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Prostate Specific Antigen Kinetics in the Management of Prostate Cancer
Review Articles Prostate Specific Antigen Kinetics in the Management of Prostate Cancer Shomik Sengupta,* Christopher Amling,† Anthony V. D’Amico* and Michael L. Blute*,‡ From the Department of Urology, Mayo Clinic, Rochester, Minnesota (SS, MLB), Department of Urology, University of Alabama, Birmingham, Alabama (CA), and Department of Radiation Oncology, Brigham and Women’s Hospital, and the Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts (AVD)
Purpose: We review the usefulness of prostate specific antigen kinetics (ie prostate specific antigen velocity and doubling time) in the treatment of patients with prostate cancer. Materials and Methods: The MEDLINE database was searched to identify studies investigating prostate specific antigen kinetics in patients with prostate cancer. Results: Various techniques are available for estimating prostate specific antigen kinetics, but to minimize the impact of prostate specific antigen variability on such calculations at least a 90-day period and preferably more than 2 measurements should be used. There is little to suggest which measure of prostate specific antigen kinetics may be superior since both appear to provide useful prognostic information. Prostate specific antigen velocity is easier to calculate but prostate specific antigen doubling time may have greater biological justification. Retrospective studies show that before treatment prostate specific antigen kinetics provide prognostic information regarding the risk of treatment failure and subsequent death from cancer. Additionally, in patients treated surgically preoperative prostate specific antigen kinetics predict the risk of adverse pathology, while in those undergoing conservative treatment prostate specific antigen kinetics are associated with the risk of progression and need for intervention. In patients with biochemical failure after therapy prostate specific antigen kinetics predict the risk and potential site of clinical recurrence, the likely response to salvage therapy, and the risk of death from cancer. Preliminary assessments also suggest that prostate specific antigen kinetics may serve as a surrogate end point to replace cancer specific mortality. Conclusions: Although prospective studies are lacking, the current literature suggests that prostate specific antigen kinetics provide valuable prognostic information, and should be further evaluated in clinical decision making and as a surrogate end point for future trials. Key Words: prostatic neoplasms, prostate-specific antigen, prostatectomy, radiotherapy, survival
with time. PSAV was originally described by Carter et al based on the Baltimore Longitudinal Study of Aging.1 Subsequently PSADT was described by Schmid et al and was studied extensively in patients treated with radiotherapy for prostate cancer.2 An increasing body of work suggests that these 2 measures of PSA kinetics may be useful in managing prostate cancer. We review the available data related to PSAV and PSADT in various clinical settings. It is notable that the literature on PSA kinetics is largely retrospective, resulting from the fact that PSA kinetic data are easier to interpret after a number of measurements have been collected. In contrast, as new PSA readings are obtained in clinical practice, it may be difficult to discern changes reflecting cancer behavior from those reflecting confounding processes such as inflammation.
ince its advent in clinical practice in the 1980s, PSA has had a significant impact on the management of prostate cancer. Most notably, by allowing the early detection of asymptomatic disease it has been responsible for the stage migration of prostate cancer during the last 2 decades. Additionally, serum PSA has become indispensable for prognostication and surveillance. However, PSA remains an imperfect test. In the diagnostic setting noncancerous causes of PSA increase such as benign hypertrophy or inflammation of the prostate frequently confound the clinical picture. Prostate cancers of widely disparate biology may present with comparable PSAs, thus, undermining the prognostic reliability of a single PSA measurement. Given the prolonged natural history of prostate cancer, the implications of changes in serum PSA after therapy are often unclear on short-term followup. A way to overcome some of the limitations of PSA testing has been to examine PSA kinetics or the rate of PSA change
S
PSA KINETIC PARAMETERS: ESTIMATION AND ERROR Because PSAV and PSADT are measures of the rate of PSA change with time, their estimation relies on the statistical
Submitted for publication April 22, 2007. * Nothing to disclose. † Financial interest and/or other relationship with Johnson & Johnson, TAP Pharmaceuticals and Sanofi-Aventis. ‡ Correspondence: Department of Urology, Mayo Clinic, 200 First St. SW, Rochester, Minnesota 55905 (telephone: 507-284-3987; FAX: 507-284-4987; e-mail: [email protected]).
0022-5347/08/1793-0821/0 THE JOURNAL OF UROLOGY® Copyright © 2008 by AMERICAN UROLOGICAL ASSOCIATION
Editor’s Note: This article is the first of 5 published in this issue for which category 1 CME credits can be earned. Instructions for obtaining credits are given with the questions on pages 1208 and 1209.
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Vol. 179, 821-826, March 2008 Printed in U.S.A. DOI:10.1016/j.juro.2007.10.023
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PROSTATE SPECIFIC ANTIGEN KINETICS AND PROSTATE CANCER
technique of regression. The calculation of PSAV is based on the assumption that PSA increases in a linear fashion with time and, therefore, uses linear regression analysis. In practice this translates into a fairly simple slope calculation of the formula, PSAV ⫽ change in PSA/time between measurements. If more than 2 PSA readings are available PSAV may simply be averaged. For example, for 3 PSA measurements, PSAV ⫽ [{(PSA2 – PSA1)/interval1} ⫹ {(PSA3 – PSA2)/interval2}]/2. In contrast, PSADT assumes an exponential increase in PSA and, therefore, requires a somewhat more complex analysis for estimation. Regression techniques for the estimation of PSADT require the logarithmic transformation of available PSA values by the somewhat daunting formula, PSADT ⫽ t ⫻ natural log2/natural log (ratio of PSAs). In practice the calculation of PSADT requires the use of statistical software or online algorithms, although a recently published graphical tool allows the estimation of PSADT in practice settings without electronic resources.3 The measurement of serum PSA is susceptible to error from several sources, most notably from interassay and biological variations, and a number of precautions are required to minimize the impact of such errors on estimates of PSA kinetics. Thus, sequential PSA readings should ideally be obtained from the same laboratory using a well calibrated assay. Furthermore, the greater the number of PSA measurements used and the longer the interval during which they are obtained, the more likely it is that the resulting estimate of PSA kinetics truly reflects cancer growth. However, the need for expedient decision making and the costs of repeat PSA testing usually place practical limits on the number and spacing of available PSA measurements. Additionally, since cancer biology may evolve, leading to variation in PSA kinetics with time, it seems prudent to restrict PSA kinetic assessments to a maximum of 12 to 24 months.4 Two PSA readings separated by at least 3 months appear to provide a reasonably accurate estimate of PSADT, but a minimum of 3 readings during at least 6 months should be obtained when possible.
or frail patients treated conservatively because of limited life expectancy may have intermediate to high risk tumors, younger patients placed on AS protocols are usually selected on the basis of low risk features. Not surprisingly, PSA is found to increase relatively slowly in most of these patients with PSADT longer than 10 years in the majority. The rate of PSA increase appears to be related to the aggressiveness of the prostate cancer as indicated by an association with clinical stage, biopsy grade and initial PSA,5,6 although these findings vary somewhat among series (table 1).7,8 Another difficulty in interpreting the predictive value of PSA kinetics in this setting is that since an increase in PSA is often a trigger for intervention, men with rapid PSA kinetics are over represented in the treated subgroup, thus leading to selection bias. In fact, some active surveillance protocols explicitly incorporate PSA kinetic measures as criteria for intervention. For example, Choo et al offer curative surgery to men under active surveillance with a PSADT of less than 3 years.7 However, a number of other studies that did not formally use PSA kinetics for decisions on intervention have reported a significant association between PSA kinetics and the need for intervention or time to intervention, thus providing support for this concept.9 –11 Furthermore, PSADT has been shown to correlate with other measures of progression such as DRE, repeat biopsy or bone scan.6,9 Finally, PSA kinetic measures appear to be associated with the risk of death from prostate cancer in men treated conservatively.12,13 Despite these findings doubts remain regarding the usefulness of PSA kinetic measures in an individual patient given the wide variation and significant overlap.6 – 8 Additionally, variability in PSA kinetics with time is pronounced, further complicating the application of these measures in decision making during the conservative management of prostate cancer. 4,8 Currently it seems sensible to incorporate PSA kinetics along with other criteria in AS and WW protocols, although individualized rather than universal cutoff points may be preferable.5
PSA KINETICS AND CONSERVATIVE MANAGEMENT
PSA KINETICS AND RADICAL PROSTATECTOMY
Men with prostate cancer may be treated conservatively with planned delayed intervention with curative AS or palliative WW intent. Although serial PSA data are usually available for men undergoing such conservative treatment, published reports are few and somewhat difficult to interpret. Many studies are retrospective, and include patients with a broad spectrum of disease pathologies treated with AS and WW. While elderly
As serial PSA testing becomes more common, preoperative PSA kinetic data are increasingly available for patients treated surgically. Preoperative PSA kinetic measures are associated with aggressive pathological features at prostatectomy, including local and nodal stage, specimen Gleason score, and involvement of surgical margins. Although early studies suggested that preoperative PSA kinetics were not predictive of postoperative outcomes, they were likely lim-
TABLE 1. Relationship of PSA kinetics to clinical features, risk of progression and need for intervention in patients with prostate cancer treated conservatively Hardie et al5 No. pts PSA kinetic p Value: Age PSA T stage Biopsy grade Progression Time to treatment * Multivariate analysis.
80 PSADT NS 0.039 0.036* NS
Stephenson et al6 94 PSADT NS NS 0.04 NR DRE 0.019, biopsy 0.03
Choo et al7
Gerber et al8
134 PSADT
49 PSAV
NS NS NS NS
NS NS NS NS
McLaren et al9 113 PSADT
DRE ⬍0.01, clinical ⬍0.0001 ⬍0.0001
PROSTATE SPECIFIC ANTIGEN KINETICS AND PROSTATE CANCER
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TABLE 2. Relationship of preoperative PSA kinetics with pathologic findings and survival in surgically treated patients D’Amico et al14 No. pts PSA kinetic p Value: Stage Grade Pos surgical margin Survival*
Sengupta et al15
1,069 PSAV ⬍0.05 ⬍0.05 CSS ⬍0.001, OS ⬍0.01
Patel et al16
2,290 PSAV ⫹ PSADT
202 PSAV
⬍0.0001 ⬍0.0001 PSAV ⬍0.0001, PSADT NS CSS ⬍0.0001
0.007 0.04 0.01 RFS 0.03
* Multivariate analysis.
ited in power, and more recent series have confirmed preoperative PSA kinetics to be predictive of the risk of progression and death after radical prostatectomy (table 2). D’Amico et al analyzed a cohort of 1,069 men who had undergone serial PSA testing at the same laboratory before surgery, and PSAV greater than 2.0 ng/ml per year was associated with a significantly increased risk of death from prostate cancer and from all causes.14 Sengupta et al compared preoperative PSAV and PSADT, and reported that PSADT was a stronger predictor of clinical recurrence or death from cancer.15 Preoperative PSA kinetics do not appear to simply be surrogate markers for conventional clinical or histological indicators of aggressive disease, since the prognostic value of PSA kinetics persists on multivariate analysis.14 –16 The inclusion of PSA kinetics causes preoperative PSA to drop out of multivariate models, suggesting that the rate of increase may be more important prognostically than the absolute PSA value.15 In the postoperative setting, since all PSA producing tissue has been removed, serum PSA is expected to be undetectable. Although a detectable PSA is taken to be presumptive evidence of cancer recurrence, only about a third of these patients have clinically evident recurrence. Defining recurrence by biochemical criteria remains controversial, with various cut points used in the literature. It has been reported that a PSA increase of less than 0.4 ng/ml was rarely associated with further subsequent increases, suggesting that this threshold is most appropriate. Stephenson et al also found a PSA cutoff of 0.4 ng/ml to be associated with subsequent PSADT and risk of metastasis.17 Even in patients with biochemical recurrence a subgroup can be identified with slowly increasing PSA, delayed and infrequent clinical recurrence, and low risk of death from cancer who may be best treated conservatively.18 When clinical recurrence is local, that is at the site of resection, salvage therapy may be considered. When recurrence is systemic, palliative hormonal therapy becomes most appropriate. PSADT after recurrence is predicted by preoperative risk factors, pathological findings and time to biochemical failure,19 and
these factors may help delineate the risk of metastatic vs local recurrence.20 –23 Early studies suggested that the likely site of recurrence may be predicted based on PSAV24 or PSADT25 after biochemical recurrence. Subsequent reports have confirmed a clear association between rapid PSA kinetics and the subsequent risk of metastatic recurrence (table 3). Recently an association between PSA kinetics after recurrence and survival has been established, with a 5-year cancer specific mortality of 31% vs 1% for patients with PSADT less than 3 months vs 3 months or greater,26 suggesting that PSADT may be useful as a surrogate end point for cancer death.27 Notably, prostate cancer predominates as a cause of death in men with PSA recurrence after surgery, even up to a PSADT of 15 months.28 Additionally, in patients receiving salvage radiotherapy PSA kinetics before radiation appear to be an important prognostic factor,29 while high risk patients treated with adjuvant hormonal therapy are most likely to benefit if they have a rapid PSADT.30 Furthermore, in the face of an increasing PSA while on hormonal therapy after initial local therapy, PSA kinetic measures predict subsequent survival and may have some use in decision making regarding additional therapy.31 PSA KINETICS AND RADIOTHERAPY Data on PSA kinetics in patients treated with external or interstitial radiation largely parallel those described in surgically treated patients (table 4). Thus, Hanks et al found the pretreatment PSADT and the radiation dose to be significant multivariate predictors of biochemical recurrencefree survival.32 Recently D’Amico et al reported that pretreatment PSAV greater than 2.0 ng/ml per year was associated with an increased risk of biochemical recurrence, death from cancer and death from any cause after external beam radiation regardless of the risk group.33 Eggener et al observed that a pretreatment PSAV cutoff of 2.0 ng/ml per year is also predictive of biochemical outcomes after brachytherapy.34 D’Amico et al further reported that patients with
TABLE 3. Relationship of post-recurrence PSA kinetics and survival in surgically treated patients
No. pts No. PSA recurrence PSA kinetic Association with survival (p value) Comments
* Multivariate analysis.
Dotan et al20
Pound et al22
Roberts et al23
239
1,997 315
2,809 879 (587 with PSADT) PSADT Systemic PFS (⬍0.001), PFS (⬍0.001)* PSADT less than 6 mos predicts systemic progression
PSAV Bone metastasis (OR 0.93, p ⬍0.003)*
PSADT Systemic PFS (⬍0.001)
Zhou et al26 NS 498 PSADT PSADT less than 3 mos predicts prostate cancer specific mortality (HR 54.9)
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PROSTATE SPECIFIC ANTIGEN KINETICS AND PROSTATE CANCER TABLE 4. Relationship of pretreatment PSA kinetics with survival in patients treated with radiotherapy Hanks et al32
D’Amico et al33
No. pts Treatment PSA kinetic
99 External beam (dose NS) PSADT
358 External beam (77 Gy) PSAV
Association with survival Comments
bRFS 50% bRFS at 18 mos in pts with PSADT less than 12 mos
bRFS, CSS ⫹ OS (each p ⬍0.01) Low risk ⫹ high risk groups
a rapid pretreatment PSAV benefit from the addition of androgen deprivation to external beam radiation.35 PSA kinetics after radiation are confounded by the continuing production of PSA by the prostate, which is susceptible to a number of influences. Thus, the concomitant use of androgen deprivation and radiation often causes a withdrawal effect, leading to more rapid PSA increases, which may lead to misclassification of biochemical failure.36,37 In fact, during the initial period after external beam radiotherapy, PSA decreases and the negative PSA kinetics as well as the PSA nadir appear to be prognostic of overall survival.38 After interstitial seed placement the phenomenon of PSA bounce may occur and cause confusion with early biochemical relapse. In fact, the PSA kinetics for the 2 events appear to be similar, and the time from therapy may be the most reliable distinguishing characteristic with bounces typically occurring earlier than recurrence.39 PSADT after recurrence may also be useful in classifying the likely site of recurrence in patients treated with radiotherapy, with those with local relapse amenable to salvage therapies.40 The success rate of salvage cryotherapy in this setting also depends on PSADT before salvage.41 Zagars and Pollack,42 and Lee et al43 reported that PSADT less than 8 months after relapse is associated with the risk of metastatic disease and death from all causes in patients treated with external beam radiotherapy alone42 or in combination with androgen deprivation (table 5).43 Using 3-dimensional conformal intensity modulated radiation therapy Zelefsky et al observed a similar relationship between PSADT and metastatic recurrence.44 Cancer specific mortality after external beam radiation for prostate cancer is strongly associated with PSADT after recurrence, and is 75% vs 15% for PSADT less than 3 months vs 3 months or greater in patients with Gleason score greater than 7, and 35% vs 4%, respectively, in those with Gleason score 7 or less.26 Similarly, for patients treated with interstitial seed placement 10-year CSS is 30% for patients with a PSADT of 6 months or less vs 98% for those with a PSADT of more than 10 months.45
Eggener et al34
Eggener et al34
83 External beam (dose NR) PSAV (greater than 2 ng/ml/yr) bRFS 80% Vs 55% at 6 yrs
47 Brachytherapy PSAV (greater than 2 ng/ml/yr) bRFS 88% Vs 65% at 6 yrs
CLINICAL USE AND FUTURE DIRECTIONS The application of PSA kinetic measures in clinical practice is really no more than a formalization of serial PSA testing. While regular PSA measurements for surveillance after treatment have long been routine, it has recently become more common in other clinical settings. Thus, many patients now undergo repeat PSA screening before prostate cancer diagnosis. The indication for prostatic biopsy in these patients is typically an increase in PSA beyond a threshold level. However, controversy persists regarding the optimal PSA cutoff, with emerging data indicating that the risk of prostate cancer remains significant even with a nominally normal PSA. It remains uncertain whether PSA kinetic measures are likely to be helpful in this setting. In the prospective Prostate Cancer Prevention Trial PSAV based on at least 2 PSAs in 3 years was not a significant predictor of a positive end of study biopsy.46 In contrast, short-term PSAV more than 2 months before biopsy was associated with the presence of malignancy in patients with an abnormal PSA.47 It is also notable that data from the Baltimore Longitudinal Study of Aging revealed differences in PSAV years before prostate cancer diagnosis.1 A problem with retrospective analyses of the diagnostic value of PSA kinetics is that not all men undergo biopsy, resulting in assignment bias.48 Further prospective study of this issue is awaited, but in younger men rapid unexplained increases in PSA, even in the normal range, need to be viewed with concern. For patients with a prostate cancer diagnosis PSA kinetics appear to convey prognostic information that should be considered with conventional prognostic factors such as absolute PSA, clinical stage and biopsy grade. Although PSA kinetics are of the greatest relevance immediately before diagnosis, PSA velocity can provide prognostic information years ahead.13 PSA kinetics are likely to be useful not only in counseling patients regarding likely outcomes after treatment, but also in suggesting experimental multimodal ther-
TABLE 5. Relationship of post-recurrence PSA kinetics with survival in patients treated with radiotherapy Zagars and Pollack42 No. pts Treatment No. relapse PSA kinetic Association with survival Comments
841 60–78 Gy 263 PSADT less than 8 mos sRFS 93% Vs 46% at 7 yrs
Lee et al43
Zelefsky et al44
Sartor et al40
Zhou et al26
Stock et al45
399
NS External beam, dose NS 661 PSADT CSS
1,561 Brachytherapy ⫾ external beam ⫾ ADT 131 PSADT CSS
621 76 Gy ⫹ ADT
1,650 64–81 Gy ⫾ ADT
70 Gy
75 PSADT Clinical RFS p ⬍0.001, OS p ⫽ 0.015
381 PSADT sRFS ⫹ OS
234 (increasing PSA) PSADT sRFS, local RFS
PSADT less than 6 mos vs greater than 12 mos, HR greater than 6.6
Site of recurrence
PROSTATE SPECIFIC ANTIGEN KINETICS AND PROSTATE CANCER apy protocols for those with aggressive disease. Finally, in the context of AS protocols, PSA kinetic measures may be crucial criteria for intervention, although precise cutoff levels require further investigation. Biochemical recurrence after treatment leads inevitably to consideration of PSA kinetics in clinical decision making. In this context, along with known pretreatment and posttreatment prognostic factors, PSA kinetics may allow an assessment of the probability of relapse and the likely site, thereby facilitating rational decisions regarding the need for and type of salvage therapy. For instance, it appears that for men with biochemical recurrence after radical prostatectomy or external beam radiation and a PSADT of less than 3 months, earlier initiation of hormonal therapy delays the development of bony metastases, thereby improving quality of life even if survival is not prolonged.27 This group of men may also be usefully studied in randomized trials of systemic chemotherapy such as docetaxel. Similarly for men with metastatic prostate cancer PSA kinetic measures may be used to guide the initiation of hormonal therapy and secondary intervention during the hormone refractory phase.49 In these clinical situations either measure of PSA kinetics may be applied. There is empirical evidence that prostate cancer biology does in fact conform to an exponential model and, therefore, PSADT may be more accurate.2,50 This is partially supported by the results of a large retrospective study of PSA kinetics before prostatectomy.15 However, during short intervals the linear and exponential curves closely approximate each other and, therefore, PSAV provides a satisfactory alternative that is usually easier to calculate. Finally, it should be noted that PSAV and PSADT are related to each other and to serum PSA by the formula, PSAV ⬁ PSA/PSADT. In a linear model (constant PSAV) PSADT is assumed to vary with PSA, and vice versa in an exponential model (constant PSADT). In reality, for a particular cancer in a particular man the exact pattern of PSA increase with time may not conform exactly to either model, and whichever model is used ends up being an approximation.
Abbreviations and Acronyms ADT AS bRFS CSS DRE NS NR OS PFS PSA PSADT PSAV RFS sRFS WW
⫽ ⫽ ⫽ ⫽ ⫽ ⫽ ⫽ ⫽ ⫽ ⫽ ⫽ ⫽ ⫽ ⫽ ⫽
androgen deprivation therapy active surveillance biochemical RFS cancer specific survival digital rectal examination not statistically significant not reported overall survival progression-free survival prostate specific antigen PSA doubling time PSA velocity recurrence-free survival systemic RFS watchful waiting
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with risk of prostate cancer progression following brachytherapy and external beam radiation therapy. J Urol 2006; 176: 1399. D’Amico AV, Loffredo M, Renshaw AA, Loffredo B and Chen MH: Six-month androgen suppression plus radiation therapy compared with radiation therapy alone for men with prostate cancer and a rapidly increasing pretreatment prostate-specific antigen level. J Clin Oncol 2006; 24: 4190. Bates AT, Pickles T and Paltiel C: PSA doubling time kinetics during prostate cancer biochemical relapse after external beam radiation therapy. Int J Radiat Oncol Biol Phys 2005; 62: 148. Buyyounouski MK, Hanlon AL, Horwitz EM, Uzzo RG and Pollack A: Biochemical failure and the temporal kinetics of prostate-specific antigen after radiation therapy with androgen deprivation. Int J Radiat Oncol Biol Phys 2005; 61: 1291. Cheung R, Tucker SL and Kuban DA: First-year PSA kinetics and minima after prostate cancer radiotherapy are predictive of overall survival. Int J Radiat Oncol Biol Phys 2006; 66: 20. Ciezki JP, Reddy CA, Garcia J, Angermeier K, Ulchaker J, Mahadevan A et al: PSA kinetics after prostate brachytherapy: PSA bounce phenomenon and its implications for PSA doubling time. Int J Radiat Oncol Biol Phys 2006; 64: 512. Sartor CI, Strawderman MH, Lin XH, Kish KE, McLaughlin PW and Sandler HM: Rate of PSA rise predicts metastatic versus local recurrence after definitive radiotherapy. Int J Radiat Oncol Biol Phys 1997; 38: 941. Spiess PE, Lee AK, Leibovici D, Wang X, Do KA and Pisters LL: Presalvage prostate-specific antigen (PSA) and PSA doubling time as predictors of biochemical failure of salvage cryotherapy in patients with locally recurrent prostate cancer after radiotherapy. Cancer 2006; 107: 275. Zagars GK and Pollack A: Kinetics of serum prostate-specific antigen after external beam radiation for clinically localized prostate cancer. Radiother Oncol 1997; 44: 213. Lee AK, Levy LB, Cheung R and Kuban D: Prostate-specific antigen doubling time predicts clinical outcome and survival in prostate cancer patients treated with combined radiation and hormone therapy. Int J Radiat Oncol Biol Phys 2005; 63: 456. Zelefsky MJ, Ben-Porat L, Scher HI, Chan HM, Fearn PA, Fuks ZY et al: Outcome predictors for the increasing PSA state after definitive external-beam radiotherapy for prostate cancer. J Clin Oncol 2005; 23: 826. Stock RG, Cesaretti JA and Stone NN: Disease-specific survival following the brachytherapy management of prostate cancer. Int J Radiat Oncol Biol Phys 2006; 64: 810. Thompson IM, Ankerst DP, Chi C, Goodman PJ, Tangen CM, Lucia MS et al: Assessing prostate cancer risk: results from the Prostate Cancer Prevention Trial. J Natl Cancer Inst 2006; 98: 529. Lynn NN, Collins GN and O’Reilly PH: The short-term prostate-specific antigen velocity before biopsy can be used to predict prostatic histology. BJU Int 2000; 85: 847. Loeb S, Roehl KA, Catalona WJ and Nadler RB: Prostate specific antigen velocity threshold for predicting prostate cancer in young men. J Urol 2007; 177: 899. Loberg RD, Fielhauer JR, Pienta BA, Dresden S, Christmas P, Kalikin LM et al: Prostate-specific antigen doubling time and survival in patients with advanced metastatic prostate cancer. Urology, suppl., 2003; 62: 128. Vollmer RT, Egawa S, Kuwao S and Baba S: The dynamics of prostate specific antigen during watchful waiting of prostate carcinoma: a study of 94 Japanese men. Cancer 2002; 94: 1692.
Purpose: We review the usefulness of prostate specific antigen kinetics (ie prostate specific antigen velocity and doubling time) in the treatment of patients with prostate cancer. Materials and Methods: The MEDLINE database was searched to identify studies investigating prostate specific antigen kinetics in patients with prostate cancer. Results: Various techniques are available for estimating prostate specific antigen kinetics, but to minimize the impact of prostate specific antigen variability on such calculations at least a 90-day period and preferably more than 2 measurements should be used. There is little to suggest which measure of prostate specific antigen kinetics may be superior since both appear to provide useful prognostic information. Prostate specific antigen velocity is easier to calculate but prostate specific antigen doubling time may have greater biological justification. Retrospective studies show that before treatment prostate specific antigen kinetics provide prognostic information regarding the risk of treatment failure and subsequent death from cancer. Additionally, in patients treated surgically preoperative prostate specific antigen kinetics predict the risk of adverse pathology, while in those undergoing conservative treatment prostate specific antigen kinetics are associated with the risk of progression and need for intervention. In patients with biochemical failure after therapy prostate specific antigen kinetics predict the risk and potential site of clinical recurrence, the likely response to salvage therapy, and the risk of death from cancer. Preliminary assessments also suggest that prostate specific antigen kinetics may serve as a surrogate end point to replace cancer specific mortality. Conclusions: Although prospective studies are lacking, the current literature suggests that prostate specific antigen kinetics provide valuable prognostic information, and should be further evaluated in clinical decision making and as a surrogate end point for future trials. Key Words: prostatic neoplasms, prostate-specific antigen, prostatectomy, radiotherapy, survival
with time. PSAV was originally described by Carter et al based on the Baltimore Longitudinal Study of Aging.1 Subsequently PSADT was described by Schmid et al and was studied extensively in patients treated with radiotherapy for prostate cancer.2 An increasing body of work suggests that these 2 measures of PSA kinetics may be useful in managing prostate cancer. We review the available data related to PSAV and PSADT in various clinical settings. It is notable that the literature on PSA kinetics is largely retrospective, resulting from the fact that PSA kinetic data are easier to interpret after a number of measurements have been collected. In contrast, as new PSA readings are obtained in clinical practice, it may be difficult to discern changes reflecting cancer behavior from those reflecting confounding processes such as inflammation.
ince its advent in clinical practice in the 1980s, PSA has had a significant impact on the management of prostate cancer. Most notably, by allowing the early detection of asymptomatic disease it has been responsible for the stage migration of prostate cancer during the last 2 decades. Additionally, serum PSA has become indispensable for prognostication and surveillance. However, PSA remains an imperfect test. In the diagnostic setting noncancerous causes of PSA increase such as benign hypertrophy or inflammation of the prostate frequently confound the clinical picture. Prostate cancers of widely disparate biology may present with comparable PSAs, thus, undermining the prognostic reliability of a single PSA measurement. Given the prolonged natural history of prostate cancer, the implications of changes in serum PSA after therapy are often unclear on short-term followup. A way to overcome some of the limitations of PSA testing has been to examine PSA kinetics or the rate of PSA change
S
PSA KINETIC PARAMETERS: ESTIMATION AND ERROR Because PSAV and PSADT are measures of the rate of PSA change with time, their estimation relies on the statistical
Submitted for publication April 22, 2007. * Nothing to disclose. † Financial interest and/or other relationship with Johnson & Johnson, TAP Pharmaceuticals and Sanofi-Aventis. ‡ Correspondence: Department of Urology, Mayo Clinic, 200 First St. SW, Rochester, Minnesota 55905 (telephone: 507-284-3987; FAX: 507-284-4987; e-mail: [email protected]).
0022-5347/08/1793-0821/0 THE JOURNAL OF UROLOGY® Copyright © 2008 by AMERICAN UROLOGICAL ASSOCIATION
Editor’s Note: This article is the first of 5 published in this issue for which category 1 CME credits can be earned. Instructions for obtaining credits are given with the questions on pages 1208 and 1209.
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Vol. 179, 821-826, March 2008 Printed in U.S.A. DOI:10.1016/j.juro.2007.10.023
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PROSTATE SPECIFIC ANTIGEN KINETICS AND PROSTATE CANCER
technique of regression. The calculation of PSAV is based on the assumption that PSA increases in a linear fashion with time and, therefore, uses linear regression analysis. In practice this translates into a fairly simple slope calculation of the formula, PSAV ⫽ change in PSA/time between measurements. If more than 2 PSA readings are available PSAV may simply be averaged. For example, for 3 PSA measurements, PSAV ⫽ [{(PSA2 – PSA1)/interval1} ⫹ {(PSA3 – PSA2)/interval2}]/2. In contrast, PSADT assumes an exponential increase in PSA and, therefore, requires a somewhat more complex analysis for estimation. Regression techniques for the estimation of PSADT require the logarithmic transformation of available PSA values by the somewhat daunting formula, PSADT ⫽ t ⫻ natural log2/natural log (ratio of PSAs). In practice the calculation of PSADT requires the use of statistical software or online algorithms, although a recently published graphical tool allows the estimation of PSADT in practice settings without electronic resources.3 The measurement of serum PSA is susceptible to error from several sources, most notably from interassay and biological variations, and a number of precautions are required to minimize the impact of such errors on estimates of PSA kinetics. Thus, sequential PSA readings should ideally be obtained from the same laboratory using a well calibrated assay. Furthermore, the greater the number of PSA measurements used and the longer the interval during which they are obtained, the more likely it is that the resulting estimate of PSA kinetics truly reflects cancer growth. However, the need for expedient decision making and the costs of repeat PSA testing usually place practical limits on the number and spacing of available PSA measurements. Additionally, since cancer biology may evolve, leading to variation in PSA kinetics with time, it seems prudent to restrict PSA kinetic assessments to a maximum of 12 to 24 months.4 Two PSA readings separated by at least 3 months appear to provide a reasonably accurate estimate of PSADT, but a minimum of 3 readings during at least 6 months should be obtained when possible.
or frail patients treated conservatively because of limited life expectancy may have intermediate to high risk tumors, younger patients placed on AS protocols are usually selected on the basis of low risk features. Not surprisingly, PSA is found to increase relatively slowly in most of these patients with PSADT longer than 10 years in the majority. The rate of PSA increase appears to be related to the aggressiveness of the prostate cancer as indicated by an association with clinical stage, biopsy grade and initial PSA,5,6 although these findings vary somewhat among series (table 1).7,8 Another difficulty in interpreting the predictive value of PSA kinetics in this setting is that since an increase in PSA is often a trigger for intervention, men with rapid PSA kinetics are over represented in the treated subgroup, thus leading to selection bias. In fact, some active surveillance protocols explicitly incorporate PSA kinetic measures as criteria for intervention. For example, Choo et al offer curative surgery to men under active surveillance with a PSADT of less than 3 years.7 However, a number of other studies that did not formally use PSA kinetics for decisions on intervention have reported a significant association between PSA kinetics and the need for intervention or time to intervention, thus providing support for this concept.9 –11 Furthermore, PSADT has been shown to correlate with other measures of progression such as DRE, repeat biopsy or bone scan.6,9 Finally, PSA kinetic measures appear to be associated with the risk of death from prostate cancer in men treated conservatively.12,13 Despite these findings doubts remain regarding the usefulness of PSA kinetic measures in an individual patient given the wide variation and significant overlap.6 – 8 Additionally, variability in PSA kinetics with time is pronounced, further complicating the application of these measures in decision making during the conservative management of prostate cancer. 4,8 Currently it seems sensible to incorporate PSA kinetics along with other criteria in AS and WW protocols, although individualized rather than universal cutoff points may be preferable.5
PSA KINETICS AND CONSERVATIVE MANAGEMENT
PSA KINETICS AND RADICAL PROSTATECTOMY
Men with prostate cancer may be treated conservatively with planned delayed intervention with curative AS or palliative WW intent. Although serial PSA data are usually available for men undergoing such conservative treatment, published reports are few and somewhat difficult to interpret. Many studies are retrospective, and include patients with a broad spectrum of disease pathologies treated with AS and WW. While elderly
As serial PSA testing becomes more common, preoperative PSA kinetic data are increasingly available for patients treated surgically. Preoperative PSA kinetic measures are associated with aggressive pathological features at prostatectomy, including local and nodal stage, specimen Gleason score, and involvement of surgical margins. Although early studies suggested that preoperative PSA kinetics were not predictive of postoperative outcomes, they were likely lim-
TABLE 1. Relationship of PSA kinetics to clinical features, risk of progression and need for intervention in patients with prostate cancer treated conservatively Hardie et al5 No. pts PSA kinetic p Value: Age PSA T stage Biopsy grade Progression Time to treatment * Multivariate analysis.
80 PSADT NS 0.039 0.036* NS
Stephenson et al6 94 PSADT NS NS 0.04 NR DRE 0.019, biopsy 0.03
Choo et al7
Gerber et al8
134 PSADT
49 PSAV
NS NS NS NS
NS NS NS NS
McLaren et al9 113 PSADT
DRE ⬍0.01, clinical ⬍0.0001 ⬍0.0001
PROSTATE SPECIFIC ANTIGEN KINETICS AND PROSTATE CANCER
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TABLE 2. Relationship of preoperative PSA kinetics with pathologic findings and survival in surgically treated patients D’Amico et al14 No. pts PSA kinetic p Value: Stage Grade Pos surgical margin Survival*
Sengupta et al15
1,069 PSAV ⬍0.05 ⬍0.05 CSS ⬍0.001, OS ⬍0.01
Patel et al16
2,290 PSAV ⫹ PSADT
202 PSAV
⬍0.0001 ⬍0.0001 PSAV ⬍0.0001, PSADT NS CSS ⬍0.0001
0.007 0.04 0.01 RFS 0.03
* Multivariate analysis.
ited in power, and more recent series have confirmed preoperative PSA kinetics to be predictive of the risk of progression and death after radical prostatectomy (table 2). D’Amico et al analyzed a cohort of 1,069 men who had undergone serial PSA testing at the same laboratory before surgery, and PSAV greater than 2.0 ng/ml per year was associated with a significantly increased risk of death from prostate cancer and from all causes.14 Sengupta et al compared preoperative PSAV and PSADT, and reported that PSADT was a stronger predictor of clinical recurrence or death from cancer.15 Preoperative PSA kinetics do not appear to simply be surrogate markers for conventional clinical or histological indicators of aggressive disease, since the prognostic value of PSA kinetics persists on multivariate analysis.14 –16 The inclusion of PSA kinetics causes preoperative PSA to drop out of multivariate models, suggesting that the rate of increase may be more important prognostically than the absolute PSA value.15 In the postoperative setting, since all PSA producing tissue has been removed, serum PSA is expected to be undetectable. Although a detectable PSA is taken to be presumptive evidence of cancer recurrence, only about a third of these patients have clinically evident recurrence. Defining recurrence by biochemical criteria remains controversial, with various cut points used in the literature. It has been reported that a PSA increase of less than 0.4 ng/ml was rarely associated with further subsequent increases, suggesting that this threshold is most appropriate. Stephenson et al also found a PSA cutoff of 0.4 ng/ml to be associated with subsequent PSADT and risk of metastasis.17 Even in patients with biochemical recurrence a subgroup can be identified with slowly increasing PSA, delayed and infrequent clinical recurrence, and low risk of death from cancer who may be best treated conservatively.18 When clinical recurrence is local, that is at the site of resection, salvage therapy may be considered. When recurrence is systemic, palliative hormonal therapy becomes most appropriate. PSADT after recurrence is predicted by preoperative risk factors, pathological findings and time to biochemical failure,19 and
these factors may help delineate the risk of metastatic vs local recurrence.20 –23 Early studies suggested that the likely site of recurrence may be predicted based on PSAV24 or PSADT25 after biochemical recurrence. Subsequent reports have confirmed a clear association between rapid PSA kinetics and the subsequent risk of metastatic recurrence (table 3). Recently an association between PSA kinetics after recurrence and survival has been established, with a 5-year cancer specific mortality of 31% vs 1% for patients with PSADT less than 3 months vs 3 months or greater,26 suggesting that PSADT may be useful as a surrogate end point for cancer death.27 Notably, prostate cancer predominates as a cause of death in men with PSA recurrence after surgery, even up to a PSADT of 15 months.28 Additionally, in patients receiving salvage radiotherapy PSA kinetics before radiation appear to be an important prognostic factor,29 while high risk patients treated with adjuvant hormonal therapy are most likely to benefit if they have a rapid PSADT.30 Furthermore, in the face of an increasing PSA while on hormonal therapy after initial local therapy, PSA kinetic measures predict subsequent survival and may have some use in decision making regarding additional therapy.31 PSA KINETICS AND RADIOTHERAPY Data on PSA kinetics in patients treated with external or interstitial radiation largely parallel those described in surgically treated patients (table 4). Thus, Hanks et al found the pretreatment PSADT and the radiation dose to be significant multivariate predictors of biochemical recurrencefree survival.32 Recently D’Amico et al reported that pretreatment PSAV greater than 2.0 ng/ml per year was associated with an increased risk of biochemical recurrence, death from cancer and death from any cause after external beam radiation regardless of the risk group.33 Eggener et al observed that a pretreatment PSAV cutoff of 2.0 ng/ml per year is also predictive of biochemical outcomes after brachytherapy.34 D’Amico et al further reported that patients with
TABLE 3. Relationship of post-recurrence PSA kinetics and survival in surgically treated patients
No. pts No. PSA recurrence PSA kinetic Association with survival (p value) Comments
* Multivariate analysis.
Dotan et al20
Pound et al22
Roberts et al23
239
1,997 315
2,809 879 (587 with PSADT) PSADT Systemic PFS (⬍0.001), PFS (⬍0.001)* PSADT less than 6 mos predicts systemic progression
PSAV Bone metastasis (OR 0.93, p ⬍0.003)*
PSADT Systemic PFS (⬍0.001)
Zhou et al26 NS 498 PSADT PSADT less than 3 mos predicts prostate cancer specific mortality (HR 54.9)
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PROSTATE SPECIFIC ANTIGEN KINETICS AND PROSTATE CANCER TABLE 4. Relationship of pretreatment PSA kinetics with survival in patients treated with radiotherapy Hanks et al32
D’Amico et al33
No. pts Treatment PSA kinetic
99 External beam (dose NS) PSADT
358 External beam (77 Gy) PSAV
Association with survival Comments
bRFS 50% bRFS at 18 mos in pts with PSADT less than 12 mos
bRFS, CSS ⫹ OS (each p ⬍0.01) Low risk ⫹ high risk groups
a rapid pretreatment PSAV benefit from the addition of androgen deprivation to external beam radiation.35 PSA kinetics after radiation are confounded by the continuing production of PSA by the prostate, which is susceptible to a number of influences. Thus, the concomitant use of androgen deprivation and radiation often causes a withdrawal effect, leading to more rapid PSA increases, which may lead to misclassification of biochemical failure.36,37 In fact, during the initial period after external beam radiotherapy, PSA decreases and the negative PSA kinetics as well as the PSA nadir appear to be prognostic of overall survival.38 After interstitial seed placement the phenomenon of PSA bounce may occur and cause confusion with early biochemical relapse. In fact, the PSA kinetics for the 2 events appear to be similar, and the time from therapy may be the most reliable distinguishing characteristic with bounces typically occurring earlier than recurrence.39 PSADT after recurrence may also be useful in classifying the likely site of recurrence in patients treated with radiotherapy, with those with local relapse amenable to salvage therapies.40 The success rate of salvage cryotherapy in this setting also depends on PSADT before salvage.41 Zagars and Pollack,42 and Lee et al43 reported that PSADT less than 8 months after relapse is associated with the risk of metastatic disease and death from all causes in patients treated with external beam radiotherapy alone42 or in combination with androgen deprivation (table 5).43 Using 3-dimensional conformal intensity modulated radiation therapy Zelefsky et al observed a similar relationship between PSADT and metastatic recurrence.44 Cancer specific mortality after external beam radiation for prostate cancer is strongly associated with PSADT after recurrence, and is 75% vs 15% for PSADT less than 3 months vs 3 months or greater in patients with Gleason score greater than 7, and 35% vs 4%, respectively, in those with Gleason score 7 or less.26 Similarly, for patients treated with interstitial seed placement 10-year CSS is 30% for patients with a PSADT of 6 months or less vs 98% for those with a PSADT of more than 10 months.45
Eggener et al34
Eggener et al34
83 External beam (dose NR) PSAV (greater than 2 ng/ml/yr) bRFS 80% Vs 55% at 6 yrs
47 Brachytherapy PSAV (greater than 2 ng/ml/yr) bRFS 88% Vs 65% at 6 yrs
CLINICAL USE AND FUTURE DIRECTIONS The application of PSA kinetic measures in clinical practice is really no more than a formalization of serial PSA testing. While regular PSA measurements for surveillance after treatment have long been routine, it has recently become more common in other clinical settings. Thus, many patients now undergo repeat PSA screening before prostate cancer diagnosis. The indication for prostatic biopsy in these patients is typically an increase in PSA beyond a threshold level. However, controversy persists regarding the optimal PSA cutoff, with emerging data indicating that the risk of prostate cancer remains significant even with a nominally normal PSA. It remains uncertain whether PSA kinetic measures are likely to be helpful in this setting. In the prospective Prostate Cancer Prevention Trial PSAV based on at least 2 PSAs in 3 years was not a significant predictor of a positive end of study biopsy.46 In contrast, short-term PSAV more than 2 months before biopsy was associated with the presence of malignancy in patients with an abnormal PSA.47 It is also notable that data from the Baltimore Longitudinal Study of Aging revealed differences in PSAV years before prostate cancer diagnosis.1 A problem with retrospective analyses of the diagnostic value of PSA kinetics is that not all men undergo biopsy, resulting in assignment bias.48 Further prospective study of this issue is awaited, but in younger men rapid unexplained increases in PSA, even in the normal range, need to be viewed with concern. For patients with a prostate cancer diagnosis PSA kinetics appear to convey prognostic information that should be considered with conventional prognostic factors such as absolute PSA, clinical stage and biopsy grade. Although PSA kinetics are of the greatest relevance immediately before diagnosis, PSA velocity can provide prognostic information years ahead.13 PSA kinetics are likely to be useful not only in counseling patients regarding likely outcomes after treatment, but also in suggesting experimental multimodal ther-
TABLE 5. Relationship of post-recurrence PSA kinetics with survival in patients treated with radiotherapy Zagars and Pollack42 No. pts Treatment No. relapse PSA kinetic Association with survival Comments
841 60–78 Gy 263 PSADT less than 8 mos sRFS 93% Vs 46% at 7 yrs
Lee et al43
Zelefsky et al44
Sartor et al40
Zhou et al26
Stock et al45
399
NS External beam, dose NS 661 PSADT CSS
1,561 Brachytherapy ⫾ external beam ⫾ ADT 131 PSADT CSS
621 76 Gy ⫹ ADT
1,650 64–81 Gy ⫾ ADT
70 Gy
75 PSADT Clinical RFS p ⬍0.001, OS p ⫽ 0.015
381 PSADT sRFS ⫹ OS
234 (increasing PSA) PSADT sRFS, local RFS
PSADT less than 6 mos vs greater than 12 mos, HR greater than 6.6
Site of recurrence
PROSTATE SPECIFIC ANTIGEN KINETICS AND PROSTATE CANCER apy protocols for those with aggressive disease. Finally, in the context of AS protocols, PSA kinetic measures may be crucial criteria for intervention, although precise cutoff levels require further investigation. Biochemical recurrence after treatment leads inevitably to consideration of PSA kinetics in clinical decision making. In this context, along with known pretreatment and posttreatment prognostic factors, PSA kinetics may allow an assessment of the probability of relapse and the likely site, thereby facilitating rational decisions regarding the need for and type of salvage therapy. For instance, it appears that for men with biochemical recurrence after radical prostatectomy or external beam radiation and a PSADT of less than 3 months, earlier initiation of hormonal therapy delays the development of bony metastases, thereby improving quality of life even if survival is not prolonged.27 This group of men may also be usefully studied in randomized trials of systemic chemotherapy such as docetaxel. Similarly for men with metastatic prostate cancer PSA kinetic measures may be used to guide the initiation of hormonal therapy and secondary intervention during the hormone refractory phase.49 In these clinical situations either measure of PSA kinetics may be applied. There is empirical evidence that prostate cancer biology does in fact conform to an exponential model and, therefore, PSADT may be more accurate.2,50 This is partially supported by the results of a large retrospective study of PSA kinetics before prostatectomy.15 However, during short intervals the linear and exponential curves closely approximate each other and, therefore, PSAV provides a satisfactory alternative that is usually easier to calculate. Finally, it should be noted that PSAV and PSADT are related to each other and to serum PSA by the formula, PSAV ⬁ PSA/PSADT. In a linear model (constant PSAV) PSADT is assumed to vary with PSA, and vice versa in an exponential model (constant PSADT). In reality, for a particular cancer in a particular man the exact pattern of PSA increase with time may not conform exactly to either model, and whichever model is used ends up being an approximation.
Abbreviations and Acronyms ADT AS bRFS CSS DRE NS NR OS PFS PSA PSADT PSAV RFS sRFS WW
⫽ ⫽ ⫽ ⫽ ⫽ ⫽ ⫽ ⫽ ⫽ ⫽ ⫽ ⫽ ⫽ ⫽ ⫽
androgen deprivation therapy active surveillance biochemical RFS cancer specific survival digital rectal examination not statistically significant not reported overall survival progression-free survival prostate specific antigen PSA doubling time PSA velocity recurrence-free survival systemic RFS watchful waiting
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