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Editorial: Prostate Cancer
0022-S347/97/1571-0207$03.00/0
Tiit JoLTRNAI. OF UROLOCV Cup! right 0 1997 by AMERICAN UROLOGICAL ASSOCUTION, INC
Val. 157,207-208. January 1997 Printed in U.S.A.
EDITORIAL: PROSTATE CANCER The diagnosis of prostatic carcinoma has undergone a con- divided by prostate volume) was not helpful in predicting siderable evolution during the last decade. Primarily due to carcinoma. the clinical application of prostate specific antigen (PSA), in This study and several other reports13 suggest that the conjunction with transrectal ultrasound and the spring free-to-total PSA ratio will enhance specificity. However, it loaded biopsy devices, we have seen staggering changes in achieves this effect a t the cost of decreasing sensitivity. It is the indication for and performance of prostatic biopsy. De- unclear to me whether urologists will be willing to miss the spite these significant advances considerable efforts have diagnosis of carcinoma in approximately 10% of the biopsy been made to enhance the performance of our diagnostic patients to avoid 20 to 40% of negative biopsies. Perhaps the algorithms. In general, clinicians and their patients desire a free-to-total PSA ratio will show its greatest potential in highly sensitive test that will detect the majority of prostate determining which men, after an initially negative systemcancers. In addition, we wish to offer assurance to our pa- atic sector biopsy, need further evaluation for the potential of tients that if the biopsy is negative the man is free of disease. missed carcinoma. Another intriguing observation in this Unfortunately these 2 goals tend to be mutually exclusive, report is that the free-to-total PSA ratio was not related to that is enhancement of test sensitivity (an abnormal finding prostatic volume. The authors concluded that the physiologin a man with prostate cancer) is almost always inversely ical basis of free PSA remains enigmatic. Perhaps this staterelated to specificity (the assurance that a negative test in- ment is applicable to PSA in general, since we do not totally dicates freedom from disease). The preceding 5 articles in understand all of the factors that contribute to the serum level. this issue of the journal address several of these concerns. Omstein et a1 (page 195)performed an important investiIrani et a1 (page 185)conducted a novel investigation of the relationship of urinary and serum PSA. Previously, they gation evaluating the biological variation and effect of prosdemonstrated that men with benign prostatic hyperplasia tatic perturbation on free as well as total PSA. In men re(BPH) had increased urinary levels of PSA. They compared cruited to an extensive PSA based screening program they 73 men with BPH and 57 with prostate carcinoma, and observed a biological variation of total PSA of 14.7% and a measured the serum-to-urinary PSA ratio, which had been slightly lower 14% variation of the percentage of free PSA in adjusted for the urinary creatinine level. For the entire PSA 3 separate determinations for a 30-day period. Moreover, range all tests (that is serum and urine PSA, and serum-to- they observed that the percentage of free PSA increased urine PSA ratio) stratified men with and without carcinoma. above the expected biological variation in 48% of men 1 hour However, for the clinically relevant serum PSA range of 4.0 after digital rectal examination. As expected, prostate needle to 10.0 ng./ml. (50 men), only urinary PSA and serum-to- biopsy caused a sigmficant increase in free and total PSA. urinary PSA ratio provided statistically sigmficant separa- However, while the latter remained elevated for at least 1 tion. week in most men, the percentage of free PSA returned to This method of enhancing the specificity of PSA is encour- baseline within 24 hours in 90% of the subjects. This report aging, particularly since it provided clinically useful informa- provides useful information about factors affecting serum tion in the area of diagnostic dilemma (PSA 4.0 to 10.0 PSA, and confirmed the suspicion of others that physiological ng./ml.). However, several problems exist in making this factors result in significant changes in serum PSA with approach clinically useful. Most significantly, lrani et a1 used time.4 Obviously this finding has significant implication in pooled collection of urine for 24 hours and, as noted, needed our monitoring of patients for the potential development of to adjust the specimen for serum creatinine level. These prostate cancer and makes one question the potential use requirements add considerable cost and raise the issue of of PSA velocity. Of great interest is the significant influence of prostatic perturbation on free PSA level, and parcompliance. Prestigiacomo and Stamey (page 189)investigated a con- ticularly differential time to return to baseline of free and secutive biopsy series of 104 men with significant prostate total PSA. The rapid clearance of the smaller moiety free cancer (greater than 3 mm.3) and 110 consecutive men who PSA after prostate biopsy compared to complexed PSA will had negative prostate biopsies. They measured the free-to- have a significant effect on the free-to-total PSA ratio. total ratio of PSA and noted enhanced predictability of pros- Obviously this effect has implication in our potential use of tate cancer with this ratio compared to total PSA alone. free-to-total PSA. Until further data emerge it is probably Several observations stem from this investigation, which add incumbent on the clinician to wait at least 1 month after to our emerging literature on the use of the free-to-total PSA biopsy before determining this ratio. Despite the fact that transrectal ultrasound guided biopsy ratio. For the entire PSA range the authors noted that with a PSA cutoff of 23%, 22.7% negative biopsies could be pre- has clearly emerged as the optimum strategy for biopsy of the vented. The cost was a sensitivity of only 90.4%. In the prostate, the most appropriate method of performing this clinically relevant range of 4.0 to 10.0 ng./ml., for which now routine urological procedure still must be defined. many authorities have suggested the free-to-total PSA ratio Eskew et a1 (page 199)investigated 119 patients, 48 of whom is most likely to have a role, 44.4% of men with negative had carcinoma. They performed 6 systematic sector biopsies biopsies were correctly identified using a cutoff of 20% free- of the peripheral zone as described initially by Hodge et al.5 to-total PSA. Sensitivity was 90.9%. For men with a PSA of In addition, 2 biopsies were obtained from each lateral aspect greater than 10.0 ng./ml. an 18% free-to-total PSA ratio of the gland and 3 from the transition zone. The authors cutoff identified 30.2% of patients with a negative biopsy, observed that the additional biopsies identified cancer in 17 with a sensitivity of 90.7%. Intriguingly, the authors noted patients not diagnosed on the systematic sector biopsies. Of that for the entire PSA range prostate volume was as good a note, however, in only 2 of these men was cancer found in the predictor of carcinoma as the free-to-total PSA ratio. How- transition zone biopsies. Indeed, 41 of the 48 men with cancer ever, this finding did not hold true when subset analyses, would have had the cancer identified with the 4 laterally based on the aforementioned PSA cutoffs, were observed. The directed peripheral zone biopsies. It is intriguing to speculate authors noted that the free PSA density (free PSA level whether 6 laterally directed systematic biopsies, as has been 207
208
PROSTATE CANCER
recently recommended by the Stanford group: would have to men with a PSA of greater than 10.0 ngJml. who have had identified some or all of the additional men with carcinoma. negative systematic sector biopsies. Although it is obvious that performing more biopsies will Michael K. Brawer identlfy more cancers, one must consider the additional morDepartment of Urology bidity and associated patient discomfort. In the report by University of Washington Eskew et al, the patients had intravenous sedation, which Seattle Veterans w a i r s Medical Center may or may not have been required for the minimum of 13 Seattle, Washington biopsies obtained from each patient. Moreover, although they suggest that few, if any, clinically insignificant cancers were REFERENCES identified based on Gleason grade, this event becomes more 1. Luderer, A. A, Chen, Y.-T., Soriano, T. F., Kramp, W. J., likely as more biopsies are obtained. Carlaon, G., Cuny, C., Sharp, T., Smith, w.,Petteway, J., Tems et al (page 204) confirm our contention that 6 laterBrawer, M. K and Thiel, R.: Measurement of the proportion of ally placed systematic sector biopsies are probably adequate free to total prostate-s@c antigen improves the diagnostic for most men. They compared 736 men undergoing sextant gray zone of total prostate-specific antigen. urology, 48: 187, biopsies, of which 42% revealed carcinoma, to 161 men un1995. dergoing combined sextant transition zone and seminal ves2. Chen, Y.-T., Luderer, A. A, Thiel, R. P., Carlson, G., Cuny, C. L. icle biopsies (34.2% had carcinoma). Of the 55 men with and Soriano, T. F.: Using proportion~of free to total prostate carcinoma in the latter group 43 had cancer only in the specific antigen (PSA), age, and total PSA to predict the probability of prostate cancer. Urology, in press. systematic sector biopsies. In 11 patients (20%) the transi3. Catalona, W. J., Smith, D. S., Wolfert, R. L., Wang, T. J., tion zone as well as systematic sector biopsies revealed canRittenhouse, H. G., R aw,T. L. and Nadler, R. B.: Evaluation cer. Only 1 patient had carcinoma only in the transition zone of percentage of free serum prostate-specific antigen to im(1.8% of men with cancer), while 10.9%had carcinoma in the prove specificity of prostate cancer screening. J.A.M.A., 274: seminal vesicles. This investigation provides assurance that 1214,1995. the majority of prostate cancers will be identified with 6 4. Lam, K. J., Wener, M. H., Brawer, M. IL, Strobel, S. A., Smith, systematic sector biopsies. Seminal vesicle biopsies probably K M. and Parson, R. E.: Biologic variation in serum PSA level. should be limited to men with significant risk of pathological J. Urol, part 2,166: 696& abstract 1542,1996. 5. Hodge, K. K, McNeal, J. E., Terris, M. K and Stamey, T. A,: up staging due to digital rectal examination findings or Random systematic vemus directed ultrasound guided transmarkedly elevated serum PSA Transition zone biopsies rectal core biopsies of the prostate. J. Urol., 142: 71, 1989. should be restricted to men with a negative systematic sector 6. Stamey, T.A: Making the most of six systematic sextant biopbiopsy, particularly since anterior biopsies are associated sies. Urology, rM: 2, 1996. with increased patient discomfort. Urologists should know 7. Stamey, T. A, Dietick, D. D. and Issa, M. M.: Large, organ that even men with significantly elevated serum PSA may confined, impalpable transition zone prostate cancer: associahave organ confined disease if the carcinoma is limited to the tion with metastatic levels of prostate specific antigen. transition zone.? Generally, we limit transition zone biopsies J. Urol., 149 510, 1993.
Tiit JoLTRNAI. OF UROLOCV Cup! right 0 1997 by AMERICAN UROLOGICAL ASSOCUTION, INC
Val. 157,207-208. January 1997 Printed in U.S.A.
EDITORIAL: PROSTATE CANCER The diagnosis of prostatic carcinoma has undergone a con- divided by prostate volume) was not helpful in predicting siderable evolution during the last decade. Primarily due to carcinoma. the clinical application of prostate specific antigen (PSA), in This study and several other reports13 suggest that the conjunction with transrectal ultrasound and the spring free-to-total PSA ratio will enhance specificity. However, it loaded biopsy devices, we have seen staggering changes in achieves this effect a t the cost of decreasing sensitivity. It is the indication for and performance of prostatic biopsy. De- unclear to me whether urologists will be willing to miss the spite these significant advances considerable efforts have diagnosis of carcinoma in approximately 10% of the biopsy been made to enhance the performance of our diagnostic patients to avoid 20 to 40% of negative biopsies. Perhaps the algorithms. In general, clinicians and their patients desire a free-to-total PSA ratio will show its greatest potential in highly sensitive test that will detect the majority of prostate determining which men, after an initially negative systemcancers. In addition, we wish to offer assurance to our pa- atic sector biopsy, need further evaluation for the potential of tients that if the biopsy is negative the man is free of disease. missed carcinoma. Another intriguing observation in this Unfortunately these 2 goals tend to be mutually exclusive, report is that the free-to-total PSA ratio was not related to that is enhancement of test sensitivity (an abnormal finding prostatic volume. The authors concluded that the physiologin a man with prostate cancer) is almost always inversely ical basis of free PSA remains enigmatic. Perhaps this staterelated to specificity (the assurance that a negative test in- ment is applicable to PSA in general, since we do not totally dicates freedom from disease). The preceding 5 articles in understand all of the factors that contribute to the serum level. this issue of the journal address several of these concerns. Omstein et a1 (page 195)performed an important investiIrani et a1 (page 185)conducted a novel investigation of the relationship of urinary and serum PSA. Previously, they gation evaluating the biological variation and effect of prosdemonstrated that men with benign prostatic hyperplasia tatic perturbation on free as well as total PSA. In men re(BPH) had increased urinary levels of PSA. They compared cruited to an extensive PSA based screening program they 73 men with BPH and 57 with prostate carcinoma, and observed a biological variation of total PSA of 14.7% and a measured the serum-to-urinary PSA ratio, which had been slightly lower 14% variation of the percentage of free PSA in adjusted for the urinary creatinine level. For the entire PSA 3 separate determinations for a 30-day period. Moreover, range all tests (that is serum and urine PSA, and serum-to- they observed that the percentage of free PSA increased urine PSA ratio) stratified men with and without carcinoma. above the expected biological variation in 48% of men 1 hour However, for the clinically relevant serum PSA range of 4.0 after digital rectal examination. As expected, prostate needle to 10.0 ng./ml. (50 men), only urinary PSA and serum-to- biopsy caused a sigmficant increase in free and total PSA. urinary PSA ratio provided statistically sigmficant separa- However, while the latter remained elevated for at least 1 tion. week in most men, the percentage of free PSA returned to This method of enhancing the specificity of PSA is encour- baseline within 24 hours in 90% of the subjects. This report aging, particularly since it provided clinically useful informa- provides useful information about factors affecting serum tion in the area of diagnostic dilemma (PSA 4.0 to 10.0 PSA, and confirmed the suspicion of others that physiological ng./ml.). However, several problems exist in making this factors result in significant changes in serum PSA with approach clinically useful. Most significantly, lrani et a1 used time.4 Obviously this finding has significant implication in pooled collection of urine for 24 hours and, as noted, needed our monitoring of patients for the potential development of to adjust the specimen for serum creatinine level. These prostate cancer and makes one question the potential use requirements add considerable cost and raise the issue of of PSA velocity. Of great interest is the significant influence of prostatic perturbation on free PSA level, and parcompliance. Prestigiacomo and Stamey (page 189)investigated a con- ticularly differential time to return to baseline of free and secutive biopsy series of 104 men with significant prostate total PSA. The rapid clearance of the smaller moiety free cancer (greater than 3 mm.3) and 110 consecutive men who PSA after prostate biopsy compared to complexed PSA will had negative prostate biopsies. They measured the free-to- have a significant effect on the free-to-total PSA ratio. total ratio of PSA and noted enhanced predictability of pros- Obviously this effect has implication in our potential use of tate cancer with this ratio compared to total PSA alone. free-to-total PSA. Until further data emerge it is probably Several observations stem from this investigation, which add incumbent on the clinician to wait at least 1 month after to our emerging literature on the use of the free-to-total PSA biopsy before determining this ratio. Despite the fact that transrectal ultrasound guided biopsy ratio. For the entire PSA range the authors noted that with a PSA cutoff of 23%, 22.7% negative biopsies could be pre- has clearly emerged as the optimum strategy for biopsy of the vented. The cost was a sensitivity of only 90.4%. In the prostate, the most appropriate method of performing this clinically relevant range of 4.0 to 10.0 ng./ml., for which now routine urological procedure still must be defined. many authorities have suggested the free-to-total PSA ratio Eskew et a1 (page 199)investigated 119 patients, 48 of whom is most likely to have a role, 44.4% of men with negative had carcinoma. They performed 6 systematic sector biopsies biopsies were correctly identified using a cutoff of 20% free- of the peripheral zone as described initially by Hodge et al.5 to-total PSA. Sensitivity was 90.9%. For men with a PSA of In addition, 2 biopsies were obtained from each lateral aspect greater than 10.0 ng./ml. an 18% free-to-total PSA ratio of the gland and 3 from the transition zone. The authors cutoff identified 30.2% of patients with a negative biopsy, observed that the additional biopsies identified cancer in 17 with a sensitivity of 90.7%. Intriguingly, the authors noted patients not diagnosed on the systematic sector biopsies. Of that for the entire PSA range prostate volume was as good a note, however, in only 2 of these men was cancer found in the predictor of carcinoma as the free-to-total PSA ratio. How- transition zone biopsies. Indeed, 41 of the 48 men with cancer ever, this finding did not hold true when subset analyses, would have had the cancer identified with the 4 laterally based on the aforementioned PSA cutoffs, were observed. The directed peripheral zone biopsies. It is intriguing to speculate authors noted that the free PSA density (free PSA level whether 6 laterally directed systematic biopsies, as has been 207
208
PROSTATE CANCER
recently recommended by the Stanford group: would have to men with a PSA of greater than 10.0 ngJml. who have had identified some or all of the additional men with carcinoma. negative systematic sector biopsies. Although it is obvious that performing more biopsies will Michael K. Brawer identlfy more cancers, one must consider the additional morDepartment of Urology bidity and associated patient discomfort. In the report by University of Washington Eskew et al, the patients had intravenous sedation, which Seattle Veterans w a i r s Medical Center may or may not have been required for the minimum of 13 Seattle, Washington biopsies obtained from each patient. Moreover, although they suggest that few, if any, clinically insignificant cancers were REFERENCES identified based on Gleason grade, this event becomes more 1. Luderer, A. A, Chen, Y.-T., Soriano, T. F., Kramp, W. J., likely as more biopsies are obtained. Carlaon, G., Cuny, C., Sharp, T., Smith, w.,Petteway, J., Tems et al (page 204) confirm our contention that 6 laterBrawer, M. K and Thiel, R.: Measurement of the proportion of ally placed systematic sector biopsies are probably adequate free to total prostate-s@c antigen improves the diagnostic for most men. They compared 736 men undergoing sextant gray zone of total prostate-specific antigen. urology, 48: 187, biopsies, of which 42% revealed carcinoma, to 161 men un1995. dergoing combined sextant transition zone and seminal ves2. Chen, Y.-T., Luderer, A. A, Thiel, R. P., Carlson, G., Cuny, C. L. icle biopsies (34.2% had carcinoma). Of the 55 men with and Soriano, T. F.: Using proportion~of free to total prostate carcinoma in the latter group 43 had cancer only in the specific antigen (PSA), age, and total PSA to predict the probability of prostate cancer. Urology, in press. systematic sector biopsies. In 11 patients (20%) the transi3. Catalona, W. J., Smith, D. S., Wolfert, R. L., Wang, T. J., tion zone as well as systematic sector biopsies revealed canRittenhouse, H. G., R aw,T. L. and Nadler, R. B.: Evaluation cer. Only 1 patient had carcinoma only in the transition zone of percentage of free serum prostate-specific antigen to im(1.8% of men with cancer), while 10.9%had carcinoma in the prove specificity of prostate cancer screening. J.A.M.A., 274: seminal vesicles. This investigation provides assurance that 1214,1995. the majority of prostate cancers will be identified with 6 4. Lam, K. J., Wener, M. H., Brawer, M. IL, Strobel, S. A., Smith, systematic sector biopsies. Seminal vesicle biopsies probably K M. and Parson, R. E.: Biologic variation in serum PSA level. should be limited to men with significant risk of pathological J. Urol, part 2,166: 696& abstract 1542,1996. 5. Hodge, K. K, McNeal, J. E., Terris, M. K and Stamey, T. A,: up staging due to digital rectal examination findings or Random systematic vemus directed ultrasound guided transmarkedly elevated serum PSA Transition zone biopsies rectal core biopsies of the prostate. J. Urol., 142: 71, 1989. should be restricted to men with a negative systematic sector 6. Stamey, T.A: Making the most of six systematic sextant biopbiopsy, particularly since anterior biopsies are associated sies. Urology, rM: 2, 1996. with increased patient discomfort. Urologists should know 7. Stamey, T. A, Dietick, D. D. and Issa, M. M.: Large, organ that even men with significantly elevated serum PSA may confined, impalpable transition zone prostate cancer: associahave organ confined disease if the carcinoma is limited to the tion with metastatic levels of prostate specific antigen. transition zone.? Generally, we limit transition zone biopsies J. Urol., 149 510, 1993.