Research ArticleClinical Studies
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Identification of Factors Contributing to Testosterone Recovery After Hormone Therapy Combined With External Radiation Therapy

YUMIKO YOKOMIZO, YUSUKE ITO, TAKASHI KAWAHARA, NARIHIKO HAYASHI, YASUHIDE MIYOSHI, KAZUHIDE MAKIYAMA, MASAHARU HATA and HIROJI UEMURA
In Vivo July 2024, 38 (4) 2074-2079; DOI: https://doi.org/10.21873/invivo.13666

Abstract

Background/Aim: When hormone therapy (HT) is combined with radiotherapy, understanding the recovery of testosterone levels after the end of HT becomes crucial for considering subsequent therapy. The aim of this study was to determine the factors influencing the time to recovery of testosterone levels after discontinuation of HT and the likelihood of recovery. Patients and Methods: The study included a total of 108 patients with prostate cancer who were treated with GnRH agonist in combination with radiotherapy and followed up for at least 12 months after discontinuation of the GnRH agonist. The presence of recovery of testosterone levels and the time to recovery were investigated. Univariate and multivariate analyses were performed on several factors contributing to testosterone recovery, including age at initiation of HT, and the duration of HT. Results: Testosterone levels recovered in 61 cases (56.5%). The median time to recovery was 14.8 months. There was a significant difference in the recovery of testosterone levels between patients aged ≥71 years and those aged <71 years at the start of HT (p=0.002), and between those who had been on HT for ≥34 months and those for <34 months (p=0.031). In both univariate and multivariate analyses, age at initiation of HT and duration of HT contributed to the recovery of testosterone levels. Conclusion: The rate of recovery of testosterone levels after long-term (median 34.3 months) HT was lower in patients who were older than 71 years at the start of HT.

Key Words:

In recent years, prostate specific antigen (PSA) screening has become more widespread in Japan and the proportion of early-stage prostate cancer has increased. Total prostatectomy and radiotherapy are the main treatment options for early-stage prostate cancer. In advanced prostate cancer, hormone therapy (HT) plays a crucial role in both stages, with or without metastases. More recently, metastatic prostate cancer has been treated with doublet therapy, which combines androgen deprivation therapy (ADT) with novel hormonal agents (abiraterone, enzalutamide and apalutamide) as initial treatment, or with the addition of docetaxel (ADT+ darolutamide+docetaxel) triplet therapy. Metastatic advanced prostate cancer is treated with HT, which involves the consistent long-term administration of ADT.

Intermittent HT is considered a viable alternative to continuous HT in terms of reducing adverse events associated with long-term HT, maintaining quality of life, and being more cost-effective. Non-inferiority of intermittent HT for advanced prostate cancer with metastases was not demonstrated, whereas non-inferiority of intermittent HT for recurrent cases after radical therapy for localized prostate cancer was demonstrated (1, 2). For intermittent HT, information on the recovery of testosterone levels during withdrawal is useful.

Radiotherapy and HT are often combined for advanced localized prostate cancer. Long-term HT of 2-3 years is known to be effective, especially for high-risk localized prostate cancer (3, 4). In addition, if HT is used in combination with radiotherapy as curative therapy, understanding the recovery of testosterone levels after completion of HT is important for assessing potential complications due to low testosterone levels. There is no need to continue treatment unnecessarily if testosterone levels remain low after HT.

The aim of this study was to determine the time to recovery of testosterone levels in patients with localized prostate cancer treated with external-beam radiation therapy (EBRT) followed by HT for a certain period of time, and to identify the factors influencing the likelihood of recovery after discontinuation of HT.

Patients and Methods

Radiation and hormone therapy. We conducted a retrospective review of patients with prostate cancer who underwent intensity-modulated radiation therapy (IMRT) at our institution between March 2005 and March 2014. One hundred eight patients received HT (androgen deprivation therapy: ADT and/or bicalutamide) before IMRT and continued HT. HT was typically initiated at least three months before IMRT treatment and continued for two to three years afterwards.

Testosterone measurement. Serum testosterone was measured every three months after cessation of HT until the normal range of testosterone. Patients whose testosterone levels could be evaluated over time were followed for at least 12 months after the cessation of HT. The recovery date of testosterone level was calculated from the cessation of HT to time of testosterone recovery. Testosterone levels were considered to recover to the normal level when they were above the institutional standard of 131 ng/dl.

Statistics. Univariate and multivariate analyses were performed on age at initiation of HT, duration of HT, initial PSA, Gleason Score, and prostate cancer National Comprehensive Cancer Network (NCCN) risk classification as factors contributing to testosterone recovery. Estimated effects of predictors were validated using odds ratios (ORs) and 95% confidence intervals (CI). The statistical analysis software used was SPSS 18.0 (SPSS, Inc., Chicago, IL, USA).

Results

Characteristics of patients. The median age at the end of HT was 74 (57-87) years, and the median serum PSA level at diagnosis was 11.6 ng/ml (4.1-62.1 ng/ml) (Table I). The median Gleason score of the biopsy diagnoses was seven (5-9), and all patients received 76 Gy (38 fr) of IMRT. The median duration of neo-adjuvant or adjuvant HT with radiotherapy was 34.3 months (8.8-154.7 months). The median age at the start of HT was 71 (54-84) years, and the median age at the end of HT was 74 (57-87) years. For NCCN prostate cancer risk classification, the low-, intermediate-, and high-risk categories included 4, 29, and 75 cases, respectively. The median observation period after HT was 43.5 months (12-145 months). The median age at testosterone recovery was 71 years (58-81 years). The median time to testosterone recovery was 14.8 months (3.1-38.8 months) (Table II). Overall survival was 98.2% (106 patients), with 2 deaths from other causes and no deaths because of prostate cancer; only 7 patients (6.4%) had PSA recurrence (nadir+2 ng/ml), and one patient had a PSA bounce (Table II). Seventeen patients (27.9%) recovered within one year after cessation of HT and 39 patients (63.9%) recovered within one to two years (Figure 1).

View this table:
Table I.

Characteristics of patients (n=108).

View this table:
Table II.

Results of clinical data (n=108).

Figure 1.
Figure 1.

The number of patients with testosterone recovery over time. Seventeen patients (27.9%) recovered within one year after HT and 39 patients (63.9%) recovered within one to two years.

Recovery rate of testosterone. Overall, testosterone levels recovered in 61 patients (56.5%) and the median time of restoration to normal testosterone levels was 21.3 months (95%CI=14.7-28.0) (Figure 2). No cases reached normal testosterone levels after 39 months from cessation of HT (Figure 2). Univariate and multivariate analyses were performed to examine factors contributing to testosterone recovery after HT. The results showed that in the univariate analysis, age at the start of HT (OR=3.201; 95%CI=1.445-7.089, p=0.004) and duration of HT (OR=2.376; 95%CI=1.087-45.193, p=0.03) contributed to the recovery of testosterone levels (Table III). Furthermore, the results of multivariate analysis showed similar trends; age at the start of HT (OR=3.287; 95%CI=1.355-7.972, p=0.008) and duration of HT (OR=2.755; 95%CI=1.176-6.455, p=0.02) remained influential. Initial PSA, Gleason score, and prostate cancer risk classification had no effect on testosterone level recovery (Table III).

Figure 2.
Figure 2.

Cumulative rates of testosterone recovery defined as levels within the normal range. The median date of restoration to normal testosterone levels was 21.3 months (95%CI=14.7-28.0).

View this table:
Table III.

Univariate and multivariate logistic regression analysis of factors significantly associated with testosterone recovery.

Cumulative rates of testosterone recovery. There was a significant difference in the recovery of testosterone levels between patients aged 71 years or older and those aged <71 years at the start of HT (log-lank test, 95%CI=12.3-18.8 months, p=0.002). The median testosterone recovery time was 15.6 months in the cohort younger than 71 years. Along with age at initiation of HT, age at completion of therapy (74 years or older or younger) also significantly affected testosterone recovery (Figure 3). There was also a significant difference in the recovery of testosterone levels between patients who had been on HT for more than 34 months and those who had been on HT for less than 34 months (p=0.031) (Figure 4).

Figure 3.
Figure 3.

Cumulative rates of testosterone recovery by age. There was a significant difference in testosterone recovery time between patients aged ≥71 years and those aged <71 years (log-lank test, 95%CI=12.3-18.8 months, p=0.002). The median testosterone recovery time was 15.6 months in the cohort aged <71 years.

Figure 4.
Figure 4.

Cumulative rates of testosterone recovery by duration of hormone therapy administration. There was a significant difference in the recovery of testosterone levels between patients who received hormone therapy for ≥34 months and <34 months (p=0.031).

Discussion

This study investigated the use of IMRT combined with HT for the treatment of localized prostate cancer and the status of testosterone recovery after discontinuation of HT. The results showed that the overall recovery rate of testosterone after discontinuation of HT was 56.5%, and the factors contributing to testosterone recovery were duration of HT and age at the start of endocrine therapy. There was a significant difference in the recovery of testosterone levels when comparing patients receiving HT for more than 34 months and less than 34 months (p=0.031). There was also a significant difference in the recovery of testosterone levels between those aged over 71 years and those aged less than 71 years at the start of HT (p=0.002). Overall survival was good, and despite the high number of high-risk cases (69.4%), overall survival was high (98.2%), with no cancer deaths and only two deaths from other causes.

What is the optimal duration of HT in radiotherapy? When looking at overall survival as an outcome, there are some reports showing a better prognosis for the long-term combined HT group compared to the radiotherapy alone group, with a cut-off of one or two years (3-6). However, some reports indicate that prolonged HT of more than 2 years does not contribute to overall survival (7, 8). The discrepancy in the effectiveness of long-term duration of HT on overall survival may possibly be due to no consideration of testosterone. Maintaining testosterone levels in the castrate range by long-term administration of HT is expected to reduce recurrence and progression of prostate cancer. Fujimoto et al. reported that after discontinuation HT with radiotherapy the patients with higher testosterone levels showed significantly higher PSA recurrence than those with lower testosterone (9). Furthermore, they estimated that younger age and earlier testosterone recovery groups were at higher risk of PSA recurrence. Therefore, when radiotherapy is combined with HT, the age-appropriate duration of HT is important.

The age of Japanese patients with prostate cancer is older than in the rest of the world, with a median age of 74 years in our study. The older the patient, the slower testosterone recovery with HT is, and in our study the testosterone recovery rate was less than 50% in patients over 71 years of age. However, Nejat et al. conducted a prospective study and reported that the results of a short HT period (median 9 months; 3-122 months) showed that age at the time of HT administration did not affect testosterone recovery (10). Nam et al. investigated testosterone recovery during ADT treatment before and after total prostatectomy, and their results showed that the duration of ADT treatment (median 17 months) and age (age 66 years at the start of ADT) were significantly differentially related to testosterone recovery (11). In Japan, Egawa et al. reported that the duration of HT affects it (12). Depending on the length of treatment, age will affect testosterone recovery.

There have been reports on whether radiotherapy affects testosterone. Pompe et al. investigated the effects of external radiation on testosterone and biochemical recurrence (13). Surprisingly, radiation alone resulted in a reduction in testosterone levels in 75% of cases, while 63% of cases recovered to 90% of baseline testosterone levels. Approximately 45% were shown to have low testosterone levels in biochemical hypogonadism. There are reports that proton radiotherapy and brachytherapy alone have no effect on testosterone levels. However, cases with high baseline testosterone levels showed a decrease in testosterone with brachytherapy (14). Presumably, scattered radiation is responsible for the reduced function of Leydig cells. However, as radiotherapy alone is not expected to completely reduce testosterone levels to the castration zone, the synergistic effect of radiotherapy and HT should be used to enhance the effectiveness of local prostate cancer treatment.

There are various analyses of factors contributing to testosterone recovery after radiotherapy in combination with HT. Some reports suggest that the only factor contributing to recovery of testosterone levels is the duration of HT, while others suggest age, pre-treatment testosterone levels and the type of drug administered (10, 15). The duration of HT and age were involved in the present study, which is consistent with various reports. There have been reports of a decrease in Leydig cells and fibrosis of the surrounding tissue following administration of GnRH agonist. Therefore, it is thought that permanent impairment or suppression of Leydig cells may be induced in cases of long-term administration (16, 17). In our study, there were no cases in which testosterone levels recovered after 39 months. It should be considered that long-term HT may not permanently restore testosterone levels.

Adverse events (AEs) of HT should be noted, especially long-term administration is likely to induce a variety of AEs. Cardiovascular events due to HT have received more attention in the past. In particular, patients with prostate cancer are elderly, and cardiovascular complications are common at the start of treatment. GnRH agonists and antagonists are available for ADT treatment, but GnRH antagonists have been reported to induce fewer cardiovascular events than GnRH agonists and should be used, especially in patients with a history of cardiovascular events (18). Furthermore, long-term HT in elderly patients over 71 years of age, as shown in our study, may not allow testosterone levels to recover even after ADT treatment in some cases. Therefore, testosterone levels must be monitored after HT treatment and cardiovascular events must be kept in mind. It would be inexcusable for cancer treatment to be fatal owing to cardiovascular events, even when cancer control has been achieved.

Study limitations. First, the number of analyzed cases is small (n=108) and the analysis was retrospective. It is also a heterogeneous population with a risk classification breakdown of local prostate cancer that includes low and intermediate risk (3.7% and 26.9% respectively). However, the radiotherapy dose was unified at 76 Gy (38 fraction). All cases were confirmed on imaging to have localized cancer, but the PSA at diagnosis was in a slightly larger range (4.2-62.1 ng/ml). The duration of HT administration varied (12-145 months) and was at the discretion of the physicians. AEs from radiotherapy and HT were not detailed, but we understood that there were few AEs involving life expectancy, given that there were no deaths because of cancer. As cases of combined radiotherapy plus HT tend to be elderly patients with comorbidities, the incidence of AEs caused by HT should also be analyzed.

Conclusion

In many cases of relatively long-term HT, testosterone levels do not recover even after discontinuation of HT. The recovery rate of testosterone levels after the end of HT is low in patients who are older than 71 years at the start of HT and over 74 years old at the end of HT, and complications due to low testosterone levels should be considered.

Footnotes

  • Authors’ Contributions

    Yumiko Yokomizo and Hiroji Uemura: Conceptualization, data collection, methodology, writing–original draft, writing–review & editing. Yusuke Ito, Takashi Kawahara, Narihiko Hayashi, Kazuhide Makiyama, and Masaharu Hata: data analysis and discussion.

  • Conflicts of Interest

    The Authors have no conflicts of interest to declare in relation to this study.

  • Received April 4, 2024.
  • Revision received May 1, 2024.
  • Accepted May 7, 2024.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).

References

  1. ↵
    1. Crook JM,
    2. O’Callaghan CJ,
    3. Duncan G,
    4. Dearnaley DP,
    5. Higano CS,
    6. Horwitz EM,
    7. Frymire E,
    8. Malone S,
    9. Chin J,
    10. Nabid A,
    11. Warde P,
    12. Corbett T,
    13. Angyalfi S,
    14. Goldenberg SL,
    15. Gospodarowicz MK,
    16. Saad F,
    17. Logue JP,
    18. Hall E,
    19. Schellhammer PF,
    20. Ding K,
    21. Klotz L
    : Intermittent androgen suppression for rising PSA level after radiotherapy. N Engl J Med 367(10): 895-903, 2012. DOI: 10.1056/NEJMoa1201546
    OpenUrlCrossRefPubMed
  2. ↵
    1. Tsai HT,
    2. Penson DF,
    3. Makambi KH,
    4. Lynch JH,
    5. Van Den Eeden SK,
    6. Potosky AL
    : Efficacy of intermittent androgen deprivation therapy vs. conventional continuous androgen deprivation therapy for advanced prostate cancer: a meta-analysis. Urology 82(2): 327-333, 2013. DOI: 10.1016/j.urology.2013.01.078
    OpenUrlCrossRef
  3. ↵
    1. Feng FY,
    2. Blas K,
    3. Olson K,
    4. Stenmark M,
    5. Sandler H,
    6. Hamstra DA
    : Retrospective evaluation reveals that long-term androgen deprivation therapy improves cause-specific and overall survival in the setting of dose-escalated radiation for high-risk prostate cancer. Int J Radiat Oncol Biol Phys 86(1): 64-71, 2013. DOI: 10.1016/j.ijrobp.2012.11.024
    OpenUrlCrossRef
  4. ↵
    1. Shilkrut M,
    2. McLaughlin PW,
    3. Merrick GS,
    4. Vainshtein JM,
    5. Hamstra DA
    : Treatment outcomes in very high-risk prostate cancer treated by dose-escalated and combined-modality radiation therapy. Am J Clin Oncol 39(2): 181-188, 2016. DOI: 10.1097/COC.0000000000000043
    OpenUrlCrossRef
  5. ↵
    1. Liss AL,
    2. Abu-Isa EI,
    3. Jawad MS,
    4. Feng FY,
    5. Vance SM,
    6. Winfield RJ,
    7. Narayana V,
    8. Sandler HM,
    9. McLaughlin PW,
    10. Hamstra DA
    : Combination therapy improves prostate cancer survival for patients with potentially lethal prostate cancer: The impact of Gleason pattern 5. Brachytherapy 14(4): 502-510, 2015. DOI: 10.1016/j.brachy.2015.02.389
    OpenUrlCrossRef
  6. ↵
    1. Shilkrut M,
    2. Merrick GS,
    3. McLaughlin PW,
    4. Stenmark MH,
    5. Abu-Isa E,
    6. Vance SM,
    7. Sandler HM,
    8. Feng FY,
    9. Hamstra DA
    : The addition of low-dose-rate brachytherapy and androgen-deprivation therapy decreases biochemical failure and prostate cancer death compared with dose-escalated external-beam radiation therapy for high-risk prostate cancer. Cancer 119(3): 681-690, 2013. DOI: 10.1002/cncr.27784
    OpenUrlCrossRef
  7. ↵
    1. Kasuya G,
    2. Ishikawa H,
    3. Tsuji H,
    4. Nomiya T,
    5. Makishima H,
    6. Kamada T,
    7. Akakura K,
    8. Suzuki H,
    9. Shimazaki J,
    10. Haruyama Y,
    11. Kobashi G,
    12. Tsujii H, Working Group for Genitourinary Tumors
    : Significant impact of biochemical recurrence on overall mortality in patients with high-risk prostate cancer after carbon-ion radiotherapy combined with androgen deprivation therapy. Cancer 122(20): 3225-3231, 2016. DOI: 10.1002/cncr.30050
    OpenUrlCrossRef
  8. ↵
    1. Guarneri A,
    2. Botticella A,
    3. Filippi AR,
    4. Ruggieri A,
    5. Piva C,
    6. Munoz F,
    7. Ragona R,
    8. Gontero P,
    9. Ricardi U
    : Radical radiotherapy in high-risk prostate cancer patients with high or ultra-high initial PSA levels: a single institution analysis. J Cancer Res Clin Oncol 139(7): 1141-1147, 2013. DOI: 10.1007/s00432-013-1426-0
    OpenUrlCrossRef
  9. ↵
    1. Fujimoto N,
    2. Kubo T,
    3. Tomisaki I
    : Cessation of primary androgen deprivation therapy for men with localized prostate cancer. Clin Genitourin Cancer 13(4): 359-363, 2015. DOI: 10.1016/j.clgc.2015.02.013
    OpenUrlCrossRefPubMed
  10. ↵
    1. Nejat RJ,
    2. Rashid HH,
    3. Bagiella E,
    4. Katz AE,
    5. Benson MC
    : A prospective analysis of time to normalization of serum testosterone after withdrawal of androgen deprivation therapy. J Urol 164(6): 1891-1894, 2000.
    OpenUrlCrossRefPubMed
  11. ↵
    1. Nam W,
    2. Choi SY,
    3. Yoo SJ,
    4. Ryu J,
    5. Lee J,
    6. Kyung YS,
    7. Han JH,
    8. You D,
    9. Jeong IG,
    10. Hong JH,
    11. Ahn H,
    12. Kim CS
    : Factors associated with testosterone recovery after androgen deprivation therapy in patients with prostate cancer. Investig Clin Urol 59(1): 18-24, 2018. DOI: 10.4111/icu.2018.59.1.18
    OpenUrlCrossRef
  12. ↵
    1. Egawa S,
    2. Okusa H,
    3. Matsumoto K,
    4. Suyama K,
    5. Baba S
    : Changes in prostate-specific antigen and hormone levels following withdrawal of prolonged androgen ablation for prostate cancer. Prostate Cancer Prostatic Dis 6(3): 245-249, 2003. DOI: 10.1038/sj.pcan.4500675
    OpenUrlCrossRefPubMed
  13. ↵
    1. Pompe RS,
    2. Karakiewicz PI,
    3. Zaffuto E,
    4. Smith A,
    5. Bandini M,
    6. Marchioni M,
    7. Tian Z,
    8. Leyh-Bannurah SR,
    9. Schiffmann J,
    10. Delouya G,
    11. Lambert C,
    12. Bahary JP,
    13. Beauchemin MC,
    14. Barkati M,
    15. Ménard C,
    16. Graefen M,
    17. Saad F,
    18. Tilki D,
    19. Taussky D
    : External beam radiotherapy affects serum testosterone in patients with localized prostate cancer. J Sex Med 14(7): 876-882, 2017. DOI: 10.1016/j.jsxm.2017.04.675
    OpenUrlCrossRef
  14. ↵
    1. Taniguchi H,
    2. Kawakita S,
    3. Kinoshita H,
    4. Murota T,
    5. Matsuda T
    : Testosterone profiles after brachytherapy for localized prostate cancer. Urology 126: 121-127, 2019. DOI: 10.1016/j.urology.2019.01.022
    OpenUrlCrossRef
  15. ↵
    1. Pickles T,
    2. Agranovich A,
    3. Berthelet E,
    4. Duncan GG,
    5. Keyes M,
    6. Kwan W,
    7. McKenzie MR,
    8. Morris WJ, British Columbia Cancer Agency, Prostate Cohort Outcomes Initiative
    : Testosterone recovery following prolonged adjuvant androgen ablation for prostate carcinoma. Cancer 94(2): 362-367, 2002. DOI: 10.1002/cncr.10219
    OpenUrlCrossRefPubMed
  16. ↵
    1. Miller LR,
    2. Partin AW,
    3. Chan DW,
    4. Bruzek DJ,
    5. Dobs AS,
    6. Epstein JI,
    7. Walsh PC
    : Influence of radical prostatectomy on serum hormone levels. J Urol 160(2): 449-453, 1998.
    OpenUrlCrossRefPubMed
  17. ↵
    1. Kuber W,
    2. Viehberger G,
    3. Zeillinger R,
    4. Spona J
    : Effects of the duration of therapy with the LHRH agonist D-ser (BUT)6 Azgly10-LHRH (ICI 118-630) on the steroid hormone content and the morphology of human testicular tissue in the treatment of patients with advanced prostate cancer. Urol. Res. 19(1): 19-24, 1991. DOI: 10.1007/BF00294016
    OpenUrlCrossRefPubMed
  18. ↵
    1. Klotz L,
    2. Miller K,
    3. Crawford ED,
    4. Shore N,
    5. Tombal B,
    6. Karup C,
    7. Malmberg A,
    8. Persson B
    : Disease control outcomes from analysis of pooled individual patient data from five comparative randomised clinical trials of Degarelix versus Luteinising hormone-releasing hormone agonists. Eur Urol 66(6): 1101-1108, 2014. DOI: 10.1016/j.eururo.2013.12.063
    OpenUrlCrossRefPubMed
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Identification of Factors Contributing to Testosterone Recovery After Hormone Therapy Combined With External Radiation Therapy
YUMIKO YOKOMIZO, YUSUKE ITO, TAKASHI KAWAHARA, NARIHIKO HAYASHI, YASUHIDE MIYOSHI, KAZUHIDE MAKIYAMA, MASAHARU HATA, HIROJI UEMURA
In Vivo Jul 2024, 38 (4) 2074-2079; DOI: 10.21873/invivo.13666
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