Testosterone therapy in patients with locoregional prostate cancer treated with prior androgen deprivation therapy and radiation: a retrospective single center review

Introduction

Since its discovery in the 1940s, androgen deprivation therapy (ADT) has remained a cornerstone in the treatment of prostate cancer (PC) (1). ADT is frequently employed for a duration of 4 to 24 months in conjunction with definitive or salvage radiation therapy (RT), depending on the risk and stage of disease (2,3). Since medical castration is intended to be of limited duration, this is typically achieved with gonadotropin-releasing hormone (GnRH) agonists and antagonists. Unfortunately, a significant proportion of men are left with testosterone deficiency (TD) after ADT. In some cases, TD can be long-term, which prolongs adverse effects and diminishes quality of life for these patients. In one study, after 18 months of ADT 45.4% and after 36 months 54.9% of patients failed to recover to eugonadism with over a decade of follow-up. In men who recovered, it took 5.1 years on average for that recovery in the 36-month group (4). A second study showed similar findings, noting that about one-quarter of patients failed to reach normal levels of testosterone (T), with around 10% remaining at castrate levels up to 24 months post-ADT (5).

Historically, grounded in the androgen hypothesis, experts were concerned that T stimulated prostate cancer growth. This led to reluctance to treat TD with exogenous T in men history of prostate cancer due to fears of cancer progression. This concern originated in Huggins’ seminal work in 1941, where he treated three men with metastatic prostate cancer with androgen injections, resulting in a sharp increase in serum acid phosphatase levels. In 1967, Prout and Brewer treated men with prostate cancer with T propionate, and a subset who had previously undergone castration experienced rapid cancer progression, fueling further concern (6). In retrospect, reluctance to use testosterone therapy (TTh) in this population stemmed from treating a small number of patients with advanced disease and prior castration, but these studies were limited in their scope and did not represent the broad range of disease severity seen in prostate cancer.

Due to the implications of the androgen hypothesis, thousands of men with prostate cancer have been committed to prolonged TD, which is known to cause a broad spectrum of side effects. These symptoms may be even more significant after ADT given the profound degree of T suppression. TTh has been shown to significantly mitigate these short and long-term toxicities in patients without cancer. The Testosterone Trials treated men with TD with TTh and found improvements in libido, erections, physical activity, mood, bone density, and anemia (7). Further studies have shown TTh leads to an increase in lean body mass, decreased adiposity (8,9) increased insulin sensitivity (10,11) and decrease in glycemic indices (12). While additional associations have been shown between TD and increased cardiovascular mortality and overall mortality (13,14). This underscores the critical need for comprehensive evaluation and management of TD after ADT to mitigate the long-term impact on patients’ well-being after definitive prostate cancer treatments.

In 2023, the TRAVERSE Study showed that men with hypogonadism treated with TTh were not at increased risk of high-grade or any-grade prostate cancer (15). Experts have slowly become more comfortable using TTh to treat patients with a history of low-risk or definitively treated prostate cancers. A large review of the topic found no increased risk of recurrence in studies in men with prior prostatectomy, external radiation or brachytherapy treated with TTh (16). And a population-based study found TTh did not increase the risk of prostate-directed therapy or mortality in men with prostate cancer on active surveillance (17). There is very limited data on the safety of TTh following ADT and RT. This has mostly been confined to case series. The largest of these reviewed 98 men treated with radiation, 50 of whom also received ADT. All 98 were treated with TTh with long-term follow-up. Mean prostate-specific antigen (PSA) was 0.08 at baseline and 0.09 after TTh and just six cases of biochemical recurrence were seen (6.1%) in the full study population (18).

A notable difference between those treated with surgery or radiation alone compared with those who have been treated with ADT is the degree of T suppression seen in the latter, where the baseline T level before TTh can be more deeply suppressed after ADT. The saturation model has been proposed, where the androgen receptor is maximally stimulated at a T level of approximately 250 ng/dL (19). There is laboratory data treating LnCap cells (20), C4-2 and C4-2AT6 cells (21), animal models (22), and human data (23) reinforcing this theory and cut-off level. Theoretically, a patient pre-treated with ADT who maintains a T level <50 ng/dL over time could be suppressing cancer recurrence. However, the goal at treatment initiation was transient T suppression with eventual T recovery, which begs the question if there is a difference between endogenous versus exogenous T recovery. Should that cancer recur after TTh, there are many examples where intermittent ADT could then be effectively employed to control that recurrence (24,25).

Herein, we present Lahey Hospital & Medical Center’s experience with patients receiving TTh after previous treatment with ADT and RT, with the goal of adding to the current literature regarding the safety of TTh in this population to set the stage for a prospective trial. We present this article in accordance with the STROBE reporting checklist (available at https://tau.amegroups.com/article/view/10.21037/tau-24-422/rc).

Methods

We retrospectively abstracted clinical data from hospital records of patients with stage I–IVA prostate cancer [American Joint Committee on Cancer (AJCC) 8th edition], treated with prior concurrent ADT and radiation and subsequently with TTh between January 1, 2014 and September 30, 2023.

Extracted data included patient demographics, details on cancer diagnosis, staging and treatment, cancer-related outcomes, and metabolic parameters. For TTh, all oral, injectable and topical formulations of T were included and tamoxifen, clomiphene and human chorionic gonadotropin were also included. The co-primary endpoints were change in PSA and incidence of prostate cancer recurrence.

Statistical analysis

Statistical analysis included descriptive statistics with means, medians and interquartile ranges (IQRs). PSA velocity (ng/dL/year) was calculated using linear regression model. Shapiro-Wilk test was used to test for normality. If the data followed a normal distribution, paired t-test was used to evaluate for significant differences in outcomes. Otherwise, Wilcoxon Rank Sum Test was used.

Ethical statement

The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was reviewed by the Institutional Review Board (IRB) of Lahey Hospital & Medical Center, which determined that the study met the criteria for exemption from IRB review as well as informed consent (study No. 20233068).

Results

We identified 21 patients meeting criteria with a median age of 77 years (IQR, 66–79 years), all of whom were White. The distribution of International Society of Urological Pathology (ISUP) grade groups (GG) showed that 38% of patients were classified as GG3, while GG5 accounted for 33.3%. Smaller proportions were noted in GG1, GG2, and GG4, each constituting 9.5% of the cohort. Staging based on the AJCC 8th edition revealed that 23.8% of patients had stage IIIC disease, and an additional 23.8% presented with stage IVA. National Comprehensive Cancer Network (NCCN) risk classification indicated that the majority fell into the unfavorable intermediate (23.8%), high (19.0%), very high (19.0%), or pelvic lymph node metastatic (23.8%) risk categories. RT was delivered definitively in 85.7% of cases, with the remainder receiving salvage therapy. Regarding ADT, 66.7% received monotherapy, while 28.6% were treated with bicalutamide, and 4.8% with abiraterone/prednisone. Leuprolide was used for ADT in all cases. The median duration of ADT was 8 months (IQR, 5–17 months). The median interval from radiation to TTh was 19 months (IQR, 12–44 months) and the median interval from the end of ADT to TTh was 17 months (IQR, 7–34 months). Patient and baseline disease characteristics are presented in Table 1.

Prior to TTh, the median T level was 38 ng/dL (IQR, 23–73 ng/dL). TTh formulations included 6 treated with T cypionate injections, 4 with tamoxifen, 1 with clomiphene, 12 with T gel, and 2 with T patch. Four patients were treated with two different formulations. The median follow-up period from the start of TTh was 15 months (IQR, 9–48 months), and the median duration on TTh was 10 months (IQR, 5–15 months). At data cutoff in March, 2024, TTh was ongoing in 15 (71.4%) patients and discontinued in 6 (28.6%). Reasons for discontinuation included T recovery (n=1), hospice (not related to PC) (n=2), no perceived benefit (n=2), and physician concern for PSA rise (n=1). TTh characteristics are summarized in Table 2.

After TTh, the median T level was 318 ng/dL (IQR, 191.3–544.5 ng/dL). Mean PSA pre- and post-TTh were 0.086 and 0.193 ng/dL, respectively (one-sided P=0.008). The mean PSA velocity was 0.084 ng/dL/year. All PSA and T levels during follow-up are presented in spider plots in Figure 1.

Figure 1 Spider plot of total testosterone (A) and PSA (B) values over time. PSA, prostate-specific antigen.

None of the subjects experienced prostate cancer recurrence or prostate cancer-specific mortality (PCSM). One patient showed a PSA bounce without recurrence. In this patient, baseline PSA was 0.9 ng/dL which rose to 2.0 ng/dL after 1 month on tamoxifen. PSA peaked at 2.9 ng/dL after 3 months and was 1.9 ng/dL after 6 months. Tamoxifen was discontinued at the 6-month mark. With nearly 3 years of follow-up, T remained at 330.3 ng/dL and PSA had declined to 0.1 ng/dL.

Mean body mass index (BMI) was unchanged before (28.3 kg/m²) and after (27.7 kg/m²) TTh (P=0.50). Due to the retrospective nature of the study, quality of life measures and metabolic parameters (hemoglobin A1c, lipid values) could not be systematically abstracted.

Discussion

Historically, rooted in the androgen hypothesis, there has been significant reluctance to use TTh to treat men with a history of prostate cancer. As a result, many patients with iatrogenic hypogonadism have gone untreated. Slowly, practitioners have begun to treat more men with a prostate cancer diagnosis, including those with prior prostatectomy or radiation and even those with biochemical recurrence or on active surveillance. There is even emerging data where, high dose T, so-called bipolar androgen therapy, may provide a therapeutic cancer benefit in castration resistant disease due to altered androgen receptor expression (26). However, few reports have described TTh in men treated definitively with ADT as part of their regimen. This may be in part due to the profound levels of T suppression that occur with ADT, many times in a prolonged fashion. The saturation model has suggested that there is a point beyond which no further androgen-driven prostate tissue growth occurs, and ADT-treated men will typically fall well below that threshold, which could spur additional concern. Relatively few and small case series have looked at this patient population with prior ADT in conjunction with definitive RT. Four such series included between 6 and 50 patients treated with TTh after prior ADT and recurrent cancer was described in just 0–6% of patients in these studies (18,27-29). This is likely in keeping, if not below, what would be expected of a matched population.

We performed a retrospective analysis of patients who received TTh following ADT and radiation for prostate cancer, aiming to assess the risk of recurrence. We identified 21 subjects that represent the diversity of locoregional prostate cancer covering a wide range of ISUP GG and AJCC 8^th edition stages, including many in the high and very high-risk categories. Patients were profoundly T suppressed with a median of 38 ng/dL at baseline, well below the saturation point. The modality of TTh varied with many receiving injectable and topical T formulations, but also tamoxifen and clomiphene. After starting TTh, there was an appropriate increase in T levels in all subjects. The follow-up period after initiating TTh is relatively short, but initial analysis shows a modest, likely clinically insignificant, rise in mean PSA, and no cases of prostate cancer recurrence were detected. While a matched control was not included, from other large radiation studies, incidence of PSA recurrence after RT rises in a roughly linear fashion over 10–15 years and these studies suggest an annual PSA relapse rate of approximately 2–5% per year. Despite short follow-up, the study population here compares favorably to these historical controls (30,31). Given how T-suppressed this population was, we would posit that the follow-up time is sufficient to draw some meaningful conclusions about the low rate of cancer recurrence given how quickly T levels rose along the androgen receptor saturation curve. TTh was ongoing at data cut-off in the majority of patients, and of the six that discontinued TTh, only one did so for concern of cancer recurrence. This case turned out to be to show a PSA bounce rather than recurrence. While no PCSM was observed, the follow-up duration was not sufficient to detect this. Given the nature of the study and follow-up time, we were not able to evaluate change in metabolic parameters nor quality of life. No change was seen in median BMI before and after TTh, but perhaps this was limited by length of follow-up.

The study presents several limitations that could impact the interpretation and generalizability of its findings, including the retrospective design, the inclusion of various forms of TTh, lack of racial diversity, and relatively small sample size and follow-up. However, despite these limitations, the study aligns very closely with prior series to suggest that TTh appears safe from a cancer recurrence standpoint in men treated with prior ADT and definitive or salvage radiation. Nevertheless, these constraints, as well as historic reluctance to treat men like this, underscore the need for a robust, prospective study to safely treat this compromised group of patients.

Conclusions

We evaluated patients with prostate cancer who remained hypogonadal after prior ADT and radiation for locoregional disease, we found that TTh was not associated with a clinically significant rise in mean PSA and no cases of prostate cancer recurrence were documented. This study adds to existing literature supporting the case for a prospective clinical trial utilizing TTh in this patient population.

Acknowledgments

The authors would like to acknowledge Dr. Andrew McCullough and Dr. Christopher Tretter for their expert clinical care for the majority of the patients included in this study, as well as the Lahey Hospital & Medical Center Comparative Effectiveness Research Institute for conducting the medical record abstraction. The authors also acknowledge that preliminary data from this study were presented in electronic abstract form at the 2024 Annual Meeting for the American Society of Clinical Oncology (Volume 42, Issue 16, e24045-e24045).

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tau.amegroups.com/article/view/10.21037/tau-24-422/rc

Data Sharing Statement: Available at https://tau.amegroups.com/article/view/10.21037/tau-24-422/dss

Peer Review File: Available at https://tau.amegroups.com/article/view/10.21037/tau-24-422/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-24-422/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013).The study was reviewed by the Institutional Review Board (IRB) of Lahey Hospital & Medical Center, which determined that the study met the criteria for exemption from IRB review as well as informed consent (study No. 20233068).

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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