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Nadir PSA is a Strong Predictor of Treatment Outcome in Intermediate and High Risk Localized Prostate Cancer Patients Treated by Definitive External Beam Radiotherapy and Androgen Deprivation: Beyond the Abstract

Typical prognostic factors for prostate cancer include clinical stage, Gleason’s score (GS), and baseline PSA (bPSA). Current treatment strategies and protocols are designed based on the combination of these factors to stratify patients by risk category (low, intermediate, and high). For instance, the decision to add or not adjunctive androgen deprivation therapy (ADT) in clinical practice is directly linked to these risk categories which are entirely dependent on these parameters (stage, GS, bPSA). In addition, the duration of ADT also follows these risk categories without particular attention to the patient’s response to therapy. Over the years, researchers have reported that response to therapy (after radiation, ADT, or both) measured by PSA decline, has prognostic significance but there was not a uniform parameter identified that could be used in clinical management (1,8). In these studies, nadir PSA (nPSA) was overwhelmingly found to be a good prognostic parameter but its absolute value varied significantly between studies mainly because the evaluated patient populations had variable types of treatments, radiation, ADT, or both, which affected the absolute value of nPSA.   In this study (9) we retained patients with a defined risk category (intermediate and high) that were all treated by a combined radiation and ADT. Along with all known prognostic factors, we found that nPSA is a very strong predictor of biochemical relapse in both univariate and multivariate analyses. The cut-off value was 0.06 ng/ml which was identified using the receiver operating characteristic (ROC) method, a statistical technique that allows the identification of the optimal point that best separates two prognostic groups around a given parameter. Conversely, and like in many other studies, time to nadir was not found to be significant in both univariate and multivariate analyses. This indicates that achieving a certain level of response is much more important than the time to achieve it.

There are two other very important and clinically relevant findings in this study that might affect patient management. First, nPSA came out in multivariate analysis as a strongly significant and independent parameter while bPSA was not. This indicates that nPSA may be more relevant than bPSA to determine patient prognosis and those high risk patients because of a high bPSA can move into a lower risk category if they show a good response and attain a nPSA of 0.06 ng/ml or lower. This could be potentially used to escalate or de-escalate patient treatment as a way to optimize outcome. Second, when we examined the prognostic value of nPSA below the most commonly used cut-off in the literature, that is of 0.5 ng/ml, we still found additional predictive power which indicates that the value of 0.06 ng/ml provides additional prognostic and clinically relevant information (table 4 , figure 4). Again this adds to this parameter’s utility for patient response adapted therapy.

In summary, our study showed that nPSA is a useful and strong prognosticator in intermediate and high risk localized prostate cancer treated by combined radiation and ADT. This treatment response parameter should be factored in the estimation of the patient’s risk and might help implement patient adapted therapy. 

Written by: Fady B. Geara MD, PhD, Professor and Chairman, Dept of Radiation Oncology, The American University of Beirut Medical Center

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References

1.     Tseng YD, Chen M, Beard C, Martin N, Orio PF, Loffredo M, et al. Posttreatment prostate specific antigen nadir predicts prostate cancer specific and all-cause mortality. J Urol. 2012;187(6):2068–73.Posttreatment prostate specific antigen nadir predicts prostate cancer specific and all-cause mortality. J Urol. 2012;187(6):2068–73.

2.     Ray ME, Thames HD, Levy LB, Horwitz EM, Kupelian PA, Martinez AA, Kuban DA. PSA nadir predicts biochemical and distant failures after external beam radiotherapy for prostate cancer: a multi-institutional analysis. Int J Radiat Oncol Biol Phys. 2006;64(4):1140–50.

3.     Alcántara P, Hanlon A, Buyyounouski MK, Horwitz EM, Pollack A. Prostate-specific antigen nadir within 12 months of prostate cancer radiotherapy predicts metastasis and death. Cancer. 2007;109(1):41–7.

4.     Zelefsky MJ, Shi W, Yamada Y, Kollmeier MA, Cox B, Park J, Seshan VE. Postradiotherapy 2-year prostate-specific antigen nadir as a predictor of long-term prostate cancer mortality. Int J Radiat Oncol Biol Phys. 2009;75(5):1350–6.

5.     D'amico AV, Chen M, Castro MD, Loffredo M, Lamb DS, Steigler A, Denham JW. Surrogate endpoints for prostate cancer-specific mortality after radiotherapy and androgen suppression therapy in men with localised or locally advanced prostate cancer: an analysis of two randomised trials. Lancet Oncol. 2012;13(2):189–95.

6.     Son CH, Hamstra DA, Feng FY, Liauw SL. High-risk prostate cancer treated with dose-escalated RT: an analysis of hormonal therapy use and duration, and prognostic implications of PSA nadir 0.2 to select men for short-term hormonal therapy. Am J Clin Oncol. 2014:40(4):348-52.

7.     Johnson SB, Jackson WC, Murgic J, Feng FY, Hamstra DA. Time to nadir PSA: of popes and PSA–the immortality bias. Am J Clin Oncol. 2015;38(5):465–71.

8.     Critz FA, Levinson AK, Williams WH, Holladay DA, Holladay CT. The PSA nadir that indicates potential cure after radiotherapy for prostate cancer. Urology. 1997;49(3):322–6.