EDITORIAL
Serum Prostate-Specific Antigen: The Most Useful Tumor Marker
PROSTATE-SPECIFIC antigenand(PSA) is a serine protease that is functionally immunologically
distinct from prostatic acid phosphatase. 1 The exact physiologic role of PSA is not certain, but it seems to have protease activity for certain seminal vesical proteins and is thought to have a role in the liquefaction of the seminal coagulum. In contrast to prostatic acid phosphatase, PSA is found only in the prostate within the epithelial cells of the acini and ducts. The mechanism by which PSA enters the serum in men with normal prostates, benign prostatic hyperplasia, or prostate cancer is unknown. Extensive clinical evaluation, such as the report by Ritter et a12 in this issue of the Journal of ClinicalOncology, suggests that serum PSA is one of the most useful tumor markers in oncology. Serum PSA provides the clinician with unique and important information about the diagnosing, staging, and monitoring of patients with prostate cancer. The optimal use of serum PSA in the diagnosis of prostate cancer is emerging. Initially, PSA was considered to have limited use as a diagnostic tool. It was reasoned that although the majority of men (70% to 95%) with prostate cancer have elevated serum PSA levels, a considerable proportion of men with benign prostatic hyperplasia (BPH) (20% to 60%) also have elevated serum levels.3 -5 Because the prevalence of BPH exceeds that of prostate cancer, an elevated serum PSA level in an individual patient was judged to have a low specificity (ie, an unacceptably high false-positive rate) as a diagnostic test for prostate cancer. However, recent studies have led to a new understanding of the role of serum PSA as a diagnostic test for prostate cancer. Studies of patients who were referred for urologic evaluation of prostatic symptoms or an abnormal-feeling prostate have shown that serum PSA is the single most important predictor of prostate cancer compared with other diagnostic tests, which include digital rectal examination, age, and transrectal ultrasound.6 ,7 A representative study of symptomatic patients was reported by Cooner et al in 1990.6 In that study, almost 2,000 men older than 50 years of age underwent serum PSA, digital rectal examination, and transrectal ultrasound biopsy of the prostate. Approximately one third of patients with a suspicious digital rectal examination or an elevated serum PSA level had prostate cancer. When patients had abnormalities of both tests, more than 60% had prostate cancer. If both tests were normal, only 2% had prostate cancer. Digital rectal examination detected 70% of the cancers, whereas serum PSA detected 80%.
Overall, 16% of cancer patients had elevated serum PSA as their sole diagnostic abnormality. Studies such as this demonstrate that in the clinical evaluation of symptomatic patients, digital rectal examination can no longer be considered the gold standard for the detection of prostate cancer because serum PSA provides unique information for a significant proportion of men with cancer. Because of the demonstrated importance of serum PSA in the diagnosis of prostate cancer among symptomatic men, PSA has been investigated as a screening tool for prostate cancer. 7 Leaving aside the debate on the pros and cons of screening for prostate cancer, PSA seems to be preferable to digital rectal examination or ultrasonography as the primary means of screening for prostate cancer. PSA testing is better accepted by patients than either rectal examination or ultrasonography, and is an objective, quantitative test. PSA testing is independent of the examiner's skill; therefore, it is not necessary to spend physician time when large numbers of men are screened. Lastly, screening by the other modalities has been shown to be ineffective; digital rectal examination-based screening has a low cancer detection rate (only 1% to 2%). Many (30% to 50%) of the cancers are advanced clinically at the time of detection. Ultrasound-based screening has many disadvantages, which include cost, discomfort, and an unacceptably high false-positive rate (up to 70%). Based on these considerations, a PSA-based screening program was instituted at Washington University in 1989.7 Evaluation of more than 16,000 men with serum PSA values alone or with serum PSA and digital rectal examination has shown that fewer than 10% of ambulatory volunteers older than 50 years of age have elevated serum PSA values. Twenty-five percent of volunteers whose serum PSA is between 4 and 10 ng/mL have prostate cancer, and if the serum PSA is more than 10 ng/mL, almost 60% have cancer. By using only serum PSA as a screening test, the overall cancer detection rate (on the first screen) is 3%; approximately 8% of volunteers underwent biopsy. If digital rectal examination is added to serum PSA testing, the cancer detection rate increases to almost 5% but at the expense of added biopsies (approximately 20% of volunteers). When PSA and digital rectal examination are compared in the screening setting, approximately one half of men with both an elevated PSA and a suspicious digital rectal examination have cancer. Approximately 20% with an elevated PSA alone and 10% with a suspicious digital rectal examination alone have prostate cancer. These
Journalof Clinical Oncology, Vol 10, No 8 (August), 1992: pp 1205-1207
Downloaded from ascopubs.org by University of Newcastle Upon Tyne on April 7, 2019 from 128.240.208.034 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
1205
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GERALD L. ANDRIOLE
studies confirm that serum PSA is a more powerful diagnostic tool than digital rectal examination, but also that both tests are important means of detecting cancer. More than 90% of cancers that are detected by PSA-based screening are localized clinically, and approximately 65% are organ-confined pathologically. Thus, the proportion of pathologically organ-confined prostate cancer detected by PSA-based screening is twice that when traditional diagnostic approaches are used (ie, if prostatic biopsy is performed only, if the digital rectal examination is suspicious, or if prostatic symptoms are present). The highest proportion of pathologically organconfined prostate cancer may be detected in patients who are evaluated with serial PSA values. In the short-term follow-up of our studies, 1.7% of volunteers had cancer detected on the basis of an elevated serial PSA value. Individuals whose initial PSA values were normal but whose subsequent (ie, serial) serum PSA was elevated have prostate cancer that was pathologically organ-confined nearly three quarters of the time. Thus, serial monitoring of PSA is an extremely important means of detecting pathologically organ-confined prostate cancer. Very few of the tumors detected by PSA-based screening are considered incidental (ie, latent) cancers because the majority have a high volume and/or have a high Gleason score (> 4). Based on the 30% autopsy prevalence of prostate cancer in men older than 50 years of age, the 3% to 5% detection rate of PSA-based screening suggests that only one in seven to 10 of the cancers actually present are being detected. It is most probable that the largest, most clinically significant tumors are being diagnosed. However, further studies that demonstrate a screening-induced decrease in cancerspecific mortality are necessary to confirm that screening for prostate cancer is beneficial. Generally, serum PSA levels increase with advancing clinical and pathologic stages of prostate cancer and are directly related to the volume of prostate cancer. However, there is considerable overlap of serum PSA levels among individual patients with different stages of prostate cancer. This overlap makes it difficult to use serum PSA levels to predict the final pathologic stage of an individual with prostate cancer. No level of serum PSA reliably differentiates between pathologically organconfined or advanced disease, but pretreatment PSA values may provide a rough guide. Bone and lymph node metastases are rare if PSA is less than 20 ng/mL, and advanced disease is uncommon if PSA is less than 4.8 Serum PSA is unsurpassed as a tool to monitor patients after primary therapy for prostate cancer. This is especially true after radical prostatectomy. If surgery
has removed the entire prostate and all prostate cancer cells, the postoperative serum PSA value should be undetectable. Several studies9-11 have demonstrated that a high proportion (approximately 90%) of men who undergo radical prostatectomy for pathologically organconfined tumor have undetectable postoperative serum PSA levels. However, patients with microscopically advanced disease (ie, microscopic capsular penetration, positive urethral or bladder neck margins, or seminal vesical invasion or lymph node metastases) have progressively higher probabilities of ultimately having detectable postoperative serum PSA values (20% to 30% for capsular perforation or positive margins, 50% to 70% for seminal vesical invasion, and 80% for positive lymph nodes). A detectable postoperative serum PSA value after radical prostatectomy almost uniformly implies persistence of tumor, although the occasional patient may have had a technically inadequate operation, and small amounts of residual prostate tissue may have been left behind. It currently seems that the majority of patients who are destined to have detectable postoperative serum PSA levels develop them within the first 2 years after surgery. The interpretation of serum PSA values after definitive radiation therapy for clinically localized prostate cancer is more problematic. Posttreatment serum PSA usually remains measurable because of residual normal prostate or possibly because of inadequately treated prostate cancer. The elegant study by Ritter et a12 demonstrates the usefulness of serum PSA in monitoring patients after radiation. In their study of 41 patients who had no evidence of treatment failure after radiation therapy, more than half had a normal PSA value within 2 months and 90% had normal PSA values at 18 months. On the other hand, of the 22 failing patients, only nine achieved normal posttreatment PSA values. Every patient with a posttreatment increase in serum PSA has manifested clinical evidence of failure, either distant disease (within 4 to 5 months of the PSA increase) or local recurrence (usually within 7 months). The adverse implication of an increasing postradiation serum PSA was also demonstrated by Kabalin et a112 who showed that greater than 90% of such patients had positive prostatic biopsy results more than 18 months after radiation therapy even if the digital rectal examination was unchanged and the serum PSA was normal. Longer follow-up of radiation-treated patients with serum PSA will determine the exact ability of this modality to control organ-confined prostate cancer. Hormonal therapy remains the mainstay of treatment for patients with stage D 2 (bone metastatic) prostate cancer. More than 98% of patients with stage D2
Downloaded from ascopubs.org by University of Newcastle Upon Tyne on April 7, 2019 from 128.240.208.034 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
EDITORIAL
1207
prostate cancer have elevated serum PSA values. The rate of decrease of serum PSA after hormone therapy may be predictive of outcome; patients whose serum PSA drops more than 80% within 1 month have significantly longer progression-free survival compared with those with lesser declines in PSA.' 3 Others have demonstrated that normalization of PSA levels within 6 months is also favorable.14 Patients whose serum PSA values increase after hormonal therapy uniformly manifest some clinically detectable evidence of failure often within 12 months. It is important to consider that the expression of serum PSA may be under endocrine control and that some hormonally treated patients with normal PSA values may have clinically active disease.13 Therefore, a normal serum PSA level in a hormonally treated patient should not give the clinician a false sense of security.
One additional caveat when interpreting serum PSA values in men with prostate cancer pertains to neuroendocrine tumors of the prostate (ie, small-cell carcinomas). Characteristically, these tumors do not produce PSA, and patients may have advancing cancer with normal or unchanging serum PSA. In summary, PSA is emerging as the most clinically useful tumor marker in oncology. Its application to diagnosing, staging, and monitoring of prostate cancer has revolutionized the care of men with this common disease. It seems probable that as more is learned about serum PSA, its role in managing men with prostate cancer will continue to expand. Gerald L. Andriole Washington University School of Medicine St Louis, MO
REFERENCES 1. Wang MC, Valenzulela LA, Murphy GP, et al: Purification of a human prostate specific antigen. Invest Urol 17:159-163, 1979 2. Ritter MA, Messing EM, Shanahan TG, et al: Prostatespecific antigen as a predictor of radiotherapy response and patterns of failure in localized prostate cancer. J Clin Oncol 10:1208-1217, 1992 3. Stamey TA, Yang N, Hay AR, et al: Prostate specific antigen as a serum marker for adenocarcinoma of the prostate. N Eng J Med 317:909-916, 1987 4. Ercole CJ, Lange PH, Mathisen M, et al: Prostate specific antigen and prostatic acid phosphatase in the monitoring and staging of patients with prostate cancer. J Urol 138:1181-1184, 1987 5. Hudson MA, Bahnson RR, Catalona WJ: Clinical use of prostate specific antigen in patients with prostate cancer. J Urol 142:1011-1017, 1989 6. Cooner WH, Mosley BR, Rutherford CL, Jr, et al: Prostate cancer detection in a clinical urological practice by ultrasonography, digital rectal examination and prostate specific antigen. J Urol 143:1146-1152, 1990 7. Catalona WJ, Smith DS, Ratliff TL, et al: Measurement of prostate specific antigen in serum as a screening test for prostate cancer. N Eng J Med 324:1156-1161, 1991 8. Chybowski FM, Larson Keller JJ, Bergstralh EJ, et al: Predicting radionuclide bone scan findings in patients with newly
diagnosed, untreated prostate cancer: Prostate specific antigen is superior to all other clinical parameters. J Urol 145:313-318, 1991 9. Stamey TA, Kabalin JN, McNeal JE, et al: Prostate specific antigen in the diagnosis and treatment of adenocarcinoma of the prostate. II. Radical prostatectomy treated patients. J Urol 141: 1076-1083, 1989 10. Lange PH, Ercole CJ, Lightner DJ, et al: The value of serum prostate specific antigen determinations before and after radical prostatectomy. J Urol 141:873-879, 1989 11. Stein A, deKernion JB, Smith RB, et al: Prostate specific antigen levels after radical prostatectomy in patients with organ confined or locally extensive prostate cancer. J Urol 147:942-946, 1992 12. Kabalin JN, Hodge KK, McNeal JE, et al: Identification of residual cancer in the prostate following radiation therapy: Role of transrectal ultrasound guided biopsy and prostate specific antigen. J Urol 142:326-331, 1989 13. Leo ME, Bilhartz DL, Bergstralh EJ, et al: Prostate specific antigen in hormonally treated stage D2 prostate cancer: Is it always an accurate indicator of disease status? J Urol 145:802-806, 1991 14. Miller JI, Ahmann FR, Drach GW, et al: Clinical usefulness of serum prostate specific antigen after hormonal therapy in metastatic prostate cancer. J Urol 147:956-961, 1992
Downloaded from ascopubs.org by University of Newcastle Upon Tyne on April 7, 2019 from 128.240.208.034 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
Serum Prostate-Specific Antigen: The Most Useful Tumor Marker
PROSTATE-SPECIFIC antigenand(PSA) is a serine protease that is functionally immunologically
distinct from prostatic acid phosphatase. 1 The exact physiologic role of PSA is not certain, but it seems to have protease activity for certain seminal vesical proteins and is thought to have a role in the liquefaction of the seminal coagulum. In contrast to prostatic acid phosphatase, PSA is found only in the prostate within the epithelial cells of the acini and ducts. The mechanism by which PSA enters the serum in men with normal prostates, benign prostatic hyperplasia, or prostate cancer is unknown. Extensive clinical evaluation, such as the report by Ritter et a12 in this issue of the Journal of ClinicalOncology, suggests that serum PSA is one of the most useful tumor markers in oncology. Serum PSA provides the clinician with unique and important information about the diagnosing, staging, and monitoring of patients with prostate cancer. The optimal use of serum PSA in the diagnosis of prostate cancer is emerging. Initially, PSA was considered to have limited use as a diagnostic tool. It was reasoned that although the majority of men (70% to 95%) with prostate cancer have elevated serum PSA levels, a considerable proportion of men with benign prostatic hyperplasia (BPH) (20% to 60%) also have elevated serum levels.3 -5 Because the prevalence of BPH exceeds that of prostate cancer, an elevated serum PSA level in an individual patient was judged to have a low specificity (ie, an unacceptably high false-positive rate) as a diagnostic test for prostate cancer. However, recent studies have led to a new understanding of the role of serum PSA as a diagnostic test for prostate cancer. Studies of patients who were referred for urologic evaluation of prostatic symptoms or an abnormal-feeling prostate have shown that serum PSA is the single most important predictor of prostate cancer compared with other diagnostic tests, which include digital rectal examination, age, and transrectal ultrasound.6 ,7 A representative study of symptomatic patients was reported by Cooner et al in 1990.6 In that study, almost 2,000 men older than 50 years of age underwent serum PSA, digital rectal examination, and transrectal ultrasound biopsy of the prostate. Approximately one third of patients with a suspicious digital rectal examination or an elevated serum PSA level had prostate cancer. When patients had abnormalities of both tests, more than 60% had prostate cancer. If both tests were normal, only 2% had prostate cancer. Digital rectal examination detected 70% of the cancers, whereas serum PSA detected 80%.
Overall, 16% of cancer patients had elevated serum PSA as their sole diagnostic abnormality. Studies such as this demonstrate that in the clinical evaluation of symptomatic patients, digital rectal examination can no longer be considered the gold standard for the detection of prostate cancer because serum PSA provides unique information for a significant proportion of men with cancer. Because of the demonstrated importance of serum PSA in the diagnosis of prostate cancer among symptomatic men, PSA has been investigated as a screening tool for prostate cancer. 7 Leaving aside the debate on the pros and cons of screening for prostate cancer, PSA seems to be preferable to digital rectal examination or ultrasonography as the primary means of screening for prostate cancer. PSA testing is better accepted by patients than either rectal examination or ultrasonography, and is an objective, quantitative test. PSA testing is independent of the examiner's skill; therefore, it is not necessary to spend physician time when large numbers of men are screened. Lastly, screening by the other modalities has been shown to be ineffective; digital rectal examination-based screening has a low cancer detection rate (only 1% to 2%). Many (30% to 50%) of the cancers are advanced clinically at the time of detection. Ultrasound-based screening has many disadvantages, which include cost, discomfort, and an unacceptably high false-positive rate (up to 70%). Based on these considerations, a PSA-based screening program was instituted at Washington University in 1989.7 Evaluation of more than 16,000 men with serum PSA values alone or with serum PSA and digital rectal examination has shown that fewer than 10% of ambulatory volunteers older than 50 years of age have elevated serum PSA values. Twenty-five percent of volunteers whose serum PSA is between 4 and 10 ng/mL have prostate cancer, and if the serum PSA is more than 10 ng/mL, almost 60% have cancer. By using only serum PSA as a screening test, the overall cancer detection rate (on the first screen) is 3%; approximately 8% of volunteers underwent biopsy. If digital rectal examination is added to serum PSA testing, the cancer detection rate increases to almost 5% but at the expense of added biopsies (approximately 20% of volunteers). When PSA and digital rectal examination are compared in the screening setting, approximately one half of men with both an elevated PSA and a suspicious digital rectal examination have cancer. Approximately 20% with an elevated PSA alone and 10% with a suspicious digital rectal examination alone have prostate cancer. These
Journalof Clinical Oncology, Vol 10, No 8 (August), 1992: pp 1205-1207
Downloaded from ascopubs.org by University of Newcastle Upon Tyne on April 7, 2019 from 128.240.208.034 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
1205
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GERALD L. ANDRIOLE
studies confirm that serum PSA is a more powerful diagnostic tool than digital rectal examination, but also that both tests are important means of detecting cancer. More than 90% of cancers that are detected by PSA-based screening are localized clinically, and approximately 65% are organ-confined pathologically. Thus, the proportion of pathologically organ-confined prostate cancer detected by PSA-based screening is twice that when traditional diagnostic approaches are used (ie, if prostatic biopsy is performed only, if the digital rectal examination is suspicious, or if prostatic symptoms are present). The highest proportion of pathologically organconfined prostate cancer may be detected in patients who are evaluated with serial PSA values. In the short-term follow-up of our studies, 1.7% of volunteers had cancer detected on the basis of an elevated serial PSA value. Individuals whose initial PSA values were normal but whose subsequent (ie, serial) serum PSA was elevated have prostate cancer that was pathologically organ-confined nearly three quarters of the time. Thus, serial monitoring of PSA is an extremely important means of detecting pathologically organ-confined prostate cancer. Very few of the tumors detected by PSA-based screening are considered incidental (ie, latent) cancers because the majority have a high volume and/or have a high Gleason score (> 4). Based on the 30% autopsy prevalence of prostate cancer in men older than 50 years of age, the 3% to 5% detection rate of PSA-based screening suggests that only one in seven to 10 of the cancers actually present are being detected. It is most probable that the largest, most clinically significant tumors are being diagnosed. However, further studies that demonstrate a screening-induced decrease in cancerspecific mortality are necessary to confirm that screening for prostate cancer is beneficial. Generally, serum PSA levels increase with advancing clinical and pathologic stages of prostate cancer and are directly related to the volume of prostate cancer. However, there is considerable overlap of serum PSA levels among individual patients with different stages of prostate cancer. This overlap makes it difficult to use serum PSA levels to predict the final pathologic stage of an individual with prostate cancer. No level of serum PSA reliably differentiates between pathologically organconfined or advanced disease, but pretreatment PSA values may provide a rough guide. Bone and lymph node metastases are rare if PSA is less than 20 ng/mL, and advanced disease is uncommon if PSA is less than 4.8 Serum PSA is unsurpassed as a tool to monitor patients after primary therapy for prostate cancer. This is especially true after radical prostatectomy. If surgery
has removed the entire prostate and all prostate cancer cells, the postoperative serum PSA value should be undetectable. Several studies9-11 have demonstrated that a high proportion (approximately 90%) of men who undergo radical prostatectomy for pathologically organconfined tumor have undetectable postoperative serum PSA levels. However, patients with microscopically advanced disease (ie, microscopic capsular penetration, positive urethral or bladder neck margins, or seminal vesical invasion or lymph node metastases) have progressively higher probabilities of ultimately having detectable postoperative serum PSA values (20% to 30% for capsular perforation or positive margins, 50% to 70% for seminal vesical invasion, and 80% for positive lymph nodes). A detectable postoperative serum PSA value after radical prostatectomy almost uniformly implies persistence of tumor, although the occasional patient may have had a technically inadequate operation, and small amounts of residual prostate tissue may have been left behind. It currently seems that the majority of patients who are destined to have detectable postoperative serum PSA levels develop them within the first 2 years after surgery. The interpretation of serum PSA values after definitive radiation therapy for clinically localized prostate cancer is more problematic. Posttreatment serum PSA usually remains measurable because of residual normal prostate or possibly because of inadequately treated prostate cancer. The elegant study by Ritter et a12 demonstrates the usefulness of serum PSA in monitoring patients after radiation. In their study of 41 patients who had no evidence of treatment failure after radiation therapy, more than half had a normal PSA value within 2 months and 90% had normal PSA values at 18 months. On the other hand, of the 22 failing patients, only nine achieved normal posttreatment PSA values. Every patient with a posttreatment increase in serum PSA has manifested clinical evidence of failure, either distant disease (within 4 to 5 months of the PSA increase) or local recurrence (usually within 7 months). The adverse implication of an increasing postradiation serum PSA was also demonstrated by Kabalin et a112 who showed that greater than 90% of such patients had positive prostatic biopsy results more than 18 months after radiation therapy even if the digital rectal examination was unchanged and the serum PSA was normal. Longer follow-up of radiation-treated patients with serum PSA will determine the exact ability of this modality to control organ-confined prostate cancer. Hormonal therapy remains the mainstay of treatment for patients with stage D 2 (bone metastatic) prostate cancer. More than 98% of patients with stage D2
Downloaded from ascopubs.org by University of Newcastle Upon Tyne on April 7, 2019 from 128.240.208.034 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
EDITORIAL
1207
prostate cancer have elevated serum PSA values. The rate of decrease of serum PSA after hormone therapy may be predictive of outcome; patients whose serum PSA drops more than 80% within 1 month have significantly longer progression-free survival compared with those with lesser declines in PSA.' 3 Others have demonstrated that normalization of PSA levels within 6 months is also favorable.14 Patients whose serum PSA values increase after hormonal therapy uniformly manifest some clinically detectable evidence of failure often within 12 months. It is important to consider that the expression of serum PSA may be under endocrine control and that some hormonally treated patients with normal PSA values may have clinically active disease.13 Therefore, a normal serum PSA level in a hormonally treated patient should not give the clinician a false sense of security.
One additional caveat when interpreting serum PSA values in men with prostate cancer pertains to neuroendocrine tumors of the prostate (ie, small-cell carcinomas). Characteristically, these tumors do not produce PSA, and patients may have advancing cancer with normal or unchanging serum PSA. In summary, PSA is emerging as the most clinically useful tumor marker in oncology. Its application to diagnosing, staging, and monitoring of prostate cancer has revolutionized the care of men with this common disease. It seems probable that as more is learned about serum PSA, its role in managing men with prostate cancer will continue to expand. Gerald L. Andriole Washington University School of Medicine St Louis, MO
REFERENCES 1. Wang MC, Valenzulela LA, Murphy GP, et al: Purification of a human prostate specific antigen. Invest Urol 17:159-163, 1979 2. Ritter MA, Messing EM, Shanahan TG, et al: Prostatespecific antigen as a predictor of radiotherapy response and patterns of failure in localized prostate cancer. J Clin Oncol 10:1208-1217, 1992 3. Stamey TA, Yang N, Hay AR, et al: Prostate specific antigen as a serum marker for adenocarcinoma of the prostate. N Eng J Med 317:909-916, 1987 4. Ercole CJ, Lange PH, Mathisen M, et al: Prostate specific antigen and prostatic acid phosphatase in the monitoring and staging of patients with prostate cancer. J Urol 138:1181-1184, 1987 5. Hudson MA, Bahnson RR, Catalona WJ: Clinical use of prostate specific antigen in patients with prostate cancer. J Urol 142:1011-1017, 1989 6. Cooner WH, Mosley BR, Rutherford CL, Jr, et al: Prostate cancer detection in a clinical urological practice by ultrasonography, digital rectal examination and prostate specific antigen. J Urol 143:1146-1152, 1990 7. Catalona WJ, Smith DS, Ratliff TL, et al: Measurement of prostate specific antigen in serum as a screening test for prostate cancer. N Eng J Med 324:1156-1161, 1991 8. Chybowski FM, Larson Keller JJ, Bergstralh EJ, et al: Predicting radionuclide bone scan findings in patients with newly
diagnosed, untreated prostate cancer: Prostate specific antigen is superior to all other clinical parameters. J Urol 145:313-318, 1991 9. Stamey TA, Kabalin JN, McNeal JE, et al: Prostate specific antigen in the diagnosis and treatment of adenocarcinoma of the prostate. II. Radical prostatectomy treated patients. J Urol 141: 1076-1083, 1989 10. Lange PH, Ercole CJ, Lightner DJ, et al: The value of serum prostate specific antigen determinations before and after radical prostatectomy. J Urol 141:873-879, 1989 11. Stein A, deKernion JB, Smith RB, et al: Prostate specific antigen levels after radical prostatectomy in patients with organ confined or locally extensive prostate cancer. J Urol 147:942-946, 1992 12. Kabalin JN, Hodge KK, McNeal JE, et al: Identification of residual cancer in the prostate following radiation therapy: Role of transrectal ultrasound guided biopsy and prostate specific antigen. J Urol 142:326-331, 1989 13. Leo ME, Bilhartz DL, Bergstralh EJ, et al: Prostate specific antigen in hormonally treated stage D2 prostate cancer: Is it always an accurate indicator of disease status? J Urol 145:802-806, 1991 14. Miller JI, Ahmann FR, Drach GW, et al: Clinical usefulness of serum prostate specific antigen after hormonal therapy in metastatic prostate cancer. J Urol 147:956-961, 1992
Downloaded from ascopubs.org by University of Newcastle Upon Tyne on April 7, 2019 from 128.240.208.034 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
