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Journal of Clinical Oncology, Vol 26, No 6 (February 20), 2008: pp. 823-824 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.15.1902
Prostate-Specific Antigen (PSA) and PSA Velocity: Competitors or Collaborators in the Prediction of Curable and Clinically Significant Prostate CancerDepartment of Radiation Oncology, Brigham and Women's Hospital, and Dana Farber Cancer Institute, Boston, MA Several investigators have conducted studies evaluating whether the serum prostate-specific antigen (PSA) velocity is associated with the detection of prostate cancer after adjusting for the PSA level.1-19 While these studies are potentially important, the results will remain underutilized unless they are able to provide information on how to address clinically relevant questions. For example, in men with competing causes of mortality or of advanced age, could a PSA threshold for biopsy of 4.0 ng/mL be modified to also include a PSA velocity mandate, such as more than 1.25 ng/mL/yr? This could maximize the detection of clinically significant cancers that are still curable, as compared with sustaining the potential morbidities associated with the treatment of diagnosing a clinically insignificant cancer. An example of this is a Gleason 3 + 3 in one of an extended 16-core needle biopsy performed as a result of a PSA level over 4 ng/mL, driven by PSA elaborated predominately from benign prostatic hyperplasia. The ideal way to answer this question in men with competing causes of mortality or of advanced age is with a prospective screening study. Such a study would be powered to assess overall survival, with randomization to either have a biopsy recommended when a PSA threshold level of 4 ng/mL is exceeded or when both a PSA velocity threshold of at least 1.25 ng/mL/yr and a PSA threshold level of 4 ng/mL were exceeded. In other words: rather than having PSA and PSA velocity compete, why not ask them to collaborate? In the current issue of the Journal of Clinical Oncology, a study by Ulmert and colleagues20 brings PSA and PSA velocity into competition for significance to justify their use in clinical practice. Their study utilized data from a subset of 4,907 (23%) of a 21,277 population–based Swedish male cohort who participated in the Malmo Preventive Medicine study21 and who had serum samples available for biomarker analysis on two separate occasions separated by a median of 6 years (interquartile range, 5 to 7 years). Prostate biopsy was sextant in at least half of the men and was recommended when the PSA level exceeded 3.0 ng/mL, whereas before the late 1990s, this threshold value was 4.0 ng/mL. Prostate cancer was identified in 443 (9%) of 4,907 men by December 31, 2003, and the median time from the second serum sample to prostate cancer diagnosis was 16.1 years (range, 1.7 to 22.0 years).
Shown in their study are the results of the multivariable Cox proportional hazards regression analyses22 determining whether various PSA constructs such as PSA velocity and percent-free PSA were significantly associated with prostate cancer detection after adjusting for the PSA level for all men and for the subgroups of men with a PSA level of at least 0.7, 1.2, and 2.0 ng/mL. For all men and for those in the PSA subgroups examined, PSA velocity was observed to add significantly to the PSA level (P Given the evidence from the study by Ulmert et al20 showing that PSA velocity adds significantly to PSA in predicting the presence of cancer, what remains to be determined is whether investigators can use both of these parameters. The goal would be to address the clinically important issue of maximizing detection of life-threatening prostate cancer at a time while it is still curable without also increasing overdiagnosis of clinically insignificant prostate cancer. While only a prospective screening study can accomplish this, clues on how to best design such a study and parameters that could be considered for clinical use are beginning to be elucidated. In particular, data from the Baltimore Longitudinal Study on Aging reported by Carter and colleagues2 suggested that a PSA velocity above 0.35 ng/mL/yr might be able to identify life-threatening prostate cancers at a PSA level (generally < 4.0 ng/mL) when it is often curable. However, as Etzioni and colleagues note in a recent commentary,24 what remains to be determined from these data is how many additional cancers will be cured using an early detection strategy that recommends biopsy if the PSA velocity exceeds 0.35 ng/mL/yr and at what cost, if any, in terms of overdiagnosis. The data by Carter and colleagues2 bring us a step forward toward the design of a prospective study that could address the questions raised in that commentary and perhaps afford insight on how to proceed in today's practice for young men with a PSA level less than 4 ng/mL. For men with a PSA level more than 4 ng/mL, a PSA velocity of 0.75 ng/mL/yr or less has been suggested to identify men with slow-growing cancers or benign prostatic disease and who therefore may not need treatment.25 Yet, as men age or accumulate comorbidities, the PSA velocity threshold necessary to minimize overdiagnosis of clinically insignificant cancers appears to increase as suggested by a recent study7 by Punglia and colleagues using the Center for Prostate Disease Research database. In that study, for men with a PSA level more than 4 ng/mL, a PSA velocity threshold for biopsy of 1.25 ng/mL/yr was observed to sacrifice little sensitivity in terms of the detection of Gleason 7 to 10 cancers, while also reducing the number of biopsies in which no or Gleason 6 or less cancer was identified. While bringing us a step forward, it would require a prospective study to prove whether such an algorithm using both PSA level and PSA velocity will reduce overdiagnosis while still detecting potentially curable high-grade cancers. Finally, in addition to the question of how to best combine PSA and PSA velocity to detect curable and clinically significant prostate cancer, the question of how to utilize these two constructs in subgroups using other predictive factors26 such as family history, ethnicity, digital rectal examination findings, and age groupings needs to be addressed. An initial step towards answering this question was provided by Thompson and colleagues,1 who used data from the Prostate Cancer Prevention Study to create an algorithm based on predictive factors providing an estimate of the risk of any grade or high-grade prostate cancer. However, the impact on life expectancy of detecting such cancers in a given individual remains unanswered. Ideally, what is needed is a prospective randomized study in which stratification using these additional predictive factors occurs prior to random assignment to one of two criteria for prostate biopsy; (a) when a PSA level exceeds a specific threshold value; or (b) when both the PSA level and PSA velocity exceed prespecified values. The sample size of the study would need to be large enough to permit the analysis of overall survival in the subgroups that these additional predictive factors define. In closing, the study by Ulmert and colleagues20 in conjunction with those by Carter,2 Punglia,7 their colleagues and many others 1,3-6,8-19 provide the basis on which to design a prospective screening study that can definitively answer the questions raised in this editorial and in the commentary by Etzioni et al.24 Specifically, a study would assess in subgroups defined by age, ethnicity, digital rectal examination status, and family history whether a lower value of PSA velocity (0.35 ng/mL/yr) than currently used (0.75 ng/mL/yr) can identify life-threatening prostate cancer in young and healthy men when the PSA level is less than 4 ng/mL and still potentially curable. It would also test whether values of PSA velocity (1.25 ng/mL/yr) higher than currently used (0.75 ng/mL/yr) when the PSA level is over 4 ng/mL can minimize overdiagnosis and detect clinically significant cancers when curable in men of advanced age or who have significant comorbidities. AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. REFERENCES
1. Thompson IM, Ankerst DP, Chi C, et al: Assessing prostate cancer risk: Results from the Prostate Cancer Prevention Trial. J Natl Cancer Inst 98:529-534, 2006 2. 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 98:1521-1527, 2006 3. Roobol MJ, Kranse R, de Koning HJ, et al: Prostate-specific antigen velocity at low prostate-specific antigen levels as screening tool for prostate cancer: Results of second screening round of ERSPC (Rotterdam). Urology 63:309-313, 2004[CrossRef][Medline] 4. Raaijmakers R, Wildhagen MF, Ito K, et al: Prostate-specific antigen change in the European Randomized Study of Screening for Prostate Cancer, section Rotterdam. Urology 63:316-320, 2004[CrossRef][Medline] 5. Schröder FH, Roobol MJ, van der Kwast TH, et al: Does PSA velocity predict prostate cancer in pre-screened populations? Eur Urol 49:460-465, 2006[CrossRef][Medline] 6. Pinsky PF, Andriole G, Crawford ED, et al: Prostate-specific antigen velocity and prostate cancer Gleason grade and stage. Cancer 109:1685-1695, 2007 7. Punglia RS, Cullen J, Mcleod DG, et al: Prostate-specific antigen velocity and the detection of Gleason score 7 to 10 prostate cancer. Cancer 110:1973-1978, 2007[CrossRef][Medline] 8. Loeb S, Roehl KA, Catlaona WJ, et al: Prostate specific antigen velocity threshold for predicting prostate cancer in young men. J Urol 177:899-902, 2007[CrossRef][Medline] 9. 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 177:499-503, 2007[CrossRef][Medline] 10. Ito K, Yamamoto T, Ohi M, et al: Usefulness of prostate-specific antigen velocity in screening for prostate cancer. Int J Urol 9:316-321, 2002[CrossRef][Medline] 11. Fall K, Garmo H, Andren O, et al: Prostate-specific antigen levels as a predictor of lethal prostate cancer. J Natl Cancer Inst 99:526-532, 2007 12. Berger AP, Deibl M, Strasak A, et al: Large-scale study of clinical impact of PSA velocity: Long-term PSA kinetics as method of differentiating men with from those without prostate cancer. Urology 69:134-138, 2007[CrossRef][Medline] 13. Spurgeon SE, Mongoue-Tchokote S, Collins L, et al: Assessment of prostate-specific antigen doubling time in prediction of prostate cancer on needle biopsy. Urology 69:931-935, 2007[CrossRef][Medline] 14. Krejcarek SC, Chen MH, Renshaw AA, et al: Prediagnostic prostate-specific antigen velocity and probability of detecting high-grade prostate cancer. Urology 69:515-519, 2007[CrossRef][Medline] 15. Loeb S, Roehl KA, Yu X, et al: Use of prostate-specific antigen velocity to follow up patients with isolated high-grade prostatic intraepithelial neoplasia in prostate biopsy. Urology 69:108-112, 2007[CrossRef][Medline] 16. Sun L, Moul JW, Hotaling JM, et al: Prostate-specific antigen (PSA) and PSA velocity for prostate cancer detection in men aged < 50 years. BJU Int 99:753-757, 2007[CrossRef][Medline] 17. Park SJ, Miyake H, Hara I, et al: Predictors of prostate cancer on repeat trasnrectal ultrasound-guided systematic prostate biopsy. Int J Urol 10:68-71, 2003[CrossRef][Medline] 18. GM, Paez BA, Romero CI, et al: Role of PSA velocity in the detection of prostate cancer: A study of 986 males. Actas Urol Esp 25:193-199, 2001[Medline] 19. Djavan B, Zlotta A, Kratzik C, et al: PSA, PSA density, PSA density of transition zone, free/total PSA ratio, and PSA velocity for early detection of prostate cancer in men with serum PSA 2.5 to 4.0 ng/mL. Urology 54:517-522, 1999[CrossRef][Medline] 20. Ulmert D, Serio AM, O'Brien M, et al: Long-term prediction of prostate cancer: PSA velocity is predictive but does not improve the predictive accuracy of a single PSA measurement 15 years or more before cancer diagnosis in a large, representative, unscreened population. J Clin Oncol 26:835-841, 2008 21. Berguland G, Eriksson KF, Israelsson B, et al: Cardiovascular risk groups and mortality in an urban Swedish male population: The Malmo Preventive Project. J Intern Med 239:489-497, 1996[CrossRef][Medline] 22. Klein JP, Moeschberger ML: Semiparametric proportional hazards regression with fixed covariates, in Klein JP, Moeschberger ML (eds): Survival Analysis: Techniques for Censored and Truncated Data (ed 2). New York, NY, Springer Publishing, 2003, pp 243-293 23. Pencina MJ, D'Agostino RB: Overall C-statistic as a measure of discrimination in survival analysis: Model specific population value and confidence interval estimation. Stat Med 23:2109-2123, 2004[CrossRef][Medline] 24. Etzioni RD, Ankerst DP, Weiss NS, et al: Is prostate-specific antigen velocity useful in the early detection of prostate cancer? A critical appraisal of the evidence. J Natl Cancer Inst 99:1510-1515, 2007 25. Carter HB, Pearson JD, Metter EJ, et al: Longitudinal evaluation of prostate-specific antigen levels in men with and without prostate disease. JAMA 267:2215-2220, 1992[Abstract] 26. Bostwick DG, Burke HB, Djakiew D, et al: Human prostate cancer risk factors. Cancer 101:2371-2490, 2004 (suppl)[CrossRef][Medline] Related Article
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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.002) in predicting the presence of any cancer despite the high correlation coefficient of 0.93 between these two PSA constructs. Given this high degree of correlation, the authors stated "we did not estimate hazard ratios from the multivariable analysis because of the high correlation between these PSA forms." They also state in the discussion section, "If 2 variables are highly correlated, using both provides little additional information over using only 1." Therefore, using the concordance index
