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Ultrasensitive Prostate Specific Antigen and Its Role after Radical Prostatectomy: A Systematic Review Derya Tilki,*,† Sun Il Kim,† Brian Hu, Marc A. Dall’Era and Christopher P. Evans From the Martini-Clinic Prostate Cancer Center and Department of Urology, University Hospital Hamburg-Eppendorf (DT), Hamburg, Germany, Department of Urology, School of Medicine, University of California-Davis (DT, SIK, BH, MAD, CPE), Sacramento, California, and Department of Urology, Ajou University School of Medicine (SIK), Suwon, Republic of Korea
Purpose: Prostate specific antigen is an important tool to monitor patients with prostate cancer after radical prostatectomy. Ultrasensitive prostate specific antigen assays are increasingly used with a lower limit of detection as low as 0.001 ng/ml. We systematically reviewed currently available ultrasensitive prostate specific antigen technologies and the role of this method in monitoring patients after radical prostatectomy. Materials and Methods: We searched the relevant literature using the MEDLINEÒ database. For various study objectives the series eligible for review provided serial ultrasensitive prostate specific antigen (lower detection limit less than 0.1 ng/ml) data on men after radical prostatectomy as well as comparative data on standard prostate specific antigen (lower detection limit 0.1 ng/ml or greater). Results: Ultrasensitive prostate specific antigen could potentially detect prostate cancer recurrence years earlier than standard prostate specific antigen assays. The specificity of detectable ultrasensitive prostate specific antigen is low. Ultrasensitive prostate specific antigen kinetics may improve the positive predictive value for detecting cancer recurrence. However, the usefulness of prostate specific antigen doubling time at the ultrasensitive level remains controversial. Undetectable nadir ultrasensitive prostate specific antigen after radical prostatectomy confers a low risk of disease recurrence while a detectable nadir above 0.01 ng/ml requires additional measurement and consideration of other risk factors to determine management and avoid overtreatment. This monitoring method may spare patients with high risk disease adjuvant radiation therapy and enable more selective early salvage radiation. Currently no data demonstrates improved survival after early salvage therapy prompted by ultrasensitive prostate specific antigen surveillance. Conclusions: Ultrasensitive prostate specific antigen is useful in the early diagnosis of cancer recurrence after radical prostatectomy but specificity is poor. To date there is a lack of evidence that earlier detection of recurrence translates into prolonged time to metastasis. Integrating ultrasensitive prostate specific antigen with other clinicopathological factors can help determine optimal adjuvant and salvage therapy.
Abbreviations and Acronyms BCR ¼ biochemical recurrence ePSADT ¼ early PSADT LLD ¼ lower detection limit PCa ¼ prostate cancer PPV ¼ positive predictive value PSA ¼ prostate specific antigen PSADT ¼ PSA doubling time RP ¼ radical prostatectomy TRIFA ¼ time resolved immunofluorometric assay uPSA ¼ ultrasensitive PSA XRT ¼ external radiation therapy Accepted for publication October 16, 2014. * Correspondence and requests for reprints: Martini-Clinic Prostate Cancer Center, University Hospital Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany (e-mail: [email protected]). † Equal study contribution. Supplementary references 31 to 58 for this article can be obtained at http://jurology.com/.
Key Words: prostatic neoplasms; prostate-specific antigen; prostatectomy; neoplasm recurrence, local; diagnosis
0022-5347/15/1935-0001/0 THE JOURNAL OF UROLOGY® © 2015 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION AND RESEARCH, INC.
Dochead: Adult Urology
http://dx.doi.org/10.1016/j.juro.2014.10.087 Vol. 193, 1-7, May 2015 Printed in U.S.A.
www.jurology.com
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SINCE PSA was approved by the United States FDA (Food and Drug Administration), it has become the most widely used tool to monitor and detect PCa. Annual screening in the prostate portion of the PLCO (Prostate, Lung, Colorectal and Ovarian) Cancer Screening Trial was not associated with decreased PCa specific mortality.1,2 A significant portion of men would be over diagnosed and over treated as a result of PSA screening.3 On the other hand, PSA derivatives such as PSAD appear to identify patients at low risk with PCa who would not need active treatment.4 In the context of monitoring patients after therapy PSA kinetics better predicted the outcome than a single PSA measurement.5,6 Low PSA predicted a lower long-term risk of PCa and all-cause mortality in longitudinal community studies.7,8 RP remains a widely used treatment for localized PCa, although up to 35% of patients experience relapse postoperatively.9 Intervention before clinical recurrence gives patients the opportunity for better long-term cancer-free survival.10 The sensitivity of detecting BCR is directly related to the sensitivity of the PSA assay. The LLD of commercial first generation PSA assays is 0.3 to 0.4 ng/ml and any detectable serum PSA after RP could be rightfully interpreted as residual or recurrent cancer.11,12 Since that time, second generation uPSA assays have improved sensitivity with most manufacturers offering assays with a LLD of 0.1 ng/ml or less.13,14 This sensitivity level satisfies current AUA (American Urological Association) and EAU (European Association of Urology) guidelines that define BCR after RP as PSA 0.2 ng/ml or greater. Further technical advances enabled assays to be developed with a LLD as low as 0.001 ng/ml, which allowed BCR detection months to years earlier compared to standard assays.15e17 The use of uPSA is increasing in the urological community. However, no clear guidelines exist on its role in monitoring patients after RP. Earlier detection may translate to more efficacious salvage therapy and potential for improved survival. In this review we systematically analyzed available evidence on uPSA performance in the followup of patients after RP. We also established a practical guideline for using uPSA to monitor patients after RP.
PATIENTS AND METHODS No clear definition of uPSA exists in the literature. Early reports used the term ultrasensitive for second generation assays with a detection limit of 0.1 ng/ml, which may be misleading in the current era.13,14 Thus, we considered an assay ultrasensitive only when PSA less Dochead: Adult Urology
172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 ½F1 200 201 202 203 RESULTS 204 BCR Diagnosis Lead Time 205 Time from first detectable uPSA to more tradition206 ally defined BCR was based on multiple stored 207 serum samples from patients with known BCR, 208 which was presented as an efficacy uPSA assay 209 end point in earlier studies (table 1).15,16,19e22 ½T1 210 Detection limits of uPSA assays were 2.5 to 25 211 times lower than those of standard assays used for 212 comparison. Average lead time to BCR diagnosis 213 was 1 year (range 9 to 29 months). Notably tumor 214 characteristics and other factors such as followup, 215 which influence this lead time, were heterogeneous 216 or not mentioned in some studies. Moreover, the 217 BCR definition was not universal, limiting data 218 generalizability. 219 220 uPSA 221 PPV. PSA has been detected in men who undergo 222 cystoprostatectomy for bladder cancer without 223 identifiable PCa. This was hypothesized to arise 224 from the periurethral glands.23 Even in some women 225 serum PSA is detectable by an ultrasensitive 226 assay.24,25 Several groups reported serum uPSA 227 levels in control populations lacking the prostate 228
than 0.1 ng/ml was reported, in contrast to standard PSA assays for which PSA less than 0.1 ng/ml is reported as undetectable. In July 2014 we searched the MEDLINE database. Only original articles in English were considered for review. Search terms included ultrasensitive, prostatespecific antigen and prostatectomy. Other descriptive terms that are interchangeable with ultrasensitive (ie supersensitive, hypersensitive and sensitive) were included. Lower limit of detection and other terms that specify the assay sensitivity level (ie lower detection threshold, lower detection sensitivity, lower limit and analytical sensitivity) were also used. To identify relevant reports that may not mention ultrasensitivity or specify a detection limit of the assay we included specific values, ranging from 0.01 to 0.09 ng/ml at 0.01 ng/ml increments. The same strategy was applied for 0.001 to 0.009 ng/ml. This study was developed according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses).18 Eligibility criteria for study inclusion considered participants, intervention, comparators, outcomes and study design. Eligible studies included patients who underwent RP with serial postoperative uPSA data and standard PSA data or a traditional definition of BCR as comparators. Outcome included 1 of certain topics, including lead time to BCR diagnosis, BCR PPV, uPSA kinetics, prognostic significance of the undetectable uPSA nadir and implications for adjuvant/salvage XRT. All study designs except case reports were included in analysis. Figure 1 shows the study search and selection flow diagram.
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286 229 287 230 288 231 289 232 290 233 291 234 292 235 293 236 294 237 295 238 296 239 297 240 298 241 299 242 300 243 301 244 302 245 303 246 304 247 305 248 306 249 307 250 308 251 309 252 310 253 311 254 Figure 1. Study search and selection. 312 255 313 256 314 257 ½T2 (table 2).14e17,20,24e27 Pooled analysis of studies with risk after RP were followed the uPSA increases 315 258 a LLD of 0.01 ng/ml or less indicate that the chance contributed by benign prostatic tissue (0.6%) or 29 316 259 of finding detectable (0.01 ng/ml or greater) PSA in cancer recurrence (0.3%) were equally rare. A 317 260 women, men after cystoprostatectomy and men in clear conclusion about the source of these low PSA 318 261 a long-term recurrence-free state after RP is 17%, levels is limited by the paucity of data. Nonetheless, 15,25e27 319 262 12% and 41%, respectively. the specificity of uPSA for PCa recurrence appears In these studies 320 263 to be adversely affected. a single subject often contributed several samples 321 264 The PPV of detectable uPSA to predict BCR was and residual cancer could not be completely ruled 15,19,22,27,30 265 calculated in 5 studies (table 3). out in patients treated with RP. Assays ½T3322 323 266 In contrast, a comparative study of 3 uPSA assay with a relatively low cutoff of 0.008 and 0.02 ng/ml 324 267 methods in patients after cystoprostatectomy and were associated with a low PPV of 37% and 15,27 325 268 RP demonstrated only a small difference between 30%, respectively. Instead of using a single 326 269 the 2 groups, suggesting a negligible contribution cutoff integrating PSA kinetics into the BCR defi28 327 270 of the periurethral glands to serum PSA. nition resulted in an 86% PPV despite a low LLD In 22 328 271 of 0.001 ng/ml. another study in which patients at extremely low 329 272 330 273 Table 1. BCR diagnosis lead time by various uPSA assays in patients after RP 331 274 332 275 BCR Cutoff (ng/ml) 333 276 References Assay No. Pts uPSA Traditional PSA Mean Lead Time (mos) 334 277 Chemiluminescent (Hybritech, Scottsdale, AZ) 24 0.008 0.1 22.3 Ellis et al15 335 278 TRIFA 10 0.04 0.1, 0.3 13.8, 29.0 Yu et al16 19 336 279 Lyophilization* 28 0.025 0.1 8.8 Haese et al Lyophilization, filtration† 31 0.023, 0.023 0.07, 0.07 11.9, 12.6 Pruthi et al20 337 280 IMx (Abbott, Abbott Park, IL), Tandem-E multipoint (Hybritech) 12 0.04, 0.04 1.0, 1.0 10.7, 12.1 van Iersel et al21 338 281 TRIFA 31 0.001‡ 0.1§ 18.0 Vassilikos et al22 339 282 * Serum concentration enhanced assay sensitivity fourfold. 340 283 † Serum concentration enhanced each assay sensitivity threefold. 341 284 ‡ LLD, 2 or more consecutive serum PSA increases resulting in at least initial PSA doubling. 342 285 § LLD, 2 or more consecutive PSA measurements greater than 0.2 or greater than 0.1 ng/ml. Dochead: Adult Urology
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343 344 345 346 347 348 349 350 351 352 353 354 355 356 357 358 359 360 361 362 363 364 365 366 367 368 369 370 371 372 373 374 375 376 ½T4 377 378 379 380 381 382 383 384 385 386 387 388 389 390 391 392 393 394 395 396 397 398 399
Table 2. Serum findings by uPSA cutoff in women, in men after cystoprostatectomy and in long-term recurrence-free men after RP for small low grade cancer No. Pts (ng/ml uPSA cutoff) References Women: Vessella et al14 Ellis et al15 Yu and Diamandis17 Pruthi et al20 Khosravi et al24 Yu and Diamandis25 Liedtke et al26 Witherspoon and Lapeyrolerie27 Ellis et al,15 Yu and Diamandis,25 Liedtke et al,26 Witherspoon and Lapeyrolerie27 (%) Men after cystoprostatectomy: Vessella et al14 Ellis et al15 Pruthi et al20 Liedtke et al26 Ellis15 and Liedtke26 et al (%) Men with potential post-RP cure: Vessella et al14 Ellis et al15 Yu et al16 Pruthi et al20 Khosravi et al24 Yu and Diamandis25 Liedtke et al26 Ellis15 and Yu et al,16 Yu and Diamandis,25 Liedtke et al26 (%)
Assay IMx Chemiluminescent TRIFA AIA-Pack (Tosoh, Tokyo, Japan) Immunoenzymometric TRIFA Modified Tandem-E ImmuliteÔ
IMx Chemiluminescent AIA-Pack Modified Tandem-E IMx Chemiluminescent TRIFA AIA-Pack Immunoenzymometric TRIFA Modified Tandem-E
Less Than 0.01
Less Than 0.02
Less Than 0.05
Not determined 117 Not determined Not determined 73 Not determined 37* 882 24 120 1,143 (83)
25 5 30 (88) 24 12
0 Not determined Not determined Not determined e
22 1 20
Less Than 0.1
0.1 or Greater
50 Not determined Not determined 0
0 3 2 0
3 0 2 0
Not determined 155 Not determined 3 0 22 1 202 (15) e
Not determined Not determined Not determined 0 e Not determined Not determined
Less Than 0.06
39 4
0 e
1 0 0 0 0
ND 10 0 e
0 4 (12) 0 Not determined
35 Not determined
Not determined 21* 43 6 85 (59)
4 11 0 1 15 (1)
40 Not determined Not determined 0 e
0 e
3 1 13 0 12 36 0 50 (34)
0 16 1 1 18 (1)
0 0 0 0 0 0 0 0 0 6 10 0 10 (7)
* uPSA less than 0.012 ng/ml.
Several groups defined a subset of patients in whom uPSA reached a detectable or a certain predefined level but never attained a level traditionally defined as BCR within a median of 15 to more than 85 months (table 4).15,19,22,27,31 Considering that some men are at risk for future recurrence after longer followup this new patient cohort should be better defined in the future. Kinetics. PSA kinetics at the ultrasensitive level may improve the low PPV of detectable uPSA for cancer recurrence. In a study using an assay with a LLD of 0.001 ng/ml Yu et al redefined BCR as satisfying 1 or more of certain criteria, including 2 or more consecutive serum PSA increases that resulted in
at least the doubling of initial PSA, any increase that resulted in a value greater than 0.1 ng/ml or a tenfold increase between 2 serum collections.32 By applying this definition 100% to 150% more recurrences were detected compared to what would have been detected using the criterion of serum PSA greater than 0.1 ng/ml.22,31,32 Several earlier studies showed that PSADT at the ultrasensitive level had mixed results.16,20,32,33 However, these studies incorporated PSA values well above the BCR level in the uPSADT calculations. A more recent attempt to calculate uPSADT and uPSA velocities based on prospectively collected periodic measurements did not yield meaningful results due to fluctuations in the uPSA range.34
Table 3. uPSA assay PPV for recurrent cancer in patients after RP BCR Cutoff (ng/ml) References 15
Ellis et al Vassilikos et al22 Haese et al19 Witherspoon and Lapeyrolerie27 Shinghal et al30
Assay
No. BCR Pts (uPSA/traditional PSA)
uPSA
Traditional PSA
% PPV
Chemiluminescent TRIFA Lyophilization* Immulite AIA (Tosoh)
65/24 36/31 88/65 66/20 158/144
0.008 0.001† 0.025 0.02 0.07
0.1 0.1‡ 0.1 Clinical recurrence Clinical recurrence
37 86 74 30 91
* Serum concentration enhanced assay sensitivity fourfold. † LLD, 2 or more consecutive serum PSA increases resulting in at least doubling of initial PSA and crossing 0.1 ng/ml earlier than 4 years after RP. ‡ LLD, 2 or more consecutive PSA measurements greater than >0.2 or PSA greater than 0.1 ng/ml. Dochead: Adult Urology
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Table 4. Patients identified as having biochemical recurrence by ultrasensitive prostate-specific antigen cutoff value only and not by traditional cutoff value References 15
Ellis et al Witherspoon and Lapeyrolerie27 Arai et al31 Haese et al19 Vassilikos et al22
Assay
No. Pts
Mean Followup (mos)
uPSA Range (ng/ml)
Description
Chemiluminescent Immulite Immulite Lyophilization* TRIFA
34, 7 11 4 23 30
Median 15, mean greater than 85 Mean 36 Not determined Not determined Mean 45
0.01e0.03, 0.04e0.08 0.01e0.02 0.01e0.02 0.025e0.1 0e0.1
Recurrence undetermined Slowly increasing PSA Recurrence undetermined Recurrence undetermined Slow recurrence
* Serum concentration enhanced assay sensitivity fourfold.
Shimizu et al generated a computer model that simulated increasing longitudinal uPSA and concluded that specificity based on 2 consecutive increases was inadequate, suggesting the need for at least 3 consecutive measurements.35 They also calculated uPSADT in 52 patients with BCR but the resulting values were inadequate. The larger coefficient of variation seen with lower PSA values, a possibly nonexponential increase in uPSA and a limited number of values used to calculate uPSADT were presented as possible reasons for the inadequacy.36 In a larger population of patients from the SEARCH (Shared Equal Access Regional Cancer Hospital) database Teeter et al investigated whether ePSADT calculated from the first detectable uPSA after RP to the first PSA of 0.2 ng/ml or greater correlated with standard PSADT.37 Although they found a significant correlation between ePSADT and standard PSADT, the overall association was moderate to poor. Also, the PPV to predict aggressive recurrence was low at different ePSADT thresholds. In addition, in another study they did not find that uPSADT was an independent predictor of aggressive recurrence after RP.38 uPSADT calculated from the CaPSUREÒ database also correlated poorly with PSADT.39 In that study uPSADT calculated at the PSA change between 0.05 and 0.2 ng/ml was often much more rapid than PSADT calculated at a PSA of greater than 0.2 ng/ml, which may lead to overestimating the recurrence risk.
LLD as low as 0.01 pg/ml showed a 69% to 72% PPV at a 0.003 ng/ml cutoff.48,49 Different definitions of BCR as well as different assay techniques and uPSA nadir cutoffs were used, making pooled analysis impossible. In a study of the impact of post-RP PSA nadir at an ultrasensitive level after salvage XRT 3-year BCR-free survival did not significantly differ between the undetectable (nadir uPSA less than 0.05 ng/ml) and detectable groups.50 Eisenberg et al proposed using early postoperative uPSA at 1 to 3 months instead of nadir uPSA.51 On multivariate analysis detectable postoperative uPSA greater than 0.05 ng/ml was an independent predictor of BCR. Moreover, patients with positive surgical margins or stage pT3 with undetectable uPSA had better BCR-free rates than those with detectable uPSA, suggesting that postoperative uPSA status may be considered in the decision to administer adjuvant therapy in patients with adverse pathological features. In a SEARCH database study Moreira et al similarly observed that failure to achieve uPSA less than 0.03 ng/ml within 6 months of RP, defined as PSA persistence, was associated with an increased risk of BCR.52 In an updated series of 1,156 patients Moreira et al found that PSA persistence was also a significant predictor of overall survival.47 Malik et al addressed the long-term usefulness of uPSA, reporting that uPSA less than 0.04 ng/ml measured 3 years after RP was an independent predictor of delayed relapse.53
Undetectable. The significance of an undetectable
Adjuvant and salvage therapy. Adjuvant XRT im-
uPSA nadir after RP was addressed in several studies in which uPSA was applied prospectively at a 3 to 6-month interval after RP (supplementary table, http://jurology.com/).34,40e49 Most studies included 0.01 ng/ml as the undetectable uPSA cutoff. In most of these studies multivariate analysis revealed that uPSA was an independent predictor of BCR alone or with other clinicopathological factors. At a uPSA cutoff of 0.01 ng/ml the negative predictive value was high at between 95% and 100%. PPV varied between 30% and 76%. Two pilot studies in which a novel, single molecule enzyme-linked immunosorbent assay technique was used with a
proves biochemical disease-free survival in patients with adverse pathological features and it also improves overall survival.54,55 However, adjuvant XRT is often not recommended by urologists, mainly due to concern over unnecessary adverse effects in a considerable portion of patients in whom recurrence would never develop. Thus, these patients are often placed on surveillance and receive early salvage therapy. uPSA is commonly applied in this treatment algorithm. Typically adjuvant therapy begins 3 to 9 months postoperatively to allow for adequate recovery of urinary and erectile function. Within this window several uPSA values
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ULTRASENSITIVE PROSTATE SPECIFIC ANTIGEN AND ITS ROLE AFTER PROSTATECTOMY
can help determine whether adjuvant therapy is indicated. Although to our knowledge no group has examined the ideal uPSA interval after RP, in men with detectable uPSA the frequency of followup should remain similar to that for standard PSA assays. Three or 4 consecutive values could be obtained during this window to help determine the significance of detectable uPSA. In men with undetectable values less frequent followup is unlikely to cause the loss of a therapeutic window. Shen et al proposed that men with a uPSA nadir of less than 0.01 ng/ml in year 1 must undergo uPSA measurement annually.41 Given that uPSA has 96% to 100% negative predictive value at the 0.01 ng/ml cutoff, this seems to be a reasonable recommendation but it requires validation. uPSA improves the time to detection of PCa relapse by months to years. This lead time to relapse would seem to improve the patient chance of durable progression-free survival with salvage therapy given at a lower cancer burden and a wider window for cure.56 Using uPSA Terai et al followed patients after RP, of whom 37 were able to receive early salvage XRT at a median PSA of 0.146 ng/ml.57 PreXRT uPSA 0.15 ng/ml or less
predicted nonprogression after XRT. However, this study was limited by small patient number and short followup. Mir et al recently analyzed the risk of PSA, defined as a PSA increase of greater than 0.1 ng/ml above BCR, and treatment progression after BCR based on 14 BCR definitions in 2,348 patients with detectable PSA 0.03 ng/ml or greater after RP.58 They concluded that BCR definitions below currently accepted PSA thresholds appear to be valid to select patients with adverse clinicopathological risk factors for secondary therapy.
CONCLUSIONS To monitor patients with PCa after RP uPSA detects recurrence months to years earlier than standard PSA assays. An undetectable uPSA nadir is prognostic of a lower risk of future recurrence while the PPV of detectable uPSA is low. Serial uPSA measurements are more useful to determine cancer recurrence, although the usefulness of uPSADT in this setting is controversial. Currently no data demonstrate that earlier intervention associated with uPSA improves survival or cancer outcomes. Post-RP uPSA monitoring complements traditional clinicopathological factors to determine the need
Figure 2. Evolving algorithm of surveillance using uPSA in first 2 years after (s/p) RP based on limited evidence and best interpretation of available data combined with expert opinion. CAPRA, Cancer of Prostate Risk Assessment. Dotted outlines indicate suggestions requiring consensus.
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ULTRASENSITIVE PROSTATE SPECIFIC ANTIGEN AND ITS ROLE AFTER PROSTATECTOMY
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for adjuvant or salvage therapy. Most available data consist of short-term to intermediate term observational studies with a small sample size. Based on limited evidence and the best interpretation of available data combined with our expert opinion
7
746 we propose an algorithm for surveillance after RP with uPSA (fig. 2). This algorithm can help in un- ½F2 747 748 derstanding the role of uPSA in surveillance after 749 RP. However, further prospective studies are 750 needed to evaluate uPSA benefits and risks.
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11. Stamey TA, Kabalin JN, McNeal JE et al: Prostate specific antigen in the diagnosis and treatment of adenocarcinoma of the prostate. II. Radical prostatectomy treated patients. J Urol 1989; 141: 1076. 12. Lightner DJ, Lange PH, Reddy PK et al: Prostate specific antigen and local recurrence after radical prostatectomy. J Urol 1990; 144: 921. 13. Graves HC, Wehner N and Stamey TA: Ultrasensitive radioimmunoassay of prostatespecific antigen. Clin Chem 1992; 38: 735. 14. Vessella RL, Noteboom J and Lange PH: Evaluation of the Abbott IMxÒ automated immunoassay of prostate-specific antigen. Clin Chem 1992; 38: 2044. 15. Ellis WJ, Vessella RL, Noteboom JL et al: Early detection of recurrent prostate cancer with an ultrasensitive chemiluminescent prostatespecific antigen assay. Urology 1997; 50: 573. 16. Yu H, Diamandis EP, Prestigiacomo AF et al: Ultrasensitive assay of prostate-specific antigen used for early detection of prostate cancer relapse and estimation of tumor-doubling time after radical prostatectomy. Clin Chem 1995; 41: 430. 17. Yu H and Diamandis EP: Ultrasensitive timeresolved immunofluorometric assay of prostatespecific antigen in serum and preliminary clinical studies. Clin Chem 1993; 39: 2108. 18. Moher D, Liberati A, Tetzlaff J et al: Preferred reporting items for systematic reviews and metaanalyses: the PRISMA statement. PLoS Med 2009; 6: e1000097. 19. Haese A, Huland E, Graefen M et al: Ultrasensitive detection of prostate specific antigen in the followup of 422 patients after radical prostatectomy. J Urol 1999; 161: 1206. 20. Pruthi RS, Haese A, Huland E et al: Use of serum concentration techniques to enhance early detection of recurrent prostate cancer after radical prostatectomy. Urology 1997; 49: 404. 21. van Iersel MP, Thomas CM, Segers MF et al: The use of ’ultrasensitive’ prostate-specific antigen assays in the detection of biochemical
recurrence after radical prostatectomy. Br J Urol 1996; 77: 418. 22. Vassilikos EJ, Yu H, Trachtenberg J et al: Relapse and cure rates of prostate cancer patients after radical prostatectomy and 5 years of follow-up. Clin Biochem 2000; 33: 115. 23. Iwakiri J, Grandbois K, Wehner N et al: An analysis of urinary prostate specific antigen before and after radical prostatectomy: evidence for secretion of prostate specific antigen by the periurethral glands. J Urol 1993; 149: 783. 24. Khosravi MJ, Papanastasiou-Diamandi A and Mistry J: An ultrasensitive immunoassay for prostate-specific antigen based on conventional colorimetric detection. Clin Biochem 1995; 28: 407. 25. Yu H and Diamandis EP: Measurement of serum prostate specific antigen levels in women and in prostatectomized men with an ultrasensitive immunoassay technique. J Urol 1995; 153: 1004. 26. Liedtke RJ, Kroon G and Batjer JD: Modified assay of prostate-specific antigen with a detection limit < 0.01 microgram/L. Clin Chem 1993; 39: 2150. 27. Witherspoon LR and Lapeyrolerie T: Sensitive prostate specific antigen measurements identify men with long disease-free intervals and differentiate aggressive from indolent cancer recurrences within 2 years after radical prostatectomy. J Urol 1997; 157: 1322. 28. Oesterling JE, Tekchandani AH, Martin SK et al: The periurethral glands do not significantly influence the serum prostate specific antigen concentration. J Urol 1996; 155: 1658. 29. Godoy G, Tareen BU and Lepor H: Does benign prostatic tissue contribute to measurable PSA levels after radical prostatectomy? Urology 2009; 74: 167. 30. Shinghal R, Yemoto C, McNeal JE et al: Biochemical recurrence without PSA progression characterizes a subset of patients after radical prostatectomy. Prostate-specific antigen. Urology 2003; 61: 380.
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Ultrasensitive Prostate Specific Antigen and Its Role after Radical Prostatectomy: A Systematic Review Derya Tilki,*,† Sun Il Kim,† Brian Hu, Marc A. Dall’Era and Christopher P. Evans From the Martini-Clinic Prostate Cancer Center and Department of Urology, University Hospital Hamburg-Eppendorf (DT), Hamburg, Germany, Department of Urology, School of Medicine, University of California-Davis (DT, SIK, BH, MAD, CPE), Sacramento, California, and Department of Urology, Ajou University School of Medicine (SIK), Suwon, Republic of Korea
Purpose: Prostate specific antigen is an important tool to monitor patients with prostate cancer after radical prostatectomy. Ultrasensitive prostate specific antigen assays are increasingly used with a lower limit of detection as low as 0.001 ng/ml. We systematically reviewed currently available ultrasensitive prostate specific antigen technologies and the role of this method in monitoring patients after radical prostatectomy. Materials and Methods: We searched the relevant literature using the MEDLINEÒ database. For various study objectives the series eligible for review provided serial ultrasensitive prostate specific antigen (lower detection limit less than 0.1 ng/ml) data on men after radical prostatectomy as well as comparative data on standard prostate specific antigen (lower detection limit 0.1 ng/ml or greater). Results: Ultrasensitive prostate specific antigen could potentially detect prostate cancer recurrence years earlier than standard prostate specific antigen assays. The specificity of detectable ultrasensitive prostate specific antigen is low. Ultrasensitive prostate specific antigen kinetics may improve the positive predictive value for detecting cancer recurrence. However, the usefulness of prostate specific antigen doubling time at the ultrasensitive level remains controversial. Undetectable nadir ultrasensitive prostate specific antigen after radical prostatectomy confers a low risk of disease recurrence while a detectable nadir above 0.01 ng/ml requires additional measurement and consideration of other risk factors to determine management and avoid overtreatment. This monitoring method may spare patients with high risk disease adjuvant radiation therapy and enable more selective early salvage radiation. Currently no data demonstrates improved survival after early salvage therapy prompted by ultrasensitive prostate specific antigen surveillance. Conclusions: Ultrasensitive prostate specific antigen is useful in the early diagnosis of cancer recurrence after radical prostatectomy but specificity is poor. To date there is a lack of evidence that earlier detection of recurrence translates into prolonged time to metastasis. Integrating ultrasensitive prostate specific antigen with other clinicopathological factors can help determine optimal adjuvant and salvage therapy.
Abbreviations and Acronyms BCR ¼ biochemical recurrence ePSADT ¼ early PSADT LLD ¼ lower detection limit PCa ¼ prostate cancer PPV ¼ positive predictive value PSA ¼ prostate specific antigen PSADT ¼ PSA doubling time RP ¼ radical prostatectomy TRIFA ¼ time resolved immunofluorometric assay uPSA ¼ ultrasensitive PSA XRT ¼ external radiation therapy Accepted for publication October 16, 2014. * Correspondence and requests for reprints: Martini-Clinic Prostate Cancer Center, University Hospital Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany (e-mail: [email protected]). † Equal study contribution. Supplementary references 31 to 58 for this article can be obtained at http://jurology.com/.
Key Words: prostatic neoplasms; prostate-specific antigen; prostatectomy; neoplasm recurrence, local; diagnosis
0022-5347/15/1935-0001/0 THE JOURNAL OF UROLOGY® © 2015 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION AND RESEARCH, INC.
Dochead: Adult Urology
http://dx.doi.org/10.1016/j.juro.2014.10.087 Vol. 193, 1-7, May 2015 Printed in U.S.A.
www.jurology.com
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SINCE PSA was approved by the United States FDA (Food and Drug Administration), it has become the most widely used tool to monitor and detect PCa. Annual screening in the prostate portion of the PLCO (Prostate, Lung, Colorectal and Ovarian) Cancer Screening Trial was not associated with decreased PCa specific mortality.1,2 A significant portion of men would be over diagnosed and over treated as a result of PSA screening.3 On the other hand, PSA derivatives such as PSAD appear to identify patients at low risk with PCa who would not need active treatment.4 In the context of monitoring patients after therapy PSA kinetics better predicted the outcome than a single PSA measurement.5,6 Low PSA predicted a lower long-term risk of PCa and all-cause mortality in longitudinal community studies.7,8 RP remains a widely used treatment for localized PCa, although up to 35% of patients experience relapse postoperatively.9 Intervention before clinical recurrence gives patients the opportunity for better long-term cancer-free survival.10 The sensitivity of detecting BCR is directly related to the sensitivity of the PSA assay. The LLD of commercial first generation PSA assays is 0.3 to 0.4 ng/ml and any detectable serum PSA after RP could be rightfully interpreted as residual or recurrent cancer.11,12 Since that time, second generation uPSA assays have improved sensitivity with most manufacturers offering assays with a LLD of 0.1 ng/ml or less.13,14 This sensitivity level satisfies current AUA (American Urological Association) and EAU (European Association of Urology) guidelines that define BCR after RP as PSA 0.2 ng/ml or greater. Further technical advances enabled assays to be developed with a LLD as low as 0.001 ng/ml, which allowed BCR detection months to years earlier compared to standard assays.15e17 The use of uPSA is increasing in the urological community. However, no clear guidelines exist on its role in monitoring patients after RP. Earlier detection may translate to more efficacious salvage therapy and potential for improved survival. In this review we systematically analyzed available evidence on uPSA performance in the followup of patients after RP. We also established a practical guideline for using uPSA to monitor patients after RP.
PATIENTS AND METHODS No clear definition of uPSA exists in the literature. Early reports used the term ultrasensitive for second generation assays with a detection limit of 0.1 ng/ml, which may be misleading in the current era.13,14 Thus, we considered an assay ultrasensitive only when PSA less Dochead: Adult Urology
172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 ½F1 200 201 202 203 RESULTS 204 BCR Diagnosis Lead Time 205 Time from first detectable uPSA to more tradition206 ally defined BCR was based on multiple stored 207 serum samples from patients with known BCR, 208 which was presented as an efficacy uPSA assay 209 end point in earlier studies (table 1).15,16,19e22 ½T1 210 Detection limits of uPSA assays were 2.5 to 25 211 times lower than those of standard assays used for 212 comparison. Average lead time to BCR diagnosis 213 was 1 year (range 9 to 29 months). Notably tumor 214 characteristics and other factors such as followup, 215 which influence this lead time, were heterogeneous 216 or not mentioned in some studies. Moreover, the 217 BCR definition was not universal, limiting data 218 generalizability. 219 220 uPSA 221 PPV. PSA has been detected in men who undergo 222 cystoprostatectomy for bladder cancer without 223 identifiable PCa. This was hypothesized to arise 224 from the periurethral glands.23 Even in some women 225 serum PSA is detectable by an ultrasensitive 226 assay.24,25 Several groups reported serum uPSA 227 levels in control populations lacking the prostate 228
than 0.1 ng/ml was reported, in contrast to standard PSA assays for which PSA less than 0.1 ng/ml is reported as undetectable. In July 2014 we searched the MEDLINE database. Only original articles in English were considered for review. Search terms included ultrasensitive, prostatespecific antigen and prostatectomy. Other descriptive terms that are interchangeable with ultrasensitive (ie supersensitive, hypersensitive and sensitive) were included. Lower limit of detection and other terms that specify the assay sensitivity level (ie lower detection threshold, lower detection sensitivity, lower limit and analytical sensitivity) were also used. To identify relevant reports that may not mention ultrasensitivity or specify a detection limit of the assay we included specific values, ranging from 0.01 to 0.09 ng/ml at 0.01 ng/ml increments. The same strategy was applied for 0.001 to 0.009 ng/ml. This study was developed according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses).18 Eligibility criteria for study inclusion considered participants, intervention, comparators, outcomes and study design. Eligible studies included patients who underwent RP with serial postoperative uPSA data and standard PSA data or a traditional definition of BCR as comparators. Outcome included 1 of certain topics, including lead time to BCR diagnosis, BCR PPV, uPSA kinetics, prognostic significance of the undetectable uPSA nadir and implications for adjuvant/salvage XRT. All study designs except case reports were included in analysis. Figure 1 shows the study search and selection flow diagram.
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286 229 287 230 288 231 289 232 290 233 291 234 292 235 293 236 294 237 295 238 296 239 297 240 298 241 299 242 300 243 301 244 302 245 303 246 304 247 305 248 306 249 307 250 308 251 309 252 310 253 311 254 Figure 1. Study search and selection. 312 255 313 256 314 257 ½T2 (table 2).14e17,20,24e27 Pooled analysis of studies with risk after RP were followed the uPSA increases 315 258 a LLD of 0.01 ng/ml or less indicate that the chance contributed by benign prostatic tissue (0.6%) or 29 316 259 of finding detectable (0.01 ng/ml or greater) PSA in cancer recurrence (0.3%) were equally rare. A 317 260 women, men after cystoprostatectomy and men in clear conclusion about the source of these low PSA 318 261 a long-term recurrence-free state after RP is 17%, levels is limited by the paucity of data. Nonetheless, 15,25e27 319 262 12% and 41%, respectively. the specificity of uPSA for PCa recurrence appears In these studies 320 263 to be adversely affected. a single subject often contributed several samples 321 264 The PPV of detectable uPSA to predict BCR was and residual cancer could not be completely ruled 15,19,22,27,30 265 calculated in 5 studies (table 3). out in patients treated with RP. Assays ½T3322 323 266 In contrast, a comparative study of 3 uPSA assay with a relatively low cutoff of 0.008 and 0.02 ng/ml 324 267 methods in patients after cystoprostatectomy and were associated with a low PPV of 37% and 15,27 325 268 RP demonstrated only a small difference between 30%, respectively. Instead of using a single 326 269 the 2 groups, suggesting a negligible contribution cutoff integrating PSA kinetics into the BCR defi28 327 270 of the periurethral glands to serum PSA. nition resulted in an 86% PPV despite a low LLD In 22 328 271 of 0.001 ng/ml. another study in which patients at extremely low 329 272 330 273 Table 1. BCR diagnosis lead time by various uPSA assays in patients after RP 331 274 332 275 BCR Cutoff (ng/ml) 333 276 References Assay No. Pts uPSA Traditional PSA Mean Lead Time (mos) 334 277 Chemiluminescent (Hybritech, Scottsdale, AZ) 24 0.008 0.1 22.3 Ellis et al15 335 278 TRIFA 10 0.04 0.1, 0.3 13.8, 29.0 Yu et al16 19 336 279 Lyophilization* 28 0.025 0.1 8.8 Haese et al Lyophilization, filtration† 31 0.023, 0.023 0.07, 0.07 11.9, 12.6 Pruthi et al20 337 280 IMx (Abbott, Abbott Park, IL), Tandem-E multipoint (Hybritech) 12 0.04, 0.04 1.0, 1.0 10.7, 12.1 van Iersel et al21 338 281 TRIFA 31 0.001‡ 0.1§ 18.0 Vassilikos et al22 339 282 * Serum concentration enhanced assay sensitivity fourfold. 340 283 † Serum concentration enhanced each assay sensitivity threefold. 341 284 ‡ LLD, 2 or more consecutive serum PSA increases resulting in at least initial PSA doubling. 342 285 § LLD, 2 or more consecutive PSA measurements greater than 0.2 or greater than 0.1 ng/ml. Dochead: Adult Urology
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343 344 345 346 347 348 349 350 351 352 353 354 355 356 357 358 359 360 361 362 363 364 365 366 367 368 369 370 371 372 373 374 375 376 ½T4 377 378 379 380 381 382 383 384 385 386 387 388 389 390 391 392 393 394 395 396 397 398 399
Table 2. Serum findings by uPSA cutoff in women, in men after cystoprostatectomy and in long-term recurrence-free men after RP for small low grade cancer No. Pts (ng/ml uPSA cutoff) References Women: Vessella et al14 Ellis et al15 Yu and Diamandis17 Pruthi et al20 Khosravi et al24 Yu and Diamandis25 Liedtke et al26 Witherspoon and Lapeyrolerie27 Ellis et al,15 Yu and Diamandis,25 Liedtke et al,26 Witherspoon and Lapeyrolerie27 (%) Men after cystoprostatectomy: Vessella et al14 Ellis et al15 Pruthi et al20 Liedtke et al26 Ellis15 and Liedtke26 et al (%) Men with potential post-RP cure: Vessella et al14 Ellis et al15 Yu et al16 Pruthi et al20 Khosravi et al24 Yu and Diamandis25 Liedtke et al26 Ellis15 and Yu et al,16 Yu and Diamandis,25 Liedtke et al26 (%)
Assay IMx Chemiluminescent TRIFA AIA-Pack (Tosoh, Tokyo, Japan) Immunoenzymometric TRIFA Modified Tandem-E ImmuliteÔ
IMx Chemiluminescent AIA-Pack Modified Tandem-E IMx Chemiluminescent TRIFA AIA-Pack Immunoenzymometric TRIFA Modified Tandem-E
Less Than 0.01
Less Than 0.02
Less Than 0.05
Not determined 117 Not determined Not determined 73 Not determined 37* 882 24 120 1,143 (83)
25 5 30 (88) 24 12
0 Not determined Not determined Not determined e
22 1 20
Less Than 0.1
0.1 or Greater
50 Not determined Not determined 0
0 3 2 0
3 0 2 0
Not determined 155 Not determined 3 0 22 1 202 (15) e
Not determined Not determined Not determined 0 e Not determined Not determined
Less Than 0.06
39 4
0 e
1 0 0 0 0
ND 10 0 e
0 4 (12) 0 Not determined
35 Not determined
Not determined 21* 43 6 85 (59)
4 11 0 1 15 (1)
40 Not determined Not determined 0 e
0 e
3 1 13 0 12 36 0 50 (34)
0 16 1 1 18 (1)
0 0 0 0 0 0 0 0 0 6 10 0 10 (7)
* uPSA less than 0.012 ng/ml.
Several groups defined a subset of patients in whom uPSA reached a detectable or a certain predefined level but never attained a level traditionally defined as BCR within a median of 15 to more than 85 months (table 4).15,19,22,27,31 Considering that some men are at risk for future recurrence after longer followup this new patient cohort should be better defined in the future. Kinetics. PSA kinetics at the ultrasensitive level may improve the low PPV of detectable uPSA for cancer recurrence. In a study using an assay with a LLD of 0.001 ng/ml Yu et al redefined BCR as satisfying 1 or more of certain criteria, including 2 or more consecutive serum PSA increases that resulted in
at least the doubling of initial PSA, any increase that resulted in a value greater than 0.1 ng/ml or a tenfold increase between 2 serum collections.32 By applying this definition 100% to 150% more recurrences were detected compared to what would have been detected using the criterion of serum PSA greater than 0.1 ng/ml.22,31,32 Several earlier studies showed that PSADT at the ultrasensitive level had mixed results.16,20,32,33 However, these studies incorporated PSA values well above the BCR level in the uPSADT calculations. A more recent attempt to calculate uPSADT and uPSA velocities based on prospectively collected periodic measurements did not yield meaningful results due to fluctuations in the uPSA range.34
Table 3. uPSA assay PPV for recurrent cancer in patients after RP BCR Cutoff (ng/ml) References 15
Ellis et al Vassilikos et al22 Haese et al19 Witherspoon and Lapeyrolerie27 Shinghal et al30
Assay
No. BCR Pts (uPSA/traditional PSA)
uPSA
Traditional PSA
% PPV
Chemiluminescent TRIFA Lyophilization* Immulite AIA (Tosoh)
65/24 36/31 88/65 66/20 158/144
0.008 0.001† 0.025 0.02 0.07
0.1 0.1‡ 0.1 Clinical recurrence Clinical recurrence
37 86 74 30 91
* Serum concentration enhanced assay sensitivity fourfold. † LLD, 2 or more consecutive serum PSA increases resulting in at least doubling of initial PSA and crossing 0.1 ng/ml earlier than 4 years after RP. ‡ LLD, 2 or more consecutive PSA measurements greater than >0.2 or PSA greater than 0.1 ng/ml. Dochead: Adult Urology
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Table 4. Patients identified as having biochemical recurrence by ultrasensitive prostate-specific antigen cutoff value only and not by traditional cutoff value References 15
Ellis et al Witherspoon and Lapeyrolerie27 Arai et al31 Haese et al19 Vassilikos et al22
Assay
No. Pts
Mean Followup (mos)
uPSA Range (ng/ml)
Description
Chemiluminescent Immulite Immulite Lyophilization* TRIFA
34, 7 11 4 23 30
Median 15, mean greater than 85 Mean 36 Not determined Not determined Mean 45
0.01e0.03, 0.04e0.08 0.01e0.02 0.01e0.02 0.025e0.1 0e0.1
Recurrence undetermined Slowly increasing PSA Recurrence undetermined Recurrence undetermined Slow recurrence
* Serum concentration enhanced assay sensitivity fourfold.
Shimizu et al generated a computer model that simulated increasing longitudinal uPSA and concluded that specificity based on 2 consecutive increases was inadequate, suggesting the need for at least 3 consecutive measurements.35 They also calculated uPSADT in 52 patients with BCR but the resulting values were inadequate. The larger coefficient of variation seen with lower PSA values, a possibly nonexponential increase in uPSA and a limited number of values used to calculate uPSADT were presented as possible reasons for the inadequacy.36 In a larger population of patients from the SEARCH (Shared Equal Access Regional Cancer Hospital) database Teeter et al investigated whether ePSADT calculated from the first detectable uPSA after RP to the first PSA of 0.2 ng/ml or greater correlated with standard PSADT.37 Although they found a significant correlation between ePSADT and standard PSADT, the overall association was moderate to poor. Also, the PPV to predict aggressive recurrence was low at different ePSADT thresholds. In addition, in another study they did not find that uPSADT was an independent predictor of aggressive recurrence after RP.38 uPSADT calculated from the CaPSUREÒ database also correlated poorly with PSADT.39 In that study uPSADT calculated at the PSA change between 0.05 and 0.2 ng/ml was often much more rapid than PSADT calculated at a PSA of greater than 0.2 ng/ml, which may lead to overestimating the recurrence risk.
LLD as low as 0.01 pg/ml showed a 69% to 72% PPV at a 0.003 ng/ml cutoff.48,49 Different definitions of BCR as well as different assay techniques and uPSA nadir cutoffs were used, making pooled analysis impossible. In a study of the impact of post-RP PSA nadir at an ultrasensitive level after salvage XRT 3-year BCR-free survival did not significantly differ between the undetectable (nadir uPSA less than 0.05 ng/ml) and detectable groups.50 Eisenberg et al proposed using early postoperative uPSA at 1 to 3 months instead of nadir uPSA.51 On multivariate analysis detectable postoperative uPSA greater than 0.05 ng/ml was an independent predictor of BCR. Moreover, patients with positive surgical margins or stage pT3 with undetectable uPSA had better BCR-free rates than those with detectable uPSA, suggesting that postoperative uPSA status may be considered in the decision to administer adjuvant therapy in patients with adverse pathological features. In a SEARCH database study Moreira et al similarly observed that failure to achieve uPSA less than 0.03 ng/ml within 6 months of RP, defined as PSA persistence, was associated with an increased risk of BCR.52 In an updated series of 1,156 patients Moreira et al found that PSA persistence was also a significant predictor of overall survival.47 Malik et al addressed the long-term usefulness of uPSA, reporting that uPSA less than 0.04 ng/ml measured 3 years after RP was an independent predictor of delayed relapse.53
Undetectable. The significance of an undetectable
Adjuvant and salvage therapy. Adjuvant XRT im-
uPSA nadir after RP was addressed in several studies in which uPSA was applied prospectively at a 3 to 6-month interval after RP (supplementary table, http://jurology.com/).34,40e49 Most studies included 0.01 ng/ml as the undetectable uPSA cutoff. In most of these studies multivariate analysis revealed that uPSA was an independent predictor of BCR alone or with other clinicopathological factors. At a uPSA cutoff of 0.01 ng/ml the negative predictive value was high at between 95% and 100%. PPV varied between 30% and 76%. Two pilot studies in which a novel, single molecule enzyme-linked immunosorbent assay technique was used with a
proves biochemical disease-free survival in patients with adverse pathological features and it also improves overall survival.54,55 However, adjuvant XRT is often not recommended by urologists, mainly due to concern over unnecessary adverse effects in a considerable portion of patients in whom recurrence would never develop. Thus, these patients are often placed on surveillance and receive early salvage therapy. uPSA is commonly applied in this treatment algorithm. Typically adjuvant therapy begins 3 to 9 months postoperatively to allow for adequate recovery of urinary and erectile function. Within this window several uPSA values
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can help determine whether adjuvant therapy is indicated. Although to our knowledge no group has examined the ideal uPSA interval after RP, in men with detectable uPSA the frequency of followup should remain similar to that for standard PSA assays. Three or 4 consecutive values could be obtained during this window to help determine the significance of detectable uPSA. In men with undetectable values less frequent followup is unlikely to cause the loss of a therapeutic window. Shen et al proposed that men with a uPSA nadir of less than 0.01 ng/ml in year 1 must undergo uPSA measurement annually.41 Given that uPSA has 96% to 100% negative predictive value at the 0.01 ng/ml cutoff, this seems to be a reasonable recommendation but it requires validation. uPSA improves the time to detection of PCa relapse by months to years. This lead time to relapse would seem to improve the patient chance of durable progression-free survival with salvage therapy given at a lower cancer burden and a wider window for cure.56 Using uPSA Terai et al followed patients after RP, of whom 37 were able to receive early salvage XRT at a median PSA of 0.146 ng/ml.57 PreXRT uPSA 0.15 ng/ml or less
predicted nonprogression after XRT. However, this study was limited by small patient number and short followup. Mir et al recently analyzed the risk of PSA, defined as a PSA increase of greater than 0.1 ng/ml above BCR, and treatment progression after BCR based on 14 BCR definitions in 2,348 patients with detectable PSA 0.03 ng/ml or greater after RP.58 They concluded that BCR definitions below currently accepted PSA thresholds appear to be valid to select patients with adverse clinicopathological risk factors for secondary therapy.
CONCLUSIONS To monitor patients with PCa after RP uPSA detects recurrence months to years earlier than standard PSA assays. An undetectable uPSA nadir is prognostic of a lower risk of future recurrence while the PPV of detectable uPSA is low. Serial uPSA measurements are more useful to determine cancer recurrence, although the usefulness of uPSADT in this setting is controversial. Currently no data demonstrate that earlier intervention associated with uPSA improves survival or cancer outcomes. Post-RP uPSA monitoring complements traditional clinicopathological factors to determine the need
Figure 2. Evolving algorithm of surveillance using uPSA in first 2 years after (s/p) RP based on limited evidence and best interpretation of available data combined with expert opinion. CAPRA, Cancer of Prostate Risk Assessment. Dotted outlines indicate suggestions requiring consensus.
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for adjuvant or salvage therapy. Most available data consist of short-term to intermediate term observational studies with a small sample size. Based on limited evidence and the best interpretation of available data combined with our expert opinion
7
746 we propose an algorithm for surveillance after RP with uPSA (fig. 2). This algorithm can help in un- ½F2 747 748 derstanding the role of uPSA in surveillance after 749 RP. However, further prospective studies are 750 needed to evaluate uPSA benefits and risks.
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Dochead: Adult Urology
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