Prostate-specific antigen (PSA) and PSA velocity: competitors or collaborators in the prediction of curable and clinically significant prostate cancer.

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. 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 colleagues 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 study 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 analyses 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 .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 to test whether the predictive accuracy of detecting prostate cancer using a model with PSA alone or a model with both PSA and PSA velocity, and to conclude, “although PSA velocity is significantly increased in men with prostate cancer up to 2 decades before diagnosis, it does not aid long-term prediction of prostate cancer,” should be viewed with caution. Given the evidence from the study by Ulmert et al 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 colleagues 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, 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 colleagues 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 JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 26 NUMBER 6 FEBRUARY 2