The Association Between Hot Flashes and Renal Dysfunction after Androgen Deprivation Therapy with Radiotherapy in Japanese Patients with High-Risk Prostate Cancer - Beyond the Abstract

Androgen deprivation therapy (ADT) is the major treatment for progressive prostate cancer (PCa). Although ADT has been shown to improve oncological outcomes,1 it is associated with a non-negligible risk of important side effects.1-3 There are numerous well recognized adverse effects of ADT, which include hot flashes (HF), loss of libido, fatigue, gynecomastia, anemia, and osteoporosis. In addition, obesity, insulin resistance, and dyslipidemia were recently suggested to be potential metabolic complications of ADT.4 The long-term use of ADT also has deleterious effects on cardiovascular health.5 Although it has been reported that the use of ADT is significantly associated with an increased risk of acute kidney injury (AKI) in patients with newly diagnosed non-metastatic PCa (mPCa),6 there have been few studies about the outcomes of renal function after the discontinuation of ADT. We reported that renal dysfunction occurred relatively early during ADT and that hypertensive PCa patients that receive ADT are at high risk of developing renal dysfunction.7 Furthermore, we reported that the discontinuation of ADT tended to result in improvements in renal function and that the renal dysfunction caused by 6 months’ ADT is transient.8 However, to the best of our knowledge, no studies have been performed to assess renal function after 2 years of ADT. It would be very interesting to examine whether renal function improves after prolonged ADT.

Therefore, we investigated the trends and characteristics of renal function in Japanese patients with high-risk PCa who underwent radiotherapy and long-term ADT.

This was a retrospective study based on data extracted from electronic records. Patients that underwent prostate biopsy examinations (PBx) at the Department of Urology, Teikyo University Chiba Medical Center (Ichihara, Japan), between April 2009 and August 2015 were included in this study. All of the patients who participated in this study had been pathologically diagnosed with PCa and had undergone ADT for 24 months and radiotherapy for stage B or C disease. The standard treatment for high-risk PCa at our institution involves ADT for 6 months, followed by radiotherapy, and then ADT for a further 18 months. Regarding the ADT, all of the patients received 24 months of treatment with a luteinizing hormone-releasing hormone (LH-RH) agonist (10.8 mg goserelin acetate or 11.25 mg leuprolide acetate). An oral non-steroidal antiandrogen (80 mg bicalutamide daily) was administered at the initiation of ADT, and combined androgen blockade (CAB) was also performed. The rate of change in the estimated glomerular filtration rate (ΔeGFR) was used to evaluate renal function in each period. The ΔeGFR was calculated using the following formula: (eGFR at 1/3/6/12/18/24/36 months-pretreatment eGFR)/pretreatment eGFR×100). We investigated the following factors as potential risk factors for renal dysfunction after 24 months’ ADT and at 12 months after the discontinuation of ADT (at 36 months): age; the levels of PSA, testosterone, and hemoglobin; clinical stage, body mass index, the Gleason score, the presence/absence of HF, the presence/absence of hypertension, the presence/absence of diabetes mellitus, and the presence/absence of dyslipidemia.

Thirty-six patients who underwent ADT for 24 months and radiotherapy were evaluated in this study. Regarding the presence/absence of renal dysfunction at 36 months, renal dysfunction was observed in 27 of the 36 cases (75%). During the ADT, the patients’ eGFR tended to decrease until 24 months but increased during the period from 24 to 36 months (Figure 1). Multivariate analysis showed that the presence/absence of HF (odds ratio=7.77, 95% confidence interval=1.4-76.1, p=0.0172) was an independent predictor of renal dysfunction at 36 months. In a comparison of the estimated ΔeGFR with the measured ΔeGFR, at 12 months after the discontinuation of ADT the measured ΔeGFR was insignificantly lower than the estimated ΔeGFR but tended to have increased (Figure 2).

Figure 1. The rate of change in renal function during 24 months of androgen deprivation therapy (ADT) and after the discontinuation ADT (24-36 months) in patients with high-risk prostate cancer. There was no statistically significant change in the ΔeGFR during the ADT.
 
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This was the first study to investigate the changes in renal function that occur after the discontinuation of ADT in Japanese patients with high-risk PCa. Moreover, it was confirmed that 75% of the patients treated with ADT for 24 months exhibited reduced renal function at 12 months after the discontinuation of ADT; i.e., at 36 months. We previously reported that renal dysfunction due to ADT for PCa occurs early in the course of treatment.7 Moreover, we reported that the renal dysfunction caused by 6 months’ ADT is transient.8 However, in the present study renal function tended to decrease after ADT, and it was suggested that renal function may improve after the discontinuation of ADT in Japanese high-risk PCa patients. Specifically, our findings indicated that the renal dysfunction induced by 24 months’ ADT is temporary. The current study revealed that renal dysfunction is unlikely to occur in the presence of HF. Therefore, it is suggested that there is a strong association between ADT-related renal dysfunction and testosterone. Investigating the relationship between the levels of testosterone and the eGFR would be of great interest. In the future, we consider that we will be able to clarify the relationship between improvements in renal function and the recovery of testosterone levels after the discontinuation of ADT. The presence/absence of HF was identified as a predictor of renal dysfunction after ADT. The presence/absence of HF after ADT was identified as a predictor of renal dysfunction at 12 months after the discontinuation of ADT. It is very important to explain to patients that ADT can cause renal dysfunction before ADT is performed and that presence/absence of HF is a predictor of such renal dysfunction.

Figure 2. Comparison between the measured ΔeGFR and estimated ΔeGFR. The measured ΔeGFR tended to increase from 24 to 36 months.

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Written by: Hiroshi Masuda MD, Department of Urology, Teikyo University Chiba Medical Center, Chiba, Japan.

References:

  1. Sharifi N, Gulley JL, Dahut WL. Androgen deprivation therapy for prostate cancer. JAMA 294(2): 238–244, 2005. PMID: 16014598. DOI: 10.1001/jama.294.2.238
  2. Shahinian VB, Kuo YF, Freeman JL, et al. Increasing use of gonadotropin-releasing hormone agonists for the treatment of localized prostate carcinoma. Cancer 103(8): 1615–1624, 2005. PMID: 15742331. DOI: 10.1002/cncr.20955
  3. Keating NL, O’Malley AJ, Freedland SJ, et al. Does comorbidity influence the risk of myocardial infarction or diabetes during androgen-deprivation therapy for prostate cancer? Eur Urol 64(1): 159–166, 2013. PMID: 22537796. DOI: 10.1016/j.eururo.2012.04.035
  4. Hamed A, Siamak D. Androgen deprivation therapy for prostate cancer: long-term safety and patient outcomes. Patient Related Outcome Measures 5: 63–70, 2014. PMID: 25045284. DOI: 10.2147/PROM.S52788
  5. Hamed A, Siamal D. Androgen deprivation therapy: evidence-based management of side effects. BJU Int 111(4): 543–548, 2013. PMID: 23351025. DOI: 10.1111/j.1464-410X.2012.11774.x
  6. Lapi F, Azoulay L, Niazi MT, et al. Androgen deprivation therapy and risk of acute kidney injury in patients with prostate cancer. JAMA 310(3): 289–296, 2013. PMID: 23860987. DOI: 10.1001/jama.2013.8638
  7. Masuda H, Sugiura M, Hou K, et al. Impact of hypertension on early renal dysfunction in Japanese prostate cancer patients treated with androgen deprivation therapy. Cancer Diagn Progn 1(3): 179-183, 2021. DOI: 10.21873/cdp.10024
  8. Masuda H, Fujimoto A, Kanesaka M, et al. Renal function improves after the discontinuation of androgen deprivation therapy in Japanese patients with prostate cancer. Anticancer Research 41(9):4443-4446, 2021. PMID: 34475067. DOI: 10.21873/anticanres.15252

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