We have analyzed perhaps the only dataset available that can evaluate the guidelines concerning PSA velocity. We found no evidence to support prostate biopsy in men with high PSA velocity in the absence of other indications, such as a positive DRE or high PSA. Overall, PSA velocity did not importantly add predictive accuracy to a standard predictive model or to just PSA alone and, more specifically, PSA velocity cut points had inferior risk separation compared with PSA cut points in men with low PSA and negative DRE. In other words, if a clinician feels that the current PSA thresholds are insufficiently sensitive, he or she would be better off identifying patients to biopsy by using low PSA thresholds than by adding PSA velocity as a criterion for biopsy.
Our findings appear to contradict a body of evidence apparently supporting the relationship between PSA velocity and prostate cancer, but this contradiction is more apparent than real. First, like other authors, we found strong evidence for a univariate association between PSA velocity and positive biopsy (P
< .001). In general, this lead to higher risks of cancer above specific PSA velocity cut points than below. However, we also found that PSA velocity does not add important predictive value to PSA and other standard predictors; in other words, we did not find that the use of a PSA velocity criterion for biopsy would improve clinical decision making. To our knowledge, these questions have not been addressed by prior authors (18
). That PSA velocity is strongly associated with biopsy outcome on univariate, but not multivariable, analysis, is easily explained by collinearity. The correlation between PSA and PSA velocity was close to 0.9 when analyzing all PSA values before biopsy, and it is naturally difficult for a marker to add value to a predictor with which it has a strong correlation.
Our findings are consistent with several other studies. Investigators from the Rotterdam center of the European Randomized trial of Screening for Prostate Cancer (ERSPC) have reported that PSA velocity does not help predict biopsy outcome (19
) or clinically significant prostate cancer (20
). Eggener et al. (21
) used a more sophisticated modeling approach to find a very small increment in predictive accuracy associated with PSA velocity, largely as a result of a small number of men with very high PSA velocities and a reduced risk of cancer. This negative association was likely attributable to high PSA velocity being associated with benign inflammatory conditions (21
). Eggener’s result was replicated almost exactly by our own recent study (22
) of two ERSPC cohorts, in which we similarly found a very small increment in predictive accuracy associated with PSA velocity, again explained largely by a minority of men with reduced risk at high PSA velocities (22
). Together with these prior reports, our findings suggest that men with a sudden large rise in PSA should be carefully evaluated for benign disease, possibly including a repeat PSA, before referral for prostate biopsy.
One possible argument against our conclusions might be that, although PSA velocity does not help find prostate cancer, it does help detect the aggressive cancers most likely to shorten a man’s life; that is, PSA velocity is of value for prognostication if not detection. Supporters of this argument might point to Carter’s findings (10
) that a PSA velocity of 0.35 ng mL−1
is associated with aggressive cancers diagnosed many years later (10
), or D’Amico's oft-cited finding (23
) that a PSA velocity of 2.0 ng at the time of definitive treatment is a predictor of cancer-specific death (23
). Yet, we found no evidence that PSA velocity helps to detect more aggressive cancers. Indeed, the small increment in predictive accuracy associated with PSA velocity was reduced when we restricted our analyses to high-grade cancers or those that met the Epstein definition of clinical significance.
Moreover, doubts can be raised about whether PSA velocity is indeed of value for prognostication. Carter (10
) and D’Amico's (23
) articles were based on a small number of events (20 and 27, respectively) and neither examined whether PSA velocity was of incremental benefit, for example, by comparing AUC with and without PSA velocity. Indeed, in a systematic review of the literature (18
), we found a near complete absence of evidence that PSA velocity adds predictive value to PSA. Our own group has evaluated all 22 definitions of PSA velocity and PSA doubling time on a radical prostatectomy dataset (24
). We found that most definitions did not add predictive accuracy to PSA alone for the end point of either recurrence or metastasis; a small number of definitions added a small amount to the AUC, although not importantly more than would be expected by chance. Furthermore, no definition added to the prediction of both recurrence and metastasis, and the previously cited “red flag” of 2 ng mL−1
did not help predict either outcome.
This work has several potential limitations. First, it is possible that there might be better schedules to measure PSA and better methods to calculate PSA velocity. Yet, patients in the PCPT were scheduled by protocol to have yearly PSA testing, in line with typical guidelines on PSA screening, including those of the NCCN. Moreover, we analyzed our findings using a large number of different approaches to the calculation of PSA velocity and did not find important differences in our results. Second, we have previously been criticized as inappropriately focusing on accuracy rather than reclassification (25
). We believe that both are important when evaluating a marker. It is hard to see how a marker can lead to important reclassification if it does not materially add to prediction and therefore report both in this study. Most pertinently, our study is a direct evaluation of a published guideline, and the appropriate methods are self-evident. Third, it might also be suggested that the cancers detected in PCPT were “clinically irrelevant” because of the inclusion of the end-of-study biopsy for men with low PSAs. Yet, our results were similar when analyses were restricted to high-grade cancers or to clinically significant cancers; furthermore, our study methods are able to replicate exactly those recommended in the NCCN and AUA guidelines, biopsy for men with low PSA but high PSA velocity.
It is impossible to prove a negative and it is not inconceivable that PSA velocity could have a role in prostate cancer detection. For example, the men in our study with low PSA and negative DRE were screened for 7 years; therefore, conceivably, PSA velocity could be of value for men with either greater or fewer years of screening. Similarly, although we found no evidence that PSA velocity differentially detected aggressive cancers, our cohort has not been followed until death, and it is conceivable that some differences may emerge on very long-term follow-up. That said, guidelines should generally be based on the presence of positive evidence, not on the absence of negative evidence. It is difficult to support the inclusion of PSA velocity in a guideline on the grounds that it might conceivably be shown to be of benefit in some future study.
In conclusion, we have formally evaluated published guidelines on PSA velocity for prostate cancer detection, examining several definitions of cancer and numerous different methods of calculating PSA velocity. We found no reason to believe that implementation of the guideline would improve patient outcomes; indeed, its use would lead to a large number of unnecessary biopsies. We therefore recommend that organizations issuing policy statements related to PSA and prostate cancer detection remove references to PSA velocity.