An increasing body of evidence suggests that PSAV is a useful predictor for pCA aggressiveness. D'Amico et al showed that men with a PSAV >2 ng/ml per year in the year prior to diagnosis had a 9.8-fold increased risk of PCa-specific mortality after radical prostatectomy compared to men with a lower PSAV [2
]. Our research group subsequently confirmed that in men from the BLSA, a PSAV >2 ng/ml per year within 2 yr of diagnosis was associated with a 20.4-fold increased relative risk of pCA death—similar to the unadjusted rate of D'Amico et al [3
]. Similar results have been reported in men undergoing radiation therapy for clinically localized disease [11
In addition, our group recently showed that even the PSAV measured 10–15 yr before diagnosis (when most men had PSA levels <4.0 ng/ml) was associated with cancer-specific survival 25 yr later [3
]. Specifically, men with a PSAV ≤0.35 ng/ml per year had a cancer-specific survival of 92% compared to 54% in men with a PSAV >0.35 ng/ml per year.
PSA DT has been shown to predict cancer-specific survival after treatment but not in all studies [6
]. In general, less is known about the performance of PSA DT in the pretreatment setting. Thus, our objective was to expand upon our prior work in defining the performance characteristics of PSAV for the prediction of high-risk disease and to determine whether PSA DT provides similar prognostic value.
Similar to our prior findings within 10–15 yr prior to diagnosis, in this study, we found that PSAV within 5 yr prior to diagnosis was associated with the presence of high-risk and fatal pCA. In contrast, PSA DT was not associated with high-risk or fatal pCA and instead was a marginal predictor for the presence of good-risk disease (AUC = 0.636).
Several possible explanations exist for the differences between our findings with respect to PSA DT and those of others [8
]. First, our population was derived from an unselected cohort of men in an aging study, whereas others have studied highly selected patient populations, such as men enrolled in surveillance programs or those undergoing radical prostatectomy [6
]. That notwithstanding, studies discussing the PSA kinetics among men involved in surveillance programs must be interpreted with caution, because such protocols often differentially remove from surveillance those with faster rises in PSA (shorter PSA DTs). Meanwhile, men with stable or declining PSA values are more likely to remain on surveillance without further evaluation [8
]. This creates a “self-fulfilling prophesy,” wherein physicians are more likely to recommend treatment for men on surveillance with a rising PSA, creating the appearance that PSA DT is associated with a greater likelihood of “failing” surveillance. Indeed, when we excluded men with a negative PSA slope from analysis, we likewise found an improvement in the performance characteristics of pretreatment PSA DT. However, in a clinical setting, it would be difficult to select only patients with a rising PSA, because those with a negative slope at one point may still harbor life-threatening disease.
Another difference between our study and others was that the development of high-risk or fatal pCA was our outcome of interest rather than the length of time from diagnosis to treatment [8
], clinical progression of disease without treatment [12
], or treatment outcomes following radical prostatectomy [8
]. Nevertheless, it is not surprising that others have found a relationship between a short PSA DT and surrogates of pCA aggressiveness, given the known relationship between a rapidly rising pretreatment PSA and worse treatment outcomes [2
]. That notwithstanding, showing a relationship between PSA DT and surrogates for poor outcome (cancer grade and stage) is not equivalent to demonstrating that PSA DT can be used to select appropriate candidates for active surveillance or to trigger intervention during a window of curability. On the contrary, our findings would argue that PSA DT does not accurately distinguish between those with and without life-threatening disease. Further, if PSA DT (eg, ≤3 yr) were used to trigger intervention in a surveillance program, it is possible that cure would be less likely by the time intervention occurred because men with PSA DTs in this range have a higher PSAV that has been associated with an increased risk of pCA death [2
Several limitations should be considered when interpreting our data. First, detailed biopsy core data was not available, so its impact on cancer detection is unknown. Second, biopsy was recommended for a PSA >4 ng/ml or abnormal DRE, raising the possibility of detection bias. Furthermore, these results may not apply to men with a PSA <4 ng/ml and normal DRE. Another limitation is that although we used all available clinical information to retrospectively categorize our cohort into groups, the potential for misclassification bias exists. For example, it is possible that some men were misclassified with regard to cause of death. Also, it is unknown whether all “high-risk” men would have had adverse outcomes because only 56% died of their disease. To address this issue, we performed separate analyses including the subset of 15 men with confirmed pCA death and found similar results. However, the sample size was small, limiting the study power.
Another limitation common to studies on PSA kinetics is the exclusion of men without repeated PSA measurements (n
= 131 men in our population). Conversely, a strength of our study is that 82% of the men had three or more serial PSA values. Correspondingly, in clinical practice, it is not always possible to apply PSA kinetics measurements for patients diagnosed with pCA at the initial screening visit. However, the results of ROC analysis suggest that total PSA may provide a useful prognostic indicator for such patients. Indeed, the PSA at diagnosis is such a powerful predictor of outcomes and is so closely correlated with PSAV that it can be difficult to statistically separate their effects [15
]. This does not mean that PSAV does not provide useful information; rather, it suggests that both parameters may offer more information in specific populations, and PSAV may be particularly useful years before diagnosis at a time when PSA is low. In contrast, PSA DT was only useful if negative values were excluded (approximately 25% of the study population), highlighting the difficulty in applying this parameter in daily clinical practice. It is noteworthy that the addition of PSAV to the base model led to a statistical improvement in the concordance index using a bootstrapping approach but not with the method of Hanley et al [10
]. Nevertheless, numerous methods are available for comparing concordance indices, and some believe that the Hanley [10
] approach may be inappropriate for testing diagnostic accuracies [16
Other limitations of our study were that the same assay was used for all PSA measurements, and the average interval between PSA measurements was approximately 2 yr. If PSA were measured using different assays and/or more frequent PSA determinations were available, our results might have been different. For example, studies calculating PSAV based upon two PSA measurements separated by ≥4 yr have found divergent results [17
], suggesting the importance of time interval and method of calculation [18
]. A final limitation of our study was that pCA treatment information was not available and could have influenced the outcome.