Less advanced disease at initiation of salvage androgen deprivation therapy is associated with decreased mortality following biochemical failure post-salvage radiation therapy

It is estimated that the majority of patients receiving salvage radiation therapy (SRT) for biochemically recurrent prostate cancer post-radical prostatectomy (RP) will not achieve long-term disease control [1]. Eventually, many such patients will once again develop a rising prostate-specific antigen (PSA) after radiotherapy (RT), suggesting the presence of residual local or metastatic disease. Having exhausted their options for local therapy, only systemic treatments remain for these patients with recurrence post-SRT. One common intervention in this setting is the initiation of salvage androgen deprivation therapy (SADT).

While SADT is clearly beneficial for metastatic prostate cancer [2] and initiating SADT while disease burden is low in the setting of advanced disease appears to be clinically advantageous [3], the optimal clinical context for initiation of SADT following the development of biochemical failure (BF) in the absence of metastatic disease remains controversial [4],[5]. Much of this controversy stems from the lack of prospective, randomized trials investigating the potential benefits of initiating SADT while disease burden is low for patients experiencing BF alone after local treatment [4],[6]. Nonetheless, retrospective studies have consistently suggested that beginning SADT early in the clinical course of recurrent disease post-definitive RT is associated with improved overall survival [7]-[11]. The purpose of this retrospective analysis is to assess whether less advanced disease at initiation of SADT is similarly associated with improved clinical outcomes following BF post-SRT.

We performed a single-institution, retrospective review examining prognostic factors for PCSM and OM for men experiencing BF after SRT. These data are limited by selection bias and their non-randomized nature. Despite these limitations, they suggest a decreased risk of PCSM and OM associated with the initiation of SADT while patients have a PSADT >3 months in the absence of DM following BF post-SRT. Whether the relationship between a longer PSADT at SADT initiation and improved clinical outcomes is cause and effect or simply an association observed in this cohort is unknown. However, it does not seem unreasonable that initiating SADT while patients have a lower disease burden or less aggressive clinical characteristics would associate with improved clinical outcomes as this is in accordance with a recent meta-analysis of randomized trials performed in those with advanced prostate cancer [3]. Our findings are the first to indicate that less advanced recurrent disease at the time of SADT initiation post-SRT may be beneficial and, to our knowledge, no other similar retrospective studies in the post-SRT setting have been completed to date. Moreover, prospective trials demonstrating a survival benefit associated with the initiation of SADT early in the disease course for patients experiencing BF alone following RP, definitive RT, or SRT are lacking [4],[6].

Of note, our results do not support initiation of SADT in all patients with less advanced disease following BF post-SRT. The lack of a significant difference in PCSM and OM between patients receiving SADT with a low disease burden (group 1) and patients not receiving SADT during follow-up (group 4) suggests that there is a subset of patients for whom initiating SADT while they have less advanced disease may not be beneficial. Given the very long PSADTs and long median IBF for patients in group 4, it is likely that patients experiencing late BF with a gradual, slow rise in PSA may not be reasonable candidates for initiation of SADT. Freedland et al. discovered that patients with PSADTs >15 months post-RP were at very low risk for PCSM, confirming that initiating SADT while disease burden is low may not be clinically advantageous for patients with especially long PSADTs [14]. Supporting this possibility is the fact that, like Freedland et al., no patient in the currently analyzed cohort with a PSADT >15 months experienced PCSM. Therefore, it may be reasonable to initially observe patients with very long PSADTs after BF post-SRT and reconsider starting SADT should these patients go on to develop shortened PSADTs during follow-up. On the other hand, for patients with PSADTs that are short enough to put them at a less than negligible risk for PCSM, starting SADT prior to the development of metastasis or a PSADT <3 months is associated with a decreased risk of PCSM and OM based on our findings.

Interestingly, we demonstrated that patients without DM who do not receive SADT until they have a PSADT <3 months have a risk of PCSM and OM comparable to those who start SADT with known DM, which is consistent with similar findings in the post-definitive RT setting [9]. Therefore, patients without DM who do not receive SADT until they have developed short PSADTs may already harbor disease that is sufficiently aggressive to lessen SADT’s therapeutic benefits. Additionally, among patients without DM prior to starting SADT, those with a pre-SADT PSADT <3 months were found to be at a significantly increased risk for PCSM and OM despite having received SADT more quickly than patients with longer PSADTs. Thus, close monitoring of PSADT following BF post-SRT may be warranted to identify even small windows of opportunity to start SADT before the development of a short PSADT.

In our analysis, PSADT before the initiation of SADT was shown to be strongly prognostic of both PCSM and OM on univariate and multivariate analysis. The c-index value of 0.74 for PCSM and 0.71 for OM is further evidence of the prognostic utility of PSADT prior to starting SADT. For comparison purposes, the Stephenson nomogram, which predicts the likelihood of developing BF post-SRT based on eleven clinical and pathologic variables, had a c-index value of 0.69 in the dataset from which the nomogram was derived [1] and a c-index of 0.71 in the dataset from which our presented data was extracted. The fact that PSADT prior to the initiation of SADT demonstrates similar predictive accuracy for the development of PCSM and OM following BF post-SRT highlights its clinical importance.

Our findings contribute to a growing body of work identifying the potential benefits of initiating SADT while patients have less advanced disease. Previous studies examining the benefits of initiating SADT early in the disease course for patients experiencing BF without metastatic disease are solely retrospective and performed in the post-RP or post-definitive RT settings [7]-[11],[21]. In one such study, Moul et al. demonstrated the ability of SADT initiation to delay the development of metastasis in high-risk patients with PSA-only failure post-RP [21]. Several other retrospective studies have shown improved overall survival when SADT is started early in the course of recurrent disease following BF post-definitive RT [7]-[11]. Our results are similar to those reported by Mydin et al. who were able to show that patients with a pre-SADT PSA ≤10 ng/mL in the absence of DM had improved overall survival post-definitive RT in a secondary analysis of Irish Clinical Oncology Research Group 97–01 [7]. However, PSADT prior to the initiation of SADT was not prognostic for overall survival on multivariate analysis while timing of SADT administration based on PSA level and presence or absence of DM at initiation of SADT was prognostic for this endpoint [7]. In contrast, Tenenholz et al. have previously shown PSADT prior to the initiation of SADT to be the most powerful predictor of overall survival and disease-specific survival in a retrospective analysis of patients experiencing BF post-definitive RT [9]. Thus, findings regarding whether PSA or PSADT prior to starting SADT is a superior prognostic factor for outcomes post-definitive RT are mixed. Our results suggest that a PSADT <3 months prior to starting SADT is more prognostic for risk of PCSM and OM than the pre-SADT PSA level in the post-SRT setting. This is not surprising considering that patients post-prostatectomy should have uniformly low PSA levels, and those harboring aggressive disease may develop short PSADTs even before their PSA levels have a chance to become markedly elevated once again. Another prognostic factor that has been utilized to assess clinical risk is the IBF after the start of SRT [19], which likely has some overlap with PSADT in that they may be measuring similar biological processes. In the current analysis, it appeared that a very short PSADT still added significant clinical value when including both of these metrics in our multivariate Cox proportional hazards models.

As previously discussed, the inherent limitations to this study secondary to its retrospective design warrant further validation of our findings. A second limitation of this analysis is that we were unable to assess toxicity related to the use of SADT. The potential negative health effects of ADT and ADT’s adverse effects on quality of life must be considered when contemplating the appropriate clinical context for its initiation. For instance, long-term use of ADT is known to increase the risk of experiencing a skeletal fracture and is associated with a higher risk of developing type 2 diabetes mellitus [22]. Additionally, ADT puts one at a higher risk for mortality secondary to cardiovascular disease and is known to cause vasomotor hot flashes and sexual side effects that can be associated with a lower quality of life [22],[23]. Thus, the administration of ADT is not benign and the decision to initiate this treatment should be made after carefully considering the potential risks and benefits of this therapeutic intervention. Nevertheless, the possibility that survival may be prolonged by initiating SADT when patients have less advanced recurrent disease post-SRT make this approach an attractive option, especially in high-risk patients such as ours who have exhausted localized treatment options [6].

Overall, our results suggest that initiating SADT while patients have less advanced disease following BF post-SRT may be a sensible treatment option associated with a decreased risk of PCSM and OM. However, observation may be a reasonable alternative for patients with especially long PSADTs given their very low risk of experiencing PCSM. Furthermore, a PSADT <3 months before the initiation of SADT appears to significantly predict an increased risk of PCSM and OM for patients with biochemically recurrent disease following SRT. Future prospective studies examining the optimal clinical context for starting SADT post-SRT should consider using the development of a short PSADT as a condition for initiation of SADT given the significant ability of pre-SADT PSADT <3 months to predict mortality in our analysis.