Hormonal therapy and radiation for prostate cancer: is it safe?

Over the last few decades, hormonal therapy (HT) has emerged as an important component in the curative management of men with locally advanced or localized unfavorable-risk prostate cancer (PC). Multiple randomized, controlled trials have consistently demonstrated a cause-specific and/or an overall survival benefit when HT is added to radiation therapy (RT) to treat this group of men [1–5]. As a result, combined modality therapy consisting of RT plus HT is now widely used and is a well-accepted regimen in the treatment of men with aggressive PC.

Despite these successes of HT in helping to eradicate PC, the downside rests in its potential effects on a patient’s quality of life. The adverse effects of use have been widely studied and reported. In addition to the sexual side effects of a decreased libido and impotence [6], HT has been shown to lead to insulin resistance, dyslipidemia and the development of metabolic syndrome [7–9].

Given these potential risks, multiple investigators have assessed for an association with cardiovascular morbidity or mortality in men with PC treated with HT. In multiple series, HT use has been shown to increase the risk of developing diabetes mellitus, cardiac disease or cardiovascular mortality [9–12].

Although there are no data to suggest efficacy in adding HT to RT in men with favorable-risk PC, it is still utilized to downsize the prostate gland in order to allow selected patients to become eligible for brachytherapy [13]. Since HT use has never been demonstrated to improve PC-specific or overall outcomes in men with favorable-risk disease, cohort analyses within this setting are well suited to address the potential detrimental effects of HT use in men treated for PC.

Nanda and colleagues recently reported on a single-institution retrospective practice experience of 5077 men consecutively treated with curative brachytherapy-based RT, with or without HT [14]. The goal of this cohort analysis was to determine whether HT use was associated with the risk of all-cause mortality (ACM) in men belonging to three distinct cardiovascular comorbidity groups: those with no history of cardiac comorbidity; those with a single risk factor for coronary artery disease (CAD), including diabetes mellitus, hypercholesterolemia or hypertension; and those with CAD-induced conditions, including a history of congestive heart failure (CHF) or myocardial infarction (MI). Utilizing a Cox regression multivariable analysis, HT use was not significantly associated with an increased risk of ACM (adjusted hazard ratio [HR]: 1.08; 95% CI: 0.88–1.33; p = 0.46) for the entire cohort of men after a median follow-up of 4.8 years. However, a significant interaction was observed to exist between HT use and comorbid CHF or MI (adjusted HR: 2.11; 95% CI: 1.08–4.13; p = 0.03). When the three comorbidity groups were analyzed separately, HT use was significantly associated with an increased risk of ACM in men with a prior history of CHF or MI (adjusted HR: 1.96; 95% CI: 1.04–3.71; p = 0.04) but not in those with no comorbidity (adjusted HR: 0.97; 95% CI: 0.72–1.32; p = 0.86) or a single CAD risk factor (adjusted HR: 1.04; 95% CI: 0.75–1.43; p = 0.82). The 5-year age-adjusted point estimates for ACM in men treated with or without HT were 6.5 (95% CI: 4.6–8.4) versus 7.2% (95% CI: 5.8–8.7) for men with no comorbidity; 10.6 (95% CI: 7.4–13.8) versus 8.6% (95% CI: 6.7–10.5) for men with a single CAD risk factor; and 24.4 (95% CI: 15.5–33.3) versus 10.7% (95% CI: 3.9–17.6) for men with a history of CHF or MI [14].

Several points of further discussion arise when interpreting these findings. This study is the first to identify a specific cohort of men in whom HT use may potentially be detrimental and validates a recent post-randomization analysis of a clinical trial consisting of men treated with RT plus or minus 6-months of HT [15]. That study was designed to assess whether pre-existing comorbidity based on the Adult Comorbidity Evaluation (ACE)-27 comorbidity index [16] could affect the survival advantage resulting from the addition of HT to RT in men with localized, unfavorable-risk PC. Although an interaction, between worsening comorbidity and HT use was hypothesized based on a loss of survival advantage for men with moderate to severe comorbidity, the identity of specific comorbid conditions that may have directly contributed towards this observation remained unknown [15].

Second, although previous studies have sought to address the impact of HT use prior to brachytherapy on the risk of ACM, none have stratified men by comorbidity risk groups. As a result, the data have been conflicting, with some reports showing no effect [17] and others demonstrating a significantly increased risk of ACM [18]. Recently, a retrospective, multi-institutional community-based experience attempted to clarify this issue by limiting their analysis to elderly men and demonstrated an increased risk of ACM with HT use [19]. The study by Nanda and colleagues [14] further reconciles these previous analyses by indicating that HT use may have been positively associated with the risk of ACM in two out of the three prior studies with more elderly patients as pre-existing CAD could have been more prevalent within these cohorts.

Third, although the analysis by Nanda and colleagues raises important clinical implications with regards to the risks of HT use [14], it is important to keep in mind the limitations of this study. Given its retrospective design, the results from this study need to be taken as hypothesis-generating level II evidence. Furthermore, this study was performed within the context of men receiving brachytherapy-based treatments at a single institution. Prospective validation by other groups in a multi-institutional setting, employing additional RT techniques will ultimately be required to more comprehensively estimate the true risk of HT use in men treated for PC. Furthermore, the results from this study raise additional questions that have yet to be addressed. For instance, does revascularization or aggressive management of CAD risk factors in men with a history of CHF or MI affect the impact of HT use in this population? Also, what is the impact of HT use on men with multiple CAD risk factors and is there a differential effect when stratified by underlying PC risk status?

Finally, in terms of synthesizing all of the current data, how do we ultimately address the question of whether it is safe to use HT with RT in the treatment of men with PC? Based on first principles, we need to initially rely on level I evidence, which has consistently demonstrated a survival advantage when HT is added to RT in the management of men with aggressive PC [1–5]. It is important to keep in mind that in the study by Nanda and colleagues only 5% of the cohort had a history of CHF or MI [14]. The 10-year life expectancy rule [20] is a generally accepted principle applied to both screening and the definitive management of men with PC and, because of this, it is likely that the proportion of men with underlying CAD in the various randomized controlled studies assessing the addition of HT to RT [1–5] were limited, allowing the survival advantage of HT in men with no CAD to overwhelm the potentially detrimental effect of HT in men with CAD-induced conditions. So, while randomized, controlled studies are considered the holy grail of clinical medicine, upon which treatment paradigms are based, the latter point sheds some light on the potential limitations of such studies, which may not necessarily capture the heterogeneity with regard to physical, clinical and/or molecular characteristics that exists within the general population. Sometimes, prerandomization stratification is performed, but even this adjustment may be unable to account for a previously unidentified factor, such as CAD-induced CHF or MI [14]. It is also important to consider that a history of CHF or MI is likely to be only part of the explanation. For instance, a recently reported population-based study from Sweden has shown that HT use posed the highest risk of thromboembolic disease in men treated for PC [21]. Therefore, at this time, based on current assessment of both level I and level II data, a joint consensus panel statement was issued by the American Heart Association, American Cancer Society and American Urologic Association asserting that, although there may be a link between HT use and cardiovascular events, in the absence of level I evidence there is no reason to believe that men with aggressive disease for whom HT may be efficacious should seek additional evaluation by an internist, cardiologist or endocrinologist prior to initiation of HT. Furthermore, this statement adds that, for men with PC who present with a history of CAD, the decision to treat or not treat with HT based on the risks and benefits to a particular patient should most appropriately be made in conjunction with the physician treating the underlying PC [22]. Additionally, we underscore the point that future randomized controlled trials utilizing HT in men with PC will need to be performed with upfront stratification by the presence or absence of CAD in order to provide level I evidence that may definitively demonstrate an interaction between HT use and cardiovascular comorbidity.

In the current era of personalized medicine, it is important to keep in mind each patient’s individual profile when making management decisions. As we become more facile in identifying relevant patient-related factors that may significantly interact with the treatment delivered, it will become ever more important for us to be able to design clinical trials that can adequately account for each parameter so as to allow for a maximally unbiased analysis when assessing for prognostic factors and treatment effects in men with PC. The implementation of this more individualized approach should facilitate a custom-designed therapeutic regimen for each patient that allows both maximal efficacy and minimal morbidity.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.