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Management of patients with rising prostate-specific antigen after radical prostatectomy
REVIEW CME ARTICLE
MANAGEMENT OF PATIENTS WITH RISING PROSTATE-SPECIFIC ANTIGEN AFTER RADICAL PROSTATECTOMY MENACHEM LAUFER, CHARLES R. POUND, MICHAEL A. CARDUCCI, MARIO A. EISENBERGER
D
uring 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.1,2 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.3,4 After 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.5 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.6,7 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.5 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.7–10 Various factors, including differences in patient populations, duration of followup, 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 From the Johns Hopkins Oncology Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Urology, Tel Aviv-Sourasky Medical Center, Tel Aviv, Israel; and Department of Urology, James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland Reprint requests: Mario Eisenberger, M.D., Johns Hopkins Oncology Center, 600 North Wolfe Street, Baltimore, MD 212878936 Submitted: July 30, 1999, accepted (with revisions): September 28, 1999 © 2000, ELSEVIER SCIENCE INC. ALL RIGHTS RESERVED
AND
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 RECURRENCE The 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).7,11–14 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.9,11,15 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).8,12,14,16 In addition to standard pathologic examination, various histopathologic determinants and molecular markers have been evaluated for prediction of UROLOGY 55: 309 –315, 2000 • 0090-4295/00/$20.00 PII S0090-4295(99)00465-3 309
TABLE I. Prediction models for recurrence after radical prostatectomy Author
Prediction Parameters 14
Bauer et al.
D’Amico et al.12
Kattan et al.8
Partin et al.16
Race Preoperative PSA* Prostatectomy Gleason Capsular status Preoperative PSA Pathologic stage Surgical margins status Prostatectomy Gleason Preoperative PSA Prostatectomy Gleason Pathologic stage Preoperative PSA* Prostatectomy Gleason Surgical margin status
Recurrence End Point
Application
Relative risk for recurrence
Equation
2-year PSA failure rate
Nomogram
7-year PSA failure rate
Nomogram
Log relative risk of recurrence
Equation
score
score score
score
KEY: PSA ⫽ prostate-specific antigen. * Sigmoid transformation of serum PSA level.
PSA recurrence and survival. Bauer et al.14 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.17,18 Other possible prognostic factors include expression of Ki-67, p27, apoptotic index, DNA ploidy, and tumor angiogenesis (microvessel density).18 –22 PSA SURVEILLANCE AND DEFINITION OF RECURRENCE On 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.5,23 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.24 The need for lifetime follow-up after RP is also controversial. Kattan et al.8 reported that recurrence beyond the 7-year point was rare, and the Johns Hopkins series reported by Pound et al.25 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 310
by today’s commercial assays is 0.1 ng/mL (undetectable levels are expressed as less than 0.1 ng/ mL).5 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.5,9,25 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.25,26 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.27 It is also well documented that minute concentrations of PSA originating from nonmalignant extraprostatic sources may be detected by ultrasensitive assays.28 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 RELAPSES The availability of local modalities of salvage treatment such as radiotherapy clearly supports UROLOGY 55 (3), 2000
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.7 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 %.5,29 The 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.30 –33 Preliminary data on endorectal coil magnetic resonance imaging were reported as encouraging34; 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.35 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.7,35 In their series, a PSA velocity greater than 0.75 ng/mL/yr enhanced the predictive value for distant disease.35 Others have reported that a PSA doubling time of less than 6 months was associated with the development of distant metastatic disease.36 The correlation between positive surgical margins and isolated local recurrence is controversial.35,37 Although it can be assumed that most local recurrences will develop from non-organ-confined tumors, so would most of the distant failures.13,25 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. UROLOGY 55 (3), 2000
NATURAL HISTORY OF PSA RELAPSES It 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.23 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 10year survival rate in patients without biochemical failure.9,25,38 – 40 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.25 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).25 According to this algorithm, patients with a Gleason score of 7 or less, a biochemical relapse 311
TABLE II. Estimation of metastasis-free rates following PSA failure after radical prostatectomy Metastasis-Free Survival (%) Prognostic Factors All men with PSA recurrence Gleason score 5–7 PSA recurrence ⬎2 yr PSA doubling time ⬎10 mo PSA doubling time ⱕ10 mo PSA recurrence ⱕ2 yr PSA doubling time ⬎10 mo PSA doubling time ⱕ10 mo Gleason score 8–10 PSA recurrence ⬎2 yr PSA recurrence ⱕ2 yr
At 3 yr 78 86 89 95 82 80 79 81 63 77 53
(73–84) (79–90) (81–94) (83–96) (54–94) (68–88) (65–88) (57–93) (52–73) (55–89) (39–66)
At 5 yr 63 73 82 86 69 62 76 35 40 60 31
(56–70) (65–80) (71–94) (74–92) (40–86) (49–73) (61–86) (16–56) (28–54) (33–79) (17–45)
At 7 yr 52 62 77 82 60 47 59 15 29 47 21
(44–60) (52–71) (65–86) (69–90) (32–80) (33–60) (40–73) (4–33) (16–43) (17–72) (9–35)
KEY: PSA ⫽ prostate-specific antigen. Numbers in parentheses are 95% confidence intervals. Data from Pound et al.25
after 2 years, and a PSA doubling time of more than 10 months have a probability of remaining metastasis free of 82% (95% confidence interval [CI] 69% to 90%) at 7 years. Patients with a Gleason score of 8 to 10 and PSA recurrence at 2 years or less have a probability of only 21% (95% CI 9% to 35%) for the same interval. Although this algorithm undoubtedly provides the most comprehensive information available to date, more data are needed on patients with Gleason scores of 8 to 10 and about the prognostic role of additional parameters, especially molecular markers. SALVAGE RADIOTHERAPY FOR LOCAL RECURRENCE Salvage radiotherapy is the recommended terminology for curative-intended radiation for postoperative PSA relapses as opposed to adjuvant radiotherapy administered shortly after RP on the basis of adverse pathologic findings.41 The American Society for Therapeutic Radiology and Oncology (ASTRO) consensus panel recently published preliminary guidelines for salvage radiotherapy.41 Unfortunately, most reports on salvage radiotherapy consist of small, uncontrolled retrospective series, with limited follow-up and almost no survival data. The available data revealed that 60% to 90% of the patients achieved an undetectable PSA after radiation41,42; however, only 10% to 45% remained free of PSA recurrence at 5 years.41– 43 It has been demonstrated that the serum PSA level before radiation is at this time the most powerful predictive factor for the response to salvage radiotherapy.44 The ASTRO consensus committee suggested that a threshold value of less than 1.5 ng/mL should be considered for the administration 312
of treatment.41 The prognostic role of adverse pathologic findings such as seminal vesicle or lymph node involvement and high tumor grade remains controversial.41,43,45 The timing of the PSA recurrence, which was reported as an important factor in the assessment of local versus distant relapse,36 and positive biopsy of the anastomotic site are also of questionable value.41,46,47 There is general agreement that adequate treatment requires a dose of 64 to 65 Gy, with standard fractionation.41 The combined use of hormonal therapy and salvage radiotherapy has been recently suggested48; however, this approach cannot be supported by any existing data and should not be used outside of an investigational setting. In conclusion, the role of salvage radiotherapy in the management of biochemical failure remains inconclusive. Although long-term PSA responses can be seen, the true benefit in terms of objective progression-free survival and overall survival is unproved. A preradiation PSA level of less than 1.5 ng/mL appears to be the most important factor predicting the response. It is important to recognize that a substantial proportion of patients with “indolent” biochemical relapses characterized by low serum PSA values, a long PSADT, a Gleason score of 7 or less, and no other adverse pathologic findings may have outstanding long-term outcome figures without any intervention. Conversely, patients with early relapses, a short PSADT, and Gleason scores of 8 to 10 are likely to harbor distant metastases. The treatment is costly, time consuming, and associated with a known rate of complications, and it should be reserved for patients with a high likelihood of isolated local recurrence in whom benefit is more likely. UROLOGY 55 (3), 2000
SYSTEMIC APPROACHES At present, there is no accepted standard approach for the systemic treatment of patients with biochemical recurrence. Androgen deprivation is frequently used, even though the side effects are considerable and the benefit, in terms of future quality of life and overall survival, remains undefined. Ongoing studies are addressing various aspects of endocrine interventions for patients with biochemical recurrence, such as early versus delayed, comparisons between different regimens and schedules (intermittent versus continuous androgen deprivation), and nonsteroidal antiandrogens or 5-alpha-reductase inhibitors as single agents. At present, the data are limited and preliminary, and the application of early hormonal intervention should be reserved for an investigational setting. The data on the natural history of PSA relapse discussed in the present report provide the initial groundwork for the design of clinical trials in the absence of standard treatment in this patient population. High-risk patients, as defined by the mathematical models in Table I and by the algorithm by Pound et al.,25 are likely to show clinical disease progression a relatively short time after PSA recurrence. These patients are the most suitable for clinical trials; patients with a rising PSA only and otherwise low-risk clinical and pathologic parameters may benefit from observation. Studies in this setting should primarily focus on conventional end points such as progression and, if feasible, survival. However, since patients who demonstrate PSA recurrence usually have no other evidence of disease, our ability to estimate response is limited. Therefore, studies should also be designed to evaluate the role of potential markers for biologic activity (intermediate) or treatment benefit (surrogate). An isolated PSA decline or a change in the PSA slope have yet to be validated as surrogate markers.49 Interpretation of PSA changes is further confounded by agents that may directly influence PSA production and by antiprogression compounds with no net tumoricidal effect. Candidate alternative markers for disease progression are several growth factors, such as insulin-like growth factor I,50 vascular endothelial growth factor,51 basic fibroblast growth factor,52 transforming growth factor-beta,53 Ki-67,54 and cell adhesion molecules.55 Understanding the molecular mechanisms of cancer growth, differentiation, invasion, and metastasis has provided the opportunity to identify important steps of this process that may serve as targets for novel therapeutic interventions by specifically designed compounds. As a result, the current armamentarium for the treatment of cancer includes new compounds, which act differently UROLOGY 55 (3), 2000
from conventional cytotoxic agents and are usually less toxic. These new approaches are probably more adequately tested in populations with favorable clinical and biologic conditions before the development of overt metastatic disease (minimal tumor burden). Given the unconfirmed value of early hormonal intervention and the overall modest efficacy of cytotoxic drugs in prostate cancer,56 the investigation of new approaches is fully justified. Various novel approaches such as immunotherapy, gene therapy, angiogenesis inhibitors, growth factor inhibitors, and differentiating agents have recently been introduced for the treatment of patients with PSA recurrence. In addition, the increasing focus on complementary medicine may demonstrate a role in the treatment of these patients in the future.57 Data regarding the efficacy of novel compounds are preliminary and deserve separate discussion, which is beyond the scope of this review. However, we would like to illustrate a strategy currently used for studying a class of drugs known to produce inhibition of tumor invasion and metastasis. Matrix metalloproteinases are a family of enzymes that are normally responsible for remodeling of the extracellular matrix.58 In a number of human cancers, including prostate cancer, this family of enzymes has been found to play an active role in the process of tumor invasion, dissemination, and angiogenesis through their capability for degrading extracellular matrix components.58 A number of potent inhibitors of these enzymes (matrix metalloproteinases inhibitors [MMPI]) have recently been developed as anti-invasion, antimetastatic compounds. Among those in active development are the oral compounds marimastat (British Biotech), AG3340 (Auguron), and BAY 12-9566 (Bayer). Marimastat is a broad spectrum MMPI that has excellent oral bioavailability and is currently undergoing testing in a variety of epithelial cancers, including prostate cancer. An initial Phase I study in patients with advanced metastatic prostate cancer demonstrated a much lower rate of objective and PSA progression with higher doses of this compound, thus suggesting a dose-response relationship. The most important toxicity was reversible musculoskeletal symptoms that were most likely dose related.59 A schema of an ongoing clinical trial at Johns Hopkins Hospital is shown in Figure 1. The study includes patients with evidence of PSA recurrence after RP or radiotherapy, who are at high risk for a progressive and rapid rise in PSA and for the development of distant metastases. It was designed to evaluate the possible effect of marimastat in three different doses on the rate of disease progression. The design of this trial and the selection of marimastat illustrate some of the challenges associated with therapeutic interventions in 313
FIGURE 1. Schema of ongoing study using the MMPI marimastat (British Biotech) in patients with PSA recurrence after definitive therapy for localized prostate cancer.
patients with a rising PSA and present one possible approach. CONCLUSIONS The treatment of patients with a rising PSA after RP poses a set of challenges of major magnitude. Major efforts should be directed toward the study of the natural history of these patients, with special emphasis on defining the relative risk for the development of metastatic disease and death caused by prostate cancer. The role of conventional treatments (local and systemic) in patients with evidence of biochemical failure remains undefined and requires careful study. The effects of any treatment should primarily be evaluated by conventional end points of disease progression, survival, and quality of life. The significance of changes in serum PSA values (such as decline, velocity, slope, and rise) and other alternative markers need to be evaluated prospectively with regard to their role as surrogate markers for response, progression, and survival. REFERENCES 1. Landis SH, Murray T, Bolden S, et al: Cancer Statistics, 1999. CA Cancer J Clin 49: 8 –31, 1999. 2. Moul JW: Epidemiology and screening for prostate cancer. Am J Manag Care 3: 1200 –1205, 1997. 3. Litwin MS, Pasta DJ, Stoddard ML, et al: Epidemiological trends and financial outcomes in radical prostatectomy among Medicare beneficiaries, 1991 to 1993. J Urol 160: 445– 448, 1998. 4. Gee WF, Holtgrewe HL, Blute ML, 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 160: 1804 –1807, 1998. 5. Partin AW, and Oesterling JE: The clinical usefulness of prostate specific antigen: update 1994. J Urol 15: 1358 –1368, 1994. 6. Goldrath DE, and Messing EM: Prostate specific antigen: not detectable despite tumor progression after radical prostatectomy. J Urol 142: 1082–1084, 1989. 7. Pound CR, Partin AW, Epstein JI, et al: Prostate-specific 314
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MANAGEMENT OF PATIENTS WITH RISING PROSTATE-SPECIFIC ANTIGEN AFTER RADICAL PROSTATECTOMY MENACHEM LAUFER, CHARLES R. POUND, MICHAEL A. CARDUCCI, MARIO A. EISENBERGER
D
uring 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.1,2 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.3,4 After 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.5 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.6,7 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.5 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.7–10 Various factors, including differences in patient populations, duration of followup, 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 From the Johns Hopkins Oncology Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Urology, Tel Aviv-Sourasky Medical Center, Tel Aviv, Israel; and Department of Urology, James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland Reprint requests: Mario Eisenberger, M.D., Johns Hopkins Oncology Center, 600 North Wolfe Street, Baltimore, MD 212878936 Submitted: July 30, 1999, accepted (with revisions): September 28, 1999 © 2000, ELSEVIER SCIENCE INC. ALL RIGHTS RESERVED
AND
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 RECURRENCE The 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).7,11–14 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.9,11,15 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).8,12,14,16 In addition to standard pathologic examination, various histopathologic determinants and molecular markers have been evaluated for prediction of UROLOGY 55: 309 –315, 2000 • 0090-4295/00/$20.00 PII S0090-4295(99)00465-3 309
TABLE I. Prediction models for recurrence after radical prostatectomy Author
Prediction Parameters 14
Bauer et al.
D’Amico et al.12
Kattan et al.8
Partin et al.16
Race Preoperative PSA* Prostatectomy Gleason Capsular status Preoperative PSA Pathologic stage Surgical margins status Prostatectomy Gleason Preoperative PSA Prostatectomy Gleason Pathologic stage Preoperative PSA* Prostatectomy Gleason Surgical margin status
Recurrence End Point
Application
Relative risk for recurrence
Equation
2-year PSA failure rate
Nomogram
7-year PSA failure rate
Nomogram
Log relative risk of recurrence
Equation
score
score score
score
KEY: PSA ⫽ prostate-specific antigen. * Sigmoid transformation of serum PSA level.
PSA recurrence and survival. Bauer et al.14 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.17,18 Other possible prognostic factors include expression of Ki-67, p27, apoptotic index, DNA ploidy, and tumor angiogenesis (microvessel density).18 –22 PSA SURVEILLANCE AND DEFINITION OF RECURRENCE On 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.5,23 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.24 The need for lifetime follow-up after RP is also controversial. Kattan et al.8 reported that recurrence beyond the 7-year point was rare, and the Johns Hopkins series reported by Pound et al.25 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 310
by today’s commercial assays is 0.1 ng/mL (undetectable levels are expressed as less than 0.1 ng/ mL).5 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.5,9,25 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.25,26 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.27 It is also well documented that minute concentrations of PSA originating from nonmalignant extraprostatic sources may be detected by ultrasensitive assays.28 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 RELAPSES The availability of local modalities of salvage treatment such as radiotherapy clearly supports UROLOGY 55 (3), 2000
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.7 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 %.5,29 The 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.30 –33 Preliminary data on endorectal coil magnetic resonance imaging were reported as encouraging34; 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.35 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.7,35 In their series, a PSA velocity greater than 0.75 ng/mL/yr enhanced the predictive value for distant disease.35 Others have reported that a PSA doubling time of less than 6 months was associated with the development of distant metastatic disease.36 The correlation between positive surgical margins and isolated local recurrence is controversial.35,37 Although it can be assumed that most local recurrences will develop from non-organ-confined tumors, so would most of the distant failures.13,25 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. UROLOGY 55 (3), 2000
NATURAL HISTORY OF PSA RELAPSES It 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.23 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 10year survival rate in patients without biochemical failure.9,25,38 – 40 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.25 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).25 According to this algorithm, patients with a Gleason score of 7 or less, a biochemical relapse 311
TABLE II. Estimation of metastasis-free rates following PSA failure after radical prostatectomy Metastasis-Free Survival (%) Prognostic Factors All men with PSA recurrence Gleason score 5–7 PSA recurrence ⬎2 yr PSA doubling time ⬎10 mo PSA doubling time ⱕ10 mo PSA recurrence ⱕ2 yr PSA doubling time ⬎10 mo PSA doubling time ⱕ10 mo Gleason score 8–10 PSA recurrence ⬎2 yr PSA recurrence ⱕ2 yr
At 3 yr 78 86 89 95 82 80 79 81 63 77 53
(73–84) (79–90) (81–94) (83–96) (54–94) (68–88) (65–88) (57–93) (52–73) (55–89) (39–66)
At 5 yr 63 73 82 86 69 62 76 35 40 60 31
(56–70) (65–80) (71–94) (74–92) (40–86) (49–73) (61–86) (16–56) (28–54) (33–79) (17–45)
At 7 yr 52 62 77 82 60 47 59 15 29 47 21
(44–60) (52–71) (65–86) (69–90) (32–80) (33–60) (40–73) (4–33) (16–43) (17–72) (9–35)
KEY: PSA ⫽ prostate-specific antigen. Numbers in parentheses are 95% confidence intervals. Data from Pound et al.25
after 2 years, and a PSA doubling time of more than 10 months have a probability of remaining metastasis free of 82% (95% confidence interval [CI] 69% to 90%) at 7 years. Patients with a Gleason score of 8 to 10 and PSA recurrence at 2 years or less have a probability of only 21% (95% CI 9% to 35%) for the same interval. Although this algorithm undoubtedly provides the most comprehensive information available to date, more data are needed on patients with Gleason scores of 8 to 10 and about the prognostic role of additional parameters, especially molecular markers. SALVAGE RADIOTHERAPY FOR LOCAL RECURRENCE Salvage radiotherapy is the recommended terminology for curative-intended radiation for postoperative PSA relapses as opposed to adjuvant radiotherapy administered shortly after RP on the basis of adverse pathologic findings.41 The American Society for Therapeutic Radiology and Oncology (ASTRO) consensus panel recently published preliminary guidelines for salvage radiotherapy.41 Unfortunately, most reports on salvage radiotherapy consist of small, uncontrolled retrospective series, with limited follow-up and almost no survival data. The available data revealed that 60% to 90% of the patients achieved an undetectable PSA after radiation41,42; however, only 10% to 45% remained free of PSA recurrence at 5 years.41– 43 It has been demonstrated that the serum PSA level before radiation is at this time the most powerful predictive factor for the response to salvage radiotherapy.44 The ASTRO consensus committee suggested that a threshold value of less than 1.5 ng/mL should be considered for the administration 312
of treatment.41 The prognostic role of adverse pathologic findings such as seminal vesicle or lymph node involvement and high tumor grade remains controversial.41,43,45 The timing of the PSA recurrence, which was reported as an important factor in the assessment of local versus distant relapse,36 and positive biopsy of the anastomotic site are also of questionable value.41,46,47 There is general agreement that adequate treatment requires a dose of 64 to 65 Gy, with standard fractionation.41 The combined use of hormonal therapy and salvage radiotherapy has been recently suggested48; however, this approach cannot be supported by any existing data and should not be used outside of an investigational setting. In conclusion, the role of salvage radiotherapy in the management of biochemical failure remains inconclusive. Although long-term PSA responses can be seen, the true benefit in terms of objective progression-free survival and overall survival is unproved. A preradiation PSA level of less than 1.5 ng/mL appears to be the most important factor predicting the response. It is important to recognize that a substantial proportion of patients with “indolent” biochemical relapses characterized by low serum PSA values, a long PSADT, a Gleason score of 7 or less, and no other adverse pathologic findings may have outstanding long-term outcome figures without any intervention. Conversely, patients with early relapses, a short PSADT, and Gleason scores of 8 to 10 are likely to harbor distant metastases. The treatment is costly, time consuming, and associated with a known rate of complications, and it should be reserved for patients with a high likelihood of isolated local recurrence in whom benefit is more likely. UROLOGY 55 (3), 2000
SYSTEMIC APPROACHES At present, there is no accepted standard approach for the systemic treatment of patients with biochemical recurrence. Androgen deprivation is frequently used, even though the side effects are considerable and the benefit, in terms of future quality of life and overall survival, remains undefined. Ongoing studies are addressing various aspects of endocrine interventions for patients with biochemical recurrence, such as early versus delayed, comparisons between different regimens and schedules (intermittent versus continuous androgen deprivation), and nonsteroidal antiandrogens or 5-alpha-reductase inhibitors as single agents. At present, the data are limited and preliminary, and the application of early hormonal intervention should be reserved for an investigational setting. The data on the natural history of PSA relapse discussed in the present report provide the initial groundwork for the design of clinical trials in the absence of standard treatment in this patient population. High-risk patients, as defined by the mathematical models in Table I and by the algorithm by Pound et al.,25 are likely to show clinical disease progression a relatively short time after PSA recurrence. These patients are the most suitable for clinical trials; patients with a rising PSA only and otherwise low-risk clinical and pathologic parameters may benefit from observation. Studies in this setting should primarily focus on conventional end points such as progression and, if feasible, survival. However, since patients who demonstrate PSA recurrence usually have no other evidence of disease, our ability to estimate response is limited. Therefore, studies should also be designed to evaluate the role of potential markers for biologic activity (intermediate) or treatment benefit (surrogate). An isolated PSA decline or a change in the PSA slope have yet to be validated as surrogate markers.49 Interpretation of PSA changes is further confounded by agents that may directly influence PSA production and by antiprogression compounds with no net tumoricidal effect. Candidate alternative markers for disease progression are several growth factors, such as insulin-like growth factor I,50 vascular endothelial growth factor,51 basic fibroblast growth factor,52 transforming growth factor-beta,53 Ki-67,54 and cell adhesion molecules.55 Understanding the molecular mechanisms of cancer growth, differentiation, invasion, and metastasis has provided the opportunity to identify important steps of this process that may serve as targets for novel therapeutic interventions by specifically designed compounds. As a result, the current armamentarium for the treatment of cancer includes new compounds, which act differently UROLOGY 55 (3), 2000
from conventional cytotoxic agents and are usually less toxic. These new approaches are probably more adequately tested in populations with favorable clinical and biologic conditions before the development of overt metastatic disease (minimal tumor burden). Given the unconfirmed value of early hormonal intervention and the overall modest efficacy of cytotoxic drugs in prostate cancer,56 the investigation of new approaches is fully justified. Various novel approaches such as immunotherapy, gene therapy, angiogenesis inhibitors, growth factor inhibitors, and differentiating agents have recently been introduced for the treatment of patients with PSA recurrence. In addition, the increasing focus on complementary medicine may demonstrate a role in the treatment of these patients in the future.57 Data regarding the efficacy of novel compounds are preliminary and deserve separate discussion, which is beyond the scope of this review. However, we would like to illustrate a strategy currently used for studying a class of drugs known to produce inhibition of tumor invasion and metastasis. Matrix metalloproteinases are a family of enzymes that are normally responsible for remodeling of the extracellular matrix.58 In a number of human cancers, including prostate cancer, this family of enzymes has been found to play an active role in the process of tumor invasion, dissemination, and angiogenesis through their capability for degrading extracellular matrix components.58 A number of potent inhibitors of these enzymes (matrix metalloproteinases inhibitors [MMPI]) have recently been developed as anti-invasion, antimetastatic compounds. Among those in active development are the oral compounds marimastat (British Biotech), AG3340 (Auguron), and BAY 12-9566 (Bayer). Marimastat is a broad spectrum MMPI that has excellent oral bioavailability and is currently undergoing testing in a variety of epithelial cancers, including prostate cancer. An initial Phase I study in patients with advanced metastatic prostate cancer demonstrated a much lower rate of objective and PSA progression with higher doses of this compound, thus suggesting a dose-response relationship. The most important toxicity was reversible musculoskeletal symptoms that were most likely dose related.59 A schema of an ongoing clinical trial at Johns Hopkins Hospital is shown in Figure 1. The study includes patients with evidence of PSA recurrence after RP or radiotherapy, who are at high risk for a progressive and rapid rise in PSA and for the development of distant metastases. It was designed to evaluate the possible effect of marimastat in three different doses on the rate of disease progression. The design of this trial and the selection of marimastat illustrate some of the challenges associated with therapeutic interventions in 313
FIGURE 1. Schema of ongoing study using the MMPI marimastat (British Biotech) in patients with PSA recurrence after definitive therapy for localized prostate cancer.
patients with a rising PSA and present one possible approach. CONCLUSIONS The treatment of patients with a rising PSA after RP poses a set of challenges of major magnitude. Major efforts should be directed toward the study of the natural history of these patients, with special emphasis on defining the relative risk for the development of metastatic disease and death caused by prostate cancer. The role of conventional treatments (local and systemic) in patients with evidence of biochemical failure remains undefined and requires careful study. The effects of any treatment should primarily be evaluated by conventional end points of disease progression, survival, and quality of life. The significance of changes in serum PSA values (such as decline, velocity, slope, and rise) and other alternative markers need to be evaluated prospectively with regard to their role as surrogate markers for response, progression, and survival. REFERENCES 1. Landis SH, Murray T, Bolden S, et al: Cancer Statistics, 1999. CA Cancer J Clin 49: 8 –31, 1999. 2. Moul JW: Epidemiology and screening for prostate cancer. Am J Manag Care 3: 1200 –1205, 1997. 3. Litwin MS, Pasta DJ, Stoddard ML, et al: Epidemiological trends and financial outcomes in radical prostatectomy among Medicare beneficiaries, 1991 to 1993. J Urol 160: 445– 448, 1998. 4. Gee WF, Holtgrewe HL, Blute ML, 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 160: 1804 –1807, 1998. 5. Partin AW, and Oesterling JE: The clinical usefulness of prostate specific antigen: update 1994. J Urol 15: 1358 –1368, 1994. 6. Goldrath DE, and Messing EM: Prostate specific antigen: not detectable despite tumor progression after radical prostatectomy. J Urol 142: 1082–1084, 1989. 7. Pound CR, Partin AW, Epstein JI, et al: Prostate-specific 314
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