Clinical Investigation
Interval to Testosterone Recovery After Hormonal Therapy for Prostate Cancer and Risk of Death

https://doi.org/10.1016/j.ijrobp.2008.10.082Get rights and content

Purpose

To assess whether the risk of death is associated with the time to testosterone recovery (TTR) after radiotherapy (RT) and hormonal therapy (HT) for prostate cancer (PCa).

Patients and Methods

Between 1995 and 2001, 206 men with localized, unfavorable-risk PCa were randomized to receive RT or RT plus 6 months of HT. A multivariate postrandomization Cox regression analysis was used to assess whether the TTR in years was associated with the risk of death after adjusting for the known prognostic factors, age, Adult Comorbidity Evaluation-27 score, and the use of HT for recurrence.

Results

Of the 102 men randomized to receive RT and HT, 57 (56%) had a TTR of >2 years, and none of these men had died of PCa after a median follow-up of 7.6 years. As the TTR increased, the risk of death decreased significantly (adjusted hazard ratio, 0.60; 95% confidence interval, 0.43–0.84; p = .003). A significant interaction was noted between the TTR and the comorbidity score (p = .002). The survival estimates were similar (p = 0.17) across the TTR values in men with moderate to severe comorbidity; however, these estimates increased significantly (p < .001) with decreasing PCa-specific mortality (p = .006) as the TTR increased in men with no or minimal comorbidity.

Conclusion

The results of our study have shown that a longer TTR after RT plus 6 months of HT for unfavorable-risk PCa is associated with a lower risk of death in men with no or minimal comorbidity.

Introduction

On the basis of the results from randomized controlled trials 1, 2, 3, 4, a standard of care for men with locally advanced or localized unfavorable (intermediate or high)-risk prostate cancer (PCa) is to deliver 6 months to ≤3 years of hormonal therapy (HT), in conjunction with external beam radiotherapy (RT), compared with RT alone. However, concerns have been raised about the potential interaction between the comorbidity score and HT use. Specifically, although the addition of 6 months of HT to RT compared with RT alone for men with localized and unfavorable-risk PCa has been shown to prolong survival, HT use for 6 months has also been associated with a loss of that survival benefit in men with moderate to severe comorbidity, in particular, cardiovascular disease (4).

It has also been established that among men undergoing a fixed duration of HT, the time to testosterone recovery (TTR) increases with advancing age 5, 6, 7, 8, 9, reaching 2 years on average for men aged ≥70 years after 6 months of HT. Moreover, one study (5) found an association between an increasing TTR in a retrospective series of 220 men who had received 6 months of HT with RT and a lower risk of both PCa-specific mortality (PCSM) and all-cause mortality. Those data (5) have provided evidence to propose the TTR as a prognostic factor after RT and 6 months of HT.

In the previous study (5), the use of time-dependent covariates to characterize the TTR and the use of HT for recurrence and an assessment of the potential interaction of the comorbidity score and the TTR were not performed. Therefore, in the present study, we used an independent database derived from a cohort of men enrolled in a randomized trial that assessed the effect on survival of delivering 6 months of HT and RT compared with RT alone to men with localized and unfavorable-risk PCa and performed a postrandomization analysis. Specifically, we assessed whether the survival time was associated with the TTR after RT and HT and whether an interaction was present between the Adult Comorbidity Score (ACE)-27 (10) and the TTR, characterizing both the TTR and HT use for recurrence as time-dependent covariates and adjusting for age, ACE-27 comorbidity score, and known PCa prognostic factors.

Section snippets

Patient selection and treatment

At academic and community-based medical centers in Massachusetts, between December 1, 1995 and April 15, 2001, 206 men (median age, 72.5 years; range, 49–82) with 1992 American Joint Committee on Cancer clinical Stage T1b-T2bN0M0 adenocarcinoma of the prostate (11) and at least one unfavorable prognostic factor were randomized to receive three-dimensional conformal RT, alone or in combination with 6 months of HT. HT consisted of a luteinizing hormone-releasing hormone agonist and the

Distribution of baseline characteristics stratified by TTR and comorbidity level

Of the 102 men randomized to receive RT plus 6 months of HT, 57 (56%) had a TTR of >2 years. The median of the TTR was 2.1 years (interquartile range, 1.6–2.5). As shown in Table 1, men randomized to receive RT and whose TTR was ≤2 years compared with >2 years had a lower median age (p = .01). However, no significant differences were found in the distribution of the serum PSA level (p = .29), biopsy Gleason score (p = .59), clinical T category (p = .11), or comorbidity score (p = .97) among the

Discussion

Although 28 months vs. 4 months of HT provided a PCa-specific survival, but no overall survival benefit, in one randomized study (2), and noninferiority could not be shown for 6 months compared with 3 years of HT in a second randomized study (21), both of these studies contained almost exclusively men with locally advanced and not localized and unfavorable-risk PCa. In studies 3, 4 in which a significant proportion of the men entered had unfavorable-risk and localized PCa, a PCa-specific

Conclusion

Given these considerations and the results of the present study, we can conclude that a longer TTR after RT plus 6 months of HT for unfavorable-risk PCa is associated with a lower risk of death in men with no or minimal comorbidity. Whether HT use in addition to RT compared with RT alone prolongs survival in men with moderate or severe comorbidity and localized, unfavorable-risk PCa requires additional study.

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