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Screening for prostate cancer: Enthusiasm
SCREENING
FOR PROSTATE ENTHUSIASM
CANCER:
WILLIAM J. CATALONA, M.D. From the Division of Urology, Washington University School of Medicine, St. Louis. Missouri The American Cancer Society and the American Urological Association now recommend annual prostate-specific antigen (PSA) testing and rectal examinations beginning at age 50 for early prostate cancer detection, and beginning at age 40 in highrisk men. Upper age limits have not been set, but it is generally agreed that routine screening is not desirable in men with a life expectancy of less than 10 years; therefore, the upper age limit should be between 70 and 75 years of age. The controversy over screening for prostate cancer hinges on whether or not screening will reduce the prostate cancer mortality rate and what the costs will be in terms of dollars, anxiety, the morbidity and mortality of the screening tests, and of the treatment of the cancers detected. We are conducting trials involving more than 22,000 men to evaluate PSA and rectal examination (in conjunction with ultrasonography and biopsy) as screening tests for prostate cancer. Other investigators have conducted similar trials with comparable results.’ These trials have provided useful new insights concerning the use of these tests. In this editorial, I shall use our own data2e4 for purposes of illustration The lifetime risk of being diagnosed with prostate cancer is about one in nine men.5 Thus, in my view, if screening is to be done, it should be recommended for the general population. The incidence of suspicious rectal examinations or PSA elevations is only 10 to 15 percent in men aged 50 and rises to more than 40 percent at age 80; however, the percent with positive biopsy specimens is more strongly associated with PSA level than with patient’s age.4 This may seem to suggest that the yield is too low to justify screening men aged 50. However, the cancer detection rate in men fifty to sixty years old is about 3 percent, and younger men are more likely to have organ-confined cancer and also have a longer life expectancy Therefore, younger men are more likely to benefit from screening. Reports that familial prostate Submitted:
UROLOGY
May IO, 1993, accepted:
/ AUGUST 1993
May 21, 1993
I VOLUME 42, NUMBER 2
cancer may occur at an earlier age” and the frequent finding of focal prostate cancers at autopsy in young men7 suggest that beginning screening at an even earlier age may be appropriate in high-risk men. Other possible high-risk groups include AfricanAmerican men8 and possibly men who have undergone vasectomy.9 Although patients over the age of seventy have a shorter life expectancy and are more likely to have advanced disease, more than half of them do have organ-confined cancer, and many are deemed to be appropriate candidates for curative treatment.3 Such patients also will benefit from screening if prostate cancer deaths, the morbidity of metastases, and the adverse side effects of androgen deprivation can be avoided. PSA and rectal examination should be the frontline tests. Ultrasonography and systematic biopsy should be reserved for men with suspicious findings on either test. PSA and rectal examination are complementary For example, in our studies, rectal examination alone would have missed 40 percent of the cancers and PSA alone would have missed 23 percent. Using the two in combination, we detected 78 percent more organ-confined prostate cancers than would have been detected with rectal examination alone.4 Our first study of PSA-based screening showed that if the PSA level was elevated in the 4-10 ng range, 27 percent had prostate cancer detected on the first biopsy, and if the level was ~10 ng, 59 percent had cancer. Men who did not have cancer diagnosed during the first screening were screened longitudinally at six-month intervals and a substantial proportion had cancer detected on subsequent screening. Our most recent data show that if the PSA was 4-10 ng, 34 percent had cancer detected on the initial or follow-up biopsies, and if it was >lO ng, 70 percent had cancer detected.4 In the African-American community that traditionally has a low participation in cancer screening programs, screening with the blood test alone may not seriously compromise the results. In our longitudinal study testing PSA as the sole first-line 113
screening test, in men who were screened at sixmonth intervals over forty months, the cancer detection rate was 4.7 percent which was similar to the 5 percent detection rate achieved through initial (cross-sectional) screening using PSA and rectal examination together. Combining our two screening studies, we are beginning to see racial differences. For example, 17 percent of African-Americans versus 13 percent of whites had elevated PSA levels; the overall cancer detection rate was 8.2 percent in blacks versus 5.1 percent in whites. Although we have not yet observed a difference in the age at detection, fewer cancers in blacks were clinically localized (91% vs. 97%) and fewer were pathologically organ-confined (62% vs. 74%). Active screening detects prostate cancer earlier. In our concurrently studied, nonscreened cancer patients whose cancer was detected through the tradibiopsies betional approach (i.e., they underwent cause of suspicious findings on rectal examination), 57 percent had clinically or pathologically-advanced cancer at the time of detection. In screened patients whose cancer was detected through the initial PSAbased screen, only 37 percent had advanced disease while of those with cancer detected through serial PSA-based screening, only 29 percent had advanced cancer. In our second study in which men were screened with both rectal examination and PSA testing, only 28 percent had advanced cancer at the time of detection. Thus, screening doubles the proportion of organ-confined cancers detected.4 The key to early prostate cancer detection is to make the diagnosis before the PSA level rises above 10 ng/mL; PSA levels often continue to rise rapidly after they become elevated.” In our studies more than 82 percent of men with PSA levels <4 ng and more than 75 percent with levels between 4-10 ng/mL had pathologically organ-confined cancer, as compared with only 48 percent whose PSA levels were >lO ng/mL. If the rectal examination is suspicious for cancer, or if the PSA level is >4 ng/mL, systematic biopsies should be performed unless the patient is too old or too ill. PSA, rectal examination, and ultrasonography have false-positive and false-negative results. PSA is the most accurate test, with a positive predictive value of 31 percent on the initial biopsy using 4 ng/mL as the upper limit of normal. In fact, the positive predictive value of PSA for prostate cancer is higher than that of mammography for breast cancer, which is about 25 percent.” It should be remembered that PSA testing is meant to assess risk and not to diagnose cancer. PSA is not diagnostic like a pregnancy test. An elevated PSA level does not mean
114
the presence of cancer, but rather indicates the presence of prostatic disease and the need for further evaluation. The most common reasons for false-positive (for cancer) PSA elevations are benign prostatic hyperplasia (BPH) and prostatitis. In a sense, the false-negative findings are a blessing because PSA testing not only fails to detect the 20 to 40 percent of the smaller palpable cancers arising near the rectal surface of the prostate that can be detected early by rectal examination, but also fails to detect most of the micro-focal cancers that may not need treatment. Cancers less than 1 cc usually do not elevate PSA levels, whereas those larger than this usually do.12 The cancer detection rates (3-5%) in screened populations are only a fraction of the prevalence of prostate cancer (30%) documented in autopsy studies. More than 90 percent of cancers detected through PSA-based screening appear to be serious as judged by their volume and histologic grade.4J3 It has been suggested that “PSA density” may be more helpful in distinguishing BPH from cancer.14 Our studies and others have shown that the PSA density adds little to the serum PSA level alone for primary prostate cancer screening. We have found that measurements of the rate of change of PSA levels over a twelve-month interval do not distinguish between patients with and without cancer. Measurement of the rate of change of PSA levels has been shown to be helpful over longer intervals. lo The available data suggest that the most practical PSA threshold is 4 ng/mL (Hybritech). Lower cutoffs lead to more biopsies with a low yield of cancer; higher cutoffs detect more cancers too late. Some investigators recommend using 10 ng/mL as the cutoff. In our studies, men with a PSA level of 4.1 to 10 ng/mL and benign findings on rectal examination had a higher percentage of positive biopsies (21%) than those with suspicious findings on rectal examination and a normal PSA level (11%). Interestingly, more than two thirds of cancers were found in quadrants of the prostate that were not suspicious on rectal examination or ultrasonography. Thus, if the PSA level is elevated, systematic biopsies should be performed even in the absence of other abnormalities. If one waits for the PSA level to rise above 10 ng before recommending a biopsy, more than half of the cancers detected already will have spread, and the prognosis will be less favorable. In spite of these results, the value of prostate cancer screening is unproved. It is not sufficient merely to show that screening detects more early cancers; early detection may not lead to improved survival if treatments are ineffective or if the cancers detected are either latent or already incurable. Lead-time bias
UROLOGY
/ ALXXST 1993
/ VOLUME42, NLWBER2
(the apparent increase in survival when the total length of life is not prolonged) and length-time bias (the tendency to detect preferentially the slowly growing cancers through screening because they remain in the population longer) may create the false impression that early detection leads to improved survival. The National Cancer Institute is conducting a prospective, randomized trial to determine whether or not screening reduces the prostate cancer mortality rate, but it will take sixteen years to complete this study. It is estimated that half a million men will die of prostate cancer before this study is completed, and it is unrealistic to expect clinicians to refrain from using PSA for cancer detection in the meantime. There have been conflicting reports on the costs associated with screening for prostate cancer. Some reports have not used contemporary data in the statistical model and, thus, have exaggerated the costs and complications. A recent cost-effectiveness analysis suggested that because the costs of treating advanced prostate cancer are usually considerably greater than for early disease, the incremental costs of adding PSA to rectal examination for early detection are offset by lower treatment costs.15 It is my opinion that screening with an annual rectal examination and serum PSA measurement should be encouraged. If treatment of early-stage prostate cancer is effective, screening should have a substantial survival benefit. William J. Catalona, M.D. 4960 Children’s Place St. Louis, Missouri 63110 REFERENCES 1. Brawer MK, Chetner MP, Beatie J, Buchner DM, Vessella RL, and Lange PH: Screening for prostatic carcinoma with prostate specific antigen. J Urol 147: 841-845, 1992. 2. Catalona WJ, Smith DS, Ratliff TL, Dodds KM, Coplen DE, Yuan JJ, Petros JA, and Andriole GL: Measurement of
UROLOGY
/
AUGUST 1993
/
VOLUME42, NUMBER2
prostate-specific
antigen
in serum
as a screening tool for 1991. 3. Catalona WJ, Smith DS, Ratliff TL, and Basler JW: Detection of organ-confined cancer is increased through prostate specific antigen-base screening, JAMA (in press). 4. Catalona WJ, et al: Comparison of digital rectal examination and serum prostate specific antigen (PSA) in the early detection of prostate cancer: results of a multicenter clinical trial of 6,630 men, (submitted for publication). 5. Boring CC: Personal communication, 1993. 6. Steinberg GD, Carter BS, Beaty TH, Childs B, and Walsh PC: Family history and the risk of prostate cancer. Prostate 17: 337-347, 1990. 7. Sakr WA, Haas GP, Grignon DJ. Heilbrun LK, Cassin BJ, Pontes JE, and Crissman JD: High prostatic intraepithelial neoplasia (HGPIN) and prostatic adenocarcinoma between the ages of 20-69: an autopsy study of 249 cases (Abstr. 386). Mod Path01 6: 68A, 1993. 8. Boring CC, Squires TS, and Heath CW Jr: Cancer statistics for African Americans, CA Cancer J Chn 42: 7-17, 1992. 9. Giovannucci E, Ascherio A, Rimm EB, Colditz GA, Stampfer MJ, and Willett WC: A prospective cohort study of vasectomy and prostate cancer in US men. JAMA 267: 873-877, 1993. 10. Carter HB, et al: Longitudinal evaluation of prostatespecific antigen levels in men with and without prostate disease. JAMA 267: 2215-2220, 1992. 11, Kinne DW, and Kopans DB: Physical examination and mammography in the diagnosis of breast disease, in Harris JR, et al. (Eds): Breast Disease, Philadelphia, J.B. Lippincott Co., 1987, pp 54-86. 12. Brawn PN, et al: Prostate-specific antigen levels from completely sectioned, clinically benign, whole prostates. Cancer 68: 1592-1599,1991. 13. Stormont TJ, Farrow GM, Myers RP Blute ML, Zincke H, Wilson TM, and Oesterling JE: Clinical Stage B, or Tic prostate cancer: non-palpable disease identified by an elevated serum prostate-specific antigen concentration. Urology 41: 3-8,1993. 14. Benson MC, Whang S, Pantuck A, Ring K, Kaplan S, Olsson CA, and Cooner WH: Prostate-specific antigen density: a means of distinguishing BPH and prostate cancer. J Urol 147: 815-816, 1992. 15. Simpson KN: A model of potential effects and costs of adding PSA to current screening practice for prostate cancer, Presented at 120th Annual Meeting of the American Public Health Association, Session 2026, Washington, D.C., November 8-12, 1992.
prostate cancer. N Eng1 J Med 334: 1156-1161,
115
FOR PROSTATE ENTHUSIASM
CANCER:
WILLIAM J. CATALONA, M.D. From the Division of Urology, Washington University School of Medicine, St. Louis. Missouri The American Cancer Society and the American Urological Association now recommend annual prostate-specific antigen (PSA) testing and rectal examinations beginning at age 50 for early prostate cancer detection, and beginning at age 40 in highrisk men. Upper age limits have not been set, but it is generally agreed that routine screening is not desirable in men with a life expectancy of less than 10 years; therefore, the upper age limit should be between 70 and 75 years of age. The controversy over screening for prostate cancer hinges on whether or not screening will reduce the prostate cancer mortality rate and what the costs will be in terms of dollars, anxiety, the morbidity and mortality of the screening tests, and of the treatment of the cancers detected. We are conducting trials involving more than 22,000 men to evaluate PSA and rectal examination (in conjunction with ultrasonography and biopsy) as screening tests for prostate cancer. Other investigators have conducted similar trials with comparable results.’ These trials have provided useful new insights concerning the use of these tests. In this editorial, I shall use our own data2e4 for purposes of illustration The lifetime risk of being diagnosed with prostate cancer is about one in nine men.5 Thus, in my view, if screening is to be done, it should be recommended for the general population. The incidence of suspicious rectal examinations or PSA elevations is only 10 to 15 percent in men aged 50 and rises to more than 40 percent at age 80; however, the percent with positive biopsy specimens is more strongly associated with PSA level than with patient’s age.4 This may seem to suggest that the yield is too low to justify screening men aged 50. However, the cancer detection rate in men fifty to sixty years old is about 3 percent, and younger men are more likely to have organ-confined cancer and also have a longer life expectancy Therefore, younger men are more likely to benefit from screening. Reports that familial prostate Submitted:
UROLOGY
May IO, 1993, accepted:
/ AUGUST 1993
May 21, 1993
I VOLUME 42, NUMBER 2
cancer may occur at an earlier age” and the frequent finding of focal prostate cancers at autopsy in young men7 suggest that beginning screening at an even earlier age may be appropriate in high-risk men. Other possible high-risk groups include AfricanAmerican men8 and possibly men who have undergone vasectomy.9 Although patients over the age of seventy have a shorter life expectancy and are more likely to have advanced disease, more than half of them do have organ-confined cancer, and many are deemed to be appropriate candidates for curative treatment.3 Such patients also will benefit from screening if prostate cancer deaths, the morbidity of metastases, and the adverse side effects of androgen deprivation can be avoided. PSA and rectal examination should be the frontline tests. Ultrasonography and systematic biopsy should be reserved for men with suspicious findings on either test. PSA and rectal examination are complementary For example, in our studies, rectal examination alone would have missed 40 percent of the cancers and PSA alone would have missed 23 percent. Using the two in combination, we detected 78 percent more organ-confined prostate cancers than would have been detected with rectal examination alone.4 Our first study of PSA-based screening showed that if the PSA level was elevated in the 4-10 ng range, 27 percent had prostate cancer detected on the first biopsy, and if the level was ~10 ng, 59 percent had cancer. Men who did not have cancer diagnosed during the first screening were screened longitudinally at six-month intervals and a substantial proportion had cancer detected on subsequent screening. Our most recent data show that if the PSA was 4-10 ng, 34 percent had cancer detected on the initial or follow-up biopsies, and if it was >lO ng, 70 percent had cancer detected.4 In the African-American community that traditionally has a low participation in cancer screening programs, screening with the blood test alone may not seriously compromise the results. In our longitudinal study testing PSA as the sole first-line 113
screening test, in men who were screened at sixmonth intervals over forty months, the cancer detection rate was 4.7 percent which was similar to the 5 percent detection rate achieved through initial (cross-sectional) screening using PSA and rectal examination together. Combining our two screening studies, we are beginning to see racial differences. For example, 17 percent of African-Americans versus 13 percent of whites had elevated PSA levels; the overall cancer detection rate was 8.2 percent in blacks versus 5.1 percent in whites. Although we have not yet observed a difference in the age at detection, fewer cancers in blacks were clinically localized (91% vs. 97%) and fewer were pathologically organ-confined (62% vs. 74%). Active screening detects prostate cancer earlier. In our concurrently studied, nonscreened cancer patients whose cancer was detected through the tradibiopsies betional approach (i.e., they underwent cause of suspicious findings on rectal examination), 57 percent had clinically or pathologically-advanced cancer at the time of detection. In screened patients whose cancer was detected through the initial PSAbased screen, only 37 percent had advanced disease while of those with cancer detected through serial PSA-based screening, only 29 percent had advanced cancer. In our second study in which men were screened with both rectal examination and PSA testing, only 28 percent had advanced cancer at the time of detection. Thus, screening doubles the proportion of organ-confined cancers detected.4 The key to early prostate cancer detection is to make the diagnosis before the PSA level rises above 10 ng/mL; PSA levels often continue to rise rapidly after they become elevated.” In our studies more than 82 percent of men with PSA levels <4 ng and more than 75 percent with levels between 4-10 ng/mL had pathologically organ-confined cancer, as compared with only 48 percent whose PSA levels were >lO ng/mL. If the rectal examination is suspicious for cancer, or if the PSA level is >4 ng/mL, systematic biopsies should be performed unless the patient is too old or too ill. PSA, rectal examination, and ultrasonography have false-positive and false-negative results. PSA is the most accurate test, with a positive predictive value of 31 percent on the initial biopsy using 4 ng/mL as the upper limit of normal. In fact, the positive predictive value of PSA for prostate cancer is higher than that of mammography for breast cancer, which is about 25 percent.” It should be remembered that PSA testing is meant to assess risk and not to diagnose cancer. PSA is not diagnostic like a pregnancy test. An elevated PSA level does not mean
114
the presence of cancer, but rather indicates the presence of prostatic disease and the need for further evaluation. The most common reasons for false-positive (for cancer) PSA elevations are benign prostatic hyperplasia (BPH) and prostatitis. In a sense, the false-negative findings are a blessing because PSA testing not only fails to detect the 20 to 40 percent of the smaller palpable cancers arising near the rectal surface of the prostate that can be detected early by rectal examination, but also fails to detect most of the micro-focal cancers that may not need treatment. Cancers less than 1 cc usually do not elevate PSA levels, whereas those larger than this usually do.12 The cancer detection rates (3-5%) in screened populations are only a fraction of the prevalence of prostate cancer (30%) documented in autopsy studies. More than 90 percent of cancers detected through PSA-based screening appear to be serious as judged by their volume and histologic grade.4J3 It has been suggested that “PSA density” may be more helpful in distinguishing BPH from cancer.14 Our studies and others have shown that the PSA density adds little to the serum PSA level alone for primary prostate cancer screening. We have found that measurements of the rate of change of PSA levels over a twelve-month interval do not distinguish between patients with and without cancer. Measurement of the rate of change of PSA levels has been shown to be helpful over longer intervals. lo The available data suggest that the most practical PSA threshold is 4 ng/mL (Hybritech). Lower cutoffs lead to more biopsies with a low yield of cancer; higher cutoffs detect more cancers too late. Some investigators recommend using 10 ng/mL as the cutoff. In our studies, men with a PSA level of 4.1 to 10 ng/mL and benign findings on rectal examination had a higher percentage of positive biopsies (21%) than those with suspicious findings on rectal examination and a normal PSA level (11%). Interestingly, more than two thirds of cancers were found in quadrants of the prostate that were not suspicious on rectal examination or ultrasonography. Thus, if the PSA level is elevated, systematic biopsies should be performed even in the absence of other abnormalities. If one waits for the PSA level to rise above 10 ng before recommending a biopsy, more than half of the cancers detected already will have spread, and the prognosis will be less favorable. In spite of these results, the value of prostate cancer screening is unproved. It is not sufficient merely to show that screening detects more early cancers; early detection may not lead to improved survival if treatments are ineffective or if the cancers detected are either latent or already incurable. Lead-time bias
UROLOGY
/ ALXXST 1993
/ VOLUME42, NLWBER2
(the apparent increase in survival when the total length of life is not prolonged) and length-time bias (the tendency to detect preferentially the slowly growing cancers through screening because they remain in the population longer) may create the false impression that early detection leads to improved survival. The National Cancer Institute is conducting a prospective, randomized trial to determine whether or not screening reduces the prostate cancer mortality rate, but it will take sixteen years to complete this study. It is estimated that half a million men will die of prostate cancer before this study is completed, and it is unrealistic to expect clinicians to refrain from using PSA for cancer detection in the meantime. There have been conflicting reports on the costs associated with screening for prostate cancer. Some reports have not used contemporary data in the statistical model and, thus, have exaggerated the costs and complications. A recent cost-effectiveness analysis suggested that because the costs of treating advanced prostate cancer are usually considerably greater than for early disease, the incremental costs of adding PSA to rectal examination for early detection are offset by lower treatment costs.15 It is my opinion that screening with an annual rectal examination and serum PSA measurement should be encouraged. If treatment of early-stage prostate cancer is effective, screening should have a substantial survival benefit. William J. Catalona, M.D. 4960 Children’s Place St. Louis, Missouri 63110 REFERENCES 1. Brawer MK, Chetner MP, Beatie J, Buchner DM, Vessella RL, and Lange PH: Screening for prostatic carcinoma with prostate specific antigen. J Urol 147: 841-845, 1992. 2. Catalona WJ, Smith DS, Ratliff TL, Dodds KM, Coplen DE, Yuan JJ, Petros JA, and Andriole GL: Measurement of
UROLOGY
/
AUGUST 1993
/
VOLUME42, NUMBER2
prostate-specific
antigen
in serum
as a screening tool for 1991. 3. Catalona WJ, Smith DS, Ratliff TL, and Basler JW: Detection of organ-confined cancer is increased through prostate specific antigen-base screening, JAMA (in press). 4. Catalona WJ, et al: Comparison of digital rectal examination and serum prostate specific antigen (PSA) in the early detection of prostate cancer: results of a multicenter clinical trial of 6,630 men, (submitted for publication). 5. Boring CC: Personal communication, 1993. 6. Steinberg GD, Carter BS, Beaty TH, Childs B, and Walsh PC: Family history and the risk of prostate cancer. Prostate 17: 337-347, 1990. 7. Sakr WA, Haas GP, Grignon DJ. Heilbrun LK, Cassin BJ, Pontes JE, and Crissman JD: High prostatic intraepithelial neoplasia (HGPIN) and prostatic adenocarcinoma between the ages of 20-69: an autopsy study of 249 cases (Abstr. 386). Mod Path01 6: 68A, 1993. 8. Boring CC, Squires TS, and Heath CW Jr: Cancer statistics for African Americans, CA Cancer J Chn 42: 7-17, 1992. 9. Giovannucci E, Ascherio A, Rimm EB, Colditz GA, Stampfer MJ, and Willett WC: A prospective cohort study of vasectomy and prostate cancer in US men. JAMA 267: 873-877, 1993. 10. Carter HB, et al: Longitudinal evaluation of prostatespecific antigen levels in men with and without prostate disease. JAMA 267: 2215-2220, 1992. 11, Kinne DW, and Kopans DB: Physical examination and mammography in the diagnosis of breast disease, in Harris JR, et al. (Eds): Breast Disease, Philadelphia, J.B. Lippincott Co., 1987, pp 54-86. 12. Brawn PN, et al: Prostate-specific antigen levels from completely sectioned, clinically benign, whole prostates. Cancer 68: 1592-1599,1991. 13. Stormont TJ, Farrow GM, Myers RP Blute ML, Zincke H, Wilson TM, and Oesterling JE: Clinical Stage B, or Tic prostate cancer: non-palpable disease identified by an elevated serum prostate-specific antigen concentration. Urology 41: 3-8,1993. 14. Benson MC, Whang S, Pantuck A, Ring K, Kaplan S, Olsson CA, and Cooner WH: Prostate-specific antigen density: a means of distinguishing BPH and prostate cancer. J Urol 147: 815-816, 1992. 15. Simpson KN: A model of potential effects and costs of adding PSA to current screening practice for prostate cancer, Presented at 120th Annual Meeting of the American Public Health Association, Session 2026, Washington, D.C., November 8-12, 1992.
prostate cancer. N Eng1 J Med 334: 1156-1161,
115