Matters PRACTICE PRACTICE Matters

• Prostate cancer is the most common cancer and the

second leading cause of cancer deaths among men.

• It is estimated that each year nearly 200,000 new

cases of prostate cancer will be diagnosed and

40,000 men will die of prostate cancer.

• The total Medicare expenditure for treatment of

prostate cancer exceeds $1.5 billion annually. Of

that total, $500 million was for hormone therapy

with androgen suppression using LHRH agonists.

• VA’s annual expenditure for LHRH agonists is

about $40 million.

• Hormone therapy delays clinical progression and

palliates prostate cancer symptoms in the majority

of men but has not been clearly shown to improve

survival.

• The prevalence and morbidity of prostate cancer

are likely to increase with the aging of the population, as are expenditures for treatment due to

earlier detection of the disease.

• VA research has improved our understanding of

the relative effectiveness, safety and cost effectiveness of different forms of hormone therapy for

prostate cancer.

USE OF

ANDROGEN

SUPRESSION

THERAPY FOR

ADVANCED

PROSTATE

CANCER

A publication of the Management Decision and Research Center

A program within the Department of Veterans Affairs Health Services Research and Development Service

JANUARY 2001 VOL. 6 ISSUE 1
2 PRACTICE Matters

BACKGROUND:

Prostate cancer is the most common malignancy i

men and is second only to lung cancer in cancer

related deaths. Androgen suppression, or hormona

therapy, is the mainstay of treatment for recurrent

or advanced (non-localized) prostate cancer.

Androgen suppression, while not curing prostat

cancer, provides temporary palliation of symptoms

and reduction in tumor size and Prostate Specific

Antigen (PSA) levels in the vast majority of men.

Androgen suppression can result in adverse effects

including: fatigue, nausea, breast tenderness, hot

flashes, osteoporosis, erectile dysfunction, liver

function abnormalities, thromboembolic events,

diarrhea and loss of muscle mass and libido. Deter

mining the potential risks and benefits of different

methods for androgen suppression therapy, including their effects on length and quality of life, are of

great importance in delivering evidence based

health care to male veterans.

n

l

e

-

TREATMENT GOALS AND

THERAPIES:

Recent systematic reviews and technology assessment reports have evaluated the evidence regarding

efficacy, safety and cost-effectiveness of different

methods of androgen suppression in men with

advanced prostate. Three questions were addressed:

1. What are the best methods for monotherapy

(orchiectomy (removal of both testes), diethylstilbestrol (DES) luteinizing hormone releasing

hormone agonists (LHRHa), or nonsteroidal

antiandrogens (NSAA))?

2. Are there survival and quality of life differences if

using combined androgen blockade (CAB)

compared to monotherapy? and

3. Is there a difference in outcome between implementing immediate androgen suppression versus

deferring androgen suppression until signs or

symptoms of clinical progression?

The findings are highlighted in this issue of VA

Practice Matters.

Monotherapy (see Figure 1)

Monotherapy uses a single drug or surgical

procedure for androgen suppression. Evidence

indicates no overall survival difference for men

treated with LHRH agonists compared to orchiectomy or DES, nor a survival difference among men

treated with different LHRH agonists. There is a

trend toward lower survival rates for men treated

with nonsteroidal antiandrogens compared to

orchiectomy, DES, or LHRH agonists. While

LHRH agonists, DES and nonsteroidal

antiandrogens differ in their adverse effects, the

evidence does not suggest that one agent is superior

to the others with regards to adverse effects. There

is insufficient evidence to compare the effects of

monotherapies on quality of life.

Combined Androgen Blockage (CAB) vs

Monotherapy (see Figure 2)

There is no survival difference at 2 years between

men treated with CAB or monotherapy. The

difference in survival at 5 years is 3% (28% vs.

25%) and at 10 years is 2% (9% vs. 7%) in favor of

CAB. The difference in median survival is 3.4

months (33.3 months vs. 29.9 months). Survival

differences between CAB and monotherapy did not

vary by patient age or disease stage. Among men

given CAB, survival is similar regardless of the type

of nonsteroidal antiandrogen used. The evidence

comparing adverse effects is limited, but favors

monotherapy. Evidence comparing quality of life

was available from only one study with 6 month

follow-up and favored monotherapy.

Immediate compared to deferred androgen

suppression (see Figure 3)

The evidence is insufficient to determine

whether androgen suppression initiated immediately at diagnosis improves survival compared to

androgen suppression deferred until clinical signs or

symptoms of progression. However, initiating

androgen suppression immediately delays development of symptomatic disease progression and

complications compared to deferring androgen

suppression.

Androgen suppression initiated at the time of

identification of positive lymph nodes during

prostatectomy improves survival compared to

deferral until symptomatic metastasis. In men with

Continued on page 4
PRACTICE Matters 3

CLINICAL VIEWPOINT

Physicians are faced with uncertainty regarding

hormonal therapy for metastatic prostate cancer. In

the VA medical system, the decision is related to

two issues:

1. how often is hormonal therapy the primary

reason why patients transfer care to the VA

medical system, and

2. do the clinical findings reported from randomized phase III clinical trials support the use of

hormonal therapies and if so, which ones, how

often, and when should the treatment be started.

Two sources of data provide relevant information:

1. A recent survey of Veterans found that among

prostate cancer patients who transferred to the

VA, most did so because of the VA’s pharmaceutical benefit program.

2. Three recent overviews of the entirety of phase

III randomized clinical trials for metastatic

prostate cancer indicate that:

• early hormonal therapy is associated with

longer cancer-free survival times, but not

longer overall survival;

• survival is similar with the alternative medical

and surgical therapies for castration (orchiectomy, LHRH agonists, and diethylstilbestrol),

but patient preferences and costs vary; and

• combined androgen blockade with an oral

nonsteroidal antiandrogen in conjunction with

medical or surgical castration is associated with

an estimated 3% improvement in 5-year

survival rates, although quality of life and

toxicity that may occur during the first few

months of treatment may be worse.

Many Veterans with prostate cancer transfer their

medical care to the VA because of gaps in pharmaceutical benefit coverage in the non-VA setting. The

data indicate that VA patients should be counseled on

the expected benefits and toxicities of early versus

late initiation of hormonal therapy, alternative

approaches to castration, and the potential benefits

and toxicities of oral nonsteroidal antiandrogens

when used in conjunction with castration. VA physicians should be reminded that hormonal therapy of

prostate cancer should be based on a shared decision

making approach between patients and physicians.

Charles L Bennett MD PhD, Chairman

HSR&D Chicago VA/Lakeside Division

Professor of Medicine, Northwestern University

IMPLICATIONS FOR

PRACTICE

1. There is no difference in survival among different forms of monotherapy. The choice of

monotherapy should be based on patient preference but will be associated with marked differences in cost. Additionally, the availability of

DES within the VA or at outside pharmacies is

limited.

2. The small benefit in median (3.3 months) and 5

year survival (3%) with CAB compared to

monotherapy must be balanced against the cost

and adverse events associated with CAB.

3. Men who undergo immediate hormonal treatment for advanced prostate cancer should be

informed that they have a longer duration of

therapy in which they may experience adverse

effects and costs of androgen suppression. However, complications due to disease progression

may be decreased by immediate treatment. There

is no clear evidence whether immediate or

deferred treatment provides the longest survival

except in men who have also received radiotherapy.

4. There is no evidence from randomized trials to

support or refute the use of immediate hormone

therapy upon PSA rise or recurrence. Men

should be informed about potential, but unproven, risks and benefits.

VA Practice Matters is a publication for VA decision makers and practitioners that summarizes the

results of important research to help inform policy

and to promote the application of research for improved health care delivery and decision making

within VA. It is produced by HSR&D’s Information Dissemination Program in collaboration

with topic experts in the field. For more information or to provide us with your suggestions,

please contact:

Information Dissemination Program

Management Decision and Research Center (152-M)

VA Boston Health Care System

150 South Huntington Avenue

Boston, MA 02130

Phone: (617) 278-4433

FAX: (617) 278-4438

Email: geraldine.mcglynn@med.va.gov

VA Practice Matters is also available on the VA R&D

internet at www.va.gov/resdev/prt, and on our Fax on

Demand system by dialing (617) 278-4492 and

following the voice prompts.
4 PRACTICE Matters

TREATMENT GOALS AND THERAPIES

Continued from page 2

advanced prostate cancer treated with radiotherapy,

immediate addition of androgen suppression continued for several years improves survival compared

to radiotherapy alone with androgen suppression

delayed until disease progression. There is little

data on duration of androgen therapy, adverse

effects and effect on quality of life.

Cost Effectiveness (see Figure 4)

The least expensive androgen suppression option

is DES. Orchiectomy is the most cost effective with

an incremental cost-effectiveness ratio of $8100 per

quality adjusted life year relative to DES. All other

strategies — LHRHa, NSAA, and both combined

androgen blockade strategies — had higher costs and

lower quality adjusted survival than orchiectomy.

The cost-effectiveness is sensitive to the patients’

perceptions regarding the effect of orchiectomy on

the quality of their life. CAB is expensive and is, at

best, marginally cost-effective. Initiating early

androgen suppression therapy may reduce disease

related complications. However, it is associated with

higher costs and does not improve survival compared

to deferring therapy. Therefore, early hormonal

therapy may not be beneficial to patients at a time

when they are still able to enjoy a good quality of life.

The exception to this is for men treated with radical

prostatectomy who have positive lymph nodes, or

men treated with radiotherapy.

REFERENCES

Kim SP, Moran EM, Bowes ED, Tennant AG, Bennett CL.

The anti-androgen transfer. The Prostate Journal. 2000; 2:

88-93.

Aronson N, Seidenfeld J, Samson DJ, et al. Relative Effectiveness and Cost-Effectiveness of Methods of Androgen Suppression in the Treatment of Advanced Prostate Cancer. Evidence

Report/Technology Assessment No. 4. (Prepared by Blue

Cross/Blue Shield Association Evidence-based Practice Center

under Contract No. 290-97-0015. AHCPR Publication No.

99-E0012. Rockville, MD: Agency for Health Care Policy and

Research. May. 1999.

Schmitt B, Seidenfeld J, Wilt TJ, Bennett CB. Combined

androgen suppression versus monotherapy for advanced

prostate cancer. Cochrane Library. 2000; issue 2.

Schmitt B, Bennett CL, Seidenfeld J, Samson D, Wilt T.

Maximal androgen blockade for advanced prostate cancer.

[Cochrane Review]. In: The Cochrane Library, Issue 3, 2000.

Oxford: Update Software.

Prostate cancer trialists’ collaborative group. Maximum

androgen blockade in advanced prostate cancer: an overview of

the randomized trials. Lancet, 2000;355:1491-98.

Seidenfeld J, Samson DJ, Hasselblad V, Aronson N, Albertsen

PC, Bennett CL and Wilt TJ. Single-Therapy Androgen

Suppression in Men with Advanced Prostate Cancer: A Systematic Review and Meta-Analysis. Ann Intern Med. 2000;566-577.

Bayoumi AM, Brown AD, Garber AM. Cost-Effectiveness of

Androgen Suppression Therapies in Advanced Prostate Cancer.

J Natl Cancer Inst 2000;92:1731-9.

ACKNOWLEDGEMENTS

This issue of VA Practice Matters on the topic of

Use of Androgen Suppression Therapy for Advanced

Prostate Cancer, was written by Timothy J. Wilt,

MD, MPH of the HSR&D Center for Chronic

Disease Outcomes Research in Minneapolis and the

VA Cochrane Review Group in Prostatic Diseases

and Urologic Malignancies. Other contributors/

reviewers were: Charles L. Bennett, MD, PhD,

Chariman HSR&D Chicago VA/Lakeside Division

and Professor of Medicine, Northwestern University; John G. Demakis, MD, Director, VA Health

Services Research and Development Service; John

T. Wei, MD, MS, Assistant Professor of Urology/

Surgery, University of Michigan; Lynn

Steinbrenner, MD, Director of Oncology Primary

Care, VA Western New York Healthcare System

and Associate Professor of Medicine, SUNY,

Buffalo, NY. The issue was edited by Geraldine

McGlynn, M.Ed. and Diane Hanks, MA, of VA’s

Management Decision and Research Center.

Please take a moment and tell us how you feel

about Practice Matters by using our new

Instant Feedback Site for VA Health Services

Research Publications on the web at (http://

www.va.gov/resdev/prt/idp/). Your comments

and suggestions will guide us in our efforts to

provide you with important HSR&D information in future issues.
PRACTICE Matters 5

0.20 1.00 5.00

Hazard Ratio Relative to Orchiectomy

(Better than orchiectomy) (Worse than orchiectomy)

DES

(8, 993)

Leuprolide

(1, 94)

Goserelin

(7, 1137)

Buserelin

(4, 308)

LHRHa

(12, 1539)

Flutamide

(1, 44)

Bicalutamide

(5, 1452)

NSAAs

(6, 1496)

Cyproterone

(2, 93)

Antiandrogens

(8, 1589)

PRACTICE Matters

January 2001, Vol 6, Issue 1

ANDROGEN SUPPRESSION THERAPY FOR ADVANCED PROSTATE CANCER

Androgen suppression only

Androgen suppression + antiandrogen

100-

80-

60-

40-

20-

0-

0 510

Proportion alive (%)

Time since randomisation (years)

Treatment better

by 2.0% (SE 1.3)

Absolute

difference

3-2% (SE 1-5)

27-7%

24-5%

8-5%

6-6%

6500 prostate cancer

patients in 20 trials of

antiandrogen treatment plus

nilutamide or flutamide

Reprinted with permission from Annals of Internal Medicine. Seidenfeld, et al. Single-Therapy

Androgen Suppression in Men with Advanced Prostate Cancer. Ann Intern Med. 2000:132:566-

577.

Figure 1

Two year overall survival relative to orchiectomy in

men with advanced prostate cancer and treated with

various forms of monotherapy. Point estimates for

hazard ratios (center marks) and 95% CIs (error

bars) relative to orchiectomy.

Monotherapy uses a single drug or surgical procedure for androgen suppression. There were no

differences in survival for men treated with LHRH

agonists compared to orchiectomy or DES, nor

survival differences among men treated with different LHRH agonists. There is a trend toward lower

survival with NSAA compared to other

monotherapies. There is insufficient evidence to

evaluate quality of life.

Reprinted with permission from The Lancet. Labrie F, Candas B. Androgen blockade in

prostate cancer [letter}. Lancet 356(9226): 341, July 22, 2000.

Figure 2

Overall survival in men treated with Combined

Androgen Blockade (CAB) versus androgen suppression monotherapy.

CAB uses the addition of a NSAA to standard

androgen suppression monotherapy with orchiectomy, DES or LHRHa. The difference in survival

at 5 years is 3% and at 10 years is 2% (9% vs. 7%)

in favor of CAB. The difference in median survival

is 3 months (33 months vs. 30 months). Survival

differences between CAB and monotherapy did not

vary by patient age or disease stage. Evidence

comparing adverse effects and quality of life is

limited but favors monotherapy.

A publication of VA’s Health Services Research & Development Service
NSAA

DES

Orchiectomy

LHRH agonist

NSAA +

orchiectomy

NSAA + LHRH

agonist

5.20 -

5.10 -

5.00 -

4.90 -

4.80 -

4.70 -

4.60 -

4.50 -

Effectiveness (Quality Adjusted Life Years)

$0 $5K $10K $15K $20K $25K $30K $35K $40 $45K

Lifetime Cost

Alternative Efficacy Assumptions

Assumptions about efficacy reflected the point estimates from

the meta-analysis

Effectiveness

Strategy Cost (QALYs) Marginal Cost-Effectiveness

DES $3,567 4.68

Orchiectomy $6,957 5.10 $8,092/QALY

NSAA $14,382 4.61 Eliminated by strict dominance

NSAA +orchiectomy $20,857 5.08 Eliminated by strict dominace

LHRH agonist $25,709 4.89 Elimated by strict dominace

NSAA + LHRH agonist $41,443 5.13 $1,109,581/QALY

*Relative effectiveness and cost-effectiveness of androgen

suppression in the treatment of advanced prostatic cancer.

AHCPR Publication No. 99-E0012. Evidence Report/

Technology Assessment Number 4. Rockville: AHCPR. US

Department of Health & Human Services, May 1999.

Figure 3

Immediate compared to deferred androgen

suppression.*

The evidence is not sufficient to determine whether

androgen suppression initiated immediately at

diagnosis improves survival compared to androgen

suppression deferred until clinical signs or symptoms of progression. Early initiation delays development of symptomatic disease progression and

complications. However, it is associated with higher

costs of androgen suppression and exposes men to

longer treatment periods in which they may experience therapy-related adverse effects.

VACURG 1

Stage III

VACURG 1

Stage IV

VACURG 2

Stage III+IV

MRC

Combined

0.20 1.00 5.00

Hazard Ratio

(immediate better) (deferred better)

Survival at 5 years, immediate vs deferred primary hormonal

therapy for previously untreated patients

A publication of VA’s Health Services Research & Development Service

Figure 4

Costs and Outcomes with All Monotherapies and

Combined Androgen Blockade.*

The least expensive androgen suppression option is

DES (lifetime costs = $3600). Orchiectomy is the

most cost effective treatment option with an incremental cost-effectiveness ratio of $8100 per quality

adjusted life year relative to DES. Other strategiesLHRHa, NSAA and both combined androgen

blockade strategies had higher costs and lower or

equivalent quality adjusted survival compared to

orchiectomy (marginal cost effectiveness ratio of

NSAA + LHRH vs. orchiectomy = $1,110,000/

QALY). However, the cost effectiveness is sensitive

to the patients’ perception regarding the effect of

orchiectomy on the quality of their life.