The effect of the frequency and duration of PSA measurement on PSA doubling time calculations in men with biochemically recurrent prostate cancer

Abstract

Background Prostate specific antigen (PSA) doubling time (PSADT) is an attractive intermediate endpoint for assessing novel therapies in biochemically recurrent prostate cancer (BRPC). This study explores whether PSADT calculations are influenced by frequency/duration of PSA measurements, and whether statistical variability leads investigators to find false significant results. Methods In retrospective analyses of two BRPC cohorts: Johns Hopkins Hospital (JHH) patients who deferred therapy and placebo patients on a randomized clinical trial (RCT), we calculated changes in PSADT from early measurements to later measurements using subsets of available PSAs for patients with ≥6 and ≥9 PSAs. We simulated hypothetical single-arm trials using randomly selected, 50-patient subsets and simulated two-arm RCTs. Results JHH cohort (n=205) had median follow-up 58 months, median age 61 years, and median Gleason 7. PSA variability changed with duration of PSA measurement as median within-patient PSADT increases for men with >6 PSAs ranged from 1.0 to 1.4 months by PSA subset while increases for men with ≥9 PSAs ranged from 3.9 to 4.1 months. Frequency of measurement did not change PSA variability as PSADT increase was unchanged when odd values were used instead of all values. Approximately 30% of JHH men experienced >200% increases in PSADT. Up to 62% of 50-patient single-arm simulations detected significant PSADT change, whereas simulated RCTs did not. Results were supported in the RCT placebo cohort; 46% of patients experienced PSADT increases >200%. Conclusion These data suggest that calculated PSADT in BRPC may naturally increase over time in the absence of therapy and may be influenced by duration of PSA follow-up. As a result, single arm trials could show false significant increases despite the lack of active treatment of these patients. Placebo-controlled RCTs including clinical endpoints are recommended to screen novel agents in men with BRPC to mitigate bias because of natural PSADT variability.

A randomized, double-blind, placebo-controlled study of the effects of pomegranate extract on rising PSA levels in men following primary therapy for prostate cancer

“…12 Recently, is has been suggested that PSADT changes of this magnitude can be explained by natural variation in PSADT in patients with biochemically recurrent prostate cancer. 37 Paller et al 37 have recently shown in a retrospective study that PSA variability in such men can lead to a natural lengthening of PSADT over time, and they suggest that increase in PSADT of 6 months or less, even when statistically significant, are unlikely to be clinically meaningful in the absence of a placebo control and their use to be interpreted with caution in uncontrolled single-arm studies. Recently, Antonarakis et al 38 preformed a hypothesis-generating retrospective analysis of 4 phase II trials that suggests that within- subject changes in PSADT and PSA slope after initiation of experimental therapy may correlate with metastasis-free survival in men with biochemically recurrent prostate cancer, though their findings require prospective validation.…”

Management of Patients with Biochemical Recurrence After Local Therapy for Prostate Cancer

“…The use of PSA dynamics (such as PSADT, PSA slope, PSA velocity) is of unestablished clinical significance, and is often highly variable as observed even on placebo arms of trials. 54 In addition, the impact of modulating PSA kinetics on clinically defined endpoints (such as metastasis-free survival) remains uncertain. 55 …”

“…7 For trials involving patients with biochemical recurrence to provide clinically meaningful results, far more information is needed on the natural history and variation of PSADT in that patient population. 54 Despite these challenges, trials in this patient population can provide important information on drug activity, pharmacokinetics and pharmacodynamics.…”

Combination of Androgen Deprivation Therapy and Salvage Radiotherapy versus Salvage Radiotherapy Alone for Recurrent Prostate Cancer after Radical Prostatectomy

“…Additionally, in this study, PSADT was not associated with salvage failure, although it has been reported as a determinant for systemic disease in recurrent prostate cancer [27]. In a previous study, PSADT was reported to be influenced by the duration of PSA follow-up before initiation of salvage treatment because PSADT increased over time if treatment was not performed for recurrent disease [28]. In other words, presalvage PSA level, which is related to the timing of salvage treatment, could be more important for predicting oncological outcomes than PSA kinetics, including PSADT.…”