Management of patients with rising prostate-specific antigen after radical prostatectomy

Abstract

During the past 12 years, routine use of serum prostate-specific antigen (PSA) has resulted in a major rise in the proportion of patients initially diagnosed with clinically localized disease and the average age at diagnosis has declined.1Landis S.H Murray T Bolden S et al.Cancer Statistics, 1999.CA Cancer J Clin. 1999; 49: 8-31Crossref PubMed Scopus (3127) Google Scholar, 2Moul J.W Epidemiology and screening for prostate cancer.Am J Manag Care. 1997; 3: 1200-1205PubMed Google Scholar These important demographic changes, coupled with major improvements in surgical technique, resulted in a sharp increase in the number of advocates for radical prostatectomy (RP) as definitive treatment for prostate cancer.3Litwin M.S Pasta D.J Stoddard M.L et al.Epidemiological trends and financial outcomes in radical prostatectomy among Medicare beneficiaries, 1991 to 1993.J Urol. 1998; 160: 445-448Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar, 4Gee W.F Holtgrewe H.L Blute M.L et al.1997 American Urological Association Gallup survey changes in diagnosis and management of prostate cancer and benign prostatic hyperplasia, and other practice trends from 1994 to 1997.J Urol. 1998; 160: 1804-1807Abstract Full Text Full Text PDF PubMed Scopus (38) Google ScholarAfter curative RP, the serum PSA level should become undetectable, and the detection of elevated levels at any time after about 4 weeks postoperatively reflects evidence of disease recurrence.5Partin A.W Oesterling J.E The clinical usefulness of prostate specific antigen update 1994.J Urol. 1994; 15: 1358-1368Google Scholar The incidence of disease recurrence while PSA is undetectable is extremely low, although it might be observed in very poorly differentiated tumors or neoplasms of distinct histologic subtypes.6Goldrath D.E Messing E.M Prostate specific antigen not detectable despite tumor progression after radical prostatectomy.J Urol. 1989; 142: 1082-1084Abstract Full Text PDF PubMed Scopus (50) Google Scholar, 7Pound C.R Partin A.W Epstein J.I et al.Prostate-specific antigen after anatomic radical retropubic prostatectomy. Patterns of recurrence and cancer control.Urol Clin North Am. 1997; 24: 395-406Abstract Full Text Full Text PDF PubMed Scopus (533) Google Scholar The first evidence of disease recurrence after RP is manifested by a consistent elevation of serial serum PSA tests, usually without any associated objective findings.5Partin A.W Oesterling J.E The clinical usefulness of prostate specific antigen update 1994.J Urol. 1994; 15: 1358-1368Google Scholar The probability of biochemical relapse at 5 and 10 years, reported in several large series, has ranged between 20% and 31% and 27% and 53%, respectively.7Pound C.R Partin A.W Epstein J.I et al.Prostate-specific antigen after anatomic radical retropubic prostatectomy. Patterns of recurrence and cancer control.Urol Clin North Am. 1997; 24: 395-406Abstract Full Text Full Text PDF PubMed Scopus (533) Google Scholar, 8Kattan M.W Wheeler T.M Scardino P.T Postoperative nomogram for disease recurrence after radical prostatectomy for prostate cancer.J Clin Oncol. 1999; 17: 1499-1507Crossref PubMed Google Scholar, 9Zincke H Oesterling J.E Blute M.L et al.Long-term (15 years) results after radical prostatectomy for clinically localized (stage T2c or lower) prostate cancer.J Urol. 1994; 152: 1850-1857Abstract Full Text PDF PubMed Google Scholar, 10Lieskovsky G Bochner B.H Skinner E.C et al.Evaluation of 20-year experience with radical retropubic prostatectomy for adenocarcinoma of the prostate.J Urol. 1999; 161 (abstract): A329Crossref Google Scholar Various factors, including differences in patient populations, duration of follow-up, and the definition of PSA recurrence (0.2 to 0.6 ng/mL), might account for the variance in the reported rates. On the basis of the number of RPs performed and the cumulative figures of biochemical relapse rates, it can be estimated that thousands of patients present annually to clinicians throughout the world with an elevated PSA level as the only evidence of disease.At present, the natural history of the patient with biochemical relapse after RP remains poorly defined, and no criteria are uniformly accepted for implementation of treatment for these patients. The management philosophy has been influenced primarily by physicians’ and patients’ biases, and it is becoming obvious that despite the lack of consensus, early interventions are more commonly applied than observation only.Our objective was to review the published reports dealing with the evaluation, natural history, and treatment of patients with a rising PSA after RP for clinically localized prostate cancer and to provide the necessary groundwork for the development of clinical research on this challenging problem.Patient subsets at high risk of recurrenceThe relative risk for development of biochemical recurrence is dependent on various preoperative and postoperative clinical and pathologic factors. Multivariate analyses indicate that the most significant independent predictors are preoperative PSA, pathologic T stage, and final Gleason score (based on the prostatectomy specimen).7Pound C.R Partin A.W Epstein J.I et al.Prostate-specific antigen after anatomic radical retropubic prostatectomy. Patterns of recurrence and cancer control.Urol Clin North Am. 1997; 24: 395-406Abstract Full Text Full Text PDF PubMed Scopus (533) Google Scholar, 11Epstein J.I Partin A.W Sauvageot J et al.Prediction of progression following radical prostatectomy a multivariate analysis of 721 men with long-term follow-up.Am J Surg Pathol. 1996; 20: 286-292Crossref PubMed Scopus (495) Google Scholar, 12D’Amico A.V Whittington R Malkowicz S.B et al.The combination of preoperative prostate specific antigen and postoperative pathological finding to predict prostate specific antigen outcome in clinically localized prostate cancer.J Urol. 1998; 160: 2096-2101Abstract Full Text Full Text PDF PubMed Google Scholar, 13Kupelian P Katcher J Levin H et al.Correlation of clinical and pathologic factors with rising prostate-specific antigen profiles after radical prostatectomy alone for clinically localized prostate cancer.Urology. 1996; 48: 249-260Abstract Full Text PDF PubMed Scopus (190) Google Scholar, 14Bauer J.J Connelly R.R Sesterhenn I.A et al.Biostatistical modeling using traditional variables and genetic biomarkers for predicting the risk of prostate carcinoma recurrence after radical prostatectomy.Cancer. 1997; 79: 952-962Crossref PubMed Scopus (70) Google Scholar High-risk patients are usually defined as having a pathologic stage greater than T2b, Gleason score greater than 7, and preoperative PSA greater than 20 ng/mL. Additional widely accepted prognostic factors are positive surgical margins and lymph node or seminal vesicle involvement.9Zincke H Oesterling J.E Blute M.L et al.Long-term (15 years) results after radical prostatectomy for clinically localized (stage T2c or lower) prostate cancer.J Urol. 1994; 152: 1850-1857Abstract Full Text PDF PubMed Google Scholar, 11Epstein J.I Partin A.W Sauvageot J et al.Prediction of progression following radical prostatectomy a multivariate analysis of 721 men with long-term follow-up.Am J Surg Pathol. 1996; 20: 286-292Crossref PubMed Scopus (495) Google Scholar, 15Ohori M Wheeler T.M Kattan M.W et al.Prognostic significance of positive surgical margins in radical prostatectomy specimens.J Urol. 1995; 154: 1818-1824Abstract Full Text Full Text PDF PubMed Scopus (459) Google Scholar Four independent groups of investigators developed mathematical models and nomograms that allow for postoperative prediction of biochemical recurrence and the identification of defined risk groups using the known prognostic parameters (Table I). 8Kattan M.W Wheeler T.M Scardino P.T Postoperative nomogram for disease recurrence after radical prostatectomy for prostate cancer.J Clin Oncol. 1999; 17: 1499-1507Crossref PubMed Google Scholar, 12D’Amico A.V Whittington R Malkowicz S.B et al.The combination of preoperative prostate specific antigen and postoperative pathological finding to predict prostate specific antigen outcome in clinically localized prostate cancer.J Urol. 1998; 160: 2096-2101Abstract Full Text Full Text PDF PubMed Google Scholar, 14Bauer J.J Connelly R.R Sesterhenn I.A et al.Biostatistical modeling using traditional variables and genetic biomarkers for predicting the risk of prostate carcinoma recurrence after radical prostatectomy.Cancer. 1997; 79: 952-962Crossref PubMed Scopus (70) Google Scholar, 16Partin A.W Piantadosi S Sanda M.G et al.Selection of men at high risk for disease recurrence for experimental adjuvant therapy following radical prostatectomy.Urology. 1995; 45: 831-838Abstract Full Text PDF PubMed Scopus (156) Google ScholarTABLE IPrediction models for recurrence after radical prostatectomylegendKey: PSA = prostate-specific antigen.AuthorPrediction ParametersRecurrence End PointApplicationBauer et al.14Bauer J.J Connelly R.R Sesterhenn I.A et al.Biostatistical modeling using traditional variables and genetic biomarkers for predicting the risk of prostate carcinoma recurrence after radical prostatectomy.Cancer. 1997; 79: 952-962Crossref PubMed Scopus (70) Google ScholarRaceRelative risk for recurrenceEquationPreoperative PSA∗Sigmoid transformation of serum PSA level.Prostatectomy Gleason scoreCapsular statusD’Amico et al.12D’Amico A.V Whittington R Malkowicz S.B et al.The combination of preoperative prostate specific antigen and postoperative pathological finding to predict prostate specific antigen outcome in clinically localized prostate cancer.J Urol. 1998; 160: 2096-2101Abstract Full Text Full Text PDF PubMed Google ScholarPreoperative PSA2-year PSA failure rateNomogramPathologic stageSurgical margins statusProstatectomy Gleason scoreKattan et al.8Kattan M.W Wheeler T.M Scardino P.T Postoperative nomogram for disease recurrence after radical prostatectomy for prostate cancer.J Clin Oncol. 1999; 17: 1499-1507Crossref PubMed Google ScholarPreoperative PSA7-year PSA failure rateNomogramProstatectomy Gleason scorePathologic stagePartin et al.16Partin A.W Piantadosi S Sanda M.G et al.Selection of men at high risk for disease recurrence for experimental adjuvant therapy following radical prostatectomy.Urology. 1995; 45: 831-838Abstract Full Text PDF PubMed Scopus (156) Google ScholarPreoperative PSA∗Sigmoid transformation of serum PSA level.Log relative risk of recurrenceEquationProstatectomy Gleason scoreSurgical margin statuslegend Key: PSA = prostate-specific antigen.∗ Sigmoid transformation of serum PSA level. Open table in a new tab In addition to standard pathologic examination, various histopathologic determinants and molecular markers have been evaluated for prediction of PSA recurrence and survival. Bauer et al.14Bauer J.J Connelly R.R Sesterhenn I.A et al.Biostatistical modeling using traditional variables and genetic biomarkers for predicting the risk of prostate carcinoma recurrence after radical prostatectomy.Cancer. 1997; 79: 952-962Crossref PubMed Scopus (70) Google Scholar found that p53 mutation and bcl-2 over expression were independent adverse prognostic factors. The investigators constructed a mathematical model incorporating the status of p53 and bcl-2 expression with race, preoperative PSA, and pathologic findings to assess the risk of recurrence after RP. However, the predictive value of both p53 and bcl-2 was investigated by others and is still controversial.17Stapleton A.M Zbell P Kattan M.W et al.Assessment of the biologic markers p53, Ki-67, and apoptotic index as predictive indicators of prostate carcinoma recurrence after surgery.Cancer. 1998; 82: 168-175Crossref PubMed Scopus (108) Google Scholar, 18Brooks J.D Bova G.S Ewing C.M et al.An uncertain role for p53 gene alterations in human prostate cancer.Cancer Res. 1996; 56: 3814-3822PubMed Google Scholar Other possible prognostic factors include expression of Ki-67, p27, apoptotic index, DNA ploidy, and tumor angiogenesis (microvessel density).18Brooks J.D Bova G.S Ewing C.M et al.An uncertain role for p53 gene alterations in human prostate cancer.Cancer Res. 1996; 56: 3814-3822PubMed Google Scholar, 19Waltregny D de Leval L Menard S et al.Independent prognostic value of the 67-kd laminin receptor in human prostate cancer.J Natl Cancer Inst. 1997; 89: 1224-1227Crossref PubMed Scopus (44) Google Scholar, 20Yang R.M Naitoh J Murphy M et al.Low p27 expression predicts poor disease-free survival in patients with prostate cancer.J Urol. 1998; 159: 941-945Abstract Full Text Full Text PDF PubMed Scopus (274) Google Scholar, 21Lerner S.E Blute M.L Bergstralh E.J et al.Analysis of risk factors for progression in patients with pathologically confined prostate cancers after radical retropubic prostatectomy.J Urol. 1996; 156: 137-143Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar, 22Silberman M.A Partin A.W Veltri R.W et al.Tumor angiogenesis correlates with progression after radical prostatectomy but not with pathologic stage in Gleason sum 5 to 7 adenocarcinoma of the prostate.Cancer. 1997; 79: 772-779Crossref PubMed Scopus (184) Google ScholarPSA surveillance and definition of recurrenceOn the basis of the half-life of serum PSA, it is considered that the serum PSA level should decline to below detectable levels within 21 to 30 days after RP for organ-confined prostate cancer.5Partin A.W Oesterling J.E The clinical usefulness of prostate specific antigen update 1994.J Urol. 1994; 15: 1358-1368Google Scholar, 23Lange P.H Ercole C.J Lightner D.J et al.The value of serum prostate specific antigen determinations before and after radical prostatectomy.J Urol. 1989; 141: 873-879Abstract Full Text PDF PubMed Scopus (428) Google Scholar The recommended frequency of postoperative PSA determinations is inconclusive as was demonstrated in a survey among American Urological Association urologists, which showed a considerable variation among practices. However, a common practice is to obtain a serum PSA level every 3 months during the first year, every 6 months during years 2 to 5, and yearly thereafter.24Oh J Colberg J.W Ornstein D.K et al.Current follow-up strategies after radical prostatectomy a survey of American Urological Association urologists.J Urol. 1999; 161: 520-523Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar The need for lifetime follow-up after RP is also controversial. Kattan et al.8Kattan M.W Wheeler T.M Scardino P.T Postoperative nomogram for disease recurrence after radical prostatectomy for prostate cancer.J Clin Oncol. 1999; 17: 1499-1507Crossref PubMed Google Scholar reported that recurrence beyond the 7-year point was rare, and the Johns Hopkins series reported by Pound et al.25Pound C.R Partin A.W Eisenberger M.A et al.Natural history of progression after PSA elevation following radical prostatectomy.JAMA. 1999; 281: 1591-1597Crossref PubMed Scopus (2686) Google Scholar indicated that among patients with biochemical failure, PSA was first detected between 6 to 9 years in 19% and after more than 10 years in 4%. The latter observation suggests that PSA determination should continue even after a prolonged disease-free interval.The reported level of delectability of serum PSA by today’s commercial assays is 0.1 ng/mL (undetectable levels are expressed as less than 0.1 ng/mL).5Partin A.W Oesterling J.E The clinical usefulness of prostate specific antigen update 1994.J Urol. 1994; 15: 1358-1368Google Scholar Consequently, the most acceptable threshold for a detectable PSA after RP is 0.2 ng/mL, which is a measurable value above the level of assay delectability.5Partin A.W Oesterling J.E The clinical usefulness of prostate specific antigen update 1994.J Urol. 1994; 15: 1358-1368Google Scholar, 9Zincke H Oesterling J.E Blute M.L et al.Long-term (15 years) results after radical prostatectomy for clinically localized (stage T2c or lower) prostate cancer.J Urol. 1994; 152: 1850-1857Abstract Full Text PDF PubMed Google Scholar, 25Pound C.R Partin A.W Eisenberger M.A et al.Natural history of progression after PSA elevation following radical prostatectomy.JAMA. 1999; 281: 1591-1597Crossref PubMed Scopus (2686) Google Scholar Biochemical relapse is generally considered to have occurred when two separate measurements reveal a PSA of 0.2 ng/mL or greater and rising.Several new-generation ultrasensitive PSA assays with detection thresholds as low as to 0.001 to 0.01 ng/mL have been introduced during the past several years. These assays have been reported to detect the first evidence of biochemical recurrence up to 22 months earlier than conventional assays.25Pound C.R Partin A.W Eisenberger M.A et al.Natural history of progression after PSA elevation following radical prostatectomy.JAMA. 1999; 281: 1591-1597Crossref PubMed Scopus (2686) Google Scholar, 26Stamey T.A Graves H.C.B Wehner N Early detection of residual prostate cancer after radical prostatectomy by an ultrasensitive assay for prostate specific antigen.J Urol. 1993; 149: 787-792Abstract Full Text PDF PubMed Scopus (89) Google Scholar It has been shown that a significant number of patients with PSA measured by ultrasensitive assays may demonstrate levels of PSA below 0.1 ng/mL for extended periods without developing clinical recurrence.27Ellis W.J Vessella R.L Noterboom J.L et al.Early detection of recurrent prostate cancer with an ultrasensitive chemiluminescent prostate specific antigen assay.Urology. 1997; 50: 573-579Abstract Full Text PDF PubMed Scopus (52) Google Scholar It is also well documented that minute concentrations of PSA originating from nonmalignant extraprostatic sources may be detected by ultrasensitive assays.28Diamandis E.P Yu H Nonprostatic sources of prostate specific antigen.Urol Clin North Am. 1997; 24: 275-282Abstract Full Text Full Text PDF PubMed Scopus (157) Google Scholar Indeed, patients’ awareness of biochemical failure and the risk of clinical recurrence and cancer-related death has a considerable effect on emotional quality of life, and there is no evidence that early intervention may decrease future morbidity and prolong overall survival. Thus, in view of the unclear significance of measurable minute concentrations of PSA and the extra lead time provided by these assays, the routine application of these assays in clinical practice is of questionable value.Local versus distant relapsesThe availability of local modalities of salvage treatment such as radiotherapy clearly supports the need to define the site(s) of relapse. Evolving experience suggests that biochemical relapses are more commonly a manifestation of metastatic disease than local recurrence. Pound et al.7Pound C.R Partin A.W Epstein J.I et al.Prostate-specific antigen after anatomic radical retropubic prostatectomy. Patterns of recurrence and cancer control.Urol Clin North Am. 1997; 24: 395-406Abstract Full Text Full Text PDF PubMed Scopus (533) Google Scholar reported that approximately one third of the patients who eventually developed clinical recurrence had local evidence of disease and 70% had distant metastasis with or without local recurrence. Other investigators also estimated a low probability for local recurrence, ranging between 10% and 25 %.5Partin A.W Oesterling J.E The clinical usefulness of prostate specific antigen update 1994.J Urol. 1994; 15: 1358-1368Google Scholar, 29Schellhammer P.F El-Mahdi A.M Local failure and related complications after definitive treatment of carcinoma of the prostate by irradiation or surgery.Urol Clin North Am. 1990; 17: 835-851PubMed Google ScholarThe precise determination of the actual site of recurrence is frequently unsuccessful, in part because PSA failure initially is rarely associated with symptoms or any findings on physical examination or imaging modalities. Digital rectal examination, transrectal ultrasound, computed tomography, magnetic resonance imaging, indium-111-labeled capromab pendetide scan (ProstaScint), and biopsy of the anastomotic site alone or in combination have traditionally been associated with a low sensitivity and/or specificity.30Salomon C.G Flisak M.E Olson M.C et al.Radical prostatectomy transrectal sonographic evaluation to assess for local recurrence.Radiology. 1993; 189: 713-719PubMed Google Scholar, 31Kramer S Gorich J Gottfried H.W et al.Sensitivity of computed tomography in detecting local recurrence of prostatic carcinoma following radical prostatectomy.Br J Radiol. 1997; 70: 995-999PubMed Google Scholar, 32Kahn D Williams R.D Manyak M.J et al.111Indium-capromab pendetide in the evaluation of patients with residual or recurrent prostate cancer after radical prostatectomy.J Urol. 1998; 159: 2041-2046Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar, 33Foster L.S Jajodia P Fournier G et al.The value of prostate specific antigen and transrectal ultrasound guided biopsy in detecting prostatic fossa recurrences following radical prostatectomy.J Urol. 1993; 149: 1024-1028PubMed Google Scholar Preliminary data on endorectal coil magnetic resonance imaging were reported as encouraging34Silverman J.M Krebs T.L MR imaging evaluation with a transrectal surface coil of local recurrence of prostatic cancer in men who have undergone radical prostatectomy.Am J Radiol. 1997; 168: 379-385Google Scholar; however, more studies are needed before adopting this costly technique for routine use.In view of the limited role for standard diagnostic techniques, statistical models based on various clinical and pathologic risk factors have been designed specifically to estimate the probability of local versus distant relapse. Partin et al.35Partin A.W Pearson J.D Landis P.K et al.Evaluation of serum prostate specific antigen velocity after radical prostatectomy to distinguish local recurrence from distant metastases.Urology. 1994; 43: 649-659Abstract Full Text PDF PubMed Scopus (364) Google Scholar described a model based on pathologic stage, surgical Gleason score, timing of PSA recurrence, and the rate of PSA rise to differentiate between local and distant relapse. The presence of seminal vesicle invasion and/or lymph node involvement, Gleason score greater than 7, and PSA recurrence within 2 years were indicative of a low probability for local relapse only.7Pound C.R Partin A.W Epstein J.I et al.Prostate-specific antigen after anatomic radical retropubic prostatectomy. Patterns of recurrence and cancer control.Urol Clin North Am. 1997; 24: 395-406Abstract Full Text Full Text PDF PubMed Scopus (533) Google Scholar, 35Partin A.W Pearson J.D Landis P.K et al.Evaluation of serum prostate specific antigen velocity after radical prostatectomy to distinguish local recurrence from distant metastases.Urology. 1994; 43: 649-659Abstract Full Text PDF PubMed Scopus (364) Google Scholar In their series, a PSA velocity greater than 0.75 ng/mL/yr enhanced the predictive value for distant disease.35Partin A.W Pearson J.D Landis P.K et al.Evaluation of serum prostate specific antigen velocity after radical prostatectomy to distinguish local recurrence from distant metastases.Urology. 1994; 43: 649-659Abstract Full Text PDF PubMed Scopus (364) Google Scholar Others have reported that a PSA doubling time of less than 6 months was associated with the development of distant metastatic disease.36Patel A Dorey F Franklin J et al.Recurrence patterns after radical retropubic prostatectomy clinical usefulness of prostate specific antigen doubling times and log slope prostate specific antigen.J Urol. 1997; 158: 1441-1445Abstract Full Text Full Text PDF PubMed Scopus (259) Google ScholarThe correlation between positive surgical margins and isolated local recurrence is controversial.35Partin A.W Pearson J.D Landis P.K et al.Evaluation of serum prostate specific antigen velocity after radical prostatectomy to distinguish local recurrence from distant metastases.Urology. 1994; 43: 649-659Abstract Full Text PDF PubMed Scopus (364) Google Scholar, 37Connolly J.A Shinohara K Presti Jr, J.C et al.Local recurrence after radical prostatectomy characteristics in size, location, and relationship to prostate-specific antigen and surgical margins.Urology. 1996; 47: 225-231Abstract Full Text PDF PubMed Scopus (191) Google Scholar Although it can be assumed that most local recurrences will develop from non-organ-confined tumors, so would most of the distant failures.13Kupelian P Katcher J Levin H et al.Correlation of clinical and pathologic factors with rising prostate-specific antigen profiles after radical prostatectomy alone for clinically localized prostate cancer.Urology. 1996; 48: 249-260Abstract Full Text PDF PubMed Scopus (190) Google Scholar, 25Pound C.R Partin A.W Eisenberger M.A et al.Natural history of progression after PSA elevation following radical prostatectomy.JAMA. 1999; 281: 1591-1597Crossref PubMed Scopus (2686) Google Scholar Therefore, local salvage therapy should be considered only in the case of unequivocal positive margins without other adverse pathologic parameters.In summary, isolated local recurrences comprise up to 30% of PSA recurrences. The best tools to estimate the probability for local versus distant relapses are models based on histopathologic factors, time of onset of PSA failure, and PSA kinetics.Natural history of PSA relapsesIt has become increasingly apparent that the outcome for patients with biochemical recurrence is broadly heterogeneous. Data from early series indicated that PSA recurrence could precede clinical disease by several months to several years.23Lange P.H Ercole C.J Lightner D.J et al.The value of serum prostate specific antigen determinations before and after radical prostatectomy.J Urol. 1989; 141: 873-879Abstract Full Text PDF PubMed Scopus (428) Google Scholar More recent large series have revealed that the probability of remaining free of PSA recurrence at 10 years is 60% to 70%; the metastasis-free rate is higher at 80% to 85%, and the cancer-specific survival is 90% or greater and is almost identical to the 10-year survival rate in patients without biochemical failure.9Zincke H Oesterling J.E Blute M.L et al.Long-term (15 years) results after radical prostatectomy for clinically localized (stage T2c or lower) prostate cancer.J Urol. 1994; 152: 1850-1857Abstract Full Text PDF PubMed Google Scholar, 25Pound C.R Partin A.W Eisenberger M.A et al.Natural history of progression after PSA elevation following radical prostatectomy.JAMA. 1999; 281: 1591-1597Crossref PubMed Scopus (2686) Google Scholar, 38Catalona W.J Smith D.S Cancer recurrence and survival rates after anatomic radical retropubic prostatectomy for prostate cancer intermediate-term results.J Urol. 1998; 160: 2428-2434Abstract Full Text Full Text PDF PubMed Scopus (268) Google Scholar, 39Gerber G.S Thisted R.A Scardino P.T et al.Results of radical prostatectomy in men with clinically localized prostate cancer.JAMA. 1996; 276: 615-619Crossref PubMed Google Scholar, 40Jhaveri F.M Zippe C.D Klein P.A et al.Biochemical failure does not predict overall survival after radical prostatectomy for localized prostate cancer 10 year results.J Urol. 1999; 161 (abstract): A355Crossref Google Scholar In view of the median age of the patients undergoing RP, it is likely that in a substantial proportion of this population, PSA recurrence will remain the only evidence of disease activity.Direct information on the long-term natural history of this population is lacking. Large surgical series employing serial PSA determinations are only now reaching sufficient maturity (5 to 10 years). Furthermore, an increasing number of patients receive early androgen deprivation treatment solely on the basis of a rising PSA, and this prevents us from properly defining the natural history of these patients.The single most valuable report on the natural history of patients with a rising PSA was published by Pound et al.25Pound C.R Partin A.W Eisenberger M.A et al.Natural history of progression after PSA elevation following radical prostatectomy.JAMA. 1999; 281: 1591-1597Crossref PubMed Scopus (2686) Google Scholar who described their experience in 304 patients with biochemical failure (15%) of a total of 1997 patients who underwent RP during a 15-year period. Of the 304 patients, 103 (34%) subsequently developed metastases. None of these patients received androgen deprivation treatment on the basis of an elevated PSA unless distant metastatic disease was demonstrated. The median actuarial time from PSA elevation to metastasis was 8 years, and the incidence of bone metastases 5 years after PSA recurrence was 37%. The median time to death after development of metastases was slightly less than 5 years. The factors that predicted outcome in these patients included the surgical Gleason score (5 to 7 versus 8 to 10), time of PSA recurrence (greater than 2 years versus 2 years or less), and PSA doubling time (PSADT; greater than 10 months versus 10 months or less). The PSADT was significant as a predictor only for patients with a Gleason score of 7 or less, but the lack of significance in the patients with higher Gleason scores might result from the relatively small number of patients in this subgroup. To enhance its clinical applicability, the investigators developed an algorithm that estimates the probability of remaining metastasis free at 3, 5, and 7 years (Table II).25Pound C.R Partin A.W Eisenberger M.A et al.Natural history of progression after PSA elevation following radical prostatectomy.JAMA. 1999; 281: 1591-1597Crossref PubMed Scopus (2686) Google Scholar TABLE IIEstimation of metastasis-free rates following PSA failure after radical prostatectomylegendKey: PSA = prostate-specific antigen., legendNumbers in parentheses are 95% confidence intervals., legendData from Pound et al.25Prognostic FactorsMetastasis-Free Survival (%)At 3 yrAt 5 yrAt 7 yrAll men with PSA recurrence78 (73–84