We have demonstrated in an unselected cohort of men enrolled in the BLSA that PSA velocity provides information early in the disease course that is related to the chance of dying of prostate cancer. The finding that PSA velocity was associated with prostate cancer death at 10–15 years before diagnosis when PSA levels were below 4.0 ng/mL in most men ( and )—a PSA range in which most men have curable disease (15
)—suggests that PSA velocity could be useful for the identification of men with potentially life-threatening disease at a time when cure is still possible with local therapy (surgery or radiation). Conversely, men with a low PSA velocity may be more appropriate candidates for observation.
An alternative interpretation of our data is that at 10 –15 years before diagnosis PSA velocity was higher among men who died of prostate cancer because they were more likely to have been diagnosed in the absence of screening with more advanced disease than men who did not die of prostate cancer. However, when we restricted our analysis to subjects who were diagnosed before 1991 and were more likely to have had a diagnosis without PSA screening, the extent of the association between PSA velocity and prostate cancer–specific death was similar to that observed when the analysis included all subjects. This similarity suggests that the observed association with PSA velocity did not differ between the pre-PSA and PSA eras. Furthermore, there was no statistically significant interaction between PSA velocity and date of diagnosis. Thus, as much as 10–15 years before diagnosis, it would appear that PSA velocity is an indicator of disease that is destined to progress and threaten life.
The PSA velocity determinations 0–5 years before diagnosis in the current study were similar to those of D’Amico et al. (9
), which were made in the year before diagnosis; the 25th, 50th, and 75th percentile PSA velocity (ng/mL per year) values for all men with prostate cancer in the two studies were 0.25 and 0.5, 0.69 and 1.0, and 1.8 and 2.0, respectively. Furthermore, when compared with a PSA velocity of 2 ng/mL per year or less, a PSA velocity above 2 ng/mL per year within 2 years of diagnosis (not adjusted for tumor stage and cancer grade) was associated with a relative risk of prostate cancer death of 21.3 (95% CI = 5.6 to 81.3) in the current study. By comparison, in a univariate analysis, D’Amico et al. (9
) found that a PSA velocity above 2 ng/mL per year in the year before diagnosis was associated with a relative risk of prostate cancer death of 20.4 (95% CI = 6.2 to 67.9).
However, our findings differ from those of D’Amico et al. (9
) in two important ways. First, D’Amico et al. (9
) demonstrated that a high PSA velocity in the year before diagnosis and surgery was associated with an increased risk of harboring incurable prostate cancer not amenable to cure with surgery alone. By contrast, our study suggests that values above a lower threshold of PSA velocity are associated with the presence of life-threatening disease at a time when cure may be possible because PSA levels at the time of determination of PSA velocity (i.e., 10 –15 years before diagnosis) in the current study were in the range where most men have curable disease (15
). Second, the PSA velocity threshold associated with death from prostate cancer was substantially lower in the current study than in that of D’Amico et al. (0.35 versus 2) (9
). We believe that this difference can be explained by the fact that PSA velocity increases directly with the PSA level (18
). Because we determined PSA velocity a decade or more before diagnosis, at a time when PSA levels were below 4.0 ng/mL in most men (), one would expect our PSA velocity determinations to be much lower than those determined a year before diagnosis. With longer follow-up of the cohort described by D’Amico et al. (9
), it is likely that velocity thresholds below 2 ng/mL per year will be associated with prostate cancer death.
Our study has several important clinical implications. First, it has been shown that there is virtually no PSA level threshold below which men can be reassured that life-threatening prostate cancer is not present (19
). Lowering PSA level thresholds (<4.0 ng/mL) to achieve higher sensitivity for detection of life-threatening prostate cancer will increase the proportion of men who are diagnosed early but with the trade-off of detection of biologically irrelevant cancers that may have otherwise gone undetected (3
). Determining PSA velocity may provide a reasonable way to balance this trade-off by initiating screening early in life, gathering a PSA testing history with which to evaluate PSA velocity, and performing prostate biopsies on those men who have a PSA velocity that suggests the presence of life-threatening cancer, even when PSA levels are lower than the previously recommended 4.0 ng/mL threshold. This would provide an alternative to using a single PSA value as an indication for biopsy of all men—an approach that risks missing important cancers if the value is too high (e.g., 4.0 ng/mL) or detecting many unimportant cancers if the value is lowered (e.g., 2.6 ng/mL) for all men.
Second, it would appear that when PSA levels are low (<4.0 ng/mL) and indicate a greater likelihood that prostate enlargement is absent (20
), even small rises in PSA levels may indicate the presence of life-threatening prostate cancer. Recent data from the Prostate Cancer Prevention Trial support our findings in that men with high-grade cancers—those more likely to be life threatening — had faster rises in PSA levels (annual percent change in PSA levels) than men with lower grade cancers (21
). In the Prostate Cancer Prevention Trial end of study biopsies (biopsies done not for elevated PSA or abnormal digital rectal examination), men with high-grade cancers (Gleason score ≥7) had an annual change in PSA level of 11% – 12% compared with men with low-grade cancers (Gleason score ≤6), whose annual changes were 5%–6%. For a man with a starting PSA level of 2.5 ng/mL, this would be equivalent to a PSA velocity of 0.3 ng/mL per year for high-grade cancer and 0.15 ng/mL per year for low-grade cancers.
Our data provide a further argument for PSA testing that begins relatively early in life, when PSA levels are usually lower and prostate enlargement is absent, to establish a baseline for evaluating future changes in PSA levels. We previously recommended an approach to PSA testing that begins at age 40 years and tests infrequently between ages 40 and 50 years and more frequently thereafter (22
). We believe that PSA velocity may have the greatest value in predicting the presence of biologically important cancers at a curable stage in younger men (e.g., age below 60 years) without prostate enlargement and PSA levels below 4.0 ng/mL.
A number of limitations should be considered when interpreting our data. First, not all men in the BLSA had serum available for PSA testing. Second, the total number of deaths (events) from prostate cancer in this study was small. Thus, we cannot make precise estimates of the risk of death from prostate cancer based on a given PSA velocity threshold or recommend that a given PSA velocity threshold be used in clinical practice to prompt further evaluation. Third, we cannot be certain that if a life-threatening prostate cancer had been identified by PSA velocity earlier in the natural history of the disease, treatment at that point in time would have changed the outcome. Rather, PSA velocity might identify men who are destined to succumb to their disease in spite of curative intervention. Fourth, in our study, the interval between PSA level measurements was, on average, 3 years, and the same assay was used for all PSA measurements. It is possible that more frequent PSA determinations might provide a more accurate assessment of PSA velocity and an improved ability to distinguish those with life-threatening disease early. However, in clinical practice, PSA levels may be determined at irregular intervals and measured using different assays, which could result in findings that differ from the current study. Fifth, we were unable to assess the stage and grade of prostate cancer in our cohort, and this information could have provided further insight into the value of the information provided by PSA velocity. In addition, treatment given for prostate cancer subjects was not known in all cases, and treatment choice could affect outcome. Finally, our cohort was primarily white, and therefore, our findings might be less relevant for other racial/ethnic groups.
In summary, when compared with a single PSA level threshold, the rate at which PSA levels reach a threshold value (PSA velocity) may provide useful information for identifying men who need further evaluation and/or closer surveillance for the presence of life-threatening prostate cancer. When PSA levels are below 4.0 ng/mL, even small rises in PSA levels should prompt the consideration of the presence of a biologically important prostate cancer.