Costs and Effectiveness of Prostate Cancer

Screening in Elderly Men

May 1995

OTA-BP-H-145

GPO stock #052-003-01414-9
iii

Foreword

ver the last 15 years, interest in strategies to promote health and prevent disease

among elderly people has grown substantially. This trend has at least partially

resulted from the desire to moderate rising health care costs among this segment of the population. As it has done in the case of this background paper, the

House Committee on Ways and Means has periodically asked the Office of

Technology Assessment to analyze the costs and effectiveness of providing selected preventive health services to elderly men under the Medicare program. The Senate Committee

on Labor and Human Resources had earlier requested that OTA provide information on the

value of preventive services to the American people.

Past work by OTA on prevention for elderly people has focused on studies of the costs

and effectiveness of pneumococcal and influenza vaccines, and screening for breast, cervical, and colorectal cancer and for glaucoma and elevated cholesterol. This background paper focuses on the procedures of digital rectal examination and the more recently developed, less-invasive prostate-specific antigen blood test—both used to help detect prostate

cancer.

The background paper summarizes the evidence on the effectiveness and costs of prostate cancer screening and treatment in elderly men and explores the implications for Medicare of offering this preventive technology as a Medicare benefit. This analysis illustrates

the hard policy choices in deciding whether to expend federal resources for screening and

treatment as well as risk their attendant complications before scientific research has definitively established the effectiveness of different technologies attempting to cure disease detected in varying stages and circumstances.

Roger C. Herdman OTA Director

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RECOMMENDED CITATION:

U.S. Congress, Office

of Technology

Assessment, Costs and

Effectiveness of

 Prostate Cancer

Screening in Elderly

Men, OTA-BP-H-145

(Washington, DC:

U.S. Government

Printing Office,

 May 1995).
iv

Project staff

MICHAEL E. GLUCK Project Director

Romulo E. Colindres Research Assistant

ADMINISTRATIVE STAFF

Louise Staley Office Administrator

Carolyn Martin Administrative Secretary

Monica Finch Word Processing Specialist

Carolyn Swann PC Specialist

Charlotte Brown Word Processing Specialist

CONTRACTORS

Michael A. Barry Massachusetts General Hospital, Boston, Massachusetts

Christopher M. Coley Massachusetts General Hospital, Boston, Massachusetts

Craig Fleming Health Outcomes Associates, Vancouver, Washington

Joseph E. Oesterling University of Michigan Medical Center,

Ann Arbor, Michigan

Marianne C. Fahs International Longevity Center (U.S.), Department of

Community Medicine, Mt. Sinai Medical Center, New York, New York

Michael Sanders International Longevity Center (U.S.), Department of

Community Medicine, Mt. Sinai Medical Center, New York, New York

Clare Lippert International Longevity Center (U.S.), Department of Community

Medicine, Mt. Sinai Medical Center, New York, New York

Scott D. Ramsey Department of Veterans Affairs Medical Center,

Seattle, Washington

Stephen D. Finn Department of Veterans Affairs Medical Center,

Seattle, Washington

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Clyde J. Behney

Assistant Director, OTA

Sean R. Tunis

Health Program Director
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Acknowledgments

Bob Andersen U.S. Executive Office of the President, Office of Management and Budget

Hans Olov Adami Cancer Epidemiology University of Upsula, Sweden

Peter C. Albertsen Department of Urology, University of Connecticut

Gerald L. Andriole, Jr. Division of Urologic Surgery, Washington University

David Bostwick Department of Pathology, Mayo Clinic

Martin Brown National Institutes of Health, U.S. Department of Health and Human Services

Reginald Bruskewitz Department of Surgery, Medical School, University of Wisconsin-Madison

Eugene Carlton American Urological Association, Baylor College of Medicine

Nancy Carlton Merck and Company

Gerald W. Chodak Department of Urology, School of Medicine, University of Chicago

Megan Cohen American Urological Association

Morris F. Collen Division of Research, Kaiser-Permanente Medical Care Program

Louis J. Denis International Prostate Health Council, Koningin Elisabethei, Antwerp, Beligum

Jean L. Fourcroy Food and Drug Administration, U.S. Department of Health and Human Services

Gary D. Friedman Epidemiology and Biostatistics, Division of Research, Permanente Medical

Group, Inc.

Donald Gleason Pathologist, Minneapolis, Minnesota

Allen C. Goodman Department of Economics, Wayne State University

Carolyn Green Office of Health Technology Assessment, University of British Columbia, B.C.

Gabriel P. Haas Department of Urology, School of Medicine, Wayne State University

Richard J. Howe US TOO

Don Iverson, ASPN University of Colorado

Linda Ivor Government Affairs, Hybritech, Inc.

Barry Kramer Division of Cancer Prevention and Control, National Cancer Institute

Robert Lawrence Health Sciences, Rockfeller Foundation

J. Michael McGinnis D.C. Department of Health and Human Services, Office of Disease

Prevention and Health Promotion

Curtis Mettlin Roswell Park Cancer Institute

James E. Montie Department of Urology, School of Medicine, Wayne State University

Alfred I. Neugut School of Public Health, Columbia University

Paul Nutting Department of Family Medicine, Medical School, University of Colorado

Gilbert Omenn School of Public Health and Community Medicine, University of Washington

Kenneth Pienta Michigan Cancer Foundation, Prentis Comprehensive Cancer Center

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OTA wishes to thank

the individuals and

organizations listed

here for their

assistance. These

individuals and

organizations do not

necessarily

approve,

disapprove, or

endorse this

background paper.

OTA assumes full

responsibility for the

background paper

and the accuracy of

its contents.
vi

Arnold L. Potosky National Cancer Institute

Paul F. Schellhammer Eastern Virginia Graduate School

Kit Simpson Department of Health Policy and Administration, School of Public Health, University

of North Carolina

Bo Standaert Provincial Instituut voor Hygiene, Antwerp, Belgium

James Talcott Dana-Farber Cancer Institute

Lucy Thelheimer American Association of Retired Persons

Patrick Walsh Johns Hopkins Hospital

Kevin Weiss George Washington University Medical Center

Willet F. Whitmore Memorial Sloan-Kettering Cancer Center

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vii

Abbreviations

ACS American Cancer Society

ACS-NPCDP American Cancer Society National Prostate Cancer Detection Project

AMA American Medical Association

AUA American Urological Association

BPH benign prostatic hyperplasia

CA cancer

CDC Centers for Disease Control and Prevention

CI confidence interval

CPT-4 Current Procedural Terminology, 4th Edition

CT computerized tomography

DRE digital rectal examination

DRG diagnosis-related group

FDA Food and Drug Administration

HCFA Health Care Financing Administration

HMO health maintenance organization

HT hormonal therapy

LY life-years

MRI magnetic resonance imaging

ng/mL nanograms per milliliter

NPV negative predictive value

PC prostate cancer

PCS Patterns of Care Studies

PDQ Physicians Data Query

PIVOT Prostate Cancer Intervention Versus Observation Trial

PL pelvic lymph node dissection (metastasis)

PLCO Prostate, Lung, Colorectal, and Ovarian Screening Trial

pPSA predicted prostate-specific antigen

PPV positive predictive value

PSA prostate-specific antigen

PSAD prostate-specific antigen density

RBRVS resource-based relative value scale

RCT randomized controlled trial

RPX radical prostatectomy

RT radiation therapy

RTOG Radiation Therapy Oncology Group

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viii

TNM tumor-node-metastasis

TRNB transrectal needle biopsy (of the prostate)

TRUS transurethral ultrasound

TURP transrectal resection of the prostate

TX treatment

UCR usual, customary, and reasonable

VACURG Veterans Administration Cooperative Urologic Research Group

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ix

Contents

Chapter One 1 SUMMARY

1 Key Findings

3 Prostate Cancer in Older Men

3 Technologies to Detect Prostate Cancer

5 The Effectiveness of Treatment

7 Benefits, Risks, and Costs of Screening

9 Research to Resolve Uncertainties

Chapter Two 11 PROSTATE CANCER IN OLDER MEN

11 Screening Versus Diagnosis

12 Rationale for Early Detection and Treatment

13 Special Issues in Screening Medicare-Age Men

14 Conflicting-Guidelines on Early Detection

15 Basic Biology of Prostate Cancer

16 Risk Factors for Prostate Cancer

18 The Prevalence of Prostate Cancer

18 Prostate Cancer Mortality

Chapter Three 21 TECHNOLOGIES TO DETECT PROSTATE CANCER

23 Digital Rectal Examination

24 Prostate-Specific Antigen

28 Combination of DRE and PSA

28 Followup Testing

30 Screening the Medicare Population

Chapter Four 33 TREATING PROSTATE CANCER

33 Strategies to Determine Cancer Stage

34 The Effectiveness of Treatment

41 Followup Treatment after Curative Therapy

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Chapter Five 43 BENEFITS, RISKS, AND COSTS OF SCREENING

44 Modeling the Health Outcomes of Screening

58 Modeling the Cost-Effectiveness of One-Time Screening

67 Implications for Medicare

69 APPENDIXES

69 Appendix A: 

Derivation of Prostate Cancer Prevalence by Age and Tumor Volume

71 Appendix B: 

Methods Used to Estimate Likelihoods of Cancer for Particular DRE and PSA

Results

73 Appendix C: 

Studies of Digital Rectal Examination for Prostate Cancer Screening

81 Appendix D: 

Studies of Prostate-Specific Antigen for Prostate Cancer Screening

and Early Detection

87 Appendix E: 

Studies of Repeat/Serial Prostate-Specific Antigen Testing Yield for

Prostate Cancer Screening and Early Detection

91 Appendix F: 

Studies of Transrectal Ultrasound for Prostate Cancer Screening and

Early Detection

97 Appendix G: 

Methods for Estimating the Medicare Costs of Resources Used

in Detection and Care of Prostate Cancer

107 Appendix H: 

Current Research Efforts To Resolve the Effectiveness of Prostate Cancer

Screening and Treatment

109 REFERENCES

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CHAPTER

1

Summary1

rostate cancer is a common and serious malignancy among Medicare-age men.1 In

1995, 244,000 new cases and 40,400 deaths

are anticipated from this disease; men age 65

and older bear most of the burden of illness.

In recent years, the prostate cancer diagnosis rate has increased dramatically, with a slower increase in age-specific mortality. At least in part, the increasing incidence

undoubtedly reflects more aggressive efforts at early

detection of prostate cancer, particularly through the use

of a new blood test, prostate-specific antigen (PSA).

This background paper examines the implications

of a potential Medicare benefit to cover prostate cancer

screening using a combination of the PSA and digital

rectal examination (DRE), a time-honored test performed in the physician’s office. 

KEY FINDINGS

The Office of Technology Assessment (OTA) concludes that research has not yet been completed to determine whether systematic, early screening for prostate cancer extends lives. The evidence of benefit for

other preventive services already covered by Medicare

(e.g., breast and cervical cancer screening, influenza and

pneumoccocal vaccines) is substantially more developed and stronger than for prostate cancer screening. Because scientific knowledge is limited, but the consequences of prostate cancer and its treatment are

serious, an informed and reasonable patient could

equally well decide to have screening or forgo it.

Hence, each patient, in consultation with his physician,

must use his own values to weigh the potential benefits

of screening against the risks of incontinence, impotence, and other adverse outcomes that may result from

treating cancers uncovered by screening.

Given the state of current knowledge about prostate cancer, it may be reasonable for Medicare to consider reimbursement of the screening test. Reimbursement could be seen as ensuring that

out-of-pocket screening expenses (however small) not

1The literature review and quantitative analyses discussed in this background paper are drawn from a paper prepared under contract for OTA (27). OTA’s analysis

also benefited from another contract paper that reviewed the epidemiology of prostate cancer in the United States (277), and a third contract paper that provided

the estimates of resources used and costs associated with prostate cancer screening and treatment for Medicare-age men in the United States (121). However, the

conclusions and, in some cases, the analysis are solely those of OTA and do not represent those of the authors of these contract papers.

Chapter 1 is a summary of the detailed literature reviews and quantitative analyses that follow in the subsequent chapters. References to support statements in

this chapter are noted in the relevant sections of the chapters. The structure of this chapter closely parallels the organization of the remainder of the document.
2 COSTS AND EFFECTIVENESS OF PROSTATE CANCER SCREENING IN ELDERLY MEN

impede well-informed discussion and decisionmaking between physician and patient. Such a Medicare

screening benefit could be unrestricted as are similar

benefits for cervical and breast cancer screening. However, an unrestricted, permanent benefit might imply

that science actually has established the benefit of early

detection. An alternative would be to offer screening on

a temporary basis subject to reconsideration as evidence

from clinical trials about the effectiveness of screening

and treatment becomes available. Such a benefit could

also be coupled with efforts by the federal government

to involve as many patients as possible in effectiveness

research and to ensure patients and physicians are well

informed about potential benefits and risks of treating

cancers discovered by screening.

The technical analysis in this background paper

shows that in terms of the expected cost per life-year

saved, prostate cancer screening could indeed be as costeffective as other disease screening services already covered by Medicare. However, this conclusion is extremely sensitive to assumptions about: 1) the effectiveness of

treating prostate cancer, and 2) the rate at which untreated cancers spread to other parts of the body and ultimately cause death. Relatively small changes in these

assumptions make the same prostate cancer screening

benefit appear very expensive without any health benefit, and the true values for these assumptions are unknown to medical scientists due to the lack of appropriate research noted above. As also indicated above,

treatment of detected cancers would result in complications including death, substantial rates of impotence and

incontinence, and heart disease.

Why Might Screening Not Be Beneficial?

Intuitively, one would expect that early detection efforts should find more prostate cancers before they have

spread outside of the prostate gland, which should in turn

lead to more prostate cancer cures with aggressive treatment. Indeed, evidence shows that patients with cancers

discovered by screening tend to do well. Furthermore,

most men who have a positive PSA test followed by surgery that reveals the cancer has not yet spread beyond the

prostate gland strongly believe that early detection and

treatment have saved their lives. One of the factors that

may act to strengthen this belief is the fairly large number of men who become impotent or incontinent as a result of surgery. The belief that surgery was necessary to

avoid a fatal illness could be an important means of accepting these troublesome symptoms.

However, it is not clear that these outcomes are the

result of screening and subsequent treatment. Good outcomes may reflect the fact that screening advances the

point of diagnosis, without changing the destined course

of the cancer (lead-time bias); or that screening may

preferentially find slower-growing cancers already destined to do well (length bias). Because of these biases,

early diagnosis would appear to improve survival, even

if treatment were worthless (or harmful).

These problems are compounded by the fact that in

most cases, prostate cancer is a slow-growing disease.

Most men whose localized prostate cancers are discovered by screening might never suffer any effects of their

disease, ultimately dying from some other cause. Hence,

even if treatment is ultimately proven to be beneficial for

men with very aggressive localized prostate cancers, it

would still be unnecessary for most. The dilemma for policymakers arises from the fact that current diagnostic

measures are not sufficient to determine a priori and precisely which cancers are likely to cause harm. Were there

no risks or costs associated with treatment, it might more

clearly make sense to treat all cancers found. However,

in light of these treatment risks and the current uncertainty about treatment benefit, the decision about screening

and any subsequent treatment must currently rest with

the patient in consultation with his physician. As our un
CHAPTER 1SUMMARY 3

derstanding of this disease and of our ability to intervene

in it grows, science will be able to provide more definitive guidance to both clinical and policy decisions.

PROSTATE CANCER IN OLDER MEN

Screening Recommendations

While the American Cancer Society (ACS) and the

American Urological Association recommend adding

PSA to annual digital rectal examination for early detection of prostate cancer, the U.S. Preventive Services

Task Force and Canadian Task Force on the Periodic

Health Examination, citing lack of evidence of benefit

from controlled studies, do not.2 All of these groups

agree that research has yet to document that on a population-wide basis, PSA testing reduces the risk of dying

from prostate cancer. The differences in recommendations reflect different philosophies about whether clinical medicine and public policy should encourage the use

of potentially beneficial, but unproven, cancer prevention strategies before controlled studies definitively establish that they do more good than harm.

Prostate Cancer Biology and Risk Factors

The prostate is a golf-ball-sized gland that helps

produce semen, the fluid ejaculated with sperm. It is

found below the bladder and surrounds the urethra

through which urine passes as it is voided. Most early

prostate cancers seem to be slow-growing, with doubling

times of two years or more. The future course of prostate

cancer is predicted by tumor grade (the extent to which

cancerous cells are different from normal cells) and

stage (extent of cancer spread); patient age does not

seem to influence the rate at which tumors spread and become life-threatening. Determining the stage of prostate

cancer without surgery is unreliable.3 Once prostate cancer spreads to bones or other organs, hormonal treatments can only achieve temporary remissions often

measured in months.4

Those most at risk for prostate cancer are African

American men and men with a family history of prostate

cancer. Recently, prior vasectomy and a high-fat diet

have been proposed as possible additional risk factors.

In addition, the probability of harboring an asymptomatic prostate cancer increases as men age: about 22 percent

of men in their 60s and 39 percent of men in their 70s.

For those cancers greater than 0.5 mL in volume (which

are more likely to cause future problems), the age-specific probabilities of having prostate cancer are about 9

and 15 percent, respectively.

TECHNOLOGIES TO DETECT

PROSTATE CANCER

DRE and PSA are both feasible tests for early detection of prostate cancer. Transrectal ultrasound (TRUS)

and transrectal needle biopsy (TRNB) are followup tests

used to further investigate suspicious results on DRE or

2The National Cancer Institute (NCI) previously recommended that men over age 50 receive a digital rectal examination, but not a prostate-specific antigen test.

Recently, however, NCI has decided not to make any recommendations concerning cancer screening, deferring instead to the evidence-based policy guideline

development processes used by the U.S. Preventive Services Task Force and the U.S. Agency for Health Care Policy and Research (AHCPR). AHCPR has not issued

any guidelines concerning prostate cancer screening. NCI does summarize evidence on prostate screening effectiveness in its Physicians Data Query (PDQ) database, noting the existence of only one, negative case-control study of DRE and the lack of evidence from well-controlled research concerning the use of PSA for

early detection (199). The College of American Pathologists recommends that PSA not be used for screening among the general asymptomatic male population,

reserving its use in cases where prostate cancer is suspected (200).The American Association of Family Physicians and American Society of Preventive Oncologists

currently have no guidelines or recommendations concerning prostate cancer screening (31, 43). The College of American Physicians is currently developing such

guidelines (26).

3Many cancers felt to be confined to the prostate preoperatively will be found to have already spread through the prostate capsule once surgery is performed.

4However, a significant minority (about 15 percent) of men with advanced prostate cancer have long-term survival measured in years (199).
4 COSTS AND EFFECTIVENESS OF PROSTATE CANCER SCREENING IN ELDERLY MEN

PSA. The true false-negative rates5 of DRE and PSA are

unknown, because studies have generally not determined what proportion of men with nonsuspicious DRE

and PSA results in fact harbor cancer.

Digital Rectal Examinations

Among older men, digital rectal examinations are

less likely to detect small and probably insignificant cancers than PSA, but it is more likely to detect cancers that

have already spread beyond the prostate. Available data

indicate that a suspicious DRE raises the likelihood that

a patient has intracapsular (and possibly curable) prostate cancer 1 1/2- to 2-fold above the average risk faced

by men of the same age. In a recent large study, DRE was

suspicious in 15 percent of male volunteers over age 50,

and 21 percent of men with a suspicious DRE had prostate cancer at biopsy. However, these high percentages

were dependent upon a low threshold for considering the

DRE abnormal, and upon the performance of multiple

biopsies on volunteers with a suspicious DRE. In fact,

about half the cancers found by TRNB in this study were

found elsewhere in the prostate than the palpably suspicious area.6

Prostate-Specific Antigen

The prostate-specific antigen is a protein produced

by prostate tissue and measurable in blood. It can be elevated in men both with and without prostate cancer, and

the level at which a PSA measurement should be considered suspicious is controversial. On the two most commonly used assays, levels above 4 nanograms per milliliter (ng/mL) of blood are often considered abnormal.7

Available data suggest that a PSA elevation from 4.1 to

10.0 nanograms per milliliter (ng/mL) of blood raises the

likelihood that a man harbors an intracapsular prostate

cancer one and one-half to threefold above the average

risk for men his age. Methods to improve the ability of

PSA to discriminate between men with and without cancer are under active investigation; at present, there is no

consensus on an optimal method. PSA does a particularly poor job at separating men with benign prostatic hyperplasia (BPH), a common nonfatal disease of aging,

from men with intracapsular, possibly curable prostate

cancer.

Combined DRE and PSA Screening

What is gained by doing both DRE and PSA rather

than just DRE? Research indicates that by adding PSA

testing to DRE in a one-time screening program, and by

adopting an aggressive strategy of systematic prostatic

biopsies for suspicious results on either test, prostate

cancers can be found in about 4.2 percent of men age 65

(as opposed to about 2.4 percent with DRE alone), at a

cost of performing multiple biopsies in 19 percent. At

age 75, cancer would be found in about 7.2 percent of

men (as opposed to 3.5 percent with DRE alone), with

27 percent of men requiring biopsy. Some of the cancers

that are found in screening programs are discovered because of the high percentage of men who undergo multiple systematic biopsies, rather than because of the discriminating capacity of the tests themselves.

5The false-negative rate is the probability that someone with a negative screening test actually has prostate cancer. See box 3-1 for fuller description of concepts

used to describe the accuracy of screening technologies.

6Given the inaccuracies of DRE (and PSA) along with these results, screening may behave something like a lottery in determining who receives the more accurate

detection technology, TRNB.

7Alternatively, some experts recommend age-specific reference ranges, which take into account the rise in PSA levels seen with aging. For example, one study

suggests a PSA should be considered abnormal if it is above 4.5 ng/mL for men in their 60s or 6.5 ng/mL for men in their 70s.
CHAPTER 1SUMMARY 5

Followup Testing

TRUS is not accurate enough to serve as a primary

screening test. TRNB is the test usually used to confirm

whether cancer is present, and TRUS is often used to

help direct where tissue samples are taken during biopsy.

Many experts now recommend that patients with a suspicious DRE or PSA undergo multiple (four to six) prostatic biopsies (usually done in a single session). TRNB is

uncomfortable and has a low but finite risk of bleeding

and infection.

THE EFFECTIVENESS OF TREATMENT

For the early detection of prostate cancer to improve

outcomes, treatment for cancers found at screening

needs to be effective. In other words, knowledge of the

presence of cancer will not save any lives unless treating

those cancers makes a difference. There is considerable

controversy regarding optimal treatment for cancer that

does not appear to have spread beyond the prostate

gland. Urologists generally argue that radical prostatectomy, a procedure to remove the entire prostate gland, results in the best outcomes for these men. As a result, rates

of this procedure have risen dramatically in recent years,

in response to the precipitous increase in diagnosis of

early prostate cancer. However, expectant management

(also called “watchful waiting”), in which the clinician

treats symptoms and complications without attempting

a cure, and radiation therapy are two other commonly

used treatment strategies. Prostate cancer management

tends to be more conservative in Western European

countries than in the United States. No trial that shows

which of the various treatment strategies saves the most

lives (if any) has yet been completed.

Controversy about treatment effectiveness exists

because of a lack of well-controlled studies comparing

the main strategies for managing localized prostate cancer. To date, the only completed studies are based on observational studies. To the extent that any of these studies

show that patients receiving a particular treatment option do better than those receiving another treatment,

one cannot definitively conclude that the observed result

was due only to treatment and not due to other differences between the patient groups.

Determining Cancer Stage

Before men begin treatment for a prostate cancer

discovered by DRE or PSA, they would often undergo

some staging tests to help determine the best treatment

strategy. Patients with cancers that have already spread

outside the capsule of the prostate gland, and particularly

cancers that have spread to lymph nodes in the pelvic

area or to bones are much less likely to be helped by

aggressive treatments with curative intent. Computerized tomography (CT) or magnetic resonance imaging

(MRI) scans and surgical examination of pelvic lymph

glands, commonly employed to determine if the cancer

has spread, are not particularly accurate for this purpose.

As a result, even if a CT or MRI scan suggests spread,

clinicians often proceed to treatment out of fear of withholding a potential cure. Despite some substantial misclassification rates, recent mathematical models designed to predict cancer spread suggest clinicians could

use some staging tests more sparingly.8

Expectant Management

Expectant management is a strategy of reserving

treatment for symptoms or complications related to

8For example, some patients with prostate cancers discovered by screening have a low enough risk of metastasis that they do not need bone scans or surgical

removal of their pelvic lymph glands before proceeding with curative treatment.
6 COSTS AND EFFECTIVENESS OF PROSTATE CANCER SCREENING IN ELDERLY MEN

prostate cancer, without necessarily attempting a cure. It

is commonly used in Western Europe, and until recently,

for many men with cancers found incidentally during

surgery for BPH. Men treated expectantly risk developing symptoms due to local progression of their cancer

(such as bladder outflow obstruction) or from spread of

the prostate cancer to other parts of the body (which may

lead to death).9 The prognosis for men with clinically localized prostate cancer depends on the aggressiveness of

the cancer, particularly its grade. A recent synthesis of

data from several studies of expectant management suggests a 10-year cancer-specific death rate of 13 percent

for men with well and moderately differentiated prostate

cancer (the most common types found by early detection

with DRE and PSA) compared with a 66 percent death

rate for men with poorly differentiated cancers.10

Radiation Therapy

Radiation therapy for prostate cancer, most commonly delivered as external beam x-irradiation, attempts to deliver a maximal dose of radiation to the tumor while minimizing the side effects from exposure to

other, nearby radiation-sensitive tissues. Patients usually

receive five weekday treatments over six or seven weeks

(i.e. 30 to 35 treatments total). Although much recent literature has focused on surgical treatment of prostate cancer (radical prostatectomy), as late as 1990 radiotherapy

was the most common treatment administered for every

stage of prostate cancer in the United States.11

The comparative effectiveness of radiotherapy versus radical prostatectomy or expectant management has

not been well studied. The medical literature suggests

worse outcomes for patients with localized prostate cancer treated with radiotherapy compared with these other

two strategies, but results are confounded by radiotherapy series including more older patients whose tumors

have less favorable prognostic characteristics. While

urologists have raised concerns about the high proportion of patients treated with radiotherapy having subsequently positive biopsies for cancer or rising PSA levels

post-treatment, selected series suggest very good outcomes in terms of rate of future metastatic disease and

cancer death. Although radiation therapy is more likely

to result in bowel injury than is radical prostatectomy,

other side effects are less common than those associated

with prostatectomy.

Radical Prostatectomy

Radical prostatectomy entails removing the entire

prostate with its fascial coverings and the seminal vesicles. More aggressive early detection efforts for prostate

cancer in recent years have been accompanied by precipitous rises in population-based rates of radical prostatectomy. Recent modifications in surgical technique, resulting in an “anatomic” radical prostatectomy, have

reduced the risk of surgical complications in some centers. While some men with prostate cancer treated surgically have done extremely well, the benefit of radical

prostatectomy is unclear; only one controlled study has

compared its outcomes against other treatment strategies. This single randomized trial, which showed no difference in mortality between radical prostatectomy and

9Obstructions of the bladder or urinary tract may require surgery, and distant spread of the cancer is usually treated with hormonal therapy (”androgen deprivation”).

10The data did not stratify men by age, but the estimates do adjust for other potential causes of death that do vary by age. The mean age in the sample was 70.

Age was not predictive of cancer-specific survival in this study.

11Recent data suggest that this trend reversed in 1991 with radical prostatectomy become the more common treatment strategy.
CHAPTER 1SUMMARY 7

expectant management, was too small to detect a clinically important benefit from surgery, if it really existed.

The risks of radical prostatectomy include operative

death, perioperative medical complications, incontinence, impotence, and urethral stricture formation. In a

recent survey of a random sample of all Medicare patients who underwent this procedure in the United States

between 1988 and 1990, 31 percent of men were wearing

pads to help deal with wetness, 60 percent reported no

full or partial erections since the surgery, and 20 percent

indicated they had been treated for a stricture. The attributable12 30-day postsurgical death rate was 0.6 percent.

Followup Treatment

Men whose initial cancer has spread to other parts

of the body, or men who are found to have cancer that has

spread postoperatively can be treated with hormonal

(androgen deprivation13) therapy. After initial treatment

by radical prostatectomy, clinicians also often consider

adjuvant radiation or androgen deprivation therapy for

men considered at higher risk of harboring residual cancer. Cancers that have spread to other parts of the body

tend to be responsive initially to hormonal treatment, but

then become unresponsive (“refractory”). There are no

data from well-controlled studies that indicate that any

adjuvant therapies improve survival.

BENEFITS, RISKS, AND COSTS

OF SCREENING

In the absence of controlled studies documenting

that early detection of prostate cancer does more good

than harm, this analysis used a quantitative decision

model to estimate risks, benefits, and costs of an early

detection program under different sets of assumptions.

It examined the implications of an illustrative, onetime screening program for three cohorts of 100,000

men, ages 65, 70, and 75, respectively.

Realistically, a Medicare benefit would most likely

cover periodic screening, for example, a DRE and PSA

every year as the ACS currently recommends, or every

two or three years as Medicare currently does for breast

and cervical cancer screening respectively. Understanding the true effects of an actual Medicare benefit would

also require accounting for the fact that some men would

have already received screening before their 65th birthday. However, as this analysis demonstrates, current understanding does not allow a definitive assessment of the

cost-effectiveness of even a one-time benefit with its relatively simplified set of assumptions, much less a more

complex, but realistic periodic benefit. The uncertainty

concerning treatment effectiveness and the true rate at

which smaller cancers eventually spread and cause death

overwhelm other assumptions in the model.

Modeling an Illustrative Screening Benefit

The model employs a quantitative tool known as a

Markov process14 to calculate what happens to men in

each of the three age groups examined once they are

screened for prostate cancer. It initially incorporates

many assumptions favorable to early detection and treatment, including: 1) relatively high metastatic rates (that

predict a higher-than-actually-observed lifetime proba12The “attributable” death rate is the total death rate minus deaths that would have been expected to occur during the 30 days even if patients had not received

surgery.

13Clinicians can accomplish androgen deprivation through drugs or by orchiectomy (surgical removal of the testes).

14Chapter 5 provides more detail about the model and Markov processes.
8 COSTS AND EFFECTIVENESS OF PROSTATE CANCER SCREENING IN ELDERLY MEN

bility of prostate cancer death in the cohorts),15 and 2)

a 100-percent cure rate by surgery for cancers that have

not spread beyond the prostate (resulting in overall cure

rates of 97, 70, and 56 percent for all well-, moderately,

and poorly differentiated cancers respectively). The

analysis estimates the impacts of a one-time screening

program under these assumptions, and then examines

how relaxing the favorable assumptions about treatment

efficacy changes the results.

Health Effects of Screening

Using the baseline assumptions, the model predicts

a very favorable mix of potentially curable cancers

would be discovered by early detection efforts with DRE

and PSA. A large number of prostate biopsies would be

performed as a result of this program; a much higher proportion of patients would require further invasive evaluation as a result of their initial testing than for other commonly used cancer screening strategies, such as guaiac

testing for colorectal cancer or mammography for breast

cancer. The proportion of men screened who undergo

biopsy would range from 19 percent at age 65 to 27 percent at age 75. Treating cases of clinically localized

prostate cancer with radical prostatectomy would render

about 300 out of every 100,000 men screened incontinent, about 1,400 to 1,600 out of every 100,000 men

screened impotent, and an additional 400 to 500 out every 100,000 both incontinent and impotent. About

another 20 out of every 100,000 screenees would die

from biopsy or treatment complications.

However, at the same time, early detection might

save as many as 4,353 life-years in the 65-year-old cohort of 100,000 men, 2,774 life-years in the 70-year-old

cohort, and 1,415 life-years in the 75-year-old cohort.16

The benefits diminish considerably as the assumption of

relatively high rates of metastasis and treatment effectiveness are relaxed.

Cost-Effectiveness

The analysis also estimates the cost-effectiveness of

this illustrative, one-time DRE/PSA screening benefit.

Adopting a Medicare perspective to estimate costs

associated with screening and subsequent treatment, the

model incorporates charges for physician services using

the 1992 Medicare fee schedule and appropriate diagnosis related group (DRG) reimbursements for hospital services. The analysis discounts both future costs and health

benefits at 5 percent annually.

The costs per year of life saved with the favorable

assumptions (compared to doing no screening at all) was

competitive with other commonly-used early detection

maneuvers ranging from $14,200 per year of life saved

at age 65 to $51,290 per year of life saved at age 75.

However, these results are extremely sensitive to the assumptions made about the effectiveness of treatment and

the rate at which intracapsular cancers spread and cause

death. Reducing the estimates of future risk of metastases modestly to levels found elsewhere in the published

literature and assuming treatment cures only half of all

intracapsular cancers greater than 0.5 mL in volume substantially raises the estimated costs per year of life saved;

under these assumptions, these estimates would range

from $94,458 at age 65 to $506,909 at age 75.

As indicated earlier, current scientific evidence is

insufficient to know the true risk of metastasis or whether treatment actually enhances survival, and hence,

15This includes making the assumption that metastatic rates for intracapsular (and possibly curable) cancers were as high as metastatic rates for cancers that have

spread outside the prostate.

16These results do not discount future health benefits or adjust for quality of life.
CHAPTER 1SUMMARY 9

whether or not prostate screening (even under the simplified assumptions needed to analyze a one-time program)

is similar to other early detection programs for Medicare

in its cost per life-year saved, or substantially more expensive. Regardless of whether screening and subsequent treatment extend life and regardless of the cost of

any such health benefit, it is certain that populationbased screening would subject men to the risks of impotence, incontinence, and other health problems caused

by screening and treatment. 

RESEARCH TO RESOLVE

UNCERTAINTIES

Very little data from controlled studies are available

to determine whether the benefits of early detection and

treatment of prostate cancer outweigh the risks. One

case-control study suggested that digital rectal exams do

not reduce the risk of developing late-stage prostate cancer. And one trial of inadequate size showed no difference in the survival of men treated with expectant management versus radical prostatectomy. However,

researchers are now initiating a number of well-designed

randomized trials of adequate size to address this issue.

Trials comparing expectant management versus aggressive treatment with radical prostatectomy or radiation

therapy for men with known clinically localized prostate

cancer are underway or about to start in Scandinavia, the

United Kingdom, and the United States. Trials comparing intensive screening with DRE and PSA versus no

screening or “usual care” are being initiated in both Europe and the United States. Unfortunately, from the perspective of policymakers, the relatively indolent nature

of many prostate cancers means that 10 to 15 years may

be required to see enough prostate cancer deaths among

men in these studies to obtain adequate comparisons of

the strategies being tested.

This analysis of the estimated risks, benefits, and

costs of early detection of prostate cancer highlights the

uncertainty surrounding this topic. Any decision in the

shortterm about whether Medicare should cover (and,

hence, encourage) prostate cancer screening must weigh

the resources required and the known complications that

will result from screening and treatment against an uncertain health benefit.
CHAPTER

2

Prostate Cancer in Older Men

rostate cancer is a major health problem in

the United States. In 1995, 244,000 new

cases (up 44,000 from 1994) of prostate cancer and 40,400 deaths (up 2,400 from 1994)

due to this disease are expected among all

American men (199). However, most cases of prostate

cancer and deaths from the disease occur in older men.

Of the 32,378 U.S. prostate cancer deaths observed in

1990, 12,423 (38 percent) occurred in men ages 55 to 74

and 19,622 (61 percent) in men ages 75 and above. See

table 2-1 for a comparison of the number of prostate cancer deaths with other causes of death for older men (40).

The lifelong probability of dying of prostate cancer for

men in the United States is 2.5 to 3 percent (308, 314).1

Patients who are diagnosed because they report

symptoms (such as bone pain or difficulty urinating)

generally have cancer spread outside of the prostate

gland, and are incurable. Although these patients may

initially show some improvement through treatment,

these responses often do not last, and followup treatments have been disappointing (131).

Given this burden of illness and the difficulty in

treating symptomatic disease, early detection using a

simple clinical procedure called digital rectal examination (DRE) and a blood test called prostate-specific antigen (PSA) measurement would seem to be a commonsense strategy for reducing the morbidity and mortality

from prostate cancer in the United States. This background paper examines the validity of this conclusion.

This chapter gives an overview of the rationale for

screening and provides background on the nature of

prostate cancer. Chapter 3 discusses technologies for the

screening and diagnosis of prostate cancer, and chapter

4 reviews evidence on the effectiveness of treating the

disease. Chapter 5 presents some illustrative analyses of

the potential costs and effectiveness of a one-time prostate cancer screening program and considers its implications for a potential Medicare screening benefit.

SCREENING VERSUS DIAGNOSIS

Before proceeding, it is useful to consider what is

meant by the term screening and how it differs from

diagnosis. While screening is an attempt to identify a

condition in the absence of symptoms, diagnosis is performed in response to a patient’s symptoms. This distinction has important public policy implications since the

1By comparison, in 1985 the lifelong probability of dying of other cancers were: 3.37 percent for breast cancer (among women), 0.96 percent for uterine cancer

(among women), 2.8 percent for colorectal cancer, and 5.42 percent for lung cancer (308, 345).
12 COSTS AND EFFECTIVENESS OF PROSTATE CANCER SCREENING IN ELDERLY MEN

TABLE 2-1: NUMBERS OF DEATHS BY LEADING CAUSES, U.S. MEN AGES 55 TO 74 AND 75+, 1990

Ages 55 to 74 Ages 75+

All causes 430,713 All causes 447,303

Heart disease 152,323 Heart disease 173,558

Cancer (other than prostate) 129,364 Cancer (other than prostate) 75,117

Chronic obstructive lung disease 21,964 Cerebrovascular disease 33,594

Cerebrovascular disease 18,602 Chronic obstructive lung disease 25,580

Prostate cancer 12,423 Pneumonia, influenza 24,897

Prostate cancer 19,622

SOURCE: Office of Technology Assessment, 1995. Data from C.C. Boring, T.S. Squires, Tong, T., et al. “Cancer Statistics, 1994,” CA-A Cancer Journal for Clinicians

(44):7-26, 1994.

federal Medicare program that provides health insurance

to almost all Americans over age 65 pays for outpatient

diagnosis, but it only pays for limited types of disease

screening. Currently, prostate cancer screening is not

among the services covered by Medicare. In this bakground paper, the use of prostate cancer detection

technologies in mass screening programs as well as by

clinicians in their offices are considered together as “early detection.”2

RATIONALE FOR EARLY DETECTION

AND TREATMENT

Theoretically, surgical removal of the entire prostate (radical prostatectomy) or radiation therapy (curative radiotherapy) should cure prostate cancer that is

confined within the prostate capsule. The survival probabilities for patients with early-stage prostate cancer are

clearly and dramatically better than for patients with

late-stage disease, such as is commonly seen in the absence of screening. Screening tests are currently available that result in the detection of disease that is more

often localized to the prostatic capsule than would be the

case among men presenting with symptoms. Therefore,

it is tempting to conclude that screening for prostate cancer will result in the curative treatment of pre-symptomatic cancers destined to cause future morbidity and

mortality, reducing the burden of illness among older

men (95, 295). However, this hypothesis has not yet been

tested in well-controlled scientific research and, despite

its attractiveness, might not be correct.

Why might screening fail to result in reducing prostate cancer mortality and morbidity? These potential

problems are both general to screening for any cancer,

and relatively specific to prostate cancer. Data from uncontrolled screening studies that report the probability of

detected cancers progressing to more serious stages

(stage shift data) do not necessarily predict long-term reductions in cancer mortality. This is because of “leadtime bias,” the phenomenon of a screening test finding

cancers earlier in their courses without changing their ultimate outcomes, and because of “length bias,” in which

a test may preferentially find low-risk, slow-growing

2 Some experts have suggested that, since many men over age 50 have at least some lower urinary tract voiding symptoms, most office-based DREs and PSA tests are

done for diagnosis, rather than case finding (361). However, despite traditional wisdom to the contrary, recent screening studies have not suggested that lower urinary

tract symptomatology consistent with benign prostatic hyperplasia (prostatism) confers a higher risk for prostate cancer (72, 235). If symptoms of prostatism are indeed

unrelated to the presence or absence of prostate cancer, looking for cancers in these men would be considered part of early detection as well.
CHAPTER 2PROSTATE CANCER IN OLDER MEN 13

cancers (81, 136). As described by Sackett and colleagues (292), on the basis of stage shift data, “...early

diagnosis will always appear to improve survival, even

when therapy is worthless!”

Prostate cancer screening, in particular, presents

some additional conceptual challenges. Prostate cancers

are commonly discovered by chance at autopsy and during a surgical procedure called transrectal resection of

the prostate (TURP) performed for symptoms of a common, noncancerous enlargement of the prostate, benign

prostatic hyperplasia (BPH). Many of these cancers

would never have caused any symptoms, and would not

place the patient at increased future risk of more serious

cancer. Advocates of screening believe that the screening tests currently available for prostate cancer cannot

generally detect these small, harmless cancers (12, 295);

however, aggressive strategies of performing systematic

biopsies of the prostate following suspicious screening

tests will increase their detection (338). 

The true, untreated, natural history of cancers discovered by screening (i.e., whether they would ultimately cause any harm to the patient) is unknown. Because

many prostate cancers grow relatively slowly, the true

benefit of treating cancers detected by screening remains

unknown. The fact that many prostate cancers, even

those detected by screening, have already spread

through the prostate capsule, further dilute any benefit

of screening. Furthermore, according to one theory

drawn from observations of breast cancer (and untested

for prostate cancer), prostate cancers destined to cause

mortality may actually spread outside the prostate early

on, even when they appear to be confined to the prostate

upon examination of tissue removed in a prostatectomy

(17, 240). And finally, aggressive curative treatment of

prostate cancer carries risk itself; these risks, which include post-operative heart disease, impotence, incontiTABLE 2-2: LIFE EXPECTANCY FOR U.S. MEN BY AGE 

AND RACE (Years)

Life expectancy

African American

Age White men men

50 26.7 22.5

55 22.5 19.0

60 18.7 15.9

65 15.2 13.2

70 12.1 10.7

75 9.4 8.6

80 7.1 6.7

85 5.2 5.0

SOURCE: U.S. Bureau of the Census, Statistical Abstract of the United States:

1993, 113th Ed.,) (Washington, DC: U.S. Government Printing Office, 1993).

nence, and a small chance of surgical death, must be

weighed against evidence of reductions in mortality to

make screening worthwhile.

SPECIAL ISSUES IN SCREENING

MEDICARE-AGE MEN

This report focuses on screening Medicare-age

men, 65 and older. Because prostate cancer prevalence

and mortality increases substantially with age, Medicare

beneficiaries would appear especially likely to benefit

from screening (assuming treatment works). However,

these men also have a higher risk of dying from medical

problems other than prostate cancer, and they have fewer

years of life expectancy during which to reap the potential benefits of screening (see table 2-2). Furthermore,

some of the risks of aggressive prostate cancer treatment

also increase with age, making these men pay a higher

“price” for any expected benefit of screening. The difficulty of current screening technology in distinguishing

between potentially curable prostate cancer and the noncancerous condition BPH, whose prevalence increases
14 COSTS AND EFFECTIVENESS OF PROSTATE CANCER SCREENING IN ELDERLY MEN

with age, also reduces the value of screening.3 Finally,

older men are also at higher risk of harboring large cancers and cancers with a poor prognosis that have already

spread outside the prostate (233).

CONFLICTING GUIDELINES

ON EARLY DETECTION

At present, the American Cancer Society (ACS) and

the American Urological Association (AUA) recommend DRE and PSA determinations to evaluate the prostate gland for cancer starting at age 50 (age 40 for men

at increased risk), although ACS acknowledges that, “reduction in mortality from screening has not yet been documented” (11, 237). ACS recommends annual exams. In

addition, the American Medical Association (AMA)

recommends that PSA should be covered every three

years for men over age 50 as part of standard insurance

benefits package (10).

ACS and AUA do not specify a definite “stopping

age” for screening, although ACS recommendation acknowledges that, “generally, men with a life expectancy

of at least ten years after detection may benefit from examination.” These guidelines, which were adopted after

the introduction of PSA into usual urologic practice, are

consistent with recent published reviews that suggest

physicians reserve early detection and aggressive treatment for men with a life expectancy of more than ten

years (50, 204); in the United States, for men with average comorbidity, this threshold would come at about age

73. AMA recommends coverage of PSA testing up

through age 70 (10).

The 1993 U.S. Preventive Services Task Force update (352) and the 1991 Canadian Task Force on the Periodic Health Examination (57) found evidence insufficient to recommend for or against DRE, and fair

evidence to exclude PSA, from the periodic health examination. The College of American Pathologists recommends that PSA not be used for screening among the

general asymptomatic male population, reserving its use

for cases where prostate cancer is suspected (200).

The National Cancer Institute (NCI) used to recommend that men over age 50 receive a DRE, but not a PSA

test. Recently, however, NCI has decided not to make

any recommendations concerning cancer screening, deferring instead to the evidence-based policy guideline development processes used by the U.S. Preventive Services Task Force and the U.S. Agency for Health Care

Policy and Research (AHCPR) (199).4

Reasons for Conflicting Recommendations

In the absence of well-controlled studies that establish the risks and benefits of screening for prostate cancer, or even large, controlled trials that document the

benefit of aggressive curative treatment for cancer that

has not spread beyond the prostate, it is possible to interpret the nonexperimental data that do exist to support

any of these guidelines. However, differences in perspectives among policymakers, clinicians, and patients

also contribute to the current controversy about prostate

cancer screening. For example, Adami and colleagues

(2) recently concluded that, given the possibility that

early detection of prostate cancer does more harm than

3 According to one estimate, BPH is found in 40 percent of men over age 60 (133).

4 NCI does summarize evidence on prostate screening effectiveness in its Physicians Data Query (PDQ) database, noting the existence of only one, negative casecontrol study of DRE and the lack of evidence from well-controlled research concerning the use of PSA for early detection (199). AHCPR has not issued any guidelines

concerning prostate cancer screening. The American Association of Family Physicians and American Society of Preventive Oncologists currently have no guidelines

or recommendations concerning prostate cancer screening (31, 43). The College of American Physicians is currently developing such guidelines (26).
CHAPTER 2PROSTATE CANCER IN OLDER MEN 15

good, even a randomized trial of screening for prostate

cancer might be unethical.

From a policy perspective, some experts emphasize

an ethical imperative to avoid the harms of early detection efforts in general, and mass screening in particular,

unless there is definitive proof of a net benefit from clinical trials (34, 80, 167, 302, 322). Others emphasize the

need to do everything possible to lower the risk of cancer

until the results of those studies are available (12, 13, 68,

131, 217, 258). Sackett (291) has referred to the protagonists represented in these basic ideological disputes as

either advocates of the scientific method (”snails”), or

advocates of screening (“evangelists”). The former perspective is incorporated into sets of criteria used by

many groups for determining the net benefit of preventive maneuvers in general and cancer screening in particular, including the Canadian Task Force on the Periodic

Health Examination (56), the U.S. Preventive Services

Task Force (351), and the World Health Organization

(368). No matter what expert groups recommend for

populations, on the level of individual patients and clinicians, differences of opinion and variations in actual

practice will exist (219, 238, 247).

The rapid increase in medical care costs in recent

years has placed greater scrutiny on the effectiveness of

medical interventions. In the past, medical interventions

that seemed conceptually sound were often administered

until clinical trials proved they did not work (111). More

recently, the burden of proof for some interventions has

begun to shift to those who want to use the treatment,

suggesting that these interventions be withheld until

clinical trials establish that they work (112). Although

recommendations may also vary depending on whether

they consider the health care costs associated with early

FIGURE 2-1: CROSS-SECTIONAL ILLUSTRATION

OF NORMAL MALE PELVIC REGION

SOURCE: The American Prostate Society, Inc.

detection, none of the guidelines described above directly took these costs into account.

BASIC BIOLOGY OF

PROSTATE CANCER

The prostate is a golf-ball-sized gland whose primary function is the manufacture of semen, the fluid ejaculated with sperm. It is found below a man’s bladder and

surrounds the urethra through which urine passes on its

way from the bladder (see figure 2-1). Prostatic carcinoma (prostate cancer) is a relatively slow-growing malignancy, with the potential for spread related to both volume of the tumor and degree of cell differentiation (the

extent to which the cancerous cells are different from the

normal cells from which they arose),5 which themselves

are related.

5 The greater the differentiation, the less likely it is to spread and the better the prognosis for the patient.
16 COSTS AND EFFECTIVENESS OF PROSTATE CANCER SCREENING IN ELDERLY MEN

In careful studies of autopsy material, McNeal and

colleagues have documented that tumors less than

approximately 0.5 mL are commonly found among older

men, and are rarely associated with penetration of the

prostate capsule (called capsular penetration) (233).

Above 0.5 mL, penetration of the prostatic capsule begins to be seen, and overt metastases (spread of the cancer) begin to be seen with tumors above 1 mL, and particularly above 3 mL, along with more frequent capsular

penetration and invasion of the surrounding tissue. Older

patients have larger tumors, and larger tumors are more

likely to be less well differentiated. Clinically localized

cancers are estimated to have a doubling time of two

years or more (299, 325, 328). Based on epidemiologic

observations, Stamey and colleagues (328) doubt that

cancers less than 0.5 mL in volume are likely to cause

future morbidity and mortality given this long doubling

time; however, all large prostate cancers were undoubtedly small at some point.

Prostate cancers are described by tumor grade (the

extent of cell differentiation) and stage (how advanced

the cancer has become). In studies of the natural history

of prostate cancer, grade and stage are used to predict

malignant behavior. The most common grading system

is the Gleason score, which yields a sum of 2 to10 based

on the two most common patterns of cell differentiation

in the tissue sample. Tumors assigned scores of 2 to 4 are

considered “well differentiated”; 5 to 7, “moderately

differentiated”; and 8 to 10, “poorly differentiated.”

The two predominant staging systems for prostate

cancer are the Whitmore (A-D) system and the TumorNode-Metastasis (TNM) system (245).6 Table 2-3 describes the two predominant systems. Although increasing stages of prostate cancer generally indicate a poorer

prognosis, different stages can behave similarly (i.e.,

Stage T1b/A2 and T2/B1 (340).7 As will be discussed

later, clinicians’ attempts to stage patients’ cancers are

unreliable, and many cancers thought to be localized to

the prostate are found to be more advanced upon surgery.

In addition, the grade of a tumor evaluated from a biopsy

(a procedure for removing a small sample of tumor to determine if it is cancerous) may diverge from the grade determined from an examination of the surgically removed

prostate (7). These phenomena make it difficult to

compare the prognosis of prostate cancer patients staged

and treated by different methods.

RISK FACTORS FOR PROSTATE CANCER

The cause of prostate cancer is not known, although

evidence points to both genetics and environment as

having roles (62, 85, 273, 310):

 Age is the most important risk factor, with the incidence8 of both prostate cancer diagnosis and death increasing sharply with age (table 2-4).9

 Family history is also a determinant of risk. Men with

one immediate relative with prostate cancer have a

twofold increased risk, which increases to roughly

6 Other variants of these systems have been proposed (41, 42, 146, 336).

7 In these descriptions of cancer stage, the notations before the slash (T1b and T2) refer to the TNM system, and the notations after the slash (A2 and B1) refer to the

Whitmore system.

8 Incidence refers to the number of new cases of a condition found in a population during a period of time. It is distinguished from prevalence, which refers to the total

number of cases (discovered or undiscovered) of the condition in a population at a given point in time.

9 Even though prostate cancer risk rises with age, recent research has found small areas of prostate cancer in about 30 percent of men in their 30s and 40s (293).
CHAPTER 2PROSTATE CANCER IN OLDER MEN 17

TABLE 2-3: STAGING SYSTEMS FOR PROSTATE CANCER

Clinical stage

Whitmore (A-D) TNM systema Definition

1. Clinically nonpalpable cancers

A1 T1a Incidental finding of cancer in < 5% resected (removed) tissue from TURP.

A2 T1b Incidental cancer finding > 5% resected tissue. Moderately or poorly

differentiated grade with < 5% resected tissue from TURP.b

B0 T1c Cancer detected by needle biopsy (e.g., following elevated PSA).

2. Palpable cancers apparently confined within prostate capsule

B1 T2a Involves one-half of one lobe of the prostate or less.

B1 T2b Involves more than one-half of one lobe, but not both lobes.

B2 T2c Involves both lobes of gland but apparently confined (B2, but not T2c cancers

can be greater than 1.5 cm but still involve only one lobe).

3. Local extra-capsular penetration

C1 T3a-3b Penetration of the prostate capsule palpable without evidence of invasion

of the seminal vesicles outside the prostate.

C2 T3c

T4a-4b Palpable invasion of seminal vesicles. Invasion of the bladder neck, external

sphincter, rectum, or pelvic muscles.

4. Metastatic Disease

Nx Cannot assess; no apparent nodal involvement.

D1 N1 Metastasis in a single lymph node 2 cm, metastasis single

N2 nodes 2-5 cm, or multiple nodes (all >5 cm), metastasis in

N3 node > 5 cm.

D2 M1 Distant metastasis.

M1a Lymph nodes outside the region of the prostate.

M1b Bone.

M1c Other site(s).

a In the “TNM” system, “T” refers to characteristics of the tumor, “N” refers to the extent cancerous cells are found in lymph nodes, and “M” refers to the extent of

metastasis (spread of the cancer).

bCriteria for cancer grade (well-, moderately-, or poorly-differentiated) and percentage of resected volume for defining stage A2 varies across different studies.

KEY: PSA = prostate-specific antigen blood test.

TURP = Transurethral resection of the prostate, a procedure for treating benign prostatic hypertrophy (BPH), a noncancerous enlargement of the prostate, by

surgically removing parts of the gland.

SOURCE: Office of Technology Assessment, 1995. Based on information presented in M.J. Barry, C.M. Coley, C. Fleming, et. al, “The Safety, Effectiveness, and Cost of

Early Detection and Treatment of Prostate Cancer Among Older Men: A Report to the Congressional Office of Technology Assessment,” OTA contract paper no.

K3-0546.0, Massachusetts General Hospital, Boston, MA, June 30, 1994.

fivefold with two affected family members (323,

332). A recently described hereditary clustering of

prostate cancer in families may be responsible for

about 40 percent of cases in men under age 55 and 10

percent of prostate cancer cases overall (59, 60).

 African American men, who have generally been

unrepresented in voluntary prostate cancer screening

programs (104), have a 1.3 to 1.6 fold higher risk of

prostate cancer than do non-African-American men
18 COSTS AND EFFECTIVENESS OF PROSTATE CANCER SCREENING IN ELDERLY MEN

TABLE 2-4: AGE-SPECIFIC INCIDENCE AND MORTALITY

FROM PROSTATE CANCER FOR ALL U.S. MEN

Age Incidence per Deaths per

100,000 man-year 100,000 man-years

50-54 33 4

55-59 105 14

60-64 259 36

65-69 525 81

70-74 799 157

75-79 1,024 268

80-84 1,186 437

85+ 1,182 662

SOURCE: Office of Technology Assessment, 1995. Based on data from SEER,

1992.

(21). In the 50 to 54 year age group, the risk is twofold

higher (73).

 Research has shown a statistical association between

dietary fat, particularly animal fat from red meat,

and prostate cancer (142, 286). Although fat may not

directly cause prostate cancer, it may contribute indirectly by affecting certain hormone levels in men

(272).

 Several studies have found a weak statistical association between prior vasectomy and prostate cancer

(140, 141, 288). However, because the association is

weak, because contradictory data exist (14), and because there is no convincing biological explanation

for this result, causality cannot be considered proven

(153, 169).

The lack of data on risk factors that could change

(except perhaps reductions in dietary fat intake) makes

the potential for preventing prostate cancer before it develops modest at this point. However, considerable interest has arisen in trying to prevent prostate cancer with

drugs. A randomized clinical trial of prostate cancer prevention using finasteride, a drug employed in treating

some cases of BPH, is just getting underway (343).

THE PREVALENCE OF

PROSTATE CANCER

In order to analyze the potential impact of a screening program as is attempted in chapter 5, it is necessary

to know the age-specific prevalence of latent prostate

cancer in the population. Table 2-5 presents estimates for

prostate cancer prevalence derived from a synthesis of

autopsy studies (24, 113, 128, 134, 159, 222, 293, 305)

together with McNeal’s analysis of the volume of cancers found at autopsy (233). It presents estimates of the

probabilities of men age 65 and older falling into one of

the four following states of health: no cancer, cancers 0.5

mL or less in volume, cancers greater than 0.5 mL still

confined to the prostate, and cancers greater than 0.5 mL

spread beyond the prostate capsule.

Appendix A describes the methods used to derive

table 2-5. These probabilities can only be considered estimates because patients coming to autopsy may not be

representative of the general population, and because

scarce data exist describing distributions of autopsy cancers by host age, and tumor volume and extent. However,

autopsy studies were excluded from this analysis unless

patients with cancers suspected before death were specifically excluded.

PROSTATE CANCER MORTALITY

The discussion of treatment effectiveness in chapter

4 reviews epidemiologic data on the natural history of

untreated, clinically-significant prostate cancer. The

age-standardized mortality rate for prostate cancer increased from about 21 to 25 per 100,000 males in the

United States between 1960 and 1988 (39); meanwhile,

the incidence of prostate cancer in the United States has

increased much more dramatically, at first due in part to

wider use of the surgical procedure, transurethral resection of the prostate, for symptoms of BPH (274). Increasing early detection efforts have sustained this trend in re-
CHAPTER 2PROSTATE CANCER IN OLDER MEN 19

TABLE 2-5: PREVALENCE OF PROSTATE CANCER BY TUMOR VOLUME AND AGE SYNTHESIZED FROM EIGHT AUTOPSY STUDIESa

Overall Cancer Cancer Cancer

Age prevalence b < 0.5 mLc > 0.5 mL, intracapsulard > 0.5 mL, extracapsulare

40-49 12% 7.2% 3.5% 1.3%

50-59 15 9.0 4.4 1.6

60-69 22 13.2 6.4 2.4

70-79 39 23.4 11.4 4.2

80 + 43 25.8 12.6 4.6

aAppendix A describes the methods used to derive this table.

bNumbers rounded to the nearest whole. Weighted average for men over age 50 is 30% (547/1811).

cEstimated weighted mean prevalence of prostate cancers less than O.5 mL in men over age 50 is 18%.

dEstimated weighted mean prevalence of intracapsular prostate cancers exceeding 0.5 mL for men over age 50 years is 8.8%.

eEstimated weighted mean prevalence of extracapsular prostate cancer exceeding 0.5 mL in men over age 50 years is 3.2%.

SOURCE: Office of Technology Assessment, 1995. Data sources described in appendix A.

cent years (105). These trends are reflected in an

increased tendency to diagnose cancer at less advanced

stages, and improved stage-specific five-year survival

rates (238, 330).

These statistics also emphasize the danger of using

“stage shift” data to make conclusions about underlying

cancer mortality; a shift toward more localized cancers

and better outcomes for individual patients in recent

years has actually been accompanied by a small increase

in the rate of prostate cancer mortality, from a national

perspective. However, since aggressive early detection

efforts are a relatively new phenomenon, some years

may be required before this strategy results in any decrease in population-based rates of prostate cancer

mortality.
CHAPTER

3

Technologies To

Detect Prostate Cancer

he most commonly used technologies for detecting and diagnosing prostate cancer are digital

rectal examination (DRE), prostate-specific antigen (PSA) measurement, transrectal ultrasound (TRUS), and transrectal needle biopsy of

the prostate (TRNB). For primary-care based case-finding and mass screening, TRUS and TRNB would be logistically difficult to include as primary screening tests

given their relative complexity and invasive nature.

Moreover, the marginal value of TRUS above DRE and

PSA seems to be small (18, 91, 215), and the risk and discomfort of TRNB would seem to obviate its use as a primary screening test. Therefore, this chapter considers

the use of DRE and/or PSA as primary screening tests,

and TRUS and TRNB as followup, confirmatory tests.

To analyze the impact of screening, it is necessary to

know the “operating characteristics” of each screening

technology. In general, the operating characteristics,

which refer to the ability of a test to find all cancers that

would cause harm and to find only those cancers, are expressed in terms of the sensitivity and specificity of the

test. (Box 3-1 describes these concepts.) Unfortunately,

the “true” operating characteristics of DRE and PSA

cannot be defined since few studies have evaluated them

in populations where the true underlying prevalence of

clinically-significant prostate cancer is known. The fact

that small volume, well-differentiated cancers should be

considered as “nondisease” and that it is relatively easy

to detect advanced cancer which may offer no therapeutic benefit further complicates the design and analysis of

these studies.

What are usually available are studies of the “positive

predictive value” of tests, the proportion of positive or

suspicious test results that ultimately turn out to be cancer (see box 3-1); in these studies, patients with “negative” test results do not receive followup TRNB (even

though they may harbor significant prostate cancers that

the screening test did not find). Furthermore, these studies use different combinations of primary screening tests

and different strategies of followup evaluation. Finally,

the studies do not uniformly provide age-specific predictive values, which are important to an analysis of screening older men.

To overcome these problems, this analysis presents

“likelihood ratios” of disease (292) for DRE and for

PSA. These likelihood ratios are estimates of how many

times more likely a patient with a particular test result is

to have a given type of cancer than if the patient did not

have the test. The probabilities of cancer with no test are

the prevalence estimates found in table 2-5. Appendix C
22 COSTS AND EFFECTIVENESS OF PROSTATE CANCER SCREENING IN ELDERLY MEN

BOX 3-1: DESCRIBING THE ACCURACY OF SCREENING TESTS

To analyze the impact of a screening program, it is necessary to understand the accuracy of each screening technology, sometimes referred to as the “operating characteristics” of the test. These operating characteristics, which include the

ability of a test to find all existing disease and to find only disease, are usually expressed in terms of the test’s sensitivity and

specificity. Sensitivity is the percentage of all screened people with disease who test positive, while specificity is the percentage of all healthy screened people who test negative. In other words, sensitivity is the ability of a test to find people with

disease, while specificity represents the test’s ability to label healthy people correctly. These characteristics relate inversely to

the false-positive rate (the percentage of people free of disease who test positive) and the false-negative rate (the percentage of people afflicted by the disease whose screening results are negative). For example, a test with sensitivity between 70

and 95 percent would have a false-negative rate of 5 to 30 percent. The figure below displays the calculation of sensitivity

and specificity and the relationship of these indicators to false-positive and false-negative rates.

Calculating sensitivity and specificity requires

that one know the true underlying prevalence of disease in the screened population, regardless of

screening test results. In other words, it would require

performing definitive followup tests on all screenees,

even those whose screening test is negative. This is

usually not done in studies of prostate cancer screening because of the invasiveness, costs, and risks of

such followup procedures (usually transrectal needle

biopsies). Hence, most studies report a less useful

measure of a screening technology’s accuracy, the

positive predictive value (PPV). The PPV is the percentage of people with positive test results who ultimately turn out to have cancer. Conversely, the negative predictive value (NPV), is the percentage of

people with negative test results who ultimately turn

out to be free of disease. Calculation of PPV does not

require knowing the true underlying prevalence of

disease among all people screened. The PPV for a

specific condition is directly related to the prevalence of the condition being screened for and, all

else being equal, is inversely related to the false-positive rate. A low PPV usually indicates a high false-positive rate, although it is sometimes possible to have

both a low PPV and a low false-positive rate. This occurs if the disease is rare. With rare conditions, because the prevalence of a previously undetected disease would decrease as the frequency of testing increases, prolonged studies implementing periodic rescreening normally yield declining PPVs as the studies

progress.

The PPV is a limited measure of screening accuracy. In most circumstances a low PPV indicates that for every cancer

detected a substantial number of individuals undergo the risks and costs associated with followup testing. However, policymakers or clinicians may decide that reductions in mortality and morbidity associated with screening in a population are

large enough to justify the risks and costs associated with screening and followup among healthy individuals. The uncertainty

concerning whether this is true for prostate cancer screening is a major issue in the analysis presented in this background

paper.

SOURCE: Office of Technology Assessment, 1995.

SOURCE: Office of Technology Assessment, 1990.

CALCULATION OF SENSITIVITY AND SPECIFITY
CHAPTER 3TECHNOLOGIES TO DETECT PROSTATE CANCER 23

discusses the methods used in making these estimates.

The estimates themselves are presented in the sections

on DRE and PSA respectively below.1

A potential problem with these estimates is that the

positive predictive value in different studies depends

heavily on the aggressiveness of the followup strategy

employed for a suspicious test. Studies tend to find more

cancer by performing multiple systematic biopsies (and

even repeated sets of multiple systematic biopsies) in response to a suspicious primary test (70). Using this methodology, a test that has poor sensitivity and specificity

but is “positive” in a large proportion of the population

will appear to perform well if one examines only the predictive value of the strategy. For example, a strategy of

performing multiple sets of biopsies on all men with

brown eyes would probably have a rather high “yield” in

terms of the number of prostate cancers detected, despite

eye color having no information value as a test for prostate cancer. Eye color, in essence, becomes a lottery for

receiving the more accurate diagnostic test, TRNB. A recent study of DRE and PSA suggests that this phenomenon occurs with prostate cancer screening (72, 123). Although the predictive value of a suspicious DRE in this

study was about 22 percent (72), the percentage of palpably suspicious quadrants of the prostate that yielded

cancer was only about 11 percent, implying that roughly

half the cancers found as a result of selecting patients for

biopsy based on a suspicious DRE were actually found

elsewhere in the prostate as a result of the systematic

biopsy.

DIGITAL RECTAL EXAMINATION

The digital rectal examination, in which the clinician

attempts to feel abnormalities in the size or shape of the

prostate gland through the rectum, is a time-honored test

for the early detection of prostate cancer despite very

weak agreement among published guidelines about its

value (100). The DRE is limited in sensitivity because of

an inability to detect tumors deep within the prostate

gland. Because larger tumors are easier to feel, DRE is

unlikely to detect insignificant cancers (although this

risk will increase if a suspicious DRE triggers a set of

systematic biopsies in addition to a biopsy of the suspicious area). The detection of larger cancers also means

that a relatively high percentage of DRE-detected tumors (half or more) will have already spread beyond the

confines of the prostatic capsule (139, 279, 271). Many

investigators have been concerned about variation

among physicians in their ability to detect cancers by

DRE (271), especially the possibility that DREs performed by primary care physicians may not be as discriminating as urologists’ exams. However, little empirical evidence exists to address this concern (354).

Appendix C lists studies of primary DRE screening

for prostate cancer, with brief descriptions of study

methods and results. Comparisons are difficult given different patient populations, different thresholds for calling a DRE “suspicious,” and different strategies of followup testing. One study by Chodak and colleagues (79)

provides the most detailed presentation, and allows es1 This method is methodologically inferior to knowing the underlying disease state of all individuals in each study, but probably superior to the alternative methods

used in the screening literature, such as screening a population with multiple modalities (often DRE, PSA, and TRUS) and assuming all clinically significant cancers

have been detected, or testing only patients with documented clinical disease status (e.g., men scheduled for radical prostatectomy for known cancer). The former

method overestimates sensitivity and specificity since some clinically significant cancers would likely be undetected by all modalities; the latter method overestimates

sensitivity if cancers in the tested population are more advanced than those that would be identified by screening, or if the screening test were actually used in the

process of identifying them in the first place.
24 COSTS AND EFFECTIVENESS OF PROSTATE CANCER SCREENING IN ELDERLY MEN

TABLE 3-1: ESTIMATED LIKELIHOOD RATIOS FOR RESULTS OF DIGITAL RECTAL EXAMINATION CHANGING THE ODDS OF

SIGNIFICANTa PROSTATE CANCER (>0.5mL) OF DIFFERENT PATHOLOGIC EXTENTSb

Likelihood Ratio

DRE result Intracapsular cancer Extracapsular cancer

”Suspicious”

Chodak (1989)c 1.5 8.6

Richie (1993)d 2.0 2.7

“Nonsuspicious”

Chodak (1989) 0.96 0.53

Richie (1993) 0.83 0.72

a Probability of prostate cancer <0.5mL = 11% based on J.E. Oesterling, V.J. Suman, H. Zincke et al., “PSA-Detected (Clinical Stage T1c or BO) Prostate Cancer:

Pathologically Significant Tumors,” Urologic Clinics of North America 17:719-737, 1990.

b See appendix C for methods deriving these estimates.

c G.W. Chodak, P. Keller, and H.W. Schoenberg, “Assessment of Screening for Prostate Cancer Using the Digital Rectal Examination,” Journal of Urology

141:1136-1138, 1989.

dJ.P. Richie, W.J. Catalona, F.R. Ahmann, et al., “Effect of Patient Age on Early Detection of Prostate Cancer with Serum Prostate-Specific Antigen and Digital Rectal

Examination,” Urology 42:365-374, 1993.

SOURCE: Office of Technology Assessment, 1995. Based on information from M.J. Barry, C.M. Coley, C. Fleming et. al, “The Safety, Effectiveness, and Cost of Early

Detection and Treatment of Prostate Cancer Among Older Men: A Report to the Congressional Office of Technology Assessment” OTA contract paper no. K3-0546.0

Massachusetts General Hospital, Boston, MA June 30, 1994.

timation of the likelihood of cancers with and without

capsular penetration (table 3-1) for each DRE test result.2 Appendix B discusses the methods used to produce

these estimates. No clinical trials of the use of DRE alone

for the early detection of prostate cancer are available.

However, neither a case-control study (129) nor a decision model (241) has suggested an important survival

benefit for men screened with DRE.

PROSTATE-SPECIFIC ANTIGEN

Prostate-specific antigen is a glycoprotein produced

in the prostate gland with a probable role in the transport

of semen. Because cancerous prostate tissue, gram for

gram, produces greater quantities of PSA than does normal or benignly enlarged tissue, and because prostate

cancer may increase the likelihood that PSA “leaks” into

the general circulatory system, serum (blood) PSA levels appear to have some discriminating capacity for prostate cancer (99, 257). Preliminary evidence suggests

prostate cancers need to be greater than 1 mL in volume

before they cause an increase in serum PSA (49).

Three PSA assays have been commonly used clinically and described in the literature (172). Hybritech’s Tandem PSA assays detect PSA with monoclonal antibody

2 In a more recent study, with a policy of systematic biopsy for abnormal DRE results, 15 percent of 6,630 male volunteers over age 50 had an abnormal DRE, and

21 percent of the men with an abnormal DRE had cancer at biopsy; the overall detection rate of cancer for DRE in this series was 3.2 percent, reflecting the more

aggressive use of biopsies (72). A new followup study has suggested better outcomes for men diagnosed at initial rather than followup screening with DRE (139);

this finding may represent the effect of length bias with one-time screening (discussed in chapter 2).
CHAPTER 3TECHNOLOGIES TO DETECT PROSTATE CANCER 25

probes; these assays use radioactive antibodies and enzymatic reactions to perform the measurement. The Tandem PSA tests are currently the only assays approved by

the U.S. Food and Drug Administration (FDA) for use in

conjunction with DRE as an aid in the detection of prostate cancer in men over age 50.3 Abbott’s IMx PSA assay

uses a microparticle enzyme immunoassay technique.

Yang’s Pros-Check PSA assay uses a polyclonal antibody probe to measure PSA (356). The levels of PSA

measured by the Hybritech and Abbott assays appear

roughly similar (190, 355), while the polyclonal assay

runs values about 1.6-fold higher (148, 339). However,

investigators have recently raised concerns about the

calibration of the Hybritech and Abbott assays (48, 149,

226, 266), which together dominate the PSA assay market. Clinicians need to know which test their laboratory

uses, and to consider a switch in assays in the “differential diagnosis” of a changing PSA in a given patient.

One potential difficulty with this screening test is that

factors other than prostate cancer can temporarily elevate PSA levels for several weeks: acute inflammation

of the prostate (prostatitis), acute urinary retention, a

diagnostic medical procedure called rigid cystoscopy,

TRUS, TRNB, or prostate surgery (193, 262). A recent

study has also found temporary elevations in PSA following ejaculation (250). However, several studies have

now documented that there is no clinically important

elevation in PSA values following routine DRE (95,

371), an important finding since physicians often perform DRE and PSA at the same visit.

TABLE 3-2: PROPOSED AGE-SPECIFIC NORMAL

REFERENCE RANGES FOR PROSTATE-SPECIFIC ANTIGEN

MEASUREMENTS

Normal reference range (ng/mL)

Age Oesterling, 1993c a Dalkin, 1993b

40-49 0 - 2.5 -

50-59 0 - 3.5 0 - 3.5

60-69 0 - 4.5 0 - 5.4

70-79 0 - 6.5 0 - 6.3

aJ.E. Oesterling, S.J. Jacobsen, C.G. Chute, et al., “Serum Prostate-Specific Antigen in a Community-Based Population of Healthy Men: Establishment of

Age-Specific Reference Ranges,” Journal of the American Medical Association. 270:860-864, 1993.

b B.L. Dalkin, F.R. Ahmann, and J.B. Kopp, “Prostate Specific Antigen Levels in

Men Older Than 50 Years Without Clinical Evidence of Prostatic Carcinoma,”

Journal of Urology 150:1837-1839, 1993.

SOURCE: Office of Technology Assessment, 1995. Based on information from M.J.

Barry, C.M. Coley, C. Fleming et. al, “The Safety, Effectiveness, and Cost of Early

Detection and Treatment of Prostate Cancer Among Older Men: A Report to

the Congressional Office of Technology Assessment”, OTA contract paper no.

K3-0546.0, Massachusetts General Hospital, Boston, MA June 30, 1994.

Most studies consider an Abbott or Hybritech PSA

level up to 4.0 nanograms per milliliter of serum (ng/

mL) (equivalent to a Yang PSA level up to 7 ng/mL) as

nonsuspicious (148, 339).4 However, “normal” PSA values increase as a man ages, reflecting the increasing size

of the prostate with age (88). Two recent articles have

proposed age-specific reference ranges for normal PSA

values (table 3-2). One study used the 95th percentile of

serum PSA among men without evidence of prostate

cancer as the upper boundary of the reference range

3 The FDA approved the Tandem PSA assays for detection on August 25, 1994. The Tandem tests, the Abbott IMx, the Toschmedix, AIA pack, and the Ciba-Corning

ACS assays are all approved for monitoring men with previous prostate problems (228).

4 Some investigators prefer a lower threshold on the Abbott or Hybritech assays of 3.0 ng/mL to improve test sensitivity (201). For a given underlying prevalence of

true cancer, lowering the threshold increases the proportion of all true cancers found by screening, but at the cost of having to do more biopsies (which, as described

later in this paper carries cost and risk in itself) and an increased number of false-positive screening results. In other words, in setting the threshold for conducting

a biopsy, there is a tradeoff between false-negative and false-positive test results.
26 COSTS AND EFFECTIVENESS OF PROSTATE CANCER SCREENING IN ELDERLY MEN

(260, 261), while the other used a slightly different, but

methodologically similar approach5 to define the upper

limit (101).6 Another recent study compared the performances of several PSA test kits as part of an international

PSA standardization conference (329).

Appendix D lists published studies that use PSA as the

primary screening tool to detect prostate cancer (DRE

used only to followup a suspicious PSA).7 Although

these studies generally have a somewhat higher proportion of subjects with a cancer detected than do the studies

of primary DRE, these proportions are likely underestimates of the maximal attainable yield since patients

were often not biopsied unless a followup DRE or TRUS

was also suspicious. Using data from the Catalona and

Brawer studies, likelihood ratios for Hybritech PSA results of different categories were calculated as described in

appendix B and are provided in table 3-3 (44, 66, 70).8

Variations in the use of PSA for screening have been

proposed to improve the operating characteristics of this

test for prostate cancer (96, 182). These variations, each

of which has its own drawbacks, include: 1) PSA density

(PSAD), a method of correcting the raw PSA value by

the volume of the prostate, as measured by TRUS (32,

33, 284); 2) a predicted PSA (pPSA) based on gland volume against which measured PSA is compared to make

decisions about proceeding to biopsy (206); and 3) PSA

velocity, the rate of change of PSA over time (63, 64).9

Research currently underway may lead to a test for more

specific types of PSA (36, 37, 106, 211, 212, 213) or other types of biological substances (171, 298) that more

precisely identify men with prostate cancer.

One-Time Versus Repeated PSA Screening

Much less is known about the results of repeated

screening with PSA than about one-time screening. This

gap in our knowledge is significant since a Medicare

prostate cancer screening benefit would most likely cover periodic screenings, not one screening per lifetime.

The few studies that are available suggest a decrease in

the proportion of screenees with cancer over repeated

screenings (46, 47), while the proportion of patients with

cancer confined to the prostate capsule appears to increase: 71 percent as opposed to 63 percent in one series

(13, 70), and 87 percent versus 56 percent in another series (46). Appendix E summarizes these studies.

5 Dalkin and colleagues (101) selected two standard deviations above the mean of the distribution of log-transformed age-specific PSA values to define the upper

limit of the reference range.

6 If the references ranges in table 3-2 are interpreted as age-dependent thresholds for conducting followup tests, they implicitly assume that the costs of a false-positive relative to a false-negative test increase with age. This assumption makes conceptual sense, as older men have a greater risk of treatment complications, and

fewer years of life expectancy over which to reap the benefits of screening (on the other hand, younger men also have more years of life to live with any complications engendered by treatment). However, some clinicians are unwilling to trade sensitivity for specificity, regardless of age (255).

7 In addition, a single, recent case-control study published just prior to publication of this report suggests that PSA may actually preferentially identify aggressive cancers early with relatively high sensitivity and specificity (130).

8 In a recent study, a group of 72 men underwent systematic sextant biopsies despite a PSA less than 4 ng/mL and a normal digital rectal exam; these men had lung

masses on chest radiography and were being evaluated to rule out metastatic prostate cancer as a cause. Prostate cancer was discovered in 3 out of 72 men (4

percent), compared to 9 out of 77 men (12 percent) with a normal digital rectal examination but an elevated PSA (160). This data yields a likelihood ratio of 0.51

for a normal PSA and 1.51 for an elevated PSA (assuming these cases were consecutive), not inconsistent with the likelihood ratios presented in table 3-3.

9 Because of normal fluctuations in PSA values within a given patient, a PSA velocity based on only two measurements probably has little value in clinical decisionmaking (280). Most recently, the concept of adjusting serum PSA by transition zone volume, rather than whole prostate volume, has been introduced (181).
CHAPTER 3TECHNOLOGIES TO DETECT PROSTATE CANCER 27

TABLE 3-3: ESTIMATED LIKELIHOOD RATIOS FOR DIFFERENT RESULTS OF PROSTATE-SPECIFIC ANTIGEN TESTING CHANGING THE

ODDS OF SIGNIFICANT (>0.5 mL)a PROSTATE CANCERb

Likelihood ratio

PSA resultc Intracapsular cancer Extracapsular cancer

Pooled Catalona, 1991d and Brawer, 1992e

<4.0 ng/mL 0.98 0.09

4.1-10 ng/mL 1.4 5.1

>10 ng/mL 0.4 49.6

Richie, 1993f

<4.0 ng/mL 0.7 0.4

>4.1 ng/mL 3.0 4.6

Catalona, 1993cg

<4.0 ng/mL 0.8 0.5

4.1-10 ng/mL 2.8 3.2

>10 ng/mL 3.0h 23.7

a As described in appendix C, probability of a detected cancer <0.5 mL is assumed to be 11% based on J.E. Oesterling, V.J. Suman, H. Zincke, et al., “PSA-Detected

(Clinical Stage T1c or BO) Prostate Cancer: Pathologically Significant Tumors,” Urologic Clinics of North America 17:719-737, 1990.

b See appendix C for methods of deriving these estimates.

c Results based on Hybritech assay.

d W.J. Catalona, D.S. Smith, T.L.. Ratliff, et al., “Measurement of Prostate-Specific Antigen in Serum as a Screening Test for Prostate Cancer,” New England Journal of

Medicine 324:1156-1161, 1991.

e M.K. Brawer, M.P Chetner,, J. Beatie, et al., “Screening for Prostatic Carcinoma with Prostate Specific Antigen,” Journal of Urology 147:841-845, 1992.

f

 J.P Richie, W.J. Catalona, F.R. Ahmann, et al., “Effect of Patient Age on Early Detection of Prostate Cancer with Serum Prostate-Specific Antigen and Digital Rectal

Examination,” Urology 42:365-374, 1993.

g W.J. Catalona, D.S. Smith, T.L. Ratliff, et al., “Detection of Organ-Confined Prostate Cancer Is Increased Through Prostate-Specific Antigen-Based Screening,”

Journal of the American Medical Association 270:948-954, 1993.

h The discrepancy between this value and the corresponding derivation (0.4) from the pooled earlier studies is explained by the observed difference in probability

of pathological localization for cancers (>0.5 mL) detected by PSA >10 ng/mL (32% vs. 5%).

SOURCE: Office of Technology Assessment, 1995. Based on information from M.J. Barry, C.M. Coley, C. Fleming, et. al, “The Safety, Effectiveness, and Cost of Early

Detection and Treatment of Prostate Cancer Among Older Men: A Report to the Congressional Office of Technology Assessment,” OTA contract paper no.

K3-0546.0, Massachusetts General Hospital, Boston, MA June 30, 1994.

PSA Screening Among Men with

Symptoms of BPH

As noted earlier, benign prostatic hyperplasia (BPH)

can raise PSA levels complicating PSA measurement.

Given the widespread prevalence of urinary symptoms

indicative of BPH among older men, PSA screening for

prostate cancer among this large group may yield little

useful information. Men with symptoms of BPH do not

appear to be at much greater risk of harboring cancer (except as conferred by their age) (235) and in one large

study, when controlling for age, men with symptoms of

prostatism actually had a lower chance of being found to

have cancer through DRE and PSA screening (72). In addition, because BPH and prostate cancer share symptoms and the likelihood of elevated PSA levels, the specificity of PSA deteriorates to 50 to 79 percent among

men with clinical evidence of BPH (173, 309). Furthermore, there appears to be a great degree of overlap
28 COSTS AND EFFECTIVENESS OF PROSTATE CANCER SCREENING IN ELDERLY MEN

among men with localized (intracapsular) prostate cancer and BPH, further limiting the value of PSA testing

among men with these symptoms (309).10

COMBINATION OF DRE AND PSA

Although combination screening with both DRE and

PSA may currently, be the most popular strategy of

aggressive office-based early detection of prostate cancer among U.S. urologists, studies of the predictive value of this strategy are only just becoming available for

low-risk populations. DRE and PSA each detect some

cancers not identified by the other modality; therefore,

the yield of a screening program (the percentage of

screenees who ultimately have a cancer confirmed) can

be increased (to roughly 4 percent) by combining both

tests. In addition, the studies of combination testing reported recently have generally performed a set of systematic biopsies if either test is suspicious, as well as

biopsies of suspicious lesions noted on followup TRUS;

this more aggressive use of TRNB also contributes to the

higher yield seen in these studies.

However, these more aggressive strategies result in

performing biopsies on up to a third of all screenees; the

additional cancers detected must be weighed against the

cost and risk of biopsy. Furthermore, these studies were

conducted among volunteers, and some data suggest that

volunteers may have a higher “prior probability” of prostate cancer than unselected men in the community

(261).11

The newest studies where DRE and PSA are performed in the same men make it clear that PSA is a better

single test than DRE in terms of detecting cancers and of

detecting cancers still confined within the prostatic capsule (28, 72, 119, 263, 279).

FOLLOWUP TESTING

Increasingly, followup strategies for a suspicious

DRE or PSA include both TRUS and TRNB. Most investigators use TRUS to guide biopsies of areas determined

to be suspicious by DRE or TRUS. Many clinicians now

perform multiple systematic (four to six) biopsies of the

prostate (in a single procedure) in addition to biopsies of

suspicious areas, since a patient with a normal TRUS

may actually harbor cancer 12 to 33 percent of the time

(depending on the PSA level) (157). Others base decisions about whether to perform systematic biopsies on

raw PSA values or PSAD values (29, 99, 306). Although

some investigators advocate simply following men with

mild PSA elevations (i.e., in the 4.1 to 10.0 ng/mL range)

if the DRE and TRUS are negative, when aggressively

evaluated, this group yields the highest percentage of intracapsular cancers, the real targets of screening.

There is also variability in how clinicians follow men

who have a negative set of biopsies after a suspicious

PSA test. Some urologists recommend repeating the systematic biopsies at least once (particularly for a PSA

greater than 10 ng/mL); others perform followup PSA

10 As mentioned in chapter 2, the FDA has approved the drug finasteride for treatment of BPH. It reduces PSA levels through its intended physiological effects. However, it is not clear, given the need to expect lower PSA levels when screening men on finasteride for prostate cancer, that this drug reduces the (already fairly low)

information value of PSA among men with BPH (145, 154, 155, 289). Because of a trend toward less invasive management of BPH, the issue of adequate pretreatment

screening of men with a diagnosis of BPH for coexistent prostate cancer is becoming a hotly debated issue (179).

11When Oesterling (261) applied the same screening strategy to randomly selected men in the community, only 1 percent were found to have prostate cancer

compared with 4 percent in the volunteer studies.
CHAPTER 3TECHNOLOGIES TO DETECT PROSTATE CANCER 29

tests more frequently than annually and rebiopsy for either persistent elevations or a rising PSA value. Often

then, a suspicious screening test, even if followed by a

negative biopsy, will lead to heightened surveillance for

prostate cancer and further tests and biopsies in the future. On the other hand, this more intensive surveillance

in turn increases the yield of screening to some degree.

Transrectal Ultrasound

Because of the anatomy of the prostate gland itself,

TRUS has much better sensitivity for cancers found in

certain parts of the prostate than for others (334). Appendix F lists studies that use TRUS as a primary means for

early prostate cancer detection. In one of these studies,

a demonstration project of the American Cancer Society,

about 14 percent of men had a suspicious TRUS, and 15

percent of these men had cancer, a lower predictive value

than studies of DRE or PSA alone (Mettlin, 1991). In the

absence of a suspicious DRE or elevated PSA, the predictive value in this series dropped to 5.4 percent (19,

215). In a study based in a urologic practice where the

prevalence of cancer was especially high (detection rate

of 14.6 percent), and where about half of the men were

biopsied based on results of combined screening (DRE,

PSA, and TRUS), Cooner and associates found that if

men had a PSA less than 4 ng/mL and a nonsuspicious

rectal exam, the yield of ultrasonographic screening was

about 2 percent. Put in another way, the overall yield of

the testing strategy only increased from 13.5 to 14.6 percent through the performance of TRUS in addition to

DRE and PSA (91).

Several studies provide more direct evidence about

the true sensitivity and specificity of TRUS than is available for DRE and PSA. Two studies were able to estimate

the operating characteristics of preoperative TRUS performed on men already scheduled for radical prostatectomy for cancer or BPH. The study on men scheduled for

prostatectomy for cancer showed a TRUS sensitivity of

52 percent and a specificity of 68 percent (61), and the

study of men with BPH showed a sensitivity of 30 percent (315). These relatively low sensitivity estimates for

TRUS are a major reason for the increasing tendency to

perform systematic biopsies for suspicious DRE or PSA

results, even if TRUS does not indicate anything suspicious. Furthermore, these and other studies (337) suggest that TRUS tends to underestimate the size of cancers that are detected, making it a problematic

technology for identifying men with small cancers who

may not need aggressive treatment. Finally, evidence

also suggests that BPH may also erode the ability of

TRUS to detect cancer (74).

TRUS itself does not appear to pose any risk for patients, although it does pose costs to patients or their

health insurers. In 1992, Medicare reimbursements were

$89 for a diagnostic TRUS by itself and $189 for a

TRUS-guided biopsy.

Transrectal Needle Biopsy

Modern transrectal needle biopsies (TRNBs) are usually done with ultrasound guidance using a needle

mounted in a spring-loaded biopsy “gun.” Biopsies can

be directed toward areas deemed suspicious by DRE or

TRUS, or performed systematically to sample the entire

prostate; often six biopsies are taken in a sextant pattern

from different parts of the prostate gland (326). TRNB

is uncomfortable and can be complicated by infection or

bleeding (89). Complications of biopsy include urinary

tract infections in 0.5 to 5 percent of patients and urosepsis in an estimated 0.5 percent (no deaths), despite routine antibiotic prophylaxis (16, 91, 109, 160). Some patients also experience bleeding (less than 1 percent) with

very few (one out of 835 biopsies in one study) requiring

transfusion (91, 109).
30 COSTS AND EFFECTIVENESS OF PROSTATE CANCER SCREENING IN ELDERLY MEN

TRNB is often considered the “gold standard” test for

the diagnosis of prostate cancer; however, it is increasingly clear that the gold standard is “tarnished” to some

degree. In terms of the sensitivity of TRNB, investigators from Washington University have found that when

men are found to have a persistent mild elevation in PSA

(4 to 9.9 ng/mL), repeated biopsies find a large number

of cancers presumably missed by previous biopsies. In

one preliminary report, 25 percent of these men with one

previously negative biopsy had cancer, as well as 14 percent with two previously negative biopsies and 10 percent with three previously negative biopsies (187). Although many of these patients had original biopsies that

were directed by abnormal DRE or TRUS results instead

of multiple, systematic biopsies, simulation modeling

has also suggested systematic biopsies may be relatively

insensitive (103).

In terms of specificity, TRNB can detect “incidental”

cancers of less than 0.5 mL in volume, which (as discussed in chapter 2) may likely pose no threat to the patient’s health, making them conceptually equivalent to

“false positives.” This risk increases as more biopsies are

performed, and particularly with repeated systematic

biopsies. Terris and colleagues recently estimated that

the probability of finding an incidental cancer on a set of

six biopsies was approximately 4 percent (338).

SCREENING THE MEDICARE

POPULATION

Age has a complex effect on the results of screening

for prostate cancer. The prior probability of cancer increases with age, but the percentage of organ-confined

cancers decreases. Furthermore, the specificity of PSA,

and probably DRE as well, deteriorates as more men in

the population have greater amounts of BPH. Richie and

colleagues (279) present the net effect of these factors

using data from their large, six-center study of screening:

 The deteriorating specificity of the tests with age resulted in a steeply increasing number of patients with

suspicious results on either DRE or PSA that would

generate a recommendation for biopsy: 15 percent at

ages 50 to 59, 28 percent at ages 60 to 69, and 40 percent at ages 70 to 79.

 The rising prevalence of cancer maintained the predictive value relatively constant, so that cancer was

detected in 2, 4, and 7 percent of these age groups, respectively.

 Among men whose cancers were pathologically

staged, the percentages that were organ confined

(definition not specified) by age groups were 74, 76,

and 60 percent.

 In this study, for men ages 60 to 69, adding PSA increased the percentage of men with a suspicious

screening evaluation from 16 percent (with DRE

alone) to 28 percent; interestingly, the percentage of

patients with pathologically localized cancer did not

decrease with the addition of PSA in this age group.

For men ages 70 to 79, adding PSA to DRE increased

the percentage of suspicious evaluations from 20 41

percent, with an increase in the resulting percentage

of organ- confined cancers detected from 45 to 60 percent.12

All of these data suggest that as screening programs,

especially those employing PSA as one screening

technology, are directed toward older populations, the

number of patients requiring more costly, invasive, and

12 The proportion of men with organ-confined cancers in this study is much higher than in previous studies, presumably because of the performance of systematic

biopsies in all patients, rather than only screenees with an abnormal DRE or TRUS. The high proportion of screenees with an abnormal DRE in this study also suggests

a very low threshold for considering this exam suspicious.
CHAPTER 3TECHNOLOGIES TO DETECT PROSTATE CANCER 31

riskier followup also increases, with a larger number of

the cancers ultimately found being confined within the

prostate and quite possibly not destined to cause health

problems. For policymakers, the decision about whether

to support screening depends on the number of followup

tests and incidental cancers they are willing to endure in

order to find more cancers that may threaten patients’

health or lives. This balance may depend on medicine’s

ability to cure more aggressive prostate cancers, the

question addressed in chapter 4.
CHAPTER

4

Treating Prostate Cancer

here is controversy about the optimal treatment

for clinically localized prostate cancer (i.e., cancer that appears not to have spread beyond the

prostate based on information available without

performing surgery).1 In the United States, the

preference is for aggressive treatment, with urologists

generally preferring radical prostatectomy (203, 318).

However, recent research has revealed considerable variability in stage-specific treatments actually administered

(219, 238, 247). In other developed countries, urologists

have tended to be more conservative regarding both early detection (78, 302, 303) and treatment (5, 175, 364).

Although observational studies exist to determine

the outcomes of men who receive different treatments

and to measure their risks of adverse outcomes, few

well-designed trials exist to determine whether observed

outcomes are actually the result of the treatment or due

to some other uncontrolled and unmeasured factor. As

shown in chapter 5, this uncertainty about treatment effectiveness is the greatest impediment to evaluating the

cost-effectiveness of a potential Medicare prostate

screening benefit.

STRATEGIES TO DETERMINE

CANCER STAGE

One problem with current strategies for early detection of prostate cancer is that screening will detect some

cancers that are not destined to cause morbidity or

mortality and do not need treatment, as well as some cancers that have already spread through the prostate capsule and are less likely to be cured or slowed by treatment. Unfortunately, many patients may need to undergo

a surgical staging procedure such as pelvic lymphadenectomy, or even radical prostatectomy itself, to establish the true stage of their cancer. Better, less invasive

staging tests might allow physicians to withhold treatment from patients unlikely to benefit, sparing both the

risks and costs of these procedures.

In terms of determining preoperatively whether

cancers are likely to be insignificant (which this background paper defines as well-differentiated and less than

0.5 mL in volume), clinicians have developed some algorithms using data from systematic biopsies, and if necessary, rebiopsies (338). Unfortunately, however, other

investigators have documented that these algorithms

1As discussed in the preceding chapters, unless otherwise indicated, cancers that are confined within the prostate, less than 0.5 mL in volume, and well differentiated

are assumed not to pose any threat to a patient’s health and would not require treatment unless they grow or change in grade.
34 COSTS AND EFFECTIVENESS OF PROSTATE CANCER SCREENING IN ELDERLY MEN

predict incorrectly in a quarter to a third of cases (98,

191, 192).

As far as predicting preoperatively which tumors

have spread to other parts of the body, detection of metastasis to bone by using radiographic bone scans is relatively straightforward, and algorithms do exist to help

identify low-risk subsets of men in whom bone scans are

unlikely to be helpful (84, 357). However, the use of other diagnostic technologies (e.g., computerized tomography (CT), magnetic resonance imaging (MRI), transrectal ultrasound (TRUS)) have not yet replaced operative

pathological examinations to determine if the cancer has

spread to the pelvic lymph nodes (76, 164, 281) or to determine if the cancer is extracapsular (97, 137, 285).

Models that use the results of multiple tests to assess the

probability of organ confinement and lymph node involvement also result in substantial misclassification

rates for most patient groups (1, 191, 192, 267, 283, 369).

While better staging techniques, such as molecular

staging strategies currently under active investigation

(185), may allow better prediction of which tumors are

likely to be dangerous enough to threaten a patient’s longevity but still potentially curable, selective treatment of

only those tumors most likely to benefit may still be

practically difficult. As shown later in this chapter, evidence establishing the effectiveness of treatment is currently weak. Once a clinician finds cancer, in the absence

of data that there is not at least some net benefit from

treating even apparently inconsequential or unconfined

cancers, patients and physicians may have difficulty in

forgoing therapy, even when the expected net benefits

are clearly less than for other types of cancers.

Many patients with negative bone scans undergo a

dissection of the pelvic lymph nodes to determine if the

cancer has spread in the region of the prostate prior to a

radical prostatectomy, one type of treatment with curative intent.2 Most clinicians would not proceed with a

radical prostatectomy in light of the discovery of involved pelvic nodes, although a minority feel that

aggressive surgical treatment of node positive disease

improves outcomes (254, 375). Recently, some urologists have begun to question the need for a pelvic lymph

node examination prior to radical prostatectomy among

men with better differentiated tumors, or in men with

lower prostate-specific antigen (PSA) values (38, 102,

126, 138).

Another new strategy sometimes employed before

radical prostatectomy is the use of hormonal drugs to decrease the likelihood that the cancer is found to extend

beyond the outside of the prostate capsule or beyond the

surface of the surgically removed specimen (known as

surgical margin positivity). Controversy exists about

whether this treatment (known as androgen ablation

therapy) actually causes a shrinking of the tumor (regression) as opposed to only decreasing PSA levels (223,

259, 321). Although a recently presented clinical trial

suggests that preoperative androgen ablation therapy actually does cause some regression (202), there is no evidence such treatment improves patient outcomes with

prolonged followup.

THE EFFECTIVENESS OF TREATMENT

This chapter examines three strategies for treating

prostate cancer: 1) expectant management (or “watchful

2This examination can be done as a traditional, open surgical procedure or less invasively using a laproscope that requires only a small incision (188, 290, 304). It can

be done as a separate procedure, or as the first stage of a combined pelvic lymph node examination and radical prostatectomy.
CHAPTER 4TREATING PROSTATE CANCER 35

waiting”), 2) radiation therapy, and 3) radical prostatectomy.

Expectant Management

Expectant management, a commonly used strategy

for clinically localized cancer worldwide (367), can take

two basic forms: 1) only monitoring the patient for

symptoms related to cancer progression and treating

these symptoms as necessary or 2) monitoring for disease progression and attempting cure with radiation

treatment or prostatectomy in that circumstance. Even in

the United States, where the approach to prostate cancer

is much more aggressive, a 1990 study by the American

College of Surgeons Commission on Cancer found that

almost two-thirds of Stage A cancers were not actively

treated (238).

Many men with prostate cancer treated expectantly

will have evidence of local progression by digital rectal

examination (DRE) over time (342). Local progression

of prostate cancer can cause symptoms from bladder outlet obstruction or invasion of surrounding tissues. Bladder outlet obstruction can be treated mechanically (by

transrectal resection of the prostate (TURP)3 or, less

commonly, stenting).

Treatment involving deprivation of the male hormone testosterone (an androgen) is often used as part of

an expectant management therapy when the disease becomes symptomatic (168) or, more recently, for evidence of cancer progression in asymptomatic men.4 Clinicians can accomplish androgen deprivation therapy by

orchiectomy (surgical removal of the testes) or by medical means with other hormones or drugs (301). The latter

option is more common despite considerably higher

costs and the risk of patient noncompliance, at least partially because of patient preference (53, 65, 311).5 Although the initial response to hormonal therapy for advanced prostate cancer is often gratifying, it is also

frequently short-lived, with the results of subsequent

chemotherapy generally disappointing (94, 108).

What Is the Effect of Expectant Management?

Although the outcomes of expectant management

have been studied around the world (3, 4, 114, 135, 175,

176, 249), few investigators in the United States have

done so (178, 366).

A number of case series of men with clinically localized prostate cancer in “watchful waiting” strategies

have been reported from around the world. As shown in

table 4-1, a recent structured literature review and synthesis of 23 nonexperimental studies showed that receiving expectant management for localized prostate cancer

had rates of metastasis and death no different from radical prostatectomy and lower than radiation therapy

(362). However, these comparisons are inferior to wellcontrolled, experimental results (333, 362). This literature synthesis has been criticized for the inclusion of series describing predominantly the outcomes of early,

inconsequential Stage T1a/A1 cancers, and for including series using early androgen deprivation therapy

(132, 360). In addition, patients receiving radiation therapy had more poorly differentiated patients than those

receiving other treatment options.

3TURP does not seem to have an unfavorable impact on the prognosis of prostate cancer (372).

4The effect of early androgen deprivation on the natural history of clinically localized prostate cancer is not well defined; some nonexperimental studies demonstrated little effect (23, 114).

5Recently, clinicians have increasingly used combination therapy involving two agents, a GnRH agonist and an androgen blocker (flutamide), with some evidence

from clinical trials that this approach increases median survival time to a degree (94, 108).
36 COSTS AND EFFECTIVENESS OF PROSTATE CANCER SCREENING IN ELDERLY MEN

TABLE 4-1: PATIENT CHARACTERISTICS AND OUTCOMES OF LOCALIZED PROSTATE CANCER TREATMENT

Watchful waiting Radiation therapy Radical prostatectomy

Median (CI) n Median (CI) n Median (CI) n

Patient characteristics

Age 71 66 63

(69-73) 27 (64-66) 49 (61-64) 33

Percent of cancers poorly

differentiated 7 21 11

(6-11) 19 (13-24) 45 (6-25) 22

Outcomes

Annual mortality rate

All causes .060 045 .032

(.050-.04) 27 (.040-.052) 45 (.020-.044) 27

Cancer-specific .009 .023 009

(.006-.012) 23 (.010-.030) 22 (.007-.013) 23

Metastatic rate .017 .050 .023

(.011-.043) 15 (.030-.095) 17 (.014-.025) 18

KEY: CI = 95% confidence interval; n = number of studies, which varies since not all studies supply all data of interest.

SOURCE: Office of Technology Assessment, 1995. Data from J.H. Wasson, C.C. Cushman, R.C. Bruskewitz, et al, “A Structured Literature Review of Treatment for Localized Prostate Cancer,” Archives of Family Medicine 2:487-493, 1993.

A literature synthesis of seven studies (586 patients)

of outcomes of men with palpable, clinically localized

cancers (Stage T2) reported since 1980 yielded rates of

metastasis, overall mortality, and prostate cancer-specific mortality higher than those presented in the Wasson

review described above (6). However, one would expect

these higher rates in an analysis restricted to palpable

cancers. Only two studies provided data on cancer-specific survival at 10 years among men treated expectantly

with a mean of 84 percent. In this analysis, the results of

studies reporting outcomes of radical prostatectomy

were better, while studies reporting outcomes for radiation therapy were worse.

One of these expectant management studies enrolled men with localized prostate cancer from a welldefined geographic area in Sweden between 1977 and

1984 and has an unusually long duration of followup

(175, 176, 177). It excluded men with moderately or

poorly differentiated cancer or a few men receiving curative treatment, leaving a sample of 223 with a mean age

of 72. At 12.5 years of average followup, there have been

23 prostate cancer deaths in the cohort (10 percent), and

148 deaths from other causes (66 percent). Ten-year metastasis-free survival (corrected for deaths from other

causes) was 83 percent. Tumor grade was the dominant

predictor of prognosis.6

6Although this study has been criticized for enrolling too many older men and too many with insignificant cancers discovered during TURP and for having insufficient

followup to detect a late upsurge in hazard of prostate cancer death, neither age nor stage (controlling for grade) was an independent predictor of the prostate

cancer death rate in this study. In addition, the study’s “T0l” tumors (a unique stage different from T1a or A1) included tumors encompassing up to 25 percent of the

volume of the TURP specimen (as opposed to up to 5 percent for T1a or A1 tumors in the United States), and there has been no increase in hazard rate noted with

followup to 12.5 years. Moreover, a subset analysis for men who would be considered candidates for radical prostatectomy yielded similar results. Concerns have also

been raised about identification of prostate cancer by means of aspiration cytology, as was generally the mode of diagnosis in this study (214, 296); however, this

method had similar results to core biopsy in one Scandinavian study (358).
CHAPTER 4TREATING PROSTATE CANCER 37

Another recent study with long-term followup

showed similar results. It presented data from men diagnosed with clinically localized prostate cancer in Connecticut between 1971 and 1980, and treated with immediate or delayed hormonal therapy when necessary.

Again, grade, but not age, predicted cancer-specific survival. For men over 65, cause-specific 15-year survivals

were: well differentiated, 82 to 93 percent; moderately

differentiated, 67 to 78 percent; and poorly differentiated, 46 to 53 percent (194).

Chodak and colleagues have recently conducted a

meta-analysis including 828 men (mean age 70) enrolled

in expectant management studies from six centers with

10-year adjusted cancer survival rates: well differentiated, 87 percent; moderately differentiated, 87 percent;

and poorly differentiated, 34 percent (82, 83). Grade was

once again the dominant independent determinant of the

rate of prostate cancer mortality. The predicted metastasis-free survival at 10 years was lower than the survival

statistics would indicate: 81, 58, and 26 percent for well,

moderately, and poorly differentiated disease, respectively.7

The Risks of Expectant Management

The risks of expectant management for clinically

localized cancer include any higher rate of the development of metastases and prostate cancer-specific mortality that this strategy imposes over and above the rates

seen with active treatment.8 The magnitude of these added risks, if any, has not been defined. More clearly, men

managed expectantly have increased risks of local cancer progression compared with men treated with radical

prostatectomy; however, the clinical significance and

quality-of-life implications of local cancer progression

have not been well studied (343). Johansson reported

that 22 percent of the men in his study developed evidence of progression by DRE to Stage T3 over 10 years;

however, he recently reported that in only six cases were

local problems “substantial” and resistant to treatment

(176).9

Radiation Therapy

Radiation therapy administered for cure (also

known as radiotherapy) usually involves x-rays from an

external source delivered in maximal doses to the prostate, lesser doses to the seminal vesicle (located above

the prostate), and minimal radiation to the small bowel,

rectum, anal canal, and urethra (270). Adjustments are

made in the dose and targets based on the specific tumor

and host. Much less commonly, radioactive “seeds” are

placed in the prostate as primary therapy, or in combination with external beam radiotherapy, to increase the

dose delivered to the prostate while better protecting

nearby tissues. Patients usually receive external beam

radiotherapy in five weekday treatments over six or

seven weeks (20). Research is actively underway to

identify new methods of radiotherapy, such as three-dimensional conformal therapy, that may avoid underdosing the prostate while more effectively excluding surrounding normal tissues, reducing the associated risks

(209).

The relatively little attention given to radiation therapy in the recently published literature on prostate cancer detection and treatment may reflect the fact that urol7The reason for the discrepancy between the rate of metastatic disease and prostate cancer mortality, particularly for men with moderately differentiated cancer, is

not well understood; to some degree, early detection of a low burden of asymptomatic metastatic disease with periodic bone scans in these series may explain some

of the apparent delay between the development of metastases and cancer death implicit in these results (278).

8Waiting for signs of clinical progression will result in fewer cancers being pathologically localized at the time clinicians attempt curative treatment.

9Thirty patients did undergo TURP for obstructive symptoms, only about half of whom had cancer in the removed tissue (176).
38 COSTS AND EFFECTIVENESS OF PROSTATE CANCER SCREENING IN ELDERLY MEN

ogists, who most often recommend radical

prostatectomy for localized prostate cancer, have conducted these studies (362). However, as recent as 1990,

a study by the American College of Surgeons Commission on Cancer found that radiotherapy was used more

commonly than radical prostatectomy in the United

States for every stage of prostate cancer (238).10 In addition, a recent study suggested that prostate cancer patients in health maintenance organization settings were

more likely to receive radiotherapy rather than surgery

compared with patients in fee-for-service settings

(152).11

How Effective Is Radiation Therapy?

The effectiveness of radiotherapy, compared with

either expectant management or radical prostatectomy,

for reducing mortality and morbidity among men with

clinically localized cancer has not been well studied. A

single randomized clinical trial of 97 men with Stage A2

or B cancers found a significant improvement in time-torecurrence with surgery compared with radiation, but no

mortality difference (269, 359). However, because many

patients “crossed-over” to the other treatment after randomization and the analysis was based on “treatment

given” rather than “intention to treat,” these conclusions

may not be valid.

Although the results of only one imperfect clinical

trial are available, some additional evidence is available

from two cohort studies12 of patients with clinically

localized cancer treated with radiotherapy for cure -the

Patterns of Care Studies (PCS) (161, 197) and the Radiation Therapy Oncology Group (RTOG) study (#7706)

(15). At 10 years, overall survival among patients receiving radiation was no different than expected survival for

age-matched men without cancer (63 percent in PCS and

64 percent in RTOG). In the 1978 PCS, about 83 percent

of the 10 year survivors had no evidence of disease. For

men with palpable, clinically localized T2 cancers, overall survival at 10 years was 46 percent (i.e., about 20 percent lower than for cancer-free men of similar age), with

about 74 percent of the survivors classified as diseasefree (165). Radiation oncologists argue that, out to 10

years, these outcomes are equivalent to radical prostatectomy, particularly given the unknown nodal status of

the radiotherapy patients (87, 117, 161, 163, 165, 184,

208). In fact, for a subset of men in RTOG study with

negative lymph node dissections, most of whom had T2

cancers, cancer-specific survival was 86 percent after 10

years, with 79 percent metastasis-free survival (162).

In one of the literature reviews mentioned in the section on expectant management, only one study was

found to have stratified patient outcomes following

radiotherapy by grade and stage of disease (362). In all

the available cases of patients treated with radiotherapy,

these men had higher median rates of development of

distant metastases and cancer- specific mortality than

men treated with radical prostatectomy and expectant

management, but they also had more men with poorly

10Presumably, some patients who underwent a surgical examination of the pelvic lymph nodes prior to radical prostatectomy subsequently underwent radiotherapy

instead because of nodal involvement.

11However, registry data indicate that for the U.S. population as a whole, this trend reversed itself in 1991 with radical prostatectomy becoming the more commonly

used treatment strategy (166).

12Cohort studies are often used to compare the outcomes of two groups of patients similar in important characteristics other than the outcome of interest -in this case,

treatment strategy. Because of the inability to control retrospectively for all factors that might be related to treatment choice and outcome, the results of such a study

are inferior to a prospectively randomized clinical trial.
CHAPTER 4TREATING PROSTATE CANCER 39

differentiated cancers than series of either of the other

treatments (table 4-1). These nonexperimental comparisons may also be invalid because of the older age of radiotherapy patients, and the fact that patients with lymph

node involvement are included in radiotherapy series but

excluded from surgical series.

Many urologists worry that evidence of residual

cancer in many men following radiotherapy augurs

poorly for the prognosis of men treated this way (51, 75,

183, 210, 294, 297, 327, 359). On the other hand, rates

of biopsies after radiotherapy have been lower in some

recent small series of Stage T1 and T2 disease (cancers

confined to the prostate) given radiation treatment in a

particular manner (125), and the prognosis for men with

positive biopsies after radiotherapy is debated (275).

Risks of Radiation Therapy

Injury from radiotherapy to the radiosensitive tissues of the bladder and urethra can cause cystitis13 and

incontinence. Injury to the rectum can cause proctitis,14

and injury to the nerves and blood vessels adjacent to the

prostate can cause impotence (205). Table 4-2 provides

estimates of these risks based on a structured review of

the medical literature published since 1981 (362).15 This

literature does not allow estimation of the hazards of radiotherapy specifically among Medicare-age men.

However, preliminary analysis of a survey of complications of external beam radiotherapy among Medicareaged men suggests that about 5 percent of men use pads

to deal with incontinence and that 35 percent had noted

no partial or full erections since their treatments (27).

These results compare favorably to published data on the

complications of radical prostatectomy collected using

the same methods and discussed below (127).

Radical Prostatectomy

The third treatment strategy, radical prostatectomy,

entails removing the entire prostate with the tissues that

cover it and the seminal vesicles that sit above the gland.

In recent years, modification of the procedure by Walsh

and colleagues and a better understanding of the anatomy of the area (50) has allowed wider excision around

the prostate, but with special attention to nearby nerves

and blood vessels to reduce blood loss and post-operative incontinence and impotence. However, attempts to

preserve these nerves in cases of capsular penetration increases the risk of surgical margin positivity16 (267, 287).

How Effective Is Radical Prostatectomy?

Observational data indicate that men who undergo

radical prostatectomy tend to do well with prognosis dependent on disease stage (331). Those with organ-confined cancer have a low risk of recurrence and normal

life expectancies. For men with unconfined disease, one

recent study noted localized recurrence in 8 percent of

men within five years as opposed to metastases in 30 percent.17 This suggests that prostatectomy improves cancer control in the area around the prostate, even in situations when the rate of development of metastatic disease

elsewhere in the body may be unchanged (50, 248).

13Cystitis is an inflammation of the bladder.

14Proctitis is inflammation of the rectum.

15As with radical prostatectomy, complications from radiotherapy may depend on the expertise of the radiotherapist and treatment center. While some radiation

oncologists at major referral centers may have better outcomes than reflected in table 4-2, as reported recently by Shipley (312), a nationwide prostate cancer early

detection program may outstrip the capacity of these centers.

16Margin positivity refers to the discovery of cancerous tissue right up to the edge of the surgically removed tissue, raising the possibility that the operation may not

have removed all of the cancer.

17This is the opposite of the pattern described earlier for men who are treated by expectant management.
40 COSTS AND EFFECTIVENESS OF PROSTATE CANCER SCREENING IN ELDERLY MEN

TABLE 4-2: PERSISTENT ADVERSE OUTCOMES OF LOCALIZED PROSTATE CANCER TREATMENT

(from literature published since 1981) 





 Radical prostatectomy



  External beam radiation

 Mortality 

    Weighted mean

Sample size (number of men)





1.1%

400.0





0.2%

 496.0





Median probabilitya

Number of studies







2.0%

6.0

 



0.0%

8.0 

 Any incontinence 

   

Weighted mean

Sample size (number of men)





26.6%

301.0





6.1%

 443.0





Median probabilitya

Number of studies







16.0%

8.0

 



6.5%

6.0 

 Complete incontinence 

   

Weighted mean

Sample size (number of men)





6.8%

719.0





1.2%

 739.0





Median probabilitya

Number of studies







6.0%

11.0

 



1.0%

11.0 

 Any bowel injury 

    Weighted mean

Sample size (number of men)





2.7%

407.0





11.4%

 1,148.0





Median probabilitya

Number of studies







1.5%

4.0

 



13.5%

12.0 

 Bowel injury (requiring long-term treatment or colostomy) 



Weighted mean

Sample size (number of men)





1.3%

551.0





2.3%

 1,680.0





Median probabilitya

Number of studies







1.0%

6.0





1.0%

17.0



 Stricture requiring long-term treatment 



Weighted mean

Sample size (number of men)





12.4%

542.0





4.5%

 959.0





Median probabilitya

Number of studies







9.0%

9.0







2.5%

12.0





Impotence 



   

Weighted mean

Sample size (number of men)





84.6%

374.0





41.5%

 415.0





Median probabilitya

Number of studies







62.0%

7.0





44.0%

5.0







a Median probability across reported studies.

SOURCE: Office of Technology Assessment, 1995. Data from J.H. Wasson, C.C. Cushman, R.C. Bruskewitz, et al., “A Structured Literature Review of Treatment for Localized Prostate Cancer,” Archives of Family Medicine 2:487-493, 1993.
CHAPTER 4TREATING PROSTATE CANCER 41

However, the attributable benefit of radical prostatectomy is less clear.18 The structured literature synthesis of prostate cancer treatment, already described in the

discussion of expectant management, found rates of

death and metastasis that were not statistically different

for radical prostatectomy and expectant management

(table 4-1) (362). The good outcomes for men receiving

radical prostatectomy noted in observational studies are

in part due to better preoperative staging, and the exclusion of men whose cancer is found preoperatively to

have spread to the pelvic lymph nodes. Hence, nonexperimental comparisons of outcomes of expectant management, radiation therapy, and radical prostatectomy

are potentially confounded by different mixes of cancer

among these studies.

Only one clinical trial has compared expectant management and radical prostatectomy directly. In a Veterans Administration Cooperative Research Group (VACURG) clinical trial, 61 men with clinically localized

prostate cancer were randomized to radical prostatectomy and 50 men to expectant management; about half had

cancers found at TURP and half palpable cancers. After

seven years and again after 15 years, there is no statistically significant difference in survival between the two

treatment strategies (54, 147). However, the trial’s small

sample size impedes detection of any real difference that

may exist.19

The Risks of Prostatectomy

As indicated in table 4-2, Wasson’s synthesis of the

medical literature since 1981 indicates that the median

risk of death associated with radical prostatectomy itself

is about 1.1 percent; any incontinence, 27 percent; complete incontinence, 7 percent; impotence, 85 percent (31

percent in two studies of the never-sparing procedure);

and stricture (obstruction or narrowing of the urethra) requiring long-term treatment, 12 percent. However, the

definitions of adverse outcomes vary considerably among

the studies, and as with radiation therapy, the likelihood

of these outcomes are likely to vary with the experience

and skill of the surgeon and hospital (50, 69, 276). On the

other hand, these may be a lower-bound of the risks faced

by typical patients since publication bias may lead to underestimates (27). Furthermore, Medicare patients may

face higher risks because of age and comorbidities.

A recent survey that used Medicare claims data to

choose a national probability sample of men who have

received radical prostatectomy provides more generalizable estimates of the risks associated with this procedure

for Medicare beneficiaries (127).20 The results are presented in table 4-3 and stand in contrast to the less frequent adverse outcomes suggested by the preliminary

analysis mentioned earlier of a similar survey of Medicare-age men (albeit older ones) who underwent radiation therapy. Within this cohort of men over 65, the risk

of these complications was not related to age at surgery.

FOLLOWUP TREATMENT AFTER

CURATIVE THERAPY

After initial treatment by radiation or radical prostatectomy, clinicians often consider additional therapy if

18The attributable benefit is that portion of the total observed benefit in the treated population (i.e., extra years of life) actually due to radical prostatectomy as

opposed to other causes.

19After seven years, patients undergoing radical prostatectomy had a probability of death 0.01 higher than those receiving expectant management. However,

calculation of a 95-percent confidence interval around this figure indicates that the data are actually consistent with a probability of death with radical prostatectomy as much as 0.07 lower than that for expectant management as well as a probability as much as 0.09 higher than that for expectant management.

20The researchers analyzed Medicare claims data and performed a survey based on a national probability sample of 1,070 men who had radical prostatectomies

under Medicare between 1988 and 1990; they oversampled Massachusetts for a subexperiment to determine whether mode of interview (personal, mail, or phone)

gave different results. The method of interview did not affect any of the data presented in this paper (127).
42 COSTS AND EFFECTIVENESS OF PROSTATE CANCER SCREENING IN ELDERLY MEN

TABLE 4-3: ADVERSE OUTCOMES OF RADICAL PROSTATECTOMY AMONG MEDICARE BENEFICIARIES

Condition Percent of men reporting

Attributable 30-day post-operative mortalitya 0.6%

Cardiopulmonary complicationsb 4.0-5.0

Incontinence

 Wore pads or other devices for incontinencec 31.0

 Dripped more than a few drops daily 23.0

 Underwent surgical treatment for incontinence 6.0

 Had a catheter 2.0

Impotence

 Had ability to have erections prior to surgery 90.0

 No full or partial erections since surgery 61.0

 Had erections firm enough for intercourse in previous month 11.0

Underwent medical/surgical treatment for stricture,

2-4 years after surgery 20.0

a Total 30-day post-operative mortality (1%) minus probability of death for other causes.

b Congestive heart failure, myocardial infection, pulmonary embolism, or respiratory failure.

c Over 80% of these men reported dripping every day, indicating these pads and devices were not just used prophylactically.

SOURCE: Office of Technology Assessment 1995. Data from F.J. Fowler, M.S. Barry, A. Roman, et al. ”Patient-Reported Complications and

Follow-up Treatment After Radical Prostatectomy, The National Medicare Experience: 1988-1990 (Updated June 1993), ” Urology

42(6):622-629, 1993.

there is evidence of recurrence, spread, or indications

that the patients are at high risk of such problems. For

men who have had radiation treatment, the clinician can

consider “salvage” radical prostatectomy with evidence

of local progression (297, 370), but the results are usually disappointing (67).

After initial treatment by radical prostatectomy, clinicians often consider adjuvant radiation or androgen

deprivation therapy for men at higher risk of harboring

residual cancer, particularly those with positive surgical

margins or PSA test values that do not fall to female levels, although it is controversial whether these adjuvant

treatments improve survival (77, 373). Furthermore,

clinicians follow patients closely for evidence of recurrent disease with periodic DRE and PSA testing (35,

289). Men with evidence of recurrence are often considered for additional treatment with radiation. As is the

case for men treated expectantly, androgen deprivation

therapy may be instituted for men with locally symptomatic cancer recurrence, for men who develop distant metastases, or for some men without symptoms but a progressive abnormality on DRE or a rising PSA.

In the survey of Medicare-age men who underwent

radical prostatectomy between 1988 and 1990 discussed

above, 5 percent reported followup radiation therapy

within the first year (probably for residual disease), and

another 13 percent underwent radiation therapy between

the beginning of the second and the end of the fourth year

of followup (probably for evidence of recurrence). Ten

percent of men had hormonal therapy prescribed in the

four years following their operation, and 15 percent had

an orchiectomy.
CHAPTER

5

Benefits, Risks, and

Costs of Screening

his chapter draws from the literature reviewed in

the previous three chapters to analyze the impact of a hypothetical prostate cancer screening

program for Medicare-age men. In addition, it

uses data on Medicare reimbursements to examine some of the economic implications of early detection in this age group. As explained below, the screening

benefit analyzed is designed to be illustrative of the difficulties in drawing unambiguous conclusions about the

value of screening, rather than to predict the impacts of a

screening benefit as it actually would likely be implemented as part of Medicare.

A number of decision models have been published

or presented dealing with prostate cancer screening or

treatment (58, 124, 195, 196, 217, 316). These models

have yielded different results, due to widely different

“base case” assumptions about the probabilities and values of the various outcomes of these clinical policies.

The lack of definitive data on which to base such

assumption, particularly for the effectiveness of treating

localized prostate cancer, and the different values different patients may place on potential outcomes make it

possible to support analyses of screening that use divergent sets of assumptions.1

This paper only considers a one-time screening of

men at ages 65, 70, and 75. Realistically, a Medicare

benefit would most likely cover periodic screening for

example, a digital rectal examination (DRE) and prostate-specific antigen (PSA) every year as the American

Cancer Society (ACS) currently recommends, or every

two or three years as Medicare currently does for breast

and cervical cancer screening respectively. Understanding the true effects of an actual Medicare benefit would

also require accounting for the fact that some men would

have already received screening before their 65th birthdays. However, as this analysis will demonstrate, current

understanding does not allow a definitive assessment of

the cost-effectiveness of even a one-time benefit with its

relatively simplified set of assumptions, much less a

more complex, but realistic periodic benefit.

1For example, a recently published paper (30) used one of the decision analyses cited here (124) together with newer, life expectancy data that are more optimistic

than those used in the original decision analysis. The authors of the more recent paper conclude that their reanalysis leads to conclusions different from those drawn

by Fleming and colleagues. Beck and colleagues, the authors of the newer paper, suggest that radical prostatectomy for localized prostate cancer may actually

increase quality-adjusted life-years. These authors also endorse the continuation of randomized clinical trials to resolve issues of cancer progression rates and the

ultimate effectiveness of prostate cancer treatment, the two greatest unknowns in the decision about whether to screen for prostate cancer (30).
44 COSTS AND EFFECTIVENESS OF PROSTATE CANCER SCREENING IN ELDERLY MEN

The analysis is presented in three stages:

 The first stage models the health outcomes of a onetime screening program for three cohorts of 100,000

men 65, 70, and 75 years old respectively using a

baseline set of assumptions.

 The second stage adds in the costs of screening, treatment, and associated procedures to estimate the costeffectiveness of this illustrative one-time screening in

terms of dollars life-years gained compared with not

screening at all.

 The third stage examines how much these measures

of cost-effectiveness change with changes in the assumptions about the effectiveness of treating prostate

cancer and other assumptions important to screening.

MODELING THE HEALTH OUTCOMES

OF SCREENING

To estimate the health outcomes of a one-time

screening program for each of the three age groups, the

model follows a hypothetical cohort of 100,000 men. It

assumes a certain underlying distribution of prostate

cancers of different types. It subjects the men to a combined DRE/PSA screening program (using a 4 ng/mL

PSA cutpoint) and follows them with assumptions about

diagnostic and treatment strategies as well as the probabilities of the different outcomes of these strategies.

Rather than assign different “values,” or “utilities,”

to nonfatal outcomes such as postsurgical incontinence

or metastatic disease, which will be valued differently by

different patients (317), the analysis simply records the

number of patients with these problems and the lifeyears over which these problems must be endured, allowing the reader to weigh the risks and benefits of the

decision whether to screen. At this stage, the analysis

does not downvalue (discount) future years of life, or account for future life-years that would be of lower quality

due to disability, loss of independence, or other health

problems (225).2

The discussion that follows outlines the assumptions used in this model and ties them to the literature review in the preceding chapters. Table 5-1 summarizes

these assumptions for 65- and 75-year-old men. All agespecific probabilities for 70-year-old men are the average of the probabilities for those 65 and 75.

Assumptions in the Model

The model employs a Markov process that extends

one developed for a published study of the outcomes of

treating clinically localized prostate cancer (124).3 It

simulates the clinical course of each cohort of men by allowing them to make transitions from one health state to

another in increments of six months. During any six

month period, men who harbor prostate cancer in the cohort may present with either local obstruction requiring

therapy or develop new metastatic disease. Grade-specific rates of developing metastases come from a patientlevel meta-analysis recently conducted by Chodak and

colleagues (83).

Probabilities of Prostate Cancer

The model distinguishes among three types of cancer by size: 1) <0.5 mL, all assumed to be contained with

the prostate capsule; 2) >0.5 mL with <1 cm of capsular

penetration; and, 3) >0.5 mL with >1cm of capsular pen2However, the section on cost-effectiveness analysis below appropriately discounts both future years of life and future costs.

3 A Markov model is a quantitative tool useful in understanding how people move through different states of the world (in this case, states of health) over time when: 1)

there are a finite number of states, 2) any individual can fall into only one state in any given time period, 3) the probability of moving from one state to the next over any

two periods of time is known, and 4) the periods of time are uniform in length (335). In this analysis, the Markov model describes how many members of each cohort of

men experience different types of cancer, treatment complications, other symptoms, and death, when they experience each event, and (as seen later) what costs

they incur for Medicare along the way.
CHAPTER 5BENEFITS, RISKS, AND COSTS OF SCREENING 45







TABLE 5-1: BASELINE ASSUMPTIONS USED TO MODEL HEALTH OUTCOMES OF PROSTATE CANCER SCREENING OF MEN AGE 65

AND 75 WITH DIGITAL RECTAL EXAM AND PROSTATE-SPECIFIC ANTIGEN









Probability

Assumption 



65-year-old men 



75-year-old men



 Derivation of poor probabilities of prostate cancer 

   1. Probability of any cancer = (A) 0.22  0.39

 2. Probability of cancer being < 0.5 mL (insignificant, assume all confined) = (B)



 0.60

   0.60





3. Probability of cancer being > 0.5 mL (significant) with < 1 cm of capsular penetration

(intracapsular) = (C)

 



0.4x0.73=.29

 



0.4x0.73=.29





4. Probability of cancer being > 0.5 mL (significant) with > 1 cm of capsular penetration

(extracapsular) = (D)



 0.4x0.27=.11



 0.4x0.27=.11 

 5. Derived prior probability of insignificant (< 0.5 mL) cancer = (AxB)  0.132  0.234 



6. Derived prior probability of significant cancer (>0.5 mL), intracapsular = (AxC) 



0.064 

  0.114

 7. Derived prior probability of significant cancer (>0.5 mL), extracapsular = (AxD)



 0.024

   0.042

 Probabilities of cancers having different grades





    Insignificant cancers (<0.5 mL)





    8. Well differentiated



 0.65



 0.65 

 9. Moderately differentiated  0.26  0.26 



10. Poorly differentiated 



0.09 



0.09





Significant (>0.5 mL) intracapsular cancer 



   11. Well differentiated 0.33  0.33

 12. Moderately differentiated



 0.56



 0.56 

 13. Poorly differentiated  0.11  0.11 

 Significant (>0.5 mL) extracapsular cancers 

    14. Well differentiated 

 0.04  0.04   15. Moderately differentiated  0.70  0.70

 16. Poorly differentiated



 0.26

   0.26

 Derivation of screening results





    17. Probability of a suspicious DRE or PSA requiring biopsy = (E) 

 0.28  0.40 

 18. Overall probability of detection of cancer (actual yield) = (F)  0.042  0.072   19. Proportion of detected cancers with insignificant (< 0.5 mL) volume = (G)  0.11  0.11





20. Derived probability of finding an insignificant cancer among men who harbor them =

(FxG)/(AxB)

 

 0.035

 

 0.034 



21. Probability that screen detected cancers are extracapsular = (H) 



0.24 



0.40





22. Derived probability of detecting extracapsular cancers among men who harbor them

= (FxH)/(AxD)



 0.42



 0.69 

 23. Derived probability of detecting significant, intracapsular cancers among men who

harbor them =Fx(1-G-H)/(AxC)



 0.43

   0.31

 Probabilities of biopsy complications (with antibiotic prophylaxis)





    24. Urinary tract infection



 0.056



 0.056 

 25. Urosepsis  0.005  0.005

CONTINUED46 COSTS AND EFFECTIVENESS OF PROSTATE CANCER SCREENING IN ELDERLY MEN



 

TABLE 5-1: BASELINE ASSUMPTIONS USED TO MODEL HEALTH OUTCOMES OF PROSTATE CANCER SCREENING OF MEN AGE 65

AND 75 WITH DIGITAL RECTAL EXAM AND PROSTATE-SPECIFIC ANTIGEN CONTINUED  





 Probability

Assumption 

 65-year-old men  75-year-old men 

 Treatment compliance 

    26. Probability of men with confirmed cancer receiving treatment 

 0.70  0.48 

 Probabilities of radical prostatectomy complications: 

   

28. Attributable surgical mortality 



0.006 



0.006

  29. Nonfatal serious cardiopulmonary complications  0.04  0.08

 30. Probability of incontinence



 0.23

   0.23

 31. Probability of impotence



 0.61



 0.61 





  

Expected remaining years of life





Assumption 



65-year-old men 



75-year-old men





Life expectancy (in years)a 



   32. Without cancer 14.45  8.95

 33. With untreated, well-differentiated cancer, < 0.5 mL



 14.45

   8.95

 34. With untreated, well-differentiated cancer, > 0.5 mL



 12.64



 8.26 

 35. With untreated, moderately differentiated cancer  12.64  8.26 

 36. With untreated, poorly differentiated cancer  7.57  6.01 



37. With treated intracapsular cancer (< 0.5 mL and > 0.5 mL, all grades) 



14.45 



8.95

  38. With treated extracapsular, well differentiated cancer  12.64  8.26

 39. With treated extracapsular, moderately differentiated cancer



 12.64



 8.26 

 40. With treated extracapsular, poorly differentiated cancer  7.57  6.01 

 





a Metastatic rates for well (> 0.5 mL), moderately, and poorly differentiated cancers derived from G.W. Chodak, R.A. Thisted, G.S. Gerber, et al., “Results of Conservative Management of Clinically Localized Prostate Cancer,” New England Journal of Medicine 330:242-248, 1994. Metastatic rates for these cancers are assumed not

to vary by volume or capsular status (i.e., only by grade), except for well-differentiated cancers < 0.5 mL, which are assumed not to metastasize. See text for details.

SOURCE: Office of Technology Assessment, 1995. Based on data from M.J. Barry, C.M. Coley, C. Fleming, et al., “The Safety, Effectiveness, and Cost of Early Detection

and Treatment of Prostate Cancer Among Older Men: A Report to the Congressional Office of Technology Assessment,” OTA contract paper no, K3-0546.0. Massachusetts General Hospital, June 30, 1994.

etration. The underlying prevalence of each of these cancers in the population is derived from autopsy data presented in table 2-5 and explained in appendix A. Pathological data from Oesterling’s study (263) of 208

nonpalpable, PSA-detected, Stage T1c prostate cancers

provide the probabilities of each size of cancer being

well differentiated (Gleason Score of 2 to 4), moderately

differentiated (Gleason Score of 5 to 6), or poorly differentiated (Gleason Score of 7 to 10) (256).

Screening and Biopsy

The probabilities that screening yields a suspicious

DRE or PSA requiring biopsy (table 5-1, line 17) comes

from Richie and colleagues’ community-based screen-
CHAPTER 5BENEFITS, RISKS, AND COSTS OF SCREENING 47

ing study (279),4 as do the overall probabilities that

screenees will have a cancer detected and the probabilities that cancers detected through screening will not be

confined to the prostate gland (table 5-1, lines 18 and

21).5 The analysis assumes that transrectal needle biopsy

(TRNB) is the “gold standard” for confirming or rejecting suspicious DRE/PSA results. In the Richie study,

only 69 percent of men ages 60 to 69 with suspicious

PSA or DRE results actually received biopsy. For men

ages 70 to 79, the biopsy compliance rate is 68 percent.

These compliance rates are implicit in the probabilities

that screening will detect cancer in both the Richie study

and the analysis in this chapter (table 5-1, line 18). The

probabilities that detected cancers will be of small volume (< 0.5 mL) come from Oesterling and colleagues’

study of the pathology of nonpalpable T1c cancers described above.6

Combining these data on screening results with the

data on the prior probabilities of harboring cancers allow

the estimation of age- and volume-specific sensitivities

for a one-time combined DRE and PSA screening (table

5-1, lines 20, 22, and 23).7

As indicated in chapter 3, biopsy itself can result in

infection even with antibiotic prophylaxis. Assumptions

about the rates of infections confined to the urinary tract

(16, 89,) and urosepsis (91) are taken from the literature.

Treatment Strategies and Cure Rates

Because biopsy cannot determine the volume,

grade, and extent of spread of discovered cancers, this

analysis assumes all men found to have cancer are offered aggressive treatment. Based on data from Richie

(279), 70 percent of 65-year-old men are assumed to accept that recommended treatment; the analysis assumes

a 48-percent compliance rate for 75-year-old men.

4It is interesting to note that the proportion of Medicare-age screenees who would have suspicious results on DRE and PSA testing (28 to 40 percent depending on

age) is much higher than for mammography (up to 6 percent) (351), fecal occult blood testing (2 to 5 percent) (348), or Pap smears (1 to 13 percent) (347). Thus, the

level of intrusiveness of a strategy of early detection of prostate cancer, with recommendations for biopsy being generated in over a quarter of screenees, is much

greater than among other commonly used cancer screening strategies.

5These estimates of the age-specific yield of combined DRE and PSA screening, which come from the study by Richie (72, 279), favor screening since the volunteers

who participated in the study may have had an enriched prevalence of cancer. As previously noted in chapter 3, a community-based study using the same screening strategy among men ages 40 to 79 found cancer in 5 out of 537 (<1%) screenees (261).

6Among prostate-confined cancers, the Richie study (279) does not distinguish between the volume categories used in this analysis (<0.5 mL and >0.5 mL). Hence, this

analysis uses Oesterling’s 11 percent probability that detected cancers are <0.5 mL (263) even though the Oesterling data are not age-specific. The resulting mix of

cancers discovered by screening and coming to radical prostatectomy predicted by the model at age 65 are as follows: <0.5 mL, 11 percent; >0.5 mL and intracapsular, 65 percent; and .05mL and extracapsular, 24 percent. This distribution is actually considerably more favorable than the distribution of T1c cancers coming to

radical prostatectomy recently described by investigators at Johns Hopkins University (52, 119): insignificant or “minimal” (<0.5 mL), 26 percent; “moderate” (includes

some cancers with capsular penetration if well or moderately differentiated), 40 percent; and “advanced,” 34 percent. However, those investigators felt that only

tumors less than 0.2 mL with a Gleason grade less than seven were truly “insignificant,” and candidates for expectant management; this category comprised 16

percent of their T1c tumors. Oesterling (263), on the other hand, found that only 11 percent of his series of T1c cancers were less than 0.5 mL in volume, and Richie (279)

reported that only 24 percent of screen-detected cancers in men this age were unconfined; as indicated, this model reflects Oesterling and Richie’s more favorable

probabilities.

7The model-estimated sensitivities of combined PSA/DRE/biopsy are lower than many clinicians would predict. For example, at age 65, 3.5 percent of cancers less

than 0.5 mL, 42 percent of intracapsular cancers >0.5 mL, and 43 percent of extracapsular cancers >0.5 mL would be detected. However, if one assumes full compliance with biopsy for suspicious screening results (instead of 69 percent), the estimated sensitivities of DRE/PSA/biopsy would increase to 5, 60, and 62 percent,

respectively. These estimated sensitivities reflect the assumption that cancers are distributed by volume according to the autopsy study by McNeal (233) described in

table 2-5 and appendix A. Assuming different distributions of cancers by volume would affect the estimated sensitivities, but would not affect the estimated benefits of

screening, which are based on the post-test distributions of cancer reported in screening studies. For example, if only 20 percent, (rather than 40 percent) of prevalent

cancers are greater than 0.5 mL in size, as reported in some cystoprostatectomy series (328), the sensitivity of screening at age 65 for cancers less than 0.5 mL would

drop to 4 percent, and the predicted sensitivities of DRE/PSA/biopsy (assuming perfect compliance) for intracapsular and extracapsular cancers >0.5 mL would both

be over 100 percent. In other words, the yield of cancers >0.5 mL described by Richie (279) would actually be greater than the predicted prevalence of these lesions.
48 COSTS AND EFFECTIVENESS OF PROSTATE CANCER SCREENING IN ELDERLY MEN

Because there is no evidence from controlled studies that aggressive treatment (by either radical prostatectomy or radiation therapy) reduces the risk of death

compared with expectant management, this analysis assumes that men with cancers confined to the prostatic

capsule (absence of complete capsular penetration of

more than 1 cm2) are cured by aggressive treatment, regardless of other prognostic factors, such as degree of tumor differentiation. This assumption, which is favorable

to screening (all else being held equal) is based on the

work of Epstein (118), who has documented a worse

prognosis for tumors with established, complete capsular penetration, as opposed to partial capsular penetration.8

Although there are two strategies for aggressive

treatment (radical prostatectomy and radiation therapy),

the baseline analysis examines only radical prostatectomy. This initial assumption seems reasonable despite

older data that radiotherapy has been more commonly

used, as the urologic literature now strongly endorses

radical prostatectomy as the best treatment for localized

prostate cancer, and because men with suspicious

screening tests would almost always see a urologist for

TRUS and biopsy. The rapidly rising rates of radical

prostatectomy in the United States also support this initial assumption. Assuming equal effectiveness for radiation therapy (in the absence of strong evidence to the

contrary) would result in similar estimated benefits;

however, estimated risks would be much lower.9

Patients who are found to have distant metastases

are assumed to receive hormonal therapy. Patients receiving such therapy are assumed to be responsive to it

for a period of time, but then enter a “refractory” period

characterized by no further benefit as well as pain or other discomfort before dying from the cancer or, infrequently, from some other cause.

All patients with intracapsular cancers (whether

>0.5 mL or <0.5 mL in volume) who undergo and survive treatment are assumed to have the same life expectancy they would have had if they never had cancer

(14.45 years for 65-year-old men and 8.95 years for 75-

year-old men). In addition to the extra years of life they

gain, these patients also avoid years of both hormone-responsive and refractory disease and associated morbidity. At the same time, though, they do risk the complications of aggressive treatment as outlined in the next

section. Treated patients whose cancers are found to

have spread beyond the prostate capsule at time of surgery have the same life expectancy as untreated patients

with extracapsular cancer.

Finally, the analysis assumes that following radical

prostatectomy, no additional cancer treatment is administered unless patients develop documented metastatic

disease (as described below). In fact, in a survey of

Medicare beneficiaries, 18 percent of men without metastatic disease reported followup radiation therapy within

four years of radical prostatectomy, 10 percent reported

hormonal therapy, and 15 percent reported orchiectomy

(124). As is the case for primary aggressive treatment,

there is no evidence from controlled studies that any

such interventions (in the absence of documented metastases, at least) improve patient outcomes. Exclusion of

8Although some men with established capsular penetration and no evidence of the tumor on the outside of tissue removed during prostatectomy (negative surgical

margins) may be cured as well, these cases are balanced by Epstein’s observation that roughly 25 percent of men with only partial capsular penetration had in fact

demonstrated evidence of progression after eight years.

9Estimates of the treatment complications that would accrue if all patients were treated with radiotherapy, rather than radical prostatectomy, are presented later.
CHAPTER 5BENEFITS, RISKS, AND COSTS OF SCREENING 49

the costs associated with these additional treatments in

the cost-effectiveness analysis later in this chapter reduces the total costs associated with screening, thus generating more favorable cost-effectiveness ratios.

Treatment Complications

Assumptions about the rate of complications following prostatectomy come from the survey of Medicare

beneficiaries by Fowler and colleagues (124) since these

are the most generalizable data available (see table 4-3).

Among these risks, the model uses relatively conservative definitions for incontinence and impotence. Only

men who drip more than a few drops of urine every day

are considered incontinent10; while only preoperatively

sexually active men who have had no partial or full erections since surgery are considered impotent.11

Although pelvic lymphadenectomy has its own

complications (229), we assume no complications for

this procedure as some clinicians question whether it is

necessary at all. The analysis disregards other, less frequent complications of surgery and radiotherapy, such as

rectal injury (230).

Prognosis and Life Expectancy

The analysis assumes that prognosis is determined

entirely by grade, rather than extent of tumor; that is, a

moderately differentiated cancer has the same prognostic impact whether it is intracapsular or extracapsular.

The only exception is for well-differentiated tumors less

than 0.5 mL in volume, which are assumed not to have

potential for metastasis, and hence, equivalent to not

having cancer at all.

Table 5-1 details life expectancies for untreated cancers.12 Age-specific probabilities of death from causes

other than prostate cancer used in the model were

derived from U.S. life tables (350). Grade-specific rates

of developing metastatic cancer come from an individual patient level meta-analysis by Chodak and colleagues

(83). These data also generated grade-specific estimates

of life expectancy for men with untreated cancers. The

impact of treatment on rates of metastasis and these life

expectancies are described above.

To model the progression from hormonally-responsive to hormonally-refractory metastatic cancer and the

excess mortality associated with advanced prostate cancer, the model incorporates data from a randomized trial

of hormonal treatment of late-stage disease (93). The

data yield a progression rate to refractory prostate cancer

of 36 cases per 100 patient years, and an excess mortality

rate from hormonally-refractory metastatic cancer of 80

deaths per 100 patient years.13

Men who have prostate cancer are susceptible not

only to metastatic disease, but to complications from local progression as well. Obstructive symptoms or bleeding from progression in the prostate may require transurethral resection of cancer tissue for palliation. Men

who still have a prostate in place may also eventually re10If wearing pads is used to define incontinence, the risk would be higher; see table 4-3.

11Excluding consideration of all treatment-related complications other than the two most common ones, impotence and incontinence, is another assumption that

favors screening in this analysis.

12The analysis incorporates relatively high rates of grade-specific metastatic and cancer-specific death rates in this model; these rates are calibrated to the 10-year

cancer-specific survivals reported in Chodak’s (83) individual-patient-level meta-analysis, which excluded studies of Stage A1 cancers, which may well be treated

aggressively in some patients in the current environment. These metastatic and death rates are favorable to screening. As a result of these assumptions, the model

predicts that a 65-year-old man has a cumulative probability of eventually dying of prostate cancer of 4.1 percent, while the empirical epidemiologic evidence

documents this risk is 3 percent or less (308, 314). Higher metastatic rates or assignment of metastatic potential to small volume, well-differentiated tumors would cause

even greater divergence between the predicted and observed cumulative incidences of prostate cancer mortality.

13Median survival in this trial once the disease became hormonally refractory was 0.9 years.
50 COSTS AND EFFECTIVENESS OF PROSTATE CANCER SCREENING IN ELDERLY MEN

quire transrectal resection of the prostate (TURP) for

progressive benign prostatic hyperplasia (BPH). This

analysis assumes that radical prostatectomy completely

eliminates these risks and their associated costs. Assumptions used to calculate costs of transurethral resection for those men with cancer who do not receive radical

prostatectomy are reviewed in the section on costs later

in this chapter.

The assumptions about prognosis and cure rates

from treatment are particularly favorable to screening;

to the extent that relatively more future morbidity and

mortality result from cancers that have already spread

beyond the prostate (a likely scenario), the benefits of

screening will be less impressive. Another way of viewing the impact of these assumptions is through the reduction in the rate of metastases through the treatment patients receive. For well-differentiated cancers, the model

predicts a 97 percent decrease in the metastatic rate

compared with 70 percent for moderately differentiated,

and 56 percent for poorly differentiated cancers.

Net Impact of Assumptions

As indicated in the sections above, many of the assumptions made in this baseline analysis of the health

outcomes of a one-time screening benefit are favorable

to screening. These include relatively high yields of

screening itself, high rates of metastasis and cancer-specific death with untreated cancers, and 100 percent cure

rates for treated intracapsular cancers.14 Given these assumptions, the estimated health outcomes for screening

with subsequent aggressive treatment in this baseline

analysis probably represent the maximally attainable

benefits of one-time screening.

Results

Tables 5-2 through 5-4 provide “balance sheets”

with baseline estimates of the risks and maximal benefits

of a one-time screening of 100,000 men ages 65, 70, and

75 with DRE and PSA. Table 5-5 presents estimates of

treatment complications that would accrue if all patients

undergoing treatment received radiation therapy instead

of radical prostatectomy. These estimates are based on

rates of complications reported in the literature and summarized in chapter 4 (362).

The model indicates that a one-time screening

would result in a very large number of prostatic biopsies

(19,330 to 27,200 per 100,000, depending on age), a

small number of surgical deaths (18 to 23 per 100,000),

and a larger number of men rendered incontinent (260 to

311 per 100,000), impotent (1,357 to 1,622 per 100,000),

or both (405 to 483 per 100,000) as a result of surgical

treatment. Because these complications must be endured

from the start, a very large number of life-years with

these complications are generated by early detection efforts. Over time, using the optimistic assumptions about

the efficacy of treatment, 653 men age 65, 570 men age

70, and 427 men age 75 who would otherwise have developed metastatic prostate cancer (542, 449, and 314 of

whom would become hormone-refractory and die, respectively) would die of something else first in each of

these cohorts of 100,000 screenees. The net benefit of

14The fact that this part of the analysis does not “discount” future life-years relative to current life-years also favors screening as risks of treatment. Discounting accounts for the fact that future costs and benefits are valued less than the same outcomes encountered in the present. It is particularly significant in the case of prostate

cancer screening and treatment since the benefits of treatment (and risks of cancer) are faced in the future, while the risks of screening and treatment are faced in

the present. Hence, discounting would diminish the estimated life-years gained through screening. The analysis does discount future health benefits subsequently

when examining the costs and cost-effectiveness of screening.
TABLE 5-2: HEALTH OUTCOMES OF A ONE–TIME PROSTATE CANCER SCREENING OF 100,000 65-YEAR-OLD MEN WITH DRE/PSA

Cancer > 0.5 mL

No cancer Cancer < 0.5 mL Intracapsular Extracapsular Total number LY lost LY morbidity

Number screened 78,000 13,200 6,424 2,376 100,000Estimated harmCA missed by DRE/PSA/biopsy (compliance with biopsy 69%) 12,744 3,743 1,363 17,850CA detected by DRE/PSA/biopsy 456 2,681 1,013 4,150Suspicious DRE/PSA 28,000TRUS/biopsy (compliance with biopsy 69%) 19,330

Urinary tract infections from biopsy 1,083Urosepsis from biopsy 96Death from urosepsis 1 (14)a

Radical prostatectomy (compliance with RPX 70%) 320 1,877 709 2,906

Deaths from radical prostatectomy 2 12 4 18Life-years lost from radical prostatectomy deaths (28) (167) (50) (245)

Morbidity from radical prostatectomy

Incontinence: n affected

life-years affected

Impotence: n affected

life-years affected

Both incontinence and impotence n affected

life-years affected

Total harm from screening (life–years) (259) (27,510)Total harm per patient screened (days) (1) (100)Total harm per patient treated (days) (33) (3,455)

CONTINUED

Chapter 5 Benefits, Risks, and Costs of Screening 51
TABLE 5-2: HEALTH OUTCOMES OF A ONE–TIME PROSTATE CANCER SCREENING OF 100,000 65-YEAR-OLD MEN WITH DRE/PSA CONTINUED

Cancer > 0.5 mL

No cancer Cancer < 0.5 mL Intracapsular Extracapsular Total number LY saved LY improved

Estimated maximal benefit

Survive radical prostatectomy 318 1,865 705 2,888

Hormonally–responsive metastatic cancer

Number spared by treatment 45 608 0 653b

Life–years affected 72 731 0 803

Hormonally–refractory metastatic cancer

Number spared by treatment 38 504 0 542b

Life–years affected 27 260 0 287

Cancer deaths prevented 38 504 0 542bAdditional years of life attained 338 4,274 0 4,612

Total benefit from screening (life-years) 4,612 1,090Total benefit per patient screened (days) 174Total benefit per patient treated (days) 579 137

a Life-years and days lost through screening are presented in parenthesis.b Six additional cases of hormonally–responsive metastatic disease leading to five cases of hormonally refractory metastatic disease and death are averted through immediate operative deaths; these

cases are not counted as benefits.KEY: CA: cancer; DRE = digital rectal examination; LY = life-years; PSA = prostate-specific antigen; RPX = radical prostatectomy; TRUS = transrectal ultrasound.

SOURCE: Office of Technology Assessment, 1995. Based on data from M.J. Barry, C.M. Coley, C. Fleming, et al., “The Safety, Effectiveness, and Cost of Early Detection and Treatment of Prostate Cancer

Among Older Men: A Report to the Congressional Office of Technology Assessment,” OTA contract paper no. K3–0546.0, Boston, MA: Massachusetts General Hospital, June 30, 1994.

52 Costs and Effectiveness of Prostate Cancer Screening in Elderly Men
TABLE 5-3: HEALTH OUTCOMES OF A ONE–TIME PROSTATE CANCER SCREENING OF 100,000 70-YEAR-OLD MEN WITH DRE/PSA

Cancer > 0.5 mL

No cancer Cancer < 0.5 mL Intracapsular Extracapsular Total number LY lost LY morbidity

Number screened 69,500 18,300 8,906 3,294 100,000Estimated harmCA missed by DRE/PSA/biopsy (compliance with biopsy 69%) 17,674 5,671 1,460 24,805CA detected by DRE/PSA/biopsy 626 3,235 1,834 5,695Suspicious DRE/PSA 34,000TRUS/biopsy (compliance with biopsy 69%) 23,460

Urinary tract infections from biopsy 1,314Urosepsis from biopsy 117Death from urosepsis 1 (12)

Radical prostatectomy (compliance with RPX 59%) 369 1,909 1,082 3,360

Deaths from radical prostatectomy 2 12 7 21Life-years lost from radical prostatectomy deaths (27) (140) (66) (233)

Morbidity from radical prostatectomy

Incontinence: n affected 301

life-years affected (3,229)

Impotence: n affected 1,569

life-years affected (16,908)

Both incontinence and impotence n affected 467

life-years affected (5,050)

Total harm from screening (life–years) (245) (25,187)Total harm per patient screened (days) (1) (92)Total harm per patient treated (days) (27) (2,736)

CONTINUED

Chapter 5 Benefits, Risks, and Costs of Screening 53
TABLE 5-3: HEALTH OUTCOMES OF A ONE–TIME PROSTATE CANCER SCREENING OF 100,000 70-YEAR-OLD MEN WITH DRE/PSA CONTINUED

Cancer > 0.5 mL

No cancer Cancer < 0.5 mL Intracapsular Extracapsular Total number LY saved LY improved

Estimated maximal benefit

Survive radical prostatectomy 367 1,897 1,075 3,339

Hormonally–responsive metastatic cancer

Number spared by treatment 46 524 0 570a

Life–years affected 67 560 0 627

Hormonally–refractory metastatic cancer

Number spared by treatment 37 412 0 449a

Life–years affected 22 180 0 202

Cancer deaths prevented 37 412 0 449aAdditional years of life attained 254 2,765 0 3,019

Total benefit from screening (life-years) 3,019 829Total benefit per patient screened (days) 113Total benefit per patient treated (days) 328 90

a Six additional cases of hormonally–responsive metastatic disease leading to five cases of hormonally refractory metastatic disease and death are averted through immediate operative deaths; these

cases are not counted as benefits.KEY: CA: cancer; DRE = digital rectal examination; LY = life-years; PSA = prostate-specific antigen; RPX = radical prostatectomy; TRUS = transrectal ultrasound.

SOURCE: Office of Technology Assessment, 1995. Based on data from M.J. Barry, C.M. Coley, C. Fleming, et al., “The Safety, Effectiveness, and Cost of Early Detection and Treatment of Prostate Cancer

Among Older Men: A Report to the Congressional Office of Technology Assessment,” OTA contract paper no. K3–0546.0, Boston, MA, Massachusetts General Hospital, June 30, 1994.

54 Costs and Effectiveness of Prostate Cancer Screening in Elderly Men
TABLE 5-4: HEALTH OUTCOMES OF A ONE–TIME PROSTATE CANCER SCREENING OF 100,000 75-YEAR-OLD MEN WITH DRE/PSA

Cancer > 0.5 mL

No cancer Cancer < 0.5 mL Intracapsular Extracapsular Total number LY lost LY morbidity

Number screened 61,000 23,400 11,388 4,212 100,000Estimated harmCA missed by DRE/PSA/biopsy (compliance with biopsy 68%) 22,604 7,843 1,318 31,765CA detected by DRE/PSA/biopsy 796 3,545 2,894 7,235Suspicious DRE/PSA 40,000TRUS/biopsy (compliance with biopsy 68%) 27,200

Urinary tract infections from biopsy 1,523Urosepsis from biopsy 136Death from urosepsis 1 (9)

Radical prostatectomy (compliance with RPX 48%) 382 1,702 1,389 3,473

Deaths from radical prostatectomy 3 11 9 23Life-years lost from radical prostatectomy deaths (23) (100) (71) (194)

Morbidity from radical prostatectomy

Incontinence: n affected 311

life-years affected (2,597)

Impotence: n affected 1,622

life-years affected (13,598)

Both incontinence and impotence n affected 483

life-years affected (4,062)

Total harm from screening (life–years) (203) (20,257)Total harm per patient screened (days) (1) (74)Total harm per patient treated (days) (21) (2,129)

CONTINUED

Chapter 5 Benefits, Risks, and Costs of Screening 55
TABLE 5-4: HEALTH OUTCOMES OF A ONE–TIME PROSTATE CANCER SCREENING OF 100,000 75-YEAR-OLD MEN WITH DRE/PSA CONTINUED

Cancer > 0.5 mL

No cancer Cancer < 0.5 mL Intracapsular Extracapsular Total number LY saved LY improved

Estimated maximal benefit

Survive radical prostatectomy 379 1,691 1,380 3,450

Hormonally–responsive metastatic cancer

Number spared by treatment 40 387 0 427a

Life–years affected 63 417 0 480

Hormonally–refractory metastatic cancer

Number spared by treatment 30 284 0 314a

Life–years affected 3 38 0 41

Cancer deaths prevented 30 284 0 314aAdditional years of life attained 159 1,459 0 1,618

Total benefit from screening (life-years) 1,618 521Total benefit per patient screened (days) 62Total benefit per patient treated (days) 170 55

a Six additional cases of hormonally–responsive metastatic disease leading to five cases of hormonally refractory metastatic disease and death are averted through immediate operative deaths; these

cases are not counted as benefits.KEY: CA = cancer; DRE = digital rectal examination; LY = life-years; PSA = prostate-specific antigen; RPX = radical prostatectomy; TRUS = transrectal ultrasound.

SOURCE: Office of Technology Assessment, 1995. Based on data from M.J. Barry, C.M. Coley, C. Fleming , et al., “The Safety, Effectiveness, and Cost of Early Detection and Treatment of Prostate Cancer

Among Older Men: A Report to the congressional Office of Technology Assessment,” OTA contract paper no. K3–0546.0, Boston, MA, Massachusetts General Hospital, June 30, 1994.

56 Costs and Effectiveness of Prostate Cancer Screening in Elderly Men
CHAPTER 5BENEFITS, RISKS, AND COSTS OF SCREENING 57

TABLE 5-5: EXPECTED HARM FROM A ONE-TIME PROSTATE CANCER SCREENING (DRE/PSA) OF 100,000 MEN, AGES 65, 70, OR

75, FOR CURATIVE RADIATION THERAPY

  Morbidity  Life-years of morbidity

 Age 65





    Incontinence

   1,385





 Impotence



 11,275 





 Both incontinence and impotence  593 





 Total harm from screening  13,253 







Total harm per patient screened (days) 



48

 Total harm per patient treated (days) 1,664

 Age 70





    Incontinence

   1,269





 Impotence



 10,337 





 Both incontinence and impotence  544 





 Total harm from screening  12,150 







Total harm per patient screened (days) 



45

 Total harm per patient treated (days) 1,321

 Age 75





    Incontinence

   1,023





 Impotence



 8,329 





 Both incontinence and impotence  438 





 Total harm from screening  9,790 







Total harm per patient screened (days) 



36

 Total harm per patient treated (days) 1,029

SOURCE: Office of Technology Assessment, 1995. Based on data from M.J. Barry, C.M. Coley, C. Fleming, et al., “The Safety, Effectiveness, and Cost of Early Detection

and Treatment of Prostate Cancer Among Older Men: A Report to the Congressional Office of Technology Assessment.” OTA contract paper no. K3-0546.0, Massachusetts General Hospital, Boston, MA, June 30, 1994.

screening in each cohort would be 4,353, 2,774, and

1,415 life-years saved (without discounting) for the

100,000 men ages 65, 70, and 75; or 16, 10, and 5 days

per man screened, respectively. 

If, in fact, contrary to our initial, “best case” assumptions, aggressive treatment of prostate cancer is ineffective at reducing the rate of distant metastases and

death, these cohorts would loose about 200 life-years

due to operative mortality and endure over 20,000 lifeyears with incontinence, impotence, or both. The net

benefit predicted by the model is very sensitive to the assumptions regarding the efficacy of treatment. For example, if in this undiscounted analysis the proportion of

intracapsular prostate cancers that are cured by aggressive treatment is decreased from 100 to 50 percent, the

net days of life saved per patient screened at ages 65, 70,

and 75 drops to seven, four, and two days, respectively.

DRE/PSA Together Versus DRE Alone

Many physicians already perform DREs in older

men to seek evidence of both prostate and colorectal cancer. What is the marginal value of adding PSA to the
58 COSTS AND EFFECTIVENESS OF PROSTATE CANCER SCREENING IN ELDERLY MEN

DRE? In the recent combined screening described by Richie and colleagues (279), DRE, which was suspicious

in 16 percent of men ages 60-69, had a predictive value

of 21 percent, yielding cancer in 2.4 percent of the

screenees. Adding PSA increased the detection rate to

4.2 percent. Therefore, since the ratio of intracapsular to

extracapsular disease was roughly equal (at 3:1) between

the DRE-detected cancers and the cancers detected by

combination screening, one can assume that roughly 60

percent of the risks and maximal benefits presented in

table 5-2 would be accrued by screening with DRE

alone. However, such results would only be seen if DRE

were performed with a very low threshold to proceed to

systematic biopsies for any minor palpable abnormality,

an approach not common in current clinical practice.

Again, roughly half the cancers detected using this DREalone strategy would actually be found in palpably normal areas of the prostate as a result of the systematic

biopsies. For men ages 70 to 79 in the Richie study, DRE

detected cancer in 3.5 percent of screenees versus 7.2

percent for combined DRE/PSA screening, but a lower

proportion of DRE-detected cancers was intracapsular

compared with all cancers found by combined DRE/

PSA screening (45 percent versus 60 percent). Therefore, about half the risks presented in table 5-4 would be

expected to accumulate with DRE screening, accompanied by less than half the maximal benefits.

MODELING THE COST-EFFECTIVENESS

OF ONE-TIME SCREENING

The overall costs of a screening program would

comprise the upfront costs of the screening tests themselves, subsequent ultrasound (TRUS) exams and biopsies, staging tests, early treatment, and therapy for treatment complications. To the extent that early detection

and treatment are effective, savings accrue from averting costs of subsequent treatment of local cancer progression, metastatic disease, and end-stage cancer. Appropriate discounting diminishes the value of these later

savings since policymakers or patients in the present

would rather realize benefits now than in the future.

Moreover, older men treated for prostate cancer, on average, extend their lives an average of 6 (age 75) to 19 (age

65) months (see tables 5-2 through 5-4), given their risks

of death from other causes.15

Beyond whether or not a prostate cancer screening

benefit would result in net costs or savings for Medicare,

one can also consider whether the health benefit realized

for each extra dollar spent for prostate cancer screening

(and subsequent treatment) is more or less than those of

screening programs or other services already covered by

Medicare. This ratio of a benefit per dollar spent is the

“cost effectiveness” of the screening program. This section models the cost-effectiveness of the illustrative,

one-time screening benefit examined in the previous

section. As indicated earlier, the actual estimates produced in this analysis are unlikely to be the same as those

for an actual Medicare benefit since Medicare would

most likely cover multiple, periodic screenings rather

than a one-time benefit. However, as will be seen, this

simplified analysis does illustrate how sensitive the costeffectiveness of screening is to assumptions about the effectiveness of treating prostate cancer.

Cost Assumptions

The Cost of Specific Resources

To estimate the costs of an early detection program

with DRE and PSA among our hypothetical cohorts of

15Epidemiologically, cardiovascular disease and other cancers are by far the most likely causes (table 2-1). The costs of these alternative scenarios for death further

blunt any savings from averting terminal care costs for prostate cancer.
CHAPTER 5BENEFITS, RISKS, AND COSTS OF SCREENING 59

100,000 men ages 65, 70, and 75, this analysis adopts the

perspective of the Medicare program and considers only

direct medical care costs.16 Cost estimates for resource

inputs are based on the 1992 Medicare fee schedule and

diagnosis-related groups (DRG) reimbursements for

relevant hospitalizations.17 Appendix G details these

cost estimates. Tables 5-6 through 5-8 combine these

costs for individual resource inputs into low, medium,

and high estimates of the costs of different steps in the

process of early detection and treatment, respectively.

The low, medium, and high estimates reflect uncertainty

about how resources would be utilized and billed in actual practice.18 The analysis discounts all future health

care costs and health benefits are both discounted at an

annual rate of 5 percent.

Other Cost Assumptions

The analysis assumes the marginal costs for the care

of hormonally refractory prostate cancer, compared with

all other causes of death, to be $6,260 in the last year of

life (in 1992 dollars), based on the work of Riley and colleagues (282).

As indicated earlier, men who have prostate cancer

but do not receive a radical prostatectomy are susceptible not only to metastatic disease, but to complications

from local progression as well. To estimate the costs

associated with transrectal resection (TURP) to treat local cancer progression or BPH, the analysis used the

weighted average of the only two empirical estimates of

the probability of this phenomenon currently available

(176, 366).19

Also as explained in a previous section, the analysis

excludes the cost of any additional cancer treatment

(radiation therapy, hormonal therapy, or orchiectomy)

unless patients have evidence of metastatic cancer. This

assumption again favors early detection and treatment.

In estimating the costs of treating complications of

radical prostatectomy (or radiation therapy), the analysis

again makes assumptions favoring early detection and

treatment. For patients with sexual dysfunction, we ignore all costs other than for penile implants, and assume

that no additional patients require surgery for impotence

more than four years after surgery.20 For men with incon16Beyond the costs to the federal government through Medicare, patients also bear the direct and indirect nonmedical costs associated with screening and any

detected disease such as travel costs to receive medical care, lost wages, and the anxiety associated with being told they may have cancer on the basis of a suspicious screening test result. In addition, patients or third-party private insurers would bear medical care costs not covered by Medicare.

17Continuing changes in Medicare reimbursements for procedures associated with prostate cancer screening and treatment may make these 1992 costs inaccurate predictors of costs in 1995 or in subsequent years (13a).

18For example, it is unknown exactly what percentage of men would get a pelvic CT scan or bone scan as part of a staging evaluation, or what percentage of men

undergoing radical prostatectomy would be billed under DRG 335 (without comorbidity/complications) versus DRG 334 (with comorbidity/complication). An October 1993 publication by the American Urological Association entitled, “Coding Tips for the Urologist’s Office,” was helpful in preparing the ambulatory component of

these estimates.

19Johansson (176) recently updated the outcomes in his Scandinavian series of “watchful waiters” at an annual American Urological Association meeting in San

Antonio. At 12.5 years of average followup, 30 untreated cancer patients had required TURP over approximately 1,610 person-years (a rate of 0.019 TURPs per personyear); in 16 men the pathology report showed cancer, while in 14 the diagnosis was BPH. Whitmore (366), on the other hand, found that among men with T2 cancers

treated expectantly, 23 patients required 37 TURPs in approximately 803 person-years of followup (a rate of 0.046 per person year); 27 men had cancer in their resected specimens while 10 had only BPH. We use an average of these two rates (a weighted average based on person-years of followup would be closer to that of

the larger Johansson study) to calculate the costs of treatment for local progression of cancer and for BPH among men with cancer.

20For men treated with radical prostatectomy, the survey of Medicare prostatectomy patients by Fowler and colleagues (127) found that actually 15-percent report

postoperative treatment for sexual dysfunction within two to four years after surgery: eight percent with a vacuum device, 7 percent with pharmacologic erection

therapy, and 3 percent with a penile implant.
60 COSTS AND EFFECTIVENESS OF PROSTATE CANCER SCREENING IN ELDERLY MEN

TABLE 5-6: MEDICARE COST ESTIMATES FOR EARLY DETECTION AND STAGING OF PROSTATE CANCER USING DIGITAL RECTAL

EXAMS AND PROSTATIC-SPECIFIC ANTIGEN









Low estimate 



Medium estimate



High estimate 

 Initial testing 





   

PSA 



$30 



$45a 



$60a  DRE  $0  $3  $28  b  Total



 $30



 $48

   $88

 Work-up for suspicious results









    Consult (urology)



 $47



 $47



 $47 

 TRUS (diagnostic)  $0  $85  $85 

 TRUS-guided biopsy  $189  $189  $189 



Pathology (level IV) 



$208c 



$312d 



$312d   Total  $444  $633  $633

 Staging for men with cancer









    Pelvic CT scane 

 $71 (25%)



 $142 (50%)

   $213 (75%)

 Bone scane  $46 (25%)  $92 (50%)  $138 (75%) 

 Lymphadenectomye  $0 (0%)  $164f

 (25%) 

 $328f (50%) 



Visit to discuss results 



$28 



$28 



$28 



Total 



$145 



$426 

  $707 

 

 



a Assumes some repeat testing necessary.

b Assumes brief office visit specifically for a prostate evaluation.

c Four cores examined.  d Six cores examined. 

 

 



 Four cores examined.

d Six cores examined.

e Not all patients get pelvic CT scan with contrast (cost $284), bone scan ($184), or lymphadenectomy ($656); figures in parentheses indicate percentage of men who

get these studies.

f

 Includes pathology fee (level IV, two sets of nodes).

KEY: CT = computed tomography; DRE = digital rectal exam; PSA = prostate-specific antigen; TRUS = transrectal ultrasound.

SOURCE: Office of Technology Assessment, 1995. Based on information presented in M.J. Barry, C.M. Coley, C. Fleming, et. al, “The Safety, Effectiveness, and Cost of Early

Detection and Treatment of Prostate Cancer Among Older Men: A Report to the Congressional Office of Technology Assessment,” OTA contract paper no. K3-0546.0,

Massachusetts General Hospital, Boston, MA, June 30, 1994.

tinence, the analysis includes only the costs of an artificial sphincter implantation for the six percent of men

who reported corrective surgery for incontinence, ignoring the costs of pads for the 31 percent of prostatectomy

patients who report using them (124). While some of

these men may have had less aggressive and expensive

corrective surgery for incontinence (such as collagen injections), the other cost assumptions make the overall

approach to estimating costs of treatment complications

conservative.

For men with urethral strictures following radical

prostatectomy, the analysis assumes that 95 percent are

treated with a simple stricture dilation in the office,

while only 5 percent need in-hospital operative repair.

We assume no additional treatments are required beyond
CHAPTER 5BENEFITS, RISKS, AND COSTS OF SCREENING 61

TABLE 5-7: MEDICARE COST ESTIMATES FOR PROSTATE CANCER TREATMENT





Treatment 



Low estimate



Medium estimate 



High estimate



 Radical prostatectomy 





   

Hospitala 



$5,867 



$6,271 



$6,675 



Surgeon 



$1,497 



$1,497 

  $1,497

 Anesthesia



 $194



 $194

   $194

 Pathologyb  $125



 $125



 $125 

 Total  $7,680  $8,084  $8,488 

 External beam radiotherapy 





    Course 

 $3,604  $3,604  $3,604 

 Monitoring post-treatment (annual cost) 





   

Office visit and PSA 



$59 



$59 



$59

  Bone scanc  $0  $46  $92

 Total



 $59



 $105

   $151

 Diagnosis and treatment:









    Metastatic disease









    Bone scan 

 $184  $184  $184 



Orchiectomy 



$4,406 



$4,406 



$4,406 



Hormonal therapyd 



$4,224 



$5,748 

  $6,953



 

 

 

 





a Low estimate: 0% diagnosis-related groups 334 (complications) at $7,483 and 100% DRG 335 (no complications) at $5,867; medium estimate: 25% DRG 334 and 75%

DRG 335; high estimate 50% DRG 334 and 50% DRG 335.

b Level VI.

c Low estimate: 0% get bone scan each year at $184, medium estimate: 25% get bone scan each year; high estimate: 50% get bone scan each year.

d Annual cost; low estimate: 100% GnRH agonist and 0% flutamide; medium estimate: 100% GnRH agonist and 50% flutamide; high estimate: 100% GnRH agonist and

100% flutamide; includes monthly fees for an office visit ($29) with chemotherapy injection ($4).

KEY: DRG = diagnosis-related groups; PSA = prostate-specific antigen.

SOURCE: Office of Technology Assessment, 1995. Based on information presented in M.J. Barry, C.M. Coley, C. Fleming, et. al, “The Safety, Effectiveness, and Cost of Early

Detection and Treatment of Prostate Cancer Among Older Men: A Report to the Congressional Office of Technology Assessment,” OTA contract paper no. K3-0546.0,

Massachusetts General Hospital, Boston, MA, June 30, 1994.

four years after surgery,21 and ignore costs related to the

diagnosis of strictures, such as for cystourethroscopy.22

Incorporation of Costs in the Screening Model

The analysis estimates cost-effectiveness by incorporating the costs for early detection, staging, treatment

of clinically localized cancer, diagnosis of metastatic

disease, and treatment of metastatic disease by orchiectomy, into the Markov model of prognosis described earlier in the chapter. The model accumulates these costs

(with appropriate discounting) as each intervention is

21Since strictures are often recurrent, this assumption is particularly conservative.

22In Medicare survey (127), 20 percent of men reported at least one dilation or surgical procedure for what they believed to be strictures two to four years following

radical prostatectomy; 11 percent required treatment at least twice.
62 COSTS AND EFFECTIVENESS OF PROSTATE CANCER SCREENING IN ELDERLY MEN

TABLE 5-8: MEDICARE COST ESTIMATES FOR THERAPY OF PROSTATE CANCER TREATMENT COMPLICATIONS







 Low estimate Medium estimate  High estimate 

 TURP for BPH or local progression of cancer 





    Hospitala 

 $2,778  $3,069  $3,361 



Surgeon 



$898 



$898 



$898

  Anesthesia  $147  $147  $147

 Pathology



 $92



 $92

   $92

 Total



 $3,915  $4,206  $4,498 

 Treatment for cancer therapy complications









    Incontinence









    (Artificial sphincter) 

 —  $8,080  — 

 Impotence 





   (Penile implant)  —  $11,350   —  Stricture









    (Dilation)



 —  $51



 — 

 (Urethroplasty)  —  $5,259  — 



 





a Low estimate: 0% DRG 336 (complications) at $3,943 and 100% DRG 337 (no complications) at $2,778; medium estimate: 25% DRG 336 and 75% DRG 337; high

estimate 50% DRG 336 and 50% DRG 337.

KEY: BPH = benign prostatic hypertrophy; DRG = diagnosis-related group; TURP = transurethral resection of the prostate.

SOURCE: Office of Technology Assessment, 1995. Based on data from M.J. Barry, C.M. Coley, C. Fleming, et al., “The Safety, Effectiveness, and Cost of Early Detection

and Treatment of Prostate Cancer Among Older Men: A Report to the congressional Office of Technology Assessment,” OTA contract paper no. K3-0546.0, Massachusetts General Hospital, Boston, MA, June 30, 1994.

encountered. The model accumulates ongoing costs,

such as post-treatment surveillance and androgen deprivation therapy for metastatic disease, continuously

with each Markov cycle patients spend in a particular

state.

Cost-Effectiveness Results

Tables 5-9 through 5-11 present estimates of discounted costs (in dollars), discounted effectiveness (in

life-years saved), and cost per life year saved for cohorts

of 100,000 men ages 65, 70, and 75 receiving a hypothetical, one-time screening under the baseline assumptions

described in this chapter. Using the medium set of assumptions about costs, the cost per year of life saved

(compared with doing no screening) would be $14,200

at age 65, $25,290 at age 70, and $51,290 at age 75.

Sensitivity of the Results

These results are extremely sensitive to the assumption about the effectiveness of prostate cancer treatment

and, to a somewhat lesser degree, the assumption about

the rate at which cancers of different grades metastasize.

As indicated earlier, the actual effectiveness of treatment

is unknown because of the lack of randomized controlled

trials. Similarly, the true rates of future metastasis and

prostate cancer death from tumors currently discovered

by early detection are also unknown. The assumptions

about both treatment and metastasis used in the baseline
CHAPTER 5BENEFITS, RISKS, AND COSTS OF SCREENING 63

TABLE 5-9: MARGINAL COST-EFFECTIVENESS OF ONE-TIME HYPOTHETICAL DRE/PSA SCREENING VERSUS NOT SCREENING

(100,000 men, age 65)a   Marginal cost  Low Estimates Medium Estimates High Estimates



  Cost estimate (millions of dollars) 





Initial costs

 



 



 

  

Initial testing 



3.000 



4.800 

  8.800

 TRUS/biopsy



 3.045



 4.341

   4.341

 Staging



 0.602



 1.087



 1.573 

 Treatment  22.578  23.751  24.924 

 Delayed costs









    Monitoring 

 2.509  4.457  6.383 

 Future treatmentb  -5.929  -9.128  -14.808 



Total 



$25.804 



$29.308 



$31.214









Discounted life-years saved

Marginal effectiveness 



2064 



2064 



2064









Dollars per life-year

Marginal cost-effectiveness 

 $12,502  $14,200  $15,123 



 





a Both future costs and health benefits are discounted at 5% annually.

b Future treatment for local progression of prostate cancer, benign prostatic hyperplasia (BPH), metastatic prostate cancer, and therapy complications.

KEY: TRUS = transrectal ultrasound.

SOURCE: Office of Technology Assessment, 1995. Based on data from M.J. Barry, C.M. Coley, C. Fleming, et al., “The Safety, Effectiveness, and Cost of Early Detection

and Treatment of Prostate Cancer Among Older Men: A Report to the Congressional Office of Technology Assessment,” OTA contract paper no. K3-0546.0, Massachusetts General Hospital, Boston, MA, June 30, 1994.

analysis are favorable to screening. What happens when

these assumptions are relaxed?

 Reducing the grade-specific metastatic rates in this

model23 to those used in the previously published

analysis of prostate cancer treatment by Fleming and

colleagues (124), the estimate of cost per year of life

saved (discount rate 5 percent) ranges from $42,590

at age 65 to $177,094 at age 75. 

 Alternatively, assuming only half (rather than all) intracapsular cancers >0.5 mL are cured by radical

prostatectomy, the cost per year of life saved ranges

from $30,524 at age 65 to $109,721 at age 75 (same

discount rate).

 Assuming that both the lower metastatic rates from

the Fleming analysis and the lower proportion of

cures represent the true state of affairs, the cost per

year of life saved would range from $94,458 at age 65

to $506,909 at age 75.

23As mentioned earlier, the rates used in this analysis result in a lifetime cumulative risk of prostate cancer death more than a third higher than the risk actually observed

in the literature.
64 COSTS AND EFFECTIVENESS OF PROSTATE CANCER SCREENING IN ELDERLY MEN

TABLE 5-10: MARGINAL COST-EFFECTIVENESS OF ONE-TIME HYPOTHETICAL DRE/PSA SCREENING VERSUS NOT SCREENING

(100,000 men, age 70)a 



Marginal cost 



Low Estimates 



Medium Estimates



High Estimates 







Cost estimate (millions of dollars)

Initial costs 







    Initial testing 

 3.000  4.800  8.800 



TRUS/biopsy 



4.462 



6.362 

  6.362

 Staging



 0.826



 1.492

   2.158

 Treatment



 26.114



 27.472



 28.829 

 Delayed costs









    Monitoring



 2.522



 4.478



 6.407 

 Future treatmentb  -5.596  -6.165  -10.531 

 Total  $31.765  $36.467  $39.042 





 Discounted life-years saved

Marginal effectiveness 

 1,442  1,442  1,442 





 Dollars per life-year

Marginal cost-effectiveness 

 $22,059  $25,290  $27,076 



 





a Both future costs and health benefits are discounted at 5% annually.

b Future treatment for local progression of prostate cancer, benign prostatic hyperplasia, metastatic prostate cancer, and therapy complications.

KEY: DRE = digital rectal exam; PSA = prostate-specific antigen; TRUS = transrectal ultrasound.

SOURCE: Office of Technology Assessment, 1995. Based on data from M.J. Barry, C.M. Coley, C. Fleming, et al., “The Safety, Effectiveness, and Cost of Early Detection

and Treatment of Prostate Cancer Among Older Men: A Report to the Congressional Office of Technology Assessment,” OTA contract paper no. K3-0546.0, Massachusetts General Hospital, Boston, MA, June 30, 1994.

To emphasize the sensitivity of the results to these

key assumptions, figures 5-1 through 5-3 display the estimated cost per year of life saved for men ages 65, 70,

and 75, using higher (83) and lower (362, 124) metastatic

rates, and different assumptions about the proportion of

intracapsular cancers (of all grades) cured by aggressive

treatment.24

Another assumption in the baseline analysis is that

the metastatic rate is the same for each grade of tumor

(except for well-differentiated cancers less than 0.5 mL

in volume), regardless of whether the tumor is intracapsular or extracapsular. If, however, future metastatic

events are preferentially generated from extracapsular

cancers, a likely scenario, the estimated effectiveness of

treatment and screening would diminish considerably.

For example, if intracapsular cancers have the gradespecific prostate cancer mortality rates described by

Fleming (124), while extracapsular cancers have the

24The costs per year of life saved are displayed on a log scale because of the steep escalation in costs as the favorable initial assumptions are relaxed.
CHAPTER 5BENEFITS, RISKS, AND COSTS OF SCREENING 65

TABLE 5-11: MARGINAL COST-EFFECTIVENESS OF ONE-TIME HYPOTHETICAL DRE/PSA SCREENING VERSUS NOT SCREENING

(100,000 men, age 75)a 



Marginal cost 



Low Estimates 



Medium Estimates



High Estimates 







Cost estimate (millions of dollars)

Initial costs 







    Initial testing 

 3.000  4.800  8.800 



TRUS/biopsy 



6.019 



8.581 

  8.581

 Staging



 1.049



 1.896

   2.742

 Treatment



 26.991



 28.394



 29.797 

 Delayed costs









    Monitoring



 2.208



 3.919



 5.601 

 Future treatmentb  -5.596  -6.165  -10.531 

 Total  $33.671  $41.424  $44.990 





 Discounted life-years saved

Marginal effectiveness 

 808  808  808 





 Dollars per life-years saved

Marginal cost-effectiveness 

 $41.690  $51.290  $55.705 



 





a Both future costs and health benefits are discounted at 5 % annually.

b Future treatment for local progression of prostate cancer, benign prostatic hyperplasia, metastatic prostate cancer, and therapy complications.

KEY: DRE = digital rectal exam; PSA = prostate-specific antigen; TRUS = transrectal ultrasound.

SOURCE: Office of Technology Assessment, 1995. Based on data from M.J. Barry, C.M. Coley, C. Fleming, et al., “The Safety, Effectiveness, and Cost of Early Detection

and Treatment of Prostate Cancer Among Older Men: A Report to the congressional Office of Technology Assessment,” OTA contract paper no. K3-0546.0, Massachusetts General Hospital, Boston, MA, June 30, 1994.

mortality rates described by Chodak (83), the cost-effectiveness estimates for early detection (which are based

on the curability of the intracapsular lesions) would follow the higher curves in figures 5-1 through 5-3.25

Finally, a substantial component of the estimated

net benefits come from the early detection and treatment

of well-differentiated prostate cancers greater than 0.5

mL in volume. This finding is due to well differentiated

cancers having had the same cancer-specific death rates

as moderately differentiated cancers in the Chodak (83)

meta-analysis. However, Kolon (194) has recently found

that men with well-differentiated cancers treated expectantly among cases reported to the Connecticut tumor

registry had the same life expectancy as age-matched

men in the general state population. If, in fact, well-differentiated prostate cancers do not result in a higherthan-expected future mortality for men diagnosed at age

65 or above, the estimated number of deaths averted per

25This set of assumptions actually results in a prediction of the cumulative probability of a prostate cancer death for men age 65 of 2.5 percent, within the empirically

observed probability range of 2.5 to 3 percent.
66 COSTS AND EFFECTIVENESS OF PROSTATE CANCER SCREENING IN ELDERLY MEN

FIGURE 5-1: COST-EFFECTIVENESS OF ONE-TIME DRE/PSA

SCREENING OF 65-YEAR-OLD MEN FOR PROSTATE CANCER:

SENSITIVITY ANALYSIS

SOURCE: Office of Technology Assessment, 1995. Based on data from M.J. Barry,

C.M. Coley, C. Fleming, et al., “The Safety, Effectiveness, and Cost of Early

Detection and Treatment of Prostate Cancer Among Older Men: A Report to

the Congressional Office of Technology Assessment,” OTA Contract Paper No.

K3–0546.0, Massachusetts General Hospital, Boston, MA, June 30, 1994.

100,000 by screening and treatment (as presented in

tables 5-2 through 5-4) would drop from 547 to 414 at

age 65, from 431 to 325 at age 70, and from 294 to 224

at age 75. This would result in a parallel increase in the

cost per life-year saved by screening.

Turning from effectiveness to cost, how would

changes in the cost assumptions affect the cost-effectiveness ratios? Each increase of $10,000 in the costs of caring for terminal prostate cancer above the baseline estimate reduces the present value per person cost of

prostate cancer screening only by about $30. This relatively small effect on the analysis is due in large part to

the discounting of these future expenses.

FIGURE 5-2: COST-EFFECTIVENESS OF ONE-TIME DRE/PSA

SCREENING OF 70-YEAR-OLD MEN FOR PROSTATE CANCER:

SENSITIVITY ANALYSIS

SOURCE: Office of Technology Assessment, 1995. Based on data from M.J. Barry,

C.M. Coley, C. Fleming, et al., “The Safety, Effectiveness, and Cost of Early

Detection and Treatment of Prostate Cancer Among Older Men: A Report to

the Congressional Office of Technology Assessment,” OTA Contract Paper No.

K3–0546.0, Massachusetts General Hospital, Boston, MA, June 30, 1994.

Comparisons to Other Medicare

Disease Screening

How do these estimates for the cost-effectiveness of

one-time screening for prostate cancer compare with

previously published estimates for other cancer screening maneuvers among Medicare patients? Such comparisons are problematic since most cost-effectiveness

analyses of disease screening for Medicare beneficiaries

examine periodic screening rather than only a one-time

benefit. However, as part of a previous analysis by the

Office of Technology Assessment (OTA), Muller and

colleagues (347) found that a one-time screening with

cervical Pap smears at age 65 would cost $1,666 per life-
CHAPTER 5BENEFITS, RISKS, AND COSTS OF SCREENING 67

FIGURE 5-3: COST-EFFECTIVENESS OF ONE-TIME DRE/PSA

SCREENING OF 75-YEAR-OLD MEN FOR PROSTATE CANCER:

SENSITIVITY ANALYSIS

SOURCE: Office of Technology Assessment, 1995. Based on data from M.J. Barry,

C.M. Coley, C. Fleming, et al., “The Safety, Effectiveness, and Cost of Early

Detection and Treatment of Prostate Cancer Among Older Men: A Report to

the Congressional Office of Technology Assessment,” OTA Contract Paper No.

K3–0546.0, Massachusetts General Hospital, Boston, MA, June 30, 1994.

year saved.26 Among previous OTA analyses of disease

screening for Medicare beneficiaries that examined periodic screening (as opposed to one-time screening) are

two that make estimates for colorectal and breast cancer

screening. The breast cancer study concluded that annual mammography would cost Medicare $13,200 per year

of life saved (346), and the colorectal cancer study estimated that annual occult blood testing beginning at age

65 would cost $35,054 per year of life (348).27 Medicare

currently covers both cervical and breast cancer screening as periodic benefits. 

IMPLICATIONS FOR MEDICARE

What information does the analysis in this background paper yield for policymakers considering coverage of prostate cancer screening as a Medicare benefit?

Although the quantitative analysis in this chapter

focused on a hypothetical one-time benefit instead of the

periodic benefit more likely to be considered by the

Medicare program, it does offer important information

for policymakers. Most importantly, the cost-effectiveness of any Medicare prostate cancer benefit is extremely sensitive to whether or not treatment of tumors that

have not yet spread extends life or not. The analysis suggests that prostate cancer screening could prove to be as

cost effective as other disease screening services already

covered by Medicare.

On the other hand, if treatment proves to be less than

100 percent effective (or if rates of metastasis turn out to

be less than those assumed in our baseline analysis),

prostate cancer screening could end up costing much

more per life-year saved than other Medicare disease

screenings. At the same time, however, screening carries

significant risks of complications. These include the

possibility of surgical death in at least six out of 1,000

cases, urinary stricture, heart and lung disease, and years

of impotence and incontinence in substantial portions of

treated patients.

26This study also found that the cost per life- year rose as the screening frequency increased. It was $1,453 for screening every five years compared with no screening,

was $5,956 per life-year saved when moving from a five-year to a three-year screening cycle, and was $39,693 for annual screening compared with screening for

every 3 years.

27A more recent analysis of breast cancer screening found that a one-time mammography for Medicare-age women cost $23,212 per year of life saved at ages 65 to

69 and $27,983 per year of life saved at age 70 to 74 (224).
68 COSTS AND EFFECTIVENESS OF PROSTATE CANCER SCREENING IN ELDERLY MEN

The evidence of effectiveness and cost-effectiveness of other preventive services already covered by

Medicare (e.g.. breast and cervical cancer screening, influenza and pneumococcal vaccines) is substantially

stronger than for prostate cancer screening. Although

scientific knowledge is currently limited as we await the

completion of well-controlled clinical trials, the consequences of prostate cancer and its treatment remain serious. Under such circumstances, an informed and reasonable patient could equally well decide to have screening

or forgo it. Patient preferences are also a major component in deciding what to do when screening uncovers a

localized cancer. Hence, each patient, in consultation

with his physician, must use his own values to weigh the

potential benefits of screening against the risks of incontinence, impotence, and other adverse reactions that may

result from treating those localized cancers discovered

through screening.

Given the state of current knowledge about prostate

cancer, it may be reasonable for Medicare to consider reimbursement of the screening test. Reimbursement

could be seen as ensuring that out-of-pocket screening

expenses (however small) not impede well-informed

discussion and decisionmaking between physician and

patient. Such a Medicare screening benefit could be unrestricted as are similar benefits for cervical and breast

cancer screening. However, an unrestricted, permanent

benefit might imply that science actually has established

the benefit of early detection. An alternative would be to

offer it on a temporary basis subject to reconsideration

as evidence from clinical trials about the effectiveness of

screening and treatment becomes available. Such a

benefit could also be coupled with efforts by the federal

government to involve as many patients as possible in effectiveness research and to ensure patients and physicians are well-informed about potential benefits and

risks of treating cancers uncovered by screening. When

data from well-controlled trials (including those described in appendix H) tell us if treating prostate cancer

is effective, science will be able to provide more definitive guidance in facilitating clinical decisionmaking for

patients and in establishing or continuing a screening

benefit under Medicare.
APPENDIX

A

Derivation of Prostate Cancer

Prevalence by Age and Tumor Volume

his appendix describes the derivation of agespecific prevalence rates of latent prostate cancer (overall and by tumor volume) presented in

table 2-5. Overall prevalence data for each age

strata were derived by Office of Technology Assessment contractors from eight available autopsy series

that specifically excluded cases where prostate cancer

had been clinically suspected, and that provided complete age-specific prevalence by decade (24, 113, 128,

134, 159, 222, 293, 305). All eight were consecutive unselected autopsy series; seven were U.S. hospital-based,

one (Lundberg) was a community-based Swedish series.

All eight used serial step-sectioning (usually 4 mm

slices) of the entire gland.

The estimates for each prostate cancer volume and

capsular status stratum were derived by applying volume

data from McNeal (233) to the derived age-specific

prevalences. McNeal and colleagues performed morphometric autopsy analyses on 100 consecutive unselected prostates with adenocarcinoma. For all ages, 60

percent of all cancers are assumed to be 0.5 mL or less

even though cancers in men below age 70 years were

somewhat more likely to be less than 0.5 mL in volume

than for men 70 years and older (68 percent vs. 56 percent).

The remaining 40 percent were assumed to be greater

than 0.5 mL in volume. In deriving the distribution of intracapsular and extracapsular tumors for these larger

cancers, extracapsular spread was required to be greater

than 1 cm beyond capsule, although half of tumors with

volume above 0.5 mL in the McNeal study showed some

lesser degree of capsular penetration.1 Although

McNeal’s and other’s (180, 244) data suggest the proportion of cancers above 0.5 mL that are extracapsular increases for men over 70 years, the wide confidence intervals around these estimates lead us to apply a uniform 27

percent probability for all ages. Hence, we assume that

of all cancers more than 0.5 mL, 27 percent are extracapsular and 73 percent are intracapsular.

Several studies of incidental prostate cancer among

patients undergoing cystoprostatectomy for bladder cancer (180, 244, 328) suggest that only 20 percent of unrecognized prostate cancers exceed 0.5 mL. However, a recent autopsy series of 105 patients without history of

prostate cancer and with recent normal rectal exams

1 See figure 5 in the study by McNeal and colleagues (233).
70 COSTS AND EFFECTIVENESS OF PROSTATE CANCER SCREENING IN ELDERLY MEN

(mean age 66, not stratified) found a 35 percent prevalence of prostate cancer with 41 percent >0.5 mL; twothirds of these larger cancers were intracapsular (49).

Looking only at men over age 50 as a single group

from the eight autopsy studies yields an overall prevalence of prostate cancer of 30 percent. Breaking these

cancers down by volume for all men over age 50, the estimated weighted prevalence of cancers less than 0.5 mL

is 18 percent, the prevalence of intracapsular cancers exceeding 0.5 mL is 8.8 percent, and the prevalence of extracapsular cancer exceeding 0.5 mL is 3.2 percent.
APPENDIX

B

Methods Used To Estimate

Likelihoods of Cancer for

Particular DRE And PSA Results

his appendix describes the derivation of likelihood ratios of different types of cancer for various digital rectal examination (DRE) and prostate-specific antigen (PSA) measurement

results presented in tables 3-1 and 3-3 and discussed in the accompanying text. The likelihood ratios

are estimates of how many times more likely a patient

with a particular test result is to have a given type of cancer than if the patient did not have the test. The probabilities of cancer with no test are the prevalence estimates

found in table 2-5. For each test, the likelihood ratios

were estimated using the following method:

 Studies of screening tests that provided predictive values for a population of men with a specified age distribution were selected; these predictive values were

converted into post-test odds of disease.

 Next, the true underlying prevalence of prostate cancer in the general population derived from autopsy

studies, displayed in table 2-5, was assumed to be applicable to the populations in these studies of positive

predictive values.

 Finally, the post-test odds were divided by the pretest

odds of disease (and nondisease) to estimate likelihood ratios.

LIKELIHOOD RATIOS FOR DRE RESULTS

The calculations for DRE results (table 3-1) use data

from two studies (79, 279) that provided detailed age distributions of study patients and to which we could apply

the estimates of prostate cancer prevalence by tumor

volume as presented in table 2-5. Calculations are performed using data for all men ages 50 years and up.

“Suspicious” DRE results are defined as palpable asymmetries, nodules, or induration (hardness).

In the Chodak study, although 125 of the 2,131 men

ages 45 to 80 in the initial screen group had an abnormal

DRE and received a DRE-directed biopsy, the number of

men ages 45 to 50 with abnormal DRE is not provided

since no cancers were found in this subgroup. Calculations were done using the 1,894 men over 50 years (31

cancers detected in the first year of screening). Systematic biopsies were not performed and volume data for detected cancers were not provided. All were clinically

Stage B or higher by the Whitmore staging system (see

table 2-3), and it appears safe to assume none were below

0.5 mL.

Subjects in the Richie study (279) with abnormal

DRE received systematic and TRUS-guided biopsies in

addition to DRE-directed biopsies. Specific volume dis-
72 COSTS AND EFFECTIVENESS OF PROSTATE CANCER SCREENING IN ELDERLY MEN

tributions are not provided. The 8 percent of detected

cancers that were “organ-confined, well-differentiated,

and involved only one quadrant” is not necessarily tantamount to a volume below 0.5 mL. We assume 11 percent

of detected cancers are below 0.5 mL using data from

208 Stage T1c cancers reported by Oesterling (263). The

proportion of cancers in this volume category for T1c tumors (using the TNM staging system described in table

2-3) has been as high as 26 percent (119). Although only

70 percent of patients with abnormal DRE in the Richie

study (279) consented to biopsy, and only 63 percent of

cancers were surgically staged, our derivations of the

post-test odds and likelihood ratios assume perfect

biopsy compliance and a comparable proportion of organ-confined cancers in those not receiving radical prostatectomy.

LIKELIHOOD RATIOS FOR PSA RESULTS

Likelihood ratios for PSA results are based on data

from four studies: pooled results from studies by Catalona (66) and Brawer (44), results from a study by Richie

(279), and results from another study by Catalona (70).

The values derived from pooling data from Catalona

(66) and Brawer (44) are probably overestimates for the

likelihood ratios for PSA testing alone since only patients who had either abnormal DRE or TRUS in the

presence of PSA >4 ng/mL received biopsy. In addition

to DRE- and TRUS-guided biopsies, when appropriate,

systematic biopsies were performed in willing patients

who met these criteria.

Specific volume distributions are not provided by any

of the four studies. We again assume 11 percent of the detected cancers are below 0.5 mL based on the study by

Oesterling (263). Eleven percent of all PSA 4 to 10 ng/ml

detected cancers (presumed to be <0.5 mL) are subtracted from organ-confined cancers to derive the posttest odds for intracapsular cancers >0.5 mL. These likelihood ratios reflect “best case” values because we assume

perfect compliance with biopsy (compared with the actual compliance rate of 70 percent in the Oesterling study

(263) and a comparable proportion of intracapsular cancers above 0.5 mL in patients not receiving surgery.

These “adjustments” were made for data from all four

studies in table 3-3.

Patients in the Richie study (279) received both DRE

and PSA independently, and the data are presented in a

way that allows derivation of the likelihood ratio for PSA

alone. However, separate pre- and post-test odds for PSA

results of 4.1 to 9.9 ng/mL or PSA > 10 ng/mL cannot be

derived from data reported in this study.

The later (and larger) study by Catalona (70) used a

protocol similar to his earlier study (66). The derivations

of the likelihood ratios used only the data reported for the

initial screening of 9,629 volunteers. There is a major

discrepancy between the likelihood of intracapsular cancer given a PSA result of greater than 10 ng/ml (3.0) in

this study and the corresponding value (0.4) from the

earlier pooled studies. This is explained by the observed

difference in probability of pathologically localization

for cancers (>0.5 mL) detected by PSA >10 ng/mL (32

percent vs. 5 percent).
APPENDIX

C

Studies of

Digital Rectal Examination for

Prostate Cancer Screening
APPENDIX C: STUDIES OF DIGITAL RECTAL EXAMINATION FOR PROSTATE CANCER SCREENING 

   Author    Biases/ methodologic weaknesses a   Setting    Time frame (year)    Number of patients   Age (Y)  range (mean)   Abnormal criterion No. patients (%) No. patients biopsied (%)    Overall detection yieldb    Proportion detected cancers (%) clinically localized   Positive predictive value (%)   Proportion surgically stagedc (%)   Long-term  followup  



Chadwick etal., 1991

d

 

 

3,4,6,7,8  

 

Britishpopulationbased

 



1 time



 

 

814 eligible472 recruited(58%)407 DRE

    55-69



 

 

Nodule or Induration13/407(3.2%)not specified if all13 biopsied (onlyif TRUS lesion also)

 



1/472 (0.2%)



 

 

1/1 (100%)      1/13 (8%)  

 

1/1 (100%)pathologiclocalized

 









NA

  



Chodak etal., 1984

e

 

 

2,3,4,6,7,8  

 

Urologyscreening(invitational)

 



1 time



 

 

811    45-80



 

 

Nodule or induration 43/811(5.3%)but only 38 complied with biopsy(88%)

 



11/811(1.4%)



 

 

5/11(45%)     11/38(29%) [5/38 (13%)] 

 

2/11(18%)  





  



Chodak etal., 1989

f  

 

2,3,4,6,7,8  

 

Urologyscreening(invitational)

 



6-year serialaverage 2 exams/man



 

 

2,131    45-86



 

 

Nodule Induration orasym144/2131 (6.8%)143/144 (99%)biopsied.

 



36/2131(1.7%)(1.5% initial)



 

 

25/36 (69%)     36/144(25%)g 25/144(17%) 

 

18/25(72%)9/18(50%)path loc.

 





See Gerberet al., 1993

f  



Drago et al.,1992



 

 

1,2,3,5,6,7,8

 

 

AcademicUrology Clinic

 



U.S. year withannual followup. Exactno. men enrolledeach yearnot provided. 

 

 

1940“asymptomatic”Recruitmentprocess not welldescribed

    55-70 (64)



 

 

Not specified(“abnormal”). Noblinding 147(7.6%)Implied all werebiopsied [260 others biopsied forTRUS abn].

 



39/1940 (2%)



 

 

Not providedfor DREdetectedcancers.

     39/147 (27%) [not provided] 

 

Not providedforDRE-detected cancers.

 









NA

  



Faul, 1982



 

 

2,3,4,6,7,8

 

 

Germanscreening

 



1 time1978



 

 

9,000,000eligible1,500,000recruited17% participated

   >45



 

 

Induration or nodule

 



0.1%



 

 

NA

    1951/21,308(9 %)  

 

NA

 





NA

  



Frohmuller,1991



 

 

2,3,4,6,7,8

 

 

Germanscreening.Governmentinsurancesponsored(same programas Faul et al.report, 1982).

 



1987 data 1time



 

 

1,341,833participants(approx 15% of60 yr eligible, 8%of 45 year oldeligible)

     >45



 

 

Nodule or Indurationexact % prostateabn not given1.7% suspiciousprostate or genitalia

 



0.12% (1638cases)



 

 

NA

      1638/22,590 (7%)  

 

NA

 













NA

  



Gilbertson,1971

 



2,3,4,6,7,8  



Universityinvitational(general)

 



Serial exams,16-yearstudy,average 5exams/man

 



5,856     Over 45  



Nodule% abnormal notgiven

 



75/5856(1.3%)cumulative20/5856(0.34%)initial

 



Unknown(22/75detectedreceivedradical surgery)

   Unable to derive  



NA  









(5-yearsurvival 91%for surgery72% for others)h

CONTINUED

74 Costs and Effectiveness of Prostate Cancer Screening in Elderly Men
APPENDIX C: STUDIES OF DIGITAL RECTAL EXAMINATION FOR PROSTATE CANCER SCREENING CONTINUED

  Author   Biases/ methodologic weaknessesa    Setting    Time frame (year)    Number of patients    Age (Y) range (mean)    Abnormal criterion No. patients (%) No. patients biopsied (%)    Overall detection yieldb    Proportion detected cancers (%) clinically localized    Positive predictive value (%)    Proportion surgically stagedc (%)    Long-term followup  





























Guinan etal., 1980



 i

 

1,2,3.  



Inpatient AcademicUrology ServiceAll symptomaticwith varyinglevels of prostatism.Study described asmultiple “screening” test evaluation,but populationhighly enriched withprostate cancer.Not generalizableto office-based DREscreeningsituation.Selection bias. 

 

 

1 time  

 

300 (consecutiveadmissions to urology service; notknown to haveprostate cancerpreviously)

 

 

50-90(no data onmean or distribution)

 

 

Gross Asymmetry,Induration orNodule (blindedassessment).All patients received DRE, aswell asprospectivedetermination ofacid phosphatase, urine cytology (pre- and postmassage), andseveral other antiquated tests.All patients biopsied.

 



69/300(23%)



         Not provided.



 



48/72 (67%)[Sensitivity -69%Specificity -89%]



 



Notprovided



 































NA

 

















Guinan etal., 1987



 

 

1,2,3.

 



Inpatient UrologyServiceComparative studyof 5 studies, including TRUS, PSA.All symptomaticselection biasNot generalizableto office-basedpopulation. 

 

 

1 timeconveniencesample(incompletetesting)

 

 

280 (implyconsecutiveadmissions noknown cancer)

 

 

(68)

 

 

Gross Asymmetry,Induration orNodule96/258 (37%)

 



78/280(28%)



      Not specified.



 



51/96 (53%)[Sensitivity51/70 (73%)Specificity143/188(77%)]



 



not specified



 



















NA

 





Gustafssonet al.,1992

j

 

 

6,8  



Swedish screeningpopulation-based



 

 

1 time  

 

2400 eligible1788 recruited(74%)

 

 

55-70  

 

Nodule or indurationasymmetry195/1782 (11%)Implied allbiopsied.

 



42/1782(2.4%)



   22/42 (52%) 6 patients not biopsied.



 



42/195 (22%)[22/195(11%)]



 



NA



 







NA

 





Imai et al.,1988

k

 

 

2,3,4,5,6,7,8

 



Japanese massscreening



 

 

1 time

 

 

35,055 eligible5302 screened(15%)

 

 

>60

 

 

Not specified(minimal change)551 Abn by firsturologist, 202biopsied.

 



54/5302(1%)



   28/54 (52%) stage B



 



54/202(27%)28/202(14%)



 



NA



 







NA

CONTINUED

Appendix C Studies of Digital Rectal Examination for Prostate Cancer Screening 75
APPENDIX C: STUDIES OF DIGITAL RECTAL EXAMINATION FOR PROSTATE CANCER SCREENING CONTINUED

   Author    Biases/ methodologic weaknesses a   Setting    Time frame (year)    Number of patients  Age (Y) range (mean)   Abnormal criterion No. patients (%) No. patients biopsied (%)   Overall detection yield  b   Proportion detected cancers (%) clinically localized    Positive predictive value (%)   Proportion surgically stagedc (%)    Long-term followup  



Jenson, 1960



 

 

2,3,4,6,7,8  

 

UniversityInvitational(General)asymptomatic

 



Serial exams,11-yearstudy,average 7.6exam/man



 

 

4,367      Over 45 

 

Nodule or Induration

     37/4367 (0.8%) cumulative (0.32% initial exam)  

 

NA  

 

NA  

 

NA  

 

Overallsurvival 57%for cancersdetected firstexam, 86%subsequentexams   Lee et al., 1988  l    1,2,3,5,6,8    Screening invitational/ referral   1 time    784   60-86 (65)    NA    10/784 (1.3%)    Unknown for DRE itself    10/29 (34%) [not provided]    NA    NA  



Mettlin et al.,1991ACS-NPCDP



 

 

2,3,6,7,8  

 

10 Centers inU.S./CanadaHospital/ClinicInvitational

 



Initial Screen



 

 

2,425        55-70 (63)  

 

Nodule,Induration orAsymmetry153/2425 (6.3%)118/2425 (4.9%)

       33/2425 (1.4%)  

 

27/32 (84%)[missing data]

 

 

33/118 (28%)Amongpatient biopsied[27/118 (23%]

 

 

20/30 (66%)RadicalSurgery-20(missing datain 9 of 57 total cancersdetected butnot specifiedwhich wereDRE detected.)

 

 

NA

 



Mettlin et al.,1993 ACSNPCDP



 

 

2,3,6,7,8  

 

10 Centers US/CanadaHospital/ClinicInvitational

 



5-yearannualfollowup.Report on1972 menwith 2 sequentialexams withcompletedata. 

 

 

2,999 enrolledoverall Dataprovided for1972 initialexam 1899second exam.

      55-70 entry (63)  

 

Nodule, Induration of AsymmetryInitial exam.139/1972 (7%)117/1972 (6%)Second Exam82/1899 (4.3%)75/1899 (4%)

      38/1972 (1.9%) initial exam 16/1899 (0.8%) Second exam.  

 

32/37 (86%)initiall,/missing

13/13 (100% ) second, 3 missing.

 

 

38/117 (32%)[32/117(27%)]initial16/75 (21%)[13/75 (17%)]Second

 

 

18/32 (56%) resurg.7/32 (22%)XRT 6 missingdata initial12/13 (92%)surgery 1/13(8%) XRT 3missing data.

 

 

NA

 



Moon et al.,1991



 

 

2,3,4,5,6,7,8  

 

University/VeteransAdministrationUrology ClinicInvitational

 



1 time



 

 

4173 patients notbiopsied.

      40-59  

 

Not specified       30/414 (7%) overall abnormal gland (0/190 40-49 years) 29/30 (97%) implied biopsied  

 

1/414 (0.24%)overall 1/224(0.45%)for age 50-59year.

 

 

1/1 (100%)  

 

1/30 (3.3%) 

 

1/1 (100%)Stage Cpathologic.

 



Mueller et al.,1988



 

 

1,2,3,4,5,6,7,

 

 

Military UrologyClinicRetrospectiveof ongoingstudy; usedyears 1979-85.

 



7-year serialaverage 2-4exams/year



 

 

4,843

     40-79  

 

Nodule312/4843 (6.4%)imply 100% biopsylate

     122/4843 (2.5%) (1.7% initial exam 0.63% per subse- quent exam 

 

77/122 (63%)58% initial74%subsequentexam

 

 

122/312 (39%)

 

 

73% (46%initialpathologiclocal, 58%subsequentexam)

 

 

NA

CONTINUED

76 Costs and Effectiveness of Prostate Cancer Screening in Elderly Men
APPENDIX C: STUDIES OF DIGITAL RECTAL EXAMINATION FOR PROSTATE CANCER SCREENING CONTINUED

   Author    Biases/ methodologic weaknesses  a   Setting   Time frame  (year)   Number of patients    Age (Y) range (mean)    Abnormal criterion No. patients (%) No. patients biopsied (%)   Overall detection yieldb    Proportion detected cancers (%) clinically localized    Positive predictive value (%)    Proportion surgically stagedc (%)    Long-term followup  



Muschenheim et al.,1991



 



2,3,4,5,6,7,8



 

 

Invitational FreeScreen. ProstateCancer Awarenessbreak MadisonCounty NewYork 2 Sites2 urologists.

    1 time



 

 

565incompletefollowup

 

 

not provided

Not specified 83/565 (19.6%)  Abnormal DRE37/565 (6.5%)  biopsied. Patientsnot all biopsied at  Central studysites. 

 

 

16/565 (2.8%)5/16 (31%)grade “poorlydiff”(Gleasongrade notperformed)

 



13/16 (81%)althoughinsufficientdetail provided



 

 

16/37 (43%) ofthose biopsied.

 

 

Insufficientdetail 11/16 surgical treatment (3 RT) All 11surgically stagedhad no lymphnode disease.

 



Treatment:RP 11 RT 3Orchiectomy2 No. Tx 1.

  



Naito, 1988



 



1,2,3,4,5,7



 

 

JapaneseUrology ClinicCooperativereferrals for variety untreatedprostate symptomsHighly selectedall receivedDRE (unclear ifblinded assessment) and TRUS(blinded) 3.5 mH2

        1 time



 

 

109

 

 

35-89 (70)



Poorly specified 2 levels of Abnor- mal “malig. cancer not ruled out” 19/109 (17%)“malig. cancer highly suggestive”19/109 (17%) All patients biopsiedbut technique not specified 

 

 

 

22/109 (20%)

 



NANo data provided onclinical/pathstage orgrade



 

 

22/38 (69%) if lumpboth levels of abnormal DRE (notprovided) ‘sensitivity’= 22/32 (69%)‘specificity’= 61/77(79%)

 

 

NA

 



NA

   Pederson et al., 1990 m   4,6,8    Swedish population screening random selection.   1 time    1494 (1163 participate (78%)    50-69 Nodule  Induration     13/1163 (1.1%)  12/13 (92%)    13/44 (30%) 12/44 (27%)GP 15/44 (35%) Urology    10/13 (77%) 10 surgeries (7 extracap. by pathology 1xRT   NA   



Perrin et al.,1991

 n

 



1,2,3,4,6,7,8



 

 

French urologyclinic asymptomatic healthcheck

   1 time



 

 

863

 

 

50-60



Nodule orinduration 

 

 

 

0.35%, 1.9% adjusted

 



NA



 

 

3/11 (27%)

 

 

NA

 



NA

  



Richie



 



2,3,6,7,8



 

 

6 Urologyclinics.General publicrecruited.

      Initial screen data



 

 

6630  

 

50-96 (63) DRE:  Asymmetry, In

duration or  NoduleAll patients had PSA; biopsy received if PSA > 4 Abnormal DRE in982/6630 (15%) 683/982 (70%)  biopsied 

 

 

146/6630(2.2%)Cancer onbasis DREalone

 



143/146 (98%)



 

 

146/683 (21%)  

 

92/146 (63%)64/92 (70%)pathologic, confined

 



NA

 CONTINUED

Appendix C Studies of Digital Rectal Examination for Prostate Cancer Screening 77
APPENDIX C: STUDIES OF DIGITAL RECTAL EXAMINATION FOR PROSTATE CANCER SCREENING CONTINUED

  Author   Biases/ methodologic weaknessesa    Setting    Time frame (year)    Number of patients  Age (Y) range (mean)   Abnormal criterion No. patients (%) No. patients biopsied (%)   Overall detection yield  b   Proportion detected cancers (%) clinically localized    Positive predictive value (%)   Proportion surgically stagedc (%)    Long-term followup  













Thompson,1984



 

 

1,2,3,4,6,7  



Military UrologyClinicretrospectiverandom reviewof ongoingscreening study,from 1979-83.Data likely partof Mueller 1988study. 

 

 

4 year serial1.3 exam/patient

 

 

2005 part ofroutine exam 43%patients with negative biopsy had urologic symptoms.

      40-92 (58)  

 

Noduleboth lobesbiopsied routinely# per patient notspecified

      17/2005 (0.8%) 0.55% initial 0.25% second 

 

15/17 (88%)  

 

[17/65 (26%)][15/65 (22%)]

 

 

 



NASee Gerberet al 1993.

f  





















Varenhorstet al.,1992

o

 

 

4,6,8

 



Swedishpopulationinvitationalscreeningrandomselection. 9,026males eligiblefrom geographicarea. Onlygeneralpractitionersinvolved withsecond round. 

 

 

Second followup to Pedersonet al study.

 

 

1994 invitational initially; 1,163 participating firstscreen (78%) 1363invited secondscreen 953 participating second(70%).

        50-69  

 

Nodule or Induration (similarFNA biopsy technique as infirst screening).

        7/953(0.7%) 

 

5/7(71%) notspecifiedwhether 2 advancedcancers werethe 2 notscreened firstcycle.

 

 

7/42 (17%)[5/42 (12%)]

 

 

3/7 (43%)

 



NA

  





Vihko



 

 

1,2,3,4,5,6,7,8

 



Veteran’sRehabilitationUrology clinic



 

 

4 yearserial

 

 

771imply full compliance biopsyif tests abn.

    54-76  

 

Not specified27/771 (3.5%)DRE abnormal

    6/771 (0.89%)  

 

4/6 (67%)

 

 

6/27 (22%)[4/27 (15%)]

 

 

NA

 



NA

  





















Waaler



 

 

1,2,3,4,5,6,7,8  



GermanOccupationalHealth Programscreening



 

 

1 time  

 

480         45-67  

 

Not specified;Abnormal did notinclude “adenomatous enlargement”26/480 (5.4%) referred to urology,9/26 specificallysuspicious for PCin first screen.Urologists suspected PC in10/26 referred. 16patients biopsied.

        1/480 (0.2%) 

 

0/1 (0%)  

 

1/16 (6%)[0/16 (0%)]

 

  0  



NA

 a Legend for study bias/methodological weaknesses: 1) not population-based community setting; 2) selection/referral bias; 3) nonrandomly sampled study group; 4) explicit inclusion/exclusion criteria not provided; 5) abnormal test criterion not described; 6) incomplete application of appropriate reference (gold) standard (work-up bias); 7) lack of proper blinding in test interpretation; 8) failure to account completely for all enrolled subjects (include biopsy of all abnormal tests and reporting of clinical and pathologic staging information). Note that for each study listed, the presence of one or more of these methodologic deficiencies will be devoted with the particular number (1-8) in the proper cell. We chose not to grade or weigh to degree to which a study bias was present.

b Detection yield = number of patients with prostate cancer detected/number patients screened. Numbers in parenthesis refer to yield of each individual examination.c Refers to proportion of patients clinically localized who receive surgical staging.

78 Costs and Effectiveness of Prostate Cancer Screening in Elderly Men
APPENDIX C: STUDIES OF DIGITAL RECTAL EXAMINATION FOR PROSTATE CANCER SCREENING CONTINUED

d No apparent selection bias. 407 of 472 recruited patients who agreed to at least part of the “health screen” received DRE by general physician. Total of 7 cancers detected but only 1 had an abnormal DRE;

remaining 6 had elevated PSA (see table 11). Work-up bias. Only 68 of 472 received TRUS, based on either abnormal PSA or DRE. 29 patients were biopsied based on hypoechoic TRUS lesion and/or abnormalDRE.

e The 811 patients in this invitation screening study are also included in the subsequent study of 2,131 patients by Chodak (1989).f Detection rate for initial screen 1.5% (32/2131), 0.2% for second-year exam (3/1321). Long-term disease-specific survival for patients in this cohort and the similar design of Thompson et al. (1984) are reported in

Gerber et al. (1993). 56 men (mean age 65 years) were followed for median of 75 months; 3/56 men were not reported in the 2 original reports. Clinically localized cancer diagnosed in 73% on initial screen and for83% of cancers detected in subsequent examinations. Patients were treated by variety of strategies initially but in general aggressive treatment (surgery or radiation) used for those clinically localized. However,10-year disease-specific survival was 86% for men diagnosed during first screen and only 57% for subsequent exams (p=.02). This data suggest presence of length bias. Only 63% and 22% of patients in Chodak(1989) cohort returned for second and third examinations, respectively.

g Overall PV + for entire period of study; PV + for initial exam abnormalities versus subsequent ones not provided.h Unable to assess effect of lead-time and length bias.i This is the single study available that is not flawed by work-up bias. All patients received transrectal biopsies, using a modification of the Vim-Silverman needle. However, the population studied is very atypical of

men without suspected prostate cancers being followed in a routine office-based primary care setting. All men were symptomatic inpatients on urology service. The high prevalence of detected cancers, 10 to20 fold higher than typical screening studies of DRE, suggests significant selection biases. Although the comprehensive biopsy protocol explains some of this discrepancy, the prevalence is still nearly twice ashigh as an earlier hospital-based study employing routine “wedge” biopsy in a population enriched with prostatism but no suspected cancer (Hudson, 1954).

j The study cohort was derived from 2,400 patients in this age group randomly selected from a defined catchment area of the study hospital. All cases in group with prior history of prostate cancer were excluded.

Patients were invited to participate in multiphasic 1 time screening program. All 1,788 recruited patients received DRE, TRUS, and PSA with proper blinding performed. A preliminary report of this data waspublished by Norming et al. (1991). Biopsy performed selectivity for DRE positive and/or TRUS positive patients (small unspecified number for elevated PSA above 10ng/ml). Clinical staging performed by TNMsystem. 11/42 DRE positive cancers were T2A, 11 were T2B.

k “Mass screening” study organized between 1981 and 1985 by the urology department at Gunma Cancer Center Hospital. Intervention involved questionnaire, acid phosphatic (PAP), and DRE in a ”field” type

approach. “Any small change” in DRE led to ”suspicious” categorization (N=551), however, only 202/551 (37%) were biopsied after second evaluation by urologist. Thus, actual PV+ for patients receiving biopsywas 54/202 (27%) for all cancer. The mean age of patients with detected cancer was 73 years (63-87 range). The average cost of detecting each case was calculated to be equivalent to $5,358. Authorscompared clinical stage distribution in study group (52% stage B) with 93 patients diagnosed in outpatient clinic (”controls”) over same time period (16% stage B). Crude survival curves of patients (by stage) inboth groups indicate no differences at mean followup of 3 years. However, only 3/28 (11%) of stage B patients in the study agreed to surgery.

l Bias against DRE (vs. transrectal ultrasound comparison); 50% of patients reportedly had normal DRE within 1 year of study.m From a population of 9,026 men ages 50 through 69 in a defined catchment area in Sweden, 1,494 were randomly selected and invited to receive DRE by both a general practitioner and a urologist, performed

independently. These data were also presented, in virtual identical fashion, in E. Varenhorst, et al. Biopsy technique included fine needle aspiration (FNA) of suspected area and 3 samples from each lobe, usingcytologic analysis. It is not specified whether a “geographic” approach to FNA of nonsuspected areas is used.

n This study has significant methodologic flaws. The 863 patients receiving a “screening” DRE represent one subgroup receiving different interventions. The men are reportedly asymptomatic. No description of

how these men are selected for study. 61 (7%) had suspicious DRE but only 11 got biopsied revealing cancer in 3. Assuming same PV+ would apply if all 61 received biopsy, the estimated “adjusted” yield of DRE is1.9%. Because of potential uncharacterizable selection bias, the study population cannot be considered a screening cohort.

o This publication presents the second screening yield from the original study of Pederson et al. (1990). Thirteen cancers were detected in the initial round and 7 cancers during the second round 3 years later. Six

other cancers were diagnosed through routine care (4 incidentally at TURP) between screening cycles for this population. Of the combined 20 cases detected by screening, 14 (70%) had PSA > 4ng/mL,although PSA was routinely performed in this protocol. Of the 7 cancers detected in the second round, 5 had normal DRE in the first round and 2 had not participated in first round.

Appendix C Studies of Digital Rectal Examination for Prostate Cancer Screening 79
APPENDIX

D

Studies of

Prostate-Specific Antigen for

Prostate Cancer Screening and

Early Detection
APPENDIX D: STUDIES OF PROSTATE SPECIFIC ANTIGEN FOR PROSTATE CANCER SCREENING AND EARLY DETECTION: RESEARCH DESIGN AND FINDINGS 

 





 Author

 

 

Biases and 

methodologic

weaknesses

 

a



  Setting

 







Age

(year)

(mean)

 

 

Number

patients

enrolled

(%)

    Abnormal PSA criterion (%)  

  Biopsy criteria

 

 

No. patients

(%) with 

criteria

No. patients

(5) biopsied

 

  No. (%) PC detected

 

  No. (%) PC clinically localized

    No. (%) PC pathologically localized 

  PPV %b PSA

 

  Treatment  









Babaianet al.,1992ACSNPCDP



 

c



 

2,3,6,7,8  

 

10 sites inU.S./Canada,hospital/clinic-basedpublic invited

 











55-70(63)

 

 

2425over 3.5 years(PSA in 2,227)

     > 4 ng/mL (not provided) 

 

Abnormal DREand/or TRUS (11additionalbiopsies for abnPSA, most > 10ng/mL) blindingnot specified

 

 

Not provided520/2425 (21%)year 1 - 395year 2 - 102year 3 - 23

 

 

88/2,425(3.6%)no data ongrade/volume

 

 

Not provided

     Not provided 

 

59/137(43%)

 

 

Notprovided

 





Babaianet al.,1991



 

 

1,2,3,4,6,7,8  

 

Urology ClinicCancer (mostsymptomatic)referral andselectionbiases

 







50-75 (63median)

 

 

362(75 MDreferralrecorded)

    > 4 ng/mL 90/362 (25%)  

 

Abnormal DREand/or TRUS, orPSA > 20No blinding

 

 

120/362 (33%)109/362 (30%)

 

 

37/362 (10%)27/75 (36%)MD referred;10/287 (3%)self referred

 

 

23/37 (62%)    Not provided 

 

30/90(33%)

 

 

Notprovided

 









Brawer etal., 1992



 

 

2,3,6,7,8

 

 

U.S. UrologyClinicPublicrecruited

 











>50(67)

 

 

1249

     > 4 ng/mL 187/1,249 (15%)  

 

If PSA > 4, thenDRE/TRUS withsystematic biopsyadjunctblinding notspecified

 

 

187/1249 (15%)105/1249 (8.4%)

 

 

32/1249(2.6%)no data ongrade/volume

 

 

30/32 (94%)

     9/32 (28%) 4 of the 9 capsule pene- tration without perforation 16 surgical staging 

 

32/105(30%)

 

 

RP - 15PL - 1RT - 10No TX - 6

 









Catalonaet al.,1991



 

 

2,3,6,7,8  

 

U.S. UrologyClinicPublicrecruited

 











50-89  

 

1653      < 4 ng/mL 137/1653 (8.3%)  

 

If PSA > 4 on initialor 6 month re-test,then DRE andTRUS, biopsy ifeither abn blinding not specified

 

 

137/1653 (8.3%)112/1653 (6.8%)

 

 

37/1653(2.2%)dno data ongrade/volume

 

 

36/37 (97%)     12/37 (32%) 33 surgical staging  

 

37/112(33%)if PSA 4-9.919/85 (22%)if PSA > 10

18/27 (67%)

 

 

Not provided(at least 19had RP)

 





















Catalonaet al.,1993



 

 

2,3,6,7,8  

 

U.S. UrologyClinicPublicrecruited

 























50-90(63)

 

 

10,251 (but622 “protocolviolations”)9,629 initialscreen9,333 serialscreen (up to37 monthfollowup)

        > 4 ng/mL 902/9629 (9.4%) initial 873/9333 (9.4%) serial 

 

If PSA > 4 twiceinitially, or on any6 month serialcheck then DREan TRUS. If eitherabn, biopsy.No systematicbiopsy

 

 

902/9629 (9.4%)860/9629 (8.9%)initial873/9333 (9.4%)465/9333(5%)serial

 

 

296/9629(3.1%)initial195/9333(2.0%)serial491/9629(5.1%)total

 

 

277/296(94%)initial170/175(97%)serial, butmissing data

        153/262 (58%) initiate, but 27 clinically localized did not get surg stage 92/129 (71%) serial, but mis- sing data in 46 patients  

 

296/860(34%)overallinitial174/652(27%)PSA 4 - 9.9initial122/208(59%)PSA > 10,initial

 

 

Of total491:RP - 348RT - 68HT - 27No TX - 16Pending -32

 





Chadwick etal., 1991



 

 

3,4,6,7,8  

 

Britishpopulationbased general practicerecruitment

 







55-69  

 

863 eligible814 recruited472 screened437 got PSA407 got DRE

    > 4 ng/mL 63/472 (13%)  

 

If PSA > 4 and/orDRE abnormal,TRUS recommended. If TRUSabn, biopsy recommend

 

 

75/472 (16%)12 of 75 for abnDRE alone29/472 (6%)biopsied

 

 

7/472 (1.5%)(mean PSA17)No data onsize/volume

 

 

7/7 (100%)     5/7 (71%) 5 surgical stag- ing  

 

7/63 (11%) 

 

RP - 5No TX - 2

CONTINUED

82 Costs and Effectiveness of Prostate Cancer Screening in Elderly Men
APPENDIX D: STUDIES OF PROSTATE SPECIFIC ANTIGEN FOR PROSTATE CANCER SCREENING AND EARLY DETECTION: RESEARCH DESIGN AND FINDINGS CONTINUED

 





 Author

 

 

Biases and

methodologic

weaknesses

 

a



  Setting

 







Age

(year)

(mean)

 

 

Number

patients

enrolled

(%)

 

 

Abnormal

PSA

criterion (%)

 

  Biopsy criteria

    No. patients (%) with criteria No. patients (5) biopsied 

  No. (%) PC detected

 

 No. (%) PC  clinically localized

 

  No. (%) PC pathologically localized

 

  PPV %b PSA

 

  Treatment  

















Cooneret al.,1990

 



1,2,3,4,6,7,8  



U.S. GroupUrology Practice referralbias [selectedpopulationmany symptomatic withprostatism ofvaryingegree]

 

















50-89  



1,807  



> 4 ng/mL602/1,807(33%)4-10 ng/mL366/1,807(20%)> 10 ng/mL236/1,807(13%)

 



Abnormal TRUS(hypoechoic)No systematicbiopsy.DRE, PSAperformed butnot basis forbiopsyNo blinding.

      835/1,807 (46%) all biopsied  



263/1,807(14.5%)< 3.0 cc vol172/263 (65%)> 3.0 cc vol91/263 (35%)

 



136/242 (56%)of dataavailable

 



43/263 (16%)60 patientssurgically staged

 



263/835(32%)

 



RP - 57

 

















Drago etal., 1992



 e 

 

1,2,3,5,6,7,8

 



U.S.AcademicUrology Clinic



 



















55-70 (64)

 

 

1940 “asymptomatic”No cleardescription ofrecruitmentprocess.Annual followup over4.5 years.

 

 

> 4 ng/mL989/1,940(51%)

 



Abnormal DREand/or TRUSsystematic biopsynot used27 of patientsbiopsied on basisAbn PSA but levelnot specified.



      Not provided. 416/1940 (21%) biopsied Initial, 320 biop- sied 2nd, 80 biopsied 3rd, 16 biopsied  

 

79/1940(4.1%) cumulative yieldNo data ongrade/tumor[57/79 (72%)of PC hadPSA >4]

 



64/79 (81%)



 



Not provided.



 

 

57/137(42%) ofthe 989patientswith PSA> 4 not biopsied.

 

 

Notprovided.

 

























Guinanet al.,1987



 

 

1,2,3

 



Inpatient Urology ServiceComparativestudy of 5studies, including TRUS, PSA.All symptomatic selectionbias.Not generalizable to officebasedpopulation. 

 



























Mean 68

 

 

280

 

 

Not specified“Mean plus 1S.D.”Hybritech102/280 gotPSA (36%)

 



Unknown for entire group: only46/102 (45%)PSA ‘pos’All 280 biopsied



        Actual preva- lence 78/280 (28%) of PSA tested 42/102 (41%)  

 

Not specified.

 



Not specified.



 



31/46 (67%)sensitivity =31/42 (74%)specificity =45/60 (75%)



 

 

Notprovided.

 

   

























Gustafsson et al.,1992



 

 

6,8  



Swedish Urology ClinicRandomselectionpopulationbased



 



























55-70  

 

2400 eligible(censusdatabase)1,782 recruitedNo data onnumber ofpatients withurologicsymptoms orevidence ofBPH.

 

 

> 4 ng/mL306/1782(17%)

 



Abnormal DRE,TRUS or PSA > 10ng/mL (systematicbiopsy if PSA >10).Patients receivedall 3 testsAbn DRE (nodule,induration, asymmetry)TRUS (hypo orasymmetry).



        Not provided 371/1782 (21%) biopsied Average 3 fine needle aspirates/ patient and 2-4 core biopsy/ pa- tient.  

 

65/1782(3.6%)If age 55-597/481 (1.5%)age 60-6426/585 (4.4%)age 65-7032/716 (4.5%)Overall PSAalone52/1782(2.9%)

 



40/65 (62%)(2.2% of 1782)T2A or less -22T2B - 1863/65 inperipheralzone



 



Not provided.



 

 

52/306(17%)

 

 

Notprovided.

CONTINUED

Appendix D Studies of Prostate-Specific Antigen for Prostate Cancer Screening and Early Detection 83
APPENDIX D: STUDIES OF PROSTATE SPECIFIC ANTIGEN FOR PROSTATE CANCER SCREENING AND EARLY DETECTION: RESEARCH DESIGN AND FINDINGS CONTINUED

 





 Author

 

 

Biases and

methodologic

weaknesses

 

a



  Setting

 







Age

(year)

(mean)

 

 

Number

patients

enrolled

(%)

 

 

Abnormal

PSA 

criterion

(%)

 

  Biopsy criteria

 

 

No. patients

(%) with

criteria

No. patients(5) biopsied

 

 No. (%) PC  detected

 

 No. (%) PC  clinically localized

 

  No. (%) PC pathologically localized

 

  PPV %b PSA

    Treatment  





















Labrie etal., 1992



 

 

6,8  

 

CanadianUniversityCenterRandomselection,populationbased fromelectoralroles

 























45-80  

 

1002(number initially invitednot provided)

 

 

> 4 ng/mL124/1,002(12.4%)>3 ng/mL191/1,002(19%)

 

 

AbnormalDRE and/orTRUS (PSA testfor all but notbiopsy forPSA alone)If abnormalDRE but TRUSneg. six random biopsies

 

 

Not Provided.Not provided.

 



Overall57/1,002(5.7%)For PSA > 4,41/1,002(4.1%)For PSA > 3,46/1,002(4.6%)No data on volume orgrade 

 



Notprovided.



 



Not provided.



 

 

For PSA > 4,41/124 (33%)For PSA > 3,46/191 (24%)

        Not provided.  





























Mettlin etal., ACSNPCDP,1991

f

 

 

2,3,6,7,8  

 

10 sites inU.S./Canada Hospital/ClinicPublic invited

 































55-70(63)

 

 

2,425 over 3.5years(PSA in 2,227)Report on initial screen

 

 

> 4 ng/mL312/2,227(14%)

 

 

AbnormalDRE and/orTRUS (unknown numberbiopsy recommendedfor PSA > 10ng/mL)Blinding oftests notspecified

 

 

396/2425(16.3%)330/2425(13.6%)70/312 (22%)with PSA > 4were biopsied

 



57/2,425(2.4%)5 of 57 on basis of PSA > 10ng/mL alone



 



46/51 (90%)6 others missingstage data



 



21/31 (68%)3 missing surgical stage data,23 not stagedpathologically< 1.0 cm - 10> 1.0 cm - 40No size data - 7No volume dataGrade:Gleason 4-6: 43Gleason 7-8: 9No data: 5 

 

 

34/312 (11%)(5 of the 34cancers hadPSA >10)242/312 (78%)patient withPSA > 4 werenot biopsied.

          RP - 34 RT - 10 HT - 3 Orchiectomy - 1No TX - 4  

































Mettlinet al.,ACSNPCDP,1993g

 



2,3,6,7,8

 



10 sites inU.S./CanadaHospital/Clinic Publicinvited

 

































55-70 onentry(63)

 



2,999enrolledAnnualevaluation upto 5 yearsReporting on1972 menwith 2 sequential exams withcompletedata forprimaryvariables.

 



> 4 nl/mL271/1972(21%)initial exam248/1899(22%)follow-upexam

 



71/271 (26%)with PSA >4biopsiedinitial49/248 (20%)with PSA >4biopsied onfollow-up

 



326/1972(16.5%)Initial exam216/1899(11.4%)follow-up exam285/1972(14.5%)Initial196/1899 (10%)Follow-up

 



73/1972(3.7%)Initial exam33/1899(1.7%)Follow-upexam

 



79/85 (93%)No data for2156/61 (92%)Initial23/24 (96%)Follow-up

 



Not provided67/88 (76%)Gleason gradeprovided weregrade 4-5.

 



49/271 (18%)Initial Exam22/248 (9%)Follow-upExamExplicit number cancerwith PSA > 4in initial andfollow-upgroups notprovidedoverall71/106 (67%)cancers hadPSA >4.

         RP - 59 RT - 17 No TX - 6 HT - 2 Orchiectomy - 3\ No data provided - 19 

CONTINUED

84 Costs and Effectiveness of Prostate Cancer Screening in Elderly Men
APPENDIX D: STUDIES OF PROSTATE SPECIFIC ANTIGEN FOR PROSTATE CANCER SCREENING AND EARLY DETECTION: RESEARCH DESIGN AND FINDINGS CONTINUED

 

  Author

 

 

Biases and

methodologic

weaknessesa

  

 Setting

 







Age

(year)

(mean)

 

 

Number

patients

enrolled

(%)

 

 

Abnormal

PSA 

criterion

(%)

 

  Biopsy criteria

 

 

No. patients

(%) with 

criteria

No. patients

(5) biopsied

 

  No. (%) PC detected

 

  No. (%) PC clinically localized

 

  No. (%) PC pathologically localized

 

  PPV %b PSA

   Treatment   



Moon et al.,1991



 

 

2,3,4,5,6,7,8       University/ Veterans Administra- tion Urology Clinic Gener- al public recruited



 

















40-59



 

 

414  

 

> 4 ng/mL10/414(2.4%)Age 40-494/190 (2%)Age 50-5910/224(4.5%)

 



Not providedImplied thatallpatientsreceivedboth PSA andDRE with TRUSif either positive (notspecified)



 

 

Not provided11/414 (2.7%)

 

 

Overall5/414 (1.2%)If 40-49:0/190 (0%)If 50-59:5/224 (2.2%)white 2/153(1.3%)black 3/71(4.2%)

 

 

4/5 (80%)Little detailprovided

 

 

2/5 (40%)However, nouniform wholemount histologictechnique 2organ-confinedmay have beenunderstagedNo data ongrade/volume

 

 

5/10 (50%)       RP - 4   



Muschenheimet al., 1991



 

 

2,3,4,5,6,7,8

      Free screen- ingGeneral public recruited (Prostate Cancer Awareness Week)  

















notprovided



 

 

565

 

 

> 4 ng/mL59/565(10.4%)6 biopsies/patient

 



Abn DRE (notspecified)and/or PSAelevated.Noindependentblindingspecified



 

 

118/565 (21%)54/565 (9.6%)34/59 (58%)Abn. PSA biopsied

 

 

20/565(3.5%)5/20 grade“poorly diff”

 

 

17/20 (85%)althoughinsufficientdetailprovided

 

 

Not provided in sufficient detail.All 12 surgicallystaged had nolymph nodedisease.9/12 (75%) presumed localized.

 

 

15/59 (25%)For DREalone:16/83 (19%)

      RP - 12 RT - 4 Orchiecto- my - 3 No TX - 1   



Perrin et al.,1991

 h

 

 

1,2,3,4,6,7,8

      French Urology Clinic Recruited within clinic men attending for “routine” of 4-year checkup  

















50-60



 

 

863

 

 

> 4 ng/mL38/863(4.4%)

 



If DRE Abn.for those withPSA > 4



 

 

Not provided.Not provided.

 

 

3/863 (0.3%)

 

 

Not provided.

 

 

Not provided.

 

 

3/38 (8%).

      Not provided.   



Powell et al.,1989



 

 

1,2,3,4,6,7,8        Single British Urology Clinic Referral population All men had prostatism symptoms prospective accrual, pa- tients invited to “pre- screen” most

later got TURP 

 





















50-88 (68)



 

 

287 referred211 enrolled

 

 

> 10 ng/mL(Hybritech)37/211(17.5%)

 



PSA > 10DRE not uniformly performed (notavailable for23%)No TRUS used



 

 

37/211 (17.5%)36/37 (97%)

 

 

17/211 (8%) 

 

8/17 (47%) 

 

Not provided.  

 

17/37 (46%)        Not provided. CONTINUED

Appendix D Studies of Prostate-Specific Antigen for Prostate Cancer Screening and Early Detection 85
APPENDIX D: STUDIES OF PROSTATE SPECIFIC ANTIGEN FOR PROSTATE CANCER SCREENING AND EARLY DETECTION: RESEARCH DESIGN AND FINDINGS CONTINUED

 





 Author

 

 

Biases and

methodologic

weaknesses

 

a 





Setting

 

  Age (year) (mean)

 

 

Number

patients

enrolled

(%)

 

 

Abnormal

PSA

criterion

(%)

 

  Biopsy criteria

 

 

No. patients

(%) with

 criteria

No. patients(5) biopsied

 

  No. (%) PC detected

 

  No. (%) PC clinically localized

    No. (%) PC pathologically localized 

  PPV %b PSA

   Treatment   









































Richie etal., 1993



 i

 

2,3,6,7,8  









































 6University sites Public invited 

 

50-96 (63) 



6630[White - 6,098Black - 194(3%)Other - 338(5.1%)]Symptoms ofBPH:Yes - 3,500(53%)No - 3,130(47%)



 



> 4 ng/mL983/6630(14.8j%)PSA ABNstratified byage:50-59:150/2381 (6%)60-69:487/2959(17%)70-79:311/1161(27%)80+:35/129 (27%)



 

 

Abnormal DRE(asymmetry, induration ornodule) and/orPSA elevated. Ifeither abnormal, TRUS performed withguided biopsy ifabnormal andsystemic quadrant biopsies forall patients withelevated PSAeven if TRUS orDRE normal

 

 

Overall1710/6630 (26%)1167/6630(17.6%)Number of patientsmeeting criteriaby age:50-59:364/2381 (15%)60-69:828/2959 (28%)70-79:463/1161 (40%)80+:55/129 (43%)

 

 

Overall264/6630(4%)By age:50-59:48/2381 (2%)6-69:123/2959(4.2%)70-79:84/1161(7.2%)80+:9/129 (7%)Not stratifiedby presenceof symptoms

 

 

261/264(99%)

             114/160 (71%) of those received surgical staging 101 of the 261 patients with clinically local- ized cancers elected not to have surgery. 17/160 (11%) had poorly differentiated grade For PSA > 10 ng/ mL 40% organ- confined  

 

Amongpatients biopsied:Overall216/686 (31%)By age:50-59:36/113 (32%)60-69:99/336 (29%)70-79:73/216 (34%)CombinedAbn PSA orDRE PPV:Overall264/1167(23%)

            RP - 160 No other data provided.  a Legend for study biases and methodologic weaknesses: 1) not population-based or community setting; 2) selection (including self) and/or referral biases; 3) nonrandom study group accrual; 4) explicit inclusion/exclusion criteria not provided; 5) abnormal test criteria not described; 6) incomplete application of appropriate reference (gold) standard (work-up bias); 7) lack of proper blinding in test interpretation; 8) failure to account

completely for all enrolled subjects (including biopsy of all abnormal tests and reporting of clinical and pathologic stage data). For each study listed in this appendix, the presence of one or more of these deficiencies isdenoted with the corresponding number (1-8). We chose not to qualify weight to the extent of each particular methodologic weakness.

a BPA = benign prostate hypertrophy; PC = prostate cancer; PL = pelvic lymph node dissection (metastasis); PPV = positive predictive value; RP = radical prostatectomy; RT = radiation therapy; No TX = No treatment.b ACS-NPCDP = American Cancer Society National Prostate Cancer Direction Project. The ACS-NPCDP used DRE abnormality (asymmetry, induration, or nodule) and/or TRUS abnormality (hypoechoic area greater

than 5-7 mean not due to cyst, vascular structure, or artifact). Although 2,227 of 2,425 patients received PSA during first examination (with DRE and TRUS), no patient was biopsied for PSA > 4 ng/mL alone.

c 12 of 37 cancers detected had “non suspicious” DRE but 8 of the 12 had asymmetry or DRE that would have prompted biopsy elsewhere (Stamey). 14 of 16 cancers “missed” by TRUS had “abnormal but benign”

findings (e.g., asymmetry) that would have been biopsied elsewhere. Routine systematic biopsy of PSA > 4 not recommended.

d This study enrolled 1940 purportedly asymptomatic men over a 4 1/2 year period and followed them with annual DRE, TRUS, and PSA. No data on exact number of men followed per year are provided, nor is it clear how

many cancers were detected in each examination (apparent maximum of 3). It is also not clear whether all men received each test with each iteration. The data are presented in a confusing manner with multipletextual errors and miscalculations. PSA is not a major determinant of biopsy and less that one-half of those with PSA > 4 received biopsy.

e DRE detected 33 of 57 cancers found (detection rate 33/2425 = 1.4%). TRUS detected 44 of 57 cancers found (detection rate 44/2425 = 1.8%).f The ACS-NPCDP continued to rely on DRE and/or TRUS abnormalities as the main determinants for recommending biopsy, although subsequent evaluations incorporated PSA testing. For 144 of the 1972 men reported

here PSA data are unavailable. For clinical staging, this study uses a modification of Whitmore’s classification: A1 defined here as TRUS-measured tumor volume < 0.2 cm3 (average diameter less than 0.7 cm). Anunknown number of patients had biopsy within the study on the basis of PSA > 10 ng/mL, although 11 of the 106 detected cancers resulted from this effort. Patients with PSA > 10 ng/mL who had a negative set ofsystematic biopsies were re-evaluated with repeated TRUS and DRE in 12 months. It is not specified how many patients were rebiopsied if these studies remained negative. Six other detected cancers were foundthrough non-protocol means (e.g., TURP in men who were not previously recommended for biopsy). Positive Predictive Value (PPV) of DRE was 22% initially and only 14% follow-up examination. The PPV for TRUS were 14%and 8%, respectively (combined DRE/TRUS PPV 37% and 32%).

g Overall study design and mode of data presentation is poor. Description of patient cohort and method of recruitment scant. Only patients with elevated PSA who then had abnormal DRE were eligible for biopsy.

Actual number who meet criteria and then received biopsy were not reported. This study precludes fair comparison of DRE and PSA, as only patients with elevated PSA received DRE. Proper blinding was not specified.Their results have little usefulness and are not generalizable to an office-based screening population.

h Overall 68% compliance with biopsy performance for either/both DRE, PSA abnormal. The cancer detection rates and positive predictive values reported in the paper ignore noncompliance and assume same

proportion of positive biopsies would occur if all men meeting biopsy criteria actually received systematic biopsies. Unfortunately, although 53% of study group reported symptoms of prostatism, the data for predictivevalues of each test and detection are not stratified by symptoms or race. PPV for abnormal DRE among those patients biopsied is 146/683 (21%).

86 Costs and Effectiveness of Prostate Cancer Screening in Elderly Men
APPENDIX

E

Studies of

Repeat/Serial Prostate-Specific

Antigen Testing Yield for

Prostate Cancer Screening and

Early Detection
APPENDIX E: STUDIES OF REPEAT/SERIALa PROSTATE-SPECIFIC ANTIGEN TESTING YIELD FOR PROSTATE CANCER SCREENING AND EARLY DETECTION:

RESEARCH DESIGN AND FINDINGS

 

 Author

 



Biases and

methodologic

weaknesses

 

b



 Setting

 



Age

(year)

(mean)

   Number patients enrolled (%)    Abnormal PSA criterion (%)   Biopsy criteria    No. patients (%) with criteria No. patients (%) biopsied    No. (%) PC detected   No. (%) PC clinically localized   No. (%) PC pathologically localized    Positive predictive value of criteria   Treatment               Brawer et al., 1993



 c 

 

2,3,6,7,8

 

 

U.S. UrologyClinicPublic recruitedSecond yearof screeningstudyIncludes onlypatientswhose year 1PSA was < 4ng/mLMany menwere evaluated at non–study sites butthese datanot includedBlindingmethods notspecified

              > 50 (67) Similar age dis- tribution to original cohort (Brawer 1992)



 

 

701Reflects66% of original cohortwith PSA <4None ofthese hadDRE/TRUS inyear 1 ofstudy

 



20% increasein PSA aboveyear 1 level;Absolute PSA> 1.5 alsoused as criterion for biopsyrecommendation75/701 (11%)had PSA > 4at year 2, butonly 19/75(25%)receivedbiopsyPresumablyall of the 75were recommended toget biopsy,but reasonsfor noncompliance notspecified. 

 



If 20% increase PSA,then DRE withbiopsy if positiveIf absolutePSA > 1.5 ng/mL, systematic biopsy withTRUS guidance regardless of DREAbnormalDRE includedasymmetry,induration,noduleAbnormalTRUSincludedhypoechoicperipheralzone lesion



 

 

260/701 (37%)had 20% increasePSA82/701 (12%)biopsied overall159/260 (61%)had PSA > 1.5;and 71/159 (45%)agreed to DREbiopsy; 50/71(70%) had abnormal DRE; 101/260(39%) had PSA <1.5; 31/101 (31%)agreed to DRE;11/31 (36%) hadabnormal DREand got biopsy

 



14/701 (2.0%)overallAmong 260 with20% increase inPSA over 1 year,14/260 (5.4%)yield5/14 cancers hadonly asymmetryor a benign glandon DRE2/14 cancers(14%) had PSA > 417/68 benignbiopsies (25%)had PSA >4



 

















































13/14(93%)



 

 

Not known 7/8who receivedsurgical stagingwere organ–confined orhad negativemarginsNo data onprostate cancer volumes atsurgery provided

 

















































14/82 (17%)



 

 

RP–8No data forother 6

            Catalona et al., 1993



 

 

2,3,6,7,8

 

 

U.S. UrologyClinicPublic recruitedOriginal cohort 10,251men

            50–90 (63)



 

 

9,333 serialscreenees(up to 37months after initialscreeningPSA)Actualnumber ofpatientswho received multiple serialbiopsies(mean,range) notspecified

 



Overall > 4ng/mL873/9333(9.4%)if age <



 70

years693/8320(8.3%)if age > 70years180/1013(17.8%)PSA 4.1–9.9ng/mL743/9333 (8%)PSA > 10 ng/

mL130/9333(1.4%)

 



PSA > 4 ng/mL twice onany of 6month serialchecks, thenDRE andTRUS. If eitherabnormalbiopsy recommendedNo systemicbiopsies onPSA aloneIf biopsy neg.repeat PSA at6 month intervals and repeat DRE/TRUS, withbiopsy if indicated, if PSA> 4 again 

 

 

873/9,333 (9.4%)465/9,333 (5%)

 



195/9,333 (2.0%)overallIf age <



 70 years,

153/8320 (1.8%)If age > 70 years,42/1013 (4.1%)Number Cancersdetected:First biopsy 90Second biopsy 84Third biopsy 17Fourth biopsy 4Denominators notprovided

 









































170/175(97%); missing datain 20



 

 

92/129 (71%);missing data in46If age < 70

years,84/111 (76%)If age > 70years, 8/18(44%)

 









































195/465(42%), overall165/392(42%) if PSA4.1–9.9 ng/mL30/73 (41%)if PSA >



 10

ng/mLIf age < 70years,153/363(42%).if age > 70years,42/102(42%)

 

 

Results notstratified byinitialscreeningor serialscreening.See Appendix Dfor aggregatedtreatmentoutcomesfor the total 491cancersdetectedin both cohorts. Nolong–termoutcomedata.

CONTINUED

88 Costs and Effectiveness of Prostate Cancer Screening in Elderly Men
APPENDIX E: STUDIES OF REPEAT/SERIALa PROSTATE-SPECIFIC ANTIGEN TESTING YIELD FOR PROSTATE CANCER SCREENING AND EARLY DETECTION: 

RESEARCH DESIGN AND FINDINGS CONTINUED

  

 Author

 

  Biases and methodologic weaknesses

 

b

   Setting 

  Age (year) (mean)

    Number patients enrolled (%) 

  Abnormal PSA criterion (%)

 

  Biopsy criteria

  



No. patients

(%) with

criteria

No. patients

(%) biopsied

 

  No. (%) PC detected

 

  No. (%) PC clinically localized

 

  No. (%) PC pathologically localized

 

 

Positive

predictive

value

of criteria

 

  Treatment           Mettlin et al ACS– NPCDP, 1993



 

 

2,3,6,7,8           10 sites in U.S./ Canada Hospital/ Clinic Public recruited Annual evaluation up to 5 years  

 

55–70 onentry(63)2,999originalenrollees

           1899 men re- ported with 2 sequential ex- ams with com- plete data, no cancer on first exam. Only results of followup testing reported here.  

 

> 4 ng/mL248/1899(22%)follow–upPSA abnormalPatients notbiopsied forPSA resultsaloneOnly1783/1899(94%) of patients infollow–upgroupreceived PSAtest

 



AbnormalDRE and/orabnormalTRUS (unknown number biopsiesrecommended forPSA > 10 ng/mL)49/248 (20%)biopsiedwith PSA> 4 in follow–up



          216/1899 (11%) on follow–up testing 196/1899 (10%) biopsied on basis follow–up testing



 

 

33/1899(1.7%)on follow–up testingIf initially55–59years, 1%detectionrate,If 60–64years, 1.1%detectionrate, If65–70years, 3.1%detectionrate

 



23/24 (96%)missing datain 9 cases



 

 

Not providedfor follow–uptesting group

 

 

For PSA > 4,22/248 (9%)with follow–up testing11/33cancers detected infollow–uptesting grouphad PSA < 4

 

 

Not stratifiedby followuptestinggroup,See Appendix D for treatmentchoices foroverall cohort

aRefers to followup with PSA but in the case of Mettlin, (1993) PSA is not used as a primary criterion for biopsy. The criteria for biopsy in all 3 of these papers are different. However, we specifically do not include papers that

evaluate PSA or velocity as principal issue (see Carter, 1992). Rather, serial PSA refers to the detection rate and predictive value of repeated measures of PSA testing. However, use of PSA and protocol in the 3 studiesdiffer significantly.

b Legend for study biases and methodologic weaknesses: 1) not population–based or community setting; 2) selection (including self) and/or referral biases; 3) nonrandom study group accrual, 4. Explicit inclusion/exclusion criteria not provided; 5) abnormal test criteria not described; 6) incomplete application of appropriate reference (gold) standard (work–up bias); 7) lack of proper blinding in test interpretation; 8) failure to

account completely for all enrolled subjects (including biopsy of all abnormal tests and reporting of clinical and pathologic stage data). For each study listed in this appendix, the presence of one or more of thesedeficiencies is denoted with the corresponding number (1–8). We chose not to qualify weight to the extent of each particular methodologic weaknesses.

c In the Brawer study, the use of the arbitrary PSA increase of 20% serially actually constitutes a form of PSA velocity. Unlike the Catalona (1993) study that followed all patients in the original cohort regardless of initial PSA

and performed DRE/TRUS and biopsy on those with persistent or newly developed PSA, the Brawer followup study evaluates only those patients who had an original PSA < 4 ng/mL.

Appendix E Studies of Repeat/Serial Prostate-Specific Antigen Testing Yield for Prostate Cancer 89
APPENDIX

F

Studies of

Transrectal Ultrasound for

Prostate Cancer Screening and

Early Detection
APPENDIX F: STUDIES OF TRANSRECTAL ULTRASOUND FOR PROSTATE CANCER SCREENING AND EARLY DETECTION: RESEARCH DESIGN AND FINDINGS     Author 



Biases and

methodologic

weaknesses

 

a



 Setting

 









Time

frame

(years)

 









Number

patients

(N)

 



Age (Y)

range

(mean)

 



Criteria for

positive

TRUS

 







 Biopsy method

 

 Proportion BPH

 



TRUS lesionDiameter

(cm)

Range

(mean)

 



Overall

 detection

yield (%)

 

b





Proportion

detected

cancers

clinically

localized

(%)

 



Positive

predictive

valuec

(clinically

localized)

 



Proportion

detected

cancer

pathologically

localized (%)      Carter et al. (1989)



 

 

1,2,3,7

 

 

RetrospectiveAll patients with abnormal DREwho got TRUSbefore surg forknown cancer1 lobe.

 













 —

 















59 highly selected

 

 

notprovided

 



peripheralhypoechoicin contralaterallobe



 













en bloc surgicalspecimen



 

 

Notspecified.

 

 

0.5-4.5 cm(1.7 mean)

 

 

25/59patientcancer inother lobe

 

 

NASensitivity13/25 (52%)Specificity23/34 (68%)

 

 

13/24(66%)

 



NASensitivity 10/20(50%) if diameter 0.5-2.0 cm

     Coffield et al. (1992)



 

 

1,2,3,7  

 

Consecutiveautopsy no history prostatecancer; all nonsuspicious DREwithin 1 year

 









 —  











63(7 others excluded,insufficientinformation)

 

 

37-87(64)

 



Broad, anyecho suggestingspaceoccupyinglesion



 









en blocautopsy



 

 

Notspecified.

 

 

diameter notspecified,volumerange.009-6.3 ml(1.62 mlmean)

 

 

19/63cancer(30%)

 

 

Sensitivity6/19 (32%)forhypoechoicSpecificity7/44 (39%)forhypoechoic

 

 

6/33 (18%)overallHalf TRUSisoechoic

 



Surgical statenot specifiedProportionextracapsularnot given.Histologicgrade distribution not given.      Cooner et al. (1990)



 

 

1,2,3,4,6,7,8

 

 

Urologycontinuityclinic (42% new)work-up bias nopatient withsuspected PCreferral bias

 









 —

 











1807varyinglevels ofsymptoms

 

 

50-89

 



Peripheralhypoechoic



 









TRUS, DREno blindbiopsy 46%biopsied



 

 

Notspecified.

 

 

Not providedvolumerange 0.5-41ml(mean 2.2)if DRE neg.0.5-5.5 (1.2)

 

 

263/1807(14.6%) allcancers;136/1807(7.5%)clinicallylocalized

 

 

136/242(56%)

 

 

263/835(31%)all cancer

 



43/60 (72%)only 23% detected cancersurgicallystaged

      Cooner et al. (1988)



 

 

1,2,3,4,6,7,8

 

 

UrologyContinuityClinicreferral bias

 















1 time

 















255(all benignDRE)

 

 

50-89

 



Peripheral hypoechoic(>



 5 mm)

 













TRUS 43%biopsied



 

 

Not specified.

 

 

5-6 mmdiameterlowest, nodata (all lesions/Prostate Cancerinperipheral)

 

 

incompleteclinicalstaging28/225(12.4%)

 

  —

 

 

28/96 (29%)overall cancer

 



8/28 got surgical staging (7/8pathologicallylocalized)

    Dahnert (1986)



 

 

1,2,3,7  

 

Known cancer(presurgery)

 





 —  







52  

 

47-73(61)

 



Hypoechoic5.0 mHz



 





en blocsurgeryspecimens



 

 

85%pathologically evident

 

  —  

 

NA  

 

100%(preselectedfor surgery)

 

 

NA,Sensitivity64% (Unilateral)81%(Bilateral)

 



NA, 24/52 (46%)upstaged toextracapsularat surgery

       Devonac et al. (1990)



 

 

1,2,3,4,6,7,8

 

 

UrologySymptomatic(most BPHprospective)

 



















1 time

 



















666

 

 

Notprovided

 



Peripheralhypoechoic(no sizethreshold)7.0 or 7.5mHz226/666(34%)abnormalTRUS 

 

















TRUS or DREImply allabnormalTRUSbiopsied



 

 

Notspecified

 

  —

 

 

45/666(6.7%)(34/45detectedDREc)

 

 

24/45 (53%)

 

 

24/225(11%)45/246(19%)all cancer

 



unknown(no data onhistologicgrade)

 CONTINUED

92 Costs and Effectiveness of Prostate Cancer Screening in Elderly Men
APPENDIX F: STUDIES OF TRANSRECTAL ULTRASOUND FOR PROSTATE CANCER SCREENING AND EARLY DETECTION: RESEARCH DESIGN AND FINDINGS CONTINUED     Author 



Biases and

methodologic

weaknesses

 

a



 Setting

 









Time

frame

(years)

 



Number

patients

(N)

 









Age (Y)

range

(mean)

 



Criteria for

positive

TRUS

 

 Biopsy method

 







 Proportion BPH

 



TRUS 

lesion

Diameter

(cm)

Range

(mean)

 



Overall

detection

yield (%)

 

b





Proportion

detected

cancers

clinically

localized

(%)

 



Positive

predictive

valuec

(clinically

localized)

 



Proportion

detected

cancer

pathologically

localized (%)          Drago et al. (1992)



 

 

1,2,3,5,6,7,8

 

 

Urologyunknownprostatedisease-not truescreeningpopulation

 































Serial 4.5yearannualfollow-up

 

 

1940recruitment notwell described

 





























55-70(64)



 

 

Hypoechoic352/1940(18%)abnormaltest

 

 

TRUSguided abnormalDRE PSAalone in 2%of biopsies

 





























Not specified



 

  —

 

 

70/1940(3.6%)

 

 

Notspecifiedfor TRUSdetected,overall64/79cancers(81%) instudyclinicallylocalizedwhendiscoveredby anymethod.

 

 

70/352(20%)all cancers

 



—

       Guinan et al. (1987)



 

 

1,2,3  

 

InpatientUrology ServiceComparativestudy of 5 studies, including TRUS, PSA.All symptomaticselection biasNot generalizable to officebased population

 



















1 time  

 

280  

















68(mean)



 

 

3.5 mHzscanner notspecified3 “independent”reviewers84/280(30%) hadTRUS37/84 (44%)TRUS positive

 

 

All patientsbiopsied

 

















129/280(46%) onpathologybiopsyspec.



 

  —  

 

78/280 (28%)overall prevalence ofTRUSreceived22/84 (26%)cancers

 

  —  

 

NA22/37 (59%)Sensitivity =22/31 (71%)Specificity= 38/53(72%)

 



—

      Gustafsson et al. (1992)



 

 

6,8

 

 

Swedishscreeningpopulationbased randomlyselected

 















1 time

 

 

2,400eligible1,780recruited(74%)

 













55-70



 

 

Anyhypoechoicarea(non cyst) orasymmetry

 

 

TRUSguidedand/or DREguided ifPSA > 10blind bx(21% biopsied)

 













Notspecified.



 

  —

 

 

58/1780(3.3%)

 

 

34/58(59%)

 

 

34/244(14%)58/244(24%) allcancer

 



—

    Hammerer et al. (1992)



 

 

1,2,3,7,8  

 

Urologyall cancers atother site noprostatesymptoms

 





 —  

 

73  





54-70(65)



 

 

Hypoechoic 

 

TRUS, DREand systematic100%biopsied

 





Notspecified.



 

  —  

 

17/73 (23%)cancers(13/17 TRUSc)

(15/17 DREc

 

)



 

Not specified(implied allclinicallylocalized)

 

 

13/30 (43%)overall; ifDRE 1/14(7%)

 



Not provided.

     Lee et al. (1988)

d

 

 

1,2,3,6  

 

Screeninginvitational/referral

 











1 time  

 

784Half normalDRE < 1 yr.

 









60-86(65)



 

 

Peripheralhypoechoic> 5 mm64/784 (8%)TRUS abnormal

 

 

DRE or TRUS(2-foldgreater #biopsies forTRUS DXcases thanDRE 10%

 









Not specified.



 

 

0.7-3.0(1.3)

 

 

20/784 (2.6)20/22cancers TRUS

 c

 

Unknownfor TRUSalone17/22 (77%)overall DREand TRUS.

 

 

Unknown20/64 (31%)for all cancers byTRUS.

 



16/22 (73%)

 CONTINUED

Appendix F Studies of Transrectal Ultrasound for Prostate Cancer Screening and Early Detection93
APPENDIX F: STUDIES OF TRANSRECTAL ULTRASOUND FOR PROSTATE CANCER SCREENING AND EARLY DETECTION: RESEARCH DESIGN AND FINDINGS CONTINUED     Author 



Biases and

methodologic

weaknesses

 

a



 Setting

 



Time

frame

(years)

 



Number

patients

(N)

 









Age (Y)

range

(mean)

 



Criteria for

positive

TRUS

 

 Biopsy method

 







 Proportion BPH

 



TRUS lesionDiameter

(cm)

Range

(mean)

 



Overall

detection

yield (%)

 

b





Proportion

detected

cancers

clinically

localized

(%)

 



Positive

predictive

valuec

(clinically

localized)

 



Proportion

detected

cancer

pathologically

localized (%)      Mettlin et al. (1991)



 

 

2,3,6,7,8

 

 

Screeninginvitation

 

 

1st year ofserial study

 

 

2425

 













55-70(63)



 



Peripheral hypoechoic> 0.5 cm



 



TRUS, DRE fewif PSA elevated 14%biopsied)



 













135/330biopsied(41%)



 

 

10/50 < 1.0cm40/50 > 1.0cm

 

 

44/2425(1.8%)for TRUS44/57detectedca. forTRUSb

 



unknown forclinical loc.for TRUS only39/51 (76%)stage A,B foravailabledata



 



44/290 (15%)all cancer.if < 1.0 cm6/135 (7%); if>



 1.0 cm

30/136 (22%)

 

 

Unknown forTRUS only21/31 (68%)overall study foravailable data

            Naito, 1988



 

 

1,2,3,4,7  

 

seeAppendix C

 

 

1 time  

 

109  









































35-89(70)



 



Proposed byJapaneseUrologicalAssociation includingdisarrangedforms, asymmetry, discontinuityin capsule,irregularechogenicityof parenchyma(especiallyhypoechoic). Do notspecificity ifdiscretehypoechoicincluded46/109 (42%)Abnormal 

 



All patientsbiopsied buttechniquenot detailed



 











































 

 

Notprovided.

 

 

28/109(25.6%)

 



Not specified.



 



28/46 (61%)‘sensitivity’ =28/32 (88%)‘specificity’ =59/77 (77%)



 

 

Not specified.

    Nesbitt et al. (1989)



 

 

1,2,3,4,6,7,8  

 

UrologyNot purescreening

 

 

1 time  

 

240asymptomatic selfselected orreferral forunrelatedproblem

 









55-70



 



Peripheral anechoichypoechoic5.5 or 7.0mHzscan



 



TRUS, DRE(unclear ifPSAinfluenced)19% biopsied



 









Notspecified.



 

 

1.0-1.5 approximateonly

 

 

19/240(7.9%)

 



17/19 (89%)(11/19 DRE

b



)



17/45 (38%)



 

 

15/19 (79%)

     Norming et al. (1991)



 

 

6,8  

 

SwedishPopulationScreening(75%compliance)

 

 

1 time  

 

1,788  













50-70



 



HypoechoicAsymmetry(no size)246/1788(14%)TRUS abnormal



 



TRUS, DRE orPSA > 10365/1788(20%) biopsied overallproportion ofTRUS abn.biopsied notspecified 

 













Notspecified.



 

  —  

 

62/1788(3.5%)

 



Not specified for TRUSalone overall 26/62cancers T1or T2A.



 



Not specified56/246 (23%)all cancers.



 

 

Unknown (nosurgical staging).

CONTINUED

94 Costs and Effectiveness of Prostate Cancer Screening in Elderly Men
APPENDIX F: STUDIES OF TRANSRECTAL ULTRASOUND FOR PROSTATE CANCER SCREENING AND EARLY DETECTION: RESEARCH DESIGN AND FINDINGS CONTINUED     Author 



Biases and

methodologic

weaknessesa

 







 Setting

    Time frame (years)  



Number

patients

(N)

 









Age (Y)

range

(mean)

 



Criteria for

positive

TRUS

 

 Biopsy method

 

 Proportion BPH

 



TRUS

lesion

Diameter

(cm)

Range

(mean)

 



Overall

detection

yield (%)

 

b





Proportion

detected

cancers

clinically

localized

(%)

 



Positive

predictive

valuec

(clinically

localized)

 



Proportion

detected

cancer

pathologically

localized (%)     Palken et al. (1991) 



1,2,3,5,6,8

 









Urologyinvitationalreferral

   1 time  



315

 









50-86

 



2 classes“high”suspicious“low”

 



DRE, TRUSsystematic ifnegative firsttime 28biopsied

 



Notspecified.

 



—

 



14/315(4.4%)

 



Unknown14/23 (61%)cancersTRUSb.

 



Unknown14/52 (27%)all cancers.

 



—

  Perrin et al. (1989)    1,2,3,4,6,7,8  Screening invitation  1 time   666 (602 DRE)    Hypoechoic   TRUS    Not specified.   —    11/666 (1.7%)    —   11/162 (6.8%) all cancers    —   Perrin et al. (1992)



 



1,2,3,4,6,7,8  French urology referral

population 

  1 time   481   (67)    Not specified.    ‘Abnormal’ TRUS and/or abnormal DREe    —    —    83/481 (17%)    24/83 (29%)   8/233 (3%) 65/233 (28%) all cancers    —    Ragde et al. (1989)



 

 

1,2,3,4,6,7,8

 





Radiologyscreeninginvitational



   1 time 

 

1,051

 







over 50

 

 

Hypoechoic

 

 

TRUS(some DREpos. notbiopsied)

 

 

Notspecified.

 

  —

 

 

50/1051(4.8%) allcancers

 

  —

 



50/138 (36%)all cancers



 

  —      Rifkin (1988)



 

 

1,2,3,4,6,7,8  













Radiologyprospectivereferralpopulation



     1 time “all comers” to USG clinic since 1986 

 

329heterogenous nonewithknown PCincludesymptomatic “mild”Abn DRE(180)

 















45-91(64)

 

 

PeripheralhypoechoicUsed 5, 6.5,or 7.5 mHzscanner80/329 (24%)abn. TRUS

 

 

TRUS or DRE79/329 (24%)biopsied only56/180 “mildDRE”Abnormalwere biopsied

 

 

Not specified.

 

 

0.5-1.5  

 

5.2%(17/329)

 

  —  



Unknown,overall 17/79(22%) all cancers



 

  —          Shinohara et al. (1989)



 

 

1,2,3,7,8

 





























Preoperative TRUSknownclinicallylocalizedcancer(pre-surgery TRUS)



         —  

 

70

 































48-78(63)

 

 

Hypoechoic(42)Hyperechoic(1)Isoechoic(27)

 

 

en blocsurgicalspecimen

 

 

Notspecified.

 

 

Smallest lesion seenby TRUS (hypoechoic)4.5 mm(actual tumorsize)

 

 

Overall42/70 (60%)hypoechoic abnormal3/17 (18%)cancerswere < 1.0cm werehypoechoic40/52 (77%)cancers >1.0 cmwere hypoechoic

 

 

NA

 



9/25 (36%)cancers withDRE normalhad hypoechoic abn.34/45 (79%)cancer withDRE pos itivewere hypoechoic



 

 CONTINUED

Appendix F Studies of Transrectal Ultrasound for Prostate Cancer Screening and Early Detection95
APPENDIX F: STUDIES OF TRANSRECTAL ULTRASOUND FOR PROSTATE CANCER SCREENING AND EARLY DETECTION: RESEARCH DESIGN AND FINDINGS CONTINUED  

 Author

 



Biases and

methodologic

weaknesses

 

a



 Setting

 









Time

frame

(years)

   Number patients (N)  



Age (Y)

range

(mean)

 



Criteria for

positive

TRUS

 







Biopsy method

 

 Proportion BPH

 



TRUS

lesion

Diameter

(cm)

Range

(mean)

 



Overall

detection

yield (%)

 

b





Proportion

detected

cancers

clinically

localized

(%)

 



Positive

predictive

valuec

(clinically

localized)

 



Proportion

detected

cancer

pathologically

localized (%) 

Simak (1993) 

 

 

 

1,2,3,7

 



ProspectiveUrologyClinicConsecutivepatients withnonsuspiciousDRE who received TRUSand PSA priorto TURP



 























1 time

        288 All sched- uled for TURP for BPH  

 

55-84(68)

 



Hypoechoic(near capsule)32/288 (11%)TRUSAbnormal



 





















TRUSguided (noapparentsystematic)



 

 

 

 

Not providedHistologicgrade:Moderate(6)Poor (8)

 



14/288 (4.9%)by TRUS totalof 46/288(16%) cancers at TURP1/231 patients withPSA < 7 hadTRUS detected cancer (0.4%yield) 

 

 

13/14 (93%)total 45/46cancers atTURP wereclinicallylocalized

 



14/32 (44%)[13/32(41%)] for13/14 TRUSdetectedcancers,PSA > 757/288 (20%)PSA > 7



 



12/14 (86%)Overall, postTURP 44/46(96%) werepathologicallylocalized of 32cancers missedby TRUS, 7 stageA

 2 25 stage A1 

Terris et al.(1991) 

 

 

 

1,2,3,7

 



PreoperativeCystoprostatectomyfor Bladdercancer



 













 —

      51 (no known prostate cancer) 

 

31-79(64)

 



Hypoechoic



 













en blocsurgicalspecimen



 

 

Notspecified.

 

 

volume.001-5.3 ml(0.8 mLmean)

 



NA, 15/51(29%) prevalence prostate cancer



 

 

8/17 (47%)both clinicaland pathologicallylocalized

 



overallsensitivity53%specificity75%



 



Peripheral zonesens. = 70%spec. = 81%PV+ = 64%Transitionsens. = 20%spec. = 64%PV+ = 17%   Watanabe

et al. (1991) 

 

 

 

2,3,4,6,7,8  



Japanesemass screening



 







1 time    7235 asympto- matic 

 

> 55  



Hypoechoic



 





TRUSguided(smallminority ofpatientsgot DRE) 

 

  —

 

  —

 



48/7235(0.7%)



 

 

25/48 (52%)  



notprovided



 



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96 Costs and Effectiveness of Prostate Cancer Screening in Elderly Men
APPENDIX

G

Methods for Estimating the Medicare

Costs of Resources Used in

Detection and Care of Prostate Cancer

his appendix presents microlevel Medicare cost

information on the components of screening,

diagnosis, and treatment for prostate cancer.1

As described in chapter 5, these data are incorporated into a mathematical Markov model to

estimate the total costs and the cost-effectiveness of an

illustrative hypothetical Medicare benefit for prostate

cancer screening. All cost data are in 1992 dollars.2

The analysis collected and sorted Physicians’ Current Procedural Terminology, Fourth Edition (CPT-4)

codes for procedures (e.g., diagnostic tests, hospitalizations) by urological and radiation oncology billing departments at the Massachusetts General Hospital and the

Mayo Clinic. A clinical advisory panel from these institutions and outside reviewers then reviewed these codes

for completeness and accuracy.

Tables G-1, G-2, G-3, and G-5 present cost information for components of treatment for prostate cancer

grouped by general treatment category: screening and

staging, radical prostatectomy, transurethral resection of

prostate, and hormone therapy. Table G-4 differs from

the others in that it presents an episode of care for external beam radiation therapy for localized prostate cancer.

Table G-6 includes information on the cost of procedures/treatments related to complications associated

with prostate cancer (impotence, incontinence, etc.).

Table G-7 organizes the cost data by CPT-4 code or Diagnosis-related Group (DRG), allowing easy development

of cost estimates based on complete treatment protocols.

SPECIFIC ISSUES

Cost Information

We present cost information in terms of both Medicare average allowable charge data for 1992 and the

1992 Medicare fee schedule (tables G-1 through G-7).

Average allowable charges are percentages of regionally

determined “usual, customary, and reasonable” (UCR)

physician fees determined on a service-by-service basis.

The physician fee schedule is based on a resource-based

relative-value scale (RBRVS) point system to which a

monetary conversion factor is applied.

Cost-effectiveness research has historically used allowable charges for physician services. However,

1Information in this appendix is based on an OTA contract paper by Fahs and colleagues. (121).

2Continuing changes in Medicare reimbursements for procedures associated with prostate cancer screening and treatment may make these 1992 costs inaccurate

predictors of costs in 1995 or in subsequent years (13a).
98 COSTS AND EFFECTIVENESS OF PROSTATE CANCER SCREENING IN ELDERLY MEN

TABLE G-1: ESTIMATED COSTS OF SERVICES RELATED TO SCREENING AND STAGING OF PROSTATE CANCER

Medicare average Medicare fee

allowable charge, schedule

Description CPT-4 code 1992a ($) ($)

PSA 86316 $29.56 not included

DRE

 Office visit with primary care physician/urologistb 99213 3.79 4.12

TRUS 76872 76.14 84.94

 Office consult with urologist 99214 45.71 47.12

TRNB

 TRUS guidance for biopsy 76942 67.95 84.07

 Prostatic needle biopsy (single/multiple) 55700 120.54 105.09

Osseus survey for metastases 76061 32.00 54.87

Radionuclide bone scan 78306 81.02 184.14

Pelvic CT scan 72170 15.67 25.11

 with contrast 72193 93.77 283.66

Pelvic MRI 72196 247.60 450.13

Limited lymphadenectomy for staging 38562 639.55 672.11

 anesthesia 00860 203.63 194.04

a The majority of the surgical allowable charges have two components: one for the surgeon and one for surgical assistance. Composite charges are reported.

b DRE is estimated to take 13.3% of a 99213 office visit. The entire office visit average allowable charge is $28.52 and under the fee schedule is $31.

SOURCE: Office of Technology Assessment, 1995. Data are HCFA’s unpublished Medicare Average Allowable Charge data from NCH/Best system. Other categories

are unpublished data from the HCFA Office of Research provided by W.J. Sobaski, HCFA, Baltimore, MD, personal communication, 1993.

TABLE G-2: ESTIMATED COSTS FOR RADICAL PROSTATECTOMY SERVICES

Medicare average Medicare fee

allowable charge, scheduleb

Description CPT-4 code/DRG 1992a ($) ($)

Retropubic radical prostatectomy 55840 $1,450.34 1,493.82

 with lymph node biopsies 55862 1,041.51 1,135.37

 with bilateral pelvic lymphadenectomy 55845 2,097.83 2,056.62

 anesthesia 00860 203.63 194.04

Hospitalization for radical prostatectomy

and pelvic node excision

 with complications 334 NA 7,483.00

 without complications 335 NA 5,867.00

a The majority of the surgical allowable charges have two components: one for the surgeon and one for the surgical assistance. Composite charges are reported.

b For DRGs, the figures represent average expenditures per beneficiary, including Medicare reimbursement and beneficiary deductible.

KEY: NA = not applicable.

SOURCE: Office of Technology Assessment, 1995. Data are HCFA’s unpublished Medicare Average Allowable Charge data from NCH/Best system. Other categories

are unpublished data from HCFA Office of Research provided by W.J. Sobaski, Health Care Financing Administration, Baltimore, MD, personal communication, 1993.
APPENDIX GMETHODS FOR ESTIMATING COSTS OF RESOURCES USED IN DETECTION AND CARE OF PROSTATE CANCER 99

TABLE G-3: ESTIMATED COSTS FOR TRANSURETHRAL RESECTION OF THE PROSTATE

Medicare average Medicare fee

allowable charge, scheduleb

Description CPT-4 code/DRG 1992a ($) ($)

Transurethral resection of prostate (TURP) 52601 $948.10b 897.96

 anesthesia 00914 139.69 146.51

Hospitalization for TURP

 with complications 336 NA 3,943.00

 without complications 337 NA 2,778.00

a The majority of the surgical allowable charges have two components: one for the surgeon and one for surgical assistance. Composite charges are reported.

b For DRGs, the figures represent average expenditures per beneficiary, including Medicare reimbursement and beneficiary deductible.

KEY: NA = not applicable.

SOURCE: Office of Technology Assessment, 1995. 1992 HCFA data from Part B Medicare Annual Data System and Part A Medicare Annual Data System for short-stay

hospitals provided by W.J. Sobaski, Office of Research, HCFA, Baltimore, MD, personal communication, 1993.

starting in 1992, Medicare began paying physicians using a fee schedule based on RBRVS. The fee schedule attempts to measure the costs of providing services based

on resources consumed. In this way, it may be a more accurate input for cost-effectiveness analysis if that analysis attempts to relate resource use (monetary and otherwise) to benefits.

However, there has been much debate over two

components of the fee schedule: the monetary conversion factor that is applied to the RBRVS and the allocation of true practice costs. In a recent study, Hsiao and

colleagues (170) concluded that the practice-expense

component of the Medicare fee schedule was incorrectly

legislated. It is based on historical charges instead of resource costs and, thus, the Medicare fee schedule “continues to provide an overly generous rate of payment for

invasive services” (170). The authors also conclude that

the conversion factor is too low to yield sufficient net income to most physicians and warn that in the short run

this may cause access problems for Medicare beneficiaries and in the long run may discourage an adequate supply of qualified medical personnel.

One other caution on the fee schedule is in order.

The fee schedule is in transition and will not be fully implemented until 1996. This means that fees actually paid

to providers are a weighted blend of allowable charges

and the fee schedule rate (in each of 230 payment localities) (e.g., 56 FR 59502). Despite these anomalies, the

1992 fee schedule is preferable to average allowable fees

for cost-effectiveness research both because of its more

explicit relationship to resource use and because it will

be how providers are reimbursed for Medicare patients

in 1996.

One must use caution in interpreting and applying

any “cost” information for medical care (122). The

“cost” of a procedure may bear little resemblance to the

charge submitted, which will probably only be paid on

a percentage basis anyway. In attempting to provide inputs for a cost-effectiveness analysis for the addition of

a screening benefit for prostate cancer to the Medicare

program, we present the reimbursement amounts that

Medicare pays out, not the submitted charge or an estimated “cost” of the procedure.
100 COSTS AND EFFECTIVENESS OF PROSTATE CANCER SCREENING IN ELDERLY MEN

TABLE G-4: ESTIMATED COSTS OF SERVICES FOR TREATING

LOCALIZEDa PROSTATE CANCER BY RADIATION THERAPY

(based on Medicare fee schedule)

Calculation of

Description total cost ($)

Radiation treatment $3,604.41

Hospital

Simple (77406) 19 @ $58.59 = $1,113.21

Complex (77416) 19 @ $76.88 = $1,460.72

Radiation oncologist

Simple (77420) 4 @ $79.67 = $318.68

Complex (77430) 4 @ $177.95 = $711.80

Complex treatment planning (77263) 154.69

Complex treatment simulation (77263) 154.69

Dosimetry calculation (77300) 75.02

Weekly evaluation of dosage (77336) 861.63

7 evaluations @ $123.09

Isodose plan for teletherapy (77315) 185.89

Radiation oncologist

Consult (99244) 113.46

a Stage A and B cancers.

SOURCE: Office of Technology Assessment, 1995. Data are HCFA’s unpublished

Medicare Average Allowable Charge data from NCH/Best system. Other

categories are unpublished data from HCFA Office of Research provided by

W.J. Sobaski, HCFA, Baltimore, MD, personal communication, 1993.

This caution in using “cost” information may be

particularly relevant for services provided to elderly

men, regardless of the source of the “cost” information.

The disease processes, as well as the psychosocial, environmental and financial attributes of geriatric patients

have been suggested to be out of sync with payment

structures derived from acute care services for younger

populations (120). In other words, payment structures

may not adequately reflect the additional resources required by geriatric patients as compared with younger

patients, including longer time spent dressing and

undressing, or in communication with the physician on

the risks and benefits of clinical choices.

Digital Rectal Examination

One of the standard screening procedures for prostate cancer examined in this analysis is the digital rectal

examination (DRE). This procedure is considered to be

part of a routine physical exam (349). It is estimated that

this procedure requires two minutes to perform (265).

This analysis assumes the cost of this procedure is 13.3

percent of a standard 15-minute (CPT-4 code 99213) office visit. It is worth noting that if this DRE were found

abnormal, it would likely be repeated by a urologist.

Treatment Costs

We present the cost of drugs for hormone therapy at

specified dosages. The total will depend on the combination of drugs and the length of treatment/research that is

ongoing (107, 319). Some drugs for hormone therapy require implantation. Cost data for this procedure are not

available. An estimate for the cost of implantation can

perhaps be imputed using implantation fees for related

procedures. This estimate will be added to the drug costs,

pending physician consultation.

Surgical Procedures

Costs for surgical procedures include both surgeon

and surgical assistance fees.

Diagnostic Radiology

Diagnostic radiology is composed of two components: technical and professional. Oftentimes the two

components are billed by the same provider, who receives a composite payment. Sometimes different providers are involved and each is paid according to the

component provided. However, the composite payment

for each CPT-4 code is not necessarily the sum of the

components for a variety of reasons (i.e., different localities, different modifiers, etc.). We advise using the com-
APPENDIX GMETHODS FOR ESTIMATING COSTS OF RESOURCES USED IN DETECTION AND CARE OF PROSTATE CANCER 101

TABLE G-5: ESTIMATED COSTS OF HORMONE THERAPY SERVICES FOR PROSTATE CANCER

Medicare average Medicare fee

allowable charge, scheduleb

Description CPT-4 code/DRG 1992a ($) ($)

GnRH agonist

(does not include fees for monthly implantation)

 Zoladex @ 3.6 mg/month NA $318.75/month NA

 Lupron @ 7.5 mg/month NA 437.50/month NA

Flutamide (Eulexin) @ 250 mg NA 135.42/100 NA

Diethylstilbesterol (DES) tablets @ 1 mg/day NA 9.14/100 NA

Orchiectomy 54520 516.16 408.16

 anesthesia 00920 97.93 105.25

Hospitalization for bilateral orchiectomy 338 NA 3,893.00

a The majority of the surgical allowable charges have two components: one for the surgeon and one for surgical assistance. Composite charges are reported.

b For DRGs, the figures represent average expenditures per beneficiary, including Medicare reimbursement and beneficiary deductible.

KEY: NA = not applicable.

SOURCE: Office of Technology Assessment, 1995. Data are HCFA’s unpublished Medicare Average Allowable Charge data from NCH/Best system. Other categories

are unpublished data from HCFA Office of Research provided by W.J. Sobaski, HCFA, Baltimore, MD, personal communication, 1993. Pharmaceutical costs are

wholesale prices as reported in the 1993 Red Book published by Medical Economics Data, Montvale, NJ.

posite payment, rather than adding the two components

together for two reasons: predominantly, one provider

performs both components and, thus, it is the composite

rate that is most commonly paid; and because Medicare

is moving toward a fee structure where the components

add to the composite rate (320).

Anesthesia Services

Costs for anesthesia services are provided for the

P1, P2, and P3 severity of illness categories as well as

both with and without CPT-4 code 99100 (an adjustment

for patients over age 70). However, there are many other

modifiers that could be applied, and they may or may not

affect reimbursement. For some time, the Health Care

Financing Administration (HCFA) has not incorporated

many of these modifiers into their reimbursement

amounts (231). The cost figures presented are calculated

based on the average time associated with each CPT-4

code. Time is the most significant component of the cost

of anesthesia, overshadowing the application of modifiers (320).

Courses of Treatment

The analysis uses the total costs for a six-week episode of external beam radiotherapy treatment for localized (T1/T2) cancer (26). The costs associated with complications (proctitis, incontinence, etc.) are presented

separately (313, 363), as well as average allowable charges

and Medicare fee schedule amounts for the entire range

of related radiotherapy procedures (that are to be organized into treatment protocols relevant to T3 cancer).

The course of medical treatment for advanced, hormone-sensitive prostate cancer is difficult to specify.

There are numerous clinical trials incorporating a significant number of drugs both singly and in combination

(107, 319). This analysis estimates costs for related

drugs (27l) using the Red Book of wholesale drug prices

for 1993.
102 COSTS AND EFFECTIVENESS OF PROSTATE CANCER SCREENING IN ELDERLY MEN

TABLE G-6: ESTIMATED COSTS OF LOCAL SYMPTOMS/TREATMENTS/COMPLICATIONS FOR PROSTATE CANCER

Medicare average Medicare fee

allowable charge, scheduleb

Description CPT-4 code/DRG 1992a ($) ($)

Dilation of urethral stricture 53600 $31.86 $51.15

 under anesthesia 53605 33.62 58.59

 anesthesia 00910 85.20 97.16

Hospitalization for urethral stricture dilation

 with complications 312 NA 3,800.00

 without complications 323 NA 2,281.00

Urethroplasty (stricture repair) 53415 1,084.57 1,077.76

 anesthesia 00910 85.20 97.16

Hospitalization for major stricture repair

 with complications 312 NA 3,800.00

 without complications 313 NA 2,281.00

Artificial sphincter placement 53445 1,780.34 1,352.14

 anesthesia 00860 203.63 194.04

Hospitalization for artificial urinary sphincter

 with complications 308 NA 6,534.00

 without complications 309 NA 3,439.00

Penile prosthesis

 non-inflatable 54400 1,173.30 868.81

 inflatable, self-contained 54401 1,494.56 1,107.60

 inflatable, multi-component 54405 1,812.29 1,375.52

 anesthesia 00938 162.46 170.34

Hospitalization for penile prosthesis insertion 315 NA 10,072.00

a The majority of the surgical allowable charges have two components: one for the surgeon and one for the surgical assistance. Composite charges are reported.

b For DRGs, the figures represent average expenditures per beneficiary, including Medicare reimbursement and beneficiary deductible.

KEY: NA = not applicable.

SOURCE: Office of Technology Assessment, 1995. Data are HCFA’s unpublished Medicare Average Allowable Charge data from NCH/Best system. Other categories

are unpublished data from HCFA Office of Research provided by W.J. Sobaski, HCFA, Baltimore, MD, personal communication, 1993.
APPENDIX GMETHODS FOR ESTIMATING COSTS OF RESOURCES USED IN DETECTION AND CARE OF PROSTATE CANCER 103

TABLE G-7: ESTIMATED COST OF SERVICES RELATED TO PROSTATE CANCER









CPT–4 or DRG





 



Description









Chargea ($)









Fee

schedule or

DRGb ($)



  Medical

 99213



 Office visit with primary care physician or urologist



 28.52

   31.00

 Surgical 

 38562  Limited lymphadenectomy for staging (anesthesia code 00914)  639.55  672.11 



52601 



Transurethral resection of prostate (anesthesia code 00914) 



948.10 



897.96

  53415  Urethroplasty (stricture repair) (anesthesia code 00910)  1084.57  1077.76

 53445



 Artificial sphincter placement for incontinence (anesthesia 00860)



 1780.34



 1352.14 

 53600  Dilation of urethral stricture  31.86  51.15 

 53605  Dilation of urethral stricture under anesthesia (anesthesia code 00910)  33.62  58.59 







54400

54401

54405





 



Insertion of penile prosthesis for impotence (anesthesia code 00938)

non-inflatable

inflatable, self-contained

inflatable, multi-component









1173.36

1494.56

1812.29









868.81

1107.60  1375.52

 54520



 Orchiectomy (anesthesia code 00920)



 516.22

   408.16

 55700



 Prostatic needle biopsy (single or multiple)



 120.54



 105.09 





55840

55845

55862







Retropubic radical prostatectomy (anesthesia code 00860)

with lymph node biopsies

with bilateral pelvic lymphadenectomy







1450.34

1041.51

2097.83







1493.82

1136.37

 2056.62

 Consults 

 99214  Office consultation with urologist  28.52  31.00 



99244 



Office consultation with radiation oncologist 



106.42 

  113.46

  Diagnostic radiology

 76061



 Osseus survey for metastases



 32.00



 54.87 

 76872  Transrectal ultrasound  76.14  84.94 



78306 



Radionuclide bone scan 



81.02 



184.14 



72170

72193





Pelvic CT scan

with contrast





15.67

93.77





25.11

283.66 

 72196  Pelvic MRI  247.60  450.13 



76942 



Transrectal ultrasound guidance for prostatic biopsy 



67.95 



84.07

  Diagnostic laboratory

 84060



 Phosphatase, acid; total



 10.61

   NA

 84075  Prostates, alkaline  7.64  NA 

 84403  Testosterone, total  37.86  NA   86316  Prostate-specific antigen  29.56  NA

  Radiation therapy







77261

77262

77263





 



External beam radiation clinical treatment planning

simple

intermediate

complex









78.32

119.60

177.78









68.02

103.85

 154.69

 77300  Dosimetry calculation  72.67  75.02 

 77315  Isodose plan for teletherapy  160.48  145.89

CONTINUED104 COSTS AND EFFECTIVENESS OF PROSTATE CANCER SCREENING IN ELDERLY MEN

TABLE G-7: ESTIMATED COST OF SERVICES RELATED TO PROSTATE CANCER CONTINUED 



 CPT–4 or DRG

   Description



 Chargea ($)

 



Fee

schedule or

DRGb  ($)

 77336



 Weekly evaluation of delivered dose



 87.04



 123.09 





















77401

88402

77403

77404

77406

77407

77408

77409

77411

77412

77413

77414

77416



 

















External beam radiation treatment delivery

treatment delivery

single, < 5 MeV

single area, 6–10 MeV

single area, 11–19 MeV

single area, > 20 MeV

2 areas, < 5 MeV

2 areas, 6–10 MeV

2 areas, 11–19 MeV

2 areas, > 20 MeV

3 or more areas, < 5 MeV

3 or more areas, 6–10 MeV

3 or more areas, 11–19 MeV

3 or more areas, > 20 MeV























49.13

57.62

58.08

71.60

55.44

66.99

70.10

77.59

65.67

74.87

78.22

82.85

75.64

 



















58.59

58.59

58.59

58.59

58.59

69.13

69.13

69.13

69.13

76.88

76.88

76.88

76.88 

 Diagnostic radiology 

 76061  Osseus survey for metastases  32.00  54.87   76872  Transrectal ultrasound  76.14  84.94

 78306



 Radionuclide bone scan



 81.02

   184.14





72170

72193

  

Pelvic CT scan

with contrast







15.67

93.77

 



25.11

283.66   72196  Pelvic MRI  247.60  450.13

 76942



 Transrectal ultrasound guidance for prostatic biopsy



 67.95



  84.07

 Diagnostic laboratory 

 84060  Phosphatase, acid; total  10.61  NA 



84075 



Phosphatase, alkaline 



7.64 



 NA

 84403



 Testosterone, total



 37.86

   NA

 86316



 Prostate specific antigen (PSA)



 29.56



 NA 

 Anesthesiac 







00914 

 



P1

P2

P3

All









201.00

222.50

157.00

139.69

 



 146.51 







00860 

 



P1

P2

P3

All









271.00

NA

181.00

203.63

 





194.04







00910   P1

P2

P3

All







28.52

103.80

NA

85.20

 

 97.16

CONTINUEDAPPENDIX GMETHODS FOR ESTIMATING COSTS OF RESOURCES USED IN DETECTION AND CARE OF PROSTATE CANCER 105

TABLE G-7: ESTIMATED COST OF SERVICES RELATED TO PROSTATE CANCER CONTINUED 



 CPT–4 or DRG

 

 Description

 

 Chargea ($)

 



Fee

schedule or

DRGb  ($)







00938

 





P1

P2

P3

All









NA

NA

NA

162.46

 



  170.34







00920  





P1

P2

P3

All









NA

158.00

17.00

97.93

 



 105.25 

 Hospitalizations 





308

309

 



Implantation, artificial urinary sphincter (58.93)

with complications

without complications







 



6,534

3,439 







312

313

 





Release, urethral stricture (58.5) or

Repair, urethra (58.4)

with complications

without complications









 





3,800

2,281 





315  



Penile prosthesis insertion

non-inflatable (64.95)

inflatable (64.97)







 



10,072









334

335

 





Pelvic lymph node excision (59.00) or

Prostatectomy, radical (60.5)

with complications

without complications









 





7,483  5,867







336

337

 





Prostatectomy, transurethral (60.2)

with complications

without complications









 





3,943

2,778   338  Orchiectomy, bilateral (62.4)  3,893

 Pharmaceuticalsd 





 



GnRH agonist

 Goserelin acetate implant (Zoladex) @ 3.6 mg monthly

 Leuprolide acetate depot (Lupron) @ 7.5 mg monthly







318.75

437.50

 

  

 Flutamide (Eulexin) @ 250 mg  135.42/100    Diethylstilbesterol (DES) @ 1 mg  9.14/100  





 Macrodantin @ 50 mg (cystitis)



 66.13/100

   



 Prednisone @ 10 mg  3.30/100    





Methylprednisolone acetate @ 10 ml 



6.00 

NOTES: 

a Medicare Average Allowable Charge, 1992.

b Medicare Fee Schedule, 1992 and Average Expenditure per Beneficiary (DRG), 1992.

c Medicare fee schedule anesthesia costs are not adjusted for supervision of more than one patient.

d Pharmaceutical prices are wholesale costs as found in the 1993 Red Book, Montvale, NJ.

KEY: NA = not included in fee schedule.

SOURCE: Office of Technology Assessment, 1995. Data are HCFA’s unpublished Medicare Average Allowable Charge data from NCH/Best system. Other categories

are unpublished data from HCFA Office of Research provided by W.J. Sobaski, HCFA, Baltimore, MD, personal communication, 1993.
APPENDIX

H

Current Research Efforts To Resolve

the Effectiveness of Prostate Cancer

Screening and Treatment

ost evidence-based criteria for evaluating screening maneuvers demand evidence from controlled studies on which

to base recommendations. Randomized

controlled trials (RCTs) are the best

studies on which to base such recommendations. In the

absence of RCTs, researchers and policymakers often

examine less desirable cohort studies with concurrent

nonrandomized controls and case-control studies. Unfortunately, in the area of early detection and treatment

of prostate cancer, little controlled data are available, regardless of study design. A single case-control study has

shown no evidence of benefit from digital rectal examination (DRE), in terms of lower exposure odds to

DRE within the prior 10-year period among men with

metastatic prostate cancer compared to controls (129).

The point estimate of the DRE exposure odds ratio

among men with metastatic cancer compared with controls in this study was 0.9, with a 95-percent confidence

interval of 0.5 to 1.7. Similarly, a single small, underpowered randomized trial of radical prostatectomy versus expectant management showed no evidence of benefit from more aggressive treatment (54, 147), as

discussed in detail earlier in this report.

TRIALS OF TREATMENT

FOR CLINICALLY LOCALIZED

PROSTATE CANCER

However, researchers are now planning or have already initiated clinical trials to address this lack of data.

In terms of determining the optimal treatment for localized prostate cancer, the Scandinavian Prostate Cancer

Group began a randomized trial of radical prostatectomy

versus deferred treatment in 1989. Men less than age 75

with well or moderately differentiated (but not Stage

T1a) cancer are eligible for the trial. Men randomized to

surgery undergo a pelvic lymph node dissection, and

proceed to radical prostatectomy if the nodes are uninvolved. However, an “intention to treat” analysis is

planned to avoid biasing the results in favor of surgical

treatment. The investigators plan to randomize 520 men

and follow them for a minimum of 10 years to have adequate power to “rule out” a true improvement in 10-year

cancer-specific survival from 85 to 95 percent, which

represents a two-thirds reduction in cancer-specific

mortality. This trial is more than halfway to its accrual

target.
108 COSTS AND EFFECTIVENESS OF PROSTATE CANCER SCREENING IN ELDERLY MEN

In the United Kingdom, the Medical Research Council has just opened a trial comparing the strategies of no

immediate treatment, external beam radiotherapy, and

radical prostatectomy for men with T1b/T1c/T2 N0 M0

prostate cancer (Trial PRO6). As part of the design, patients can be randomized among all three or any two of

the treatment strategies, at the discretion of the physician

and patient. Primary endpoints will be the development

of documented metastases and survival time. The PRO6

protocol calls for the randomization of 400 men into

each treatment arm over three years to achieve 90 percent power to detect a 10 percent difference in survival

between any two arms.

Another large trial has been initiated in the United

States. The Prostate Cancer Intervention Versus Observation Trial (PIVOT) is to be conducted as a collaboration between the Veterans Administration Cooperative

Studies Program and the National Cancer Institute. The

investigators plan to enroll about 2,000 men up to age 75

with clinically localized prostate cancer of all grades.

Men who provide consent would be randomized to a

strategy of immediate radical prostatectomy with additional aggressive treatment for evidence of residual or

recurrent disease, or a strategy of expectant management

with treatment for symptomatic local progression or metastases. PIVOT started late in 1994, and will accrue patients over three years with an additional 12 years of followup. PIVOT is powered to detect a 15 percent

decrease in overall mortality with radical prostatectomy,

or roughly a one-third reduction in cancer-specific

mortality.

TRIALS OF EARLY DETECTION OF

PROSTATE CANCER

Randomized trials of early detection of prostate cancer are also being planned and initiated. The National

Cancer Institute’s Prostate, Lung, Colorectal, and Ovarian (PLCO) Screening Trial is a ten-center study designed

to measure the net benefit of screening for a number of

common malignancies. For the prostate cancer component, 74,000 men ages 60 to 74 will be randomized to

four annual screens with PSA and DRE, versus “usual

care.” The study was initiated in 1993, and may need to

continue as long as 16 years to have adequate power to

detect a 20 percent reduction in prostate cancer mortality, allowing for some “dilution” in the intervention

group (due to incomplete compliance with followup of

suspicious screening studies) and “contamination” in the

control group (due to DREs and prostate-specific antigen tests that may be done as part of usual care).

Finally, a European screening study is currently being

planned, and a number of preparatory pilot studies have

been conducted in Belgium and the Netherlands. The

main study is currently envisioned as involving about

50,000 men in a number of European countries. Details

of the design are still being finalized.

Despite many reasonable individual concerns about

the designs of the PLCO and PIVOT studies, support for

these trials was recently expressed by a group of U.S.

prostate cancer experts at a meeting cosponsored by the

American Urological Association and the American

Cancer Society (253). As Kaufman (186) has recently reminded the medical community, well-designed clinical

trials, even in the controversial area of cancer treatment,

are “good medicine.”
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110 COSTS AND EFFECTIVENESS OF PROSTATE CANCER SCREENING IN ELDERLY MEN

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36 Bjartell, A., Bjork, T., Matikainen, M.T., et al., “Production of Alpha-1-Antichymotrypsin by

PSA-Containing Cells of Human Prostate Epithelium,” Urology 42:502-510, 1993.

37 Bjork, T., Bjartell, A., Abrahamsson, P.A., et al., “Alpha1-Antichymotrypsin Production in

PSA-Producing Cells Is Common in Prostate Cancer But Rare in Benign Prostatic Hyperplasia,”

Urology 43:427-434, 1994.

38 Bluestein, D.L., Bostwick, D.G., Bergstralh, E.J., et al., “Eliminating the Need for Bilateral Pelvic

Lymphadenectomy in Select Patients with Prostate Cancer,” Journal of Urology 151:1315-1320,

1994.

39 Boring, C.C., Squires, T.S., Tong, T., et al., “Cancer Statistics 1993; Staging of Early Prostate

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40 Boring, C.C., Squires, T.S., Tong, T., et al., “Cancer Statistics, 1994,” Ca: A Cancer Journal for

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41 Bostwick, D.G., “The Pathology of Early Prostate Cancer,” Ca: A Cancer Journal for Clinicians

39:325-393, 1989.

42 Bostwick, D.G., Graham, S.D., Napalkov, P., “Staging of Early Prostate Cancer: A Proposed

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43 Bowser, J., Executive Director, American Society of Preventive Oncology, personal

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44 Brawer, M.K., Chetner, M.P., Beatie, J., et al., “Screening for Prostatic Carcinoma with Prostate

Specific Antigen,” Journal of Urology 147:841- 845, 1992.

45 Brawer, M.K., Aramburu, E.A., Chen, G.L., et al., “The Inability of Prostate Specific Antigen Index

To Enhance the Predictive Value of Prostate Specific Antigen in the Diagnosis of Prostatic

Carcinoma,” Journal of Urology 150:369-373, 1993.

46 Brawer, M.K., Beatie, J., Wener, M.H., “PSA as the Initial Test in Prostate Carcinoma Screening:

Results of the Third Year” (abstract), Journal of Urology 149:299a, 1993.

47 Brawer, M.K., Beatie, J., Wener, M.H., et al., “Screening for Prostatic Carcinoma with Prostate

Specific Antigen: Results of the Second Year,” Journal of Urology 150:106-109, 1993.

48 Brawer, M.K., Wener, M.H., Daum, P.R., et al., “Method to Method Variation in Assays for

Prostate Specific Antigen,” Journal of Urology 151:450a, 1994.

49 Brawn, P.N., Speights, V.O., Kuhl, D., et al., “Prostate-Specific Antigen Levels from Completely

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50 Brendler, C.B., and Walsh, P.C., “The Role of Radical Prostatectomy in the Treatment of Prostate

Cancer,” Ca: A Cancer Journal for Clinicians 42:212-222, 1992.

51 Brendler, C.B., “Editorial: Prostate Cancer,” Journal of Urology 150:1865-1866, 1993.

52 Brendler, C.B., Carmichael, M., Walsh, P.C., et al., “Radical Prostatectomy (RP) for

Non-Palpable Prostate Cancer Diagnosed by Needle Biopsy: Pathologic and Clinical

Findings,” Journal of Urology 149:378, 1993.

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112 COSTS AND EFFECTIVENESS OF PROSTATE CANCER SCREENING IN ELDERLY MEN

53 Breslin, D.S., Muecke, E.C., Reckler, J.M., et al., “Changing Trends in the Management of

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54 Byar, D., Corle, D., “Vacurg Randomized Trial of Radical Prostatectomy for Stages I and II

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55 Cadeddu, J.A., Pearson, J.D., Partin, A.W., et al., “Relationship Between Changes in

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56 Canadian Task Force on the Periodic Health Examination, “The Periodic Health Examination,”

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57 Canadian Task Force on the Periodic Health Examination, “Periodic Health Examination, 1991

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58 Cantor, S.B., Spann, S.J., Volk, R.J., et al., “Prostate Cancer Screening: A Decision Analysis,”

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59 Carter, B.S., Beaty, T.H., Steinberg, G.D., et al., “Mendelian Inheritance of Familial Prostate

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60 Carter, B.S., Bova, G.S., Beaty, T.H., et al., “Hereditary Prostate Cancer: Epidemiologic and

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61 Carter, H.B., Hamper, U.M., Sheth, S., et al., “Evaluation of Transrectal Ultrasound in the Early

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62 Carter, H.B., Piantadosi, S., and Isaacs, J.T., “Clinical Evidence for the Implication of the

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63 Carter, H.B., Pearson, J.D., Metter, E.J., et al., “Longitudinal Evaluation of Prostate-Specific

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64 Carter, H.B., and Pearson, J.D., “PSA Velocity for the Diagnosis of Early Prostate Cancer,”

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65 Cassileth, B.R., Soloway, M.S., Vogelzang, N.J., et al., “Patients’ Choice of Treatment in Stage D

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66 Catalona, W.J., Smith, D.S., Ratliff, T.L., et al., “Measurement of Prostate-Specific Antigen in

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67 Catalona, W.J., “Radical Surgery for Advanced Prostate Cancer and for Radiation Failures”

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68 Catalona, W.J., “Screening for Prostate Cancer: Enthusiasm,” Urology 42:113-115, 1993.

69 Catalona, W.J., and Basler, J.W., “Return of Erections and Urinary Continence Following Nerve

Sparing Radical Retropubic Prostatectomy,” Journal of Urology 150:905-907, 1993.

70 Catalona, W.J., Smith, D.S., Ratliff, T.L., et al., “Detection of Organ-Confined Prostate Cancer Is

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71 Catalona, W.J., “Reply to Letter to the Editor Re: PSA and the Detection of Prostate Cancer,”

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REFERENCES 113

72 Catalona, W.J., Richie, J.P., Ahmann, F.R., et al., “Comparison of Digital Rectal Examination

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73 Centers for Disease Control and Prevention, Public Health Service, U.S. Department of Health

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74 Chancellor, M.B., and Van Appledorn, C.A., “Value of Transrectal Prostate Ultrasonography

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75 Chang, S.J., Goad, J., Kassabian, V.S., et al., “Disease Progression After Definitive Irradiation for

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76 Chelsky, M.J., Schnall, M.D., Seidmon, E.J., et al., “Use of Endorectal Surface Coil Magnetic

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77 Cheng, W.S., Frydenberg, M., Bergstralh, E.J., et al., “Radical Prostatectomy for Pathologic

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78 Chisholm, G.D., “Prostate Cancer Screening: Accepting the Consequences of PSA Testing”

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79 Chodak, G.W., Keller, P., and Schoenberg, H.W., “Assessment of Screening for Prostate Cancer

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80 Chodak, G.W., “Questioning the Value of Screening for Prostate Cancer in Asymptomatic

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81 Chodak, G.W., “Screening for Prostate Cancer in 1993: Is It Appropriate Or Not?,” Seminars in

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82 Chodak, G.W., Thisted, R., Gerber, G., et al., “Multi-Variate Analysis of Outcome Following

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83 Chodak, G.W., Thisted, R.A., Gerber, G.S., et al., “Results of Conservative Management of

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84 Chybowski, F.M., Keller, J.J., Bergstralh, E.J., et al., “Predicting Radionuclide Bone Scan Findings

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85 Coffey, D.S., “Prostate Cancer: An Overview of An Increasing Dilemma,” Cancer

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86 Cole, H.M., (ed.), Diagnostic and Therapeutic Technology Assessment (DATTA), “Transrectal

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87 Coleman, C.N., Beard, C.J., Kantoff, P.W., et al., “Rate of Relapse Following Treatment for

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114 COSTS AND EFFECTIVENESS OF PROSTATE CANCER SCREENING IN ELDERLY MEN

88 Collins, G.N., Lee, R.J., McKelvie, G.B., et al., “Relationship Between Prostate Specific Antigen,

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89 Collins, G.N., Lloyd, S.N., Hehir, M., et al., “Multiple Transrectal Ultrasound-Guided Prostatic

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90 Consensus Conference on Prostate Cancer, Office of Medical Applications of Research,

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91 Cooner, W.H., Mosley, B.R., Rutherford, C.L.J., et al., “Prostate Cancer Detection in a Clinical

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92 Corral, D.A., and Bahnson, R.B., “Survival of Men with Clinically Localized Prostate Cancer

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93 Crawford, E.D., Eisenberger, M.A., MacLeod B.G., et al., “A Control Trial Leuprolide with and

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94 rawford, E.D., “Challenges in the Management of Prostate Cancer,” British Journal of Urology

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95 Crawford, E.D., Schutz, M.J., Clejan, S., et al, “The Effect of Digital Rectal Examination on

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96 Crawford, E.D., and Deantoni, E.P., “PSA As A Screening Test for Prostate Cancer,” Urologic

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97 Culkin, D.J., Zitman, R.I., Mata, J.A., et al., “Reliability of Trus and PSA in Prediction of Stage C

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98 Cupp, M.R., Bostwick, D.G., and Oesterling, J.E., “Tumor Volume in Prostate Cancer: Lack of

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99 Cupp, M.R., and Oesterling, J.E., “Prostate-Specific Antigen, Digital Rectal Examination, and

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100 Czaja, R., Mcfall, S.F., Warnecke, R.B., et al., “Preferences of Community Physicians for Cancer

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101 Dalkin, B.L., Ahmann, F.R., and Kopp, J.B., “Prostate Specific Antigen Levels in Men Older Than

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102 Danella, J.F., Dekernion, J.B., Smith, R.B., et al., “The Contemporary Incidence of Lymph Node

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103 Daneshgari, F., Taylor, G.D., Miller, G.J., et al., “Calculating the Probability of Detecting Low

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106 Demura, T., Watari, Y., Togashi, M., et al., “Measurement of Prostate Specific Antigen and

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109 Desmond, P.M., Clark, J., Thompson, I.M., et al., “Morbidity with Contemporary Prostate

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110 Dorr, V.J., Williamson, S.K., and Stephens, R.L., “An Evaluation of Prostate-Specific Antigen as a

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111 Eddy, D.M., “Clinical Decision Making: from Theory to Practice; Three Battles to Watch in the

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112 Eddy, D.M., “Clinical Decision Making: From Theory to Practice; Principles for Making Difficult

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113 Edwards, C., Steinthorsson, N., and Nicholson, D., “An Autopsy Study of Latent Prostatic

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114 Egawa, S., Go, M., Kuwao, S., et al., “Long-Term Impact of Conservative Management on

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115 Ellis, W.J., Amburu, E., Chen, G.L., et al., “The Inability of Prostate Specific Antigen Density to

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116 Ellis, W.J., and Bawer, M.K., “PSA in Benign Prostatic Hyperplasia and Prostatic Intraepithelial

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117 Epstein, B.E., and Hanks, G.E., “Prostate Cancer: Evaluation and Radiotherapeutic

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119 Epstein, J.I., Walsh, P., Carmichael, M., et al., “Pathologic and Clinical Findings to Predict Tumor

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116 COSTS AND EFFECTIVENESS OF PROSTATE CANCER SCREENING IN ELDERLY MEN

122 Finkler, S.A., “The Distinction Between Cost and Charges,” Annals of Internal Medicine

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123 Flanigan, R.C., Catalona, W.J., Richie, J.P., et al., “Success Rate of Digital Rectal Examination

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125 Forman, J.D., Oppenheim, T., Liu, H., et al., “Frequency of Residual Neoplasm in the Prostate

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126 Fournier, G.R., Narayan, P., “Re-Evaluation of the Need for Pelvic Lymphadenectomy in Low

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127 Fowler, F.J., Barry, M.J., Roman, A., et al., “Patient-Reported Complications and Follow-Up

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128 Franks, L.M., “Latent Carcinoma of the Prostate,” Journal of Pathology and Bacteriology

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129 Friedman, G.D., and Hiatt, R.A., Quesenberry, C.P., et al., “Case-Control Study of Screening for

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131 Garnick, M.B., “Prostate Cancer: Screening, Diagnosis and Management,” Annals of Internal

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132 Garnick, M.B., “The Dilemmas of Prostate Cancer,” Scientific American 270(4):72-81, 1994.

133 Garraway, W.M., Collins, G.N., and Lee, R.J., “High Prevalence of Benign Prostatic Hypertrophy

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134 Gaynor, E.P., “Zur Frage Des Prostatakrebes Virchows,” Archives of Pathology and Anatomy

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135 George, N.J., “Natural History of Localized Prostatic Cancer Managed by Conservative

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136 Gerber, G.S., and Chodak, G.W., “Routine Screening for Cancer of the Prostate,” Journal of

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137 Gerber, G.S., Goldberg, R., and Chodak, G.W., “Local Staging of Prostate Cancer by Tumor

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138 Gerber, G.S., Rukstalis, D.B., and Chodak, G.W., “Correlation of Prostate Specific Antigen and

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139 Gerber, G.S., Thompson, I.M., Thisted, R., et al., “Disease-Specific Survival Following Routine

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REFERENCES 117

140 Giovannucci, E., Ascherio, A., Rimm, E.B., et al., “A Prospective Cohort Study of Vasectomy

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141 Giovannucci, E., Tosteson, T.D., Speizer, F.E., et al., “A Retrospective Cohort Study of Vasectomy

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142 Giovannucci, E., Rimm, E.B., Colditz, G.A., et al., “A Prospective Study of Dietary Fat and Risk of

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143 Gittes, R., “Carcinoma of the Prostate,” New England Journal of Medicine 324:236-245, 1991.

144 Gleason, D.F., “Histologic Grading and Clinical Staging of Prostatic Carcinoma,” Urologic

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145 Gormley, G.J., Ng, J., Stoner, E., et al., “Effect of Finasteride on Prostate-Specific Antigen

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146 Graham, S.D., “Critical Assessment of Prostate Cancer Staging,” Cancer 70(suppl.):269-274,

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147 Graversen, P.H., Nielsen, K.T., Gasser, T.C., et al., “Radical Prostatectomy Versus Expectant

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148 Graves, H.C.B., Wehner, N., Stamey, T.A., “Comparison of a Polyclonal and Monoclonal

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149 Graves, H.C.B., “Standardization of Immunoassays for Prostate-Specific Antigen,” Cancer

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150 Greene, D.R., Wheeler, T.M., Egawa, S., et al., “Relationship Between Clinical Stage and

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151 Greene, D.R., Rogers, E., Wessels, E.C., et al., “Some Small Prostate Cancers Are Nondiploid by

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152 Greenwald, H.P., and Henke, C.J., “HMO Membership, Treatment, and Mortality Risk Among

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153 Guess, H.A., “Is Vasectomy A Risk Factor for Prostate Cancer?,” European Journal of Cancer

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155 Guess, H.A., Heyse, J.F., Gormley, G.J., et al., “Effect of Finasteride on Serum PSA

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156 Gustafsson, O., Norming, U., Almgard, L.E., et al., “Diagnostic Methods in the Detection of

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118 COSTS AND EFFECTIVENESS OF PROSTATE CANCER SCREENING IN ELDERLY MEN

157 Guthman, D.A., Bergstralh, E.J., Wilson, T.M., et al., “Biopsy-Proved Prostate Cancer in 100

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158 Hahn, D.L., and Roberts, R.G., “PSA Screening for Asymptomatic Prostate Cancer: Truth in

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159 Halpert, B., and Schmalhorst, W.R., “Carcinoma of the Prostate in Patients 70 to 79 Years Old,”

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160 Hammerer, P., and Huland, H., “Systematic Sextant Biopsies in 651 Patients Referred for Prostate

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161 Hanks, G.E., “External-Beam Radiation Therapy for Clinically Localized Prostate Cancer:

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162 Hanks, G.E., Asbell, S., Krall, J.M., et al., “Outcome for Lymph Node Dissection Negative T-1b,

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163 Hanks, G.E., “External Beam Radiation Treatment for Prostate Cancer: Still the Gold Standard,”

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164 Hanks, G.E., Krall, J.M., Pilepich, M.V., et al., “Comparison of Pathologic and Clinical Evaluation

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165 Hanks, G.E., Krall, J.M., Hanlon, A.L., et al., “Patterns of Care and Rtog Studies in Prostate

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167 Hinman, F.J., “Screening for Prostatic Carcinoma,” Journal of Urology 145:126-129, Discussion:

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168 Howard, G.C., “The Management of Carcinoma of the Prostate After Failed Primary Therapy,”

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169 Howards, S.S., and Peterson, H.B., “Vasectomy and Prostate Cancer; Chance, Bias, Or a

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171 Huang, C.L., Brassil, D., Rozzell, M., et al., “Comparison of Prostate Secretory Protein with

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172 Hudson, M.A., “Prostate-Specific Antigen and the Clinician,” Advances in Urology 6:157-186,

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178 Jones, G.W., “Prospective, Conservative Management of Localized Prostate Cancer,” Cancer

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179 Kabalin, J.N., “Stage a Prostate Cancer Today,” Journal of Urology 150:1749-1750, 1993.

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190 Klee, G.G., Dodge, L.A., Zincke, H., et al., “Measurement of Serum Prostate Specific Antigen

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191 Kleer, E., Larson-Keller, J.J., Zincke, H., et al., “Ability of Preoperative Serum Prostate-Specific

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120 COSTS AND EFFECTIVENESS OF PROSTATE CANCER SCREENING IN ELDERLY MEN

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202 Labrie, F., Dupont, A., Gomez, J.L., et al., “Beneficial Effect of Combination Therapy

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203 Lange, P.H., “Controversies in Management of Apparently Localized Carcinoma of Prostate,”

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204 Lange, P.H., “The Next Era for Prostate Cancer: Controlled Clinical Trials,” Journal of the

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205 Lawton, C.A., Won, M., Pilepich, M.V., et al., “Long-Term Treatment Sequelae Following

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207 Lee, J.M., “Screening and Informed Consent,” New England Journal of Medicine 328:438-440,

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208 Lee, R.J., and Sause, W.T., “Surgically Staged Patients with Prostatic Carcinoma Treated with

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210 Lerner, S., Seale-Hawkins, C., Carlton, C., et al., “The Risk of Dying of Prostate Cancer in

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215 Littrup, P.J., Lee, F.L., and Mettlin, C., “Prostate Cancer Screening: Current Trends and Future

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216 Littrup, P.J., Kene, R.A., Williams, C.R., et al., “Determination of Prostate Volume with Transrectal

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217 Littrup, P.J., Goodman, A.C., Mettlin, C.J., et al., “The Benefit and Cost of Prostate Cancer Early

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218 Lookner, D.H., Crawford, E.D., Donohue, R.E., et al., “Prostate Specific Antigen and Prostate

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220 Lu-Yao, G.L., “An Assessment of Radical Prostatectomy,” Journal of the American Medical

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225 Manton, K.G., Corder, L.S., and Stallard, E., “Estimates of Change in Chronic Disability and

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122 COSTS AND EFFECTIVENESS OF PROSTATE CANCER SCREENING IN ELDERLY MEN

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230 McLaren, R.H., Barrett, D.M., and Zincke, H., “Rectal Injury Occurring at Radical Retropubic

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235 Mettlin, C., Lee, F., Drago, J., et al., “The American Cancer Society National Prostate Cancer

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236 Mettlin, C., Murphy, G.P., and Menck, H., “Trends in Treatment of Localized Prostate Cancer by

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240 Meyers, F.J., and Gumerlock, P.H., “Prostate Cancer Screening: What We Know and What We

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242 Monath, J.R., Pittaway, D.E., Burkart, J.M., et al., “Effects of Hemodialysis on Prostate-Specific

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243 Monda, J.M., Barry, M.J., and Oesterling, J.E., “Prostate Specific Antigen Cannot Distinguish

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245 Montie, J.E., “1992 Staging System for Prostate Cancer,” Seminars in Urology 11:10-13, 1993.

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252 Murphy, G.P., Natarajan, N., Pontes, J.E., et al., “The National Survey of Prostate Cancer in the

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124 COSTS AND EFFECTIVENESS OF PROSTATE CANCER SCREENING IN ELDERLY MEN

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128 COSTS AND EFFECTIVENESS OF PROSTATE CANCER SCREENING IN ELDERLY MEN

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