less than one half of one lobe of prostate.

1.2.1 Risk Stratification of Prostate Cancer

To help identify low, intermediate and high risk patients, risk stratification is determined by using Prostate Specific Antigen (PSA), the grading of the prostate cancer cells by Gleason Scores, and the TNM (Tumour, Node and Metastasis) clinical staging of the cancer (Alberta Cancer Board, 2007; Cancer Care Nova Scotia, 2006). The stratification is presented in Table 2 (Alberta Cancer Board, 2007; B.C. Cancer Agency, 2008).

Table 2: Alberta Cancer Board & BC Cancer Agency - Risk Stratification of Prostate Cancer (Alberta Cancer Board, 2007; B.C. Cancer Agency, 2008)

Risk Stratification PSA Gleason score Clinical stage

Low risk < 10 ng/mL and ≤ 6 and T1-T2b

Intermediate risk 10–20 ng/mL or 7 or T2c

High risk > 20 ng/mL or ≥8 or T3-T4

PSA (Prostate Specific Antigen)

PSA in blood is elevated in patients with prostate cancer and is regulated by androgen such as testosterone (B.C. Cancer Agency). The PSA test is the most effective screening test currently available for the early detection of prostate cancer and is also used to monitor disease progress; however, it has relatively low specificity which can lead to high false positive rates (Stangelberger et al, 2008).

Gleason Scores

Gleason scores are graded in the range of 2 to 10 by using biopsy samples. Tumours may be defined as well differentiated (typically Gleason 2-6), moderately

4 differentiated (Gleason 7) and poorly differentiated (Gleason 8-10) (Cancer Care Nova Scotia, 2006). The more poorly differentiated (i.e., the more that tissues lose their tissue-specific appearance), the more advanced or aggressive the prostate cancer.

TNM (Tumour, Node, Metastasis)

T stands for Tumour. T staging gives details about the original tumour (the first tumour found, before spreading may have occurred). N stands for Nodes. N staging determines whether or not the cancer has spread into nearby lymph nodes. M stands for Metastasis. M staging determines if the cancer has metastasized, or spread, beyond the lymph nodes into other parts of the body (also known as distant metastasis, or distant spreading).

Low Risk

For patients with low risk disease, expectant management is one of the treatment options which include “watchful waiting” or “active observation”. For patients on “watchful waiting”, hormonal therapy (also known as androgen deprivation therapy) will be initiated at the time of clinical/symptomatic progression of disease (Alberta Cancer Board, 2007).

Intermediate or High Risk

For patients with intermediate or high risk disease, androgen deprivation therapy is offered as a treatment option.

Therefore, regardless of patients’ risk, androgen deprivation therapy is offered as a treatment option; however, anti-androgen is usually only given in conjunction with a LHRH agonist in metastatic or high risk patients.

1.2.2 Androgen Deprivation Therapy

Androgen deprivation therapy (ADT) removes (or suppresses) testosterone from the body to control prostate cancer. ADT can be accomplished by using medication to prevent the production or block the effect of testosterone (androgen) on prostate cells (www.prostate-cancer.com). Long-acting synthetic LHRH agonists were introduced

5 in the 1980s and improved the treatment of prostate cancer by allowing effective reduction of testosterone levels (Crawford, 2004).

The suppression of testosterone by medication is also known as medical castration (Conti et al, 2007). Unfortunately, there is an initial rise of testosterone level using LHRH agonists that can lead to clinical flare symptoms (potential negative effects of the treatment), especially in metastatic prostate cancer patients.

1.2.3 LHRH Agonists

There are six LHRH agonists available on the Canadian market; they are listed in Table 3. All are available at different strengths and treatment intervals. Based on Brogan (market analysis) data, the Zoladex 10.8 mg 3-month formulation makes up majority of the Canadian market.

Table 3: Marketed LHRH Agonists

Marketing company Brand name Delivery Dose Treatment Cost/Year* route (mg) interval Leuprolide acetate Sanofi-Aventis Canada Eligard® SC 7.5 1 month $4,123 Inc. 22.5 3 months $3,564 30 4 months $3,856 45 6 months $3,564 Abbott Lupron® IM 7.5 1 month $4,656 22.5 3 months $4,284 30 4 months $4,284 Goserelin acetate AstraZeneca Zoladex® SC 3.6 1 month $4,581 10.8 3 months $4,352 Triptorelin Watson Pharma, Inc Trelstar® (triptorelin IM 3.75 1 month $3,492 pamoate) 11.25 3 months $3,564 Buserelin acetate Sanofi-Aventis Suprefact® SC 6.3 2 months $4,020 SC 9.45 3 months $3,960 Abbreviations: IM, intramuscular; SC, subcutaneous * Ontario Drug Benefit prices March, 2009

There is no evidence to show that there is a difference in effectiveness amongst the different LHRH agonists (Seidenfeld et al, 2000).

1.2.3 Issues with LHRH Agonists – Testosterone Surge

There was no standard definition of testosterone surge found except that temporary increases of testosterone levels are measured from day 3 and on from initial injection

6 of LHRH agonists. An initial testosterone surge can induce a number of clinical flare symptoms such as bone pain, spinal cord compression, or ureteric obstruction or even sudden death (Bubley, 2001).

Not only do LHRH agonists cause an initial spike of testosterone level i.e., testosterone surge, but also LHRH agonists may not reduce serum testosterone to castrated levels until up to four weeks after the first administration (Zinner et al, 2004). Up to 13% of patients fail to even achieve castration levels during LHRH agonist treatment (Oefelein et al, 2000).

The incidence of flare is from 4 to 63% (Mahler, 1993; Kahan et al, 1984; Kuhn et al, 1989; Thompson, 2001; Trachtenberg, 1983; Waxman, 1988).

Guidelines (Alberta Cancer Board, 2007; Nova Scotia Cancer Care, 2005) suggest using an anti-androgen along with an initial injection of LHRH agonist to prevent flare; however, the percentage of patients who use anti-androgen with the initial injection of LHRH agonist is unknown. There is no available market research data or literature that can provide the percentage of patients who are concurrently on anti- androgen with the initial injection of LHRH agonist. Therefore, current practice may include patients who are on LHRH agonist alone or LHRH agonist + an anti- androgen. It may be a worthwhile question to answer for the payers when conducting future market research.

Although no known percentage of patients who use anti-androgen with initial injection of LHRH agonist, it is worthwhile to puruse the existing evidence to determine whether Guidelines` recommendations are justified.

1.3 Overview of New Technology

Degarelix is a new class of drug, LHRH receptor antagonist. In Canada, there are currently no LHRH antagonists available.

Following injection, degarelix binds to and competitively blocks LHRH receptors in the pituitary gland, which prevents the release of luteinizing hormone (LH) and follicle stimulating hormone (FSH) from the pituitary (which normally stimulates the release of testosterone from the testes) (Broqua et al, 2002). Degarelix achieves an

7 immediate suppression of testosterone to castrated levels in 92% of patients within three days of starting treatment (Klotz et al, 2008).

Degarelix does not cause testosterone surge. In patients with metastatic disease, the initial elevation in testosterone level with LHRH agonists risks an acute stimulation of prostate cancer tumour growth (Sasagawa et al, 1998; Tomera et al, 2001), which can increase the risk of having flare symptoms.

Chapter 2 SYSTEMATIC REVIEW

2.1 The Issue

In Canada, up to 4 weeks administration of anti-androgen with initial injection of LHRH agonist in metastatic prostate cancer patients is recommended to prevent flare symptoms (Cancer Care Nova Scotia, 2006; Mahler, 1993). The main objective of hormonal treatment using LHRH agonists is to decrease tumour size and activity by suppressing testosterone or the action of testosterone.

A new class of drug called LHRH antagonist, specifically degarelix, for the treatment of prostate cancer is soon to be introduced into the Canadian market. One of its advantages is the lack of initial testosterone surge that is associated with LHRH agonists. Initial testosterone surge with LHRH agonists usually lasts up to 4 weeks (Thompson, 2001). There is uncertainty about the cost utility from the lack of flare symptoms with LHRH antagonist compared to LHRH agonist alone or with LHRH agonist + anti-androgen. Decision makers (e.g., provincial payers) and society would benefit from cost utility analysis to determine whether degarelix would have incremental value compared to LHRH agonist alone or LHRH agonist + anti- androgen.

2.2 Objectives

The aim was to evaluate the clinical significance of flare symptoms and to explore the cost utility of LHRH antagonist for the treatment of metastatic hormone dependent prostate cancer compared to LHRH agonist alone or LHRH agonist + anti-androgen.

The following question was asked in the systematic review:

Is there a clinical difference in terms of flare symptoms between patients initiated on LHRH agonist alone, LHRH agonist + anti-androgen or antagonist alone?

The systematic review evaluated literatures using the following methods.

P Population Prostate cancer patients with no previous hormone therapy

I Interventions LHRH Agonist + Anti-Androgen (e.g., Leuprolide + Bicalutamide)

LHRH Antagonist alone (Abarelix, Degarelix)

C Comparator LHRH Agonist alone (e.g., leuprolide, goserelin, triptorelin, buserelin)

O Outcomes Primary Outcome: Reduction of clinical flare/disease flare symptoms (e.g., bladder dysfunction, bone pain, paralysis, death)

Secondary Outcome: Testosterone level pre- and post- treatment

Since the intent of the cost utility analysis was only for prostate cancer patients who were on LHRH agonist ± anti-androgens to prevent or reduce incidence of flare symptoms, only studies which included patients who received hormone therapy and were not concurrently using radiation or chemotherapy were included.

It must be noted in the original search, it was intended that the population included only metastatic prostate cancer patients, but only three studies were found. Therefore, a broader search with all prostate cancer patients was conducted instead, which found more relevant studies.

2.3 Methods

A systematic review was conducted to identify randomized controlled trials (RCTs) and quasi-randomized that evaluated flare symptoms for LHRH agonist alone compared to LHRH antagonist OR LHRH agonist + anti-androgen.

2.3.1 Literature search strategy

Comprehensive searches were developed by an information specialist who used predefined search terms, as listed and in Appendix 2.

(Luteinising-hormone adj releasing adj hormone$1) or (Luteinizing-hormone adj releasing adj hormone$1) or (Luteinising adj hormone adj releasing adj hormone$1) or (Luteinizing adj hormone adj releasing adj hormone$1) or Eligard$ or Lupron$ or (leuprolide adj acetate) or Suprefact$1 or buserelin or Trelstar$ or triptorelin$ or Zoladex$ or goserelin$

WITH

(Gonadotropin-releasing adj hormone$1) or (Gonadotrophin-releasing adj hormone$1) or (Gonadotropin adj releasing adj hormone$1) or (Gonadotrophin adj releasing adj hormone$1)

AND

(antiandrogen$1 or anti-androgen$1 or (anti adj androgen$1) or Casodex$ or bicalutamide$ or cyproterone$ or Anandron$1 or nilutamide$)

AND flare$1 or surge$1

AND compar$5

Searches were conducted in the following electronic databases: Medline, Embase, Biosis, Current Content, Derwent drug file, Int. Pharmaceutical Abstracts, SciSearch, Adis Reactions Database, EMCare, PASCAL and ToxFile (1980 to March 2009), Medline in Process, Biosis Previews, Embase alerts (latest few weeks prior to February 2009), Cochrane databases and DARE. No language restriction was applied.

Electronic searches were supplemented by manual searches of reference lists of included studies. The original search was performed on February 23, 2008. On March 16, 2009, the searches were updated using the original search strategies.

2.3.2 Selection criteria and method a) Selection criteria

Inclusion criteria

Publication type: randomized controlled trials and quasi-randomized studies.

To be included in the systematic review, a study must include prostate cancer patients who only received androgen deprivation therapy i.e., LHRH agonists, but no other treatment is given i.e., radiation, chemotherapy, surgery. Other concurrent treatments could affect occurrence of flare symptoms.

Since there was no standard definition of testosterone surge and clinical flare identified, any studies that evaluated testosterone level pre and post treatment and clinical flare symptoms were included.

Exclusion criteria

A study was excluded according to the following criteria:

• Letter, editorial, narrative review, lay press article or case studies

• Endpoints did not include evaluation of flare symptoms

• Patients who were on Triple Androgen Blockade (TAB) therapy.

o This is combination therapy using three classes of drugs, 1) 5-alpha reductase inhibitor (finasteride or dutasteride) 2) LHRH agonists and 3) anti-androgens. Since TAB therapy can affect the testosterone level and the occurrence of clinical flare, these studies were excluded. Furthermore, TAB is not standard therapy for prostate cancer patients.

• Combined Androgen Blockade (CAB)

o Long term use of LHRH agonist plus anti-androgen. Studies evaluating long term use of CAB were excluded from the review unless short term outcomes (within one month of initial injection of LHRH agonist) evaluated testosterone surge and/or clinical flare were included.

It was hyothesized that CAB may have improved survival, but Cancer Care Ontario guideline states that the small statistically significant survival benefit found with CAB using nonsteroidal anti-androgens (e.g., flutamide or nilutamide) is of questionable clinical significance and does not outweigh the negative side-effects of such long term combination treatment (Cancer Care Ontario, 2003).

Therefore, CAB should not be routinely offered as treatment for patients with documented metastatic prostate cancer beyond the purpose of blocking testosterone flare (Cancer Care Ontario, 2003).

• Patients who were using hormone therapy for other types of cancer.

• Studies that evaluated intermittent androgen deprivation therapy.

o Since intermittent therapy can bias the results (i.e., lowers the number of side effects with treatments) and it is not considered standard therapy.

• Studies that did not include a relevant comparator or had no comparator i.e., an anti-androgen with LHRH agonist or LHRH agonist alone.

• Studies that compared drug treatment to surgical castration

• Non-human studies. b) Selection method

The screening was based on the titles, abstracts, and keywords of each study. The screening criteria were applied as broadly as possible to ensure that only irrelevant studies were excluded. The full-text reports of all potentially relevant articles and of articles that were designated as “unclear” were retrieved for review.

There were 2 reviewers and discrepancies were resolved by discussion.

Appendix 3 provides a list of the included and excluded studies.

2.3.3 Data extraction

Data were extracted using the data extraction form (Appendix 4) and entered into Excel. The data extracted included study design, stage and grade of disease, type of treatment and ages of studied groups, appearance or increased bone pain, disease flare and testosterone surge. One person performed the data extraction.

2.3.4 Strategy for quality assessment

The methodological quality of each study depends on internal and external validity. Internal validity, which is considered to be the most important element of study quality, is the confidence that the design, conduct and report of a trial prevent or reduce bias in the outcomes.

The methodological quality of RCTs was assessed using the Jadad scale (Jadad,

1996). It is a validated five-point scale with five questions that require a yes or a no answer and that are related to internal validity: randomization, double-blinding, and a description of withdrawals and dropouts. The quality assessment can be found in Appendix 5.

2.4 Results

2.4.1 Quantity of research available

The searches of electronic databases and hand searches of reference lists resulted in the identification of 90 citations. Of these, 28 were originally excluded based on abstracts. The full texts of the 62 potentially relevant studies were assessed based on the inclusion criteria and 47 studies were further excluded. One of the 90 citations was abstract, the others were full text studies. Thirteen studies were considered to be relevant to address flare symptoms and testosterone surge. There were 4 of 13 included studies that evaluated short-term outcomes from CAB therapy.

It was originally intended to exclude patients who underwent radiation therapy or chemotherapy. But it was not possible since there was only one included study that patients did not receive chemotherapy or radiation therapy (Crawford et al, 1989). It is more conservative to include these patients in the final analysis since patients who had

14 these treatments could affect flare symptoms positively (i.e., the tumours may have been shrunk so that the effect of the testosterone on the tumours would be less.) This would be against the effect that LHRH antagonist could have on the tumours.

Figure 1 shows the process of study selection.

Figure 1: Clinical Trials Search Results

Potentially relevant citations Potentially relevant citations identified after liberal screening of identified identified through other the electronic search (n=45) sources (n=45)

Citations excluded (n=28)

Narrative review: n=14 No/irrelevant comparator: n=7 Studies screened: n=90 Combined androgen blockage (long term use endpoint): n=3 Editorial/commentary: n=4

Studies excluded (after evaluation of full text) with reasons: n=47 Full‐text articles assessed for eligibility: n=62 Narrative review: n=16 No/irrelevant comparator: n=20 Combined androgen blockage (long term use endpoint): n=6 Non-human study: n=2 Abstract: n=1 Surgical castration comparator: n=2 Relevant studies included in Case studies: n=2 systematic review (n=13)

a) Study characteristics

Thirteen studies were included in this clinical review: 11 RCTs and 2 prospective non-randomized studies. The studies were published between 1987 and 2008 (median year of publication was 1998). The studies were conducted in Canada, Denmark, Japan, United States, France, Germany, Netherlands, Switzerland, South Africa, Italy, New Zealand, Finland, Ireland, Stockholm, U.K. and Japan. The number of study participants ranged from 18 to 610. A detailed description of the study characteristics can be found in Appendix 6 and patient characteristics of included studies can be found in Appendix 7. b) Study funding and setting

Six studies reported receiving industry funding (Schroeder et al, 1987; Trachtenberg et al, 2002; Klotz et al, 2008; Tyrrell et al, 1991; McLeod et al, 2001; DeVoogt et al,

1998). Six studies did not report their funding source, but two of these could be funded by industry (Garnick et al, 2000; Tomera et al, 2001). One study had no industry funding.

2.4.2 Quality of included studies

Randomized controlled trials

The methodological quality of the RCTs was low, 1 study with Jadad score 0/5 (Schroeder et al, 1987); 1 study with score 1/5 (Kreis et al, 1988); five studies with Jadad score 2/5 (Kotake et al, 1999; Schulze et al, 1990; Tyrrell et al, 1991; DeVoogt et al, 1998; Trachtenberg et al, 2002); and 3 with score 3/5 (Klotz et al, 2008; Crawford et al, 1989; McLeod et al, 2001); however, one study had good methodological quality with a Jadad score of 4/5 (Kuhn et al, 1989) (Appendix 5). Most of the RCTs lacked a description of the method of randomization and double- blinding was not reported. The concealment of allocation was unclear.

Summary

Overall, the RCTs were given a Jadad score that indicated low methodological quality and the concealment of allocation was unclear.

2.4.3 Data analyses and synthesis

The statistical method used for data analyses was calculating odds ratio [odds of patients experiencing flare symptoms in experimental group (LHRH antagonist or LHRH agonist + anti-androgen) over the odds of patients not experiencing events with control (LHRH agonist alone)]. a) Primary Endpoint - Clinical Flare

There were six studies that evaluated clinical flare (Table 4). Of these studies, four studies evaluated long-term use of combined androgen blockade (CAB) but reported short term outcomes (Kotake et al, 1999; Tyrrell et al, 1991; Schroeder et al, 1987; Crawford et al, 1989). All of the six studies compared LHRH agonist alone versus

LHRH agonist + anti-androgen. There was no comparison for LHRH antagonist versus other treatments in the studies for clinical flare symptoms.

Table 4: Study and Patient Characteristics with Clinical Flare

Author Definition of Clinical Flare Number of Number of Odds Ratio Patients who Patients who experienced experienced clinical flare in clinical flare in LHRH Agonist LHRH Agonist + AA Group Group Kotake Disease flare - aggravation or 4/95 7/91 = 4.3%; 0.53; 95% CI development of cancer-related symptoms = 7.9% p=0.149 [0.15, 1.87] (including difficulty on voiding, urinary retention, hematuria, cancer pain, arthralgia and perineal pain) attributable to a transient testosterone level elevation within 1 week of goserelin acetate administration

CAB with short term outcomes Kreis Death 1/6 0/12; p= Not 0.15; 95% CI provided [0.01, 4.20] Schroeder Death 3/58 0/13; p= Not 0.59; 95% CI provided [0.03, 12.06] CAB with short term outcomes Kuhn Bone pain - Visual analog scale 0-100mm 5/17= 29% 12/19= 63%; 0.24; 95% CI p<0.05 [0.06, 0.98] Tyrrell Bone pain – Adverse event reporting 3/287= 1.0% 10/284= 3.5%; 0.29; 95% CI p=0.036 [0.08, 1.06] CAB with short term outcomes Crawford Overall pain worse in week 1 17/224 23/233; p=0.2 0.75; 95% CI [0.39, 1.44] CAB with short term outcomes

Disease Flare

One randomized controlled trial (Kotake et al, 1999) with 420 patients evaluated long term combined androgen blockade but reported short term outcomes including flare symptoms. There were 4 arms to the study: Group 1: Goserelin 3.6 mg sc q4 weeks alone; Group 2: Goserelin 3.6 mg sc q4 weeks + chlormadione 50 mg po bid long term (at least 28 months); Group 3: Goserelin 3.6 mg sc q4 weeks + chlormadione 50 mg po bid short term (8 weeks) and; Group 4: Goserelin 3.6 mg sc q4 weeks + diethylstilbestrol (DES) 100 mg tid short term (8 weeks). Chlormadione is a steroidal anti-androgen.

Disease flare was reported within 1 week with 4 of 95 patients who received goserelin and chlormadione short term experienced disease flare and 7 of 91 patients who

17 received goserelin alone experienced disease flare (p=0.149). Although the difference was non-statistically significant, patients enrolled in the study were in stages C, D1 and D2. Overall, there were about 25% of patients with Stage C disease. Stages A and B cancers are considered curable. Stages C and D are treatable, but their prognoses are discouraging (Oncology Channel). Since some patients were in Stage C, evidence of disease flare may not be as notable as patients in Stage D1 or D2. Disease flare had an odds ratio of 0.53 [95% CI; 0.15, 1.87] means that the likelihood of disease flare is decreased by 47% with using agonist + an anti-androgen (p=0.32).

Death

In the study by Kreis et al, one episode of spinal cord compression in 91-year-old patient who received goserelin (LHRH agonist) alone was documented. This was diagnosed 11 days after first depot was administered and the patient died 12 days later. It was concluded that death was definitely related to therapy. In the intervention group (LHRH agonist + anti-androgen), no patient died.

In Shroeder et al, 3 patients died within 1 month in the LHRH agonist group. Because of possibility that acute exacerbation of tumour owing to elevation of plasma testosterone values during week 1 (flare up) may have caused the death; however, in the LHRH agonist + anti-androgen group, none of the 3 patients had tumour flare-up documented. The authors stated that it cannot be excluded as a contributing cause of death though. The statistical significance of these study results was not reported.

Although it may have been useful to conduct a meta-analysis with these two studies, it was not possible since only two studies of extremely small sample sizes and limited numbers of events (with the intervention groups having zero events) could not allow for a reliable overall combined estimate.

Bone Pain

Kuhn et al was a randomized trial with 36 patients with Stage D2 disease. Bone pain was evaluated using visual analog scale on days 1 to 14, then on days 18, 22, and 29. It was found that patients who had some bone pain pretreatment, all patients on LHRH agonist alone had increased bone pain, whereas 5 of 8 patients had increased bone pain with combination therapy (LHRH agonist + anti-androgen) (p value, not

18 reported). In patients who had no bone pain pretreatment, 3 of 10 patients had bone pain with LHRH agonist alone and none of 9 patients had bone pain with combination therapy (p value, not reported). Overall, 12 of 19 patients appeared or increased bone pain with LHRH agonist, whereas 5 of 17 patients had appeared or increased bone pain with LHRH agonist + anti-androgen (p<0.05). The odds ratio was calculated from overall value to be 0.24 [95% CI; 0.06, 0.98] meant that the likelihood of occurrence or increased bone was decreased by 76% with use of LHRH agonist + anti-androgen; p=0.05.

Tyrell et al (1991) was a randomized controlled trial with 571 T3, T4 or metastatic disease patients. The study evaluated long term use of combined androgen blockade but with short term outcomes. Bone pain was reported as an adverse drug reaction within the one month timeframe; 3 of 287 patients reported bone pain with combination therapy and 10 of 284 patients with LHRH agonist alone (p=0.036). The odds ratio was determined to be 0.29 [95% CI; 0.08, 1.06] which meant that there was a 71% less probability that patients would experience bone pain with LHRH agonist + anti-androgen (p=0.06).

Overall Pain

Crawford et al (1989) was a randomized controlled trial with over 600 patients evaluated long term use of combined androgen blockade. Overall pain was evaluated at week 1 to determine whether combination therapy lessen flare symptom. At week 1, 17 of 224 patients experienced overall pain with combined androgen blockade, whereas, 23 of 233 experienced overall pain with LHRH agonist alone (p=0.2). The odds ratio was determined to be 0.75 [95% CI, 0.39 to 1.44] although this was not statistically significant (p=0.39).

Since there was no direct comparison between LHRH antagonist and LHRH agonist alone or LHRH agonist + anti-androgen, indirect comparison was not possible. If data was available, it could have been attempted. Appendix 8 provides how indirect comparison can be made if data was available.

19 b) Secondary Endpoint - Testosterone Surge

Six studies reported testosterone surge and three studies evaluated testosterone levels. For breakdown of study characteristics, please refer to Appendix 9.

Testosterone Surge between LHRH Agonist alone vs. LHRH Antagonist

In the two studies (Klotz et al, 2008; McLeod et al, 2001), testosterone surge was defined as an increase of testosterone ≥ 10 or 15% from baseline within 1 or 2 weeks. Both studies included patients with advanced disease. The odds ratio was calculated to be zero [95% CI; 0, 0] since no patient on LHRH antagonist had testosterone surge (p<0.00001).

If one event was assumed in each study for LHRH antagonist, the odds ratio remained to be zero [95% CI (0, 0.01)].

Testosterone Surge between LHRH Agonist alone vs. LHRH Agonist + Anti-Androgen

The odds ratio between LHRH agonist alone versus LHRH agonist + anti-androgen was 0.67 [95% CI; 0.25, 1.82], which meant that the odds of having a testosterone surge was decreased by 33% with LHRH agonist + anti-androgen, but this was not statistically significant p=0.43 (Klotz et al, 2008).

Testosterone Surge between LHRH Agonist + Anti-Androgen vs LHRH Antagonist

Although anti-androgen is used with LHRH agonist to prevent testosterone surge, there is a statistically significant odds ratio 0.02 [95% CI; 0, 0.29] difference that the sole use of LHRH antagonist prevents testosterone surge better than combination use of LHRH agonist + anti-androgen (p=0.005). In the study, 12/83 patients who used LHRH agonist + anti-androgen had testosterone surge compared to 0/168 patients in the LHRH antagonist group; p<0.001 (Trachtenberg et al, 2002). If 1 patient had testosterone surge in the LHRH antagonist group, the odds ratio would be 0.04 [95% CI; 0, 0.28] and continued to be statistically significant.

Graphical representations of the odds ratio for testosterone surge between the different treatments can be found in Appendix 10.

2.5 Summary

The avoidance in testosterone surge was statistically lower for treatment with LHRH antagonist compared to LHRH agonist + anti-androgen use, which meant that LHRH antagonist was more effective in avoiding testosterone surge than the standard therapy of LHRH agonist + anti-androgen.

As for clinical flare, no standard definition of flare symptoms was found. The studies evaluated bone pain, disease flare, death resulting from flare and overall pain as flare symptoms. Although in all situations, there was a reduction in the odds of getting flare symptoms associated with the use of LHRH agonist + anti-androgen versus LHRH agonist alone, only the odds ratio measured for bone pain was statistically significant (p=0.05). Unfortunately, there was no direct comparison between LHRH antagonist versus LHRH agonist alone or LHRH agonist + anti-androgen on flare symptoms.

The limitations of the systematic review are that overall, the quality of the included studies was low and the concealment of allocation was unclear. Therefore, the strength of the conclusions of this systematic review must be interpreted in light of the quality of the primary literature.

A small number of comparative trials evaluated flare symptoms, a lack of standard definition for flare symptoms and insufficient information from clinical trials with relevant comparators to allow the use of flare symptoms as an endpoint. Therefore, the cost utility analysis described in the next chapter focused on bone pain instead.

Chapter 3 ECONOMIC ANALYSIS – 3-MONTH HORIZON

3.1 Review of Economic Studies: Methods

3.1.1 Literature searches

A literature search was conducted in June 2009 and identified no previously published cost-effectiveness or cost utility analyses of degarelix for the management of prostate cancer.

Another literature search was conducted to determine whether there are any studies evaluating the cost effectiveness or cost utility of flare symptoms comparing LHRH agonist versus LHRH agonist + anti-androgen in prostate cancer. Two articles were found; one was an abstract of the second article found. The search strategies, database used and search results can be found in Appendix 11. Neither article was relevant since the study evaluated the cost effectiveness of combined androgen blockade (long term use of anti-androgen). Therefore, no relevant literature was found.

3.2 The Issue

A new class of drug for the treatment of prostate cancer is soon to be introduced into the Canadian market. Public payers and society will need a health economics analysis to help evaluate whether degarelix will provide incremental value.

Since one of the negative effects of LHRH agonists is the risk of clinical flare from testosterone surge and LHRH antagonists do not have this drawback, cost utility analysis would help decision makers determine LHRH antagonist’s incremental value.

Unfortunately, there was no study or data for LHRH antagonist versus LHRH agonist alone or LHRH agonist + anti-androgen regarding flare symptoms and that there was no standard definition for flare symptoms. From the systematic review, bone pain was specifically measured as a flare symptom between LHRH agonist versus LHRH agonist + anti-androgen. Therefore, it was selected for use for the economic analysis.

Therefore, a cost utility analysis was conducted using bone pain data and assumed that the absolute risk of reducing bone pain is similar between LHRH agonist + anti-

22 androgen and LHRH antagonist since the objective of using anti-androgen in combination with the initial injection of LHRH agonist is to suppress testosterone and to avoid a testosterone surge.

3.3 Primary Economic Evaluation: Methods

3.3.1 Types of economic evaluation

The aim of this cost utility analysis was to explore the incremental cost of using degarelix (LHRH antagonist) relative to LHRH agonist or LHRH agonist + anti- androgen in Canada for the management of patients with metastatic prostate cancer per unit of quality adjusted life year (QALY) gained.

The cost utility analysis was based on a model; a logical mathematical framework that permits the integration of facts and values and that links these data to outcomes that are of interest to health care decision makers (Johri, 2008).

The economic analysis was to answer the following question:

• What is the cost utility of LHRH antagonist compared to using LHRH agonist plus anti-androgen or using LHRH agonist alone to avoid or to decrease risk of bone pain?

3.3.2 Target population

Metastatic prostate cancer patients

3.3.3 Comparators

There are different drugs and formulations within the class of LHRH agonists, leuprolide, goserelin, triptorelin and buserelin, and different formulations (i.e., 1, 3, 4 or 6-month), which are covered by Ontario Drug Benefit formulary. Although degarelix is a 1-month formulation, the goserelin 3-month formulation was used as the comparator for modelling purposes. Zoladex (goserelin) 3 month formulation is the most commonly prescribed agent (Brogan Inc; Pharmastat, 2009). As stated in the CADTH guideline (CADTH, 2006), when selecting a comparator, “usual care,” which is the most common or most widely used treatment in clinical practice for the

23 condition. The most commonly used treatment that degarelix is intended to replace, replaces the treatment for the largest number of patients, would be goserelin 3-month formulation. Therefore, the comparators used were as follow: • Degarelix vs. Goserelin alone • Degarelix vs. Goserelin + anti-androgen • Goserelin alone vs. Goserelin + anti-androgen

As for anti-androgen, since there is no clinical evidence to indicate that no one anti- androgen should be used in preference to another for the short period that flare protection therapy is given, the choice of anti-androgen for flare protection therapy is more likely to be determined by clinician preference, rather than discrepancies in clinical efficacy. A review of the literature demonstrated that anti-androgens (steroidal and non-steroidal) appear to be equally efficacious in the management of prostate cancer (Migliari et al, 1999). Therefore, bicalutamide was used as the anti-androgen comparator since it is most commonly prescribed (Brogan Inc; Pharmastat, 2009).

3.3.4 Perspective

Two perspectives were conducted: 1) societal, which included patients' out-of-pocket expenses and time lost from work and 2) public payer.

The private payer perspective (i.e., insurers) was not included in this economics evaluation, but this may be of value in future studies. There are several key points to consider in future analysis that could be different from the public perspective such as higher pricing and higher dispensing fees (mark-up is regulated in Ontario to be 8% (Ministry of Health, 2007)). Public payers may have contract prices that are different from the list price and such contract prices are not made public. Although private payers may pay higher prices than public payers, this trend is changing. Private payers have been attempting to rectify the pricing differentials by making arrangements for certain medications with manufacturers (Medavie Blue Cross, 2008).

Also, cash payers were not included in the societal analysis because prostate cancer is predominantly a disease of the aged (over 65 years of age). Therefore, the percentage of cash payers could be very minimal. In other disease states, this type of payer may be more relevant.

3.3.5 Time horizon

The time horizon of the study was 1 month since flare symptoms would be experienced within a 1 month period.

5.3.6 Modelling

The cost utility model was constructed based on three treatment options; degarelix, goserelin 3-month, goserelin 3-month + bicalutamide x 28 days (Figure 2). If degarelix is given, then no anti-androgen is needed.

Figure 2: Decision Tree for Bone Pain

3.3.7 Valuing outcomes

Outcomes measured were either patients who experienced bone pain or no bone pain after initial injection of LHRH agonist compared to baseline (before start of treatment). The probability or absolute risk of experiencing bone pain by each treatment arm was derived from the systematic review.

3.3.8 Utilities

There was no utility found for disease flare or bone pain (resulting from disease flare); however, utility found for patients who were hormone responsive with distant asymptomatic disease was 0.9 (0.8–1) (Bayoumi, 2000). The Bayoumi study evaluated 65-year-old men with a clinically evident, local recurrence of prostate cancer from a societal perspective and a time horizon of 20 years. In the study, utility value of 0.9 was applied to patients with metastatic disease who received first line

25 hormonal therapy. Therefore, it was assumed that patients without symptoms would have the same utility of 0.9 for patients without bone pain. It was further assumed that patients with no bone pain would have the same utility regardless of the medication used.

For patients with bone pain, it was assumed that patients with symptomatic distant prostate cancer with utility of 0.8 (0.4 to 0.9) (Bayoumi, 2000) would be similar to patients who experience bone pain with metastatic disease who received continuous anti-androgen. The difference in utility of 0.1 seems reasonable since the relief of bone pain treatments is sufficient with mild analgesics in the cost utility analysis.

The 0.8 utility value is at the upper range between 0.4 and 0.9. The reason that it is at the upper range could be that the distribution is skewed to the right so that majority of patients may have relatively high utilities and fewer patients with low utilities. Table 5 presents the annual utilities. Since there was no data on LHRH antagonist, it was assumed that utility for LHRH antagonist has the same value as LHRH agonist + anti- androgen. This is conservative because anti-androgen has side effects associated with its use in addition to LHRH agonist.

Since there was no utility value found that specifically targets bone pain in metastatic prostate cancer patients, the utility values found in Bayoumi study were tested in sensitivity analyses. Furthermore, these utility values from the Bayoumi study were only a generalization and that the symptomatic patients refer to bone pain symptom only. This is highly unlikely that patients only experience bone pain and no other symptoms.

Table 5: Annual Utility

Annual utility Distant asymptomatic disease* (e.g., no bone pain) 0.90 Distant symptomatic disease, hormone responsive† (e.g., with bone pain) 0.80 * Applied to patients with metastatic disease receiving 1st-line hormonal therapy † Applied to patients with metastatic disease receiving continuous anti-androgen, undergoing anti-androgen withdrawal or receiving ketoconazole

Since the selection for type of treatment is determined from the start, which can have impact on yearly costs, therefore, a 1-year time horizon analysis was conducted to evaluate the results. Please refer to Chapter 4 for the 1-year model analysis and results.

3.3.9 Resource use and costs

All costs were measured in Canadian dollars. Tables 6, 7 & 8 provide a breakdown of costs and resource allocation that were used for the analysis.

Table 6: Healthcare Resource Use Associated with Drug Administration and Management of Patients Receiving Degarelix or Goserelin

Healthcare Healthcare Month Activity resource use – resource use – Assumptions degarelix goserelin Patient to get First Injection Patients to receive and start Urologist will provide prescription to anti-androgen upon initiating Urologist patient LHRH agonist Patient to receive degarelix / Pharmacist will dispense and provide Pharmacist Pharmacist goserelin from pharmacist counselling to patients First degarelix / goserelin Urologist will provide check up and Urologist Urologist injection for consult consult to patient First degarelix / goserelin Nurse Nurse Nurse will give the injection injection for injection Patient to get Lab test (PSA) Lab test (PSA) All patients will get PSA test baseline PSA 1 Patients who experience Bone Pain Patient visits urologist for Patient will visit urologist to deal with Urologist Urologist having bone pain bone pain Physician will need to determine Lab test (PSA) Lab test (PSA) Patient to get a PSA test whether disease progressed by Urologist Urologist measuring PSA level Patient will need to get prescription Physician prescribes pain Urologist Urologist from urologist and medication from relief medication Pharmacist Pharmacist pharmacist Patients experience lost Patient’s time to travel to pharmacy, None None leisure time urologist’s office, PSA lab test If patients experience bone pain Emergency room visit ER physician ER physician suddenly, then may visit emergency room for treatment

Table 7 provides a breakdown of what and when resource would be used for each product. For example, on day one, one injection is given and the resource use on that day such as urologist consult, nursing time for giving injection and pharmacist time for medication counselling. On day 7, that is possibly when bone pain can happen, which is when a patient may either see a urologist or visit emergency to evaluate the bone pain (hence the 0.5 or 50% of resource use). Also at that same visit, patients would receive a prescription to treat bone pain; hence, pharmacist consults for the new prescription. It was assumed that on day 14, bone pain may get progressively worse; hence the urologist consult and an add-on medication for bone control.

Table 7: Number of Healthcare Resource Use Associated with Drug Administration and Management of Patients Receiving Degarelix or Goserelin

WITH BONE PAIN Degarelix Days 1 7 14 28 Number of practice nurse consultations 100% 0 0 0 Number of practice nurse for injection site reaction 100% 0 0 0 Number of urologist consultations 100% 50% 100% 0 Number of urologist consultations for PSA assessment 0 0 0 100% Number of ER visit 0 50% 0 0 Number of pharmacist consultations 100% 100% 100% 0

Goserelin Days 1 7 14 28 Number of practice nurse consultations 100% 0 0 0 Number of urologist consultations 100% 50% 100% 0 Number of urologist consultations for PSA assessment 0 0 0 100% Number of ER visit 0 50% 0 0 Number of pharmacist consultations 100% 100% 100% 0

Goserelin + Bicalutamide Days 1 7 14 28 Number of practice nurse consultations 100% 0 0 0 Number of urologist consultations 100% 50% 100% 0 Number of urologist consultations for PSA assessment 0 0 0 100% Number of ER visit 0 50% 0 0 Number of pharmacist consultations 100% 100% 100% 0

Management of injection site reaction for Degarelix Cold compress Extra nursing time required for administration of cold 5 compress (mins)

The resource costs are presented in Table 8. The resource costs were derived from OHIP listed services. For the cost per practice nurse administration time, due to the extra time needed for reconstitution for degarelix, an extra 5 minutes was added to degarelix compared to goserelin.

Table 8: Unit Costs (OHIP Listed Services) Nurse / urologist / pharmacist consultations Cost per urologist consultation $22 Cost per urologist consultation for PSA level assessment $51 Cost per practice nurse consultation for DEGARELIX administration (20 mins) $35/hour $11.67 Cost per practice nurse consultation for LHRH agonist administration (15 mins) $35/hour $8.75 Cost per pharmacist consultation for 15 minutes ($50/hour) $12.50 Cost per practice nurse for DEGARELIX injection site reaction (5 mins) $2.92 Cost of ER physician $97.60

Procedural costs

Cost per PSA test (CML Healthcare, 2009) $30

The following tables provide an overview of all the drug costs associated with patients on hormonal therapy treated for bone pain (Cancer Care Nova Scotia, 2005). As for treatment of bone pain, the following algorithm from Cancer Care Nova Scotia was used (Figure 3). For modelling purposes, since acetaminophen is always used first line, it was assumed that it is continuously taken for 21 days to help with bone pain. Then as an add-on medication if acetaminophen was not enough, naproxen use was assumed to be taken for 14 days. No other add-on therapy, such as corticosteroid or biphosphonate was assumed.

Figure 3: Drugs for Cancer Pain Management (Cancer Care Nova Scotia, 2005)

Table 9 provides the Ontario formulary list prices for the drugs used in the model. Based on the Ontario and the national Joint Oncology Drug Review process, submissions to the provinces does not include mark-up or dispensing fees (Ministry of Health and Long-Term Care, 2000). Therefore, no mark-up or dispensing fees were added to the drug costs when calculating from the public perspective. From a societal perspective, mark-up of 8% to a maximum of $25 mark-up (Brogan, 2009) and dispensing fee of $7 were used in the analysis (Ministry of Health and Long-Term Care, 2009).

From a societal perspective, the costs of medications were calculated with 8% mark- up (to a maximum of $25) and a $7 dispensing fee.

In order to calculate the monthly cost of degarelix and goserelin, an average monthly cost was calculated. For goserelin, a 3-month injection of $1,088 plus $25 mark-up and $7 dispensing fee, then divided by 3 months to get the average monthly cost

[($1,088+25+7)/3 = $373]. For degarelix, the average monthly cost is starting dose, plus 2 monthly maintenance dose plus mark-up and dispensing fees, then divided by 3 [($811+$25+7)+($300*1.08+7)+($300*1.08+7)/3 = $502].

From a public payer perspective, the costs of medications were calculated without mark-up and dispensing fee. Therefore, Table 9 provides costs of medications with and without mark-up and dispensing fees for calculating incremental cost per QALY gained from societal and public payer perspectives.

Table 9: Drug Costs (Ontario Drug Benefit Formulary List, 2009)

DEGARELIX Cost per 240 mg starter injection $811 Cost per 80 mg maintenance injection $300 Average cost of injection per month (without mark-up & dispensing fee) $470 Average cost per month with mark up and dispensing fee $502

GOSERELIN Cost per 10.8 mg (3 month) injection $1088 Average cost of injection per month (without mark-up & dispensing fee) $363 Average cost per month with mark up and dispensing fee $373

BICALUTAMIDE Cost per 50 mg tablet $3.22 Cost per 3 weeks (21 days) (without mark-up & dispensing fee) $90.16 Total cost per month with mark up and dispensing fee $104.37

BONE PAIN MANAGEMENT

ACETAMINOPHEN (325-650 mg po q4h - Dose of 650 mg qid is assumed) Acetaminophen 325 mg tablet $0.0114 Number of tablets required (21 days*2 tablets*4 x/day) 168 Total cost of acetaminophen (without mark-up & dispensing fee) $1.92 Total cost per month with mark up and dispensing fee $9.07

NSAIDs (Naproxen 250 mg to 500 mg bid - Lowest dose of 250 mg bid assumed Naproxen 250 mg tablet $0.1068 Number of tablets required (14 days*2 tablets/day) 28 Total cost of NSAID (without mark-up & dispensing fee) $2.99 Total cost per month with mark up and dispensing fee $10.23

Indirect Costs – Societal Perspective

Indirect costs associated with those individuals (non-retirees) with private insurance coverage would be the loss of time from work. For those patients who are retired, the indirect costs would be the loss of leisure time.

To estimate the percentage of patients who are retirees and non-retirees, it was assumed that patients over the age of 65 would be retirees. Therefore, about 75% of patients would be retirees based on the incidence of prostate cancer in patients who were over the age of 65 (Canadian Cancer Statistics, 2008).

For retirees, the cost of loss of leisure time was calculated by using the average houseworkers’ minimum wage (Kernick DP, 2000). For 25% of the non-retirees, these patients would likely be covered by private payers; therefore, the loss of productivity was calculated using minimum wage (Ministry of Labour, 2009).

The travelling distance to the urologist’s office was assumed to be approximately 30 km in total (to/from office). This figure was used since one can travel to/from the greater Toronto area within this distance. The average cost per kilometre was calculated by using a Toyota Camry’s fuel consumption figure of 9.5L/30km (fuelconsumption.ca) at an average cost of $1 per litre of gas. The time lost in hours from work to appointment was assumed to be about 4 hours and if patients have bone pain, it was assumed the time missed from work would be longer (8 hours) – a full day’s of work.

Indirect costs were not applied from the public payer perspective calculations.

Table 10: Indirect Costs Non-Retirees and Patient (Retirees) Costs

Indirect Costs - Non-Retirees Loss of time from work Minimum wage per hour $10.25 Time lost in hours from work to urologist appointment 4 includes time to pharmacy Time lost in hours from work to appointment per episode of bone pain 8 includes time to pharmacy Total dollar lost from work missed per appointment $41.00 Total dollar lost from work per episode of bone pain $82.00

Indirect Costs - Retirees Loss of leisure time Homeworkers’ wage per hour $10.25 Time lost in hours from work to urologist appointment 4 Time lost in hours to appointment per episode of bone pain 8 includes to pharmacy time Total dollar loss of leisure time from urologist appointment $41.00 Total dollar loss of leisure time from per episode of bone pain $82.00

Travel cost Distance to urologist’s office (in km) 30 Average cost of total trip ($1/L * (9.5 L/30 km)*30km) $10 includes distance to pharmacy

3.3.10 Discount rate

No discounting was needed since this was only a 1-month timeframe analysis.

3.3.11 Variability and uncertainty

An incremental analysis of costs and consequences was done to determine the different cost per QALY ratios. The pro of doing a univariate sensitivity analysis is how much each confounder affects the ratio; however, the con is that in real life, no confounder happens one at a time. Therefore, a tornado diagram was created to help determine the results from the multiple univariate sensitivity analysis in a graphical way to determine the amount of impact of each confounder.

3.3.12 Summary of model assumptions

• Guidelines (Mongiat-Artus et al., 2005; National Institute of Clinical Excellence., 2008) recommend that anti-androgen use with initial injection of LHRH agonist for 2 and 4 weeks. A 4-week duration of anti-androgen use is assumed since metastatic patients would most likely receive the full 4 weeks treatment to avoid clinical flares.

• The dosage of the anti-androgen drug, bicalutamide was assumed to be 50 mg once daily. Although the Nova Scotia Cancer Guidelines recommends the dosage range to be 50 mg to 150 mg once daily, Alberta Cancer Board (2007), B.C. Cancer Agency and Cancer Care Ontario (Cancer Care Ontario Fact Sheet) recommend bicalutamide 50 mg once daily to be administered.

3.4 Primary Economic Evaluation: Results

3.4.1 Results – Societal Perspective

Degarelix direct costs (with and without bone pain) are presented in Tables 11 & 12. Drug costs were calculated as follow: Day 1 = cost of degarelix or goserelin; Day 7 and Day 14 were costs of bone pain medications and the costs of urologist/nursing/ pharmacist calculated from the number of visits. Two PSA lab tests were assumed to be done on Days 1 and 28 if bone pain existed. Since PSA test is used to monitor progress, the second PSA test would be done in those patients who experienced

complications such as bone pain. If patients experienced no bone pain, then only one PSA lab test was assumed on Day 1.

To calculate the total societal cost, the non-retiree costs were calculated by multiplying 25% of patients by $205.00 = $51.25 and for retiree, 75% of patients * $233.50 = $175.13. The total societal costs equated to non-retiree cost of $51.25 + retiree cost of $175.13 + public cost of $765.77 = $992.14.

Then using absolute risk for bone pain of 29% for degarelix or goserelin + bicalutamide and 63% for LHRH agonist alone (Kuhn et al, 1989), the total societal cost would be 29% * $992.14 = $287.72 for patients with bone pain.

Table 11: Degarelix Societal Costs (With Bone Pain) Direct Costs - Public & Private DEGARELIX (Worst case scenario with bone pain increasingly worse)

Urologist / Nursing / Days Drug costs PSA lab test AE costs Total cost Pharmacist consult costs 1 $501.67 $40.75 $30.00 $2.92 $575.34 7 $9.07 $63.97 $0.00 $0.00 $73.04 14 $10.23 $26.17 $0.00 $0.00 $36.40 28 $0.00 $51.00 $30.00 $0.00 $81.00 Total $520.96 $181.89 $60.00 $2.92 $765.77

DEGARELIX Indirect cost to employer (Non-Retirees) Days Loss time from work Total cost 1 $41.00 $41.00 7 $82.00 $82.00 14 $82.00 $82.00 28 $0.00 $0.00 Total $205.00 $205.00

DEGARELIX Indirect costs to patient (Retirees) Days Loss of leisure time Travelling cost Total cost

1 $41.00 $9.50 $50.50 7 $82.00 $9.50 $91.50 14 $82.00 $9.50 $91.50 28 $0.00 $0.00 $0.00 Total $205.00 $28.50 $233.50 Assumption: Since 75% of patients are over 65 years of age, 75% of patients would be retired and 25% would be private. Societal Cost per Patient (with bone pain) Public $765.77 Private (non-retiree) $51.25 = 25% * $205 Patient (retiree) $175.13 = 75% * $223.50

Total Societal Cost $992.14 Absolute risk for bone pain (Kuhn et al, 1989) A + AA or degarelix = 29% Agonist alone = 63% SOCIETAL COST PER PATIENT (WITH BONE PAIN) WITH PROBABILITY Total Societal Cost $287.72 = 29% * $992.14

In patients without bone pain, only degarelix or goserelin drug costs were included because no bone pain medication was used. Similarly, there was a lower number of visits to physicians/pharmacists if no bone pain was experienced.

The total societal cost would be (100%-29%) * $623.46 = $442.66 for patients without bone pain.

Table 12: Degarelix Societal Costs (Without Bone Pain)

DEGARELIX Direct Costs - Public & Private Urologist / Nursing / PSA lab Days Drug costs AE costs Total cost Pharmacist consult costs test 1 $501.67 $40.75 $30.00 $2.92 $575.34 7 $0.00 $0.00 0 0 $0.00 14 $0.00 $0.00 $0.00 $0.00 $0.00 28 $0.00 $0.00 $0.00 $0.00 $0.00 Total $501.67 $40.75 $30.00 $2.92 $575.34

DEGARELIX Indirect cost to employer (Non-Retirees) Days Loss time from work Total cost 1 $41.00 $41.00 7 $0.00 $0.00 14 $0.00 $0.00 28 $0.00 $0.00 Total $0.00 $41.00

DEGARELIX Indirect costs to patient (Retirees) Days Loss of leisure time Travelling cost Total cost 1 $41.00 $9.50 $50.50 7 $0.00 $0.00 $0.00 14 $0.00 $0.00 $0.00 28 $0.00 $0.00 $0.00 Total $41.00 $9.50 $50.50 Assumption: Since 75% of patients are over 65 years of age, 75% of patients would be retired and 25% would be private. Societal Cost per Patient (with bone pain) Public $575.34 Private (non-retiree) $10.25 = 25% * $41 Patient (retiree) $37.88 = 75% * $50.50 Total Societal Cost $623.46

Absolute risk for no bone pain (Kuhn et al, 1989) A + AA or degarelix =71% (100%-29%) Agonist alone = 37% (100%-39%) SOCIETAL COST PER PATIENT (WITHOUT BONE PAIN) WITH PROBABILITY Total Societal Cost $442.66 = 71% * $623.46

Therefore, the total societal cost per patient (with and without bone pain) with degarelix was calculated to be $730.38 (Table 13).

Table 13: Total Degarelix Societal Cost (With and Without Bone Pain)

SOCIETAL COST PER PATIENT WITH PROBABILITY OF HAVING BONE PAIN $287.72 + SOCIETAL COST PER PATIENT WITH PROBABILITY OF NO BONE PAIN $442.66 = TOTAL SOCIETY COST PER PATIENT FOR DEGARELIX (WITH AND WITHOUT BONE PAIN) $730.38

Goserelin societal cost (with and without bone pain) are presented in Tables 14 & 15.

Table 14: Goserelin Societal Costs (With Bone Pain) Direct Costs - GOSERELIN Public & Private Worst case scenario with bone pain increasingly worse Urologist / Nursing / PSA lab Days Drug costs AE costs Total cost Pharmacist consult costs test 1 $373.38 $37.84 $30.00 $0.00 $441.21 7 $9.07 $63.97 $0.00 $0.00 $73.04 14 $10.23 $26.17 $0.00 $0.00 $36.40 28 $0.00 $52.00 $30.00 $0.00 $82.00 Total $392.67 $179.97 $60.00 $0.00 $632.64

GOSERELIN Indirect cost to employer (Non-Retirees) Days Loss time from work Total cost

1 $41.00 $41.00 7 $82.00 $82.00 14 $82.00 $82.00 28 $0.00 $0.00 Total $205.00 $205.00

GOSERELIN Indirect costs to patient (Retirees) Days Loss of leisure time Travelling cost Total cost

1 $41.00 $9.50 $50.50 7 $82.00 $9.50 $91.50 14 $82.00 $9.50 $91.50

28 $0.00 $0.00 $0.00 Total $205.00 $28.50 $233.50 Assumption: Since 75% of patients are over 65 years of age, 75% of patients would be retired and 25% would be private. Societal Cost per Patient Public $632.64 Private (non-retiree) $51.25 = 25% * $205 Patient (retiree) $175.13 = 75% * $233.50 Total Societal Cost $859.02 Absolute risk for bone pain (Kuhn et al, 1989) A + AA or degarelix = 29% LHRH Agonist alone = 63% SOCIETAL COST PER PATIENT (WITHOUT BONE PAIN) WITH PROBABILITY Total Societal Cost $541.18 = 29% * $859.02

Table 15: Goserelin Societal Costs (Without Bone Pain)

GOSERELIN Direct Costs - Public & Private Urologist / Nursing / Days Drug costs PSA lab test AE costs Total cost Pharmacist consult costs 1 $373.38 $37.84 $30.00 $0.00 $441.21 7 $0.00 $0.00 $0.00 $0.00 $0.00 14 $0.00 $0.00 $0.00 $0.00 $0.00 28 $0.00 $0.00 $0.00 $0.00 $0.00 Total $373.38 $37.84 $30.00 $0.00 $441.21

GOSERELIN Indirect cost to employer (Non-Retirees) Days Loss time from work Total cost 1 $41.00 $41.00 7 $0.00 $0.00 14 $0.00 $0.00 28 $0.00 $0.00 Total $0.00 $41.00

GOSERELIN Indirect costs to patient (Retirees) Days Loss of leisure time Travelling cost Total cost

1 $41.00 $9.50 $50.50 7 $0.00 $9.50 $9.50 14 $0.00 $9.50 $9.50 28 $0.00 $0.00 $0.00 Total $41.00 $28.50 $69.50 Assumption: Since 75% of patients are over 65 years of age, 75% of patients would be retired and 25% would be non-retirees. Societal Cost per Patient Public $441.21 Private (non-retiree) $10.25 = 25% * $41 Patient (retiree) $52.13 = 75% * $69.50 Total Societal Cost $503.59 Absolute risk for no bone pain (Kuhn et al, 1989) A + AA or degarelix =71% (100%-29%) LHRH Agonist alone = 37% (100%-39%)

SOCIETAL COST PER PATIENT (WITHOUT BONE PAIN) WITH PROBABILITY Total Societal Cost $186.33 = 37% * $503.59

Therefore, the total societal cost per patient (with and without bone pain) with goserelin is $727.51 (Table 16).

Table 16: Total Goserelin Societal Costs (With and Without Bone Pain)

SOCIETAL COST PER PATIENT WITH PROBABILITY OF HAVING BONE PAIN $541.18 + SOCIETAL COST PER PATIENT WITH PROBABILITY OF NO BONE PAIN $186.33 = TOTAL SOCIETY COST PER PATIENT FOR DEGARELIX (WITH AND WITHOUT BONE PAIN) $727.51

Goserelin + bicalutamide societal cost (with and without bone pain) are presented in Tables 17 & 18.

Table 17: Goserelin + Bicalutamide Societal Costs (With Bone Pain) Direct Costs - GOSERELIN + Public & BICALUTAMIDE Private Worst case scenario with bone pain increasingly worse Urologist / Nursing / Days Drug costs PSA lab test AE costs Total cost Pharmacist consult costs 1 $477.75 $34.92 $30.00 $0.00 $542.67 7 $9.07 $59.80 $0.00 $0.00 $68.87 14 $10.23 $26.17 $0.00 $0.00 $36.40 28 $0.00 $52.00 $30.00 $0.00 $82.00 Total $497.05 $172.88 $60.00 $0.00 $729.93

GOSERELIN + BICALUTAMIDE Indirect cost to employer (Non-Retirees) Days Loss time from work Total cost

1 $41.00 $41.00 7 $82.00 $82.00 14 $82.00 $82.00 28 $0.00 $0.00 Total $205.00 $205.00

GOSERELIN + BICALUTAMIDE Indirect costs to patient (Retirees) Days Loss of leisure time Travelling cost Total cost

1 $41.00 $9.50 $50.50 7 $82.00 $9.50 $91.50 14 $82.00 $9.50 $91.50

28 $0.00 $0.00 $0.00 Total $205.00 $28.50 $233.50 Assumption: Since 75% of patients are over 65 years of age, 75% of patients would be retired and 25% would be non-retirees (affected by private payers). Societal Cost per Patient Public $729.93 Private (non-retiree) $51.25 = 25% * $205.00 Patient (retiree) $175.13 = 75% * $233.50 Total Societal Cost $956.31 Absolute risk for bone pain (Kuhn et al, 1989) A + AA or degarelix = 29% LHRH Agonist alone = 63% SOCIETAL COST PER PATIENT (WITHOUT BONE PAIN) WITH PROBABILITY Total Societal Cost $277.33 = 29% * $956.31

Table 18: Goserelin + Bicalutamide Societal Costs (Without Bone Pain) GOSERELIN + BICALUTAMIDE Direct Costs - Public & Private Urologist / Nursing / Days Drug costs PSA lab test AE costs Total cost Pharmacist consult costs 1 $477.75 $34.92 $30.00 $0.00 $542.67 7 $0.00 $0.00 $0.00 $0.00 $0.00 14 $0.00 $0.00 $0.00 $0.00 $0.00 28 $0.00 $0.00 $0.00 $0.00 $0.00 Total $477.75 $34.92 $30.00 $0.00 $542.67

GOSERELIN + BICALUTAMIDE Indirect cost to employer (Non-Retirees) Days Loss time from work Total cost 1 $41.00 $41.00 7 $0.00 $0.00 14 $0.00 $0.00 28 $0.00 $0.00 Total $0.00 $41.00 Assumption: Since 75% of patients are over 65 years of age, 75% of patients would be retired and 25% would be non-retirees (affected by private payers). GOSERELIN + BICALUTAMIDE Indirect costs to patient (Retirees)

Days Loss of leisure time Travelling cost Total cost

1 $41.00 $9.50 $50.50 7 $0.00 $0.00 $0.00 14 $0.00 $0.00 $0.00 28 $0.00 $0.00 $0.00 Total $41.00 $9.50 $50.50

Societal Cost per Patient Public $542.67 Private (non-retiree) $30.75 = 25% * $41.00 Patient (retiree) $12.63 = 75% * $50.50

Total Societal Cost $586.04 Absolute risk for no bone pain (Kuhn et al, 1989) A + AA or degarelix =71% (100%-29%) LHRH Agonist alone = 37% (100%-39%) SOCIETAL COST PER PATIENT (WITHOUT BONE PAIN) WITH PROBABILITY

Total Societal Cost $416.09 = 37% * $586.04

Therefore, the total societal cost per patient (with and without bone pain) with goserelin + bicalutamide is $693.42 (Table 19).

Table 19: Total Goserelin + Bicalutamide Societal Costs (With and Without Bone Pain)

SOCIETAL COST PER PATIENT WITH PROBABILITY OF HAVING BONE PAIN $277.33 + SOCIETAL COST PER PATIENT WITH PROBABILITY OF NO BONE PAIN $416.09 = TOTAL SOCIETY COST PER PATIENT FOR DEGARELIX (WITH AND WITHOUT BONE PAIN) $693.42

Adjusted QALY

The adjusted QALY was calculated by determining the difference between the QALY with and without bone pain (0.9-0.8 = 0.1) for the duration of one month (1/12) and the difference between the absolute risk of having bone pain and not having bone pain between two treatments, degarelix and goserelin (63%-29%=34%). Since 34% of patients would not have bone pain if degarelix was given instead of goserelin, then the adjusted QALY would be 34% of (0.1*1/12) = 0.0028333. The reverse is calculated between goserelin and goserelin + bicalutamide, which is -0.0028333 since goserelin has less utility than goserelin + bicalutamide.

It was not possible to calculate an incremental cost per QALY between degarelix and goserelin + bicaultamide because since the difference in QALY would be the difference in finding the utilities and the risk of having bone pain between the two and utilities and risks were assumed to be the same. Therefore, there would be no difference in QALY. So, it was not possible to compare these two treatments except in costs.

Total Societal Costs

The total societal costs per patient of degarelix in the first month when patients have bone pain were $730, for goserelin was $728 and for goserelin + bicalutamide was $693 (Table 20).

Incremental Cost per QALY

The incremental cost per QALY between degarelix and goserelin was the difference between the costs of degarelix ($738) and goserelin ($740), which equated to $3 and the adjusted QALY was 0.0028333. Therefore, the incremental cost per QALY between degarelix and goserelin was $3/0.0028333 = $1,013. A similar calculation was done for goserelin versus goserelin + bicalutamide, which worked out to be dominated for goserelin.

Table 20: Incremental Cost per QALY

ANNUAL UTILITY Length of time Adjusted QALY Annual with and without between degarelix and utility bone pain QALY goserelin Distant asymptomatic disease (e.g., no = 1/12 0.9*0.0833= bone pain) 0.9 = 0.083333333 0.0750 Distant symptomatic disease, hormone 0.8*0.0833= 0.0083*(63%-29%) = responsive (e.g., with bone pain) 0.8 (1 month) 0.0667 0.002833333

With and Without Bone Pain One-Month Total cost of degarelix societal cost $730 Total cost of goserelin societal cost $727 Total cost of goserelin + bicalutamide societal cost $693

Incremental Cost Incremental Cost per QALY Degarelix $730 Goserelin $727 Incremental $3 $1,013

Incremental Cost Incremental Cost per QALY Degarelix $730 Goserelin + Bicalutamide $693 Incremental $37 Not applicable

Incremental Cost Incremental Cost per QALY Goserelin $727 Goserelin + Bicalutamide $693 Dominated Incremental $34 = $34/-0.002833333

Goserelin had a favourable cost-effectiveness profile (i.e., dominated) relative to goserelin + bicalutamide. As for degarelix, it had an incremental cost per QALY of $1,013 in relation to goserelin (Table 20).

3.4.2 Sensitivity Analyses – Societal Perspective

The following tornado diagram provides a univariate analysis based on the basecase scenario of degarelix versus goserelin with a dominated incremental cost per QALY. The factors varied were the cost of degarelix, the cost of goserelin, absolute risk for bone pain with degarelix or with goserelin ± 25% from baseline. Table 21 provides the low and high value for each factor.

Table 21: Univariate Analysis

Factor Base Low High Cost of degarelix $502 $377 $628 Absolute risk for bone pain (with degarelix) 29% 22% 36% Absolute risk for bone pain (with goserelin ) 63% 47% 79% Cost of goserelin $373 $280 $467 Distant asymptomatic disease utility 0.9 0.81 1 Distant symptomatic disease utility 0.8 0.4 0.89

Table 22 provides the low and high of incremental cost per QALY for each factor.

Table 22: Univariate Analysis on Incremental Cost per QALY

Factor Low High Delta in Incremental Cost/QALY (Degarelix vs. Goserelin) Cost of degarelix Dominant $45,601 $88,588 Absolute risk for bone pain (with degarelix) $6,714 $12,745 $6,031 Absolute risk for bone pain (with goserelin) $39,825 Dominant $52,785 Cost of goserelin $33,969 Dominant $66,000 Distant asymptomatic disease utility $10,126 $506 $9,620 Distant symptomatic disease utility $203 $10,126 $9,923

Figure 4 depicts the univariate sensitivity analysis on the four factors. The biggest variant was the cost of degarelix. The incremental cost per QALY could be as much as $45,000.

Figure 4: Univariate Sensitivity Analysis (Societal Perspective)

Cost per QALY (Degarelix vs Goserelin)

-$50,000 -$40,000 -$30,000 -$20,000 -$10,000 $0 $10,000 $20,000 $30,000 $40,000 $50,000 $60,000

Cost of degarelix

Absolute risk for bone pain (w ith degarelix)

Absolute risk for bone pain (w ith goserelin)

Cost of goserelin

Distant asymptomatic disease utility

Distant symptomatic disease utility

Multivariate Sensitivity Analysis – Best Case Scenario

Table 23 presents the best case scenario for degarelix if the variants happened at the same time. These factors were chosen because these affected the incremental cost per QALY the most based on the univariate sensitivity analysis.

The reasons for the figures are as such:

• Cost of degarelix was the lowest price possible.

• Cost of goserelin was 10% higher than its current price (if Ontario Drug Benefit allows)

• Absolute for bone pain with degarelix and goserelin were changed to 0% and 100%, respectively

• Utility of distant asymptomatic disease was changed to 1, perfect health with no symptoms

• Utility of distant symptomatic disease was changed to 0.4, the lowest utility value as stated in the Bayoumi study

Table 23: Multivariants on Incremental Cost per QALY for Degarelix versus Goserelin Factor Base Best Case Scenario Cost of degarelix per month $502 $300 Absolute risk for bone pain (with degarelix) 29% 0% Absolute risk for bone pain (with goserelin) 63% 100%

Cost of goserelin $373 $410 Distant asymptomatic disease utility 0.9 1 Distant symptomatic disease utility 0.8 0.4

Based on these factors, degarelix had a favourable cost effectiveness profile (dominant) in relation to goserelin (Table 24).

Table 24: Incremental Cost per QALY – Best Case Scenario Incremental Cost Incremental Cost per QALY Degarelix $422 Goserelin $896 Incremental Dominant

Multivariate Sensitivity Analysis – Worst Case Scenario

Table 25 presents the worst case scenario for degarelix if the variants happened at the same time. These factors were chosen because these affected the incremental cost per QALY the most based on the univariate sensitivity analysis.

Table 25: Multivariants on Incremental Cost per QALY for Degarelix versus Goserelin Factor Base Worst Case Scenario Cost of degarelix per month $502 $700 Absolute risk for bone pain (with degarelix) 29% 100% Absolute risk for bone pain (with goserelin) 63% 0% Cost of goserelin $373 $187 Distant asymptomatic disease utility 0.9 0.8 Distant symptomatic disease utility 0.8 0.9

The reasons for the figures are as such:

• Cost of degarelix was the 40% higher than base price (same as the highest marketed price globally)

• Cost of goserelin was 50% lower than its current price (if generics appear)

• Absolute for bone pain with goserelin and degarelix were changed to 0% and 100%, respectively

• Utility of distant asymptomatic disease was changed to 0.8, the lowest utility value as in the Bayoumi study

• Utility of distant symptomatic disease was changed to 0.9, the highest utility value as in the Bayoumi study

Based on these factors, goserelin had favourable cost effectiveness profile in relation to degarelix (Table 26).

Table 26: Incremental Cost per QALY – Worst Case Scenario Incremental Cost Incremental Cost per QALY Degarelix $1,190 Goserelin $317 Incremental $873 $104,792

3.4.3 Results – Public Perspective

The differences between the public and the societal perspective were 1) the costs of medications did not include mark-up and dispensing fee and 2) indirect costs were excluded. Otherwise, all calculations were performed the same way as the societal perspective.

Table 27 provides degarelix, goserelin, and goserelin + bicalutamide direct costs (with bone pain) from a public payer perspective.

Table 27: Direct Costs (with Bone Pain)

DEGARELIX Urologist / Nursing / Days Drug costs PSA lab test AE costs Total cost Pharmacist consult costs 1 $470.33 $40.75 $30.00 $2.92 $544.00 7 $1.92 $63.97 $0.00 $0.00 $65.88 14 $2.99 $26.17 $0.00 $0.00 $29.16 28 $0.00 $51.00 $30.00 $0.00 $81.00 Total $475.24 $181.89 $60.00 $2.92 $720.04 GOSERELIN Urologist / Nursing / Days Drug costs PSA lab test AE costs Total cost Pharmacist consult costs 1 $362.71 $37.84 $30.00 $0.00 $430.55 7 $1.92 $63.97 $0.00 $0.00 $65.88 14 $2.99 $26.17 $0.00 $0.00 $29.16 28 $0.00 $52.00 $30.00 $0.00 $82.00 Total $367.62 $179.97 $60.00 $0.00 $607.59 GOSERELIN + BICALUTAMIDE

Urologist / Nursing / Days Drug costs PSA lab test AE costs Total cost Pharmacist consult costs 1 $452.87 $34.92 $30.00 $0.00 $517.79 7 $1.92 $59.80 $0.00 $0.00 $61.72 14 $2.99 $26.17 $0.00 $0.00 $29.16 28 $0.00 $52.00 $30.00 $0.00 $82.00 Total $457.78 $172.88 $60.00 $0.00 $690.66

Table 28 provides degarelix, goserelin, and goserelin + bicalutamide direct costs (without bone pain) from a public payer perspective.

Table 28: Direct Costs (without Bone Pain)

DEGARELIX Urologist / Nursing / Days Drug costs PSA lab test AE costs Total cost Pharmacist consult costs 1 $470.33 $40.75 $30.00 $2.92 $544.00 7 $0.00 $0.00 0 0 $0.00 14 $0.00 $0.00 $0.00 $0.00 $0.00 28 $0.00 $0.00 $0.00 $0.00 $0.00 Total $470.33 $40.75 $30.00 $2.92 $544.00 GOSERELIN Urologist / Nursing / Days Drug costs PSA lab test AE costs Total cost Pharmacist consult costs 1 $362.71 $37.84 $30.00 $0.00 $430.55 7 $0.00 $0.00 $0.00 $0.00 $0.00 14 $0.00 $0.00 $0.00 $0.00 $0.00 28 $0.00 $0.00 $0.00 $0.00 $0.00 Total $362.71 $37.84 $30.00 $0.00 $430.55 GOSERELIN + BICALUTAMIDE Urologist / Nursing / Days Drug costs PSA lab test AE costs Total cost Pharmacist consult costs 1 $452.87 $34.92 $30.00 $0.00 $517.79 7 $0.00 $0.00 $0.00 $0.00 $0.00 14 $0.00 $0.00 $0.00 $0.00 $0.00 28 $0.00 $0.00 $0.00 $0.00 $0.00 Total $452.87 $34.92 $30.00 $0.00 $517.79

The adjusted public costs with absolute risk of bone pain are presented in Table 29.

Table 29: Adjusted Public Costs

With Bone Pain Without Bone Pain Total Degarelix $209.43 $386.24 $595.67 Goserelin $384.12 $159.30 $543.43 Goserelin + Bicalutamide $200.91 $367.63 $568.54

Table 30 presents the incremental cost per QALY from a public perspective. Degarelix resulted in an incremental $18,697/QALY when compared to goserelin.

The incremental cost per QALY is dominated for goserelin relative to goserelin + bicalutamide.

Table 30: Incremental Cost per QALY

ANNUAL UTILITY Length of time Adjusted QALY Annual with and without between degarelix utility bone pain QALY and goserelin Distant asymptomatic disease 0.9*0.0833= (e.g., no bone pain) 0.9 = 1/12 0.0750 Distant symptomatic disease, = 0.083333333 0.0083*(63%- hormone responsive (e.g., with 0.8*0.0833= 29%) = bone pain) 0.8 (1 month) 0.0667 0.0028333

With and Without Bone Pain One-Month Total cost of degarelix societal cost $595 Total cost of goserelin societal cost $542 Total cost of goserelin + bicalutamide societal cost $568

Incremental Cost per Incremental Cost QALY Degarelix $595 Goserelin $542 Incremental $53 $18,697 = $53/0.0028333

Incremental Cost per Incremental Cost QALY Degarelix $595 Goserelin + Bicalutamide $568 Incremental $27 Not applicable

Incremental Cost per Incremental Cost QALY Goserelin $542 Goserelin + Bicalutamide $568 Incremental -$26 $9,119 = -$26/-0.002833333

3.4.4 Sensitivity Analyses – Public Perspective Table 31 provides the low and high of incremental cost per QALY for each factor.

Table 31: Univariate Analysis on Incremental Cost per QALY

Delta in Incremental Cost/QALY (Degarelix vs Factor Low High Goserelin) Cost of degarelix $14,245 $74,344 $60,099 Absolute risk for bone pain (with degarelix) $11,898 $29,021 $17,123

Absolute risk for bone pain (with goserelin) $35,316 $12,714 $22,602 Cost of goserelin $47,888 Dominant $66,000 Distant asymptomatic disease utility $186,965 $9,348 $177,617 Distant symptomatic disease utility $3,739 $186,965 $183,226

Figure 5 depicts the univariate sensitivity analysis on the six factors. The biggest variant was the utility values. The incremental cost per QALY could be as much as $186,000 with degarelix in relation to goserelin.

Figure 5: Univariate Sensitivity Analysis (Public Perspective)

Incremental Cost per QALY (degarelix vs goserelin)

-$50,000 $0 $50,000 $100,000 $150,000 $200,000

Cost of degarelix

Absolute risk for bone pain (w ith degarelix)

Absolute risk for bone pain (w ith goserelin)

Cost of goserelin

Distant asymptomatic disease utility

Distant symptomatic disease utility

Multivariate Sensitivity Analysis – Best Case Scenario

Table 32 presents the best case scenario for degarelix if the variants happened at the same time. These factors were chosen because these affected the incremental cost per QALY the most based on the univariate sensitivity analysis.

Table 32: Multivariants on Incremental Cost per QALY for Degarelix versus Goserelin

Factor Base Best Case Scenario Cost of degarelix per month $502 $300 Absolute risk for bone pain (with degarelix) 29% 0% Absolute risk for bone pain (with goserelin) 63% 100% Cost of goserelin $373 $410 Distant asymptomatic disease utility 0.9 1

Distant symptomatic disease utility 0.8 0.4

Based on these factors, degarelix had a favourable cost effectiveness profile (dominant) in relation to goserelin (Table 33).

Table 33: Incremental Cost per QALY – Best Case Scenario

Incremental Cost Incremental Cost per QALY Degarelix $374 Goserelin $589 Incremental Dominant

Multivariate Sensitivity Analysis – Worst Case Scenario

Table 34 presents the worst case scenario for degarelix if the variants happened at the same time. These factors were chosen because these affected the incremental cost per QALY the most based on the univariate sensitivity analysis.

Table 34: Multivariants on Incremental Cost per QALY for Degarelix versus Goserelin

Factor Base Worst Case Scenario Cost of degarelix per month $502 $700 Absolute risk for bone pain (with degarelix) 29% 100% Absolute risk for bone pain (with goserelin) 63% 0% Cost of goserelin $373 $187 Distant asymptomatic disease utility 0.9 0.8 Distant symptomatic disease utility 0.8 0.81

Based on these factors, goserelin had a favourable cost effectiveness profile in relation to degarelix (Table 35).

Table 35: Incremental Cost per QALY – Worst Case Scenario

Incremental Cost Incremental Cost per QALY Degarelix $950 Goserelin $366 Incremental $583 $205,884

3.5 Conclusion

Given the available data, a cost utility analysis was conducted to determine the implications of incremental cost per QALY in metastatic prostate cancer patients.

From a societal perspective, it appeared that goserelin + bicalutamide had a favourable cost-effectiveness profile in relation to goserelin (dominant incremental cost/QALY).

From a public payer perspective, goserelin + bicalutamide also had a favourable cost- effectiveness profile in relation to goserelin ($9,119/QALY).

Degarelix had an incremental cost of $1,013 per QALY relative to goserelin from a societal perspective, and $18,697 per QALY from a public payer perspective relative to goserelin.

From the sensitivity analyses, the cost of the interventions (degarelix or goserelin) and the utility values affected the incremental cost per QALY greatly and can affect listing decisions. Using these factors, multivariant sensitivity analyses were conducted using the best and worst case scenarios to provide a range of incremental cost per QALY for degarelix relative to goserelin. From a societal perspective, the incremental cost per QALY in relation to goserelin went from a dominant position to about $105,000 and from a public payer perspective, from a dominant position to about $205,000.

However, given the limitations of the systematic review which included the lack of quality randomized controlled trials, the limited number of trials, lack of direct comparison between the degarelix (LHRH antagonist) and LHRH agonist (e.g., goserelin) or LHRH agonist (goserelin) + anti-androgen (bicalutamide) and the weak data that links testosterone surge to clinical flare symptoms, the strength of the conclusions of this cost utility analysis must be interpreted in light of the quality of the primary literature.

Furthermore, the utility values derived from the Bayoumi study were only a generalization that the symptomatic patients refer to bone pain symptom only. This is highly unlikely that patients only experienced bone pain and no other symptoms. It would be worthwhile in future study to specifically evaluate flare symptoms using health related quality of life instrument such as the SF-36 which is credible and can provide a reliable utility value from the results.

Given that public payers may pay a lower price than private payers, if cost per QALY was calculated from a private payer perspective, the cost per QALY calculated

49 between degarelix and gosrelin could even be higher, i.e., over a cost per QALY threshold that may prevent listing.

Chapter 4

ECONOMIC ANALYSIS – 1 YEAR HORIZON

A time horizon of one year cost utility analysis was conducted to determine the incremental cost per QALY gained if costs and resources were extrapolated out to this time frame. Therefore, the target population, comparators, perspectives, modelling, outcomes, utiliy values and variability and uncertainties remain the same as the 3- month model. The changes were the number of resource use, costs and a discount rate of 5% were used for the model.

The number of resource use was expanded over a year, therefore, from a societal and public payer perspective, the number of resource use increased for degarelix, goserelin, goserelin + bicalutamide due to the number of injections given over the year. A monthly injection of degarelix would be given for 12 months and goserelin would be given every 3 months, for a total of 4 injections for 12 months.

4.1 Societal Perspective

The costs of the interventions were also increased to a 12 month period. Also, an additional week of pain treatment was extrapolated (Table 36).

Table 36: Costs of Medications Degarelix Cost per 240mg starter injection $811 Cost per 80mg maintenance injection $300 Starter injections in first 3 months 1 Average monthly cost per first 3 months $470 Total Cost per year with mark up (8%) and dispensing fee ($7) $4,484

LHRH agonist Cost per 10.8mg depot injection $1,088.13 Injections per 3 months 1 Average monthly cost per first 3 months $363 Total Cost per year with mark up (8%) and dispensing fee ($7) $4,481

Anti-androgen Cost of market share leader (Casodex®) assumed Cost per 50mg tab $3.22 Number of tabs required 28

Cost of anti-androgen $90.16 Total Cost with mark up (8%) and dispensing fee ($7) $104.37

Acetaminophen Acetaminophen 325 mg tablet $0.0114 Number of tablets required 224 Total cost of acetaminophen $2.55 Total Cost with mark up (8%) and dispensing fee ($7) $9.76

NSAIDs Naproxen 250 mg tablet $0.1068 Number of tablets required 42 Total cost of NSAID $4.49 Total Cost with mark up (8%) and dispensing fee ($7) $11.84

The costs of resources were also extended out to a one year horizon. The physician, nursing and pharmacists visits would increase according to the dosing schedule of degarelix and goserelin. For example, degarelix’s costs would increase because of monthly injections (12 total visits) whereas goserelin costs would increase by 4 visits in total because of its every 3-monthly injections. Therefore, the revised costs are outlined for degarelix in Tables 37 (with bone pain) and 38 (without bone pain).

Table 37: Degarelix Direct and Indirect Costs with Bone Pain Urologist / Nursing / Days/Year Drug costs Pharmacist consult PSA lab test AE costs Total cost costs 1 Year $4,484.00 $489.04 $30.00 $35.00 $5,038.04 Day 7 $9.76 $63.97 $0.00 $0.00 $73.72 Day 14 $11.84 $26.17 $0.00 $0.00 $38.01 Day 28 $0.00 $51.00 $30.00 $0.00 $81.00 Total $4,505.60 $630.17 $60.00 $35.00 $5,230.78

Degarelix Indirect cost to employer (non-retirees) Days/Year Loss time from work Total cost 1 Year $492.00 $492.00 Day 7 $82.00 $82.00 Day 14 $82.00 $82.00 Day 28 $0.00 $0.00 Total $656.00 $656.00

Degarelix Indirect costs to patient (retirees)

Days/Year Loss of leisure time Travelling cost Total cost

1 Year $492.00 $114.00 $606.00 Day 7 $82.00 $9.50 $91.50 Day 14 $82.00 $9.50 $91.50 Day 28 $0.00 $0.00 $0.00

Total $656.00 $133.00 $789.00

Societal Cost per Patient (with bone pain) Public $5,230.78 Private (non-retiree) $164.00 Patient (retiree) $591.75 Total Societal Cost $5,986.53

Societal Cost per Patient (with bone pain) with probability Total Societal Cost $1,736.09

Table 38: Degarelix Direct and Indirect Costs without Bone Pain

Urologist / Nursing / Days/Year Drug costs PSA lab test AE costs Total cost Pharmacist consult costs 1 Year $4,484.00 $489.04 $30.00 $35.00 $5,038.04 Day 7 $0.00 $0.00 0 0 $0.00 Day 14 $0.00 $0.00 $0.00 $0.00 $0.00 Day 28 $0.00 $0.00 $0.00 $0.00 $0.00 Total $4,484.00 $489.04 $30.00 $35.00 $5,038.04 Degarelix Indirect cost to employer (non-retirees) Days/Year Loss time from work Total cost 1 Year $492.00 $492.00 Day 7 $0.00 $0.00 Day 14 $0.00 $0.00 Day 28 $0.00 $0.00 Total $0.00 $492.00 Degarelix Indirect costs to patient (retirees) Days/Year Loss of leisure time Travelling cost Total cost 1 Year $492.00 $114.00 $606.00 Day 7 $0.00 $0.00 $0.00 Day 14 $0.00 $0.00 $0.00 Day 28 $0.00 $0.00 $0.00 Total $492.00 $114.00 $606.00 Assumption: Since 75% of patients are over 65 years of age, 75% of patients would be retired and Societal Cost per Patient (with bone pain) 25% would be private. Public $5,038.04 Private 25% Private (non-retiree) $123.00 Patient 75% Patient (retiree) $454.50 Total Societal Cost $5,615.54

Absolute risk for having Societal Cost per Patient (without bone pain) with probability no bone pain A + AA or degarelix Total Societal Cost $3,987.03 =71%

Similarly, the goserelin costs are presented in Tables 39 and 40.

Table 39: Goserelin Direct and Indirect Costs with Bone Pain Urologist / Nursing / Days/Year Drug costs PSA lab test AE costs Total cost Pharmacist consult costs 1 Year $4,480.52 $151.35 $30.00 $0.00 $4,661.87 Day 7 $9.76 $63.97 $0.00 $0.00 $73.72 Day 14 $11.84 $26.17 $0.00 $0.00 $38.01 Day 28 $0.00 $52.00 $30.00 $0.00 $82.00 Total $4,502.12 $293.48 $60.00 $0.00 $4,855.60 Goserelin Indirect cost to employer (non-retirees) Loss time from Days/Year Total cost work 1 Year $164.00 $164.00 Day 7 $82.00 $82.00 Day 14 $82.00 $82.00 Day 28 $0.00 $0.00 Total $328.00 $328.00 Goserelin Indirect costs to patient (retirees) Loss of leisure Days/Year Travelling cost Total cost time 1 Year $164.00 $38.00 $202.00 Day 7 $82.00 $9.50 $91.50 Day 14 $82.00 $9.50 $91.50 Day 28 $0.00 $0.00 $0.00 Total $328.00 $57.00 $385.00 Assumption: Since 75% of patients are over 65 years of age, 75% of Societal Cost per Patient patients would be retired and 25% would be private. Public $4,855.60 Private = 25% Private (non- retiree) $82.00 Patient = 75% Patient (retiree) $288.75 Total Societal Cost $5,226.35 Societal Cost per Patient (with bone pain) with probability Absolute risk for bone pain Total Societal Cost $3,292.60 A + AA or degarelix = 29%

Table 40: Goserelin Direct and Indirect Costs without Bone Pain Goserelin Direct Costs - Public & Private Urologist / Nursing / Days Drug costs PSA lab test AE costs Total cost Pharmacist consult costs 1 Year $4,480.52 $151.35 $30.00 $0.00 $4,661.87 Day 7 $0.00 $0.00 $0.00 $0.00 $0.00 Day 14 $0.00 $0.00 $0.00 $0.00 $0.00 Day 28 $0.00 $0.00 $0.00 $0.00 $0.00 Total $4,480.52 $151.35 $30.00 $0.00 $4,661.87 Goserelin Indirect cost to employer (non-retirees) Days/Year Loss time from work Total cost 1 Year $164.00 $164.00 54

Day 7 $0.00 $0.00 Day 14 $0.00 $0.00 Day 28 $0.00 $0.00 Total $0.00 $164.00 Goserelin Indirect costs to patient (retirees) Days/Year Loss of leisure time Travelling cost Total cost 1 Year $164.00 $38.00 $202.00 Day 7 $0.00 $0.00 $0.00 Day 14 $0.00 $0.00 $0.00 Day 28 $0.00 $0.00 $0.00 Total $164.00 $38.00 $202.00 Societal Cost per Patient Assumption: Since 75% of patients are over 65 years of age, 75% of patients would be retired and 25% would Public $4,661.87 be private. Private (non-retiree) $41.00 Private = 25% Patient (retiree) $151.50 Patient = 75% Total Societal Cost $4,854.37 Societal Cost per Patient (without bone pain) with probability Absolute risk for having no bone pain A + AA or degarelix = 71% Total Societal Cost $1,796.12 Agonist alone = 37%

Therefore, the total goserelin societal costs with and without bone pain is about $5,089 (Table 41).

Table 41: Total Goserelin Public Costs (With and Without Bone Pain)

SOCIETAL COST PER PATIENT WITH PROBABILITY OF HAVING BONE PAIN $3,292.60 + SOCIETAL COST PER PATIENT WITH PROBABILITY OF NO BONE PAIN $1,796.12 = TOTAL SOCIETAL COST PER PATIENT FOR DEGARELIX (WITH AND WITHOUT BONE PAIN) $5,088.72

Similarly, the goserelin and bicalutamide costs are presented in Tables 42 and 43.

Table 42: Goserelin + Bicalutamide Direct and Indirect Costs with Bone Pain

Urologist / Nursing / PSA Days/Year Drug costs AE costs Total cost Pharmacist consult costs lab test 1 Year $4,584.89 $139.67 $30.00 $0.00 Day 7 $9.76 $59.80 $0.00 $0.00 $4,754.56 Day 14 $11.84 $26.17 $0.00 $0.00 $69.56 Day 28 $0.00 $52.00 $30.00 $0.00 $38.01 Total $4,606.50 $277.63 $60.00 $0.00 $82.00 Goserelin + Bicalutamide Indirect cost to employer (non-retirees) Days/Year Loss time from work Total cost

1 Year $164.00 $164.00 Day 7 $82.00 $82.00 Day 14 $82.00 $82.00 Day 28 $0.00 $0.00 Total $328.00 $328.00 Goserelin + Bicalutamide Indirect costs to patient (retirees) Days/Year Loss of leisure time Travelling cost Total cost 1 Year $164.00 $38.00 $202.00 Day 7 $82.00 $9.50 $91.50 Day 14 $82.00 $9.50 $91.50 Day 28 $0.00 $0.00 $0.00 Total $328.00 $57.00 $385.00 Societal Cost per Patient Public $4,944.13 Private (non-retiree) $82.00 Patient (retiree) $288.75 Total Societal Cost $5,314.88 Societal Cost per Patient (with bone pain) with probability Total Societal Cost $1,541.31

Table 43: Goserelin + Bicalutamide Direct and Indirect Costs without Bone Pain Goserelin + Bicalutamide Direct Costs - Public & Private Urologist / Nursing / PSA lab Days/Year Drug costs AE costs Total cost Pharmacist consult costs test 1 Year $4,584.89 $139.67 $30.00 $0.00 $4,754.56 Day 7 $0.00 $0.00 $0.00 $0.00 $0.00 Day 14 $0.00 $0.00 $0.00 $0.00 $0.00 Day 28 $0.00 $0.00 $0.00 $0.00 $0.00 Total $4,584.89 $139.67 $30.00 $0.00 $4,754.56 Goserelin + Bicalutamide Indirect cost to employer (non-retirees) Days/Year Loss time from work Total cost 1 Year $164.00 $164.00 Day 7 $0.00 $0.00 Day 14 $0.00 $0.00 Day 28 $0.00 $0.00 Total $0.00 $164.00 Goserelin + Bicalutamide Indirect costs to patient (retirees) Travelling Days/Year Loss of leisure time Total cost cost 1 Year $164.00 $38.00 $202.00 Day 7 $0.00 $0.00 $0.00 Day 14 $0.00 $0.00 $0.00 Day 28 $0.00 $0.00 $0.00 Total $164.00 $38.00 $202.00 Societal Cost per Patient Public $4,754.56 Private (non-retiree) $123.00

Patient (retiree) $50.50 Total Societal Cost $4,928.06 Societal Cost per Patient (without bone pain) with probability Total Societal Cost $3,498.92

Therefore, the total goserelin + bicalutamide public costs with and without bone pain is about $5,040 (Table 44).

Table 44: Total Goserelin + Bicalutamide Societal Costs (With and Without Bone Pain)

SOCIETAL COST PER PATIENT WITH PROBABILITY OF HAVING BONE PAIN $1,541.31 + SOCIETAL COST PER PATIENT WITH PROBABILITY OF NO BONE PAIN $3,498.92 = SOCIETAL PUBLIC COST PER PATIENT FOR DEGARELIX (WITH AND WITHOUT BONE PAIN) $5,040.24

4.1.2 Results – Societal Perspective Using a discount rate of 5%, discounted utilities of 0.86 and 0.76 were calculated for asymptomatic disease and symptomatic disease, respectively (Table 49). The incremental adjusted QALY of 0.03238 was calculated by [(0.86*71%)+(0.76*29%)]- [(0.86*37%)+(0.76*29%)]. Therefore, he incremental cost per QALY for degarelix in relation to goserelin was $19,592 (Table 45).

Table 45: Societal Perspective - Incremental Cost per QALY

Incremental Incremental Adjusted Adjusted QALY QALY Degarelix Goserelin vs Annual Discounted versus goserelin + utility utility Goserelin bicalutamide Distant asymptomatic disease (e.g., no bone pain) 0.9 0.86 0.03238 -0.03238 Distant symptomatic disease, hormone responsive (e.g., with bone pain) 0.8 0.76

With and Without Bone Pain One-Month Total cost of degarelix societal cost $5,723 Total cost of goserelin societal cost $5,089 Total cost of goserelin + bicalutamide societal cost $5,040

Incremental Cost Incremental Cost per QALY Degarelix $5,723 Goserelin $5,089 Incremental $634 $19,592

Incremental Cost Incremental Cost per QALY Degarelix $5,723

Goserelin + Bicalutamide $5,040 Incremental $683 Not applicable

Incremental Cost Incremental Cost per QALY Goserelin $5,089 Goserelin + Bicalutamide $5,040 Incremental $48 Dominated

4.1.2 Univariate Sensitivity Analysis– Societal Perspective The factors used in the univariate sensitivity analysis are presented in Table 46.

Table 46: Univariate Sensitivity Analysis - Variants

Factor Base Low High Cost of degarelix $4,484 $3,363 $5,605 Cost of goserelin $4,481 $3,360 $5,601 Absolute risk for bone pain (with degarelix) (base=29%) 29% 22% 36% Absolute risk for bone pain (with goserelin) 63% 47% 79% Distant asymptomatic disease utility 0.9 0.81 1 Distant symptomatic disease utility 0.8 0.4 0.89

The incremental cost per QALY is presented in Table 47 with each univariant.

Table 47: Univariate Sensitivity Analysis – Incremental Cost/QALY

Factor Low High Cost of degarelix Dominant $54,211 Cost of goserelin $54,196 Dominant Absolute risk for bone pain (with degarelix) $15,582 $25,681 Absolute risk for bone pain (with goserelin) $40,479 $12,073 Distant asymptomatic disease utility $195,920 $9,796 Distant symptomatic disease utility $3,981 $195,920

Figure 6 presents the incremental cost per QALY graphically.

Figure 6: Univariate Sensitivity Analysis (Societal Perspective)

Cost per QALY (Degarelix vs Goserelin)

-$50,000 $0 $50,000 $100,000 $150,000 $200,000 $250,000

Cost of degarelix

Cost of goserelin

Absolute risk for bone pain (w ith degarelix)

Absolute risk for bone pain (w ith goserelin)

Distant asymptomatic disease utility

Distant symptomatic disease utility

The most prominent factors are the costs of degarelix and goserelin and the utility values. Therefore, these factors were varied in a multivariate sensivity analysis.

Multivariate Sensitivity Analysis – Best Case Scenario

Table 48 presents the best case scenario for degarelix if the variants happened at the same time. These factors were chosen because these affected the incremental cost per QALY the most based on the univariate sensitivity analysis.

Table 48: Multivariants on Incremental Cost per QALY for Degarelix versus Goserelin – Best Case Scenario

Factor Base Best Case Scenario Cost of degarelix per month $4,484 $3,600 Cost of goserelin $4,481 $4,920 Distant asymptomatic disease utility 0.9 1.0 Distant symptomatic disease utility 0.8 0.4

Based on these factors, degarelix had a favourable cost effectiveness profile (dominant) in relation to goserelin (Table 50).

Table 49: Incremental Cost per QALY – Best Case Scenario

Incremental Cost Incremental Cost per QALY Degarelix $4,839 Goserelin $5,528 Incremental Dominant

Multivariate Sensitivity Analysis – Worst Case Scenario

Table 50 presents the worst case scenario for degarelix if the variants happened at the same time. These factors were chosen because these affected the incremental cost per QALY the most based on the univariate sensitivity analysis.

Table 50: Multivariants on Incremental Cost per QALY for Degarelix versus Goserelin – Worst Case Scenario

Factor Base Worst Case Scenario Cost of degarelix per month $4,111 $8,400 Cost of goserelin $4,353 $2,244 Distant asymptomatic disease utility 0.9 0.81 Distant symptomatic disease utility 0.8 0.79

Based on these factors, goserelin had a favourable cost effectiveness profile in relation to degarelix (Table 35).

Table 51: Incremental Cost per QALY – Worst Case Scenario

Incremental Cost Incremental Cost per QALY Degarelix $9,639 Goserelin $2,852 Incremental $6,787 $2,095,963

4.2 Public Perspective

The costs of the interventions were also increased to a 12 month period. Also, an additional week of pain treatment was extrapolated (Table 52).

Table 52: Costs of Medications Degarelix Cost per 240mg starter injection $811 Cost per 80mg maintenance injection $300 Starter injections in first 12 months 1 Average monthly cost per first 3 months $4,111 LHRH agonist Cost per 10.8mg depot injection $1,088.13 Injections every 3 months 4 Average monthly cost per first 3 months $4,353 Anti-androgen Cost of market share leader (Casodex®) assumed Cost per 50mg tab $3.22 Number of tabs required 28 Cost of anti-androgen $90.16 Acetaminophen Acetaminophen 325 mg tablet $0.0114 Number of tablets required 224 Total cost of acetaminophen $2.55 NSAIDs Naproxen 250 mg tablet $0.1068 Number of tablets required 42 Total cost of NSAID $4.49

60 in total because of its every 3-monthly injections. Therefore, the revised costs are outlined for degarelix in Tables 53 (with bone pain) and 54 (without bone pain).

Table 53: Degarelix Direct Costs with Bone Pain

Drug Urologist / Nursing / Days PSA lab test AE costs Total cost costs Pharmacist consult costs 1 $4,111.00 $489.04 $30.00 $2.92 $4,632.96 7 $2.55 $63.97 $0.00 $0.00 $66.52 14 $4.49 $26.17 $0.00 $0.00 $30.65 28 $0.00 $51.00 $30.00 $0.00 $81.00 Total $4,118.04 $630.17 $60.00 $2.92 $4,811.13 Public Cost per Patient (with bone pain) with probability Total Public Cost $1,395.23

Table 54: Degarelix Direct Costs without Bone Pain Drug Urologist / Nursing / Days PSA lab test AE costs Total cost costs Pharmacist consult costs 1 $4,111.00 $489.04 $30.00 $2.92 $4,632.96 7 $0.00 $0.00 0 0 $0.00 14 $0.00 $0.00 $0.00 $0.00 $0.00 28 $0.00 $0.00 $0.00 $0.00 $0.00 Total $4,111.00 $489.04 $30.00 $2.92 $4,632.96 Public Cost per Patient (without bone pain) with probability Total Public Cost $3,289.40

Therefore, the total cost of degarelix is presented in Table 55.

Table 55: Total Degarelix Public Costs (With and Without Bone Pain)

PUBLIC COST PER PATIENT WITH PROBABILITY OF HAVING BONE PAIN $1,395.23 + PUBLIC COST PER PATIENT WITH PROBABILITY OF NO BONE PAIN $3,289.40 = TOTAL PUBLIC COST PER PATIENT FOR DEGARELIX (WITH AND WITHOUT BONE PAIN) $4,684.63

Similarly, the goserelin costs are presented in Tables 56 and 57.

Table 56: Goserelin Direct Costs with Bone Pain Urologist / Nursing / PSA Total Days Drug costs AE costs Pharmacist consult costs lab test cost 1 $4,352.52 $151.35 $30.00 $0.00 $4,533.87 7 $2.55 $63.97 $0.00 $0.00 $66.52 14 $4.49 $26.17 $0.00 $0.00 $30.65 28 $0.00 $52.00 $30.00 $0.00 $82.00 Total $4,359.56 $293.48 $60.00 $0.00 $4,713.04 Public Cost per Patient (with bone pain) with probability Total Public Cost $2,969.21

Table 57: Goserelin Direct Costs without Bone Pain Urologist / Nursing / AE Total Days Drug costs PSA lab test Pharmacist consult costs costs cost 1 $4,352.52 $151.35 $30.00 $0.00 $4,533.87 7 $0.00 $0.00 $0.00 $0.00 $0.00 14 $0.00 $0.00 $0.00 $0.00 $0.00 28 $0.00 $0.00 $0.00 $0.00 $0.00 Total $4,352.52 $151.35 $30.00 $0.00 $4,533.87 Public Cost per Patient (without bone pain) with probability Total Public Cost $1,677.53

Therefore, the total goserelin public costs with and without bone pain is about $4,646 (Table 58).

Table 58: Total Goserelin Public Costs (With and Without Bone Pain)

PUBLIC COST PER PATIENT WITH PROBABILITY OF HAVING BONE PAIN $2,969.21 + PUBLIC COST PER PATIENT WITH PROBABILITY OF NO BONE PAIN $1,677.53 = TOTAL PUBLIC COST PER PATIENT FOR DEGARELIX (WITH AND WITHOUT BONE PAIN) $4,646.75

Similarly, the goserelin and bicalutamide costs are presented in Tables 59 and 60.

Table 59: Goserelin + Bicalutamide Direct Costs with Bone Pain

Urologist / Nursing / Days Drug costs PSA lab test AE costs Total cost Pharmacist consult costs 1 $4,442.68 $139.67 $30.00 $0.00 $4,612.35 7 $2.55 $59.80 $0.00 $0.00 $62.35 14 $4.49 $26.17 $0.00 $0.00 $30.65 28 $0.00 $52.00 $30.00 $0.00 $82.00 Total $4,449.72 $277.63 $60.00 $0.00 $4,787.35 Public Cost per Patient (with bone pain) with probability Total Public Cost $1,388.33

Table 60: Goserelin + Bicalutamide Direct Costs without Bone Pain

Urologist / Nursing / Days Drug costs PSA lab test AE costs Total cost Pharmacist consult costs 1 $4,442.68 $139.67 $30.00 $0.00 $4,612.35 7 $0.00 $0.00 $0.00 $0.00 $0.00 14 $0.00 $0.00 $0.00 $0.00 $0.00 28 $0.00 $0.00 $0.00 $0.00 $0.00 Total $4,442.68 $139.67 $30.00 $0.00 $4,612.35 Public Cost per Patient (without bone pain) with probability Total Public Cost $3,274.77 Therefore, the total goserelin + bicalutamide public costs with and without bone pain is about $4,663 (Table 61).

Table 61: Total Goserelin + Bicalutamide Public Costs (With and Without Bone Pain)

PUBLIC COST PER PATIENT WITH PROBABILITY OF HAVING BONE PAIN $1,388.33 + PUBLIC COST PER PATIENT WITH PROBABILITY OF NO BONE PAIN $3,274.77 = TOTAL PUBLIC COST PER PATIENT FOR DEGARELIX (WITH AND WITHOUT BONE PAIN) $4,663.10

4.2.2 Results – Public Perspective Using a discount rate of 5%, discounted utilities of 0.86 and 0.76 were calculated for asymptomatic disease and symptomatic disease, respectively (Table 62). The incremental cost per QALY for degarelix in relation to goserelin was $4,972.

Table 62: Incremental Cost per QALY

Annual utility Discounted utility Distant asymptomatic disease (e.g., no bone pain) 0.9 0.86 Distant symptomatic disease, hormone responsive (e.g., with bone pain) 0.8 0.76

With and Without Bone Pain One-Month Total cost of degarelix public cost $4,685 Total cost of goserelin public cost $4,647 Total cost of goserelin + bicalutamide public cost $4,663

Cost per Incremental QALY Incremental Cost per QALY Degarelix $4,685 Goserelin $4,647 Incremental $38 $4,972

Incremental Cost Incremental Cost per QALY Degarelix $4,685 Goserelin + Bicalutamide $4,663 Incremental $22 Not applicable

Incremental Cost Incremental Cost per QALY Goserelin $4,647 Goserelin + Bicalutamide $4,663 Incremental -$16 $2,146

4.2.2 Univariate Sensitivity Analysis– Public Perspective The factors used in the univariate sensitivity analysis are presented in Table 63.

Table 63: Univariate Sensitivity Analysis - Variants

Factor Base Low High Cost of degarelix $4,111 $3,083 $5,139 Absolute risk for bone pain (with degarelix) 29% 22% 36% Absolute risk for bone pain (with goserelin) 63% 47% 79% Cost of goserelin $4,353 $3,265 $5,441 Distant asymptomatic disease utility 0.9 0.81 1 Distant symptomatic disease utility 0.8 0.4 0.89

The incremental cost per QALY is presented in Table 64 with each univariant.

Table 64: Univariate Sensitivity Analysis – Incremental Cost/QALY Factor Low High Cost of degarelix Dominant $139,897 Absolute risk for bone pain (with degarelix) $1,779 $52,871 Absolute risk for bone pain (with goserelin) $2,912 Dominant Cost of goserelin $147,709 Dominant Distant asymptomatic disease utility $49,719 $2,486 Distant symptomatic disease utility $994 $49,719

Figure 7 presents the incremental cost per QALY graphically.

Figure 7: Univariate Sensitivity Analysis (Public Perspective)

Incremental Cost per QALY (degarelix vs goserelin)

-$200,000 -$150,000 -$100,000 -$50,000 $0 $50,000 $100,000 $150,000 $200,000

Cost of degarelix

Absolute risk for bone pain (w ith degarelix)

Absolute risk for bone pain (w ith goserelin)

Cost of goserelin

Distant asymptomatic disease utility

Distant symptomatic disease utility

The most prominent factors are the costs of degarelix and goserelin and the utility values. Therefore, these factors were varied in a multivariate sensivity analysis.

Multivariate Sensitivity Analysis – Best Case Scenario

Table 65 presents the best case scenario for degarelix if the variants happened at the same time. These factors were chosen because these affected the incremental cost per QALY the most based on the univariate sensitivity analysis.

Table 65: Multivariants on Incremental Cost per QALY for Degarelix versus Goserelin – Best Case Scenario

Factor Base Best Case Scenario Cost of degarelix per month $4,111 $3,600 Cost of goserelin $4,353 $4,920 Distant asymptomatic disease utility 0.9 1 Distant symptomatic disease utility 0.8 0.4

Based on these factors, degarelix had a favourable cost effectiveness profile (dominant) in relation to goserelin (Table 66).

Table 66: Incremental Cost per QALY – Best Case Scenario

Incremental Cost Incremental Cost per QALY Degarelix $4,174 Goserelin $5,214 Incremental Dominant

Multivariate Sensitivity Analysis – Worst Case Scenario

Table 67 presents the worst case scenario for degarelix if the variants happened at the same time. These factors were chosen because these affected the incremental cost per QALY the most, based on the univariate sensitivity analysis.

Table 67: Multivariants on Incremental Cost per QALY for Degarelix versus Goserelin – Worst Case Scenario

Factor Base Worst Case Scenario Cost of degarelix per month $4,111 $8,400 Cost of goserelin $4,353 $2,244 Distant asymptomatic disease utility 0.9 0.8 Distant symptomatic disease utility 0.8 0.79

Based on these factors, goserelin had a favourable cost effectiveness profile in relation to degarelix (Table 68).

Table 68: Incremental Cost per QALY – Worst Case Scenario

Incremental Cost Incremental Cost per QALY Degarelix $8,974

Goserelin $2,538 Incremental $6,435 $1,987,403

4.3 Conclusion

Given the available data, another cost utility analysis was conducted to extend the time horizon of the analysis to one year to determine the implications of incremental cost per QALY in metastatic prostate cancer patients. From a societal perspective, it appeared that goserelin + bicalutamide had a favourable cost-effectiveness profile in relation to goserelin (dominant incremental cost/QALY), which goserelin was more expensive and has less utility. Degarelix had a favourable cost-effectiveness profile relative to goserelin with an incremental cost per QALY of $19,592.

From a public payer perspective, goserelin had a favourable cost-effectiveness profile in relation to goserelin + bicalutamide ($505/QALY) and degarelix relative to goserlein had a favourable cost-effectiveness profile of $1,170/QALY.

From the sensitivity analyses, the cost of the treatments (degarelix or goserelin) and the utility values could affect the incremental cost per QALY greatly. Using these factors, multivariant sensitivity analyses were conducted using the best and worst case scenario to provide a range of incremental cost per QALY for degarelix. From a societal perspective, the incremental cost per QALY in relation to goserelin went from a dominant position to about $2,000,000 and from a public payer perspective, from a dominant position to about $1,900,000. Such wide ranges of incremental cost/QALY from both societal and public perspectives in these sensitivity analyses give payers less confidence in the value calculated in the basecase scenarios. In the worst case scenarios, the incremental utility value between degarelix and goserelin was only 0.01, which led to the $2,000,000 incremental cost/QALY. Therefore, if public payers determine that in clinical practice, the difference in patients’ utilities with and without bone pain is minimal. Then degarelix would not have a favourable cost effectiveness ratio relative to goserelin. To accurately determine the utility values, the most optimal way is to do a study in metastatic prostate cancer patients to specifically evaluate their quality of life with the different treatment options using a health related quality of life instrument such as the SF-36.

Furthermore, given the limitations of the systematic review which included the lack of quality randomized controlled trials, the limited number of trials, lack of direct comparison between the degarelix (LHRH antagonist) and LHRH agonist (e.g., goserelin) or LHRH agonist (goserelin) + anti-androgen (bicalutamide) and the weak data that links testosterone surge to clinical flare symptoms, the strength of the conclusions of this cost utility analysis must be interpreted in light of the quality of the primary literature.

Chapter 5 HEALTH SYSTEM IMPACT ISSUES

Distributive justice is the notion that all persons should be treated fairly, even when their circumstances differ (Smith, 2008). Public funding is an attempt to have distributive justice for the “poor” and the “old”. Unfortunately, there may continue to be inequity between patients who are reimbursed by the public plan and those “younger” and working patients covered by private plans.

Regardless of how degarelix will be reimbursed by public plans, patients with private payer coverage tend to have earlier access to new drugs. It was found that publicly insured patients have to wait up to 1 year longer than privately insured patients to get insurance coverage for new drugs (Skinner, 2008). So, patients who have private insurance may have earlier access than publicly-funded patients to new and possibly better drugs. Not only are privately insured patients more likely to get earlier access, their coverage may also be wider. Perhaps provincial plans’ restrictiveness is their emcompassing perspective in evaluating all drugs and resources that are used within the public system.

Also patients who are self-employed may not be covered by public or private plans. These patients may need to pay for treatments out-of-pocket. Therefore, from distributive justice perspective, these patients are not treated fairly.

There are still questions that need to be answered from an equity perspective. There are two main forms of health equity identified, vertical equity (preferential treatment for those with greater health needs), and horizontal equity (equal treatment for equivalent needs) (Macinko et al, 2002). So, in terms of horizontal equity, patients with the same “need” should have equal access to healthcare. The difficulty with this is determining which patients have the same “needs” or same degree of sickness and who should decide, especially when discussing same type of cancer or even different types of cancers.

Finally, in terms of vertical equity, how do you make a system “fair” between patients in a healthy state, patients who are mildly ill and patients who are severely ill? Should

68 patients who are sicker be given preferential treatments? So, with degarelix from a societal perspective, what is its incremental value if compared to other disease states? These questions will need to be posed in the future.

Summary

When policy makers decide on coverage of degarelix or other new drugs, shortening the time between public and private payer coverage will enhance fairness to patients irrespective of their type of insurance.

There are still questions that need to be answered when it comes to vertical and horizontal equities, fairness between patients in different health states and between patients with different needs.

DISCLOSURE

The author of this review is employed by Ferring Pharmaceuticals Inc., the manufacturer of degarelix.

REFERENCES

Alberta Cancer Board. Prostate Cancer Clinical Practice Guideline. July 2007. http://www.cancerboard.ab.ca/NR/rdonlyres/D9B8A40C-A089-45CE-8FAC- D7BBE6448FFA/0/GU_004_ProstateCancer.pdf

Bayoumi AM, Brown AD, Garber AM. Cost-Effectiveness of Androgen Suppression Therapies in Advanced Prostate Cancer. Journal of the National Cancer Institute 2000 November 1;92(21):1731-1739.

B.C. Cancer Agency. What is PSA? http://www.bccrc.ca/ce/psa.htmL

B.C. Cancer Agency. Bicalutamide Fact Sheet. http://www.bccancer.bc.ca/NR/rdonlyres/70520549- A5EF-4495-920C-252A761EE0D5/28806/Bicalutamidemonograph_7Apr08_RW.pdf

BC Cancer Agency. Management. June 2008. < http://www.bccancer.bc.ca/HPI/CancerManagementGuidelines/Genitourinary/Prostate/Management/de fault.htm> Accessed January 23, 2009.

Brogan Inc. Major changes to Ontario Drug Benefit Program announced. Accessed July 23, 2009. http://www.broganinc.com/english/news/odb.html

Broqua P, Riviere P J-M, Conn PM, Rivier JE, Aubert ML, Junien J-L. Pharmacological Profile of a New, Potent, and Long-Acting Gonadotropin-Releasing Hormone Antagonist: Degarelix. JPET 2002;301:95–102.

Bubley GJ. Is the flare phenomenon clinically significant? Urology 2001; 58(2 Suppl 1):5-9.

Bucher HC, Guyatt GH, Griffith LE et al. The results of direct and indirect treatment comparisons in meta-analysis of randomized controlled trials. J Clin Epidemiol. 1997 Jun;50(6):683-91.

Canadian Agency for Drugs and Technologies in Health. Guidelines for the economic evaluation of health technologies: Canada [3rd Edition]. Ottawa: 2006.

Canadian Cancer Society. Canadian Cancer Statistics 2008.

Canadian Cancer Society/National Cancer Institute of Canada: Canadian Cancer Statistics 2008, Toronto, Canada, 2008.

Cancer Care Nova Scotia. Guidelines for the Management of Prostate Cancer 2006.

Cancer Care Nova Scotia. Guidelines for the Management of Cancer-Related Pain in Adults November 2005.

Cancer Care Ontario. Maximal Androgen Blockade for the Treatment of Metastatic Prostate Cancer. February 5, 2003. < http://www.cancercare.on.ca/common/pages/UserFile.aspx?fileId=14052> Accessed May 28, 2009.

Cancer Care Ontario. Bicalutamide Fact Sheet. http://www.cancercare.on.ca/pdfdrugs/Bicalutamide.pdf

Conti PD, Atallah AN, ArrudaH, Soares BGO, El Dib RP, Wilt TJ. Intermittent versus continuous androgen suppression for prostatic cancer. Cochrane Database of Systematic Reviews 2007, Issue 4. Art. No.: CD005009. DOI: 10.1002/14651858.CD005009.pub2.

Crawford ED, Eisenberger MA, McLeod DG et al. A controlled trial of leuprolide with and without flutamide in prostatic carcinoma. New England Journal of Medicine 1989 August 17;321(7):419-424.

Crawford ED. Hormonal therapy in prostate cancer: historical approaches. Rev Urol 2004;6(suppl 7):S3–S11.

Crawford ED. Understanding the Epidemiology, Natural History, and Key Pathways Involved in Prostate Cancer. Urology 2009; 73 Suppl 5A:4–10.

DeVoogt HJ, Klijn GM, Studer U et al. Maximum androgen blockade using LHRH agonist buserelin in combination with short-term (two weeks) or long-term (continuous) cyproterone acetate is not superior to standard androgen deprivation in the treatment of advanced prostate cancer. Final analysis of EORTC GU group trial 30843. Eur Urol 1998;33:152-158.

Fuelconsumption.ca http://www.fuelconsumption.ca/fuel/vehicles.asp?car=9 (Accessed June 28, 2009)

Garnick MB, Campion M, Abarelix Depot Study Group. Abarelix depot, a GnRH antagonist v LHRH superagonists in prostate cancer: differential effects on follicle-stimulating hormone. Molecular urology 2000;4(3):275-277.

Glenny AM, Altman DG, Song F et al. Indirect comparisons of competing interventions. Health Technology Assessment 2005 July;9(26).

Hsing AW. Hormones and prostate cancer: what's next? Epidemiol Rev. 2001;23(1):42-58. http://www.cancer.gov/cancertopics/pdq/treatment/prostate/Patient/page2 Accessed March 9, 2008. http://www.prostate-cancer.com/prostate-cancer-glossary/androgen-ablation.htmL

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.

Johri M. Economic Evaluation using Decision Analytic Modelling I. Ulysses Course 3 Presentation. Barcelona 2008.

Kahan A, Delrieu F, Amor B et al. Disease flare induced by D-Trp6-LHRH analogue in patients with metastatic prostatic cancer. The Lancet 1984 April 28;971-972.

Kernick DP, Reinhold DM, Netten A. What does it cost the patient to see the doctor? British Journal of General Practice, 2000, 50, 401-403.

Kotake T, Musami M, Akaza H et al. Goserelin acetate with or without antiandrogen or estrogen in the treatment of patients with advanced prostate cancer: a multicenter, randomized, controlled trial in Japan. Japanese Journal of Clinical Oncology 1999 Nov;29(11):562-570.

Klotz L, Boccon-Gibod L, Shore ND et al. The efficacy and safety of degarelix: a 12-month, comparative, randomized, open-label, parallel-group phase III study in patients with prostate cancer. BJU International 2008;102:1531-1538.

Kreis W, Ahmann FR, Jordan VC et al. Oestrogen pre-treatment abolishes LHRH testosterone stimulation. British Journal Urology 1988;62:352-354.

Kuhn JM, Billebaud T, Navrath MDH et al. Prevention of the transient adverse effects of a gonadotropin-releasing hormone analogue (buserelin) in metastatic prostatic carcinoma by administration of an antiandrogen (nilutamide). The New Endgland Journal of Medicine 1989 August 17;321(7):413-418.

Levy I. Trends in Incidence and Mortality of Prostate Cancer in Canada. < http://www.phac- aspc.gc.ca/publicat/cdic-mcc/16-1sup/c_e.html> Accessed September 23, 2008.

Limonta P, Moretti R.M, Dondi D et al. Androgen-dependent prostatic tumors: biosynthesis and possible actions of LHRH. The Journal of steroid biochemistry and molecular biology 1994 June;49(4- 6):347-50.

Macinko JA and Starfield B. Annotated Bibliography on Equity in Health, 1980-2001. International Journal for Equity in Health 2002:1-20. http://www.equityhealthj.com/content/pdf/1475-9276-1-1.pdf

Mahler C. Is disease flare a problem? Cancer. 1993 Dec 15;72(12 Suppl):3799-802.

McLeod D, Zinner N, Tomera K et al. A phase 3, multicenter, open-label, randomized study of abarelix versus leuprolide acetate in men with prostate cancer. Urology 2001;58:756-761.

Medavie Blue Cross Special Communiqué. Abbott Laboratories ends preferred Biaxin BID arrangement with Medavie Blue Cross 2008 March 20. https://www.medavie.bluecross.ca/cs/BlobServer?blobcol=urldata&blobtable=MungoBlobs&blobhead ervalue2=abinary%3B+charset%3DUTF-8&blobheadername2=MDT- Type&blobkey=id&blobwhere=1187211128108&blobheader=application%2Fpdf (Accessed August 6, 2009).

Migliari R, Muscas G, Murru M, Verdacchi T, De Benedetto G, De Angelis M. Antiandrogens: a summary review of pharmacodynamic properties and tolerability in prostate cancer therapy. Arch Ital Urol Androl. 1999 Dec;71(5):293-302.

Minister of Health. Canada Health Act — Annual Report 2006–2007.

Ministry of Health. Ontario Drug Benefit Formulary/Comparative Drug Index 2007 April 2;40. http://www.health.gov.on.ca/english/providers/program/drugs/formulary_40/edition_40.pdf (Accessed August 8, 2009).

Ministry of Health and Long-Term Care. Ontario Guidelines for Drug Submission and Evaluation. September 2000. http://www.health.gov.on.ca/english/providers/pub/drugs/dsguide/docs/dse_guide_20071109.pdf

Ministry of Health and Long-Term Care. Ontario Drug Benefit : Dispensing Fees. http://www.health.gov.on.ca/english/public/pub/drugs/dispense.html

Ministry of Labour. Minimum Wage. http://www.labour.gov.on.ca/english/es/guide/guide_4.html (Accessed June 28, 2009).

Mongiat-Artus P, Teillac P. Role of Luteinising Hormone Releasing Hormone (LHRH) Agonists and Hormonal Treatment in the Management of Prostate Cancer. European Urology Supplements 2005;4:4–13.

Msaouel P, Diamanti E, Tzanela M, et al. Luteinising hormone-releasing hormone antagonists in prostate cancer therapy. Expert Opin. Emerging Drugs 2007;12(2):285-299.

National Cancer Institute. Stages of Prostate Cancer 2005 May 23. http://www.cancer.gov/cancertopics/pdq/treatment/prostate/Patient/page2 (Accessed June 13, 2009)

National Cancer Institute. Prostate Cancer Treatment 2008 March 23.

National Cancer Institute. Dictionary of Cancer Terms 2009. http://www.cancer.gov/Templates/db_alpha.aspx?CdrID=560342 (Accessed June 13, 2009).

National Institute of Clinical Excellence – Prostate Cancer Diagnosis and Treatment. February 2008.

Oefelein MG, Cornum R. Failure to achieve castrate levels of testosterone during luteinizing hormone releasing hormone agonist therapy: the case for monitoring serum testosterone and a treatment decision algorithm. J Urol 2000;164:726–729.

OHIP Listed Services (Accessed June 26, 2009).

Oncology Channel. http://www.oncologychannel.com/prostatecancer/stagingsystems.shtml (Accessed May 28, 2009).

Ontario Drug Benefit Formulary 2009. https://www.healthinfo.moh.gov.on.ca/formulary/index.jsp (Accessed June 26, 2009)

Sasagawa I, Kubota Y, Nakada T, et al. Influence of luteinizing hormone-releasing hormone analogues on serum levels of prostatic acid phosphatase and prostatic specific antigen in patients with metastatic carcinoma of the prostate Int Urol Nephrol 1998;30:745–53.

Schroeder FH, Lock TMTW, Chadha DR et al. Metastatic cancer of the prostate managed with buserelin versus buserelin plus cyproterone acetate. Journal of Urology 1987 May;137:912-918.

Schulze H and Senge T. Influence of different types of antiandrogens on luteinizing hormone-releasing hormone analogue-induced testosterone surge in patients with metastatic carcinoma of the prostate. Journal of Urology 1990 October;144:934-941.

Seidenfeld J, Samson DJ, Hasselblad V, et al. Single-therapy androgen suppression in men with advanced prostate cancer: a systematic review and meta-analysis. Ann Intern Med 2000;132:566–577.

Skinner BJ. Waiting for Reimbursement of New Medicines in Canada: It's Time for a Rethink. Pharmacoeconomics 2008;26(8):629-632.

Smith GP. Distributive Justice and the New Medicine. JAMA 2009;301(13):1385-1386.

Song F, Altman DG, Glenny AM et al. Validity of indirect comparison for estimating efficacy of competing interventions: empirical evidence from published meta-analyses. BMJ 2003 March 1;326:1- 5.

Stangelberger A, Waldert M, Djavan B. Prostate Cancer in Elderly Men. Reviews in Urology 2008;10(2):111-119.

Sutton A, Ades AE, Cooper N et al. Use of Indirect and Mixed Treatment Comparisons for Technology Assessment. Pharmacoeconomics 2008; 26 (9): 753-767.

Thompson IM. Flare Associated with LHRH-Agonist Therapy. Reviews In Urology 2001; 3 Suppl. 3:S10-S.14

Tomera K, Gleason D, Gittelman M et al. The GnRH antagonist abarelix depot versus LHRH agonists leuprolide or goserelin: initial results of endocrinological and biochemical efficacies in patients with prostate cancer. Journal of Urology 2001 May;165:1585-1589.

Tomera K, Gleason D, Gittelman M, et al. The gonadotropin-releasing hormone antagonist abarelix depot versus luteinizing hormone releasing hormone agonists leuprolide or goserelin: Initial results of endocrinological and biochemical efficacies in patients with prostate cancer. J Urol 2001;165:1585– 1589.

Trachtenberg J, Gittleman M, Steidle C, et al. A phase 3, multicenter, open label, randomized study of abarelix versus leuprolide plus daily antiandrogen in men with prostate cancer. Journal of Urology 2002 April;167:1670-1674.

Trachtenberg J. The treatment of metastatic prostatic cancer with a potent luteinizing hormone releasing hormone analogue. J. Urol;1983;129:1149.

Tyrrell CJ, Altwein JR, Klippei F et al. A multicenter randomised trial comparing the LHRH analogue goserelin acetate alone and with flutamide in the treatment of advanced prostate cancer. Journal of Urology 1991 November;146:1321-1326.

Waxman J. A review of the Hammersmith Hospital, St. Bartholomew’s Hospital and Institute of Urology studies of buserelin in advanced prostate cancer. American Journal of Clinical Oncology;1988;11(1):S16.

Wells GA, Sultan SA, Chen L, Khan M, Coyle D. Indirect Evidence: Indirect Treatment Comparisons in Meta-Analysis. Ottawa: Canadian Agency for Drugs and Technologies in Health; 2009.

Wood L, Wilke D, Rendon R, Broadfield L, Rutledge R, Gupta R, Marsh S, and Members of the Genitourinary Cancer Site Team, Cancer Care Nova Scotia, 2005. Genitourinary Cancer Site Team, Guidelines for the Management of Prostate Cancer.

Zinner NR, Bidair M, Centeno A, Tomera K. Similar frequency of testosterone surge after repeat injections of goserelin (Zoladex) 3.6 mg and 10.8 mg: results of a randomized open-label trial. Urology 2004;64:1177–1181.

APPENDIX 1: Cancer Care Nova Scotia Treatment Algorithm for Prostate Cancer (Cancer Care Nova Scotia, 2006)

Prostatectomy

Low Risk: External beam radiotherapy alone T1-T2a and Low PSA (<10 ng/mL) Brachytherapy (see implant- not available in and Low Gleason Grade (<6) Expectant Management

Observation

Neoadjuvant Androgen Deprivation Therapy (ADT) and radical external beam radiotherapy (RT) (ADT for 2-8 months prior to RT or concurrent with RT)

Dose-escalated conformal external Intermediate Risk: beam (3D) radiotherapy T2b-T2c or PSA = 10-20 ng/mL: Prostatectomy or Gleason Grade = 7 ADR as primary treatment if contraindication to radiotherapy and prostatectomy

Expectant Management

Observation (for patients with significant morbidity or poor life expectancy

Neoadjuvant ADR and external beam radiotherapy (including elective treatment of pelvic lymph nodes) PLUS 2 years adjuvant hormone treatment

Prostatectomy (for highly selected patients with High Risk low volume disease; NOT RECOMMENDED T3-T4 for T3b-T4 patients) Post operative radiotherapy or and/or ADT may be required Gleason Grade >8 Or PSA >20 ng/mL ADT as primary treatment in very high risk patients with low chance of cure

Observation (for patients with significant morbidity or poor life )

APPENDIX 2: Literature Search for Flare Symptoms

Requested by: YEP Date: 16 March 2009 Executed by: Bess

Database: Medline - (MEZZ) 1980 to date Embase - (EMZZ) 1980 to date Biosis - (BIOL) 1996 to date Current Content - (CBIB) 1995 to date Derwent drug file - (DDNS) 1983 to date Int. Pharmaceutical Abstracts - (IPAB) 1980 to date SciSearch - (SCZZ) 1996 to date Medline in Process - (MEIP) latest few weeks Biosis Previews - (BIOX) Latest updates Embase alerts - (EMBA) latest 8 weeks Adis Reactions Database - (REZZ) 1983 to date EMCare - (EMCA) 1995 to date Pascal – (PASC) 1984 to date ToxFile – (TOXL) 1980 to date Search Terms: (Luteinising-hormone adj releasing adj hormone$1) or (Luteinizing-hormone adj releasing adj hormone$1) or (Luteinising adj hormone adj releasing adj hormone$1) or (Luteinizing adj hormone adj releasing adj hormone$1) or Eligard$ or Lupron$ or (leuprolide adj acetate) or Suprefact$1 or buserelin or Trelstar$ or triptorelin$ or Zoladex$ or goserelin$ WITH (Gonadotropin-releasing adj hormone$1) or (Gonadotrophin-releasing adj hormone$1) or (Gonadotropin adj releasing adj hormone$1) or (Gonadotrophin adj releasing adj hormone$1) AND antiandrogen$1 or anti-androgen$1 or (anti adj androgen$1) or Casodex$ or bicalutamide$ or cyproterone$ or Anandron$1 or nilutamide$) AND flare$1 or surge$1 AND compar$5

--- 1 EMZZ --- AN 2008555884 20090113. TI The efficacy and safety of degarelix: A 12-month, comparative, randomized, open-label, parallel-group phase III study in patients with prostate cancer. SO BJU International, {BJU-Int}, December 2008, vol. 102, no. 11, p. 1531-1538, 26 refs, CODEN: BJINF, eISSN: 1464-410X, ISSN: 1464-4096. Publisher: Blackwell Publishing Ltd, 9600 Garsington Road, Oxford, OX4 2XG, UK. AU Klotz-Laurence, Boccon-Gibod-Laurent, Shore-Neal-D, Andreou-Cal, Persson-Bo-Eric, Cantor-Per, Jensen-Jens-Kristian, Olesen-Tine-Kold, Schroeder-Fritz-H. IN L. Klotz: University of Toronto, Division of Urology, Sunnybrook Health Sciences Centre, 2075 Bayview Ave. #MG408, Toronto, ON M4N 3M5, Canada. Email: [email protected]. AB OBJECTIVE: To evaluate the efficacy and safety of degarelix, a new gonadotrophin-releasing hormone (GnRH) antagonist (blocker), vs leuprolide for achieving and maintaining testosterone suppression in a 1-year phase III trial involving patients with prostate cancer. PATIENTS AND METHODS: In all, 610 patients with adenocarcinoma of the prostate (any stage; median age 72 years; median testosterone 3.93 ng/mL, median prostate-specific antigen, PSA, level 19.0 ng/mL) were randomized and received study treatment. Androgen-deprivation therapy was indicated (neoadjuvant hormonal treatment was excluded) according to the investigator’s assessment. Three dosing regimens were evaluated: a starting dose of 240 mg of degarelix subcutaneous (s.c.) for 1 month, followed by s.c. maintenance doses of 80 mg or 160 mg monthly, or intramuscular (i.m.) leuprolide doses of 7.5 mg monthly. Therapy was maintained for the 12-month study. Both the intent- to-treat (ITT) and per protocol populations were analysed. RESULTS: The primary endpoint of the trial was suppression of testosterone to 0.5 ng/mL at all monthly measurements from day 28 to day

364, thus defining the treatment response. This was achieved by 97.2%, 98.3% and 96.4% of patients in the degarelix 240/80 mg, degarelix 240/160 mg and leuprolide groups, respectively (ITT population). At 3 days after starting treatment, testosterone levels were 0.5 ng/mL in 96.1% and 95.5% of patients in the degarelix 240/80 mg and 240/160 mg groups, respectively, and in none in the leuprolide group. The median PSA levels at 14 and 28 days were significantly lower in the degarelix groups than in the leuprolide group (P < 0.001). The hormonal side-effect profiles of the three treatment groups were similar to previously reported effects for androgen-deprivation therapy. The s.c. degarelix injection was associated with a higher rate of injection-site reactions than with the i.m. leuprolide injection (40% vs <1%; P < 0.001, respectively). There were additional differences between the degarelix and leuprolide groups for urinary tract infections (3% vs 9%. P < 0.01, respectively), arthralgia (4% vs 9%, P < 0.05, respectively) and chills (4% vs 0%, P < 0.01, respectively). There were no systemic allergic reactions. CONCLUSIONS: Degarelix was not inferior to leuprolide at maintaining low testosterone levels over a 1-year treatment period. Degarelix induced testosterone and PSA suppression significantly faster than leuprolide; PSA suppression was also maintained throughout the study. Degarelix represents an effective therapy for inducing and maintaining androgen deprivation for up to 1 year in patients with prostate cancer, and has a different mechanism of action from traditional GnRH agonists. Its immediate onset of action achieves a more rapid suppression of testosterone and PSA than leuprolide. Furthermore, there is no need for antiandrogen supplements to prevent the possibility of clinical 'flare'. © 2008 The Authors. LG English. YR 2008.

--- 2 DDNS --- AN 96-32689 960902. TI Treatment of prostate cancer with gonadotropin-releasing hormone analogue: effect on lipoprotein(a). AU Arrer-E, Jungwirth-A, Mack-D, Frick-J, Patsch-W. LO Salzburg, Austria. IN Department of Laboratory Medicine, Landeskrankenanstalten Salzburg, Muellner Hauptstrasse, 48 A-5020 Salzburg, Austria (WP). SO J-Clin-Endocrinol-Metab (81, No. 7, 2508-11, 1996) Coden: JCEMAZ ISSN: 0021-972X. AB In a study involving 12 elderly patients with advanced prostate cancer, s.c. treatment with the GnRF analog buserelin (BU; Suprefact-Depot; Hoechst) markedly reduced serum levels of lipoprotein(a) (Lp(a)) and increased apolipoprotein (apo) B, without changing other lipid factors, including serum cholesterol (CH), triglyceride, HDL-CH, LDL-CH and apo A-I. Patients also received cyproterone acetate initially to prevent disease flare-up due to transient rises in serum testosterone on starting BU. Other drugs included glibenclamide for type II diabetes, thyroid drugs, beta-blockers and diuretics for hypertension, and allopurinol. Further studies are warranted on mechanism(s) underlying Lp (a) lowering by BU, as an approach to reduce the cardiovascular risk associated with high Lp(a).

--- 3 MEZZ --- AN 17604502 Medline 20070701. TI Luteinising hormone-releasing hormone antagonists in prostate cancer therapy. SO Expert opinion on emerging drugs, {Expert-Opin-Emerg-Drugs}, May 2007, vol. 12, no. 2, p. 285-99, 102 refs, ISSN: 1744-7623. AU Msaouel-Pavlos, Diamanti-Evanthia, Tzanela-Marinela, Koutsilieris- Michael. IN University of Athens, Department of Experimental Physiology, Medical School, 75 Micras Asias, Goudi-Athens, Greece. [email protected]. AB The introduction of androgen blockade therapy using luteinising hormone-releasing hormone (LHRH)/gonadotropin-releasing hormone analogues alone or in combination with non-steroidal antiandrogens has a major impact in both survival and quality of life of patients with locally advanced and metastatic prostate cancer. The effect of LHRH agonists is based on the continuous binding to the LHRH receptor (LHRH-R) on the gonadotrope cells of the pituitary, which although initially stimulate LH release, consequently downregulates the LHRH-R, thereby suppressing serum LH, testosterone levels and 5alpha-dihydrotestosterone levels. Because this initial surge of LH and

78 testosterone can cause adverse consequences in these patients (the so-called flare-up symptoms), immediate inhibition of LH release and testosterone production is desirable and this can be achieved with the use of the LHRH antagonists. In addition, there exist data to support a direct anticancer effect of LHRH antagonists on prostate cancer cells. This review summarises the potential clinical use of the LHRH antagonists in prostate cancer patients. LG English. YR 2007.

--- 4 PASC --- AN 0013575687 20020101. TI A phase 3, multicenter, open label, randomized study of abarelix versus leuprolide plus daily antiandrogen in men with prostate cancer. Commentary. SO The Journal of urology, {J-urol}, 2002, vol. 167, no. 4, p. 1670-1674, 12 refs, CODEN: JOURAA, ISSN: 0022-5347. Publisher: Lippincott Williams & Wilkins, Hagerstown, MD, United States. AU TRACHTENBERG-John, GITTLEMAN-Marc, STEIDLE-Christopher, BARZELL-Winston, FRIEDEL-William, PESSIS-Dennis, FOTHERINGHAM-Nick, CAMPION-Marilyn, GARNICK-Marc-B, SHARIFI-Roohollah. Commentator: SHARIFI-Roohollah. IN Urology Clinic, Illinois University Hospitals, Chicago, Illinois, United States; Princess Margaret Hospital, Toronto, Canada; South Florida Medical Research, Aventura and Urology Treatment Center, Sarasota, Florida, United States; North Indiana Urology, Fort Wayne, Indiana, United States; San Diego Urology Center, La Mesa and Amgen Inc., Thousand Oaks, California, United States; Affiliated Urologists, Chicago, Illinois, United States; PRAECIS Pharmaceuticals Inc., Cambridge, Massachusetts, United States. AB Purpose: We compared the endocrinological and biochemical efficacy of abarelix depot, a gonadotropin-releasing hormone antagonist, with that of a widely used combination of luteinizing hormone releasing hormone agonist and a nonsteroidal antiandrogen. Materials and Methods: A total of 255 patients were randomized to receive open label 100 mg. abarelix depot or 7.5 mg. leuprolide acetate intramuscularly injection on days 1, 29, 57, 85, 113 and 141 for 24 weeks. Patients in the abarelix group received an additional injection on day 15 and those in the leuprolide acetate group received 50 mg bicalutamide daily. Patients could continue treatment with study drug for an additional 28 weeks. The efficacy end points were the comparative rates of avoidance of testosterone surge (greater than 10% increase) within 7 days of the first injection and the rapidity of achieving reduction of serum testosterone to castrate levels (50 ng./dl. or less) on day 8. Patients were monitored for adverse events and laboratory abnormalities. Results: Abarelix was more effective in avoidance of testosterone surge (p <0.001) and the rapidity of reduction of testosterone to castrate levels on day 8 (p <0.001) than combination therapy. No significant difference was seen between the groups in the initial rate of decline of serum prostate specific antigen or the ability to achieve and maintain castrate levels of testosterone. No unusual or unexpected adverse events were reported. Conclusions: Abarelix as monotherapy achieves medical castration significantly more rapidly than combination therapy and avoids the testosterone surge characteristic of agonist therapy. Both treatments were equally effective in reducing serum prostate specific antigen, and achieving and maintaining castrate levels of testosterone. YR 2002.

--- 5 BIXX --- AN PREV200100376186 20010101. AU Pessis-Dennis, Friedel-William, Steidle-Christopher, Trachtenberg-John, Fotheringham-Nick, Campion-Marilyn, Garnick-Marc. TI Monotherapy with a new GnRH antagonist, abarelix depot (A-D), results in more rapid testosterone (T) suppression without an initial surge compared with leuprolide acetate (L) plus bicalutamide (B): Results of a multicenter phase 3 study. SO Journal of Urology, May, 2001, vol. 165, no. 5 Supplement, p. 167, ISSN: 0022-5347. IN Pessis-Dennis, Chicago, IL, USA. LG English. YR 2001.

--- 6 EMZZ --- AN 2008245352 20080617. TI Management of advanced prostate cancer: Can we improve on androgen deprivation therapy? SO BJU International, {BJU-Int}, June 2008, vol. 101, no. 12, p. 1497-1501, 32 refs, CODEN: BJINF, eISSN: 1464-410X, ISSN: 1464-4096. AU Anderson-John, Abrahamsson-Per-Anders, Crawford-David, Miller-Kurt, Tombal-Bertrand. IN J. Anderson: Department of Urology, Royal Hallamshire Hospital, Sheffield, UK. Email: [email protected]. AB Gonadotrophin-releasing hormone (GnRH) agonists are currently the mainstay in the management of advanced prostate cancer. Used either as monotherapy or combined with antiandrogens, GnRH agonists suppress serum testosterone levels and thus slow the growth of the tumour cells that depend on testosterone for growth. GnRH agonists have largely replaced orchidectomy in the management of advanced prostate cancer, because patients are reluctant to undergo surgical castration. However, can we do better in androgen-deprivation therapy? There is some evidence to suggest that GnRH agonists do not achieve the level of testosterone suppression attained with orchidectomy, or as rapidly, factors which could be expected to affect overall survival. Together, these observations highlight the need to develop newer agents that can achieve rapid, profound and sustained testosterone suppression, equivalent to that with orchidectomy. Preliminary data for the GnRH blocker, degarelix, suggest that this new agent might overcome the shortcomings associated with GnRH agonists. Further clinical data are therefore awaited with much interest. © 2008 The Authors. LG English. YR 2008.

--- 7 DDNS --- AN 93-25503 930000. TI Disease Flare With Gonadotropin-Releasing Hormone (GnRH) Analogues. How Serious Is It. (Question.). AU Scaletscky-R, Smith-J-A-Jr. LO Nashville, Tennessee, United States. IN Department of Urology, D-4314 Medical Center North, Vanderbilt University, Nashville, TN 37232-2765, USA. SO Drug-Safety (8, No. 4, 265-70, 1993) Coden: 3674P ISSN: 0114-5916. AB Disease flare during treatment with GnRH analogs is reviewed. GnRH analogs are used clinically for reversible indirect testicular and ovarian suppression. Depot or daily GnRH analog therapy (leuprorelin (leuprolide), goserelin, triptorelin and buserelin) is an acceptable medical alternative to orchiectomy for metastatic prostatic cancer. Adverse effects are less severe than with diethylstilbestrol. An initial superstimulation causes a surge in serum testosterone associated with worsening of symptoms (tumor flare response, disease flare, testosterone flare) in about 11% of patients treated for prostate cancer. Serious flare symptoms may require ketoconazole treatment. Preventative measures include blocking testosterone action with cyproterone, flutamide or nilutamide.

--- 8 MEZZ --- AN 17155895 Medline R 20061201. TI Abarelix for injectable suspension: first-in-class gonadotropin- releasing hormone antagonist for prostate cancer. SO Future oncology (London England), {Future-Oncol}, Dec 2006, vol. 2, no. 6, p. 677-96, 103 refs, ISSN: 1479-6694. AU Debruyne-Frans, Bhat-Gajanan, Garnick-Marc-B. IN University of Nimejian, The Netherlands. AB Abarelix, a gonadotropin-releasing hormone antagonist, with its indication for advanced symptomatic prostate cancer, represents the newest category of hormonal therapy introduced in the past 15 years. Results from Phase II and III clinical trials demonstrate the advantages of abarelix over commonly used luteinizing hormone-releasing hormone (LHRH) agonist therapy: abarelix does not cause a surge in serum testosterone that can precipitate a flare phenomenon or worsening of disease, particularly dangerous for patients with metastatic, symptomatic disease, and produces medical castration more quickly. Abarelix was also demonstrated to promptly and substantially reduce follicle-stimulating hormone levels to lower than LHRH agonist. Study results

80 demonstrate effective anticancer responses during extended exposure to abarelix: improvements in pain score and/or analgesic use, improvements in urinary symptoms (including urinary catheter removal) and complete avoidance of bilateral orchiectomy for patients undergoing at least 12 weeks of treatment. In Phase III clinical trials, abarelix demonstrated a similar overall safety profile when compared with LHRH agonist monotherapy, and a superior safety profile when compared with LHRH agonist plus antiandrogen combination therapy. Abarelix patients experienced a greater incidence of immediate-onset systemic allergic reactions as compared with control arms. LG English. YR 2006.

--- 9 MEZZ --- AN 12667881 Medline R 20030101. TI Hormonal therapy: historical perspective to future directions. SO Urology, {Urology}, Feb 2003, vol. 61, no. 2 Suppl 1, p. 3-7, 35 refs, ISSN: 1527-9995. AU Mcleod-David-G. IN Urologic Oncology Clinic, Urology Service, Walter Reed Army Medical Center, Washington, DC 20307-5001, USA. [email protected]. AB Prostate cancer is second only to lung and bronchial cancer as the leading cause of cancer death in men. Local treatment, surgery, and radiation remain the mainstay of treatment for early-stage disease. However, in locally advanced and advanced disease, there has been considerable evolution in the hormonal therapies. Suppression of testosterone production, the primary goal of hormonal therapy, may be accomplished with the use of estrogens, antiandrogens, and agonists and antagonists of luteinizing hormone-releasing hormone (LHRH). This article provides an overview of the primary hormonal therapies currently used in prostate cancer. Estrogen therapy was initially the predominant medical form of hormone manipulation and an alternative to orchiectomy. However, serious thrombogenic side effects were associated with its use, which decreased after the introduction of LHRH agonists in the 1980s. Many of the side effects occurring with oral estrogen therapy may be modulated by parenteral administration, and thus estrogen use is being revisited. LHRH agonists effectively reduce testosterone levels to castration levels (<50 ng/mL) within 2 to 4 weeks, although their use is associated with tumor flare. Antiandrogen monotherapy may offer quality-of-life benefits over treatment with androgen deprivation. The additive benefit of combined androgen blockade is yet to be determined. Recent evidence suggests that hormonal therapy may offer a survival benefit when initiated in earlier stages of prostate cancer. Future investigations will be directed to determining the most efficacious regimens. LG English. YR 2003.

--- 10 BIXX --- AN PREV199344123912 19930101. AU Scaletscky-Renato, Smith-Joseph-A. TI Disease flare with gonadotrophin-releasing hormone (GnRH) analogues: How serious is it? SO Drug Safety, 1993, vol. 8, no. 4, p. 265-270, ISSN: 0114-5916. IN Smith-Joseph-A, Dep. Urol., D-4314 Medical Center North, Vanderbilt Univ., Nashville, TN 37232-2765, USA. LG English. YR 1993.

--- 11 CBIB --- AN 000089912400044 20001102. TI Abarelix Depot, a GnRH antagonist, v LHRH superagonists in prostate cancer: Differential effects on follicle-stimulating hormone. SO MOLECULAR UROLOGY, 2000, V4, N3, FAL, pp 275-277. ISSN: 1091-5362. AU Garnick-M-B ([email protected]), Campion-M. IN Reprints from: M B Garnick, Praecis Pharmaceut Inc, 1 Hampshire St, Cambridge, MA 02139, USA. Research address: Praecis Pharmaceut Inc, Cambridge, MA 02139, USA Corporate author(s): Abarelix Depot Study Grp. AB Purpose: A Phase II clinical study contrasted the endocrinologic and biochemical efficacy of Abarelix Depot, a gonadotropin-releasing hormone (GnRH) antagonist, with luteinizing hormone

81 releasing-hormone (LHRH) superagonists, with or without additional antiandrogens, in men with prostate cancer. Methods: This study was open-label and treated 242 men. Albarelix Depot 100 mg was administered by intramuscular injection to 209 men, and LHRH, with or without an antiandrogen, was administered to 33 men according to the formulation used. Serum concentrations of follicle-stimulating hormone (FSH) and other hormones were measured at baseline and at specified time points for the first 85 days of the study. Median serum concentrations of FSH at baseline were similar for the two treatment groups. Results: Men treated with LHRH superagonists, with or without an antiandrogen, had a surge in the serum concentration of FSH on day 2 before FSH concentrations started to decline. Men in the Abarelix Depot group had an immediate and sustained decrease in the serum concentration of PSH,Conclusion: Recent data suggest that FSH may be an independent growth factor for prostate cancer. The Abarelix Depot-induced decreased in FSH may have a role in the treatment of men with endocrine-responsive disease or for those men whose disease has escaped from hormone sensitivity. DE CARCINOMA. CC CLIN. GA 364UY. Document delivery available. PT Journal. AT Article. LG English. YR 2000. NU 7 references.

--- 12 MEZZ --- AN 12198632 Medline R 20020101. TI Hormonal therapy of prostate cancer. SO Seminars in urologic oncology, {Semin-Urol-Oncol}, Aug 2002, vol. 20, no. 3 Suppl 1, p. 4-9, 30 refs, ISSN: 1081-0943. AU Debruyne-Frans. IN Department of Urology, University Hospital Nijmegen, Nijmegen, The Netherlands. AB In the 60 years since Huggins first demonstrated the hormone dependency of prostate cancer, the introduction of various means of hormonal manipulation has resulted in modest achievements. Orchiectomy reduced testosterone but was irreversible and associated with reduced quality of life. Diethylstilbestrol (DES) represented the first alternative to surgical castration. However, cardiovascular adverse events severely limited its use. The luteinizing hormone-releasing hormone (LHRH) agonists offered true medical castration but suffered from problems of testosterone surge and tumor flare. The introduction of antiandrogens in combination with LHRH agonists appears on meta- analysis not to have improved survival and has implications for the cost and convenience of therapy, as well as added toxicity. Gonadotropin-releasing hormone (GnRH) antagonists offer for the first time a truly rapid medical means of reducing testosterone and also suppress follicle-stimulating hormone (FSH). However, the clinical benefit of this new class of drugs remains to be evaluated. Copyright 2002, Elsevier Science (USA). All rights reserved. LG English. YR 2002.

--- 13 EMZZ --- AN 2005400963 20050101. TI New developments in the use of peptide gonadotropin-releasing hormone antagonists versus agonists. SO Expert Opinion on Investigational Drugs, {Expert-Opin-Invest-Drugs}, September 2005, vol. 14, no. 9, p. 1085-1097, 117 refs, CODEN: EOIDE, ISSN: 1354-3784. AU Schultze-Mosgau-Askan, Griesinger-Georg, Altgassen-Christopher, von-Otte-Soeren, Hornung- Daniela, Diedrich-Klaus. IN A. Schultze-Mosgau: Medical University of Schleswig-Holstein, Department of Obstetrics and Gynecology, Ratzeburger Allee 160, 23538 Luebeck, Germany. Email: [email protected]. AB Gonadotropin-releasing hormone (GnRH) stimulates the pituitary secretion of both luteinising hormone (LH) and follicle-stimulating hormone (FSH), and thus controls the hormonal and

82 reproductive functions of the gonads. The blockade of the effects of GnRH may be sought for a variety of reasons; for example, to control premature LH surges and to reduce the cancellation rate with the aim of improving the pregnancy rate per treatment cycle or in the treatment of sex hormone- dependent disorders. Selective blockade of LH/FSH secretion and subsequent chemical castration have previously been achieved by desensitising the pituitary to continuously administered GnRH or by giving long-acting GnRH agonists. GnRH analogues are indicated for clinical situations in which the suppression of endogenous gonadotropins (precocious puberty, contraception and controlled ovarian hyperstimulation) or sexual steroids (endometriosis, prostate hyperplasia, cancer and uterine fibroids) is desired. The immediate suppression of the pituitary that is achieved by GnRH antagonists without an initial stimulatory effect is the main advantage of these compounds over the agonists. GnRH antagonists have been developed for clinical use with acceptable pharmacokinetic, safety and commercial profiles. In assisted reproduction, these compounds seem to be as effective as established therapy, but with shorter treatment times, less use of gonadotropic hormones, improved patient acceptance, and fewer follicles and oocytes. All of the current indications for GnRH agonist desensitisation may prove to be indications for a GnRH antagonist, including endometriosis, leiomyoma and breast cancer in women, benign prostatic hypertrophy and prostatic carcinoma in men, and central precocious puberty in children. However, the best clinical evidence has been in assisted reproduction and prostate cancer. © 2005 Ashley Publications Ltd. LG English. YR 2005.

--- 14 CBIB --- AN A1997YJ62700004 19980109. TI A randomized comparison of the clinical and hormonal effects of two GnRH agonists in patients with prostate cancer. SO EUROPEAN UROLOGY, 1997, V32, N4, pp 397-403. ISSN: 0302-2838. AU Kuhn-J-M, Abourachid-H, Brucher-P, Doutres-J-C, Fretin-J, Jaupitre-A, Jorest-R, Lambert-D, Petit-J, Pin-J, Blumberg-J, DufourEsquerre-F. IN Reprints from: J M Kuhn, CHU ROUEN, DEPT ENDOCRINOL, F-76031 ROUEN, FRANCE. AB Objective: The aims of the study were (i) to compared the efficacy of the two long-acting GnRH agonists (GnRHa) triptorelin (Trp) and leuprolide (Leu) in men with prostate cancer and (ii) to assess the pattern of plasma testosterone levels following each injection of GnRHa. Patients and Methods: 67 patients referred for prostate cancer not suitable for surgery were randomly allocated to two treatment regimens: 33 patients received 3.75 mg Trp i.m. at 4-week intervals for 3 months and 34 patients were treated with 3.75 mg Leu s.c. at the same rhythm of administration for 3 months. Results: Clinical data at entry and assessed monthly during follow-up did not differ between the two groups. Plasma prostate-specific antigen (PSA) and testosterone were measured before, 24 and 72 h after each injection of GnRHa. During treatment, PSA dropped similarly in both groups. By month 2, testosterone was < 1.0 nmol/l in 77 and 48% of patients treated with Trp and Leu, respectively (p = 0.02). 24 and 72 h after GnRHa injection, 77 (Trp) and 56% (Leu) of patients had testosterone <1.0 nmol/l (p < 0.05). Conclusions: The second and third injections of GnRHa were not followed by a significant increase in testosterone. Trp induced a higher decrease in testosterone than did Leu. The implications in terms of survival should, however, be studied in a larger and longer study. DE prostate-cancer; leuprolide; triptorelin; GnRH-analogue. GONADOTROPIN-RELEASING-HORMONE; CYPROTERONE-ACETATE; DISEASE- FLARE; CARCINOMA; ORCHIECTOMY; ANALOG; TRIAL; NILUTAMIDE; BUSERELIN; FLUTAMIDE. CC CLIN, V26, N03. GA YJ627. Document delivery available. PT Journal. AT Article. LG English. YR 1997. NU 39 references.

--- 15 MEZZ --- AN 11912385 Medline R 20020101.

TI A phase 3, multicenter, open label, randomized study of abarelix versus leuprolide plus daily antiandrogen in men with prostate cancer. SO The Journal of urology, {J-Urol}, Apr 2002, vol. 167, no. 4, p. 1670-4, ISSN: 0022-5347. AU Trachtenberg-John, Gittleman-Marc, Steidle-Christopher, Barzell-Winston, Friedel-William, Pessis-Dennis, Fotheringham-Nick, Campion-Marilyn, Garnick-Marc-B. IN Princess Margaret Hospital, Toronto, Canada. AB PURPOSE: We compared the endocrinological and biochemical efficacy of abarelix depot, a gonadotropin-releasing hormone antagonist, with that of a widely used combination of luteinizing hormone releasing hormone agonist and a nonsteroidal antiandrogen. MATERIALS AND METHODS: A total of 255 patients were randomized to receive open label 100 mg. abarelix depot or 7.5 mg. leuprolide acetate intramuscularly injection on days 1, 29, 57, 85, 113 and 141 for 24 weeks. Patients in the abarelix group received an additional injection on day 15 and those in the leuprolide acetate group received 50 mg bicalutamide daily. Patients could continue treatment with study drug for an additional 28 weeks. The efficacy end points were the comparative rates of avoidance of testosterone surge (greater than 10% increase) within 7 days of the first injection and the rapidity of achieving reduction of serum testosterone to castrate levels (50 ng./dl. or less) on day 8. Patients were monitored for adverse events and laboratory abnormalities. RESULTS: Abarelix was more effective in avoidance of testosterone surge (p <0.001) and the rapidity of reduction of testosterone to castrate levels on day 8 (p <0.001) than combination therapy. No significant difference was seen between the groups in the initial rate of decline of serum prostate specific antigen or the ability to achieve and maintain castrate levels of testosterone. No unusual or unexpected adverse events were reported. CONCLUSIONS: Abarelix as monotherapy achieves medical castration significantly more rapidly than combination therapy and avoids the testosterone surge characteristic of agonist therapy. Both treatments were equally effective in reducing serum prostate specific antigen, and achieving and maintaining castrate levels of testosterone. LG English. YR 2002.

--- 16 EMZZ --- AN 2005364159 20050101. TI Triptorelin in the treatment of prostate cancer: Clinical efficacy and tolerability. SO American Journal of Cancer, {Am-J-Cancer}, 2005, vol. 4, no. 3, p.169-183, 184 refs, CODEN: AJCMC, ISSN: 1175-6357. AU Heyns-Chris-F. IN Prof. C.F. Heyns: Department of Urology, Faculty of Health Sciences, Private Bag 19063, Tygerberg 7505, South Africa. Email: [email protected]. AB Triptorelin is a synthetic analog of gonadotropin-releasing hormone (GnRH; also known as luteinizing hormone-releasing hormone (LHRH)), which has enhanced receptor affinity, extended half-life and increased bioactivity. Triptorelin initially stimulates the pituitary land, increasing serum luteinizing hormone and testosterone levels; however, after 3-4 weeks, the pituitary becomes refractory due to receptor desensitization and/or down-regulation, resulting in castration levels of testosterone in men and postmenopausal estradiol levels in women. Pharmacologic equivalence studies have shown that triptorelin, buserelin and goserelin are equally effective in down-regulating the pituitary-gonadal axis, and the new 3- and 1-month depot formulations of triptorelin have equal efficacy. In men with locally advanced or metastatic prostate cancer, administration of triptorelin leads to subjective improvement in lower urinary tract symptoms and pain, as well as objective responses such as decreased serum levels of acid and alkaline phosphatase and prostate- specific antigen, decreased prostate volume, and regression of skeletal metastases. Randomized clinical trials comparing triptorelin with bilateral orchidectomy have shown no significant differences in clinical response, survival or side effects. The time to subjective response was shorter in patients treated with orchidectomy, but there was a trend towards reduced psychologic morbidity in those treated with triptorelin. In randomized clinical trials comparing triptorelin with leuprolide (leuprorelin), two studies concluded that triptorelin induced a more rapid decrease in testosterone levels, although both drugs had similar clinical efficacy, whereas a third study concluded that triptorelin reduced testosterone levels less rapidly than, but maintained castration levels of testosterone as effectively as, leuprolide. The 9-month survival rate was significantly higher for triptorelin (97% vs 90.5% for leuprorelin). Neoadjuvant triptorelin treatment in localized prostate

84 cancer prior to radical prostatectomy may reduce the incidence of positive surgical margins, but no survival advantage has been demonstrated. Neoadjuvant treatment before radiotherapy, by reducing prostatic volume, may decrease radiation-related complications, and may increase survival in a subset of patients with a Gleason score of 2-6. The most common adverse effects of triptorelin and GnRH agonists in general, are hot flushes, loss of libido, and impotence. The initial increase in serum testosterone levels - the 'flare' phenomenon - may lead to exacerbation of bone pain, paraplegia and (rarely) death in patients with a large tumor burden. Androgen deprivation leads to a reduction in bone mineral density of 3-5% per year, but it remains to be proven that this significantly increases the clinical fracture risk in patients with prostate cancer. In conclusion, the clinical efficacy and tolerability of triptorelin in the treatment of prostate cancer are similar to that of surgical castration and leuprolide. © 2005 Adis Data Information BV. All rights reserved. LG English. YR 2005.

--- 17 MEZZ --- AN 11502441 Medline R 20010101. TI Luteinizing hormone-releasing hormone antagonists in prostate cancer. SO Urology, {Urology}, Aug 2001, vol. 58, no. 2 Suppl 1, p. 24-7, ISSN: 1527-9995. AU Stricker-H-J. IN Department of Urology, Henry Ford Hospital, Detroit, Michigan 48202, USA. [email protected]. AB Luteinizing hormone-releasing hormone (LHRH) antagonists work by directly inhibiting LHRH without any initial stimulation of the LHRH receptor. The physiologic response is a direct and rapid decrease in luteinizing hormone, follicle-stimulating hormone, and testosterone without any flare. Although there has been extensive basic-science work on these medications, practical shortcomings have limited clinical studies in prostate cancer. Many of these compounds induce significant histamine-mediated side effects, and until recently, no depot form existed. In 2 recent phase-3 studies comparing abarelix depot with leuprolide and with leuprolide plus bicalutamide, abarelix lowered serum testosterone more quickly. None of the 89 patients on leuprolide alone were castrate on day 8 as opposed to 72% of the 180 patients randomized to abarelix (P <0.001). Similarly, none of the combination group were castrate by day 8, whereas 68% of the abarelix patients were castrate (P <0.001). In addition, 82% of the patients treated with leuprolide and 86% of those given leuprolide/bicalutamide had testosterone surge, whereas none of the abarelix patients did (P <0.001 for both studies). Both phase 2 and phase 3 data show abarelix to be well tolerated. In conclusion, LHRH antagonists offer the physiologic response of orchiectomy without surgery. These medications are well tolerated and a depot form now exists. The expansion of indications for androgen deprivation, such as downsizing or intermittent therapy, could provide many opportunities for their use. Despite these encouraging advances, however, their routine use for advanced prostate cancer may depend on demonstration of a survival advantage in avoiding flare. LG English. YR 2001.

--- 18 SCZZ --- AN 420009589 9221. AU PINSKI-J, YANO-T, MILLER-G, SCHALLY-A-V. IN VET ADM MED CTR, INST ENDOCRINE POLYPEPTIDE & CANC,151,1601 PERDIDO ST, NEW ORLEANS, LA, 70146. VET ADM MED CTR, INST ENDOCRINE POLYPEPTIDE & CANC,151,1601 PERDIDO ST, NEW ORLEANS, LA, 70146. TULANE UNIV, SCH MED, DEPT MED, EXPTL MED SECT, NEW ORLEANS, LA, 70112. TI BLOCKADE OF THE LH RESPONSE INDUCED BY THE AGONIST D-TRP-6-LHRH IN RATS BY A HIGHLY POTENT LH-RH ANTAGONIST SB-75. SO PROSTATE, 1992, V20, N3, P213-224. LG EN. AB During treatment of prostate cancer patients with luteinizing hormone-releasing hormone agonist, a transient LH and sex steroid release, which precedes the secretion blockade, may result in a flare-up of the disease, whereas the antagonists induce an immediate suppression. The administration of the modern, superactive LHRH antagonist SB-75 before or together with the agonist D-Trp-6-

LHRH should prevent the "flare-up" phenomena. In order to demonstrate that the LHRH antagonist can prevent the initial stimulation of gonadotropins in response to LHRH agonists, groups of 5-7 male rats were injected s.c. with the antagonist SB-75 in doses in 100, 500, and 1,000-mu-g/rat 1 hour prior to or 1, 2, and 3 days before administration of D-Trp-6-LHRH agonist (50-mu-g/rat). Supraphysiological doses of the agonist were used in order to obtain prolonged stimulation of LH release, which was necessary to study the duration and the extent of LH release inhibition. Blood samples were taken before and 2, 6, 24, 48, and 72 hours after D-Trp-6-LHRH stimulation for measurement of LH levels. The administration of SB-75 in doses of 500 and 1,000-mu-g/rat 3 days prior to administration of the agonist significantly lowered LH response (P < 0.01), as compared to animals injected with D-Trp-6-LHRH alone. The D-Trp-6-LHRH-stimulated LH secretion was markedly more suppressed by all 3 doses of the antagonist in rats pretreated with SB-75 2 days prior to the stimulation with the agonist. An even greater reduction in LH response could be observed in rats injected with SB-75 1 day prior to the agonist, the magnitude of LH response being decreased by 75% with 500-mu-g/rat SB-75 and by 90% with 1 mg/rat SB-75. The LH response was virtually abolished when the antagonist, SB-75 was given in doses of 500 or 1,000-mu-g/rat 1 hour prior to the D-Trp-6-LHRH injection. Under these conditions, the agonist-induced LH and testosterone secretion was completely suppressed during the whole period of the experiment. The antagonist to agonist dose ratio of 2 to 1 produced a 90% decrease in the LH response to D-Trp-6-LHRH at 2 hours and 75% at 5 hours after agonist administration. The effects of LHRH decapeptide itself (500-mu-g/rat) on LH secretion could be totally suppressed by an injection of 50-mu-g/rat of SB-75 1 hour beforehand. Likewise, the response to leuprolide (100-mu-g/rat) was suppressed more than 90% by an injection of 500-mu-g/rat of SB-75. These findings indicate that pretreatment with the LHRH antagonist SB-75 1 hour before the agonists can completely prevent the elevation of LH. Since a 10- fold lower dose of SB-75 than of LHRH suppressed the LH response, this reflects the higher affinity of SB-75 to pituitary LHRH receptors. Exclusive or combined use of a modern LHRH antagonist such as SB-75 with LHRH agonist, at an appropriate schedule, may lessen the risk of tumor flare in patients. NU 45 cited references.

--- 19 MEZZ --- AN 11502435 Medline R 20010101. TI Is the flare phenomenon clinically significant? SO Urology, {Urology}, Aug 2001, vol. 58, no. 2 Suppl 1, p. 5-9, 22 refs, ISSN: 1527-9995. AU Bubley-G-J. IN Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA. [email protected]. AB OBJECTIVES: The existing luteinizing hormone-releasing hormone (LHRH) analogs have been the preferred method of inducing androgen deprivation for prostate cancer for over a decade. These agents are well known to cause a surge in serum testosterone levels during the first week of therapy. However, there are wide discrepancies in reports of the frequency and severity of acute clinical progression or clinical flare that might result from the testosterone surge. Also, there is not a clear consensus as to whether antiandrogens should be routinely given to all patients during the first month of LHRH therapy to prevent flare responses. METHODS: Clinical trials involving LHRH analog therapy for prostate cancer were reviewed, and the frequency of clinical flare responses noted. Particular attention was given to the kinds of clinical problems associated with the flare response. The use of LHRH analog therapy in treatment of patients with prostate cancer for indications other than overt metastatic disease is discussed, because this is becoming a much more common use of these agents. This article analyzes 2 placebo-controlled, double-blind trials testing the effectiveness of existing antiandrogens in ameliorating flare responses. RESULTS: The use of LHRH analogs for patients with stage D2 disease can be associated with clinical flare in approximately 10% of D2 patients. In addition to bone pain, cord compression, and bladder outlet obstruction, another potentially severe side effect is cardiovascular risk arising presumably from hypercoagulability associated with a rapid increase in tumor burden. In clinical series involving D2 patients, the frequency of clinical flare greatly varies, probably because of the level of scrutiny of the investigator and/or the prostate-cancer tumor burden present at the initiation of therapy. Concomitant antiandrogen therapy reduces, but does not totally eliminate, the flare responses in patients at high risk for flare. Treating prostate cancer in the D0 stage or in the neoadjuvant setting will result in biochemical evidence of testosterone surge, but these patients are at very little risk for clinical flare responses. CONCLUSIONS: There is a wide variation in the reported

86 frequency of clinical flare responses from LHRH analogs during the initial treatment of patients with stage D2 disease. The risk-to-benefit ratio, especially in patients with symptomatic bone metastasis, would dictate routine use of antiandrogen therapy for the first month of LHRH analog treatment. For patients at risk for cord compression, other means of ablating testosterone might be considered, such as ketoconazole, orchiectomy, or LHRH antagonists. Clinical flare responses, as opposed to biochemical flare responses, are very rare during LHRH analog therapy for stage D0 disease and/or in the setting of neoadjuvant hormonal therapy. LG English. YR 2001.

--- 20 SCZZ --- AN 400009263 9201. AU DAWSON-N-A, WILDING-G, WEISS-R-B, MCLEOD-D-G, LINEHAN-W-M, FRANK-J-A, JACOB-J-L, GELMANN-E-P. IN WALTER REED ARMY MED CTR, DEPT MED, HEMATOL ONCOL SERV, WASHINGTON, DC, 20307. WALTER REED ARMY MED CTR, DEPT UROL, WASHINGTON, DC, 20307. NCI, DIV CANC TREATMENT, CLIN ONCOL PROGRAM, BETHESDA, MD, 20892. TI A PILOT TRIAL OF CHEMOHORMONAL THERAPY FOR METASTATIC PROSTATE CARCINOMA. SO CANCER, 1992, V69, N1, P213-218 ISSUE DATE: JAN 1. LG EN. AB Fifteen patients with previously untreated metastatic prostate cancer were treated on a pilot trial with a combination of maximal androgen blockade plus intermittent cytotoxic therapy after androgen priming to stimulate cell division. Androgen blockage was carried out using a gonadotropin-releasing hormone analog (leuprolide) plus a nonsteroidal antiandrogen (flutamide). Carboplatin (CBDCA)(800 mg/m2) was given intravenously every 28 days, preceded for 3 days and followed for 3 days by androgen treatment with fluoxymesterone (5 mg orally twice a day), during which time flutamide was discontinued. Three patients (20%) achieved a complete response (CR), and eight patients (53.3%) achieved a partial response (PR). Four patients (26.7%) had stable disease (SD). The median progression-free survival (PFS) time was 31 months. Nine of 15 patients (60%) remain alive with a median follow-up time of 42+ months (range, 22 to 54 months). Grade 4 thrombocytopenia and Grades 3 or 4 leukopenia were experienced in 87% and 80% of patients, respectively, requiring dose reductions of CBDCA in 85% of the cycles. Six of 15 patients experienced a flare in bone pain with androgen priming. There were no associated spinal cord compressions; however, exclusion of impending spinal cord compression was required before entrance on study. NU 21 cited references.

--- 21 MEZZ --- AN 11391684 Medline R 20010101. TI Why phase III trials of maximal androgen blockade versus castration in M1 prostate cancer rarely show statistically significant differences. SO The Prostate, {Prostate}, 15 Jun 2001, vol. 48, no. 1, p. 29-39, ISSN: 0270-4137. AU Collette-L, Studer-U-E, Schroeder-F-H, Denis-L-J, Sylvester-R-J. IN European Organization for Research and Treatment of Cancer, EORTC Data Center, Brussels, Belgium. [email protected]. AB BACKGROUND: The meta-analysis of maximal androgen blockade (MAB) concluded that there is no survival advantage of MAB over castration alone. However, the results from the largest trials yield conflicting results. METHODS: The design and results of three trials were examined. RESULTS: Most studies were planned to detect an over-optimistic difference in survival and immature data were published. The survival curves show that statistical assumptions are not fulfilled. Excluding from the meta-analysis all trials where a negative impact of disease flare on survival could not be excluded resulted in no difference in survival between MAB and castration. CONCLUSIONS: Trials of MAB should be planned to detect differences of no more than 5-10% in median survival. The analyses should only be carried out on mature data and should take into account the possibility of a negative impact on survival due to disease flare if no anti-androgen has been given initially with an LH-RH agonist. Copyright 2001 Wiley-Liss, Inc. Grant ID: SU10-CA11488-29, Acronym: CA, Agency: NCI NIH HHS, United States. LG English.

YR 2001.

--- 22 MEZZ --- AN 11342922 Medline R 20010101. TI The gonadotropin-releasing hormone antagonist abarelix depot versus luteinizing hormone releasing hormone agonists leuprolide or goserelin: initial results of endocrinological and biochemical efficacies in patients with prostate cancer. SO The Journal of urology, {J-Urol}, May 2001, vol. 165, no. 5, p. 1585-9, ISSN: 0022-5347. AU Tomera-K, Gleason-D, Gittelman-M, Moseley-W, Zinner-N, Murdoch-M, Menon- M, Campion-M, Garnick-M-B. IN Alaska Clinical Research Center, Anchorage, Alaska, USA. AB PURPOSE: We contrasted the endocrinological and biochemical efficacies of abarelix depot, a pure gonadotropin-releasing hormone antagonist, with a prospective concurrent control cohort receiving luteinizing hormone releasing hormone (LH-RH) agonists with or without antiandrogen for treatment of patients with prostate cancer receiving initial hormonal therapy. MATERIALS AND METHODS: In this phase 2 open label study 242 patients with prostate cancer requiring initial hormonal treatment received abarelix depot (209) or LH-RH agonists (33) with or without antiandrogen. A total of 100 mg. abarelix depot was delivered intramuscularly every 28 days with an additional injection on day 15. LH-RH agonists with or without antiandrogen were administered according to the depot formulation used. Endocrine efficacy was measured by the absence of testosterone surge and rapidity of castration onset. The rate of prostate specific antigen decrease was assessed. RESULTS: No patient treated with abarelix depot had testosterone surge during week 1 compared with 82% of those treated with LH-RH agonists. The concomitant administration of antiandrogen had no effect. During the first week of drug administration, in 75% of patients treated with abarelix depot and in 0% of those treated with LH-RH agonist medical castration was achieved. Prostate specific antigen decrease was faster, with no flare or surge in patients treated with abarelix depot. Abarelix depot was well tolerated. CONCLUSIONS: Abarelix depot represents a new class of hormonal therapy, gonadotropin releasing hormone antagonists, that has rapid medical castration and avoids the testosterone surge characteristic of LH-RH agonists. LG English. YR 2001.

--- 23 SCZZ --- AN 376021177 9100. AU DUPLESSIS-D-J. IN UNIV PRETORIA, DEPT UROL, PRETORIA, SOUTH AFRICA. TI CASTRATION PLUS NILUTAMIDE VS CASTRATION PLUS PLACEBO IN ADVANCED PROSTATE-CANCER - A REVIEW. SO UROLOGY, 1991, V37, N2, P20-24. LG EN. AB Combination of antiandrogen treatment with surgical or medical castration should improve the efficacy of endocrine treatment of prostatic cancer by blocking the effects of adrenal androgens. A nonsteroidal antiandrogen, nilutamide, has shown promising results in preliminary open studies. In a short-term (29 days) comparison of nilutamide plus buserelin and buserelin plus placebo, nilutamide (300 mg/day), significantly reduced bone pain, and fewer patients experienced worsening pain than in the control group. The initial buserelin-induced increase in prostatic acid phosphatase was prevented by nilutamide, but there was a similar increase in testosterone and gonadotropin concentrations to that seen in the control group. Thus, nilutamide can prevent the tumor flare-up associated with the start of luteinizing hormone-releasing hormone (LH-RH) treatment, even though the endocrine responses are not affected. In three multicenter, randomized, double-blind placebo-controlled trials of castration and nilutamide involving 248 patients, the combination of nilutamide and castration decreased bone pain, improved performance status, and increased the number of patients with objective regression, compared with patients who were castrated but did not receive nilutamide. Nilutamide was generally well tolerated, though visual disorders, gastrointestinal disorders, and alcohol intolerance were reported in patients receiving nilutamide. The results suggest that nilutamide improves the efficacy of castration in patients with prostatic cancer. Current studies are investigating the effects of this treatment on survival and the risk-benefit ratio. NU 12 cited references.

--- 24 MEZZ --- AN 11235144 Medline R 20010101. TI (Suppressive effects of the antiandrogen flutamide on adrenal androgens in advanced prostate cancer patients). SO Nippon Hinyokika Gakkai zasshi. The japanese journal of urology, {Nippon-Hinyokika- Gakkai-Zasshi}, Jan 2001, vol. 92, no. 1, p. 6-12, ISSN: 0021-5287. AU Nakazato-H, Suzuki-K, Ito-K, Fukabori-Y, Kurokawa-K, Yamanaka-H. IN Department of Urology, Gunma University School of Medicine. AB PURPOSE AND METHODS: We investigated the influence of flutamide on plasma adrenal androgens in advanced prostate cancer patients treated with dietylstilbestrol diphosphate (DES-DP) followed by luteinizing hormone-releasing hormone agonist (LH-RH agonist). Nine patients were enrolled in this study and they were divided into the following two treatment groups; group A: LHRH agonist mono-therapy (n = 4) and group B: LHRH agonist with flutamide (n = 5). For prevention of flare up, all patients were treated with DES-DP. RESULTS: Two-week DES-DP administration led to reduction of plasma adrenal androgen levels. These levels were kept lower for 16 weeks in group B in contrast with group A in which the levels returned to the pretreatment levels. Basal ACTH levels in group B were significantly lower than those in group A. CONCLUSION: From our observations, we found that flutamide reduced adrenal androgen levels in prostate cancer patients treated with LH-RH agonist. ACTH suppression might be related to this phenomenon. LG Japanese. YR 2001.

--- 25 SCZZ --- AN 370007073 9049. AU THOMPSON-I-M, ZEIDMAN-E-J, RODRIGUEZ-F-R. IN BROOKE ARMY MED CTR, DEPT SURG, UROL SERV, FT SAM HOUSTON, TX, 78234. TI SUDDEN-DEATH DUE TO DISEASE FLARE WITH LUTEINIZING-HORMONE- RELEASING HORMONE AGONIST THERAPY FOR CARCINOMA OF THE PROSTATE. SO JOURNAL-OF-UROLOGY, 1990, V144, N6, P1479-1480. LG EN. NU 15 cited references.

--- 26 EMZZ --- AN 1998140755 19980101. TI Clinical pharmacokinetics of the antiandrogens and their efficacy in prostate cancer. SO Clinical Pharmacokinetics, {Clin-Pharmacokinet}, 1998, vol. 34, no. 5, p. 405-417, 66 refs, CODEN: CPKND, ISSN: 0312-5963. AU Mahler-Ch, Verhelst-J, Denis-L. IN Prof. Ch. Mahler: Department of Endocrinology, AZ Middelheim, Lindendreef 1, 2020 Antwerp, Belgium. Email: [email protected]. AB Prostatic cancer is the second most common cause of cancer death in males. Treatment by radical prostatectomy and radiotherapy is useful in the early stages of the disease. Whenever metastases occur, patients are usually treated by surgical (orchidectomy) or medical (gonadotropin releasing hormone (GnRH) analogue) castration. This form of treatment is, however, associated with unwanted adverse effects, such as flushing, loss of libido and potency and all patients ultimately escape therapy after a delay of 1 to 2 years. For this reason antiandrogens have been developed as another means of endocrine ablation therapy. Antiandrogens fall in 2 groups of which the first group, the steroidal antiandrogens such as cyproterone acetate (CPA), have a direct blocking effect at the cellular level but also inhibit testosterone production by their additional gestagenic properties blocking gonadotropin secretion. Except in preventing the flare-up associated with the start of GnRH analogue therapy and in reducing flushing, no evidence exist of any superiority for CPA over classical therapy in terms of advers effects and survival. The second group, the nonsteroidal or 'pure' antiandrogens, only block androgens at the cellular level without any central effects. In contrast with other forms of castration, patients on pure antiandrogens as monotherapy preserve their sexual function and potency, at the expense of a slightly inferior androgen blockade and gynecomastia. These latter effects are explained by a compensatory rise in androgens as a result of the blockade at the central level, which weakens the androgen blockade, and by peripheral aromatisation of the increased androgens to oestrogens. In addition, some evidence exist that pure antiandrogens improve survival if combined with other forms of castration as they also inhibit the adrenal androgens, the so-called maximal androgen blockade (MAB). If patients escape control under MAB, a trial of stopping the

89 antiandrogen must always be considered, as some tumours have 'learned' to be activated by these drugs. At the moment it is not yet clear if antiandrogens are of any benefit in downstaging the extent of disease before prostatectomy and/or radiotherapy. Of the currently known pure antiandrogens, bicalutamide offers some advantages over flutamide as it possesses a much longer half-life, allowing once daily regimen, and has advantages over nilutamide in terms of fewer adverse effects. LG English. YR 1998.

--- 27 MEZZ --- AN 11062384 Medline R 20000101. TI Abarelix Depot, a GnRH antagonist, v LHRH superagonists in prostate cancer: differential effects on follicle-stimulating hormone. Abarelix Depot study group. SO Molecular urology, {Mol-Urol}, Fall 2000, vol. 4, no. 3, p. 275-7, ISSN: 1091-5362. AU Garnick-M-B, Campion-M. IN PRAECIS Pharmaceuticals Inc., Cambridge, Massachusetts 02139-1572, USA.Marc, [email protected]. AB Purpose: A Phase II clinical study contrasted the endocrinologic and biochemical efficacy of Abarelix Depot, a gonadotropin-releasing hormone (GnRH) antagonist, with luteinizing hormone releasing-hormone (LHRH) superagonists, with or without additional antiandrogens, in men with prostate cancer. Methods: This study was open-label and treated 242 men. Abarelix Depot 100 mg was administered by intramuscular injection to 209 men, and LHRH, with or without an antiandrogen, was administered to 33 men according to the formulation used. Serum concentrations of follicle-stimulating hormone (FSH) and other hormones were measured at baseline and at specified time points for the first 85 days of the study. Median serum concentrations of FSH at baseline were similar for the two treatment groups. Results: Men treated with LHRH superagonists, with or without an antiandrogen, had a surge in the serum concentration of FSH on day 2 before FSH concentrations started to decline. Men in the Abarelix Depot group had an immediate and sustained decrease in the serum concentration of FSH. Conclusion: Recent data suggest that FSH may be an independent growth factor for prostate cancer. The Abarelix Depot-induced decreased in FSH may have a role in the treatment of men with endocrine- responsive disease or for those men whose disease has escaped from hormone sensitivity. LG English. YR 2000.

--- 28 SCZZ --- AN 361011113 9040. AU SCHULZE-H, SENGE-T. IN UNIV BOCHUM, MARIEN HOSP, DEPT UROL, D-4690 HERNE 1, FED REP GER. TI INFLUENCE OF DIFFERENT TYPES OF ANTIANDROGENS ON LUTEINIZING- HORMONE-RELEASING HORMONE ANALOG-INDUCED TESTOSTERONE SURGE IN PATIENTS WITH METASTATIC CARCINOMA OF THE PROSTATE. SO JOURNAL-OF-UROLOGY, 1990, V144, N4, P934-941. LG EN. NU 34 cited references.

--- 29 EMZZ --- AN 1995006225 19950101. TI Leuprorelin. A review of its pharmacology and therapeutic use in prostatic cancer, endometriosis and other sex hormone-related disorders. SO Drugs, {DRUGS}, 1994, vol. 48, no. 6, p. 930-967, CODEN: DRUGA, ISSN:0012-6667. AU Plosker-G-L, Brogden-R-N. IN R.N. Brogden: Adis International Limited, 41 Centorian Dr., Private Bag 65901, Mairangi Bay, Auckland 10, New Zealand. AB Leuprorelin (leuprolide acetate) is a gonadotrophin-releasing hormone (GnRH) analogue used to treat a wide range of sex hormone-related disorders including advanced prostatic cancer, endometriosis and precocious puberty. It acts primarily on the anterior pituitary, inducing a transient early rise in gonadotrophin release. With continued use, leuprorelin causes pituitary desensitisation and/or down-regulation, leading to suppressed circulating levels of gonadotrophins

90 and sex hormones. Clinical trials in men with advanced prostatic cancer demonstrate that leuprorelin (usually monthly depot injections of 3.75 or 7.5 mg) is less likely to cause serious adverse cardiovascular effects than diethylstilbestrol, and has comparable efficacy to bilateral orchiectomy or other GnRH analogues. Therefore, the choice between leuprorelin and orchiectomy may be made on the basis of the patient's treatment preference, along with specific patient characteristics and cost implications. Monthly intramuscular or subcutaneous administration of depot leuprorelin 3.75 mg was superior to placebo, and comparable to oral danazol 800 mg/day or intranasal buserelin 900 mug/day, in achieving objective and subjective responses in women with endometriosis. Thus, leuprorelin is an effective alternative to other treatments for women with endometriosis, but the recommended duration of its use in this clinical setting is limited to 6 months because it reduces bone mineral density. In children with central precocious puberty, leuprorelin (usually monthly intramuscular or subcutaneous injections of depot leuprorelin 3.75 to 15 mg) decreases mean growth velocity and signs of sexual maturation and increases predicted adult height compared with baseline measurements. Although effects on final adult height are predicted from available data and require confirmation in long term follow-up studies, the absence of effective alternatives to GnRH analogues makes leuprorelin a first-line therapy for children with this rare disease. In women with uterine leiomyomata, monthly intramuscular administration of depot leuprorelin 3.75 mg for 6 months markedly reduces uterine volume and fibroid-related symptoms, but, as with other GnRH analogues, these effects dissipate following discontinuation of the drug. As adjuvant therapy in women undergoing in vitro fertilisation or gamete intrafallopian transfer; leuprorelin (usually 0.5 to 1 mg/day subcutaneously) reduces the risk of cancelled cycles for oocyte retrieval by preventing premature luteinisation. While some studies demonstrate an improvement in intermediate end-points such as increased number of mature oocytes retrieved and embryos available for transfer, a significant effect has not been demonstrated on the rate of live births per stimulated cycle. The tolerability profile of leuprorelin varies somewhat depending on the patient's gender and/or disease state because most adverse effects associated with leuprorelin result from changes in levels of circulating sex hormones. In men with prostatic cancer receiving leuprorelin, impotence and decreased libido occur almost universally, hot flushes are reported by 35 to 71% of men and exacerbation of symptoms (disease flare) occurs in approximately 10%. Hot flushes occur in approximately 80% of women receiving leuprorelin for endometriosis and other common adverse events include headache, vaginitis/vaginal dryness, insomnia and emotional lability. Children with precocious puberty appear to tolerate leuprorelin well, although long term effects on the reproductive system are unknown. The most frequently reported problem in this patient population is local reaction at the injection site, which develops in approximately 5% of children receiving leuprorelin. In general, few notable differences have been demonstrated between leuprorelin and other GnRH analogues in the limited number of comparative clinical trials conducted in patients with sex hormone-related disorders. While monthly injections of depot leuprorelin may be preferable to daily administration of other GnRH analogues in some patients, other GnRH analogues are also available in depot formulations. Thus, leuprorelin offers effective therapy for a number of sex hormone-related disorders with daily subcutaneous administration of the aqueous solution or convenient monthly injections of the depot formulation. LG English. YR 1994.

--- 30 MEZZ --- AN 09854193 Medline R 19990101. TI Arguments against the long-term use of combined androgen blockade. SO European urology, {Eur-Urol}, 1998, vol. 34 Suppl 3, p. 29-32, 24 refs, ISSN: 0302-2838. AU Studer-U-E, Mills-R-D. IN Department of Urology, University of Berne, Switzerland. AB Androgen deprivation therapy is the most effective systemic treatment for advanced prostate cancer. However, as most patients who die from prostate cancer have hormone refractory disease, fine tuning of antiandrogen treatment by combined androgen blockade (CAB) can not be expected to improve survival significantly. Only the South West Oncology Intergroup (SWOG) study 0036 has shown a significant advantage for CAB compared with luteinizing hormone-releasing hormone (LH-RH) agonist alone. However, the results of this study should be interpreted with caution as the patients had to self-administer their treatment by daily injection so compliance may not have been optimal. Also, those receiving LH-RH agonist alone were not covered against disease flare. Indeed, no trial using depot LH-RH agonist with or without flutamide has been able to show a survival benefit. When treatment with LH-RH agonist plus antiandrogen was compared with orchiectomy alone, only

91 the European Organization for Research and Treatment of Cancer (EORTC) study 30,853 showed a significant difference in favour of CAB. However, in this study an increased proportion of patients receiving CAB may have had a more favourable prognosis. Only one study comparing orchiectomy plus antiandrogen with orchiectomy alone has shown an advantage for CAB therapy, and this was only slight. Therefore, as yet there is no justification for long-term use of CAB. However, short-term antiandrogen treatment must be used to prevent disease flare during initiation of LH-RH agonist treatment. LG English. YR 1998.

--- 31 MEZZ --- AN 09563139 Medline R 19980101. TI Comparison of LH-RH analogue 1-month depot and 3-month depot by their hormone levels and pharmacokinetic profile in patients with advanced prostate cancer. SO Urologia internationalis, {Urol-Int}, 1998, vol. 60 Suppl 1, p. 9-16;discussion 16-7, ISSN: 0042- 1138. AU Tunn-U-W, Bargelloni-U, Cosciani-S, Fiaccavento-G, Guazzieri-S, Pagano-F. IN Urology Department, Academic Hospital, Offenbach, Germany. AB In an open, randomized phase II pharmacokinetic study conducted in Germany and Italy, a total of 42 patients with advanced or metastatic prostate cancer (PCa) were treated for 9 months with the luteinizing hormone-releasing hormone analogue (LH-RH-a) leuprorelin acetate depot in two different formulations. Fifteen patients received the 1-month depot and 27 patients received the newly developed 3-month depot, containing 3.75 mg and 11.25 mg, respectively. In both groups, subcutaneous injections of leuprorelin acetate injected monthly or at 3-month intervals produced a complete down-regulation of the pituitary and led to persistent suppression of testosterone and dihydrotestosterone to the castrate range (< or = 50 ng/dl for testosterone) within the first month of treatment, which thereafter could be maintained over the entire observation period of 9 months. In 10 patients, pretreatment with an antiandrogen for the prevention of clinical flare-up resulted in a slightly more profound and earlier drop in serum testosterone. The 3-month depot showed a higher median peak serum concentration (Cmax) of leuprorelin at 20.8 ng/ml than the 1-month depot at 10.7 ng/ml but, conversely, this did not influence the rise in serum testosterone levels. Cmax occurred at 3 h for the 3-month and at 1 h for the 1-month depot formulation. During the steady state, constant release could be detected, starting on day 3 and day 7 for the 1-month and 3-month depot, respectively. A marked decrease in median prostate-specific antigen levels of 97.8% (1-month depot) and 96.6% (3-month depot) compared with baseline was observed, indicating an objective clinical response for more than 80% of all patients in both arms. Based on European Organization for Research and Treatment of Cancer criteria, the best response in terms of complete/partial remissions and stabilization was comparable in the two arms at 86.7% (1-month depot) and 85.2% (3-month depot). 6.7% in the 1-month group and 3% in the 3-month depot group showed progression of the disease. The most common side effects in both treatment groups were related to hormone deprivation. Both formulations of the potent LH-RH-a leuprorelin acetate were highly effective in the treatment of advanced PCa and led to comparable endocrine and clinical effects. LG English. YR 1998.

--- 32 MEZZ --- AN 07613021 Medline R 19950101. TI Goserelin. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy in prostate cancer. SO Drugs & aging, {Drugs-Aging}, Apr 1995, vol. 6, no. 4, p. 324-43, 106 refs, ISSN: 1170-229X. AU Brogden-R-N, Faulds-D. IN Adis International Limited, Auckland, New Zealand. AB Goserelin is a gonadotrophin-releasing hormone (GnRH) analogue which during long term administration reduces circulating levels of gonadotrophins (luteinising hormone and follicle stimulating hormone) and sex hormones. Goserelin is administered subcutaneously as a biodegradable depot formulation incorporating 3.6mg of the drug, which is released continuously over 4 weeks. In men with untreated advanced prostate cancer, monthly goserelin 3.6mg has been confirmed as similar in efficacy to surgical castration and diethylstilbestrol (stilboestrol) 3mg daily

92 taken orally. Goserelin is better tolerated than diethylstilbestrol and appears to have a more favourable effect on quality of life than surgical castration. Treatment of prostate cancer with a combination of goserelin and an antiandrogen remains controversial as a result of inconsistent findings, despite extended data from a large trial which indicated an advantage for the combined regimen over surgical castration with respect to duration of time to progression and survival. Combination therapy also minimises the initial increase in signs and symptoms (disease flare) that occurs in up to 4% of patients at the beginning of treatment with a GnRH analogue. Surgical castration remains the treatment of choice in patients at risk of metastatic compression of the spinal cord or ureteric obstruction. However, goserelin is an effective alternative to surgery, or estrogen therapy, in men with previously untreated advanced prostate cancer. Goserelin seems to be preferred to surgery by the majority of patients given a choice of treatment, and importantly in a palliative care situation where there are no survival advantages for treatment alternatives, it appears to have a more beneficial effect on the quality of life than surgery. LG English. YR 1995.

--- 33 MEZZ --- AN 07688656 Medline R 19930101. TI Luteinizing hormone-releasing hormone agonists in prostate cancer. Elimination of flare reaction by pretreatment with cyproterone acetate and low-dose diethylstilbestrol. SO Cancer, {Cancer}, 1 Sep 1993, vol. 72, no. 5, p. 1685-91, ISSN:0008-543X. AU Bruchovsky-N, Goldenberg-S-L, Akakura-K, Rennie-P-S. IN Department of Cancer Endocrinology, British Columbia Cancer Agency, Vancouver Clinic, Canada. AB BACKGROUND. In response to the first administration of a luteinizing hormone-releasing hormone (LHRH) agonist, the secretion of pituitary gonadotropin increases sharply and gives rise to a transient surge in the concentration of serum testosterone. This effect reaches a peak 4 to 7 days after the start of therapy and results in the onset of clinical symptoms and signs of tumor flare in 5% to 10% of patients. METHODS. To determine whether the effects of the LHRH-induced flare reaction are preventable, cyproterone acetate (100 mg) and low-dose diethylstilbestrol (0.1 mg) were administered daily for 4 weeks to inhibit the pituitary before the initiation of therapy with a depot LHRH agonist, goserelin acetate (3.6 mg every 4 weeks). Diethylstilbestrol was stopped after 8 weeks to eliminate associated minor toxicity while administration of cyproterone acetate was continued to suppress vasomotor symptoms. Twenty-four men with histologically confirmed prostate cancer were enrolled in the study: 6 with Stage C, 2 with Stage D1, and 16 with Stage D2 disease. RESULTS. Lead-in therapy reduced the concentration of serum testosterone into the castrate range within 1 week, and no significant change was observed in the mean level after administration of goserelin acetate. Neither was there an effect on the initial rate of normalization of serum prostate specific antigen (PSA); normal PSA values were obtained in 50% of patients after 10 weeks and in 70% after 32 weeks. In the subgroup of patients with Stage D2 disease, longer median survival was predicted by a normal serum PSA, either stable or decreasing, after 32 weeks of treatment. The regimen was well tolerated with a low incidence of hot flushes. CONCLUSIONS. These results imply that in the absence of LHRH-induced tumor flare, prognosis is related to the ability of therapy to maintain a PSA nadir in the normal range. LG English. YR 1993.

--- 34 MEZZ --- AN 01492625 Medline R 19930101. TI Hormone therapy of prostatic bone metastases. SO Advances in experimental medicine and biology, {Adv-Exp-Med-Biol}, 1992, vol. 324, p. 305-16, ISSN: 0065-2598. AU Huben-R-P. IN Department of Urologic Oncology, Roswell Park Cancer Institute, Buffalo, New York 14263. AB When present at diagnosis or when developing in the course of disease, the presence of bone metastases from prostate cancer is generally considered an indication to begin endocrine therapy, as this is clearly the most effective form of treatment for this problem. Endocrine therapy can stop progression of prostate cancer in 80-85% of cases. Endocrine therapy can relieve pain, prevent pathologic fractures, and prevent neurologic complications from bone metastases from prostate cancer. Rarely, bone scans may become normal after the start of endocrine therapy, but partial

93 improvement or stabilization of bone scans are more commonly seen. While endocrine therapy has been the first line of treatment of metastatic prostate cancer for the past 50 years, the recent development of newer forms of endocrine therapy have increased the options in the past few years. In addition to orchiectomy and estrogens, newer alternatives include inhibitors of androgen synthesis, the class of agents termed antiandrogens, and luteinizing hormone releasing-hormone (LHRH) analogues either alone or in combination. Orchiectomy causes a prompt fall in serum testosterone and is regarded by many as the standard form of endocrine therapy, but there is concern about the psychologic impact of surgery. Estrogens are being used less frequently today because of their real or potential side-effects, including cardiovascular and thromboembolic complications. The development of analogues of LHRH has resulted in another major choice for endocrine therapy, and one which is therapeutically equivalent to orchiectomy or estrogens. Since LHRH analogues may cause an early rise or flare in serum testosterone before it drops to castrate level, these agents should not be given alone to patients with severe pain or neurologic problems. The newly available antiandrogen flutamide can block the flare, and may also improve survival when used with LHRH analogues or orchiectomy, especially when disease is less advanced. Not all studies of combination therapy support this conclusion. However, the use of flutamide is increasing significantly in the United States. Both the LHRH analogues and flutamide are fairly safe, but they are very expensive. Their use, in combination, is likely to become a progressively more common form of initial endocrine therapy in the future. The growing application of prostate specific antigen (PSA) as a tumor marker for prostate cancer has made the difficulty in interpreting changes in bone scans a much less critical problem in determining response to endocrine or other forms of therapy for dvanced prostate cancer. LG English. YR 1992.

--- 35 MEZZ --- AN 01794035 Medline R 19920101. TI Leuprorelin. A review of its pharmacology and therapeutic use in prostatic disorders. SO Drugs & aging, {Drugs-Aging}, Nov-Dec 1991, vol. 1, no. 6, p. 487-509, 101 refs, ISSN: 1170- 229X. AU Chrisp-P, Sorkin-E-M. IN Adis International Limited, Auckland, New Zealand. AB Leuprorelin (leuprolide acetate) is a synthetic analogue of gonadotrophin-releasing hormone (GnRH) (luteinising hormone-releasing hormone (LHRH)) which initially stimulates luteinising hormone (LH) and hence testicular androgen release; continuous administration then results in profound suppression of these hormones. Testosterone levels associated with castration are attained within 3 to 4 weeks. A biodegradable subcutaneous or intramuscular depot formulation of leuprorelin 3.75 or 7.5 mg, which releases the drug at a constant rate over 28 days, is available and may be preferred over daily subcutaneous injections. The progression of previously untreated advanced prostatic cancer is delayed in 70 to 90% of men receiving leuprorelin, with median survival of approximately 2 years. The efficacy of leuprorelin is equivalent to that of estrogen therapy, but the tolerability of the GnRH analogue is far better. In contrast to most other studies of GnRH agonists, a slight survival advantage has been reported for combined treatment with leuprorelin and the antiandrogen flutamide. Small noncomparative trials reveal that leuprorelin also causes regression of benign hyperplastic prostate tissue with corresponding relief of obstructive, but not irritative, symptoms although continuous treatment is necessary to maintain remission. Impotence and flushing occur in most leuprorelin recipients but, unlike diethylstilbestrol (stilboestrol), cardiovascular toxicity and gynaecomastia are not significant problems. Symptom flare, usually manifested as bone pain in prostate cancer patients and exacerbation of obstructive symptoms in those with benign prostatic hypertrophy, can occur in 4 to 29% at the beginning of treatment. Leuprorelin treatment is therefore an established effective palliative measure in men with previously untreated advanced prostatic cancer, and may have a role in those with benign hypertrophy who are unfit for surgery. LG English. YR 1991.

--- 36 MEZZ --- AN 01907843 Medline R 19910101. TI Long term follow-up of patients with advanced prostatic cancer treated with nasal buserelin.

SO Annals of oncology : official journal of the European Society for Medical Oncology / ESMO, {Ann-Oncol}, Apr 1991, vol. 2, no. 4, p. 303-4, ISSN: 0923-7534. AU Falkson-C-I, Falkson-G, Falkson-H-C. IN Department of Medical Oncology, University of Pretoria, Rep. of South Africa. AB Sixty one men, with advanced prostatic cancer, were entered on a trial using a nasally administered gonadotropin-releasing hormone analogue agonist, buserelin, as first line treatment. This is the first trial to use intranasal buserelin without primary injections and without antiandrogens. No 'flare' phenomenon was observed. The only side effects were hot flashes (69%) and decreased libido (25%). The response rate of 82%, with a median response duration of 16 months, compares favourably to responses reported with orchidectomy or estrogens. Serum testosterone, FSH and LH were monitored at regular intervals. Mean serum testosterone baseline values of 15 nmol/L decreased to castrate levels, and remained low while patients were on study. It is concluded that intranasal buserelin is an effective, simple and safe method to achieve androgen deprivation and is an alternative to orchidectomy in the treatment of advanced prostatic cancer. LG English. YR 1991.

--- 37 MEZZ --- AN 02151278 Medline R 19910101. TI Zoladex vs. Zoladex plus cyproterone acetate in the treatment of advanced prostatic cancer: a multicenter Italian study. SO European urology, {Eur-Urol}, 1990, vol. 18 Suppl 3, p. 54-61, ISSN:0302-2838. AU Di-Silverio-F, Serio-M, D-Eramo-G, Sciarra-F. IN Department of Urology, University of Rome, La Sapienza, Italy. AB A collaborative multicenter trial was conducted by 17 Italian groups to verify whether the so- called total androgen blockade obtained with luteinizing hormone releasing hormone (LHRH) analogs combined with antiandrogens is more effective than conventional monotherapy in the treatment of advanced prostatic cancer. A total of 328 previously untreated patients were evaluated: 163 patients received Zoladex depot alone, 3.6 mg subcutaneously every 28 days, and 165 patients received Zoladex depot plus cyproterone acetate (CPA), 200 mg/day orally. The follow-up period ranged from 41-251 weeks. Treatment was well tolerated, and side-effects in both groups mainly comprised loss of libido and erections, hot flashes and breast swelling and tenderness. There was no significant difference in objective response after 6, 12 and 24 months of treatment between the 2 groups. Median time to disease progression was comparable in both groups: 55 weeks in the Zoladex group and 54 weeks in the Zoladex plus CPA group. The time to disease progression and the survival distribution was comparable in both groups. Although there were no significant differences in the overall subjective response to both treatments, a faster improvement, with respect to pain and performance status was noted in the Zoladex plus CPA group (8 weeks) compared to Zoladex alone (12 weeks). The addition of antiandrogen, by inhibiting the initial elevation of plasma testosterone, may prevent the disease flare-up which occurs in a small number of patients during the first few days of treatment with LHRH analogs alone.(ABSTRACT TRUNCATED AT 250 WORDS). LG English. YR 1990.

--- 38 MEZZ --- AN 02108884 Medline R 19900101. TI Luteinizing hormone releasing hormone agonists: the US experience. SO The Journal of international medical research, {J-Int-Med-Res}, 1990, vol. 18 Suppl 1, p. 31-4, ISSN: 0300-0605. AU Nabors-W, Crawford-E-D. IN Division of Urology, University of Colorado, Denver 80262. AB In a large multicentre trial, 1 mg/day leuprorelin given subcutaneously was as effective as diethylstilboestrol in the treatment of prostatic cancer but with a lower incidence of side-effects, although leuprorelin could induce tumour flare-up. Total androgen ablation using a combination of leuprorelin and the non-steroidal anti-androgen flutamide in the treatment of prostatic cancer was more effective than either orchidectomy or diethylstilboestrol. The efficacy of 1 mg/day leuprorelin given subcutaneously plus 250 mg flutamide three times a day compared with leuprorelin plus placebo was confirmed in a randomized, double-blind study of 603 patients. Progression-free and overall survival were prolonged, and tumour flare-up and other side-effects were reduced in patients with untreated advanced prostatic cancer and in those with minimal disease.

LG English. YR 1990.

--- 39 MEZZ --- AN 02506941 Medline R 19890101. TI Buserelin in the treatment of prostatic cancer. SO Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, {Biomed- Pharmacother}, 1989, vol. 43, no. 4, p. 279-85, 51 refs, ISSN:0753-3322. AU Roila-F. IN Divisione Oncologia Medica, Ospedale Policlinico, Perugia, Italy. AB Buserelin is a synthetic gonadotropin-releasing hormone (GnRH) analog which is more potent than natural GnRH. Prolonged administration of the drug produces, after a short phase of stimulation, a selective and durable inhibition of secretion of pituitary gonadotropins, resulting in medical castration. In pilot and controlled studies buserelin shows a response rate that is similar to that of diethylstilbestrol or orchiectomy in the palliative treatment of advanced prostatic cancer, but larger and better designed studies are needed before reaching definitive conclusions about the duration of response and survival. The most common adverse effects of buserelin are loss of libido and/or impotence, hot flushes and possible flare-up of prostatic carcinoma symptoms in the first week of therapy. The combination of buserelin with an antiandrogen could avoid the flare syndrome; whether the combination has advantages compared to administration of buserelin alone requires confirmation from the large randomized studies still in progress. LG English. YR 1989.

--- 40 MEZZ --- AN 02853934 Medline R 19890101. TI The clinical and endocrine assessment of three different antiandrogen regimens combined with a very long-acting gonadotrophin-releasing hormone analogue. SO American journal of clinical oncology, {Am-J-Clin-Oncol}, 1988, vol. 11 Suppl 2, p. S152-5, ISSN: 0277-3732. AU Waxman-J, Williams-G, Sandow-J, Hewitt-G, Abel-P, Farah-N, Fleming-J, Cox-J, O-Donoghue-E-P, Sikora-K. IN Department of Clinical Oncology, Hammersmith Hospital, London, England. AB Tumor flare is reported in up to 40% of patients treated with gonadotrophin-releasing hormone analogues for prostate cancer. In order to investigate the optimal way to eliminate tumor flare, we have treated patients with one of three different antiandrogen regimens used in combination with gonadotrophin-releasing hormone (GnRH) agonist. The early results of this study are presented here. Thirty patients with advanced symptomatic disease were randomized to receive either cyproterone acetate 50 or 100 mg three times daily or flutamide 250 mg three times daily given for 1 week before and during the first month of GnRH agonist treatment. The endocrine profiles of these patients were compared with those of historic controls treated with depot agonist alone. Three patients treated with low-dose cyproterone acetate and one with flutamide developed a transient exacerbation of their disease. No patients treated with the higher-dose cyproterone acetate regimen developed tumor flare. No patients treated with cyproterone acetate had an increase in serum testosterone above baseline following depot GnRH agonist implantation. All patients treated with flutamide had increases in serum testosterone, but this did not significantly increase further with implantation. This study suggests that all patients receiving GnRH agonist treatment should be pretreated with cyproterone acetate 100 mg three times daily for 1 week before implantation and for the first treatment month. LG English. YR 1988.

--- 41 MEZZ --- AN 03071951 Medline R 19890101. TI Antiandrogens in combination with LH-RH agonists in prostate cancer. SO American journal of clinical oncology, {Am-J-Clin-Oncol}, 1988, vol. 11 Suppl 2, p. S132-47, 153 refs, ISSN: 0277-3732. AU Raynaud-J-P. IN Direction Innovation et Prospective, Roussel-Uclaf, Paris, France.

AB The rationale of the combination of a nonsteroid antiandrogen with an LH-RH analogue (LH- RH-A) in the treatment of prostate cancer is discussed. Whereas the LH-RH-A depresses testosterone (T) levels via an action on the hypothalamus-pituitary-gonad axis, the antiandrogen counters the effect of any residual T, from the testes or adrenals, on the target organ, the prostate. Although bilateral orchiectomy and administration of estrogen or LH-RH-A give equivalent low T levels over long-term treatment, the manner and rate at which T suppression is achieved vary and each treatment presents characteristic disadvantages. Orchiectomy is irreversible, and it is known that approximately 20% of patients will not benefit from such endocrine manipulation, estrogen use is associated with cardiovascular disease, and LH-RH analogues produce an early surge in T. None of these treatments has any significant effect on adrenal androgen levels, which may contribute toward the progression of disease. Nonsteroid antiandrogens such as anandron and flutamide inhibit the uptake of androgen by the prostate by an action that probably involves the androgen receptor. They do not possess the progestational and glucocorticoid component of steroid antiandrogens or their pituitary inhibitory activity but do exert some inhibition of the 17 alpha-hydroxylase and 17,20- lyase enzyme systems. Unlike steroids, the nonsteroid antiandrogens potentiate the activity of LH- RH-A at the central level in the rat. The inhibitory action of the combined treatment of anandron + buserelin on the prostate is greater than that of each compound alone. Clinical pharmacology studies have demonstrated that both steroid and nonsteroid antiandrogens can help to control the effect of increased T levels (disease flare) that occur on initiating LH-RH-A administration. Prostatic acid phosphatase (PAP) levels decrease immediately in spite of the increase in T. The decrease appears faster when nonsteroid antiandrogens are used. Nonsteroid antiandrogens sensitize the pituitary to stimulation by LH-RH in eugonadal volunteers. The results of randomized clinical studies with the combination of nonsteroid antiandrogen + LH-RH-A have established a definite trend toward greater efficacy of the combined treatment over monotherapy. Further data are needed to confirm this trend. In particular, further dose-ranging studies are warranted since the need for LH-RH-A doses that reduce T down to castration levels may not be justified in the presence of a potent antiandrogen.(ABSTRACT TRUNCATED AT 400 WORDS). LG English. YR 1988.

--- 42 MEZZ --- AN 03048618 Medline R 19880101. TI Human chorionic gonadotropin and luteinizing hormone-releasing hormone reverse the blockade of ovulation in pregnant mare's serum gonadotropin-primed immature rats by the anti-androgenic drug, hydroxyflutamide. SO Canadian journal of physiology and pharmacology, {Can-J-Physiol-Pharmacol}, Jun 1988, vol. 66, no. 6, p. 783-7, ISSN: 0008-4212. AU Chandrasekhar-Y, Armstrong-D-T. IN MRC Group in Reproductive Biology, University of Western Ontario, London, Canada. AB The present study was designed to examine mechanism(s) of the anti-ovulatory action of the anti-androgen, hydroxyflutamide (OH-F). Prepubertal rats were treated with 4 IU pregnant mare's serum gonadotropin (PMSG) (day -2) to induce first estrus and ovulation. They received OH-F in sesame oil or oil alone at 08:00 and 20:00 h on day 0 (the day of proestrus) and ovulations were assessed on the morning of day 1. Eighty-three percent of control animals ovulated with a mean of 7.7 +/- 1.1 corpora lutea per rat. Hydroxyflutamide blocked ovulation in all but 2 of the 12 rats receiving this drug alone. All of OH-F treated rats that received 5 and 25 IU human chorionic gonadotropin (hCG) ovulated with means +/- SEM of 9.1 +/- 0.1 and 7.3 +/- 1.4 corpora lutea per rat, respectively. The dose of 0.2 IU hCG was essentially ineffective, while the effect of 1.0 IU hCG was intermediate. At the dose of 20 ng and above (100 and 500 ng) luteining hormone-releasing hormone (LHRH) completely overcame the ovulation blockade in the OH-F treated animals, while a 4-ng dose was ineffective. At 18:00 h on the day of proestrus, serum LH levels in control animals were 17.56 +/- 2.60 ng/mL, which were 920% above basal levels (1.90 +/- 0.13) indicating a spontaneous LH surge. This surge was suppressed in OH-F treated rats. Injection of LHRH, at the dose of 20 ng and above, reinstated the LH release in OH-F treated animals. Thus, the anti-androgen, OH-F, inhibits ovulation in PMSG-treated immature rats through its interference with the preovulatory LH surge; the inhibition can be reversed by hCG or LHRH. Hydroxyflutamide does not appear to interfere at the level of the pituitary, but may have direct action at the hypothalamic and (or) extrahypothalamic sites involved in the generation of positive feedback signals that control LH release. LG English.

YR 1988.

--- 43 MEZZ --- AN 03309363 Medline R 19870101. TI Flutamide eliminates the risk of disease flare in prostatic cancer patients treated with a luteinizing hormone-releasing hormone agonist. SO The Journal of urology, {J-Urol}, Oct 1987, vol. 138, no. 4, p. 804-6, ISSN: 0022-5347. AU Labrie-F, Dupont-A, Belanger-A, Lachance-R. IN Department of Molecular Endocrinology, Laval University Medical Center, Quebec, Canada. AB Although chronic treatment with luteinizing hormone-releasing hormone agonists achieves castration levels without side effects other than those related to hypoandrogenism, a limitation to their use alone for the treatment of prostatic cancer is the transient increase in serum androgens that lasts for 5 to 8 days at the start of treatment with the risk of disease flare. Our data show that the concomitant administration of the pure antiandrogen flutamide in association with the luteinizing hormone-releasing hormone agonist (D-Trp6) luteinizing hormone-releasing hormone ethylamide caused a 64 to 78 per cent decrease in serum prostatic acid phosphatase on days 3 and 7 after the start of treatment in 70 patients with previously untreated stage D2 prostatic cancer. Pain which was present in 41 patients at the start of treatment, did not increase in any patient, it decreased in 7 at 1 week and it disappeared or decreased in 27 at 2 weeks. Performance, which originally was abnormal in 34 patients, became normal in 7 within 1 week and in 20 within 1 month (59 per cent). These data show that the addition of flutamide completely eliminates the risks of disease flare associated with the use of the otherwise exceptionally well tolerated luteinizing hormone-releasing hormone agonists in patients treated for prostatic cancer. LG English. YR 1987.

--- 44 MEZZ --- AN 02947053 Medline R 19870101. TI Phase II trial with D-Trp-6-LH-RH in prostatic carcinoma: comparison with other hormonal agents. SO The Prostate, {Prostate}, 1986, vol. 9, no. 4, p. 327-42, ISSN: 0270-4137. AU Mathe-G, Schally-A-V, Comaru-Schally-A-M, Mauvernay-R-Y, Vovan-M-L, Machover-D, Misset-J-L, Court-B, Bouchard-P, Duchier-J, et al. AB Various approaches to hormonal treatment of prostate carcinoma are discussed. Eighty-one patients with prostatic carcinoma, eight with stage B, nine with stage C, and 64 with stage D disease, were treated subcutaneously daily for 3 months with the LH-RH agonist D-Trp-6-LH-RH (Decapeptyl) in order to evaluate the incidence of remissions according to WHO recommendations for oncologic trials. The findings were compared to those obtained with other hormonal therapies of prostatic carcinoma according to the statistical method of expected response rate as adapted by Lee and Wesley for phase II trials. Treatment with D-Trp-6-LH-RH greatly reduced serum LH and testosterone levels without raising serum prolactin. After 1-2 weeks of therapy, there was relief of subjective symptoms and a reversal of the signs of prostatism as well as a marked decrease in bone pain. At 90 days 52 patients had complete relief of prostatism and 21 had only mild signs and symptoms. Seventy patients were experiencing no bone pain and an additional six had only mild pain. Prostatic size, evaluated by rectal examination and transabdominal ultrasonography, reverted to normal in 26.4% of patients (complete remission) and was reduced by more than 50% in an additional 17.6% (partial remission), the overall rate of complete plus partial regression of prostatic enlargement being 44%. Scans showed a major improvement of bone lesions in 14.8% of cases. This response increased to 37% after more than 6 months of follow-up. Prostatic acid phosphatase levels were decreased by more than 50% in 61% of the patients, but this test appears to be a less valid marker than the lipid-associated sialic acid (LASA). The increase in LASA before treatment and a reduction after treatment can frequently be correlated with the objective volume of the neoplasms. No flare-up of the disease was encountered, and there were no side effects except for impotence. Statistical analyses of results by the method of Lee and Wesley indicated that the incidence of complete and partial regression (CR and PR) observed with D-Trp-6-LH-RH was not significantly different from that recorded in previous studies for another LH-RH analog, Buserelin. However, CR and PR obtained with D-Trp-6-LH-RH (44%) were significantly higher than with subcapsular orchiectomy (22%). Hormonal effects and some other actions of D-Trp-6-LH- RH were compared and contrasted with those produced by castration, estrogens, antiandrogens, and progestogens.(ABSTRACT TRUNCATED AT 400 WORDS).

LG English. YR 1986.

--- 45 MEZZ --- AN 06423907 Medline R 19840101. TI (New approach in the treatment of prostatic cancer: combined use of a LHRH agonist and an androgen antagonist). TT Nouvelle approche dans le traitement du cancer de la prostate : utilisation combinee d'un agoniste de la LHRH et d'un antiandrogene. SO Journal de pharmacologie, {J-Pharmacol}, 1983, vol. 14 Suppl 3, p. 117-35, 33 refs, ISSN: 0021-793X. AU Labrie-F, Dupont-A, Belanger-A, Lefebvre-F-A, Raynaud-J-P. AB Following the studies of Huggins and colleagues in 1941, the hormonal treatment of prostatic cancer has been aimed at neutralizing the influence of testicular androgens through surgical castration or the administration of high doses of estrogens. These two approaches cause a temporary improvement in 60 to 70% of advanced prostatic cancer. However, castration is not always well accepted and high doses of estrogens are frequently accompanied by lethal cardiovascular side effects. Following our observation that treatment with LHRH agonists causes a blockage in the biosynthesis of testosterone by the testis accompanied by a marked reduction in prostatic weight in the rat, the possibility was opened for a new approach in the treatment of prostatic cancer. Fortunately, among all species studied, man is the most sensitive to the inhibitory effect of LHRH agonists on testicular androgen biosynthesis and near-medical castration can be easily achieved without secondary effects other than those related to low androgen levels. Following long-term studies in the rat which have shown that the inhibitory effect of LHRH agonists is markedly potentiated by simultaneous administration of a pure antiandrogen, a study using the LHRH agonist (D-Ser(TBU)6, des-Gly-NH2(10)) LHRH ethylamide (HOE-766) and the pure antiandrogen RU- 23908 was performed in men with advanced prostatic cancer. The combined treatment with the LHRH agonist and the antiandrogen in 37 patients not previously treated caused a positive objective response in 97% of cases while, previously, partial hormonal treatment achieved through castration or high doses of estrogens caused a positive response in 60 to 70% of patients. The serum levels of prostatic acid phosphatase (PAP) were decreased to 40% of control as early as four days after starting combined hormonal therapy. By contrast, in patients previously treated with estrogens or castrated, complete neutralization of adrenal androgens by the antiandrogen led to a much lower rate of positive response ranging from 25 to 55%. In patients previously treated, there is thus a predominance of tumor cells insensitive to androgens. An additional important finding in this study is that the administration of the antiandrogen prevents the flare-up of the disease frequently observed when LHRH agonists are administered alone.(ABSTRACT TRUNCATED AT 400 WORDS). LG French. YR 1983.

END OF DOCUMENTS IN LIST

APPENDIX 3: Included and Excluded Studies

Included Studies

Type of Author Citation Studies Metastatic cancer of the prostate managed with buserelin versus buserelin plus Schroeder cyproterone acetate RCT Crawford A controlled trial of leuprolide with and without flutamide in prostatic carcinoma RCT Abarelix depot, a GnRH antagonist v LHRH superagonists in prostate cancer: differential Prospective Garnick effects on follicle-stimulating hormone study The efficacy and safety of degarelix: a 12-month, comparative, randomized, open-label, Klotz parallel-group phase III study in patients with prostate cancer RCT Goserelin acetate with or without antiandrogen or estrogen in the treatment of patients Kotake with advanced prostate cancer: a multicentre, randomized, controlled trial in Japan RCT Prevention of transient adverse effects of GnRH analogue (buserelin) in metastatic Kuhn prostatic carcinoma by administration of an antiandrogen (nilutamide) RCT Influence of different types of antiandrogens on LHRH analogue-induced testosterone Schulze surge in patients with metastatic carcinoma of the prostate RCT The GnRH antagonist abarelix depot versus LHRH agonists leuprolide or goserelin: initial Tomera results of endocrinological and biochemical efficacies in patients with prostate cancer RCT Phase 3, multicenter, open label, randomized study of abarelix versus leuprolide plus daily Prospective Trachtenberg antiandrogen in men with prostate cancer study A multicenter randomized trial comparing the LHRH analogue goserelin acetate alone and Tyrrell with flutamide in the treatment of advanced prostate cancer RCT A phase 3, multicenter, open-label, randomized study of abarelix versus leuprolide acetate Prospective McLeod in men with prostate cancer study Maximum androgen blockade using LHRH agonist buserelin in combination with short- term (two weeks) or long-term (continuous) cyproterone acetate is not superior to standard De Voogt androgen deprivation in the treatment of advanced prostate cancer RCT Kreis Oestrogen pre-treatment abolishes LHRH testosterone stimulation RCT

100

Excluded Studies

Author Citation Type of Studies Agarwal Differential response of prostate specific antigen to testosterone surge after LHRH analogue in prostate cancer and benigh prostatic hyperplasia No/irrelevant comparator Akaza Superior anti-tumor efficacy of bicalutamide 80 mg in combination with a LHRH agonist versus LHRH agonist monotherapy as first line Combined androgen treatment for advanced prostate cancer: interim results of a randomized study in japanese patients blockade Akaza A randomized phase II trial of flutamide vs chlormadinone acetate in previously untreated advanced prostatic cancer No/Irrelevant comparator Anderson Management of advanced prostate cancer: can we improve on androgen deprivation therapy? Review Appu Effectiveness of cyproterone acetate in achieving castration and preventing luteinizing hormone releasing hormone analogue induced No/Irrelevant comparator testosterone surge in patients with prostate cancer Boccardo Goserelin acetate with or without flutamide in the treatment of patients with locally advanced or metastatic prostate cancer Combined androgen blockade Boccon-Gibod Cyproterone acetate lead-in prevents initial rise of serum testosterone induced by LHRH analogs in the treatment of metastatic carcinoma of the No/Irrelevant comparator prostate Brawer Challenges with LHRH agonists: flare and surge Review Brogden Goserelin: a review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy in prostate cancer Review Bruchovsky Pre-suppression of the pituitary: an adjunct to LHRH agonist therapy of prostate cancer Editorial/commentary Bruchovsky LHRH agonists in prostate cancer. Elimination of flare reaction by pretreatment with cyproterone acetate and low-dose DES No/Irrelevant comparator Bubley Is flare phenomenon clinically significant? Review Chandrasekhar Human chorionic gonadotropin and LHRH reverse the blockade of ovulation in pregnant mare's serum gonadotropin-primed immature rats by Non-human study the anti-androgenic drug, hydroxyflutamide Chrisp Leuprorelin: a review of its pharmacology and therapeutic use in prostatic disorder Review Cikes Randomized trial of buserelin (HOE 766) alone versus buserelin and antiandrogens in advanced prostatic cancer No/Irrelevant comparator Collette Why phase III trials of maximal androgen blockade versus castration in M1 prostate cancer rarely show statistically significant differences Combined androgen blockade Crawford Leuprolide with and without flutamide in advanced prostate cancer Combined androgen blockade Dawson A pilot trial of chemohormonal therapy for metastatic prostate carcinoma No/Irrelevant comparator De Voogt Orchidectomy versus buserelin in combination with cyproterone acetate, for 2 weeks or continuously, in the treatment of metastatic prostatic Surgical castration cancer, preliminary results of EORTC-trial 30843 comparator Debruyne Abarelix for injectable suspension: first-in-class GnRH antagonist for prostate cancer Review Debruyne Gonadotropin-releasing hormone antagonist in the management of prostate cancer Review Debruyne Hormonal therapy of prostate cancer Review Deghenghi Disease flare induced by LHRH analogues in cancer patients Editorial/commentary Di Silverio Zoladex vs Zoladex plus cyproterone acetate in the treatment of advanced prostatic cancer: a multicenter Italian study Combined androgen blockage Dionisius Castration plus nilutamide vs castration plus placebo in advanced prostate cancer - a review Surgical castration 101

comparator Epstein Sudden death due to disease flare with LHRH agonist therapy for carcinoma of the prostate Editorial/commentary Falkson Long term follow-up of patients with advanced prostatic cancer treated with nasal buserelin No/Irrelevant comparator Faure Preliminary results on the clinical efficacy and safety of androgen inhibition by a LHRH agonist alone or combined with an antiandrogen in the No/Irrelevant comparator treatment of prostatic carcinoma Ferrari Combination treatment versus LHRH alone in advanced prostatic cancer Combined androgen blockage Goldenberg Use of cyproterone acetate in prostate cancer Review Haggman Neoadjuvant GnRH-agonist treatment (triptorelin and cyproterone acetate for flare protection) and total prostatectomy No/irrelevant comparator Heyns Comparative efficacy of triptorelin pamoate and leuprolide acetate in men with advanced prostate cancer No/irrelevant comparator Heyns Triptorelin in the treatment of prostate cancer: clinical efficacy and tolerability Review Huben Hormone therapy of prostatic bone metastases Review Johns Leuprolide therapy for prostate cancer an association with scintigraphic flare on bone scan No/Irrelevant comparator Kahan Disease flare induced by D-Trp6-LHRH analogue in patients with metastatic prostatic cancer Case study Kirschenbaum Management of hormonal treatment effects Review Klign Combined treatment with buserelin and cyproterone acetate in metastatic prostatic carcinoma Editorial/commentary Labrie Combination therapy with flutamide and castration (orchiectomy or LHRH agonist): the minimal endocrine therapy in both untreated and Combined androgen previously treated patients with advanced prostate cancer blockade Labrie Nouvelle approche dans le traitement du cancer de la prostate: utilisation combinee d'un agoniste de la LHRH et d'un antiandrogene No/Irrelevant comparator Labrie New approach in the treatment of prostate cancer: complete instead of partial withdrawal of androgens No/Irrelevant comparator Labrie New hormonal therapy in prostatic carcinoma: combined treatment with an LHRH agonist and an antiandrogen No/Irrelevant comparator Labrie Flutamide eliminates the risk of disease flare in prostatic cancer patients treated with LHRH agonist No/Irrelevant comparator Mahler Clinical pharmacokinetics of antiandrogens and their efficacy in prostate cancer Review Mahler Is disease flare a problem? Review Mathe Phase II trial with D-Trp-6-LH-RH in prostatic carcinoma: Comparison with other hormonal agents No/Irrelevant comparator McLeod Hormonal therapy: historical perspective to future directions Review Molinier Methodological considerations in cost of prostate cancer studies: a systematic review Review Mongiat-Artus Role of LHRH agonists and hormonal treatment in the management of prostate cancer Review Msaouel LHRH antagonists in prostate therapy Review Nabors LHRH agonists: the US experience Review Nakazato Suppressive Effects of the Antiandrogen Flutamide on Adrenal Androgens in Advanced Prostate Cancer Patients No/Irrelevant comparator Peeling Phase III studies to compare goserelin (zoladex) with orchiectomy and with diethylstilbestrol in treatment of prostatic carcinoma No/Irrelevant comparator Pessis Monotherapy with a new GnRH antagonist, abarelix depot, results in more rapid testosterone suppression without an initial surge compared Abstract with leuprolide acetate plsu bicalutamide: results of a multicenter phase 3 study Pinski Blockade of LH response induced by agonist D-TRP-6-LHRH in rats Non-human study Plosker Leuprorelin: a review of its pharmacology and therapeutic use in prostatic cancer, endometriosis and other sex hormone-related disorders Review

102

Raynaud Antiandrogens in combination with LHRH agonists in prostate cancer Review Roila Buserelin in the treatment of prostatic cancer Review Sarosdy Comparison of goserelin and leuprolide in combined androgen blockade therapy Combined androgen blockade Scaletscky Disease flare with GnRH analogues. How serious is it. Review Schultze New developments in the use of peptide gonadotropin-releasing hormone antagonists versus agonists Review Soloway A controlled trial of casodex (bicalutamide) vs flutamide, each in combination with LHRH analogue therapy in patients with advanced prostate No/Irrelevant comparator cancer Stricker LHRH antagonists in prostate therapy Review Studer Arguments against the long-term use of combined androgen blockade Review Sugiono Bicalutamide vs cyproterone acetate in preventing flare with LHRH analogue therapy for prostate cancer - a pilot study No/Irrelevant comparator Thompson Flare associated with LHRH agonist therapy Review Thompson Sudden death due to disease flare with LHRH agonist therapy for carcinoma of the prostate Case study Thurairaja The flare phenomenon: should we be concerned? Review Tsushima Optimal starting time for flutamide to prevent disease flare in prostate cancer patients treated with a GnRH agonist No/Irrelevant comparator Tunn Comparison of LHRH analogue 1-month depot and 3-month depot by their hormone levels and pharmacokinetic profile in patients with No/Irrelevant comparator advanced prostate cancer Vallis Tumour flare in hormonal therapy Review van Poppel Testosterone surge: rationale for GnRH hormone blockers? Review Waxman The Clinical and Endocrine Assessment of Three Different Antiandrogen Regimens Combined with a Very Long-Acting Gonadotrophin- No/Irrelevant comparator Releasing Hormone Analogue Waxman Importance of early tumour exacerbation in patients treated with long acting analogues of gonadotrophin releasing hormone for advanced No/Irrelevant comparator prostatic cancer. White Quality of life in men with locally advanced adenocarcinoma of the prostate: an exploratory analysis using data from the CaPSURE database No/Irrelevant comparator Wu Health related quality of life in patients treated with multimodal therapy for prostate cancer No/Irrelevant comparator Yoon Testosterone recovery after prolonged androgen suppression in patients with prostate cancer Combined androgen blockade

103

APPENDIX 4: Data Extraction Form

Flare Symptoms of Using LHRH agonists vs LHRH agonists + anti- Category: Review: Y /N androgen RCT: Y /N Quasi-randomized Y /N Data Extraction Form Case studies/series Y /N Others (specify): 1.

Authors: Citation: Country Studied: Randomized: Y / N Method: Blinded: Y / N Method: Account for Withdrawal/Dropout: Y / N ITT:Y /N Allocation Concealment: Y /N Control:

Comparators/Interventions (including brand name):

Population:

Ages:

Non-steroidal Antiandrogen Agents Used: Y / N (Name of Drug)

Length of Treatment (Intention/Actual) Length of Follow-Up (Intention/Actual)

Stage and grade of Disease: Outcomes Studied:

Inclusion Exclusion Conclusion(s): Results: Comments

Bone pain Yes No N/A Bladder outlet obstruction Yes No N/A Ureteral obstruction Yes No N/A Sexual function i.e., impotence Yes No N/A Spinal cord compression Yes No N/A i.e., paralysis Cardiovascular effect Yes No N/A

104

APPENDIX 5: Quality Assessment Forms

Jaded scale for RCTs

1) Schroeder - Metastatic cancer of the prostate managed with buserelin versus buserelin plus cyproterone acetate

YES NO 1. Was the study described as randomized (this includes the use 1 0 of words such as randomly, random and randomized)? 2. Was the study described as double-blind? 1 0 3. Was there a description of withdrawals and drop-outs? 1 0 4. Method to generate the sequence of randomization was 1 0 Described and was appropriate (e.g. table of random numbers, Computer generated, coin tossing, etc.) 5. Method of double-blinding described and appropriate 1 0 (identical placebo, active placebo, dummy.) 6. Method of randomization described and it was inappropriate -1 0 (allocated alternately, according to date of birth, hospital number, etc.) 7. Method of double-blinding described but it was inappropriate -1 0 (comparison of tablet vs. injection with no double dummy). OVERALL SCORE (Maximum 5) 0

2) Crawford - A controlled trial of leuprolide with and without flutamide in prostatic carcinoma

105

3) Klotz - The efficacy and safety of degarelix: a 12-month, comparative, randomized, open-label, parallel-group phase III study in patients with prostate cancer YES NO 1. Was the study described as randomized (this includes the use 1 0 of words such as randomly, random and randomized)? 2. Was the study described as double-blind? 1 0 3. Was there a description of withdrawals and drop-outs? 1 0 4. Method to generate the sequence of randomization was 1 0 Described and was appropriate (e.g. table of random numbers, Computer generated, coin tossing, etc.) 5. Method of double-blinding described and appropriate 1 0 (identical placebo, active placebo, dummy.) 6. Method of randomization described and it was inappropriate -1 0 (allocated alternately, according to date of birth, hospital number, etc.) 7. Method of double-blinding described but it was inappropriate -1 0 (comparison of tablet vs. injection with no double dummy). OVERALL SCORE (Maximum 5) 3

4) Kotake - Goserelin acetate with or without antiandrogen or estrogen in the treatment of patients with advanced prostate cancer: a multicentre, randomized, controlled trial in Japan

106

5) Kuhn - Prevention of transient adverse effects of GnRH analogue (buserelin) in metastatic prostatic carcinoma by administration of an antiandrogen (nilutamide) YES NO 1. Was the study described as randomized (this includes the use 1 0 of words such as randomly, random and randomized)? 2. Was the study described as double-blind? 1 0 3. Was there a description of withdrawals and drop-outs? 1 0 4. Method to generate the sequence of randomization was 1 0 Described and was appropriate (e.g. table of random numbers, Computer generated, coin tossing, etc.) 5. Method of double-blinding described and appropriate 1 0 (identical placebo, active placebo, dummy.) 6. Method of randomization described and it was inappropriate -1 0 (allocated alternately, according to date of birth, hospital number, etc.) 7. Method of double-blinding described but it was inappropriate -1 0 (comparison of tablet vs. injection with no double dummy). OVERALL SCORE (Maximum 5) 4

6) McLeod - A phase 3, multicenter, open-label, randomized study of abarelix versus leuprolide acetate in men with prostate cancer

YES NO 1. Was the study described as randomized (this includes the use 1 0 of words such as randomly, random and randomized)? 2. Was the study described as double-blind? 1 0 3. Was there a description of withdrawals and drop-outs? 1 0 4. Method to generate the sequence of randomization was 1 0 described and was appropriate (e.g. table of random numbers, Computer generated, coin tossing, etc.) 5. Method of double-blinding described and appropriate 1 0 (identical placebo, active placebo, dummy.) 6. Method of randomization described and it was inappropriate -1 0 (allocated alternately, according to date of birth, hospital number, etc.) 7. Method of double-blinding described but it was inappropriate -1 0 (comparison of tablet vs. injection with no double dummy). OVERALL SCORE (Maximum 5) 3

107

7) Schulze - Influence of different types of antiandrogens on LHRH analogue-induced testosterone surge in patients with metastatic carcinoma of the prostate

8) Trachtenberg - Phase 3, multicenter, open label, randomized study of abarelix versus leuprolide plus daily antiandrogen in men with prostate cancer

108

9) Tyrrell - A multicenter randomised trial comparing the LHRH analogue goserelin acetate alone and with flutamide in the treatment of advanced prostate cancer

10) DeVoogt - Maximum androgen blockade using LHRH agonist buserelin in combination with short-term (two weeks) or long-term (continuous) cyproterone acetate is not superior to standard androgen deprivation in the treatment of advanced prostate cancer. Final analysis of EORTC GU group trial 30843

109

11) Kreis - Oestrogen pre-treatment abolishes LHRH testosterone stimulation

YES NO 1. Was the study described as randomized (this includes the use 1 0 of words such as randomly, random and randomized)? 2. Was the study described as double-blind? 1 0 3. Was there a description of withdrawals and drop-outs? 1 0 4. Method to generate the sequence of randomization was 1 0 described and was appropriate (e.g. table of random numbers, Computer generated, coin tossing, etc.) 5. Method of double-blinding described and appropriate 1 0 (identical placebo, active placebo, dummy.) 6. Method of randomization described and it was inappropriate -1 0 (allocated alternately, according to date of birth, hospital number, etc.) 7. Method of double-blinding described but it was inappropriate -1 0 (comparison of tablet vs. injection with no double dummy). OVERALL SCORE (Maximum 5) 1

110

APPENDIX 6: Study Characteristics of Included Studies

Author Location Funding Study Design Number of Study Trial Quality Patients Duration Jadad Score Klotz Canada, USA, Yes - Randomized 610 12 months 3 France, Denmark, Industry Netherlands Crawford USA Yes - National Randomized 603 Not 3 Cancer Institute indicated Kotake Japan Not indicated Randomized 420 3 years 2 Schulze Germany Not indicated Randomized 21 28 days 2 Tyrrell U.K., Germany, Yes - Randomized 571 1.5 years 2 South Africa, Italy, Industry (for New Zealand, drugs) Switzerland, Finland, Ireland, Stockholm McLeod USA Yes - Randomized 269 1 year 3 Industry DeVoogt Netherlands, Italy Yes - Randomized 354 5 years 2 Industry Kreis USA Not indicated Randomized 18 90 days 1 Schroeder The Netherlands Yes - Randomized 71 1 year 0 Industry Trachtenberg Canada and USA Yes - Randomized 251 1 year 2 Industry Kuhn France Not indicated Randomized 36 1 year 4 Garnick USA Yes - Prospective – 242 85 days N/A Industry non randomized Tomera USA Yes - Prospective – 242 85 days N/A Industry non randomized

111

APPENDIX 7: Patient Characteristics of Included Studies

Author Eligibility Criteria Age Disease Stage Previous Previous Secondary Hormonal Surgery Cancer Treatment Schroeder All patients had 44 to 89 M1, N1 to N4 No No No histologically proved years prostatic carcinoma. Distant metastases had to be present and, if possible, to be proved by biopsy. Plasma testosterone levels at entry into the study had to be greater than 8 nmol/L. Patients between 40 and 90 years old were acceptable. The WHO performance index had to range between 0 and 2. Crawford Untreated, histologically 44 to 98 Minimal or severe No No No confirmed stage D2 prostate years disease. Minimal disease cancer, with bone or was defined as absence of measurable soft-tissue disease in ribs, long metastases; ECOG bones, skull, or soft performance status between tissue, other than lymph 0-3 node involvement.

Regional and distant node involvement, lung, liver and metastatic bone involvement. Garnick Men with prostate cancer 49 to 93 D1 and D2 UNK UNK UNK years D1= pelvic lymph node metastases; D2=extrapelvic soft tissue or bone metastases Klotz The population included 50 to 98 Localized T1/2, NX or No UNK UNK patients with an increasing years N0, M0, Locally PSA level after treatment advanced T3/4, NX and with curative intent, i.e. those M0 or N1 and M0 with biochemical failure and those with metastatic disease (hormone-sensitive). Patients were required to have a screening serum testosterone level of >1.5 ng/mL, an Eastern Cooperative Oncology Group score of ≤ 2, and a PSA level of ≥2 ng/mL. Kotake Histologically proven, newly 65 to 81 Stage C, D1, D2 No UNK No diagnosed, stage C or D years prostate cancer; ECOG performance status of grade 0-3 or apparent grade 4 due to bone metastasis; expected survival of 3 months or longer Kuhn Plasma levels of prostatic 60 to 82 Stage D2 No Yes UNK acid phosphatase at least years

112

twice the upper limit of the normal range measured on 2 occasions Schulze Only patients with elevated 57 to 82 Metastatic patients No No UNK serum PAP at start of years treatment *Tomera Histologically confirmed 49 to 93 D1 and D2 UNK UNK UNK prostate cancer amenable to years D1= pelvic lymph node initial hormonal therapy or metastases; increasing PSA after D2=extrapelvic soft definitive local therapy for tissue or bone metastases prostate cancer Trachtenberg Histologically documented 49 to 93 Stage D1 (TxN+Mx) or No UNK UNK prostate cancer and were years D2 (TxN+Mx) candidates for androgen ablation therapy, had increasing PSA levels after definitive localized therapy Tyrrell Patients with histological Mean age Locally advanced (stages No No UNK confirmation of disease of 72 T3 and T4) or metastatic years (any T category, M1) McLeod Candidates for neoadjuvant 49 to 89 Stage T1-T4, D0-D1 No UNK No hormonal therapy; had years metastatic disease (Stage D1 or D2); had increasing PSA levels after radical prostatectomy, radiation therapy, or other local therapy DeVoogt WHO performance status not UNK Metastatic patients (M1, No UNK No worse than 2 M0N4) Kreis Previously untreated UNK Advanced prostate cancer No UNK UNK advanced prostate cancer *Garnick is a sub-analysis of the Tomera study.

113

APPENDIX 8: Indirect Comparison

Indirect Comparison Although RCTs are most valid study design (Glenny et al, 2005) used for systematic review, if no direct comparison is found in the systematic review, then an indirect comparison was attempted to evaluate flare symptoms associated with antagonist (i.e., degarelix) compared to agonist or agonist + anti-androgen.

If direct comparison data on flare symptoms was available between antagonist and agonist alone or antagonist and agonist + anti-androgen, then indirect comparison is not necessary. Unfortunately, there was no head to head study comparing antagonist versus agonist alone or versus agonist + anti-androgen in evaluating flare symptoms. Therefore, an indirect comparison cannot be made. In order for an indirect comparison to be made, the following comparisons are needed: 1) antagonist versus agonist + anti-androgen and 2) agonist versus agonist + anti-androgen (Figure 1). Figure 1 depicts the concept behind indirect comparison where A=Agonist; B=Antagonist and C=Agonist + Anti-Androgen. The agonist + anti-androgen combined therapy is the common link between the three different treatments.

Figure 1: Theory behind Indirect Comparison (Sutton A, 2008)

Agonist

Agonist + Anti-Androgen

Antagonist

Unfortunately, the only studies available for flare symptoms were agonist versus agonist + anti-androgen and given the lack of data for antagonist versus agonist + anti-androgen, an indirect comparison could not be done.

Alternatively, a comparison could be made using intermediate marker testosterone surge, which can possibly lead to clinical flare symptoms. For the comparison to be made there must be evidence to link testosterone surge to clinical flare.

A discussion was done to compare the pros and cons between these two options 1) indirect comparison using Bucher method (with mock data) and 2) direct comparison between antagonist and agonist and link intermediate marker (i.e., testosterone surge) to final outcome i.e., clinical flare.

114

Method Since no direct comparison was available between antagonist versus agonist + anti- androgen or antagonist versus agonist alone in terms of flare symptoms, an indirect comparison was done by using the Bucher Method to evaluate significance of clinical flare from data generated for agonist versus antagonist. Testosterone surge was used as an intermediate marker to determine the likelihood of flare symptoms. a) Bucher Method The Bucher method is an indirect comparison method that considers indirect treatment comparisons in meta-analyses of RCTs for discrete data. The main assumption is that the relative efficacy of the treatments is the same in all trials. This model was developed with odds ratio (OR) as the measure of treatment effect, and was specifically designed for the indirect comparison of A versus C when direct evidence of A versus B and B versus C were available (Wells GA et al, 2009; Bucher HC et al, 1997). Since there is no data to measure B versus C (agonist + anti-androgen versus antagonist), indirect method is not possible.

However, to further understand the method of indirect comparison, a simulated indirect comparison is made using testosterone surge data (instead of clinical flare) that provides data for A versus B and B versus C. Figure 2 presents the odds ratio for indirect comparison between agonist and antagonist.

Figure 2: Odds Ratio for Indirect Comparison between Agonist and Antagonist (Klotz L et al, 2008; Trachtenberg J et al, 2002)

ORAB=1.49 ORBC=28.23 (95% CI: 0.55, 4.08) Agonist + AA (95% CI: 3.6, 221.19)

Agonist Antagonist

Indirect estimate using ITC program: ORAC=42.063 (95% CI: 4.26, 415.321) Test of association = 0.00468

The odds ratio from the indirect comparison using the Indirect Treatment Comparison (ITC) (Wells et al, 2009) program is 42 (OR>1), which means that the odds of having testosterone surge is much more likely with agonist compared to antagonist. The confidence intervals between the three treatments are very wide, which mean the results are not very precise and none of the comparisons are statistically significant. Although the result shows that antagonist therapy has less likelihood of having testosterone surge, the main limitation to this analysis is the small number of trials. The effect measure should be dependent on the amalgamated data from different RCTs rather than a single trial, which in this case, contains single trial. Amalgamated data provides assurance that the difference is less likely due to patient differences and that amalgamated data provides internal validity of the studies.

115

b) Direct Comparison between Antagonist and Agonist by Using Testosterone Surge followed by Review Another way to answer the research question was to use available data from direct comparison between agonist and antagonist by using testosterone surge. Since testosterone surge is an intermediate marker, a systematic review can be done to determine whether there is a causal relationship between testosterone surge and clinical flare. A literature search was conducted to determine if such data was available.

From the literature search, there were two studies (Bubley, 2001; Limonta et al, 1994) out of eleven studies which were relevant. Neither was a randomized control trial. Limonta concluded that the prostatic cell line regulating tumour cell proliferation appear to be modulated by testosterone. Bubley concluded that there is a wide variation in the reported frequency of clinical flare responses from LHRH agonists during the initial treatment of patients with stage D2 disease. The risk-to-benefit ratio, especially in patients with symptomatic bone metastasis, would dictate routine use of anti-androgen therapy for the first month of LHRH agonist treatment. For patients at risk for cord compression, other means of ablating testosterone might be considered, such as LHRH antagonists.

Unfortunately, neither one of these is a RCT which can provide definitive link between testosterone surge and clinical flare; however, there is a possibility that may be a relationship between testosterone surge and flare symptoms.

Between these two methods, depending on available studies and data, either method may provide a reasonable answer.

Results An indirect comparison using the Bucher method was attempted to determine the difference in clinical flare symptoms between agonist and antagonist since no direct comparison was available; however, since there was no data evaluating flare symptoms between antagonist and other treatments in terms of flare symptoms. This attempt was not possible.

Since there was data available for testosterone surge, application of indirect comparison using testosterone surge was conducted instead. (Note: An indirect comparison was done for educational purposes only using testosterone surge since direct comparison between agonist and antagonist and antagonist versus agonist + anti-androgen was available.) It was found that the likelihood of having testosterone surge was higher with agonist alone than antagonist (OR of 42.063; 95% CI: 4.26, 415.321). Unfortunately, there is weak evidence to provide a causal relationship between testosterone surge and flare symptoms.

Limitations Indirect comparison using a common comparator (i.e., agonist + anti-androgen) would provide estimates for use in decision making, but the caveat is that the available studies have to have similar outcomes and that the studies have to have similar methods assess these outcomes (i.e., dosing, patient population, staging of disease) (Song et al, 2003).

116

The limitations of this indirect comparison are as follow: 1) mock data (i.e., testosterone surge rather than clinical flare) was used to understand indirect comparison 2) assumption that abarelix has the same efficacy as degarelix (both are antagonists) 3) only 1 study is available for each comparison arm 4) definition of testosterone surge was different between the two studies (i.e., testosterone increase of ≥ 15% from baseline in Klotz and 10% in Trachtenberg study) 5) Klotz included patients from localized (not spread) to metastatic whereas Trachtenberg only included patients in locally advanced (outside of prostate) to metastatic 6) Trachtenberg had 4 times more patients in the agonist + anti-androgen group than the Klotz study, which can affect the weighting and hence the odds ratio calculated between the studies

As for the second option of using testosterone surge as an intermediate marker, from the data provided, there is data to conclude that the odds of antagonist causing testosterone surge is zero compared to agonist alone (p<0.00001). The literature review revealed only two articles (one is a narrative review and the other is a cellular study) that discussed a link between testosterone surge and clinical flare.

Conclusion Since a direct comparison could not be made, other methods had to be sought to determine the clinical significance of flare symptoms between antagonist and agonist and antagonist versus agonist + anti-androgen.

Therefore, depending on available data; both indirect method and direct method using testosterone surge as intermediate marker were tested. Unfortunately, neither method provided an answer.

Reference: Wells GA, Sultan SA, Chen L, Khan M, Coyle D. Indirect treatment comparison [computer program]. Version 1.0. Ottawa: Canadian Agency for Drugs and Technologies in Health; 2009.

117

APPENDIX 9: Studies that Evaluated Testosterone Flare and Testosterone Levels

Study Testosterone Surge Time Agonist Alone Agonist + Antagonist P value (Definition) Measured Anti- Androgen Schroeder No definition given Week 1 Significant No initial Not increase until testosterone provided day 5, but no surge value given. Klotz Testosterone increase of ≥ Within first 144/178 = 17/23 = 74% 0/207 Not 15% from baseline, on any 2 two weeks 81% patients = provided days during the first 2 0% in weeks antagonist group

Kotake Significant elevation of At 3 days Log mean Log mean P<0.05 testosterone levels value 2.88 value 1.41 compared with pretreatment mean values Tomera Increase in testosterone by Days 2, 4 or 27/33 patients No patient in Abarelix = Not 10% or greater, above 8 = 82% this group 0% provided baseline values on any 2 of 0/209 the days 2, 4 or 8. patients Trachtenberg Avoidance of testosterone Days 2, 4 No patient on 12/83 patients Abarelix = p<0.001 surge (>10% increase on 2 and 8 agonist alone = 1.2% 0% of 3 days on days 2, 4 and 0/168 8) within 7 days of first patients injection.

McLeod Serum testosterone Days 2, 4 82% = 73/89 No patient in Abarelix = P<0.001 measurement that exceeded and 8 patients this group 0% (no the baseline level by value given) 10% or greater on any two of days 2, 4, or 8 0/180 patients Testosterone Level Measurement Kreis Measured testosterone only, Days 3, 8 Median Median Statistically not for testosterone surge and 22 testosterone testosterone significant concentration concentrations differences rose 75% by almost for day 3, falling reaching testosterone back to castrate level were found baseline levels by day -20. for the 1st 3 by day 8 and days of the then crossing study but into castrate not later on. range (0.5 ug/L) by day 22 Kuhn Measured testosterone only, Samples Median Median Not not for testosterone surge were drawn maximal level maximal level provided on days 1 20.7 nmol/L 18.4 nmol/L and 29 (6.7 to 39.8) (3.1 to 47.1)

Schulze Measured testosterone only, Days 1-7, No value was No value was Not not for testosterone surge 14, 21 and given. given. provided 28

118

APPENDIX 10: Graphical Representations of Testosterone Surge Odds Ratios

Figure 1a: Testosterone Surge Odds Ratio (Antagonist vs Agonist)

Antagonist Agonist Alone Odds Ratio Odds Ratio Study or Subgroup Events Total Events Total Weight M-H, Fixed, 95% CI M-H, Fixed, 95% CI Klotz 2008 0 207 144 178 61.3% 0.00 [0.00, 0.01] McLeod 2001 0 180 73 89 38.7% 0.00 [0.00, 0.01]

Total (95% CI) 387 267 100.0% 0.00 [0.00, 0.00] Total events 0 217 Heterogeneity: Chi² = 0.00, df = 1 (P = 0.97); I² = 0% 0.001 0.1 1 10 1000 Test for overall effect: Z = 7.19 (P < 0.00001) Favours Antagonist Favours Agonist + AA

Figure 1b: Testosterone Surge Odds Ratio (Antagonist vs Agonist)

Antagonist Agonist Alone Odds Ratio Odds Ratio Study or Subgroup Events Total Events Total Weight M-H, Fixed, 95% CI M-H, Fixed, 95% CI Klotz 2008 1 207 144 178 61.3% 0.00 [0.00, 0.01] McLeod 2001 1 180 73 89 38.7% 0.00 [0.00, 0.01]

Total (95% CI) 387 267 100.0% 0.00 [0.00, 0.01] Total events 2 217 Heterogeneity: Chi² = 0.00, df = 1 (P = 0.96); I² = 0% 0.001 0.1 1 10 1000 Test for overall effect: Z = 9.11 (P < 0.00001) Favours Antagonist Favours Agonist + AA

Figure 2: Testosterone Surge Odds Ratio (Agonist vs Agonist + AA)

Agonist + AA Agonist Odds Ratio Odds Ratio Study or Subgroup Events Total Events Total Weight M-H, Fixed, 95% CI M-H, Fixed, 95% CI Klotz 2008 17 23 144 178 100.0% 0.67 [0.25, 1.82]

Total (95% CI) 23 178 100.0% 0.67 [0.25, 1.82] Total events 17 144 Heterogeneity: Not applicable 0.01 0.1 1 10 100 Test for overall effect: Z = 0.79 (P = 0.43) Favours Agonist+AA Favours Agonist

Figure 3a: Testosterone Surge Odds Ratio (Agonist + AA vs Antagonist)

Antagonist Agonist + Anti-Androgen Odds Ratio Odds Ratio Study or Subgroup Events Total Events Total Weight M-H, Fixed, 95% CI M-H, Fixed, 95% CI Trachtenberg 2002 April 0 168 12 83 100.0% 0.02 [0.00, 0.29]

Total (95% CI) 168 83 100.0% 0.02 [0.00, 0.29] Total events 0 12 Heterogeneity: Not applicable 0.01 0.1 1 10 100 Test for overall effect: Z = 2.81 (P = 0.005) Favours Antagonist Favours Agonist + AA

119

Figure 3b: Adjusted Testosterone Surge Odds Ratio (Agonist + AA vs Antagonist)

Antagonist Agonist + Anti-Androgen Odds Ratio Odds Ratio Study or Subgroup Events Total Events Total Weight M-H, Fixed, 95% CI M-H, Fixed, 95% CI Trachtenberg 2002 April 1 168 12 83 100.0% 0.04 [0.00, 0.28]

Total (95% CI) 168 83 100.0% 0.04 [0.00, 0.28] Total events 1 12 Heterogeneity: Not applicable 0.01 0.1 1 10 100 Test for overall effect: Z = 3.18 (P = 0.001) Favours Antagonist Favours Agonist + AA

120

APPENDIX 11: Literature Search on Economic evaluation of agonist versus agonist + anti-androgen in prostate cancer

Search strategy:

1. (PHARMACOECONOM$) OR (PHARMACO ADJ ECONOM$) OR ECONOM$ OR (HEALTH ADJ ECONOM$) OR (COST ADJ UTILIT$) OR (COST ADJ EFFECTIV$) or (cost adj benefi$4) 2. PROSTAT$2 ADJ (CANCER OR CARCINOMA) 3. (VERSUS OR COMPAR$5).ti,ab. 4. 1 and 2 and 3 5. agonist.ti. 6. 4 and 5

Requested by: Yeesha Poon Date: June 24 2009 Executed by: Bess

Database: Medline - (MEZZ) 1950 to date Embase - (EMZZ) 1970 to date Biosis - (BIOL) 1996 to date Current Content - (CBIB) 1995 to date Derwent drug file - (DDNS) 1983 to date Int. Pharmaceutical Abstracts - (IPAB) 1970 to date SciSearch - (SCZZ) 1996 to date Medline in Process - (MEIP) latest few weeks Biosis Previews - (BIOX) Latest updates Embase alerts - (EMBA) latest 8 weeks Adis Reactions Database - (REZZ) 1983 to date EMCare - (EMCA) 1995 to date

AN PREV200700479934 20070912. AU Penson-D, Ramsey-S, Veenstra-D, Clarke-L, Gandhi-S, Hirsch-M. TI Combination therapy with bicalutamide 50mg plus a luteinising hormone-releasing hormone agonist (LHRHa) is cost effective compared with an LHRHa alone in metastatic prostate cancer. SO EJC Supplements, OCT 2005, vol. 3, no. 2, Suppl. S, p. 258, ISSN: 1359-6349. IN Penson-D, Keck Sch Med, Dept Urol, Los Angeles, CA USA. LG English. YR 2005.

AN 16006889 Medline R 20050101. TI The cost-effectiveness of combined androgen blockade with bicalutamide and luteinizing hormone releasing hormone agonist in men with metastatic prostate cancer. SO The Journal of urology, {J-Urol}, Aug 2005, vol. 174, no. 2, p. 547-52; discussion 552, ISSN: 0022-5347. AU Penson-David-F, Ramsey-Scott, Veenstra-David, Clarke-Lauren, Gandhi-Sanjay, Hirsch-Mark. IN Department of Urology and Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California 90089, USA. [email protected]. AB PURPOSE: Combined androgen blockade therapy (CAB) has been shown to have a small survival advantage over luteinizing hormone releasing hormone LH-RH agonists (LH-RHa) alone in men with metastatic prostate cancer. The goal of this study was to assess the cost-effectiveness of CAB with bicalutamide and LH-RH agonist therapy to LH-RH agonist therapy alone. MATERIALS AND METHODS: A macro-simulation model was developed to compare the cost- effectiveness of 2 interventions for stage D2 prostate cancer, 1) CAB with bicalutamide 50 mg per day and monthly dosing of an LH-RHa or 2) monthly LH-RH agonist therapy. Cost and outcomes are tabulated in 5 and 10-year time horizons. Model assumptions were taken from the published literature. Appropriate 1-way and multi-way sensitivity analyses were performed. RESULTS: At 5 years, the incremental cost-effectiveness ratio (ICER) for CAB, when compared with LH-RHa monotherapy, was US dollars 33,677 per quality-adjusted life-year. In other words, for every additional quality-adjusted life year that a patient lived because he received CAB, it cost US dollars 33,677. At 10 years the ICER for CAB was US dollars 20,053 (well within the accepted cost-

121 effectiveness threshold). If quality adjustment was not included, the ICER for CAB was even more favorable (US dollars 20,489 at 5 years and US dollars 13,313 at 10 years). The model was most sensitive to the estimates of effectiveness (survival) of LH-RHa therapy alone and CAB therapy. The model was also fairly sensitive to the quality of life effect of having late stage prostate cancer and the cost of bicalutamide. CONCLUSIONS: CAB with bicalutamide is cost-effective when compared with LH-RH monotherapy in men with stage D2 prostate cancer. LG English. CM Comment in: J Urol. 2005 Aug; 174(2):415-6. YR 2005.

122

APPENDIX 12: Literature Search Testosterone and Tumour Growth in Prostate Cancer

Search strategy:

((grow$3 or size or increas$3 or development) adj (tumour$2 or tumor$2 or neoplasm$2))

and

(prostate or prostatic) near (cancer or carcinoma)

and testosterone

Requested by: Yeesha Poon Date: June 11 2009 Executed by: MOL

1. AN 000249390700024 20071011. TI Association of prostate size and tumor grade in Korean men with clinically localized prostate cancer. SO UROLOGY, 2007, V70, N1, JUL, pp 91-95. ISSN: 0090-4295. AU Hong-Sung-Kyu, Yu-Ji-Hyung, Han-Byung-Kyu, Chang-In-Ho, Jeong-Seong-Jin, Byun-Seok-Soo, Lee-Hak-Jong, Choe-Gheeyoung, Lee-Sang-Eun (selee @snubhorg). IN Reprints from: S E Lee, Seoul Natl Univ, Bundang Hosp, 300, Guini-dong, Seoul, South Korea. Research addresses: Seoul Natl Univ, Bundang Hosp, Dept Urol, Songnam 151, South Korea; Seoul Natl Univ, Bundang Hosp, Dept Radiol, Songnam 151, South Korea; Seoul Natl Univ, Bundang Hosp, Dept Pathol, Songnam 151, South Korea. AB OBJECTIVES To investigate the association of prostate size with aggressiveness of prostate cancer in Korean men who received radical retropubic prostatectomy (RRP) for clinically localized prostate cancer. METHODS We evaluated the association of RRP specimen weight and prostate volume measured by transrectal ultrasound (TRUS) with pathologic tumor grade, extraprostatic extension of disease, surgical margin status, and seminal vesicle invasion by reviewing data of 346 consecutive patients who underwent RRP for clinically localized prostate cancer at our institution without receiving preoperative radiation or hormonal treatment. RESULTS A strong correlation was observed between RRP specimen weight and TRUS-measured prostate volume (Spearman r = 0.76; P < 0.001). After adjustment for multiple variables including age, body mass index, and preoperative prostate-specific antigen level, RRP specimen weight was observed to be significantly associated with presence of Gleason pattern 4 or greater at RRP in an inverse fashion (P = 0.03). Regarding other adverse pathologic features, prostate weight was also significantly inversely associated with extraprostatic extension of prostate cancer (P = 0.04) and

123

Surgical margin positivity (P = 0.002). When TRUS-measured prostate volume was applied in place of RRP specimen weight, results were the same. CONCLUSIONS Our data indicate that prostate size may be a useful predictor of tumor aggressiveness in Korean men with clinically localized prostate cancer. Further efforts should be made to elucidate actual mechanisms behind the association of prostate size and/or in vivo androgenicity with aggressiveness of prostate cancer. DE LOW-SERUM-TESTOSTERONE; RADICAL-PROSTATECTOMY; PREDICTS; ANTIGEN; LEVEL; RISK. CC CLIN. GA 209LT. Document delivery available: 000249390700024. PT Journal. AT Article. LG English. YR 2007. NU 20 references.

2. AN 18336613 Medline 20080501. TI Management of advanced prostate cancer: can we improve on androgen deprivation therapy? SO BJU international, {BJU-Int}, Jun 2008 (epub: 11 Mar 2008), vol. 101, no. 12, p. 1497-501, 32 refs, ISSN: 1464-410X. AU Anderson-John, Abrahamsson-Per-Anders, Crawford-David, Miller-Kurt, Tombal-Bertrand. IN Department of Urology, The Royal Hallamshire Hospital, Sheffield, UK. [email protected]. AB Gonadotrophin-releasing hormone (GnRH) agonists are currently the mainstay in the management of advanced prostate cancer. Used either as monotherapy or combined with antiandrogens, GnRH agonists suppress serum testosterone levels and thus slow the growth of the tumour cells that depend on testosterone for growth. GnRH agonists have largely replaced orchidectomy in the management of advanced prostate cancer, because patients are reluctant to undergo surgical castration. However, can we do better in androgen-deprivation therapy? There is some evidence to suggest that GnRH agonists do not achieve the level of testosterone suppression attained with orchidectomy, or as rapidly, factors which could be expected to affect overall survival. Together, these observations highlight the need to develop newer agents that can achieve rapid, profound and sustained testosterone suppression, equivalent to that with orchidectomy. Preliminary data for the GnRH blocker, degarelix, suggest that this new agent might overcome the shortcomings associated with GnRH agonists. Further clinical data are therefore awaited with much interest. LG English. YR 2008.

3. AN PREV199900047521 19990101. AU Gregory-Christopher-W, Hamil-Katherine-G, Kim-Desok, Hall-Susan-H, Pretlow-Thomas-G, Mohler-James-L, French-Frank-S. TI Androgen receptor expression in androgen-independent prostate cancer is associated with increased expression of androgen-regulated genes. SO Cancer Research, Dec. 15, 1998, vol. 58, no. 24, p. 5718-5724, ISSN: 0008-5472. IN French-Frank-S, Lab. Reprod. Biol., Dep. Pediatr., CB No. 7500, 382 MSRB, Univ. N.C., Chapel Hill, NC 27599, USA. LG English. YR 1998. AB The human prostate cancer (CaP) xenograft, CWR22, mimics human Cap. CWR22 grows in testosterone-stimulated nude mice, regresses after castration, and recurs after 5-6 months in the absence of testicular androgen. Like human CaP that recurs during androgen deprivation therapy, the recurrent CWR22 expresses high levels of androgen receptor (AR). Immunohistochemical, Western, and Northern analyses demonstrated that AR expression in the androgen-independent CWR22 is similar to AR expression in the androgen-dependent CWR22 prior to castration. Expression of prostate-specific antigen and human kallikrein-2 mRNAs, two well-characterized androgen-regulated genes in human CaP, was androgen dependent in CWR22. Despite the absence of testicular androgen, prostate-specific antigen and human kallikrein-2 m RNA levels in recurrent CWR22 were higher than the levels in regressing CWR22 tumors from 12-day castrate mice and similar to those in the androgen stimulated CWR22. Other AR-regulated genes followed a similar pattern of expression. Differential expression screening identified androgen regulation of alpha-enolase and alpha-tubulin as well as other

124 unknown mRNAs. Insulin-like growth factor binding protein-5, the homeobox gene Nkx 3.1, the AR coactivator ARA-70, and cell cycle genes Cdk1 and Cdk2 were androgen regulated in CWR22. In recurrent CWR22, the steady-state levels of all these AR-dependent mRNAs were similar to those in the androgen-stimulated CWR22, despite the absence of testicular androgen. Expression of R and AR- regulated genes in the androgen-deprived recurrent CWR22 at levels similar to the androgen- stimulated CWR22 suggests that AR is transcriptionally active in recurrent CWR22. Induction of these AR-regulated genes may enhance cellular proliferation in relative androgen absence but through an AR-dependent mechanism. Alternatively, in androgen-independent tumors, induced expression of the AR-regulated gene network might result from a non-AR transcription control mechanism common to these genes.

4. AN 000170422300002 20010824. TI Is the flare phenomenon clinically significant? SO UROLOGY, 2001, V58, N2A, AUG, SS, pp 5-9. ISSN: 0090-4295. AU Bubley-G-J ([email protected]). IN Reprints from: G J Bubley, Beth Israel Deaconess Med Ctr, 1047 HIM Bldg, East Campus,330 Brookline Ave, Boston, MA 02215, USA. Research addresses: Beth Israel Deaconess Med Ctr, Boston, MA 02215, USA; Harvard Univ, Sch Med, Boston, MA, USA. AB Objectives: The existing luteinizing hormone-releasing hormone (LHRH) analogs have been the preferred method of inducing androgen deprivation for prostate cancer for over a decade. These agents are well known to cause a surge in serum testosterone levels during the first week of therapy. However, there are wide discrepancies in reports of the frequency and severity of acute clinical progression or clinical flare that might result from the testosterone surge. Also, there is not a clear consensus as to whether antiandrogens should be routinely given to all patients during the first month of LHRH therapy to prevent flare responses. Methods: Clinical trials involving LHRH analog therapy for prostate cancer were reviewed, and the frequency of clinical flare responses noted. Particular attention was given to the kinds of clinical problems associated with the flare response. The use of LHRH analog therapy in treatment of patients with prostate cancer for indications other than overt metastatic disease is discussed, because this is becoming a much more common use of these agents. This article analyzes 2 placebo-controlled, double-blind trials testing the effectiveness of existing antiandrogens in ameliorating flare responses. Results: The use of LHRH analogs for patients with stage D2 disease can be associated with clinical flare in approximately 10% of D2 patients. In addition to bone pain, cord compression, and bladder outlet obstruction, another potentially severe side effect is cardiovascular risk arising presumably from hypercoagulability associated with a rapid increase in tumor burden. In clinical series involving D2 patients, the frequency of clinical flare greatly varies, probably because of the level of scrutiny of the investigator and/or the prostate-cancer tumor burden present at the initiation of therapy. Concomitant antiandrogen therapy reduces, but does not totally eliminate, the flare responses in patients at high risk for flare. Treating prostate cancer in the DO stage or in the neoadjuvant setting will result in biochemical evidence of testosterone surge, but these patients are at very little risk for clinical flare responses. Conclusions: There is a wide variation in the reported frequency of clinical flare responses from LHRH analogs during the initial treatment of patients with stage D2 disease. The risk-to-benefit ratio, especially in patients with symptomatic bone metastasis, would dictate routine use of antiandrogen therapy for the first month of LHRH analog treatment. For patients at risk for cord compression, other means of ablating testosterone might be considered, such as ketoconazole, orchiectomy, or LHRH antagonists. Clinical flare responses, as opposed to biochemical flare responses, are very rare during LHRH analog therapy for stage DO disease and/or in the setting of neoadjuvant hormonal therapy.

DE PROSTATE-SPECIFIC-ANTIGEN; DISEASE-FLARE; HORMONE-ANALOG; EXOGENOUS-TESTOSTERONE; CYPROTERONE-ACETATE; CANCER; CARCINOMA; THERAPY; DIETHYLSTILBESTROL; LEUPROLIDE. CC CLIN. GA 462LV. Document delivery available. PT Journal. AT Article. LG English. YR 2001. NU 22 references.

125

5. AN 000265585000006 19980108. AU Lopez-Fontana-Constanza, Maselli-Artola-M-Eugenia, Vanrell-Rodriguez-M-Cristina, Di-Milta- Monaco-Nicolds-A, Perez-Elizalde-Rafael, Lopez-Laur-Jose-D. IN Reprints from: CL Fontana, Acceso Este 2245 Lateral Sur, RA-5519 Mendoza, Argentina. Research addresses: Jose D. Lopez Laur: Univ Nacl Cuyo, Fac Ciencias Med, Catedra Clin Urol, RA-5500 Mendoza, Argentina; Constanza Lopez Fontana, M. Eugenia Maselli Artola, M. Cristina Vanrell Rodriguez, Nicolds A. Di Milta Monaco, Rafael Perez Elizalde: Univ Juan Agustin Maza, Fac Farm & Bioquim, Lab Enfermedades Metab & Canc, RA-5500 Mendoza, Argentina. Email: [email protected]. TI Advances on the influence of adipose tissue on prostate cancer. SO ACTAS-UROLOGICAS-ESPANOLAS, 2009, V33, N3, MAR, pp 242-248. ISSN: 0210-4806. LG SP. AB Numerous studies have investigated the association between obesity and prostate cancer (CaP), although the results have not been concluding due to the great difficulty to evaluate the effects of obesity on the development of this type of tumor. The aim of this study was to carry out a comprehensive over-view of the existing evidence about the role of adipose tissue in the prostate carcinogenesis. Recent evidence suggests that androgens. leptin. IL-6. VEGF.insulin and IGF-I may play a role in PC progression while adiponectin and IGFBP-3 may act as "anti- prostatic cancer" adipokines. The potential mechanisms by which obesity may initiate, promote or facilitate the progression of CaP are low levels of testosterone and high levels of estrogen, coexisting metabolic syndrome, increased secretion of leptin. VEGF, IL-6 and TNF-alpha and decreased adiponectin, and excessive intake of saturated fat. Conclusion: Obesity may promote the progression of established PC rather than being a risk factor for the development of this tumour. However, additional studies are needed to clarify the relationship between adipokines and PC before developing new preventive or treatment strategies for this tumor. NU 49 references.

6. AN 08043499 Medline R 19940101. TI Androgen-dependent prostatic tumors: biosynthesis and possible actions of LHRH. SO The Journal of steroid biochemistry and molecular biology, {J-Steroid-Biochem-Mol-Biol}, Jun 1994, vol. 49, no. 4-6, p. 347-50, 28 refs, ISSN:0960-0760. AU Limonta-P, Moretti-R-M, Dondi-D, Marelli-M-M, Motta-M. IN Department of Endocrinology, University of Milano, Italy. AB Testosterone (T) is the major exogenous stimulus for the growth of prostatic carcinoma. It is believed that the proliferative action of T may be mediated by locally expressed growth modulatory factors. Recent evidence from our laboratory suggests that a LHRH (or a LHRH-like) loop might be expressed in human prostatic tumor cells. To verify this hypothesis, we have studied whether a mRNA for LHRH is expressed in the human androgen-responsive prostatic cancer cell line LNCaP, using the reverse transcription-polymerase chain reaction technique in the presence of a pair of specific oligonucleotide primers. A cDNA band of the expected size was obtained from LNCaP cells; this band hybridized with a 32P-labeled LHRH oligonucleotide probe and its sequence showed a complete match with the reported sequence of the human placental LHRH cDNA. These observations indicate that the mRNA coding for LHRH is expressed in LNCaP cells and suggest that a LHRH (or a LHRH-like) peptide might be produced by these cells. To clarify the possible action of this peptide, LNCaP cells were grown in a steroid-free medium and treated with a LHRH antagonist. The treatment resulted in a significant increase of tumor cell growth. These data clearly indicate that the LHRH system expressed in LNCaP cells plays an inhibitory role on cell proliferation, and that this system seems to be regulated in a negative way by steroids. An EGF/TGF alpha autocrine stimulatory loop (peptides, receptors, intracellular signals) is also functional in these cells. Treatment of LNCaP cells grown in serum-free conditions (i.e. in the absence of exogenous growth factors) with a monoclonal antibody against the EGF receptor, or with immunoneutralizing antibodies against EGF or TGF alpha, resulted in a significant decrease of cell proliferation. T positively regulates this EGF/TGF alpha system by increasing the concentration of EGF binding sites. The present data indicate that an inhibitory LHRH (or LHRH-like) system is expressed in LNCaP cells and participates in the local mechanisms regulating tumor cell proliferation together with an EGF/TGF alpha stimulatory loop. Both systems appear to be modulated by T. LG English. YR 1994.

126

7. AN 03407635 Medline R 19880101. TI Hemostatic effects of hormonal stimulation in patients with metastatic prostate cancer. SO American journal of hematology, {Am-J-Hematol}, Jul 1988, vol. 28, no. 3, p. 141-5, ISSN: 0361- 8609. AU Al-Mondhiry-H, Manni-A, Owen-J, Gordon-R. IN Department of Medicine, Pennsylvania State University College of Medicine, Hershey. AB Hemostatic abnormalities are common in patients with metastatic malignancy and are attributed, in part, to materials secreted by tumor cells. Tumor stimulation might therefore cause further perturbation of hemostasis. This article reports observations on the effects of androgen stimulation on multiple hemostatic parameters in patients with metastatic prostate cancer. Testosterone was given before chemotherapy in an experimental protocol designed to increase tumor sensitivity to cytotoxic agents. The following parameters were measured on day 0 (before) and days 2 and 4 of fluoxymesterone administration: PT, APTT, platelet count, plasma betathromboglobulin (BTG), platelet factor 4 (PF4), fibrinogen, fibrin(ogen) split products (FSP), factor VIII coagulant activity (VIII C), von Willebrand factor antigen (vWF Ag), fibrinopeptide A (FPA), antithrombin III (AT III), and protein C antigen (PC). Ten patients were studied during 17 cycles of hormonal stimulation. Baseline levels of BTG, PF4, fibrinogen, FSP, factor VIII C, vWF Ag, and FPA were significantly elevated compared with normal control. Although androgen stimulation resulted in elevation of BTG, FPA, and FSP levels by day 4 in many patients, the changes for the entire group were not statistically significant. Other parameters remained unchanged or were only slightly elevated. Two patients developed laboratory evidence of disseminated intravascular coagulation (DIC) but were clinically unaffected. Our data suggest that most patients with metastatic prostate cancer show evidence of ongoing activation of platelets, coagulation, and fibrinolysis. In a few individual patients, androgen stimulation of this hormonally dependent tumor may cause further activation of platelets, coagulation, and fibrinolysis. LG English. YR 1988.

8. AN 376039173 9100. AU VANWEERDEN-W-M, VANKREUNINGEN-A, MOERINGS-E-P-C-M, DEJONG-F-H, VANSTEENBRUGGE-G-J, SCHRODER-F-H. IN ERASMUS UNIV, DEPT UROL, EXPTL SURG LAB, POB 1738, 3000 DR ROTTERDAM, NETHERLANDS. ERASMUS UNIV, DEPT BIOCHEM 2, 3000 DR ROTTERDAM, NETHERLANDS. TI THE BIOLOGICAL SIGNIFICANCE OF LOW TESTOSTERONE LEVELS AND OF ADRENAL ANDROGENS IN TRANSPLANTABLE PROSTATE-CANCER LINES. SO UROLOGICAL-RESEARCH, 1991, V19, N1, P1-5. LG EN. AB The transplantable androgen-dependent human prostate tumor models PC-82 and PC-EW were used to study whether low levels of testosterone and androgens of adrenal origin were capable of stimulating the growth of prostatic carcinoma cells in these tumor models. At all circulating plasma testosterone levels applied in this study, much lower levels of dihydrotestosterone were found in PC-EW tumor tissue than in PC-82 tumor tissue. Nevertheless, both prostate tumor models had a similar threshold level of dihydrotestosterone for growth stimulation, i.e. 3-4 pmol/g tissue. This critical androgen level for tumor growth amounted to 2-3 times the tissue level found in castrated animals. At this threshold level approximately 2% of the cells showed proliferative activity, as assessed by bromodeoxyuridine incorporation into DNA. The adrenal androgen dehydroepiandrosterone did not stimulate PC-82 tumor growth, whereas androstenedione did induce a moderate increase in tumor volume. It is concluded that the adrenal androgen androstenedione exerts a stimulating effect on prostatic cancer cells when its conversion results in intra-tissue testosterone and dihydrotestosterone levels exceeding the threshold level for tumor growth. NU 34 cited references.

9. AN 03868029 Medline R 19860101. TI On the effects of oestrogen in the male. Some effects of different oestrogenic substances in rats and men with prostatic carcinoma. SO Scandinavian journal of urology and nephrology. Supplementum, {Scand-J-Urol-Nephrol-Suppl}, 1985, vol. 91, p. 1-44, ISSN: 0300-8886. AU Daehlin-L.

127

AB In vitro incubations of human testicular tissue responded to human chorionic gonadotrophin with testosterone release in a dose-dependent manner. The release of testosterone increased with incubation time. The stimulated release of testosterone was inhibited by oestradiol and ethinyl oestradiol in a dose-dependent manner, suggesting that these oestrogens exert direct inhibitory effects on the human Leydig cells. Estramustine phosphate, estromustine, diethylstilboestrol and diethylstilboestrol diphosphate did not inhibit testosterone release. Hypophysectomized rats were treated for 8-9 days with human chorionic gonadotrophin, which maintained testicular blood flow within the physiological range. Some of the animals received additional treatment with oestradiol or estromustine. Oestradiol and estromustine depressed plasma testosterone concentration. In contrast to estromustine, oestradiol inhibited testicular blood flow, as measured by the microsphere technique. Intact rats were castrated, supplemented with testosterone and concomitantly treated with different oestrogenic substances. Testosterone supplementation induced increase of prostatic blood flow, which was inhibited by oestradiol, ethinyl oestradiol or diethylstilboestrol. Estramustine and estromustine had no effect on prostatic blood flow. The growth of a transplantable rat prostatic carcinoma (Dunning R3327H) was studied after castration, testosterone substitution or testosterone substitution in combination with oestradiol treatment. Oestradiol inhibited tumour growth, possibly by direct action. The blood flow in tumours in intact animals decreased with increasing tumour volume. Oestradiol treatment enhanced tumour blood flow. The oestrogenic effects of estramustine phosphate, ethinyl oestradiol/polyoestradiol phosphate or orchiectomy were studied in previously untreated prostatic carcinoma patients by measuring serum levels of liver proteins (pregnancy zone protein and sex hormone binding globulin) and pituitary hormones (luteinizing hormone, follicle stimulating hormone and prolactin) during a 6 month period. Both medical treatments induced marked but quite comparable changes of the proteins. Apart from the increase of follicle stimulating and luteinizing hormones, no changes were observed in these serum proteins after orchiectomy. LG English. YR 1985.

10. AN 00870137 Medline R 19770101. TI Hormonal pattern in prostatic carcinoma following orchidectomy: 5-year follow-up. SO British journal of urology, {Br-J-Urol}, Apr 1977, vol. 49, no. 2, p. 161-6, ISSN: 0007-1331. AU Bracci-U, Di-Silverio-F, Sciarra-F, Sorcini-G, Piro-C, Santoro-F. AB Clinical and hormonal findings have been collected from 14 patients affected by carcinoma of the prostate observed over a 5-year period following orchidectomy. Plasma testosterone decreased significantly after surgery (62 ng +/- 21 SD/100 ml), remaining below 100 ng/100 ml even in cases showing only a partial regression or increase of the tumour. Gonadotropin FSH increased 1 year after orchidectomy to 28 mIU + /- 5/ml and remained constantly elevated up to the 5th year, whilst LH increased progressively up to the 5th year (30 mIU +/- 12/ml). Finally, plasma cortisol increased progressively up to 23.2 microng +/- 17.4/100 ml at the 5th year post-orchidectomy, especially in those cases showing partial regression or increase of the tumoral mass, indicating an adrenal hyperfunction which is probably responsible for increased production of weak androgens that can be transformed in the prostate into more active compounds. These results suggest therefore that after orchidectomy, cortisol and adrenal androgen determination may be of value in detecting the potential activation of prostatic adenocarcinoma. LG English. YR 1977.

11. AN 1974002193 19740101. TI Plasma testosterone and androstenedione after orchiectomy in prostatic adenocarcinoma. SO Clinical Endocrinology, {CLIN-ENDOCRINOL}, 1973, vol. 2, no. 2, p.101-109, CODEN: CLENA, ISSN: 0300-0664. AU Sciarra-F, Sorcini-G, Di-Silverio-F, Gagliardi-V. IN Ist. Patol. Spec. Med. Metodol. Clin. II, Univ. Rome, Italy. AB Orchiectomy is often used in the management of metastatic adenocarcinoma of the prostate, an androgen dependent tumour, since it markedly reduces the concentrations of plasma testosterone (to a mean level of 28±16 (SD) ng/100 ml) and temporarily inhibits the growth of the neoplasm. In some orchiectomized patients, however, the values of plasma testosterone and androstenedione do not drop to these levels, but remain higher, around 137±23 ng/100 ml and 213±39 ng/100 ml respectively. In these patients, treatment with dexamethasone significantly decreased the levels of testosterone and androstenedione to 22±20 ng/100 ml (P<0.0005) and 43±11 ng/100 ml (P<0.0005) respectively. It can therefore be assumed that in orchiectomized patients these compounds are produced in the adrenal

128 cortex, which in some cases is stimulated to produce a larger amount of strong androgens such as testosterone and weaker androgens such as androstenedione. It has also been observed that those patients with an inadequate lowering of plasma testosterone levels after orchiectomy, did not show clinical improvement. Further studies in a larger number of patients are needed in order to support this finding. LG English. YR 1973.