A statistical evaluation of rules for biochemical failure after radiotherapy in men treated for prostate cancer

The "PSA nadir + 2 rule," defined as any rise of 2 ng/ml above the current prostate-specific antigen (PSA) nadir, has replaced the American Society for Therapeutic Radiology and Oncology (ASTRO) rule, defined as three consecutive PSA rises, to indicate biochemical failure (BF) after radiotherapy in patients treated for prostate cancer. We propose an original approach to evaluate BF rules based on the PSAdt as the gold standard rule and on a simulation process allowing us to evaluate the BF rules under multiple settings (different frequency, duration of follow-up, PSA doubling time [PSAdt]).

We relied on a retrospective, population-based cohort of individuals identified by the Connecticut Tumor Registry and treated for localized prostate cancer with radiotherapy. We estimated the 470 underlying true PSA trajectories, including the PSAdt, using a Bayesian hierarchical changepoint model. Next, we simulated realistic, sophisticated data sets that accurately reflect the systematic and random variations observed in PSA series. We estimated the sensitivity and specificity by comparing the simulated PSA series to the underlying true PSAdt.

For follow-up of more than 3 years, the specificity of the PSA nadir + 2 rule was systematically greater than that of the ASTRO criterion. In few settings, the nadir + 2 rule had a lower sensitivity than the ASTRO. The PSA nadir + 2 rule appeared less dependent on the frequency and duration of follow-up than the ASTRO.

Our results provide some refinements to earlier findings as the BF rules were evaluated according to various parameters. In most settings, the PSA nadir + 2 rule outperforms the ASTRO criterion.