We analyzed biochemical relapse and sexual function in patients treated for prostate cancer with proton therapy (PT) and later treated with testosterone replacement therapy (TRT) for hypogonadism.
Twenty-three patients with biopsy-proven, localized prostate cancer were treated with definitive PT at our institution from 2006 to 2012. Each patient had hypogonadal symptoms and low serum testosterone and received TRT after PT. Biochemical failure was defined by the Phoenix criteria. Sexual function was reported using patient-reported data from the Expanded Prostate Cancer Index Composite (EPIC) questionnaire. Rates of sexual potency are also reported.
The median follow-up was 38 months after completing PT and 14 months after initiating TRT. After 1 to 6 months on TRT, the median serum testosterone level increased from 238 to 497. No patient experienced biochemical failure. Median prostate-specific antigen did not significantly rise. Median EPIC sexual summary, sexual function, and sexual bother scores all increased after TRT. Use of TRT also improved sexual potency rates from 50% to 68% after 7 months.
For patients diagnosed with hypogonadism who were previously treated for prostate cancer, TRT does not result in biochemical failure or an increase in median prostate-specific antigen. TRT may also improve sexual function.
Late-onset hypogonadism is an increasingly recognized condition among aging men in the United States. It is characterized by low serum testosterone and symptoms of androgen deficiency, which can include fatigue, decreased muscle mass and bone density, erectile dysfunction, inability to achieve orgasm, changes in mood, and impaired cognition. Testosterone replacement therapy (TRT) has been shown to raise serum testosterone and improve the symptoms associated with hypogonadism. Specifically, several studies have indicated that TRT can improve sexual function, increase energy, reduce bone loss, increase muscle strength, and improve overall quality of life for men suffering from hypogonadism [1–5]. In general, treatment is indicated in symptomatic men with testosterone levels below 300 ng/dL and those without any contraindications to therapy.
One controversial contraindication to TRT has been a previous diagnosis of prostate cancer. Conflicting clinical data exploring the relationship between testosterone level and prostate cancer have provided room for debate. On the one hand, several randomized trials have demonstrated that androgen-deprivation therapy (ADT) improves overall survival for many patients with advanced or metastatic prostate cancer [6–8]. These studies indicate that prostate cancer in an advanced form is sensitive to testosterone levels and that lowering testosterone levels improves the likelihood of cure. On the other hand, recent retrospective studies of men treated successfully for prostate cancer have shown that if these men are given TRT cautiously for hypogonadism no decrement in biochemical progression-free survival occurs when these patients are compared with historical controls [9, 10]. Furthermore, some studies suggest that men who have hypogonadism after treatment for prostate cancer may benefit from TRT in terms of quality of life . Indeed, because of the negative effects of cancer therapy, the benefits of TRT may be greater for men previously treated for prostate cancer than for other men with late-onset hypogonadism.
The aim of our study was to retrospectively review records of patients who received definitive proton therapy (PT) for prostate cancer followed by TRT. Our goals were to evaluate biochemical relapse after PT and TRT and the effect of TRT on patient-reported quality of life and sexual function.
Materials and Methods
Under an institutional review board–approved protocol, we retrospectively reviewed the medical records of men with biopsy-proven localized prostate cancer treated definitively with PT at our institution between 2006 and 2012. All study subjects were required to have symptoms of hypogonadism and low serum testosterone. The specific lower testosterone limit was determined by the treating physician; however, in general, symptomatic patients with a level below 300 ng/dL were considered to have hypogonadism. Patients could be diagnosed with hypogonadism before, during, or after completing PT. Patients were treated with TRT after PT. Patients with clinical T3 prostate cancer or node-positive disease were not offered TRT. To be included in the present analysis, all patients had to have at least 6 months of follow-up after initiation of TRT.
All patients had pathology-confirmed prostate cancer based on biopsy of a minimum of 10 prostate zones as well as a bone scan, chest X-rays within 6 months of enrollment, computed tomography (CT) scans, magnetic resonance imaging of the pelvis, and a prostate-specific antigen (PSA) test. Every patient received PT with or without ADT. The decision to receive ADT was based on individual physician and patient choice, but patients with National Comprehensive Cancer Network (NCCN) high-risk prostate cancer or intermediate-risk disease and unfavorable characteristics were encouraged to receive ADT. No patient on ADT was offered TRT until ADT had been discontinued for at least 6 months.
Proton Therapy and Testosterone Replacement Therapy
The University of Florida Proton Therapy Institute simulation, planning, and treatment guidelines for prostate cancer have previously been published . In brief, all patients underwent CT simulation with fiducial markers in place. Immediately after CT simulation, a magnetic resonance imaging scan was obtained and the CT and magnetic resonance images were fused. The prostate, seminal vesicles, penile bulb, bladder, rectum, bowel, and femoral heads were contoured. A planning target volume was constructed from the prostate and/or seminal vesicles with margins of 4 mm in the anteroposterior and lateral directions, and 6 mm in the superior-inferior direction. Image-guided treatment was performed using orthogonal kilovolt imaging for fiducial localization. Patients were treated with 2 Gy (RBE) per fraction to a total dose of 76 to 82 Gy (RBE) or at 2.5 Gy (RBE) per fraction to a total dose of 70 to 72.5 Gy (RBE).
The TRT was administered by our institutional physicians, outside general medicine physicians, or urologists per physician discretion. Patients could be treated with topical testosterone gel, testosterone injections, or transdermal patch. Testosterone injections were typically delivered every 2 weeks and at a dose of 200 mg per injection. Testosterone 1% gel was typically given topically 50 mg initially, and the dose was titrated up as needed. The goal of TRT for each patient was to raise the testosterone level to clinically normal and ameliorate the symptoms of hypogonadism. Patients continued on TRT unless they experienced side effects, if the physician recommended stopping TRT, or if testosterone replacement proved to be ineffective in improving symptoms.
Patient medical histories were recorded before treatment and included pretreatment diagnoses of diabetes mellitus, hypertension, cardiovascular disease, and hypogonadism. Patients' PSA levels were assessed before treatment, at the end of treatment, and at 3-month intervals after completing PT. Biochemical failure was defined by the Phoenix definition, which is nadir PSA + 2 ng/dL measured on at least 2 visits. The PSA bounce was defined as a rise in PSA ≥ 0.2 ng/dL with subsequent PSA values falling to pre-bounce levels. Testosterone levels were measured every 3 to 6 months while on TRT. Patient-reported quality of life parameters were assessed before PT and at 6- to 12-month intervals using the Expanded Prostate Cancer Index Composite (EPIC). Erectile dysfunction was defined as suggested by Alemozaffar et al by evaluating the sexual domain of the EPIC questionnaire . More specifically, sexual potency meant that when asked the EPIC-26 question, “How would you describe the usual quality of your erections during the last 4 weeks?” the patient responded “firm enough for intercourse.”
Patient and Tumor Characteristics
Characteristics of the entire cohort can be seen in Table 1. Twenty-seven men received TRT after PT. Four men were excluded because of inadequate follow-up, leaving a total of 23 men included in the analysis. The median age was 64 years and the median pretreatment PSA was 5.0 (range, 1.3 to 11.1). Ninety-six percent (21/23) had a pretreatment PSA level below 10. Overall, 78% (18/23) of patients had clinical stage T1 disease and 22% (5/23) had T2 disease. No patient with clinical stage T3 or node-positive disease received TRT. Most patients had NCCN-designated low-risk or intermediate-risk prostate cancer. Only 2 of 23 patients had NCCN high-risk disease, and both of these patients had a Gleason score ≥ 8 as their only high-risk factor.
As Table 2 shows, all men were treated with definitive PT to a median dose of 78 Gy (RBE). The median follow-up after PT was 38 months. Two patients received 6 months of ADT (1 neadjuvant, 1 adjuvant) and 1 patient received 6 months of antiandrogen therapy. No patient received TRT within 1 year of the last receipt of ADT or antiandrogen. The median time to start TRT after PT was 12 months. The median duration of TRT was 14 months (range, 1 to 33 months). The modality of TRT varied based on physician discretion. Fourteen patients (58%) received testosterone injections. Eight patients (38%) received testosterone gel, and 1 patient received a testosterone transdermal patch. The median duration of TRT was 14 months (range, 1 to 34 months). The median follow-up after initiating TRT was 19 months (range, 7 to 54 months).
Effect of Testosterone Replacement Therapy on Serum Testosterone
There was no decrease in median testosterone level after PT. The median testosterone score prior to PT was 231, and before TRT the median score was 238. The median testosterone level increased for the study population after the initiation of TRT. The median testosterone score for the time period 1 to 6 months after initiating TRT rose to 497 and then fell slightly to 435, 7 months after initiating testosterone.
Prostate-Specific Antigen Kinetics and Biochemical Failure after Proton Therapy and Testosterone Replacement Therapy
The median PSA follow-up was 39 months after PT and the median time to start TRT after PT was 14 months. Figure 1 shows median PSA values over time after PT. Figure 2 shows median PSA values after TRT. In general, the trend for all patients was for PSA to decline with time after PT, although a small rise in median PSA of 0.2 ng/dL occurred at 25 to 30 months. By 31+ months, the median PSA had returned to the prior low for the cohort. After TRT, the median PSA ranged from 0.6 to 0.7 at each time period. No patient experienced biochemical failure after TRT. Transient PSA bounce was found in 9 of 23 (39%) patients during follow-up after initiating TRT. The median time to PSA bounce was 9 months after TRT and 25 months after completing PT, and the median bounce was 0.45 (range, 0.3 to 2.7). Of note, the highest bounce occurred in a patient diagnosed with prostatitis. He had a rise in PSA from 2.2 to 4.9, and after antibiotic treatment, his PSA fell to 1.3, which was below his pre-prostatitis level. At the last follow-up, PSA level was ≤ 0.5 for 14 of 23 (61%) patients, < 1 for 19 of 23 (83%) patients, and < 3 for all of the patients.
Post-treatment Quality of Life and Sexual Potency
The percentage of men answering EPIC questionnaires before PT was 96%, 78%, 52%, and 70%, respectively. The median EPIC sexual summary, function, and bother scores are displayed in Table 3. For all three measures, scores were at their highest level before PT. After radiation, median scores fell and continued to fall 1 to 6 months after TRT. Only after 7 months of TRT did patients display an improvement in EPIC sexual summary, function, and bother scores. The improvement led each subscore to approximate its median preradiation level. Overall, median sexual bother scores increased from 43.8 before TRT to 59.4 at 7 months after initiating TRT. The median sexual summary score improved from 50 to 61.8, and the median sexual function score improved from 41.7 to 53 over the same period. Additionally, as Figure 3 shows, the number of men who were sexually potent increased from 50% before TRT to 68% 7 months after initiating TRT. Of note, 7 of 23 (30%) men used phosphodiesterase inhibitors for erectile dysfunction before being treated with radiation, compared to 10 of 23 (43%) men after radiation treatment.
This study evaluates the risk for biochemical failure in men treated with definitive PT for prostate cancer followed by TRT for symptomatic hypogonadism. To our knowledge, this is the first study to also attempt to determine the benefits of TRT in terms of sexual potency and sexual function using EPIC sexual domain scores for men previously treated for prostate cancer with radiation therapy.
Although the follow-up period was short, our results suggest that TRT may not increase the risk of early biochemical failure for men treated for prostate cancer. Indeed, there was no occurrence of biochemical failure in the men in this study cohort. Median PSA also did not significantly rise with treatment. The PSA bounce occurred in 39% of patients following TRT at a median time of 24 months after PT. This rate of PSA bounce is similar to that found in other studies. For example, Sheinbein et al  reported a 32% rate of PSA bounce after intensity-modulated radiotherapy for prostate cancer. Additionally, our study indicates that patients may benefit in terms of sexual potency after treatment with TRT. Patients had improved sexual potency and improved EPIC sexual summary, function, and bother scores after TRT. It took more than 7 months from the start of TRT for these scores to improve, but all of the median values improved and approximated preradiation therapy levels.
Other small, single-institution studies have indicated that TRT may be safe for men after successful treatment of prostate cancer. Pastuszak et al  reported the biochemical relapse rate for 103 men treated for prostate cancer with radical prostatectomy. All patients were subsequently treated with TRT for symptomatic hypogonadism. At a median follow-up of 27.5 months after initiating TRT, 4 (3.9%) patients relapsed biochemically after TRT compared with 8 of 49 (16%) patients in a reference group also treated with radical prostatectomy but without TRT. All men in the TRT group who failed had high-risk prostate cancer. Of note, the authors found that the median PSA level began to increase 18 to 24 months after initiating TRT, and the rise was statistically significant. In comparison, median PSA did not significantly increase in the control group during the same follow-up period. The median PSA rise in the TRT group did not suggest prostate cancer regrowth as the median PSA velocity was 0.002 ng/mL per year for both the TRT group and the reference group.
Sarosdy  reported outcomes for a series of men with localized prostate cancer treated with brachytherapy followed by TRT for hypogonadism. Thirty-one men received TRT for a median of 4.5 years. The TRT started at a median of 2 years after brachytherapy. After 5 years of follow-up, no patient had failed biochemically. The authors noted that only 1 patient experienced a PSA bounce after initiation of TRT and indicated that TRT is likely safe for select patients after brachytherapy. However, it should be delayed until 18 months after completion of the brachytherapy implant to reduce the chance of confusing a PSA rise due to TRT with the common PSA bounce that happens 24 to 36 months after brachytherapy.
Agarwal and Oefelein  published a report on a series of 10 patients treated for prostate cancer with radical prostatectomy and then TRT for hypogonadism. Patients were followed for a median of 19 months after starting TRT. No patient experienced biochemical failure. TRT significantly improved scores from the hormone domain of the EPIC questionnaire, mainly by boosting energy and reducing hot flashes .
Our study supports the major findings from other retrospective series evaluating the safety and utility of TRT for men treated for prostate cancer. The limitations of our study include its retrospective design, our small study population, and the short follow-up duration. Indeed, a larger prospective trial with more than 5 to 10 years of follow-up after initiation of TRT will be necessary to provide more definitive evidence of the efficacy and safety of TRT for patients previously treated for prostate cancer and to determine optimal delivery and monitoring strategies for TRT in future patients. Still, our results, when combined with the results of other studies, indicate that TRT may be safe for men at low risk for treatment failure. At this point, we recommend it be used only in men with low-risk to intermediate-risk prostate cancer with symptomatic hypogonadism. We recommend that TRT be started several months after completion of radiation therapy and that PSA be monitored closely, every 3 months during the first 3 years of treatment and at 6-month intervals thereafter. Given the promising outcomes of TRT in this small series of definitively treated patients with prostate cancer patients and symptomatic hypogonadism, we believe further study of TRT is warranted, as it appears to be safe and effective in improving sexual health.
For patients diagnosed with hypogonadism after prostate cancer treatment, the cautious use of TRT may not result in biochemical failure or in an increased PSA level. Furthermore, TRT may improve sexual function in some men over time, despite potential negative effects of cancer therapy. Our data support the further study of the effects of TRT on patients treated for prostate cancer who also have symptomatic hypogonadism. In particular, a prospective trial with long-term follow-up is required to validate our findings.
ADDITIONAL INFORMATION AND DECLARATIONS
Conflicts of Interest: The authors have no conflicts of interest to disclose.