- Email: [email protected]
Can Prostate Specific Antigen Velocity Thresholds Decrease Insignificant Prostate Cancer Detection?
Can Prostate Specific Antigen Velocity Thresholds Decrease Insignificant Prostate Cancer Detection? Stacy Loeb, Kimberly A. Roehl, Brian T. Helfand, Donghui Kan and William J. Catalona*,† From the Department of Urology, The Johns Hopkins School of Medicine (SL), Baltimore, Maryland, Department of Psychiatry, Washington University School of Medicine (KAR), St. Louis, Missouri, and Department of Urology, Northwestern Feinberg School of Medicine (BTH, DK, WJC), Chicago, Illinois
Abbreviations and Acronyms DRE ⫽ digital rectal examination PSA ⫽ prostate specific antigen PSAV ⫽ PSA velocity Submitted for publication May 21, 2009. Study received institutional review board approval. Supported by the Urological Research Foundation, Prostate SPORE Grant P50 CA90386-05S2 and Robert H. Lurie Comprehensive Cancer Center Grant P30 CA60553. * Correspondence: 675 North Saint Clair St., Suite 20-150, Chicago, Illinois 60611 (telephone: 312-695-4471; FAX: 312-695-1482; e-mail: [email protected]). † Financial interest and/or other relationship with Beckman Coulter.
Purpose: A controversy of current prostate specific antigen based prostate cancer screening is the over detection of potentially insignificant prostate cancer. Because PSA kinetics were previously linked to prostate cancer specific mortality, we determined whether prostate specific antigen velocity is associated with clinically significant prostate cancer. Materials and Methods: A total of 1,073 men underwent radical prostatectomy from 1992 to 2008 with data available on prostate specific antigen velocity and tumor volume. Insignificant cancer was defined by the Ohori criteria as organ confined, tumor volume 0.5 cc or less and no primary or secondary Gleason pattern 4 or 5. We calculated the proportion of men with pathologically insignificant prostate cancer stratified by prostate specific antigen velocity. Results: Preoperative prostate specific antigen velocity greater than 0.4 ng/ml per year was significantly associated with high grade disease (p ⫽ 0.008), positive surgical margins (p ⫽ 0.003) and seminal vesicle invasion (p ⫽ 0.007) at radical prostatectomy. Median tumor volume was also significantly higher in men with preoperative prostate specific antigen velocity greater than 0.4 ng/ml per year (3.1 vs 2.4 cc, p ⫽ 0.0001). Overall 69 men (6%) met the Ohori criteria for insignificant cancer. Patients with preoperative prostate specific antigen velocity greater than 0.4 ng/ml per year were 50% less likely to have insignificant disease (10% vs 5%, p ⫽ 0.003). Conclusions: A prostate specific antigen velocity threshold of 0.4 ng/ml per year was associated with the likelihood of insignificant prostate cancer. This suggests that prostate specific antigen velocity may be a useful adjunct in prostate cancer screening to increase specificity for identifying patients with clinically significant disease. Key Words: prostate, prostatic neoplasms, mass screening, prostate-specific antigen, prostatectomy
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CURRENTLY there is controversy about PSA based screening. The European Randomized Study of Screening for Prostate Cancer showed a 20% decrease in cancer specific mortality in the screening arm but reported that 1,410 men would need to be screened and 48 would need to be treated to
prevent 1 prostate cancer death.1 Correspondingly there is concern about the over diagnosis of potentially insignificant prostate cancer. Nevertheless, current clinical staging modalities are limited in their ability to accurately predict tumor biology, which has fueled an ongoing search
0022-5347/10/1831-0112/0 THE JOURNAL OF UROLOGY® Copyright © 2010 by AMERICAN UROLOGICAL ASSOCIATION
Vol. 183, 112-117, January 2010 Printed in U.S.A. DOI:10.1016/j.juro.2009.08.156
PROSTATE SPECIFIC ANTIGEN VELOCITY AND PROSTATE CANCER DETECTION
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University with data available on tumor volume and PSAV. Compared to 808 excluded men from Northwestern University without PSAV study participants were older (59 vs 58 years, p ⫽ 0.02), and had similar racial distribution (p ⫽ 0.80) and pathological tumor stage (p ⫽ 0.14). The combined overall study population included 1,073 men, including 13 with PSA less than 1 ng/ml who were diagnosed with prostate cancer due to suspicious findings on DRE. Compared to the 556 men from the screening study the 517 from Northwestern University were significantly younger (p ⬍0.001) but racial (p ⫽ 0.14) and pathological stage (p ⫽ 0.08) distributions were not significantly different. Clinical and pathological features were recorded in a prospective database. Tumor volume was primarily determined by visual estimation, which correlates well with the grid morphometric method.10 Insignificant prostate cancer was defined according to the previously published Ohori criteria, including organ confined, tumor volume 0.5 cc or less and no Gleason pattern 4 or 5.11 PSAV was calculated by regression analysis of PSA measurements within the year before prostate cancer diagnosis, as previously described.4 The t, chi-square and Wilcoxon rank sum tests were used to compare clinicopathological features based on PSAV. Logistic regression was used for univariate and multivariate analyses to predict significant prostate cancer. Neither race nor family history was a significant predictor on multivariate analysis and so these variables were removed from the final model. ROC analysis was performed using MedCalc®. Subgroup analysis was also done in the 464 men with preoperative PSA less than 4 ng/ml to examine the ability of PSAV to distinguish insignificant prostate cancer at lower PSA. SAS® was used for all statistical analysis.
for more specific markers of clinically significant prostate cancer. A promising marker is PSAV (rapidly increasing PSA).2 Our research group previously noted a relationship between PSAV and Gleason grade in the radical prostatectomy specimen.3 Specifically median preoperative PSAV was 0.84, 0.97 and 1.39 ng/ml per year in patients with a prostatectomy Gleason score of 6, 7 and 8 –10, respectively (p ⫽ 0.05). Other studies have shown a relationship between pretreatment PSAV and the risk of prostate cancer specific mortality.4 – 6 Together these findings suggest that PSAV may be a surrogate marker for prostate cancer aggressiveness. Conversely low PSAV (small PSA increase with time) may indicate a greater likelihood of indolent disease. The 2010 National Comprehensive Cancer Network Guidelines and others suggest a PSAV threshold of about 0.35 to 0.4 ng/ml per year in prostate cancer screening protocols.7,8 We tested whether this PSAV threshold is associated with the pathological features and likelihood of finding histologically insignificant prostate cancer at radical prostatectomy.
METHODS From 1992 to 2002 approximately 26,000 men participated in a prostate cancer screening study, as previously described.9 PSA and DRE were performed at 6 to 12month intervals and biopsy was recommended for PSA greater than 4.0 ng/ml before 1995 or greater than 2.5 ng/ml after 1995, or findings suspicious for cancer (induration or irregularity) on DRE. Of this population 1,374 men underwent radical prostatectomy by 1 of various surgeons. Of these men 556 met study inclusion criteria, including tumor volume data and multiple preoperative PSA measurements available to enable PSAV calculation. Men included in the screening study were older (64 vs 63 years, p ⫽ 0.02), slightly more likely to be white (92% vs 89%, p ⫽ 0.09) and more likely to have organ confined disease at radical prostatectomy (78% vs 67%, p ⬍0.0001) than those excluded from study. From 2003 to 2008 another 517 men underwent radical prostatectomy done by a single surgeon at Northwestern
RESULTS Table 1 shows study population demographic characteristics. Mean patient age was 62 years and most men were white. Median PSA at diagnosis was 4.3 ng/ml. Most patients had clinical stage T1c prostate cancer with a biopsy Gleason score of 6. Men with PSAV greater than 0.4 ng/ml per year had higher PSA at diagnosis (4.5 vs 4.0 ng/ml, p ⬍0.0001) and significantly fewer had clinical stage
Table 1. Study population clinical characteristics
Mean age (range) Race (% black) Family history Mean/median ng/ml PSA (range) No. clinical stage (%): T1 T2 or Greater No. biopsy Gleason score (%): 6 7 or Greater
Overall
PSAV Less Than 0.4 ng/ml/yr
PSAV Greater Than 0.4 ng/ml/yr
p Value
62 (41–78) 50 (5) 223/740 (30) 5.1/4.3 (0.2–63.3)
62 (43–78) 20 (5) 65 (25) 4.2/4.0 (0.2–28.8)
62 (41–77) 30 (4) 158 (33) 4.5/4.5 (1.1–63.3)
0.42 0.74 0.05 ⬍0.0001 0.0005
842 228
(79) (21)
270 102
(73) (27)
572 126
(82) (18)
848 219
(79) (21)
304 66
(82) (18)
544 153
(78) (22)
0.13
PROSTATE SPECIFIC ANTIGEN VELOCITY AND PROSTATE CANCER DETECTION
T2 or greater disease (18% vs 27%, p ⫽ 0.0005) than those with PSAV less than 0.4 ng/ml per year (table 1). Age, race and biopsy Gleason score were similar between the groups. At radical prostatectomy 858 men (80%) had organ confined disease (table 2). Positive surgical margins were significantly more likely in men with PSAV greater than 0.4 ng/ml per year (19% vs 12%, p ⫽ 0.003), as was seminal vesicle invasion (4% vs 1%, p ⫽ 0.007). Similarly patients with PSAV greater than 0.4 ng/ml per year had significantly higher tumor volume than those with PSAV less than 0.4 ng/ml per year (p ⫽ 0.0001) and were significantly more likely to have a Gleason score of 7 or greater (p ⫽ 0.008). Median PSAV was 0.79, 0.92 and 2.78 ng/ml per year in patients with a prostatectomy Gleason score of 6 or less, 7 and 8 to 10, respectively (p ⬍0.0001). On ROC analysis PSAV had an AUC of 0.70 to predict a prostatectomy Gleason score of 8 to 10. Overall 69 men (6%) had pathologically insignificant cancer according to the Ohori criteria.11 Insignificant disease was significantly more likely in men with preoperative PSAV less than 0.4 ng/ml per year (10% vs 5%, p ⫽ 0.003). Median PSAV was 0.36 vs 0.89 ng/ml per year in men with insignificant disease vs men who did not meet insignificant disease criteria (p ⫽ 0.005). Of the 1,055 men with PSA less than 15 ng/ml insignificant disease was reported in 10% vs 5% of those with PSAV less than 0.4 vs greater than 0.4 ng/ml per year (p ⫽ 0.005). On univariate analysis age (OR 1.0, 95% CI 1.0 – 1.1, p ⫽ 0.04), Gleason score (OR 9.3, 95% CI 2.3–38.3, p ⫽ 0.02), PSA (OR 1.4, 95% CI 1.2–1.7, p ⬍0.0001) and PSAV greater than 0.4 ng/ml per year (OR 2.0, 95% CI 1.2–3.3, p ⫽ 0.004) were significantly associated with significant prostate cancer. The figure shows the ROC curve to predict significant prostate cancer using PSAV alone. On multivariate analysis PSAV was an independent predictor of significant prostate cancer after controlling for age, clinical stage and biopsy Gleason score (OR 1.8, 95% CI 1.1–3.0, p ⫽ 0.02, table 3). After additional adjustment for PSA PSAV was as-
100 80 Sensitivity
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60 40 20 0 0
20
40 60 100-Specificity
80
100
ROC analysis of significant prostate cancer prediction by PSAV
sociated with a nonsignificantly increased likelihood of significant disease (table 3). On ROC analysis a model including age, clinical stage, biopsy Gleason score and PSA had an AUC of 0.73, which increased to 0.74 after adding PSAV. Finally, of the subset of 464 men with total PSA less than 4 ng/ml 48 (10%) met the Ohori criteria for insignificant prostate cancer. As in the overall population, men with PSAV less than 0.4 ng/ml per year were twice as likely to have pathologically insignificant prostate cancer than those with PSAV greater than 0.4 ng/ml per year (14% vs 7%, p ⫽ 0.02). PSAV greater than 0.4 ng/ml per year was also associated with significantly higher tumor volume (2.3 vs 2.1 cc, p ⫽ 0.03) and a greater incidence of Gleason 7 or greater tumors at prostatectomy (36% vs 22%, p ⫽ 0.002). In men at low risk with PSA less than 4 ng/ml and a biopsy Gleason score of 6 PSAV greater than 0.4 ng/ml per year was associated with a 2.1-fold increased odds of significant cancer on multivariate analysis with age and clinical stage (p ⫽ 0.03, table 3).
Table 2. Study population pathological features by PSAV Overall No. organ confined (%) No. pos surgical margins (%) No. extracapsular extension only (%) No. seminal vesicle invasion (%) No. lymph node metastasis (%) No. prostatectomy Gleason score (%): 6 7 or Greater Mean/median cc tumor vol (range)
858 173 140 31 5
(80) (16) (13) (3) (0.5)
688 (64) 385 (36) 4.3/2.9 (0.05–71.2)
PSAV Less Than 0.4 ng/ml/yr
PSAV Greater Than 0.4 ng/ml/yr
p Value
309 43 50 4 2
549 130 90 27 3
(79) (19) (13) (4) (0.4)
0.13 0.003 0.85 0.007 0.99
428 (61) 271 (39) 4.6/3.1 (0.05–71.2)
0.008
(83) (12) (13) (1) (0.6)
260 (70) 114 (30) 3.8/2.4 (0.05–37.8)
0.0001
PROSTATE SPECIFIC ANTIGEN VELOCITY AND PROSTATE CANCER DETECTION
Table 3. Multivariate analysis to predict significant prostate cancer overall and in subset with PSA less than 4 ng/ml and biopsy Gleason score 6
Overall: Age Clinical stage Biopsy Gleason score PSAV greater than 0.4 ng/ml/yr Adjusted for PSA: Age Clinical stage Gleason score PSA PSAV greater than 0.4 ng/ml/yr PSA less than 4 ng/ml ⫹ biopsy Gleason score 6: Age Clinical stage PSAV greater than 0.4 ng/ml/yr
OR (95% CI)
p Value
1.04 (0.99–1.07) 1.0 (0.6–1.9) 8.9 (2.2–36.7) 1.8 (1.1–3.0)
0.07 0.93 0.003 0.02
1.04 (0.99–1.08) 1.5 (0.8–3.0) 7.0 (1.7–28.9) 1.4 (1.2–1.6) 1.4 (0.8–2.4)
0.07 0.20 0.007 0.0002 0.18
1.06 (1.01–1.11) 1.3 (0.6–2.7) 2.1 (1.1–4.1)
0.02 0.55 0.03
DISCUSSION PSA has been criticized as a marker due to its limited specificity for prostate cancer. As a result, PSA kinetics measurements, such as PSAV, have recently gained considerable attention. In the initial clinical report in 1992 Carter et al compared longitudinal changes in PSA among 20 men with BPH, 18 with prostate cancer and 16 controls from the Baltimore Longitudinal Study on Aging.12 In this nonscreening population PSAV greater than 0.75 ng/ml per year was useful for distinguishing prostate cancer from benign conditions (p ⬍0.01). Subsequently Smith and Catalona tested these results in 9,492 men with serial PSA measurements from a formal prostate cancer screening study.13 Of these men 982 underwent prostate biopsy. Prostate cancer was detected in 47% of men with PSAV greater than 0.75 ng/ml per year vs only 11% of those with lower PSAV. Because these early studies were based on men with PSA greater than 4 ng/ml, their generalizability to men with lower total PSA is unclear. Nevertheless, most men who are 40 years old or older have PSA less than 4 ng/ml. According to National Health and Nutrition Examination Survey 2001 to 2002 data overall estimated mean and median PSA was 1.56 (95% CI 1.37–1.74) and 0.9 ng/ml (25th–75th percentiles 0.5–1.4), respectively, in 40 to 84-yearold American men.14 Interestingly Carter et al noted that prostate cancer specific mortality was significantly higher in men with PSAV greater than 0.35 ng/ml per year more than a decade before diagnosis at a time when total PSA levels were low.6 Correspondingly some groups now recommend a PSAV threshold in the range of 0.3 to 0.5 ng/ml per year.7,15 The 2010 National Comprehensive Cancer Network guide-
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lines recommend considering prostate biopsy in men with PSA 2.5 ng/ml or less and PSAV greater than 0.35 ng/ml per year.8 It is unclear whether these lower PSAV thresholds will merely increase the detection of insignificant prostate cancer or conversely enhance the specificity of PSA based screening for identifying clinically significant disease. Thus, we compared tumor features and the proportion of pathologically insignificant tumors in men with pretreatment PSAV less vs greater than 0.4 ng/ml per year. Men with PSAV greater than 0.4 ng/ml per year were significantly more likely to have adverse pathological features at radical prostatectomy, including positive surgical margins, seminal vesicle invasion, Gleason score 7 or greater and higher tumor volume. The PSAV distribution was significantly different between men who did and who did not meet the Ohori criteria11 for insignificant prostate cancer. Specifically pathologically insignificant disease was 50% less likely in men with preoperative PSAV greater than 0.4 ng/ml per year. After controlling for age, clinical stage and Gleason score PSAV greater than 0.4 ng/ml per year was associated with approximately a 2-fold increased odds of pathologically significant prostate cancer. Although this association was slightly attenuated by adding PSA to the model, this was likely related to the strong interaction between the variables and requires further exploration. Interestingly in a subset analysis of men at low risk with PSA less than 4 ng/ml and a biopsy Gleason score of 6 PSAV greater than 0.4 ng/ml per year was similarly associated with a 2-fold increased odds of significant disease in a multivariate model. These results suggest that PSAV may be useful to distinguish clinically significant prostate cancer in patients otherwise at low risk. The limitations of our study include the small sample size with insignificant disease, decreasing our statistical power. Also, the optimal method of PSAV calculation and the definition of pathologically insignificant11 prostate cancer are subject to debate. There are insufficient data to prove that individuals who meet pathological criteria for insignificant prostate cancer will not experience metastasis or prostate cancer death in the long term. Thus, we also provide data on the relationship between PSAV and specific pathological tumor features as additional support for its role as a potential marker of prostate cancer aggressiveness. Finally, we selected the threshold of 0.4 ng/ml per year for analysis based on prior literature and National Comprehensive Cancer Network guidelines.6 – 8,15 However, this may not represent the optimal cutoff and this issue requires further prospective study.
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CONCLUSIONS Patients with preoperative PSAV greater than 0.4 ng/ml per year were significantly less likely to have pathologically insignificant prostate cancer and had significantly higher tumor volume at radical prostatectomy. On multivariate analysis with age, clinical stage and Gleason score PSAV was significantly associated with the risk of clinically significant pros-
tate cancer. Similarly in men with PSA less than 4 ng/ml per year and a biopsy Gleason score of 6 PSAV greater than 0.4 ng/ml was associated with 50% decreased odds of a finding of pathologically insignificant prostate cancer. These results suggest that PSAV may be useful in conjunction with other variables to help enhance the specificity of prostate cancer screening to detect clinically significant prostate cancer.
REFERENCES 1. Schroder FH, Hugosson J, Roobol MJ: Screening and prostate-cancer mortality in a randomized European study. N Engl J Med 2009; 360: 1320. 2. Sutcliffe P, Hummel S, Simpson E et al: Use of classical and novel biomarkers as prognostic risk factors for localised prostate cancer: a systematic review. Health Technol Assess 2009; 13: iii. 3. Loeb S, Sutherland DE, D’Amico AV et al: PSA velocity is associated with Gleason score in radical prostatectomy specimen: marker for prostate cancer aggressiveness. Urology 2008; 72: 1116.
6. Carter HB, Ferrucci L, Kettermann A et al: Detection of life-threatening prostate cancer with prostate-specific antigen velocity during a window of curability. J Natl Cancer Inst 2006; 98: 1521.
11. Ohori M, Wheeler TM, Dunn JK et al: The pathological features and prognosis of prostate cancer detectable with current diagnostic tests. J Urol 1994; 152: 1714.
7. Moul JW, Sun L, Hotaling JM et al: Age adjusted prostate specific antigen and prostate specific antigen velocity cut points in prostate cancer screening. J Urol 2007; 177: 499.
12. Carter HB, Pearson JD, Metter EJ et al: Longitudinal evaluation of prostate-specific antigen levels in men with and without prostate disease. JAMA 1992; 267: 2215.
8. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology. Prostate Cancer Early Detection. Available at http://www.nccn. org/professionals/physician_gls/PDF/prostate_ detection.pdf. Accessed September 2, 2009.
13. Smith DS and Catalona WJ: Rate of change in serum prostate specific antigen levels as a method for prostate cancer detection. J Urol 1994; 152: 1163.
4. D’Amico AV, Chen MH, Roehl KA et al: Preoperative PSA velocity and the risk of death from prostate cancer after radical prostatectomy. N Engl J Med 2004; 351: 125.
9. Smith DS and Catalona WJ: The nature of prostate cancer detected through prostate specific antigen based screening. J Urol 1994; 152: 1732.
14. Porter MP, Stanford JL and Lange PH: The distribution of serum prostate-specific antigen levels among American men: implications for prostate cancer prevalence and screening. Prostate 2006; 66: 1044.
5. D’Amico AV, Renshaw AA, Sussman B et al: Pretreatment PSA velocity and risk of death from prostate cancer following external beam radiation therapy. JAMA 2005; 294: 440.
10. Humphrey PA and Vollmer RT: Percentage carcinoma as a measure of prostatic tumor size in radical prostatectomy tissues. Mod Pathol 1997; 10: 326.
15. Loeb S, Roehl KA, Nadler RB et al: Prostate specific antigen velocity in men with total prostate specific antigen less than 4 ng/ml. J Urol 2007; 178: 2348.
EDITORIAL COMMENTS PSA kinetics are associated with Gleason score (reference 3 in article) and disease specific outcomes in men with prostate cancer (references 4 and 5 in article). In the year before diagnosis PSAV 2 ng/ml per year or more was associated with a 10-fold greater risk of prostate cancer death after radical prostatectomy than PSAV less than 2 ng/ml per year (reference 4 in article). PSAV greater than 0.35 ng/ml per year was associated with lethal prostate cancer more than a decade before diagnosis (reference 6 in article). Thus, it seems logical to ask whether PSAV is associated with small volume, low grade cancer (insignificant disease), given the over treatment of prostate cancer that occurs with PSA screening. These authors noted that of men with median PSA 4 ng/ml and mostly nonpalpable disease those with PSAV greater than 0.4 ng/ml per year were twice as likely to have significant cancer whether or not PSA was less than 4 ng/ml and more likely to
have adverse pathological features at radical prostatectomy, eg positive surgical margins, seminal vesicle invasion, Gleason score 7 or greater and higher tumor volume. Thus, in addition to others, PSAV is an indicator suggesting significant disease,1 which may be helpful for selecting men for prostate biopsy and prostate cancer surveillance. Some would argue that there is no need to look at PSA history since that information is available from a single PSA measurement.2 Given the current study and prior series showing the associations between PSAV and important patient outcomes, most urologists would be appropriately unwilling to ignore a rapid PSA increase regardless of absolute PSA. H. Ballentine Carter Department of Urology The Johns Hopkins School of Medicine Baltimore, Maryland
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REFERENCES 1. Scardino PT: Clinical decisions. N Engl J Med 2008; 359: 2607. 2. O’Brien MF, Cronin AM, Fearn PA et al: Pretreatment prostate-specific antigen (PSA) velocity and doubling time are associated with outcome but neither improves prediction of outcome beyond pretreatment PSA alone in patients treated with radical prostatectomy. J Clin Oncol 2009; 27: 3591.
These authors provide further evidence of the usefulness of PSAV in the year before diagnosis to identify men with significant prostate cancer. Based on previous publications (references 3 to 5 in article) this is a logical next step in the use of PSAV. The authors report that PSAV greater than 0.4 ng/ml per year was associated with adverse pathological features, such as Gleason score 7 or greater, higher tumor volume and seminal vesicle invasion, as well as with a decreased likelihood of clinically insignificant cancer (10% vs 5%). The 0.4 ng/ml per year cutoff was chosen for analysis based on recent publications and National Comprehensive Cancer Network guidelines (references 6 to 8 and 15 in article). Importantly the authors identified that this may not represent the optimal cutoff and it requires further prospective study. In this regard it is similar to the study by Carter et al who suggested a cutoff of 0.35 ng/ml per year but stipulated that 0.35 ng/ml per year may be 1 reasonable choice among others to balance sensitivity and specificity to detect life threatening cancer (reference 6 in article). On assessing the ROC curve it is obvious that no definitive
cutoff can reliably predict insignificant prostate cancer (see figure). I suspect that ROC curves to predict the other adverse pathological features described would have a similar pattern. Recent trends in recommending lower PSAV cutoffs are reminiscent of what happened in the mid 1990s with total PSA. Initially similar prostate cancer levels were found in men with total PSA less than 4.0 ng/ml, leading to the recommendation of lower PSA cutoffs.1 The Prostate Cancer Prevention Trial then showed that there is no PSA cutoff that definitively excludes prostate cancer but there is rather a continuum of risk.2 I suspect that the same may be true for PSAV,3 in that there are no definitive cutoffs but a continuum of risk for cancer diagnosis or adverse pathological features. This must be considered when counseling men considering prostate biopsy or radical therapy. David Connolly Department of Urology Belfast City Hospital Belfast, United Kingdom
REFERENCES 1. Catalona WJ, Smith DS and Ornstein DK: Prostate cancer detection in men with serum PSA concentrations of 2.6 to 4.0 ng/ml and benign prostate examination. Enhancement of specificity with free PSA measurements. JAMA 1997; 277: 1452.
2. Thompson IM, Pauler DK, Goodman PJ et al: Prevalence of prostate cancer among men with a prostate-specific antigen level ⬍ or ⫽4.0 ng per milliliter. N Engl J Med 2004; 350: 2239.
3. Connolly D, Black A, Murray LJ et al: The utility of prostate-specific antigen velocity thresholds in clinical practice: a population-based analysis. BJU Int 2008; 101: 1507.
Abbreviations and Acronyms DRE ⫽ digital rectal examination PSA ⫽ prostate specific antigen PSAV ⫽ PSA velocity Submitted for publication May 21, 2009. Study received institutional review board approval. Supported by the Urological Research Foundation, Prostate SPORE Grant P50 CA90386-05S2 and Robert H. Lurie Comprehensive Cancer Center Grant P30 CA60553. * Correspondence: 675 North Saint Clair St., Suite 20-150, Chicago, Illinois 60611 (telephone: 312-695-4471; FAX: 312-695-1482; e-mail: [email protected]). † Financial interest and/or other relationship with Beckman Coulter.
Purpose: A controversy of current prostate specific antigen based prostate cancer screening is the over detection of potentially insignificant prostate cancer. Because PSA kinetics were previously linked to prostate cancer specific mortality, we determined whether prostate specific antigen velocity is associated with clinically significant prostate cancer. Materials and Methods: A total of 1,073 men underwent radical prostatectomy from 1992 to 2008 with data available on prostate specific antigen velocity and tumor volume. Insignificant cancer was defined by the Ohori criteria as organ confined, tumor volume 0.5 cc or less and no primary or secondary Gleason pattern 4 or 5. We calculated the proportion of men with pathologically insignificant prostate cancer stratified by prostate specific antigen velocity. Results: Preoperative prostate specific antigen velocity greater than 0.4 ng/ml per year was significantly associated with high grade disease (p ⫽ 0.008), positive surgical margins (p ⫽ 0.003) and seminal vesicle invasion (p ⫽ 0.007) at radical prostatectomy. Median tumor volume was also significantly higher in men with preoperative prostate specific antigen velocity greater than 0.4 ng/ml per year (3.1 vs 2.4 cc, p ⫽ 0.0001). Overall 69 men (6%) met the Ohori criteria for insignificant cancer. Patients with preoperative prostate specific antigen velocity greater than 0.4 ng/ml per year were 50% less likely to have insignificant disease (10% vs 5%, p ⫽ 0.003). Conclusions: A prostate specific antigen velocity threshold of 0.4 ng/ml per year was associated with the likelihood of insignificant prostate cancer. This suggests that prostate specific antigen velocity may be a useful adjunct in prostate cancer screening to increase specificity for identifying patients with clinically significant disease. Key Words: prostate, prostatic neoplasms, mass screening, prostate-specific antigen, prostatectomy
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CURRENTLY there is controversy about PSA based screening. The European Randomized Study of Screening for Prostate Cancer showed a 20% decrease in cancer specific mortality in the screening arm but reported that 1,410 men would need to be screened and 48 would need to be treated to
prevent 1 prostate cancer death.1 Correspondingly there is concern about the over diagnosis of potentially insignificant prostate cancer. Nevertheless, current clinical staging modalities are limited in their ability to accurately predict tumor biology, which has fueled an ongoing search
0022-5347/10/1831-0112/0 THE JOURNAL OF UROLOGY® Copyright © 2010 by AMERICAN UROLOGICAL ASSOCIATION
Vol. 183, 112-117, January 2010 Printed in U.S.A. DOI:10.1016/j.juro.2009.08.156
PROSTATE SPECIFIC ANTIGEN VELOCITY AND PROSTATE CANCER DETECTION
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University with data available on tumor volume and PSAV. Compared to 808 excluded men from Northwestern University without PSAV study participants were older (59 vs 58 years, p ⫽ 0.02), and had similar racial distribution (p ⫽ 0.80) and pathological tumor stage (p ⫽ 0.14). The combined overall study population included 1,073 men, including 13 with PSA less than 1 ng/ml who were diagnosed with prostate cancer due to suspicious findings on DRE. Compared to the 556 men from the screening study the 517 from Northwestern University were significantly younger (p ⬍0.001) but racial (p ⫽ 0.14) and pathological stage (p ⫽ 0.08) distributions were not significantly different. Clinical and pathological features were recorded in a prospective database. Tumor volume was primarily determined by visual estimation, which correlates well with the grid morphometric method.10 Insignificant prostate cancer was defined according to the previously published Ohori criteria, including organ confined, tumor volume 0.5 cc or less and no Gleason pattern 4 or 5.11 PSAV was calculated by regression analysis of PSA measurements within the year before prostate cancer diagnosis, as previously described.4 The t, chi-square and Wilcoxon rank sum tests were used to compare clinicopathological features based on PSAV. Logistic regression was used for univariate and multivariate analyses to predict significant prostate cancer. Neither race nor family history was a significant predictor on multivariate analysis and so these variables were removed from the final model. ROC analysis was performed using MedCalc®. Subgroup analysis was also done in the 464 men with preoperative PSA less than 4 ng/ml to examine the ability of PSAV to distinguish insignificant prostate cancer at lower PSA. SAS® was used for all statistical analysis.
for more specific markers of clinically significant prostate cancer. A promising marker is PSAV (rapidly increasing PSA).2 Our research group previously noted a relationship between PSAV and Gleason grade in the radical prostatectomy specimen.3 Specifically median preoperative PSAV was 0.84, 0.97 and 1.39 ng/ml per year in patients with a prostatectomy Gleason score of 6, 7 and 8 –10, respectively (p ⫽ 0.05). Other studies have shown a relationship between pretreatment PSAV and the risk of prostate cancer specific mortality.4 – 6 Together these findings suggest that PSAV may be a surrogate marker for prostate cancer aggressiveness. Conversely low PSAV (small PSA increase with time) may indicate a greater likelihood of indolent disease. The 2010 National Comprehensive Cancer Network Guidelines and others suggest a PSAV threshold of about 0.35 to 0.4 ng/ml per year in prostate cancer screening protocols.7,8 We tested whether this PSAV threshold is associated with the pathological features and likelihood of finding histologically insignificant prostate cancer at radical prostatectomy.
METHODS From 1992 to 2002 approximately 26,000 men participated in a prostate cancer screening study, as previously described.9 PSA and DRE were performed at 6 to 12month intervals and biopsy was recommended for PSA greater than 4.0 ng/ml before 1995 or greater than 2.5 ng/ml after 1995, or findings suspicious for cancer (induration or irregularity) on DRE. Of this population 1,374 men underwent radical prostatectomy by 1 of various surgeons. Of these men 556 met study inclusion criteria, including tumor volume data and multiple preoperative PSA measurements available to enable PSAV calculation. Men included in the screening study were older (64 vs 63 years, p ⫽ 0.02), slightly more likely to be white (92% vs 89%, p ⫽ 0.09) and more likely to have organ confined disease at radical prostatectomy (78% vs 67%, p ⬍0.0001) than those excluded from study. From 2003 to 2008 another 517 men underwent radical prostatectomy done by a single surgeon at Northwestern
RESULTS Table 1 shows study population demographic characteristics. Mean patient age was 62 years and most men were white. Median PSA at diagnosis was 4.3 ng/ml. Most patients had clinical stage T1c prostate cancer with a biopsy Gleason score of 6. Men with PSAV greater than 0.4 ng/ml per year had higher PSA at diagnosis (4.5 vs 4.0 ng/ml, p ⬍0.0001) and significantly fewer had clinical stage
Table 1. Study population clinical characteristics
Mean age (range) Race (% black) Family history Mean/median ng/ml PSA (range) No. clinical stage (%): T1 T2 or Greater No. biopsy Gleason score (%): 6 7 or Greater
Overall
PSAV Less Than 0.4 ng/ml/yr
PSAV Greater Than 0.4 ng/ml/yr
p Value
62 (41–78) 50 (5) 223/740 (30) 5.1/4.3 (0.2–63.3)
62 (43–78) 20 (5) 65 (25) 4.2/4.0 (0.2–28.8)
62 (41–77) 30 (4) 158 (33) 4.5/4.5 (1.1–63.3)
0.42 0.74 0.05 ⬍0.0001 0.0005
842 228
(79) (21)
270 102
(73) (27)
572 126
(82) (18)
848 219
(79) (21)
304 66
(82) (18)
544 153
(78) (22)
0.13
PROSTATE SPECIFIC ANTIGEN VELOCITY AND PROSTATE CANCER DETECTION
T2 or greater disease (18% vs 27%, p ⫽ 0.0005) than those with PSAV less than 0.4 ng/ml per year (table 1). Age, race and biopsy Gleason score were similar between the groups. At radical prostatectomy 858 men (80%) had organ confined disease (table 2). Positive surgical margins were significantly more likely in men with PSAV greater than 0.4 ng/ml per year (19% vs 12%, p ⫽ 0.003), as was seminal vesicle invasion (4% vs 1%, p ⫽ 0.007). Similarly patients with PSAV greater than 0.4 ng/ml per year had significantly higher tumor volume than those with PSAV less than 0.4 ng/ml per year (p ⫽ 0.0001) and were significantly more likely to have a Gleason score of 7 or greater (p ⫽ 0.008). Median PSAV was 0.79, 0.92 and 2.78 ng/ml per year in patients with a prostatectomy Gleason score of 6 or less, 7 and 8 to 10, respectively (p ⬍0.0001). On ROC analysis PSAV had an AUC of 0.70 to predict a prostatectomy Gleason score of 8 to 10. Overall 69 men (6%) had pathologically insignificant cancer according to the Ohori criteria.11 Insignificant disease was significantly more likely in men with preoperative PSAV less than 0.4 ng/ml per year (10% vs 5%, p ⫽ 0.003). Median PSAV was 0.36 vs 0.89 ng/ml per year in men with insignificant disease vs men who did not meet insignificant disease criteria (p ⫽ 0.005). Of the 1,055 men with PSA less than 15 ng/ml insignificant disease was reported in 10% vs 5% of those with PSAV less than 0.4 vs greater than 0.4 ng/ml per year (p ⫽ 0.005). On univariate analysis age (OR 1.0, 95% CI 1.0 – 1.1, p ⫽ 0.04), Gleason score (OR 9.3, 95% CI 2.3–38.3, p ⫽ 0.02), PSA (OR 1.4, 95% CI 1.2–1.7, p ⬍0.0001) and PSAV greater than 0.4 ng/ml per year (OR 2.0, 95% CI 1.2–3.3, p ⫽ 0.004) were significantly associated with significant prostate cancer. The figure shows the ROC curve to predict significant prostate cancer using PSAV alone. On multivariate analysis PSAV was an independent predictor of significant prostate cancer after controlling for age, clinical stage and biopsy Gleason score (OR 1.8, 95% CI 1.1–3.0, p ⫽ 0.02, table 3). After additional adjustment for PSA PSAV was as-
100 80 Sensitivity
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60 40 20 0 0
20
40 60 100-Specificity
80
100
ROC analysis of significant prostate cancer prediction by PSAV
sociated with a nonsignificantly increased likelihood of significant disease (table 3). On ROC analysis a model including age, clinical stage, biopsy Gleason score and PSA had an AUC of 0.73, which increased to 0.74 after adding PSAV. Finally, of the subset of 464 men with total PSA less than 4 ng/ml 48 (10%) met the Ohori criteria for insignificant prostate cancer. As in the overall population, men with PSAV less than 0.4 ng/ml per year were twice as likely to have pathologically insignificant prostate cancer than those with PSAV greater than 0.4 ng/ml per year (14% vs 7%, p ⫽ 0.02). PSAV greater than 0.4 ng/ml per year was also associated with significantly higher tumor volume (2.3 vs 2.1 cc, p ⫽ 0.03) and a greater incidence of Gleason 7 or greater tumors at prostatectomy (36% vs 22%, p ⫽ 0.002). In men at low risk with PSA less than 4 ng/ml and a biopsy Gleason score of 6 PSAV greater than 0.4 ng/ml per year was associated with a 2.1-fold increased odds of significant cancer on multivariate analysis with age and clinical stage (p ⫽ 0.03, table 3).
Table 2. Study population pathological features by PSAV Overall No. organ confined (%) No. pos surgical margins (%) No. extracapsular extension only (%) No. seminal vesicle invasion (%) No. lymph node metastasis (%) No. prostatectomy Gleason score (%): 6 7 or Greater Mean/median cc tumor vol (range)
858 173 140 31 5
(80) (16) (13) (3) (0.5)
688 (64) 385 (36) 4.3/2.9 (0.05–71.2)
PSAV Less Than 0.4 ng/ml/yr
PSAV Greater Than 0.4 ng/ml/yr
p Value
309 43 50 4 2
549 130 90 27 3
(79) (19) (13) (4) (0.4)
0.13 0.003 0.85 0.007 0.99
428 (61) 271 (39) 4.6/3.1 (0.05–71.2)
0.008
(83) (12) (13) (1) (0.6)
260 (70) 114 (30) 3.8/2.4 (0.05–37.8)
0.0001
PROSTATE SPECIFIC ANTIGEN VELOCITY AND PROSTATE CANCER DETECTION
Table 3. Multivariate analysis to predict significant prostate cancer overall and in subset with PSA less than 4 ng/ml and biopsy Gleason score 6
Overall: Age Clinical stage Biopsy Gleason score PSAV greater than 0.4 ng/ml/yr Adjusted for PSA: Age Clinical stage Gleason score PSA PSAV greater than 0.4 ng/ml/yr PSA less than 4 ng/ml ⫹ biopsy Gleason score 6: Age Clinical stage PSAV greater than 0.4 ng/ml/yr
OR (95% CI)
p Value
1.04 (0.99–1.07) 1.0 (0.6–1.9) 8.9 (2.2–36.7) 1.8 (1.1–3.0)
0.07 0.93 0.003 0.02
1.04 (0.99–1.08) 1.5 (0.8–3.0) 7.0 (1.7–28.9) 1.4 (1.2–1.6) 1.4 (0.8–2.4)
0.07 0.20 0.007 0.0002 0.18
1.06 (1.01–1.11) 1.3 (0.6–2.7) 2.1 (1.1–4.1)
0.02 0.55 0.03
DISCUSSION PSA has been criticized as a marker due to its limited specificity for prostate cancer. As a result, PSA kinetics measurements, such as PSAV, have recently gained considerable attention. In the initial clinical report in 1992 Carter et al compared longitudinal changes in PSA among 20 men with BPH, 18 with prostate cancer and 16 controls from the Baltimore Longitudinal Study on Aging.12 In this nonscreening population PSAV greater than 0.75 ng/ml per year was useful for distinguishing prostate cancer from benign conditions (p ⬍0.01). Subsequently Smith and Catalona tested these results in 9,492 men with serial PSA measurements from a formal prostate cancer screening study.13 Of these men 982 underwent prostate biopsy. Prostate cancer was detected in 47% of men with PSAV greater than 0.75 ng/ml per year vs only 11% of those with lower PSAV. Because these early studies were based on men with PSA greater than 4 ng/ml, their generalizability to men with lower total PSA is unclear. Nevertheless, most men who are 40 years old or older have PSA less than 4 ng/ml. According to National Health and Nutrition Examination Survey 2001 to 2002 data overall estimated mean and median PSA was 1.56 (95% CI 1.37–1.74) and 0.9 ng/ml (25th–75th percentiles 0.5–1.4), respectively, in 40 to 84-yearold American men.14 Interestingly Carter et al noted that prostate cancer specific mortality was significantly higher in men with PSAV greater than 0.35 ng/ml per year more than a decade before diagnosis at a time when total PSA levels were low.6 Correspondingly some groups now recommend a PSAV threshold in the range of 0.3 to 0.5 ng/ml per year.7,15 The 2010 National Comprehensive Cancer Network guide-
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lines recommend considering prostate biopsy in men with PSA 2.5 ng/ml or less and PSAV greater than 0.35 ng/ml per year.8 It is unclear whether these lower PSAV thresholds will merely increase the detection of insignificant prostate cancer or conversely enhance the specificity of PSA based screening for identifying clinically significant disease. Thus, we compared tumor features and the proportion of pathologically insignificant tumors in men with pretreatment PSAV less vs greater than 0.4 ng/ml per year. Men with PSAV greater than 0.4 ng/ml per year were significantly more likely to have adverse pathological features at radical prostatectomy, including positive surgical margins, seminal vesicle invasion, Gleason score 7 or greater and higher tumor volume. The PSAV distribution was significantly different between men who did and who did not meet the Ohori criteria11 for insignificant prostate cancer. Specifically pathologically insignificant disease was 50% less likely in men with preoperative PSAV greater than 0.4 ng/ml per year. After controlling for age, clinical stage and Gleason score PSAV greater than 0.4 ng/ml per year was associated with approximately a 2-fold increased odds of pathologically significant prostate cancer. Although this association was slightly attenuated by adding PSA to the model, this was likely related to the strong interaction between the variables and requires further exploration. Interestingly in a subset analysis of men at low risk with PSA less than 4 ng/ml and a biopsy Gleason score of 6 PSAV greater than 0.4 ng/ml per year was similarly associated with a 2-fold increased odds of significant disease in a multivariate model. These results suggest that PSAV may be useful to distinguish clinically significant prostate cancer in patients otherwise at low risk. The limitations of our study include the small sample size with insignificant disease, decreasing our statistical power. Also, the optimal method of PSAV calculation and the definition of pathologically insignificant11 prostate cancer are subject to debate. There are insufficient data to prove that individuals who meet pathological criteria for insignificant prostate cancer will not experience metastasis or prostate cancer death in the long term. Thus, we also provide data on the relationship between PSAV and specific pathological tumor features as additional support for its role as a potential marker of prostate cancer aggressiveness. Finally, we selected the threshold of 0.4 ng/ml per year for analysis based on prior literature and National Comprehensive Cancer Network guidelines.6 – 8,15 However, this may not represent the optimal cutoff and this issue requires further prospective study.
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PROSTATE SPECIFIC ANTIGEN VELOCITY AND PROSTATE CANCER DETECTION
CONCLUSIONS Patients with preoperative PSAV greater than 0.4 ng/ml per year were significantly less likely to have pathologically insignificant prostate cancer and had significantly higher tumor volume at radical prostatectomy. On multivariate analysis with age, clinical stage and Gleason score PSAV was significantly associated with the risk of clinically significant pros-
tate cancer. Similarly in men with PSA less than 4 ng/ml per year and a biopsy Gleason score of 6 PSAV greater than 0.4 ng/ml was associated with 50% decreased odds of a finding of pathologically insignificant prostate cancer. These results suggest that PSAV may be useful in conjunction with other variables to help enhance the specificity of prostate cancer screening to detect clinically significant prostate cancer.
REFERENCES 1. Schroder FH, Hugosson J, Roobol MJ: Screening and prostate-cancer mortality in a randomized European study. N Engl J Med 2009; 360: 1320. 2. Sutcliffe P, Hummel S, Simpson E et al: Use of classical and novel biomarkers as prognostic risk factors for localised prostate cancer: a systematic review. Health Technol Assess 2009; 13: iii. 3. Loeb S, Sutherland DE, D’Amico AV et al: PSA velocity is associated with Gleason score in radical prostatectomy specimen: marker for prostate cancer aggressiveness. Urology 2008; 72: 1116.
6. Carter HB, Ferrucci L, Kettermann A et al: Detection of life-threatening prostate cancer with prostate-specific antigen velocity during a window of curability. J Natl Cancer Inst 2006; 98: 1521.
11. Ohori M, Wheeler TM, Dunn JK et al: The pathological features and prognosis of prostate cancer detectable with current diagnostic tests. J Urol 1994; 152: 1714.
7. Moul JW, Sun L, Hotaling JM et al: Age adjusted prostate specific antigen and prostate specific antigen velocity cut points in prostate cancer screening. J Urol 2007; 177: 499.
12. Carter HB, Pearson JD, Metter EJ et al: Longitudinal evaluation of prostate-specific antigen levels in men with and without prostate disease. JAMA 1992; 267: 2215.
8. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology. Prostate Cancer Early Detection. Available at http://www.nccn. org/professionals/physician_gls/PDF/prostate_ detection.pdf. Accessed September 2, 2009.
13. Smith DS and Catalona WJ: Rate of change in serum prostate specific antigen levels as a method for prostate cancer detection. J Urol 1994; 152: 1163.
4. D’Amico AV, Chen MH, Roehl KA et al: Preoperative PSA velocity and the risk of death from prostate cancer after radical prostatectomy. N Engl J Med 2004; 351: 125.
9. Smith DS and Catalona WJ: The nature of prostate cancer detected through prostate specific antigen based screening. J Urol 1994; 152: 1732.
14. Porter MP, Stanford JL and Lange PH: The distribution of serum prostate-specific antigen levels among American men: implications for prostate cancer prevalence and screening. Prostate 2006; 66: 1044.
5. D’Amico AV, Renshaw AA, Sussman B et al: Pretreatment PSA velocity and risk of death from prostate cancer following external beam radiation therapy. JAMA 2005; 294: 440.
10. Humphrey PA and Vollmer RT: Percentage carcinoma as a measure of prostatic tumor size in radical prostatectomy tissues. Mod Pathol 1997; 10: 326.
15. Loeb S, Roehl KA, Nadler RB et al: Prostate specific antigen velocity in men with total prostate specific antigen less than 4 ng/ml. J Urol 2007; 178: 2348.
EDITORIAL COMMENTS PSA kinetics are associated with Gleason score (reference 3 in article) and disease specific outcomes in men with prostate cancer (references 4 and 5 in article). In the year before diagnosis PSAV 2 ng/ml per year or more was associated with a 10-fold greater risk of prostate cancer death after radical prostatectomy than PSAV less than 2 ng/ml per year (reference 4 in article). PSAV greater than 0.35 ng/ml per year was associated with lethal prostate cancer more than a decade before diagnosis (reference 6 in article). Thus, it seems logical to ask whether PSAV is associated with small volume, low grade cancer (insignificant disease), given the over treatment of prostate cancer that occurs with PSA screening. These authors noted that of men with median PSA 4 ng/ml and mostly nonpalpable disease those with PSAV greater than 0.4 ng/ml per year were twice as likely to have significant cancer whether or not PSA was less than 4 ng/ml and more likely to
have adverse pathological features at radical prostatectomy, eg positive surgical margins, seminal vesicle invasion, Gleason score 7 or greater and higher tumor volume. Thus, in addition to others, PSAV is an indicator suggesting significant disease,1 which may be helpful for selecting men for prostate biopsy and prostate cancer surveillance. Some would argue that there is no need to look at PSA history since that information is available from a single PSA measurement.2 Given the current study and prior series showing the associations between PSAV and important patient outcomes, most urologists would be appropriately unwilling to ignore a rapid PSA increase regardless of absolute PSA. H. Ballentine Carter Department of Urology The Johns Hopkins School of Medicine Baltimore, Maryland
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REFERENCES 1. Scardino PT: Clinical decisions. N Engl J Med 2008; 359: 2607. 2. O’Brien MF, Cronin AM, Fearn PA et al: Pretreatment prostate-specific antigen (PSA) velocity and doubling time are associated with outcome but neither improves prediction of outcome beyond pretreatment PSA alone in patients treated with radical prostatectomy. J Clin Oncol 2009; 27: 3591.
These authors provide further evidence of the usefulness of PSAV in the year before diagnosis to identify men with significant prostate cancer. Based on previous publications (references 3 to 5 in article) this is a logical next step in the use of PSAV. The authors report that PSAV greater than 0.4 ng/ml per year was associated with adverse pathological features, such as Gleason score 7 or greater, higher tumor volume and seminal vesicle invasion, as well as with a decreased likelihood of clinically insignificant cancer (10% vs 5%). The 0.4 ng/ml per year cutoff was chosen for analysis based on recent publications and National Comprehensive Cancer Network guidelines (references 6 to 8 and 15 in article). Importantly the authors identified that this may not represent the optimal cutoff and it requires further prospective study. In this regard it is similar to the study by Carter et al who suggested a cutoff of 0.35 ng/ml per year but stipulated that 0.35 ng/ml per year may be 1 reasonable choice among others to balance sensitivity and specificity to detect life threatening cancer (reference 6 in article). On assessing the ROC curve it is obvious that no definitive
cutoff can reliably predict insignificant prostate cancer (see figure). I suspect that ROC curves to predict the other adverse pathological features described would have a similar pattern. Recent trends in recommending lower PSAV cutoffs are reminiscent of what happened in the mid 1990s with total PSA. Initially similar prostate cancer levels were found in men with total PSA less than 4.0 ng/ml, leading to the recommendation of lower PSA cutoffs.1 The Prostate Cancer Prevention Trial then showed that there is no PSA cutoff that definitively excludes prostate cancer but there is rather a continuum of risk.2 I suspect that the same may be true for PSAV,3 in that there are no definitive cutoffs but a continuum of risk for cancer diagnosis or adverse pathological features. This must be considered when counseling men considering prostate biopsy or radical therapy. David Connolly Department of Urology Belfast City Hospital Belfast, United Kingdom
REFERENCES 1. Catalona WJ, Smith DS and Ornstein DK: Prostate cancer detection in men with serum PSA concentrations of 2.6 to 4.0 ng/ml and benign prostate examination. Enhancement of specificity with free PSA measurements. JAMA 1997; 277: 1452.
2. Thompson IM, Pauler DK, Goodman PJ et al: Prevalence of prostate cancer among men with a prostate-specific antigen level ⬍ or ⫽4.0 ng per milliliter. N Engl J Med 2004; 350: 2239.
3. Connolly D, Black A, Murray LJ et al: The utility of prostate-specific antigen velocity thresholds in clinical practice: a population-based analysis. BJU Int 2008; 101: 1507.