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The Role of Prostate Specific Antigen as a Tumor Marker in Men with Advanced Adenocarcinoma of the Prostate
0022-534 7/89 /1416-1378$02.00 /0 Vol. 141, June Printed in U.S.A.
THE JOURNAL OF UROLOGY
Copyright© 1989 by Williams & Wilkins
THE ROLE OF PROSTATE SPECIFIC ANTIGEN AS A TUMOR MARKER IN MEN WITH ADVANCED ADENOCARCINOMA OF THE PROSTATE THOMAS J. MAATMAN From the Department of Urology, Metropolitan Hospital, Grand Rapids, Michigan
ABSTRACT
Serial serum prostate specific antigen levels were obtained every 4 hours during a 24-hour interval from 8 men with stage D adenocarcinoma of the prostate. No therapeutic or diagnostic manipulations occurred during sample procurement, so that the amount of f,.ictuation of serum prostate specific antigen levels that can be expected in these patients could be determined. The coefficient of variation for each man ranged from 1.16 to 10.94 per cent, which was not statistically higher than the expected 4.39 and 11.44 per cent coefficient of variation determined with a control sample. The maximum percentage variations above and below the mean were 19.3 and 17.7 per cent, respectively. The average percentage variation in all patients was within 7.6 per cent greater than and 7.6 per cent less than the mean value of prostate specific antigen. Thus, prostate specific antigen appears to be a reliable tumor marker because there is minimal random fluctuation when serial levels are obtained in men with advanced prostate cancer. Based on these findings certain guidelines are suggested. (J. Ural., 141: 1378-1380, 1989) Prostate specific antigen is not effective in screening the general population for carcinoma of the prostate. 1- 3 It appears to have a more important role in staging men with prostate cancer because the concentration of serum prostate specific antigen is proportional to the clinical stage of prostate cancer in untreated patients and prostate specific antigen has been shown to be proportional to the volume of cancerous tumor within the prostate. 4 Its most important clinical role may be to monitor the effect of therapy and progression of disease, that is as a tumor marker. 4 - 7 If prostate specific antigen is to be used as a tumor marker it is important to determine the amount of variation in serial prostate specific antigen in men with cancer of the prostate than can be expected during an interval unrelated to therapy and disease progression, and to define precisely what constitutes a significant increase or decrease in prostate specific antigen. We used a solid phase, 2-site, immunoradiometric assay to determine serial prostate specific antigen every 4 hours for a 24-hour period in 8 men with documented stage D adenocarcinoma of the prostate. The purpose of this study was to determine the normal fluctuation in prostate specific antigen unrelated to therapy or disease progression, if a diurnal, circadian or otherwise predictable fluctuation existed in serum prostate specific antigen, and possible guidelines to assess significant increases or decreases in serum prostate specific antigen in men with advanced cancer of the prostate. MATERIALS AND METHODS
A total of 8 men with histologically confirmed stage D adenocarcinoma of the prostate was entered voluntarily into the study protocol. Patient age ranged from 64 to 95 years. No therapeutic changes were made less than 6 months before entering the study. None of the men received antineoplastic agents. No therapeutic interventions, rectal examinations or endoscopic procedures for prostate cancer were made immediately before or during the study. Urinary drainage was satisfactory in all men. Blood (10 ml.) was obtained from each man for serum prostate specific antigen determinations every 4 hours for a 24-hour interval, beginning at 8 a.m. during the hospitalization.
Serum prostate specific antigen levels were determined by a solid phase, 2-site, immunoradiometric assay with commercially available reagents.* A whole blood specimen was obtained by standard medical technique. The blood was allowed to clot and the serum was separated by centrifugation. Serum samples were stored with appropriate refrigeration before assay determination. Serum prostate specific antigen concentration was measured by reacting the blood specimen with mouse monoclonal lgG (against prostate specific antigen) coated on plastic beads in a buffer containing 0.1 per cent sodium azide as a preservative (anti-prostate specific antigen coated bead), 50 µl. human serum containing no detectable (Ong. prostate specific antigen per ml.) concentration of prostate specific antigen and 0.1 per cent sodium azide as a preservative (zero diluent per calibrator), and 200 µl. mouse monoclonal lgG (against prostate specific antigen) labeled with 125iodine in a protein matrix containing less than 10 µCi. per vial, a blue dye and 0.1 per cent sodium azide as a preservative (anti-prostate specific antigen tracer antibody). The specimen then was incubated for 2 hours at room temperature using a horizontal rotator set at 170 revolutions per minute. After the formation of a solid phase/ prostate specific antigen/labeled antibody sandwich, the bead was washed to remove unbound labeled antibody. Radioactivity bound to the solid phase was measured in a gamma counter. The amount of radioactivity measured is directly proportional to the concentration of prostate specific antigen in the test sample, which is determined from the standard curve. The normal range of prostate specific antigen in our laboratory is O to 4.0 ng./ml. Low and high prostate specific antigen controls were run concurrently during this study for quality control. The coefficient of variation with a high control was 4.39 per cent and for the low control it was 11.44 per cent. RESULTS
The values of serum prostate specific antigen for each man are shown in table 1 according to the time when the specimen was obtained. There appeared to be no diurnal, circadian or otherwise predictable fluctuation in serial prostate specific antigen levels determined by the solid phase, 2-site, immunoradiometric assay during a 24-hour interval. The values of * Hybritech, Inc., San Diego, California.
Accepted for publication December 14, 1988. 1378
1379
ROLE OF PROSTATE SPECIFIC ANTIGEN AS TUMOR MARKER
serum prostate specific antigen, determined from a control sample measured repeatedly biweekly during the study interval, ranged from 37.3 to 41.36 ng,/mL, with a mean of 39.90 for the high control and 2.6 to 3.81 ng./ml., with a mean of 3.04 for the low control. The mean, range, variance, standard deviation and coefficient of variation for each of the 8 patients are listed in table 2. The coefficient of variation is the ratio of the standard deviation divided by the mean, usually expressed as a percentage, and it is a method of comparing the variability within groups of data with different mean values. A large coefficient of variation indicates increased variability within that group of data. The coefficient of variation for the 8 patients ranged from 1.16 to 10.94 per cent. For each patient the coefficient of variation was not statistically different from the coefficient of variation of the control samples. The maximum percentage deviation above and below the mean in this series was 19.3 per cent (patient 5) and 17.7 per cent (patient 7), respectively, while the average percentage variation ranged from 2.3 to 7.6 per cent above the mean and 2.3 to 7.6 per cent below the mean (table 3). DISCUSSION
The inability to quantitate accurately the extent and progression of disease is a major limitation in the evaluation and treatment of men with advanced cancer of the prostate. Prostate cancer typically metastasizes to the regional lymph nodes and bone. Current clinical modalities used to monitor this spread, including bone scan, and acid and alkaline phosphatase determinations, offer a crude estimate of activity at best. Prostatic acid phosphatase measured by a sensitive radioimmunoassay has been shown to fluctuate as high as 79 per cent above and 50 per cent below the mean value when serial levels are obtained every 4 hours during a 48-hour period in men with documented stage D adenocarcinoma of the prostate. 8 Because of this marked random fluctuation, the use of prostatic acid phosphatase determined by radioimmunoassay as a clinical tumor marker is limited by the number of serial evaluations
needed to establish a mean by which to compare subsequent increases or decreases in serum prostatic acid phosphatase in the course of the disease. It has been suggested that the most useful marker in prostate cancer is prostate specific antigen.4· 7 , 9 To use prostate specific antigen logically as a tumor marker in men with prostate cancer, it is important to determine the amount of normal fluctuation in prostate specific antigen unrelated to therapy or disease progression and if a diurnal, circadian or otherwise predictable fluctuation exists in serum prostate specific antigen levels. In this series the maximum fluctuation of prostate specific antigen was 19.3 per cent greater than and 17. 7 per cent less than the mean. More importantly, the average percentage variation for all patients was within 7.6 per cent above and below the mean. It appears that the random fluctuation of prostate specific antigen obtained serially in men with advanced prostate cancer is less than that seen in prostatic acid phosphatase obtained serially in such men. In addition, there appeared to be no diurnal or circadian fluctuation in serum prostate specific antigen levels. A random fluctuation of prostate specific antigen was observed but this amount of fluctuation was well within the expected fluctuation of the test, since the coefficients of variation of the patient samples were not significantly different than the coefficients of variation of the control samples. For these reasons, it appears that prostate specific antigen is a reliable tumor marker to monitor prostate cancer. Therefore, several guidelines for the use of prostate specific antigen as a tumor marker in men with prostate cancer are suggested. A favorable response to therapy is indicated when serum prostate specific antigen returns to normal. A persistent decrease by 10 per cent or more from the mean value of prostate specific antigen levels determined serially suggests a favorable response to therapy. A persistent increase by 10 per cent or greater from the mean values suggests progression of disease.
Percentage deviation above and below mean of serum prostate specific antigen measured by a solid phase, 2-site, immunoradiometric assay
TABLE 3. TABLE
Pt. No. 1 2 3 4
5 6 7 8
L Individual serum prostate specific antigen levels for each patient according to the time of sample measurement Time 8A.M.
12 P.M.
4P.M.
8P.M.
12 A.M.
4A.M.
1,025 697 3,149 3,7 139 37,3 409 91.3
981 697 3,368 3.6 167 37,9 321 83,5
949 759 3,616
1,037 685 3,476 4,2 131 38,2 392 99,3
1,038 705 3,221 3,6 143 36.8 389 88.4
994
4,4
142 43,9 452 96.9
2 3 4 5 6 7
1,004.0 709,17 3,355,0 3,92 140.0 39,03 390.17 90,65
8
Vaiues are given in µg./1. (ng./ml.).
TABLE
Mean
712
3,300 4.0 118 40.1 378 84,5
Maximum Deviation(%)
Pt. No.
Av. Deviation ( % )
Above Mean
Below Mean
Above Mean
Below Mean
3.3 7.0 3,6 12,2 19.3 12.5 15,9 9.5
5,5 3.4 6,0
2,9 2,3 3,9 7,1 7,6 7,6 7,1 5.7
2.9 2.3 3.9 7,3 7,6 3,8 7,0 5.7
8.2
15.7 5,7 17,7 7,9
2. Mean, range, variance, standard deviation and coefficient of variation for each patient and control sample Mean Values (range)*
Difference Between High and Low Value*
1,004.0 (994-1,037) 709.17 (685-759) 3,355.0 (3,149-3,616) 3,92 (3,6-4.4) 140.0 (118-167) 39,03 (36.8-43,9) 390.17 (321-452) 90.65 (83,5-99.3)
43 74 467 0,8 49 7,1 131 15.8
Pt. No. 1 2 3 4
5 6 7 8 Control Sample: High Low
39.90 (37.3-43.12) 3,04 (2.6-3,81)
5,82 1.21
Variance*
Standard Deviation*
Coefficient of Variation (%)t
1,268 677.77 29,269.60 0,114 261.60 6,96 1,822.97 41.66
35,61 26.03 171.08 0.34 16.17 2.64 42.70 6.45
3.55 3.67 5.10 8.60 1.16 6,76 10.94 7.12
1.75 0,35
4.39 11.44
3.07 0.12
* Values are given in µg,/1. (ng,/ml.).
t For each patient the coefficient of variation was not statistically different than the
coefficient of variation for the control samples.
1380
MAATMAN REFERENCES
1. Seamonds, B., Yang, N., Anderson, K., Whitaker, B., Shaw, L. M. and Bollinger, J. R.: Evaluation of prostate-specific antigen and prostatic acid phosphatase as cancer markers. Urology, 28: 472, 1986. 2. Allhoff, E. P., Proppe, K. H., Chapman, C. M., Lin, C.-W. and Prout, G. R., Jr.: Evaluation of prostate specific acid phosphatase and prostate specific antigen in identification ofprostatic cancer. J. Urol., 129: 315, 1983. 3. Kuriyama, M., Wang, M. C., Papsidero, L. D., Killian, C. S., Shimano, T., Valenzuela, L., Nishiura, T., Murphy, G. P. and Chu, T. M.: Quantitation of prostate-specific antigen in serum by a sensitive enzyme immunoassay. Cancer Res., 40: 4658, 1980. 4. Stamey, T. A., Yang, N., Hay, A. R., McNeal, J.E., Freiha, F. S. and Redwine, E.: Prostate-specific antigen as a serum marker for adenocarcinoma of the prostate. New Engl. J. Med., 317: 909, 1987. 5. Killian, C. S., Yang, N., Emrich, L. J., Vargas, F. P., Kuriyama, M., Wang, M. C., Slack, N. H., Papsidero, L. D., Murphy, G. P. and Chu, T. M.: Prognostic importance of prostate-specific antigen for monitoring patients with stages B2 to D prostate cancer. Cancer Res., 45: 886, 1985. 6. Guinan, P., Bhatti, R. and Ray, P.: An evaluation of prostate specific antigen in prostatic cancer. J. Urol., 137: 686, 1987. 7. Ahmann, F. R. and Shifman, R. B.: Prospective comparison between serum monoclonal prostate specific antigen and acid phosphatase measurements in metastatic prostatic cancer. J. Urol., 137: 431, 1987. 8. Maatman, T. J., Gupta, M. K. and Montie, J.E.: The role of serum prostatic acid phosphatase as a tumor marker in men with advanced adenocarcinoma of the prostate. J. Urol., 132: 58, 1984. 9. Wang, M. C., Valenzuela, L.A., Murphy, G. P. and Chu, T. M.: Purification of a human prostate specific antigen. Invest. Urol., 17: 159, 1979.
EDITORIAL COMMENT Serum determinations of prostate specific antigen have become indispensable to monitor patients especially after initial therapies. Therefore, it is important to understand the fluctuations in prostate specific antigen values that might occur for reasons other than cancer. The author found that in 8 patients with stage D2 disease daily fluctuations above and below the mean were 7.6 per cent with a maximum of 19.3 per cent above and 17.9 per cent below. Since these fluctuations showed no pattern and were within the expected fluctuations of the assay on test sera the author concludes that a variation in
prostate specific antigen of more than 10 per cent is clinically significant. We do not believe these findings are the last word and we believe that the incorporation of a greater than 10 per cent value into formalized response criteria is premature if not inaccurate. Fluctuations in prostate specific antigen values for reasons other than cancer could be due to assay inaccuracies (inter-assay and intraassay) and/or to physiological causes. Assay variability can be expressed as the coefficient of variation. In several reports of prostate specific antigen assays the coefficient of variation has ranged from 1 to 8 per cent. 1• 2 What is important is that the lowest mean value prostate specific antigen level used for the calculation of coefficient of variation was 3.9. Our observations indicate that at lower levels (less than 2 ng./ml.) the coefficient of variation is significantly greater. 3 Physiological fluctuations in prostatic acid phosphatase certainly occur (as much as 50 per cent at high levels). Others have observed that prostate specific antigen levels fluctuate for physiological reasons as well4 but only by 6.2 per cent from the mean. However, this topic requires further investigation. For example, only 18 patients with stage D2 disease have been studied to date. More data, especially involving other clinical stages, may yield different results. Also, more studies are required on the fluctuations that might occur in prostate specific antigen levels that are observed in patients after radical prostatectomy (for example less than 1 ng./ml.). Finally, Stamey and associates suggested that prostate specific antigen values can vary considerably depending on whether the patient is active or sedentary (reference 4 in article). Nonetheless, the data in this study will bring us closer to the inevitable, that is serial prostate specific antigen levels will be developed into quantifiable response criteria that will improve and expedite future clinical studies in prostate cancer. Paul H. Lange and Michael Brawer Department of Urologic Surgery University of Washington School of Medicine Seattle, Washington 1. Chan, D. W., Bruzek, D. J., Oesterling, J. E., Rock, R. C. and Walsh, P. C.: Prostate-specific antigen as a marker for prostatic cancer: a monoclonal and polyclonal immunoassay compared. Clin. Chem., 33: 1916, 1987. 2. Hortin, G. L., Bahnson, R. R., Daft, M., Chan, K. M., Catalona, W. J. and Ladenson, J. H.: Differences in values obtained with 2 assays of prostate specific antigen. J. Urol., 139: 762, 1988. 3. Lange, P. H., Ercole, C. J., Lightner, D. J., Fraley, E. E. and Vessella, R.: The value of serum prostate specific antigen determinations before and after radical prostatectomy. J. Urol., 141: 000, 1989. 4. Schifman, R. B., Ahmann, F. R., Elvick, A., Ahmann, M., Coulis, K. and Brawer, M. K.: Analytical and physiological characteristics of prostate-specific antigen and prostatic acid phosphatase in serum compared. Clin. Chem., 33: 2086, 1987.
THE JOURNAL OF UROLOGY
Copyright© 1989 by Williams & Wilkins
THE ROLE OF PROSTATE SPECIFIC ANTIGEN AS A TUMOR MARKER IN MEN WITH ADVANCED ADENOCARCINOMA OF THE PROSTATE THOMAS J. MAATMAN From the Department of Urology, Metropolitan Hospital, Grand Rapids, Michigan
ABSTRACT
Serial serum prostate specific antigen levels were obtained every 4 hours during a 24-hour interval from 8 men with stage D adenocarcinoma of the prostate. No therapeutic or diagnostic manipulations occurred during sample procurement, so that the amount of f,.ictuation of serum prostate specific antigen levels that can be expected in these patients could be determined. The coefficient of variation for each man ranged from 1.16 to 10.94 per cent, which was not statistically higher than the expected 4.39 and 11.44 per cent coefficient of variation determined with a control sample. The maximum percentage variations above and below the mean were 19.3 and 17.7 per cent, respectively. The average percentage variation in all patients was within 7.6 per cent greater than and 7.6 per cent less than the mean value of prostate specific antigen. Thus, prostate specific antigen appears to be a reliable tumor marker because there is minimal random fluctuation when serial levels are obtained in men with advanced prostate cancer. Based on these findings certain guidelines are suggested. (J. Ural., 141: 1378-1380, 1989) Prostate specific antigen is not effective in screening the general population for carcinoma of the prostate. 1- 3 It appears to have a more important role in staging men with prostate cancer because the concentration of serum prostate specific antigen is proportional to the clinical stage of prostate cancer in untreated patients and prostate specific antigen has been shown to be proportional to the volume of cancerous tumor within the prostate. 4 Its most important clinical role may be to monitor the effect of therapy and progression of disease, that is as a tumor marker. 4 - 7 If prostate specific antigen is to be used as a tumor marker it is important to determine the amount of variation in serial prostate specific antigen in men with cancer of the prostate than can be expected during an interval unrelated to therapy and disease progression, and to define precisely what constitutes a significant increase or decrease in prostate specific antigen. We used a solid phase, 2-site, immunoradiometric assay to determine serial prostate specific antigen every 4 hours for a 24-hour period in 8 men with documented stage D adenocarcinoma of the prostate. The purpose of this study was to determine the normal fluctuation in prostate specific antigen unrelated to therapy or disease progression, if a diurnal, circadian or otherwise predictable fluctuation existed in serum prostate specific antigen, and possible guidelines to assess significant increases or decreases in serum prostate specific antigen in men with advanced cancer of the prostate. MATERIALS AND METHODS
A total of 8 men with histologically confirmed stage D adenocarcinoma of the prostate was entered voluntarily into the study protocol. Patient age ranged from 64 to 95 years. No therapeutic changes were made less than 6 months before entering the study. None of the men received antineoplastic agents. No therapeutic interventions, rectal examinations or endoscopic procedures for prostate cancer were made immediately before or during the study. Urinary drainage was satisfactory in all men. Blood (10 ml.) was obtained from each man for serum prostate specific antigen determinations every 4 hours for a 24-hour interval, beginning at 8 a.m. during the hospitalization.
Serum prostate specific antigen levels were determined by a solid phase, 2-site, immunoradiometric assay with commercially available reagents.* A whole blood specimen was obtained by standard medical technique. The blood was allowed to clot and the serum was separated by centrifugation. Serum samples were stored with appropriate refrigeration before assay determination. Serum prostate specific antigen concentration was measured by reacting the blood specimen with mouse monoclonal lgG (against prostate specific antigen) coated on plastic beads in a buffer containing 0.1 per cent sodium azide as a preservative (anti-prostate specific antigen coated bead), 50 µl. human serum containing no detectable (Ong. prostate specific antigen per ml.) concentration of prostate specific antigen and 0.1 per cent sodium azide as a preservative (zero diluent per calibrator), and 200 µl. mouse monoclonal lgG (against prostate specific antigen) labeled with 125iodine in a protein matrix containing less than 10 µCi. per vial, a blue dye and 0.1 per cent sodium azide as a preservative (anti-prostate specific antigen tracer antibody). The specimen then was incubated for 2 hours at room temperature using a horizontal rotator set at 170 revolutions per minute. After the formation of a solid phase/ prostate specific antigen/labeled antibody sandwich, the bead was washed to remove unbound labeled antibody. Radioactivity bound to the solid phase was measured in a gamma counter. The amount of radioactivity measured is directly proportional to the concentration of prostate specific antigen in the test sample, which is determined from the standard curve. The normal range of prostate specific antigen in our laboratory is O to 4.0 ng./ml. Low and high prostate specific antigen controls were run concurrently during this study for quality control. The coefficient of variation with a high control was 4.39 per cent and for the low control it was 11.44 per cent. RESULTS
The values of serum prostate specific antigen for each man are shown in table 1 according to the time when the specimen was obtained. There appeared to be no diurnal, circadian or otherwise predictable fluctuation in serial prostate specific antigen levels determined by the solid phase, 2-site, immunoradiometric assay during a 24-hour interval. The values of * Hybritech, Inc., San Diego, California.
Accepted for publication December 14, 1988. 1378
1379
ROLE OF PROSTATE SPECIFIC ANTIGEN AS TUMOR MARKER
serum prostate specific antigen, determined from a control sample measured repeatedly biweekly during the study interval, ranged from 37.3 to 41.36 ng,/mL, with a mean of 39.90 for the high control and 2.6 to 3.81 ng./ml., with a mean of 3.04 for the low control. The mean, range, variance, standard deviation and coefficient of variation for each of the 8 patients are listed in table 2. The coefficient of variation is the ratio of the standard deviation divided by the mean, usually expressed as a percentage, and it is a method of comparing the variability within groups of data with different mean values. A large coefficient of variation indicates increased variability within that group of data. The coefficient of variation for the 8 patients ranged from 1.16 to 10.94 per cent. For each patient the coefficient of variation was not statistically different from the coefficient of variation of the control samples. The maximum percentage deviation above and below the mean in this series was 19.3 per cent (patient 5) and 17.7 per cent (patient 7), respectively, while the average percentage variation ranged from 2.3 to 7.6 per cent above the mean and 2.3 to 7.6 per cent below the mean (table 3). DISCUSSION
The inability to quantitate accurately the extent and progression of disease is a major limitation in the evaluation and treatment of men with advanced cancer of the prostate. Prostate cancer typically metastasizes to the regional lymph nodes and bone. Current clinical modalities used to monitor this spread, including bone scan, and acid and alkaline phosphatase determinations, offer a crude estimate of activity at best. Prostatic acid phosphatase measured by a sensitive radioimmunoassay has been shown to fluctuate as high as 79 per cent above and 50 per cent below the mean value when serial levels are obtained every 4 hours during a 48-hour period in men with documented stage D adenocarcinoma of the prostate. 8 Because of this marked random fluctuation, the use of prostatic acid phosphatase determined by radioimmunoassay as a clinical tumor marker is limited by the number of serial evaluations
needed to establish a mean by which to compare subsequent increases or decreases in serum prostatic acid phosphatase in the course of the disease. It has been suggested that the most useful marker in prostate cancer is prostate specific antigen.4· 7 , 9 To use prostate specific antigen logically as a tumor marker in men with prostate cancer, it is important to determine the amount of normal fluctuation in prostate specific antigen unrelated to therapy or disease progression and if a diurnal, circadian or otherwise predictable fluctuation exists in serum prostate specific antigen levels. In this series the maximum fluctuation of prostate specific antigen was 19.3 per cent greater than and 17. 7 per cent less than the mean. More importantly, the average percentage variation for all patients was within 7.6 per cent above and below the mean. It appears that the random fluctuation of prostate specific antigen obtained serially in men with advanced prostate cancer is less than that seen in prostatic acid phosphatase obtained serially in such men. In addition, there appeared to be no diurnal or circadian fluctuation in serum prostate specific antigen levels. A random fluctuation of prostate specific antigen was observed but this amount of fluctuation was well within the expected fluctuation of the test, since the coefficients of variation of the patient samples were not significantly different than the coefficients of variation of the control samples. For these reasons, it appears that prostate specific antigen is a reliable tumor marker to monitor prostate cancer. Therefore, several guidelines for the use of prostate specific antigen as a tumor marker in men with prostate cancer are suggested. A favorable response to therapy is indicated when serum prostate specific antigen returns to normal. A persistent decrease by 10 per cent or more from the mean value of prostate specific antigen levels determined serially suggests a favorable response to therapy. A persistent increase by 10 per cent or greater from the mean values suggests progression of disease.
Percentage deviation above and below mean of serum prostate specific antigen measured by a solid phase, 2-site, immunoradiometric assay
TABLE 3. TABLE
Pt. No. 1 2 3 4
5 6 7 8
L Individual serum prostate specific antigen levels for each patient according to the time of sample measurement Time 8A.M.
12 P.M.
4P.M.
8P.M.
12 A.M.
4A.M.
1,025 697 3,149 3,7 139 37,3 409 91.3
981 697 3,368 3.6 167 37,9 321 83,5
949 759 3,616
1,037 685 3,476 4,2 131 38,2 392 99,3
1,038 705 3,221 3,6 143 36.8 389 88.4
994
4,4
142 43,9 452 96.9
2 3 4 5 6 7
1,004.0 709,17 3,355,0 3,92 140.0 39,03 390.17 90,65
8
Vaiues are given in µg./1. (ng./ml.).
TABLE
Mean
712
3,300 4.0 118 40.1 378 84,5
Maximum Deviation(%)
Pt. No.
Av. Deviation ( % )
Above Mean
Below Mean
Above Mean
Below Mean
3.3 7.0 3,6 12,2 19.3 12.5 15,9 9.5
5,5 3.4 6,0
2,9 2,3 3,9 7,1 7,6 7,6 7,1 5.7
2.9 2.3 3.9 7,3 7,6 3,8 7,0 5.7
8.2
15.7 5,7 17,7 7,9
2. Mean, range, variance, standard deviation and coefficient of variation for each patient and control sample Mean Values (range)*
Difference Between High and Low Value*
1,004.0 (994-1,037) 709.17 (685-759) 3,355.0 (3,149-3,616) 3,92 (3,6-4.4) 140.0 (118-167) 39,03 (36.8-43,9) 390.17 (321-452) 90.65 (83,5-99.3)
43 74 467 0,8 49 7,1 131 15.8
Pt. No. 1 2 3 4
5 6 7 8 Control Sample: High Low
39.90 (37.3-43.12) 3,04 (2.6-3,81)
5,82 1.21
Variance*
Standard Deviation*
Coefficient of Variation (%)t
1,268 677.77 29,269.60 0,114 261.60 6,96 1,822.97 41.66
35,61 26.03 171.08 0.34 16.17 2.64 42.70 6.45
3.55 3.67 5.10 8.60 1.16 6,76 10.94 7.12
1.75 0,35
4.39 11.44
3.07 0.12
* Values are given in µg,/1. (ng,/ml.).
t For each patient the coefficient of variation was not statistically different than the
coefficient of variation for the control samples.
1380
MAATMAN REFERENCES
1. Seamonds, B., Yang, N., Anderson, K., Whitaker, B., Shaw, L. M. and Bollinger, J. R.: Evaluation of prostate-specific antigen and prostatic acid phosphatase as cancer markers. Urology, 28: 472, 1986. 2. Allhoff, E. P., Proppe, K. H., Chapman, C. M., Lin, C.-W. and Prout, G. R., Jr.: Evaluation of prostate specific acid phosphatase and prostate specific antigen in identification ofprostatic cancer. J. Urol., 129: 315, 1983. 3. Kuriyama, M., Wang, M. C., Papsidero, L. D., Killian, C. S., Shimano, T., Valenzuela, L., Nishiura, T., Murphy, G. P. and Chu, T. M.: Quantitation of prostate-specific antigen in serum by a sensitive enzyme immunoassay. Cancer Res., 40: 4658, 1980. 4. Stamey, T. A., Yang, N., Hay, A. R., McNeal, J.E., Freiha, F. S. and Redwine, E.: Prostate-specific antigen as a serum marker for adenocarcinoma of the prostate. New Engl. J. Med., 317: 909, 1987. 5. Killian, C. S., Yang, N., Emrich, L. J., Vargas, F. P., Kuriyama, M., Wang, M. C., Slack, N. H., Papsidero, L. D., Murphy, G. P. and Chu, T. M.: Prognostic importance of prostate-specific antigen for monitoring patients with stages B2 to D prostate cancer. Cancer Res., 45: 886, 1985. 6. Guinan, P., Bhatti, R. and Ray, P.: An evaluation of prostate specific antigen in prostatic cancer. J. Urol., 137: 686, 1987. 7. Ahmann, F. R. and Shifman, R. B.: Prospective comparison between serum monoclonal prostate specific antigen and acid phosphatase measurements in metastatic prostatic cancer. J. Urol., 137: 431, 1987. 8. Maatman, T. J., Gupta, M. K. and Montie, J.E.: The role of serum prostatic acid phosphatase as a tumor marker in men with advanced adenocarcinoma of the prostate. J. Urol., 132: 58, 1984. 9. Wang, M. C., Valenzuela, L.A., Murphy, G. P. and Chu, T. M.: Purification of a human prostate specific antigen. Invest. Urol., 17: 159, 1979.
EDITORIAL COMMENT Serum determinations of prostate specific antigen have become indispensable to monitor patients especially after initial therapies. Therefore, it is important to understand the fluctuations in prostate specific antigen values that might occur for reasons other than cancer. The author found that in 8 patients with stage D2 disease daily fluctuations above and below the mean were 7.6 per cent with a maximum of 19.3 per cent above and 17.9 per cent below. Since these fluctuations showed no pattern and were within the expected fluctuations of the assay on test sera the author concludes that a variation in
prostate specific antigen of more than 10 per cent is clinically significant. We do not believe these findings are the last word and we believe that the incorporation of a greater than 10 per cent value into formalized response criteria is premature if not inaccurate. Fluctuations in prostate specific antigen values for reasons other than cancer could be due to assay inaccuracies (inter-assay and intraassay) and/or to physiological causes. Assay variability can be expressed as the coefficient of variation. In several reports of prostate specific antigen assays the coefficient of variation has ranged from 1 to 8 per cent. 1• 2 What is important is that the lowest mean value prostate specific antigen level used for the calculation of coefficient of variation was 3.9. Our observations indicate that at lower levels (less than 2 ng./ml.) the coefficient of variation is significantly greater. 3 Physiological fluctuations in prostatic acid phosphatase certainly occur (as much as 50 per cent at high levels). Others have observed that prostate specific antigen levels fluctuate for physiological reasons as well4 but only by 6.2 per cent from the mean. However, this topic requires further investigation. For example, only 18 patients with stage D2 disease have been studied to date. More data, especially involving other clinical stages, may yield different results. Also, more studies are required on the fluctuations that might occur in prostate specific antigen levels that are observed in patients after radical prostatectomy (for example less than 1 ng./ml.). Finally, Stamey and associates suggested that prostate specific antigen values can vary considerably depending on whether the patient is active or sedentary (reference 4 in article). Nonetheless, the data in this study will bring us closer to the inevitable, that is serial prostate specific antigen levels will be developed into quantifiable response criteria that will improve and expedite future clinical studies in prostate cancer. Paul H. Lange and Michael Brawer Department of Urologic Surgery University of Washington School of Medicine Seattle, Washington 1. Chan, D. W., Bruzek, D. J., Oesterling, J. E., Rock, R. C. and Walsh, P. C.: Prostate-specific antigen as a marker for prostatic cancer: a monoclonal and polyclonal immunoassay compared. Clin. Chem., 33: 1916, 1987. 2. Hortin, G. L., Bahnson, R. R., Daft, M., Chan, K. M., Catalona, W. J. and Ladenson, J. H.: Differences in values obtained with 2 assays of prostate specific antigen. J. Urol., 139: 762, 1988. 3. Lange, P. H., Ercole, C. J., Lightner, D. J., Fraley, E. E. and Vessella, R.: The value of serum prostate specific antigen determinations before and after radical prostatectomy. J. Urol., 141: 000, 1989. 4. Schifman, R. B., Ahmann, F. R., Elvick, A., Ahmann, M., Coulis, K. and Brawer, M. K.: Analytical and physiological characteristics of prostate-specific antigen and prostatic acid phosphatase in serum compared. Clin. Chem., 33: 2086, 1987.