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Journal of Clinical Oncology, Vol 20, Issue 15 (August), 2002: 3213-3218
© 2002 American Society for Clinical Oncology

Preoperative Combined Nested Reverse Transcriptase Polymerase Chain Reaction for Prostate-Specific Antigen and Prostate-Specific Membrane Antigen Does Not Correlate With Pathologic Stage or Biochemical Failure in Patients With Localized Prostate Cancer Undergoing Radical Prostatectomy

By John Thomas, Manjula Gupta, Ying Grasso, Chandana A. Reddy, Warren D. Heston, Craig Zippe, Robert Dreicer, Patrick A. Kupelian, Jennifer Brainard, Howard S. Levin, Eric A. Klein

From the Urological Institute, Taussig Cancer Center, Lerner Research Institute, and Departments of Clinical Pathology, Radiation Oncology, and Anatomic Pathology, Cleveland Clinic Foundation, Cleveland, OH.

Address reprint requests to Eric A. Klein, MD, Urological Institute, Desk A100, Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44195; email: kleine{at}ccf.org


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
PURPOSE: We report a prospective study examining the ability of preoperative nested reverse transcriptase polymerase chain reaction (RT-PCR) for prostate-specific antigen (PSA) and prostate-specific membrane antigen (PSM) to predict pathologic stage and biochemical recurrence in patients with clinically localized prostate cancer treated with radical prostatectomy.

PATIENTS AND METHODS: One hundred forty-one patients were entered onto the study. Preoperative evaluation included clinical T stage, serum PSA, biopsy Gleason score, and serum RT-PCR for PSA/PSM. Univariate and multivariate logistic regression models, Kaplan-Meier estimates, and Cox proportional hazards modeling were used to identify predictors of pathologic stage and biochemical failure.

RESULTS: Seventy-three patients (51.8%) were RT-PCR positive for PSA, PSM, or both. In the multivariate logistic regression model, only initial PSA was an independent predictor of pathologic stage as defined by organ-confined disease (odds ratio [OR], 1.06; 95% confidence interval [CI], 1.00 to 1.13; P = .026) or organ-/specimen-confined disease (OR, 1.09; 95% CI, 1.02 to 1.16; P = .009). Overall Kaplan-Meier biochemical relapse-free survival (bRFS) was 85% at 59 months. Multivariate analysis of predictors for bRFS with the Cox proportional hazards model indicated that only initial PSA (OR, 1.05; 95% CI, 1.02 to 1.09; P = .004) and biopsy Gleason score (OR, 3.57; 95% CI, 1.37 to 9.58; P = .009) were independent predictors of biochemical failure. RT-PCR status did not predict pathologic stage or biochemical failure. Repeat analysis excluding 27 patients who received preoperative androgen-deprivation therapy did not change the results.

CONCLUSION: Combined nested RT-PCR for PSA and PSM is not an independent predictor of pathologic stage or biochemical failure in patients with localized prostate cancer undergoing radical prostatectomy. This assay has no clinical utility in this patient population.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
PROCEEDING WITH curative treatment for localized prostate cancer is generally predicated on the presence of organ-confined disease as defined by pretreatment staging modalities. It is estimated that digital rectal examination, serum prostate-specific antigen (PSA), and histologic grading will understage 20% to 40% of patients at the time of radical prostatectomy.1 Standard imaging modalities, including bone and computed tomography scans, transrectal ultrasound, and endorectal magnetic resonance imaging, do not significantly improve on the accuracy of these parameters for gauging the local extent of the tumor.2 The search for a more reliable staging modality has included reverse transcriptase polymerase chain reaction (RT-PCR) for detecting potential micrometastases in the circulation of patients with prostate cancer. RT-PCR is a sensitive technique that has been shown to detect one cancer cell in 106 mononuclear cells expressing mRNA for either PSA or prostate-specific membrane antigen (PSM). RT-PCR for PSA and PSM has been shown to be both tumor and prostate specific.3

Recently, Kantoff et al4 have indicated that RT-PCR for PSA had independent prognostic value for men with hormone-refractory disease, with median survivals of 13 v 18 months, respectively, in those with positive versus negative assays in two independent cohorts treated with unrelated therapy. Assays to detect PSA, PSM, or both have been used in many studies of patients with earlier stages of disease.4-11 Katz et al5 described initial results with PSA RT-PCR as a preoperative staging study in 1994, suggesting a correlation with pathologic stage in patients with clinically localized disease. We previously reported our initially favorable results with a combined nested RT-PCR assay for PSA and PSM as a correlate with pathologic stage.12 In the current study, we investigated the potential role of preoperative nested RT-PCR for PSA and PSM to predict pathologic stage and biochemical recurrence in a larger cohort of patients with nearly 5 years of prospective follow-up after radical prostatectomy.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patient Selection
One hundred forty-one patients with clinically localized prostate cancer who underwent radical prostatectomy were studied. The patients were staged before surgery by digital rectal examination, serum PSA (Tosoh Medics, South San Francisco, CA), and nested serum RT-PCR for PSA and PSM. All biopsy specimens were reviewed at our institution by one of four genitourinary pathologists for confirmation of diagnosis and assignment of Gleason score (GS). All patients underwent a standardized radical retropubic prostatectomy. Pelvic lymphadenectomy was omitted in those patients with low-risk characteristics (PSA < 10 ng/mL, biopsy GS <= 6, and clinical stage T1c/T2a) because we have previously demonstrated that the risk of positive nodes in this population is less than 1% and that omission of pelvic lymph node dissection does not affect the rate of biochemical failure.13 After surgery, patients were evaluated at 6 weeks and every 6 months with serum PSA. Follow-up ranged from 3 to 59 months (median, 31 months). Biochemical failure was defined as PSA level of more than 0.2 ng/mL confirmed by repeat assay at least 1 week later. Time to biochemical failure was defined as the interval between the date of surgery and the initial increase in PSA. The study was approved by our institutional review board and the Clinical Trials Scientific Review Committee. Signed, informed consent was obtained from all patients.

Nested RT-PCR Analysis of PSA and PSM Expression
Methods as previously described in detail were used.14 Briefly, Ficoll gradient centrifugation was used to collect mononuclear cells from 6 mL of whole blood collected in EDTA. Total RNA was isolated by using Trizol reagent (Life Technologies, Inc, Gaithersburg, MD) by following the manufacturer’s instructions. Reverse transcription to synthesize cDNA was performed with 1 µg of total RNA by using the Superscript preamplification system (Life Technologies). The primers and reaction parameters for nested RT-PCR were chosen according to Israeli et al9 and Loric et al,15 respectively. PSA outer primers were PSA-494, 5'-TACCCACT-GCATCAGGAACA-3'; and PSA-960, 5'-CCTTGAAGCA-CACCATTACA-3'. PSA inner primers were PSA-559, 5'-ACACAGGCCAGGTAT-TTCAG-3'; and PSA-894, 5'-GTCCAGCGTCCAGCACAG-3'. PSM outer primers were PSM-764, 5'-GAATGCCAGAGGGCGATCTA-3'; and PSM-1182, 5'-TTCTAGGAGCTTCTGTGCATCA-TAGTATCC-3'. PSM inner primers were PSM-931, 5'-AGGGGCCAAAGGAGTCAT-TCTCT-ACTCCGA-3'; and PSM-1116, 5'-CTCTGCAATTCCACGCCTAT-3'. Twenty-five cycle reactions were performed for PCRs by using both outer and inner primers. The nested PCR product was 355 base pairs (bp) for PSA and 186 bp for PSM. Control PCR for human glyceraldehyde-3-phosphate dehydrogenase, which generated a 360-bp fragment, was performed on each sample according to Wainstein et al.16 Positive and negative controls were performed in all assays. Positive controls were performed as described previously using cDNA from LNCaP, a well-established prostate cancer line.12 Three kinds of negative controls were used: (1) a tube with no addition of cDNA to the PCR mixture; (2) DNA obtained from age-matched, healthy men and women; and (3) DNA obtained from men with a history of benign prostatic hyperplasia. RT-PCR positivity was never seen in any of the negative controls. Early in our experience all samples were assayed in duplicate, but because we observed a less than 5% discordance rate, duplicates were discontinued after the first 25% of patients were enrolled onto the study. PCR products were separated by agarose gel electrophoresis and visualized by ethidium bromide staining. Results were analyzed in a blinded fashion without knowledge of pathologic stage or disease status.

Pathologic Methods
Fresh radical prostatectomy specimens were fixed in formalin for 24 hours, inked in two colors (left and right halves), and step-sectioned at 3-mm intervals. Histologic analysis included the GS and the presence or absence of prostate cancer at the inked margin, extracapsular extension (ECE), seminal vesicle involvement, and lymph node metastasis. ECE was defined as prostate cancer in extraprostatic tissue, and positive margins were defined as tumor touching ink. Organ-confined disease was defined as the absence of ECE, negative surgical margins, and no involvement of the seminal vesicles or lymph nodes. Specimen-confined disease was defined as ECE with negative surgical margins and no involvement of the seminal vesicles or lymph nodes. All other cases were considered non–organ confined.

Statistical Analysis
RT-PCR status was initially divided into four groups: PSA positive only (PSA+), PSM positive only (PSM+), positive for both (PSA+PSM+), and negative for both (PSA-PSM-). Because of the small number of patients in the PSA+ and PSA+PSM+ groups, the groups were combined into two larger ones for analysis: positive for PSA, PSM, or both (PSA+, PSM+, or PSA+PSM+; n = 73) versus negative for both (PSA-PSM-; n = 68).

Logistic regression analysis was used to predict pathologic stage. The pathologic outcomes of interest were organ confined versus not (specimen confined or non–organ confined) and organ or specimen confined versus non–organ confined. The independent variables were initial PSA (iPSA, continuous), biopsy GS (<= 6 v >= 7), clinical T stage (T1c/T2a v T2bc/T3), and RT-PCR status (PSA-PSM- v PSA+, PSM+, or PSA+PSM+).

Kaplan-Meier estimates were used to analyze the biochemical relapse-free survival (bRFS) for the study population. The effect of iPSA, T stage, biopsy GS, and RT-PCR status on bRFS was examined. The log-rank test was used to assess differences between bRFS curves. Cox proportional hazards regression was used for the multivariate analysis. The stepwise forward procedure was used to develop the final model from multivariate analysis. Separate analyses were performed for all patients and for all patients excluding those who received preoperative androgen-deprivation therapy (n = 27).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patient Characteristics
All patients had clinically localized prostate cancer and were considered candidates for cure by radical prostatectomy. The median age was 61 years (range, 41 to 74 years). Detailed preoperative characteristics are listed in Table 1. Overall, 73 patients (51.8%) were PSA+, PSM+, or PSA+PSM+ by RT-PCR assay, whereas 16 (59.3%) of 27 who received preprostatectomy androgen deprivation were RT-PCR positive.


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  		Table 1. Preoperative Characteristics for the Entire Study Group (N = 141)
 
Correlation of Pretreatment Variables With Pathologic Stage
Observed pathologic outcomes are listed in Table 2. The majority of patients (51%) had organ-confined disease, whereas 16% were specimen confined and 33% were non–organ confined. Of the 72 patients with organ-confined disease, 44.4% were PSA+, PSM+, or PSA+PSM+.


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  		Table 2. Pathologic Characteristics for the Entire Study Group (N = 141)
 
Organ-Confined Disease
In univariate analysis, iPSA, biopsy GS, and T stage were significant predictors for organ-confined disease, with odds ratios ranging from 1.07 to 3.30 (Table 3). In multivariate analysis, only iPSA remained significant. RT-PCR status was not a significant predictor for organ-confined disease in either univariate or multivariate analysis (Table 3). Repeat analysis excluding patients who received preoperative androgen-deprivation therapy did not change the results (data not shown).


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  		Table 3. Logistic Regression Model for Organ-Confined Versus Non–Organ-Confined Disease
 
Organ- or Specimen-Confined Disease
In univariate analysis, iPSA and clinical T stage were significant predictors, with odds ratios of 1.08 and 3.22, respectively (Table 4). In multivariate analysis, only iPSA remained significant. Neither biopsy GS nor RT-PCR status was an independent predictor for this end point. Repeat analysis excluding patients who received preoperative androgen-deprivation therapy did not change the results (data not shown).


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  		Table 4. Logistic Regression Model for Organ- or Specimen-Confined Versus Nonconfined Disease
 
Predictors of Biochemical Failure
Of the 141 patients in the study, 17 (12%) had biochemical failure: nine were RT-PCR negative and eight were RT-PCR positive. The overall Kaplan-Meier actuarial bRFS was 85% at 59 months (data not shown). All biochemical failures occurred within the first 32 months of follow-up. Multivariate analysis of bRFS by using the Cox proportional hazards model disclosed that iPSA and biopsy GS were significant predictors of bRFS, whereas clinical T stage and RT-PCR status were not (Table 5). Figure 1 indicates the results of the Kaplan-Meier analysis for bRFS using RT-PCR status, demonstrating no statistically significant differences in outcome between groups. The results were unchanged when patients treated with preoperative androgen-deprivation therapy were excluded (data not shown). Limiting the analysis only to patients with non–organ-confined disease also failed to demonstrate a predictive value for RT-PCR status and bRFS (P = .99).


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  		Table 5. Multivariate Analysis of bRFS Using the Cox Proportional Hazards Method
 


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  		Fig 1. Kaplan-Meier estimate of time to biochemical failure as a function of RT-PCR status by using a nested assay for PSA and PSM. Symbols indicate censored patients. BRF, biochemical relapse-free.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
RT-PCR is extremely sensitive for detecting circulating prostate cells. Most assays will detect PSA or PSM mRNA in one LNCaP cell diluted in 106 mononuclear cells. Numerous studies have attempted to show correlation of preoperative RT-PCR for PSA with pathologic stage, with conflicting results.4-11 Katz et al5 were the first investigators to propose using RT-PCR to detect circulating PSA mRNA as a preoperative staging modality in patients with clinically localized prostate cancer. Their assay had a sensitivity and specificity of 87% and 76%, respectively, for detecting margin-positive disease. In a follow-up study of 160 patients who underwent radical prostatectomy, sensitivity and specificity were 65% and 90%, respectively, for detecting extraprostatic disease.6 Cama et al10 compared molecular staging of clinically localized prostate cancer with RT-PCR for PSA versus PSM. They found that RT-PCR for PSA had a positive correlation with pathologic stage, whereas RT-PCR for PSM did not. In contrast to these studies, Sokoloff et al17 found no statistically significant relationship between positive RT-PCR for PSA and pathologic stage and highlighted a false-positive rate of 59% in patients with organ-confined disease. Ignatoff et al11 indicated that RT-PCR for PSA was good at differentiating between metastatic and localized disease, but no significant difference was found between organ-confined and non–organ-confined disease. Various explanations have been suggested to explain why these conflicting results occur. These include the lack of standardized laboratory protocols for the differing assays, use of different primers for PCR, specimen contamination, and sampling error from the intermittent spillage of tumor cells into the circulation. Also, the biologic significance of circulating PSA- or PSM-expressing cells, or both, as a harbinger of disease progression or metastases is not clearly defined.18

Perhaps the most important attribute of a preoperative staging parameter is the ability to predict the potential for cure. Several RT-PCR–based studies that used biochemical failure as a surrogate for cure have recently been reported. Mejean et al19 indicated that in patients with non–organ-confined (pT3) disease treated by radical prostatectomy, a positive RT-PCR for PSA was significantly associated with biochemical recurrence. Other investigators have suggested that when compared with other preoperative variables, RT-PCR for PSA is a good predictor of biochemical recurrence, but its predictive value disappears when it is included in a multivariate analysis that also includes pathologic stage.20 In more advanced cases, Kantoff et al4 have indicated that RT-PCR for PSA had independent prognostic value for predicting actual survival for men with hormone-refractory disease. In summary, the available data suggest that RT-PCR for PSA or PSM does not have clear-cut predictive value for adverse pathologic stage in men with localized disease undergoing radical prostatectomy, but it may have predictive value for biochemical or actual survival in more advanced (pT3 or metastatic) stages.

Like others, we have previously reported that combined nested preoperative RT-PCR for both PSA and PSM is an independent predictor of ECE on radical prostatectomy specimens.12,14 This is of clinical importance because ECE is a strong predictor for the likelihood of subsequent biochemical failure.1 In this larger study, we investigated whether RT-PCR status for PSA, PSM, or both can predict for pathologic stage in a cohort of radical prostatectomy patients. We also examined the assay’s ability to predict biochemical failure as a surrogate for cure. In both studies we used nested PCR, which can increase the sensitivity of the assay without sacrificing specificity. The majority of study patients had low-risk characteristics with traditional preoperative staging parameters, with biopsy GS <= 6 in 75.9%, PSA less than 10 in 75.9%, and clinical stage T1c or T2a in 83.7%. In contrast to our initial study, we found no correlation between RT-PCR status and final pathologic stage. Furthermore, with a median follow-up of 31 months, we found that RT-PCR status did not predict the likelihood of biochemical failure, even in those patients with non–organ-confined disease.

Our study included 27 patients who received preoperative androgen-deprivation therapy. The effect of this therapy on the sensitivity of RT-PCR assays is not clear. Olsson et al8 looked at preoperative RT-PCR for PSA to predict adverse pathology in 138 patients undergoing radical prostatectomy. The odds ratio for RT-PCR in predicting extraprostatic disease was higher in the group of men who received no preoperative androgen-deprivation therapy. It is interesting to note, however, that there were more false negatives in these patients compared with those who received neoadjuvant therapy. In our study, we observed a higher rate of RT-PCR positivity in patients receiving preoperative androgen deprivation (59% v 50%); this probably reflects our use of PSM, which is known to be upregulated by androgen withdrawal.3 However, excluding those who received androgen deprivation from the statistical analyses did not change our assay’s predictive value for either pathologic stage or biochemical failure.

There are some limitations in the interpretation of our findings. First, this study does not replicate our prior observation that RT-PCR status correlates with pathologic stage. We believe that this is due to (1) a larger sample size in this study (more than double that of our largest previous study) and (2) time-related trends in decreasing pathologic stage for a given T stage, grade, and PSA.1 A second limitation is that the statistical power of our study does not exclude small differences in bRFS between groups. However, the negative findings of this study are not encouraging with respect to performing a larger trial, and we question whether a staging or prognostic test that has only minimal discriminatory value will be clinically useful.

In summary, we have demonstrated that combined nested RT-PCR for PSA/PSM is not an independent predictor of either pathologic stage or biochemical failure in patients with localized prostate cancer undergoing radical prostatectomy. The presence of circulating cells in the peripheral blood that express these markers is not a good indicator of the likelihood of recurrent or metastatic disease within 5 years of surgery. Although longer follow-up will be needed to make this conclusion with certainty, we believe that this assay has no clinical utility in this patient population.


   ACKNOWLEDGMENTS
 
Supported by the Cleveland Clinic Foundation Research Programs Committee, Cleveland, OH.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
1. Jhaveri FM, Klein EA, Kupelian PA, et al: Declining rates of extracapsular extension after radical prostatectomy: Evidence for continued stage migration. J Clin Oncol 17: 3167-3172, 1999[Abstract/Free Full Text]

2. Haas C, Resnick MI: Trends in diagnosis, biopsy, and imaging, in Klein EA (ed): Management of Prostate Cancer. Totowa NJ, Humana Press, 2001, pp 87-102

3. Su SL, Boynton AL, Holmes EH, et al: Detection of extraprostatic prostate cells utilizing reverse transcription-polymerase chain reaction. Semin Surg Oncol 18: 17-28, 2000[CrossRef][Medline]

4. Kantoff PW, Halabi S, Farmer DA, et al: Prognostic significance of reverse transcriptase polymerase chain reaction for prostate-specific antigen in men with hormone-refractory prostate cancer. J Clin Oncol 19: 3025-3028, 2001[Abstract/Free Full Text]

5. Katz AE, Olsson CA, Raffo AJ, et al: Molecular staging of prostate cancer with the use of an enhanced reverse transcriptase-PCR assay. Urology 43: 765-775, 1994[CrossRef][Medline]

6. Katz AE, de Vries GM, Benson MC, et al: The role of the reverse-transcriptase polymerase chain reaction assay for prostate-specific antigen in the selection of patients for radical prostatectomy. Urol Clin North Am 23: 541-549, 1996[CrossRef][Medline]

7. Ellis WJ, Vessella RL, Corey E, et al: The value of reverse transcriptase polymerase chain reaction assay in preoperative staging and followup of patients with prostate cancer. J Urol 159: 1134-1138, 1998[CrossRef][Medline]

8. Olsson CA, De Vries GM, Benson MC, et al: The use of RT-PCR for prostate-specific antigen assay to predict potential surgical failures before radical prostatectomy: Molecular staging of prostate cancer. Br J Urol 77: 411-417, 1996[Medline]

9. Israeli RS, Miller WH, Su SL, et al: Sensitive nested reverse transcription polymerase chain reaction detection of circulating prostatic tumor cells: Comparison of prostate-specific membrane antigen and prostate-specific antigen-based assays. Cancer Res 54: 6306-6310, 1994[Abstract/Free Full Text]

10. Cama CC, Olsson CA, Raffo AJ, et al: Molecular staging of prostate cancer: II. A comparison of the application of an enhanced reverse transcriptase polymerase chain reaction assay for prostate specific antigen versus prostate specific membrane antigen. J Urol 153: 1373-1378, 1995[CrossRef][Medline]

11. Ignatoff JM, Oefelein MG, Watkin W, et al: Prostate specific antigen reverse transcriptase polymerase chain reaction assay in preoperative staging of prostate cancer. J Urol 158: 1870-1875, 1997[CrossRef][Medline]

12. Grasso YZ, Gupta MK, Levin HS, et al: Combined nested RT-PCR assay for prostate-specific antigen and prostate-specific membrane antigen in prostate cancer patients: Correlation with pathological stage. Cancer Res 58: 1456-1459, 1998[Abstract/Free Full Text]

13. Fergany A, Kupelian PA, Levin HS, et al: No difference in biochemical failure rates with or without pelvic lymph node dissection during radical prostatectomy in low-risk patients. Urology 56: 92-95, 2000[CrossRef][Medline]

14. Zhang Y, Zippe CD, Van Lente F, et al: Combined nested reverse transcription-PCR assay for prostate-specific antigen and prostate-specific membrane antigen in detecting circulating prostatic cells. Clin Cancer Res 3: 1215-1220, 1997[Abstract]

15. Loric S, Dumas F, Eschwege P, et al: Enhanced detection of hematogenous circulating prostatic cells in patients with prostate adenocarcinoma by using nested reverse transcriptase polymerase chain reaction assay based on prostate-specific membrane antigen. Clin Chem 41: 1698-1704, 1995[Abstract]

16. Wainstein MA, He F, Robinson D, et al: CWR22: Androgen-dependent xenograft model derived from a primary human prostatic carcinoma. Cancer Res 54: 6049-6052, 1994[Abstract/Free Full Text]

17. Sokoloff MH, Tso C, Kaboo R, et al: Quantitative polymerase chain reaction does not improve preoperative prostate cancer staging: A clinicopathological molecular analysis of 121 patients. J Urol 156: 1560-1566, 1996[CrossRef][Medline]

18. Gao C-L, Maheshwari S, Dean RC, et al: Blinded evaluation of reverse transcriptase-polymerase chain reaction prostate-specific antigen peripheral blood assay for molecular staging of prostate cancer. Urology 53: 714-721, 1999[CrossRef][Medline]

19. Mejean A, Vona G, Nalpas B, et al: Detection of circulating prostate derived cells in patients with prostate adenocarcinoma is an independent risk factor for tumor recurrence. J Urol 163: 2022-2029, 2000[CrossRef][Medline]

20. De la Taille A, Olsson CA, Buttyan R, et al: Blood-based reverse transcriptase polymerase chain reaction assays for prostatic specific antigen: Long term follow-up confirms the potential utility of this assay in identifying patients more likely to have biochemical recurrence (rising PSA) following radical prostatectomy. Int J Cancer 84: 360-364, 1999[CrossRef][Medline]

Submitted November 20, 2001; accepted April 30, 2002.


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