Use of androgen deprivation therapy as salvage treatment after primary therapy for clinically localized prostate cancer

Abstract

Purpose

The optimal use of androgen deprivation therapy as salvage treatment (sADT) for men after initial prostatectomy or radiotherapy for clinically localized prostate cancer is undefined. We describe patterns of sADT use and investigate clinical and sociodemographic characteristics of insured men who received sADT versus surveillance in managed care settings.

Methods

Using comprehensive electronic health records and cancer registry data from three integrated health plans, we identified all men with newly diagnosed clinically localized prostate cancer between 1995 and 2009 who received either prostatectomy (n = 16,445) or radiotherapy (n = 19,531) as their primary therapy. We defined sADT based on the timing of ADT following primary therapy and stage of cancer. We fit Cox proportional hazard models to identify sociodemographic characteristics and clinical factors associated with sADT.

Results

With a median follow-up of 6 years (range 2–15 years), 13 % of men who underwent primary prostatectomy or radiotherapy received sADT. After adjusting for selected covariates, sADT was more likely to be used in men who were older (e.g., HR 1.70, 95 % CI 1.48–1.96 or HR 1.33, 95 % CI 1.17–1.52 for age 70+ relative to age 35–59 for primary prostatectomy or radiotherapy, respectively), were African-American, had a short PSA doubling time, had a higher pre-treatment risk of progression, had more comorbidities, and received adjuvant ADT for initial disease.

Conclusions

In men with localized prostate cancer in community practice initially treated with prostatectomy or radiotherapy, sADT after primary treatment was more frequent for men at greater risk of death from prostate cancer, consistent with practice guidelines.

Appendix

PSA following primary therapy

We classified men’s highest post-primary therapy PSA values (ng/mL) into three categories: (1) at least one PSA ≥10, which may trigger the use of ADT [27]; (2) no PSA ≥10, but ≥2.0 above nadir (the lowest PSA level observed) for those with primary radiotherapy or ≥0.2 for those with primary prostatectomy [28]; and (3) all PSA <2.0 above nadir after radiotherapy or <0.2 after prostatectomy. These categories were mutually exclusive based on the highest PSA observed.

We estimated the PSA trajectory by calculating the PSA doubling time [21, 29] from the time of nadir after radiotherapy or undetectable PSA after prostatectomy to (1) the first sADT use or (2) the end of follow-up for patients without sADT use. The PSA doubling time was the natural log of 2 (=0.693) divided by the slope of a linear regression of the log(PSA) over time. The PSA slope was estimated with the use of linear least squares when three or more PSA values were available, or by calculation using the formula $\frac{{\log 2*\left( {T2 - T1} \right)}}{{\log {\text{PSA}}2 - \log {\text{PSA}}1}}$ when only two PSA values were available, where PSA1 and PSA2 were obtained at times T1 and T2, respectively [29]. The PSA doubling time was finally categorized into four levels (in months): <9.0, 9.0–<15.0, 15.0–<36.0, and ≥36.0 (indicating no PSA rise).

Handling of missing data

A substantial proportion of cases (20 %) had at least one or more of the key clinical prognostic variables (clinical stage, Gleason score, or baseline PSA) missing. We performed multiple imputations using all other covariates to predict values for these variables. We constructed five imputed datasets, each having estimates for the missing values for PSA, Gleason score, and T stage. We then pooled the estimates and corresponding SEs across the five imputations using Rubin’s method [30]. All model results used these imputed datasets; multivariable models using only the complete cases did not show any significant deviations from the results shown.