Adverse effects of androgen deprivation therapy in men with prostate cancer: a focus on metabolic and cardiovascular complications

Prostate cancer (PCa) is the most common malignancy in men. Prostate being an androgen responsive tissue, androgen deprivation therapy (ADT) is used in the management of locally advanced (improves survival) and metastatic (improves pain and quality of life) PCa. Over the past two decades, the use of ADT has significantly increased as it is also being used in patients with localized disease and those experiencing biochemical recurrences, though without any evidence of survival advantage. Hypogonadism resulting from ADT is associated with decreased muscle mass and strength, increased fat mass, sexual dysfunction, vasomotor symptoms, decreased quality of life, anemia and bone loss. Insulin resistance, diabetes and cardiovascular disease have recently been added to the list of these complications. As the majority of men with PCa die of conditions other than their primary malignancy, recognition and management of these adverse effects is paramount. Here we review data evaluating metabolic and cardiovascular complications of ADT.     

Considerations for the use of gonadotropin-releasing hormone agonists and antagonists in patients with prostate cancer

Prostate cancer is the second most common cause of cancer-related deaths in men, representing a major source of morbidity and mortality. Androgen deprivation therapy is the primary treatment for patients with advanced prostate cancer at disease presentation, which can be achieved either with surgical or chemical castration. The development of gonadotropin-releasing hormone agonists revolutionized the treatment of advanced prostate cancer, replacing the need for surgical castration. Agonists downregulate gonadotropin-releasing hormone agonist receptors in the pituitary gland, and thus decrease the release of luteinizing hormone and testosterone. Although agonists are a common therapeutic option to date, their use is associated with testosterone surges, metabolic dysfunction and an increase in the risk of cardiovascular disease; they might contribute to tumor flares and potentially an increase in non-cancer mortality. More recently, gonadotropin-releasing hormone antagonists have entered the prostate cancer treatment landscape. Unlike agonists, antagonists directly inhibit the androgen receptor in the pituitary gland, and thus do not cause initial testosterone surges. In this article, we provide a concise review of the mechanism of actions, safety and efficacy of the approved agonists and antagonists for prostate cancer treatment.     

雄激素剥夺治疗前列腺癌引起的骨代谢变化

雄激素剥夺治疗(androgen deprivation therapy,ADT)是治疗转移性前列腺癌(PCa)的基石,显著延长了PCa患者生存期.然而在ADT治疗的PCa患者中,每年平均骨密度下降2％～10％,导致骨折发病率、相关发病率和死亡率增加,应该引起临床医师的注意.这种骨代谢状态,目前认为主要是雄激素、雌激素...     

Use of androgen deprivation therapy for metastatic prostate cancer in older men

OBJECTIVE

To assess factors associated with early or delayed androgen deprivation therapy (ADT) among men diagnosed with metastatic prostate cancer, and to assess the relationship between ADT and overall survival, as there is uncertainty about the ideal timing for initiating ADT in men with metastatic prostate cancer.

PATIENTS AND METHODS

We studied a population‐based cohort of American men aged ≥66 years diagnosed with metastatic prostate cancer during 1992–2002 and followed to 2003. We assessed the receipt of ADT early (≤4 months from diagnosis), delayed (>4 months), or not at all, using multinomial logistic regression to identify factors associated with treatment, and Cox proportional‐hazard models to assess whether treatment was associated with survival.

RESULTS

Overall, 69.5% of men received early ADT and 7.3% delayed. Adjusted rates of early ADT were lower for black than white men (58.3% vs 71.0%), and of delayed ADT were higher for black than white men (12.7% vs 6.2%). Receipt of ADT was associated with improved survival (adjusted hazard ratio 0.69, 95% confidence interval 0.66–0.73). The benefit of early treatment did not differ from delayed treatment (P = 0.58).

CONCLUSIONS

A large minority of men with metastatic prostate cancer, particularly black men, receive delayed or no ADT. Early or delayed ADT was associated with similarly prolonged survival. After controlling for patient and tumour characteristics, survival did not differ by race, and receipt of ADT did not contribute to racial differences in survival.     

Effect of androgen deprivation therapy on quality of life in Japanese men with prostate cancer

OBJECTIVE: We evaluated health-related quality of life (HRQOL) in Japanese men receiving androgen deprivation therapy (ADT) for prostate cancer. METHODS: Fifty-six men were enrolled in this study. HRQOL was prospectively measured before ADT, and at 3, 6 and 12 months after treatment began, using a general (36-item Short-Form Health Survey) and disease-specific (the University of California, Los Angeles Prostate Cancer Index) HRQOL questionnaire. RESULTS: In the general HRQOL questionnaire, patients with stage B (n = 22) or C (n = 17) disease showed a decline in vitality at 6 and 12 months (P < 0.05 for both). Stage D patients (n = 17) had improvements in bodily pain at 3 and 12 months (P < 0.05 for both), vitality at 12 months (P < 0.05), role-emotional at 6 months (P < 0.05), and mental health at 3 months (P < 0.05). When clinical stages were not considered, there were no significant changes in the 36-item Short-Form Health Survey. As for the disease-specific HRQOL, urinary function improved after ADT at 6 and 12 months (P < 0.05 for both), and urinary bother decreased at 3 (P < 0.05), 6 (P < 0.005) and 12 months (P < 0.05). Sexual function decreased at 3 (P < 0.05), 6 (P < 0.005) and 12 months (P < 0.005) but sexual bother improved at 6 and 12 months (P < 0.05 for both). If patients were stratified by clinical stages, similar findings were observed. CONCLUSIONS: General HRQOL was mostly unaffected by ADT in Japanese men. Disease-specific questions indicated an increase in urinary function. Although deterioration of sexual function was marked, most patients did not report sexual bother. Our results shed new light on the impact of ADT on HRQOL and could provide useful information about patient-centered outcome evaluations.     

Preventive effect of risedronate on bone loss in men receiving androgen-deprivation therapy for prostate cancer

AIM: Androgen-deprivation therapy for prostate cancer decreases bone mineral density and increases the risk of fracture. The effect of risedronate, a potent third-generation oral bisphosphonate, on bone loss during androgen deprivation therapy was investigated. METHODS: Sixty-one prostate cancer patients with a mean age (+/- SD) of 79 +/- 6 years who had received androgen deprivation therapy for 42 +/- 29 months were enrolled, and were treated with 2.5 mg of risedronate daily for six months. Bone mineral density was measured at the femoral neck, lumbar spine, and ultradistal radius by dual energy X-ray absorptiometry. The percent change of bone mineral density after treatment with risedronate was calculated as the primary efficacy variable. Urinary N-telopeptide of type I collagen was measured as a bone resorption marker. RESULTS: Bone mineral density remained stable in the femoral neck and radius during risedronate therapy. In contrast, the bone mineral density of the lumbar spine showed a significant increase from 1069 +/- 488 mg/cm(2)-1112 +/- 497 mg/cm(2) (P < 0.001), representing a gain of 4.9 +/- 8.9%. Urinary N-telopeptide of type I collagen decreased significantly (P < 0.001) after three months of risedronate treatment. CONCLUSIONS: Risedronate could prevent and reverse bone loss in men receiving androgen deprivation therapy for prostate cancer by inhibiting bone resorption.     

中国汉族人群家族性前列腺癌的初步研究

目的:以中国汉族人群为研究对象,估计家族性前列腺癌的发病率,分析家族史对于前列腺癌发生的作用及家族性前列腺癌的临床和病理学特点。方法:回顾性分析我院2014年7月～2016年7月行穿刺并证实为前列腺癌的598例患者的一级亲属前列腺癌家族史。采取病例对照研究分析前列腺癌家族史对于前列腺癌发生的作用,病例组选择年龄56～79岁的495例前列腺癌患者,对照组选择同期接受穿刺且结果为前列腺增生的患者,匹配条件为年龄、民族(汉)和居住地相同。通过比较两组发病年龄、BMI、确诊时的PSA中位数、肿瘤分期、Gleason评分、D’Amico危险因素分级和首要治疗方式,来探究家族性前列腺癌患者和散发性前列腺癌患者临床病理学特点的差异。结果:年龄56～79岁且具有前列腺肿瘤家族史的患者,其前列腺癌发病率显著高于同年龄无前列腺癌家族史的人群(RR=3.0,P=0.010)。598例在我院穿刺并确诊为前列腺癌的患者中,有25例(4.2%)是家族性前列腺癌患者。和散发性前列腺癌患者相比,家族性前列腺癌患者中分级属低或中度危险分级的比例更高,但差异无统计学意义(P>0.05),并且家族性前列腺癌患者更愿意接受根治手术作为其首要治疗方式(P<0.05)。结论:在中国,家族性前列腺癌发生率远低于西方国家。前列腺癌家族史显著增加中国男性前列腺癌的发病风险。家族性与散发性前列腺癌之间并无显著的临床及病理学差异,但家族性前列腺癌患者更愿意接受根治手术作为首要的治疗方式。     

去势抵抗性前列腺癌新型内分泌治疗耐药机制研究进展

前列腺癌是男性泌尿生殖系统最常见的恶性肿瘤之一,雄激素在其发生发展中都扮演着重要角色。经去势治疗(ADT)后绝大多数前列腺癌都会进展成为去势抵抗性前列腺癌(CRPC)。肾上腺来源的雄激素和(或)雄激素受体(AR)的改变(包括AR基因扩增)驱动了瘤内雄激素的合成,进而重新雄激素轴信号通路。目前,阿比特龙、恩扎鲁胺等抗雄激素治疗药物都是CRPC患者的一线治疗用药。但是,治疗一段时间后患者仍然会出现耐药和疾病进展。因此,明确CRPC患者抗雄激素治疗耐药机制可以为克服CRPC治疗耐药和改善CRPC患者的预后提供契机。     

Androgen deprivation in combination with radical prostatectomy for localized prostate cancer

Radical prostatectomy is the only potential modality for cure in patients with localized prostate cancer. However, the lack of reliable and accurate clinical staging frequently leads to incomplete excision of tumor, with the consequences of early local recurrence or distant metastasis. Thus, the role of neoadjuvant or adjuvant hormonal treatment has been investigated in improving disease-free or cause-specific survival. This review reports the current status and problems of such androgen deprivation in combination with radical prostatectomy for localized prostate cancer.     

Use of androgen deprivation therapy in prostate cancer: indications and prevalence

Androgens play a prominent role in the development, maintenance and progression of prostate cancer. The introduction of androgen deprivation therapies into the treatment paradigm for prostate cancer patients has resulted in a wide variety of benefits ranging from a survival advantage for those with clinically localized or locally advanced disease, to improvements in symptom control for patients with advanced disease. Controversies remain, however, surrounding the optimal timing, duration and schedule of these hormonal approaches. Newer hormonal manipulations such as abiraterone acetate have also been investigated and will broaden treatment options for men with prostate cancer. This review highlights the various androgen-directed treatment options available to men with prostate cancer, their specific indications and the evidence supporting each approach, as well as patterns of use of hormonal therapies.     

Non‐steroidal antiandrogen monotherapy compared with luteinizing hormone‐releasing hormone agonists or surgical castration monotherapy for advanced prostate cancer: a Cochrane systematic review

To assess the effects of non‐steroidal antiandrogen monotherapy compared with luteinizing hormone‐releasing hormone agonists or surgical castration monotherapy for treating advanced hormone‐sensitive stages of prostate cancer. We searched the Cochrane Prostatic Diseases and Urologic Cancers Group Specialized Register (PROSTATE), the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, Web of Science with Conference Proceedings, three trial registries and abstracts from three major conferences to 23 December 2013, together with reference lists, and contacted selected experts in the field and manufacturers. We included randomized controlled trials comparing non‐steroidal antiandrogen monotherapy with medical or surgical castration monotherapy for men in advanced hormone‐sensitive stages of prostate cancer. Two review authors independently examined full‐text reports, identified relevant studies, assessed the eligibility of studies for inclusion, extracted data and assessed risk of bias as well as quality of evidence according to the GRADE working group guidelines. We used Review Manager 5.2 for data synthesis and the fixed‐effect model as primary analysis (when heterogeneity was low with I² < 50%); we used a random‐effects model when confronted with substantial or considerable heterogeneity (when I² ≥50%). A total of 11 studies involving 3060 randomly assigned participants were included in the present review. Use of non‐steroidal antiandrogens resulted in lower overall survival times (hazard ratio [HR] 1.24, 95% confidence interval [CI] 1.05–1.48, six studies, 2712 participants) and greater clinical progression (1 year: risk ratio [RR] 1.25, 95% CI 1.08–1.45, five studies, 2067 participants; 70 weeks: RR 1.26, 95% CI 1.08–1.45, six studies, 2373 participants; 2 years: RR 1.14, 95% CI 1.04–1.25, three studies, 1336 participants), as well as treatment failure (1 year: RR 1.19, 95% CI 1.02–1.38, four studies, 1539 participants; 70 weeks: RR 1.27, 95% CI 1.05–1.52, five studies, 1845 participants; 2 years: RR 1.14, 95% CI 1.05–1.24, two studies, 808 participants), compared with medical or surgical castration. The quality of evidence for overall survival, clinical progression and treatment failure was rated as moderate according to GRADE. Use of non‐steroidal antiandrogens increased the risk for treatment discontinuation as a result of adverse events (RR 1.82, 95% CI 1.13–2.94, eight studies, 1559 participants), including events such as breast pain (RR 22.97, 95% CI 14.79– 35.67, eight studies, 2670 participants) and gynaecomastia (RR 8.43, 95% CI 3.19–22.28, nine studies, 2774 participants) The risk of other adverse events, such as hot flushes (RR 0.23, 95% CI 0.19–0.27, nine studies, 2774 participants) was decreased when non‐steroidal antiandrogens were used. The quality of evidence for breast pain, gynaecomastia and hot flushes was rated as moderate according to GRADE. The effects of non‐steroidal antiandrogens on cancer‐specific survival and biochemical progression remained unclear. Non‐steroidal antiandrogen monotherapy compared with medical or surgical castration monotherapy for advanced prostate cancer is less effective in terms of overall survival, clinical progression, treatment failure and treatment discontinuation resulting from adverse events. Evidence quality was rated as moderate according to GRADE; therefore, further research is likely to have an important impact on results for patients with advanced but non‐metastatic prostate cancer treated with non‐steroidal antiandrogen monotherapy.     

Germline CAG repeat length of the androgen receptor and time to progression in patients with prostate cancer treated with androgen deprivation therapy

Study Type – Prognosis (retrospective cohort) Level of Evidence 2b What’s known on the subject? and What does the study add? Germline CAG repeat polymorphisms in the androgen receptor (AR‐CAG) have been shown to influence the activity of the androgen receptor, but there has been conflicting data from small retrospective studies evaluating the effect of CAG repeat polymorphisms on response to ADT. This is the largest published study to date investigating the association of germline AR‐CAG repeat lengths and efficacy of ADT in prostate cancer. Germline AR‐CAG repeat lengths do not predict response to ADT.

OBJECTIVES

? Germline CAG repeat polymorphisms in the androgen receptor (AR‐CAG) have been shown to influence the activity of the AR. ? The purpose of the present study was to determine if AR‐CAG repeat length correlates with time to progression on androgen deprivation therapy (ADT).

PATIENTS AND METHODS

? Germline AR‐CAG repeat lengths were determined in a cohort of 480 patients with recurrent or metastatic prostate cancer treated at a single tertiary care institution and correlated to time to progression (TTP) and overall survival.

RESULTS

? There was no significant correlation between differences in the AR‐CAG repeat lengths and TTP or overall survival in patients with prostate cancer receiving ADT. ? AR‐CAG repeat lengths did not significantly correlate with age, prostate‐specific antigen (PSA), Gleason score or clinical stage at diagnosis. ? In patients with metastatic disease, longer AR‐CAG repeat lengths (>23 vs ≤23) were associated with a longer TTP on ADT, but this finding was of borderline significance (median TTP 18.3 vs 15.5 months, P= 0.09; adjusted HR = 0.76, 95% confidence interval = 0.54–1.09).

CONCLUSIONS

? This is the largest published study to date investigating the association of germline AR‐CAG repeat lengths and efficacy of ADT in prostate cancer. ? Germline AR‐CAG repeat lengths do not predict response to ADT.     

Prognostic significance of genetic polymorphisms in disease progression and survival in prostate cancer after androgen deprivation therapy

It is believed that androgens and their receptors regulate normal prostate growth and mediate prostate cancer development. Androgen deprivation therapy is the most commonly used treatment for advanced prostate cancer. Although the therapy is initially effective, progression of the disease to castration-resistant prostate cancer is almost inevitable, leading to treatment failure. Despite the existence of current clinical parameters, new biomarkers are urgently needed to improve the prognosis. Some molecules and DNA-based genetic biomarkers are under investigation as potential prognostic factors. The advancement in molecular cytogenetic research, such as genome-wide association for single-nucleotide polymorphisms, has made possible the detection of genetic mutations. In this study, a literature search from August 1985 to April 2013 was performed through the PubMed database using the keywords “genetic polymorphisms”, “prostate cancer” and “androgen deprivation therapy”. The results revealed that several genome-wide association studies (such as rs16901979, rs7931342, HSD17B4, rs6162 in the CYP17A1, rs4243229 and rs7201637 in the HSD17B2, rs1062577 in the ESR1, SLCO1B3, SLCO2B1, rs2939244 in the ARRDC3, rs9508016 in the FLT1, rs6504145 in the SKAP1, rs7830611 in the FBXO32, rs9508016 in the FLT1, rs12529 in the AKR1C3, rs16934641 in the BNC2, rs3763763 in the TACC2, rs2051778 in the ALPK1, and rs3763763 in the TACC2, AR, ESR1, and ESR2) and single-nucleotide polymorphisms in important pathways (such as androgen signal, biosynthesis, metabolism, androgen receptor binding site, response element, androgen receptor CAG repeat polymorphism length, and estrogen receptor-binding sites) involved in prostate cancer occurrence and mechanism could serve as candidate biomarkers for the early detection of castration-resistant prostate cancer after androgen deprivation therapy. Additional investigations are required to decipher precisely the gene combinations and personalize the management of prostate cancer.     

Hormone therapy for prostate cancer and the risk of stroke: a 5-year follow-up study

Study Type – Therapy (outcomes) Level of Evidence 2c What's known on the subject? and What does the study add? Numerous studies have consistently reported that long‐term use of ADT for PC may increase the risk of fractures, metabolic syndrome and cardiovascular diseases. There was no significant difference in risk of stroke between ethnic Chinese PC patients who did and did not receive ADT.

OBJECTIVE

• ? To examine the 5‐year risk of stroke among patients with prostate cancer (PC) receiving androgen deprivation therapy (ADT) in Taiwan, using a population‐based dataset.

PATIENTS AND METHODS

• ? This prospective case–control study used data sourced from the Longitudinal Health Insurance Database.
• ? The study included 365 patients with PC; 64 (17.6%) received ADT for more than 1 month.
• ? Cox proportional hazards regression was used to evaluate the association between ADT and the risk of stroke during the subsequent 5‐year follow‐up period, after adjusting for sociodemographic characteristics and hypertension, diabetes, coronary heart disease, heart failure, atrial fibrillation and hyperlipidaemia.

RESULTS

• ? In the total sample of 365 patients with PC, 68 (18.6%) patients had strokes during the 5‐year follow‐up period. These included 11 patients with PC who received ADT (17.2% of all patients who received ADT) and 57 patients who did not receive ADT (18.9% of patients who did not receive ADT).
• ? After adjusting for potential confounders, no significant difference in the hazard of stroke was found between patients with PC who did and did not receive ADT (hazard ratio, 1.09; 95% confidence interval, 0.80–1.50).

CONCLUSION

• ? There was no significant difference in the risk of stroke between ethnic Chinese patients with PC who did and did not receive ADT, after adjusting for potential confounders.

     

Increased risk of a herpes zoster attack in patients receiving androgen deprivation therapy for prostate cancer

This study aimed to examine the association of herpes zoster (HZ) with androgen deprivation therapy (ADT) use among patients with prostate cancer (PC), using a population‐based data set. The study sample for this study was retrieved from the Taiwan Longitudinal Health Insurance Database 2005. We selected 877 patients with PC who had received ADT as the study group, while 849 patients with PC who had not received ADT served as the comparison group. Each study patient was individually tracked for a 3‐year period to discriminate those who subsequently received a diagnosis of HZ. Of the total 1,726 sampled patients, the incidence rate of HZ per 100 person‐years was 1.80 (95% CI: 1.41–2.25) during the 3‐year follow‐up period. In particular, incidence rates of HZ per 100 person‐years were 2.36 (95% CI: 1.75–3.13) and 1.24 (95% CI: 0.81–1.81), respectively, for patients with PC who had and those who had not received ADT. Furthermore, Cox proportional hazard regressions showed that the adjusted hazard ratio for an HZ attack during the 3‐year follow‐up period for patients with PC who had received ADT was 1.88 (95% CI: 1.13–3.11) than those who had not received ADT. We concluded that patients with PC who had received ADT had an increased risk of HZ.