A Screening Study of Prostate Cancer in High Risk Families

0022-534 7/92/1483-0826$03.00/0 Vol. 148, 826-828, September 1992

THE JOURNAL OF UROLOGY Copyright© 1992 by AMERICAN UROLOGICAL ASSOCIATION, INC.

Printed in U.S.A.

A SCREENING STUDY OF PROSTATE CANCER IN HIGH RISK FAMILIES WILLIAM P. McWHORTER, ALBERTO D. HERNANDEZ, A. WAYNE MEIKLE, DANIEL A. TERREROS, JOSEPH A. SMITH, JR.,* MARK H. SKOLNICK, LISA A. CANNONALBRIGHT AND HARMON J. EYRE From the Departments of Internal Medicine, Urology, Pathology and Medical Informatics, University of Utah Medical School, Salt Lake City, Utah

ABSTRACT

In a study of the familial risk of prostate cancer 17 sets of 2 brothers with prostate cancer were identified. A total of 34 first-degree relatives of these probands (sons and brothers, 55 to 80 years old) underwent an intensive screening examination that included prostate specific antigen, digital rectal examination, transrectal ultrasound and systematic as well as clinically directed core needle biopsies. Previously unsuspected and clinically relevant cancers were found in 8 men (24%), compared to the approximately 1 expected (p <0.01). Of these cancers 2 were detected by the systematic biopsies. This study emphasizes the importance of thorough screening in first-degree relatives of prostate cancer patients. KEY WORDS:

prostatic neoplasms, genetics, epidemiology, risk factors

Several retrospective studies have reported increased risk of prostate cancer in relatives of prostate cancer probands. 1- 7 The relative risk for cancer has varied with the number and closeness of the affected relatives. Having 1 affected first-degree relative has been associated with a relative risk of approximately 2 to 3, and having 2 affected relatives has been associated with a relative risk of approximately 5 to 6. To our knowledge this is the first active screening study of the familiality of prostate cancer. An intensive prostate screening protocol was used in first-degree relatives of 2 brothers previously diagnosed with prostate cancer. METHODS

The Utah Population Database consists of genealogical records linked with records from the Utah Cancer Registry. 8 This resource allowed us to select sets of 2 brothers who had been diagnosed with prostate cancer. Following a protocol approved by the Institutional Review Board of the University of Utah Medical School, physicians of the probands were asked for permission to contact these families. Eligible relatives were men 55 to 80 years old who had no personal history of prostate cancer and who were brothers or sons of the probands. No selfreferrals were allowed. After informed consent was obtained, pertinent history was taken. Blood was drawn for prostate specific antigen (PSA) determinations, which were done by immunoradiometric assay. t A digital rectal examination was followed by transrectal ultrasound imaging with a Bruel and Kjaer 1846 instrument fitted with 7 mHz. transducers. Digital rectal and ultrasound examinations were summarized as not suspicious, moderately suspicious or highly suspicious for cancer. Ultrasound-guided core needle biopsies (0.4 x 17 mm.) were performed9 with a spring-loaded 18 gauge Biopty:j: apparatus. If digital rectal or ultrasound examination was suspicious for cancer directed biopsies of those areas were taken. Systematic transrectal biopsies were also obtained in each case. FourAccepted for publication February 28, 1992. Supported in part by an American Cancer Society institutional research grant and United States Public Health Service Grants and Contracts MOI-RR-00064, P30-CA-42014 and NOI-CN-05222. * Current address: Department of Urology, Vanderbilt University Medical Center, Nashville, Tennessee 37232. t Hybritech, Inc., La Jolla, California. t C. R. Bard Co., Covington, Georgia. 826

quadrant biopsies were performed in smaller prostates, and 6 spaced biopsies were done in prostates larger than approximately 50 gm. Systematic biopsies were not repeated in areas that had been thoroughly covered by prior directed biopsies. Antibiotic prophylaxis with 500 mg. ciprofloxacin was given 1 hour before the biopsies and every 12 hours for 4 doses. Complications were limited to occasional transient mild hematuria or hemospermia. RESULTS

Of 39 men invited to enter the study 34 men in 17 families completed the protocol. Six families contributed 1 subject, 8 families contributed 2 and 1 family each contributed 3, 4 and 5 subjects. Five subjects were brothers of the probands and 29 were sons of the probands. One subject had undergone prior transurethral prostatic resection for hypertrophy. None of the men had current prostatic symptoms or was being treated for prostate disease. The age of the men examined ranged from 55 to 78 years, with a mean age of 65 years. Of the 34 men examined 8 (24 %) had previously unsuspected invasive prostate cancer. The 5 families involved in newly diagnosed cancer included 1 with 2 and 1 with 3 new cancers. The 8 men with cancer ranged from 64 to 75 years old (mean age 70 years), while the 26 men without cancer ranged from 55 to 72 years old (mean age 63 years). The frequency of cancer increased with patient age. None of 7 men 55 to 59 years old had cancer, compared to 3 of 18 (17%) 60 to 69 years old and 5 of 9 (56%) 70 to 79 years old. Four systematic biopsies were done in each of 22 men with a smaller prostate, while 6 systematic biopsies were done in each of 8 men with a larger gland. Systematic biopsies were limited to 2 or 3 in 4 men because of prior thorough coverage of suspicious areas by directed biopsies. The results of the screening examinations are summarized in the table. PSA and digital rectal examination were suspicious for cancer in only 3 and 4 of the 8 cancer patients, respectively, and the combination of these 2 tests was suspicious in only 4. Ultrasound was the most sensitive of the noninvasive screening tests, being moderately to highly suspicious in 7 of the 8 cancer patients. The case that was negative on transrectal ultrasound was also negative on PSA and digital rectal examination. Cancer was diagnosed as a direct result of the systematic biopsies in 2 instances: 1 with normal PSA, digital rectal examination

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PROSTATE CANCER !N HIGH RISK FAMILIES

Results of screening tests: number of cases Total No. Cases Ca 8 No 26 Ca

PSA Pos.* 3 3

Digital Rectal Examination Pos.t

Ultrasound Pos.:j:

4

7

4

5

Directed Biopsy No. Ca/ Total

Systematic Biopsy No. Ca/ Total

6/7 0/7

5/8 0/26

* PSA greater than or equal to 4.0 ng./ml.

t Digital rectal examination moderately to highly suspicious for cancer. :j: Transrectal ultrasound moderately to highly suspicious for cancer.

and transrectal ultrasound, and 1 in which directed biopsies were benign but systematic biopsies detected cancer. There were 3 instances in which systematic biopsies were benign but directed biopsies detected cancer. However, in these patients only 2 or 3 systematic biopsies were performed, away from suspicious areas covered by the prior directed biopsies. The American clinical stages 10 of these 8 cancers included 1 stage A, 6 stage B and 1 stage C tumors. Of these men 7 (excluding the clinical stage C cancer patient) have undergone total prostatectomy and lymph node dissection. All of these tumors were adenocarcinoma. No lymph node was positive. The pathological stages 10 included 3 stage B and 4 stage C tumors, 1 of which had seminal vesicle involvement. Gleason combined histological grades 11 included 1 gTade 3 (on a scale of 10), 2 grade 5, 1 grade 6 and 3 grade 7 lesions. DISCUSSION

Our study emphasizes the magnitude of risk of clinically significant prostate cancer in men 55 to 80 years old in families with 2 affected brothers. Nearly a fourth of these men had cancer despite the absence of symptoms, and the facts that the men knew of prostate cancer in their family and that many were undergoing regular physical examinations. Even assuming that the 5 family members who did not participate in the study were normal, the prevalence of cancer in unselected family members was 21%. We have not examined large numbers of healthy men in the general population by these screening methods, so exact estimates and statistical testing of the increased rates of cancer in these families are not possible. However, crude estimates can be made using published results of a somewhat similar protocol. Catalona et al screened 630 healthy men 50 to 79 years old with PSA followed by digital rectal examination, transrectal ultrasound and biopsy if indicated. 12 Based on the age-specific prevalence rates found by this somewhat less intensive protocol, we would expect to have discovered 0.97 cancers in our family members, for an observed-to-expected ratio of 8.2 (95% confidence interval 3.6 to 16.4, p = 0.0008). 13 This analysis does not take into account factors such as the different screening protocols or the potential nonindependence of family members. However, even doubling the expected rates would still yield an estimated relative risk of 4.1 (95% confidence interval 1.8 to 8.1, p = 0.006). In addition, to date we have examined 15 healthy men 55 to 80 years old with no family history of prostate cancer by the same protocol as our family study with results compatible with the Catalona study: 1 cancer has been found. Therefore, the estimated relative risk in the current study is compatible with those found in retrospective studies, such as the relative risk of 5 to 11 for men with 2 and 3 first-degree affected relatives. 3 The use of PSA, digital rectal examination and transrectal ultrasound in various combinations for screening men at normal risk is controversial. 14 However, the magnitude of risk in members of these families is large and would appear to justify using some type of intensive screening protocol. All of the cancers found by this protocol were clinically relevant and 7 patients have undergone potentially curative surgery to date. The complications encountered in this study were few and

transient, and none required specific treatment. Therefore, the benefits of the current protocol seem to outweigh greatly the risks in these families. The cancers found in these families have not been unusual. The cell type, stage and grade distribution were not uncommon, and the mean patient age at diagnosis of 70 years was close to the national figure for median age at diagnosis of 72 years. 15 Therefore, we would expect these tumors to have a clinical course typical of adenocarcinoma of the prostate. The use of routine systematic biopsies as well as clinically directed biopsies in high risk families appears to be supported by our results. This combination has previously been shown to provide high diagnostic accuracy in a protocol slightly different from: ours. 16 The optimal biopsy protocol is unclear; we used a protocol that varied according to the size of the gland and nature of the suspicious areas but that covered all areas of the gland with at least 1 biopsy. The patient age at which this screening should begin is not clear. We found high prevalence rates of cancer in men more than 60 years old. However, in a sample of families containing multiple first-degree relatives with prostate cancer in Utah 10% of 779 prostate cancers were diagnosed in men less than 60 years old, 4 % less than 55 years old and 1 % less than 50 years old. 17 The frequency with which this screening should occur is also unclear. After such intensive screening as in our protocol, routine biopsies may not be justified each year in the absence of abnormal findings on PSA, digital rectal examination or transrectal ultrasound. Risks for prostate cancer appear to vary with the number and closeness of relatives with prior prostate cancer but the relative risk for a man with only 1 affected first-degree relative is still approximately 2 to 3 times that of a man without this history. 2 • 3• 6 • 7 Therefore, some type of intensive screening in first-degree relatives of all men with prostatic cancer appears to be justified. Further studies will be needed to determine optimal screening regimens for men with varying characteristics. REFERENCES

1. Woolf, C. M.: An investigation of the familial aspects of carcinoma

of the prostate. Cancer, 13: 739, 1960. 2. Cannon, L., Bishop, D. T., Skolnick, M., Hunt, S., Lyon, J. L. and Smart, C. R.: Genetic epidemiology of prostate cancer in the Utah Mormon genealogy. Cancer Surv., 1: 47, 1982. 3. Steinberg, G.D., Carter, RS., Beaty, T. H., Childs, B. and Walsh, P. C.: Family history and the risk of prostate cancer. Prostate, 17: 337, 1990. 4. Krain, L. 8.: Some epidemiologic variables in prostatic carcinoma in California. Prev. Med., 3: 154, 1974. 5. Meikle, A. W., Smith, A. J. and West, D. W.: Familial factors affecting prostatic cancer risk and plasma sex-steroid levels. Prostate, 6: 121, 1985. 6. Babaian, R. J., Spitz, M. R., Currier, R. D., Fueger, J. J. and N ewe!!, G. R.: Familial patterns of prostate cancer: a case-control analysis. J. Urol., part 2, 145: 213A, abstract 4, 1991. 7. Keetch, D. W. and Catalona, W. J.: Familial aspects of prostate cancer: a case control review. J. Urol., part 2, 145: 250A, abstract 151, 1991. 8. Bishop, D. T. and Skolnick, M. H.: Genetic epidemiology of cancer in Utah genealogies: a prelude to the molecular genetics of common cancers. J. Cell Physiol., suppl., 3: 63, 1984. 9. Hodge, K. K., McNeal, J.E. and Stamey, T. A.: Ultrasound guided transrectal core biopsies of the palpably abnormal prostate. J. Urol., 142: 66, 1989. 10. Beahrs, 0. H., Henson, D. E., Hutter, R. V. P. and Myers, M. H.: Manual for Staging of Cancer, 3rd ed. American Joint Committee on Cancer. Philadelphia: J. B. Lippincott Co., 1988. 11. Gleason, D. F., Mellinger, G. T. and Veterans Administration Cooperative Urological Research Group: Prediction of prognosis for prostatic adenocarcinoma by combined histological grading and clinical staging. J. Urol., 111: 58, 1974. 12. Catalona, W. J., Smith, D. S., Ratliff, T. L., Dodds, K. M., Coplen,