Metabolic changes in patients with prostate cancer during androgen deprivation therapy

International Journal of Urology (2018) 25, 45--53 doi: 10.1111/iju.13473 Review Article Metabolic changes in patients with prostate cancer during androgen deprivation therapy Koji Mitsuzuka and Yoichi Arai Department of Urology, Tohoku University School of Medicine, Sendai, Japan Abbreviations & Acronyms ADT = androgen deprivation therapy CT = computed tomography CVD = cardiovascular disease GnRH = gonadotropinreleasing hormone HDL = high-density lipoprotein IPSS = International Prostate Symptom score LDL = low-density lipoprotein NA = not available QOL = quality of life Correspondence: Koji Mitsuzuka M.D., Ph.D., Department of Urology, Tohoku University School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan. Email: mitsuzuka@ uro.med.tohoku.ac.jp Received 1 June 2017; accepted 31 August 2017. Online publication 20 October 2017 Abstract: Androgen deprivation therapy continues to be widely used for the treatment of prostate cancer despite the appearance of new-generation androgen-receptor targeting drugs after 2000. Androgen deprivation therapy can alleviate symptoms in patients with metastatic prostate cancer and might have a survival benefit in some patients, but it causes undesirable changes in lipid, glucose, muscle or bone metabolism. These metabolic changes could lead to new onset or worsening of diseases, such as obesity, metabolic syndrome, diabetes mellitus, cardiovascular disease, sarcopenia or fracture. Several studies examining the influence of androgen deprivation therapy in Japanese patients with prostate cancer also showed that metabolic changes, such as weight gain, dyslipidemia or fat accumulation, can occur as in patients in Western countries. Efforts to decrease these unfavorable changes and events are important. First, overuse of androgen deprivation therapy for localized or elderly prostate cancer patients should be reconsidered. Second, intermittent androgen deprivation therapy might be beneficial for selected patients who suffer from impaired quality of life as a result of continuous androgen deprivation therapy. Third, education and instruction, such as diet or exercise, to decrease metabolic changes before initiating androgen deprivation therapy is important, because metabolic changes are likely to occur in the early androgen deprivation therapy period. Fourth, routine monitoring of weight, laboratory data or bone mineral density during androgen deprivation therapy are required to avoid unfavorable events. Key words: androgen deprivation therapy, metabolic change, obesity, prostate cancer, sarcopenia. Introduction Since Charles Huggins showed that surgical castration suppressed prostate cancer progression, 1 ADT, which almost completely inhibits testicular testosterone production surgically or medically, has been the mainstay of treatment for prostate cancer, despite the appearance of new-generation androgen-receptor targeting drugs, such as enzalutamide or abiraterone, in the 2010s. 2 ADT is now widely used for metastatic disease, as well as for localized or locally advanced disease, as neoadjuvant or adjuvant therapy with concurrent radiation therapy. Recently, the Japan Study Group of Prostate Cancer reported stage and treatment trends in Japanese patients with prostate cancer who were newly diagnosed as having prostate cancer in 2010. 3 In that study, >40% of patients received primary ADT. ADT can alleviate symptoms due to metastatic disease or prolong survival in conjunction with radiation therapy. However, it has a negative impact on lipid, glucose, muscle and bone metabolisms through decreases in testosterone levels, resulting in a large variety of adverse events, including obesity, metabolic syndrome, osteoporosis, sarcopenia, diabetes mellitus and cardiovascular disease. The present review focuses on negative impacts of ADT, especially the metabolic changes (Fig. 1), and discusses how we can reduce these unfavorable changes or events in patients with prostate cancer. Metabolic changes during ADT Weight gain Weight gain is one of the major metabolic changes caused by ADT, and it varied from 0.6% to 3.8% in previous studies in which the duration of ADT ranged from 3 to 12 months (Table 1). 4 14 Weight increased consistently during 1 year of ADT, but weight change was 2017 The Japanese Urological Association 45

K MITSUZUKA AND Y ARAI Lipid metabolism Androgen deprivation therapy Glucose metabolism Bone metabolism Muscle metabolism Dyslipidemia Hyperglycemia Bone loss Sarcopenia Metabolic syndrome Metabolic changes caused by ADT are associated with the incidence of metabolic syndrome. Braga-Basaria et al. found that more than half of the men receiving long-term (at least 12 months) ADT had metabolic syndrome compared with one-fifth of the men in the control groups. 20 Recently, Bosco et al. carried out a meta-analysis of metabolic syndrome caused by ADT and showed that ADT significantly increased the risk of metabolic syndrome (relative risk 1.75). 21 Fig. 1 Obesity/metabolic syndrome Diabetes mellitus Cardiovascular disease not measured beyond 1 year of ADT in most studies. Only one study showed weight change over 1 year of ADT, and the weight in the healthy cohort and prostate cancer patients without ADT was stable or slightly decreased during the 3-year study period, but the median weight change in patients with prostate cancer treated with ADT was +1.38 kg at 12 months, and it continued to increase to +2.57 kg at 24 months, and then it decreased to +2.30 kg at 36 months. 12 Weight gain was significantly higher in patients aged <65 years. Seible et al. examined factors associated with weight gain after 1 year of ADT. 13 They found that age <65 years, body mass index <30 kg/m 2 and non-diabetic status were risk factors for weight gain on univariate analyses, and that age <65 years and body mass index <30 kg/m 2 were independent predictors of weight gain on multivariate analysis. Lipid and glucose metabolism Osteoporosis Fracture Fall/frail A schema that shows metabolic changes as a result of ADT. As well as weight gain, several studies showed a mean increase of 3.2 10.6% in total cholesterol and 3.8 46.6% in triglycerides, with the duration of ADT ranging from 24 weeks to 12 months (Table 1). 5,6,8 11,14 17 These changes in lipid and glucose levels were noticeable in the first 3 or 6 months of ADT (Figs 2,3). 6,10,11,14,17 Only one study compared the differences in lipid profile according to treatment modality. 17 The study showed that there were no significant differences between GnRH agonist alone and maximal androgen blockade with bicalutamide. ADT also affects sugar metabolism, and it is associated with worsening blood sugar control and the incidence of diabetes mellitus. 5,8,9,11,14,18 Smith et al. reported that ADT decreased insulin sensitivity and increased serum insulin levels in patients who received 12 weeks of ADT. 9 These changes in lipid and glucose metabolism are related to the risk of type 2 diabetes mellitus. Keating et al. carried out an observational study of 37 443 population-based men who were diagnosed with local or regional prostate cancer. Of these, 14 597 (39%) were treated with ADT. The incidence of diabetes mellitus was 159.4 events per 1000 person-years for the ADT group and 87.5 events for the no-adt group (adjusted hazard ratio 1.28). 19 Bone metabolism ADT increases bone turnover and bone loss, resulting in a decrease in bone mineral density and an increase in the incidence of osteoporosis or fracture. Previous studies showed that bone mineral density decreases by 2 8% in the first year, 22 24 which exceeds that of postmenopausal women, who experience an annual bone loss of 2.5%. 25 The prevalence of osteoprosis during ADT was reported to be 9 53% in a meta-analysis by Lassermillante et al. 26 This large variation was partially explained by treatment duration, disease stage, ethnicity and site of osteoporosis measurement. The duration of ADT is closely related to a decrease of bone mineral density or the prevalence of osteoprosis. Morote et al. reported that the rate of normal bone mineral density decreased from 19.4% in hormone-naive patients to 17.8% after 2 years of ADT, 16.4% after 4 years, 10.8% after 6 years, 5.7% after 8 years and 0% after 10 years of ADT, and the osteoporosis rate increased from 35.4% in hormone-naive patients to 42.9% after 2 years of ADT, 49.2% after 4 years, 59.5% after 6 years, 65.7% after 8 years and 80.6% after 10 years. 27 The study based on the Surveillance Epidemiology and End Results and Medicare database showed the incidence of facture among 50 613 men who received a diagnosis of prostate cancer in the period from 1992 through 1997. 28 Of men surviving at least 5 years after diagnosis, 19.4% of those who received ADT had a fracture, as compared with 12.6% of those not receiving ADT (P < 0.001). Body composition (sarcopenic obesity) ADT increases fat accumulation concurrently with a decrease in lean mass, while methods of measuring fat or lean mass were different among the studies (Table 2). 5 7,9 11,14,18,29,30 In several studies, accumulation of adipose tissue was more noticeable in subcutaneous fat than in visceral fat in patients treated with ADT, whereas visceral fat increases predominantly compared with subcutaneous fat in usual metabolic syndrome. Smith et al. measured the cross-sectional area of subcutaneous and visceral fat by CT and showed that subcutaneous fat increased by 11.1%, but intra-abdominal fat did not change significantly in patients treated with ADT for 48 weeks. 6 We also confirmed this phenomenon in an observational study that measured areas of subcutaneous and visceral fat using CT in 88 patients who underwent 1-year treatment with ADT. In that study, the median increases in visceral and subcutaneous fat were 21.2% and 29.8%, 46 2017 The Japanese Urological Association

Metabolic changes by androgen deprivation therapy Table 1 Changes in lipid and sugar metabolic profiles by androgen deprivation therapy Study Region Year design No. patients Indications Methods of ADT ADT duration Age, years (mean or median) Weight Abdominal circumference Triglyceride (%) Total cholesterol (%) LDL cholesterol (%) HDLcholesterol (%) Fasting blood sugar (%) Hemoglobin A1c (%) Nowicki M Poland 2001 Prospective 18 Stage D GnRH agonists with et al. 4 flutamide Smith UK 2001 Prospective 22 Non-metastatic GnRH agonists (21) JC et al. 5 Orchiectomy (1) Smith USA 2002 Prospective 32 No bone GnRH agonists with MR et al. 6 metastasis bicalutamide Smith MR 7 USA 2004 Prospective 79 Non-metastatic GnRH agonists or orchiectomy with or without anti-androgen Nishiyama T Japan 2005 Prospective 49 Non-metastatic GnRH agonists or et al. 8 orchiectomy with flutamide 12 weeks 67 +2.7 kg (3.8%) 3 months 67 Unchanged +13.3 +3.2 2.3 +8.3 +3.5 48 weeks 66 +2.3 kg (2.4%) +26.5 +9.0 +7.3 +11.3 48 weeks 71 +1.4 kg (1.8%) 6 months 69 +0.5 kg (8.3%) +8.2 +6.1 +5.0 +3.5 Smith MR USA 2006 Prospective 25 Non-metastatic GnRH agonists with Japan 2011 Prospective 39 Any stage GnRH agonists with or 12 months 71 +1.8 kg (2.3%) +1.9% +46.6 +11.2 +9.0 +2.3 +0.3 +3.0 12 weeks 68 +0.6 kg (0.4%) +23.0 +9.4 +8.7 +9.9 +2.0 +2.9 et al. 9 bicalutamide Torimoto K 12 months 74 +1.37 kg +2.0 cm +14.1 +4.1 +14.8 3.2 et al. 10 without bicalutamide Hamilton EL Australia 2011 Prospective 26 Non-metastatic NA et al. 11 Timilshina N Canada 2012 Prospective 257 Non-metastatic GnRH agonists 12 months 71 +1.32 kg (1.5%) 36 months 69 +2.30 kg (2.8%) et al. 12 monotherapy (93%) Seible DM USA 2014 Retrospective 118 Non-metastatic GnRH agonists et al. 13 Mitsuzuka K Japan 2016 Prospective 177 Any stage GnRH agonists with or Norway 1995 Prospective 26 Benign prostate 12 months 75 +2.9% +3.0% +16.2 +10.6 +14.3 +7.8 +3.9 +2.7 et al. 14 without bicalutamide Eri LM GnRH agonists 24 weeks 70 +26.9 +10.6 Unchanged +8.2 et al. 15 hyperplasia Dockery F et al. 16 UK 2003 Prospective 12 NA GnRH agonists 3 months 71 +14.5 +7.3 +0.3 +20.0 Salvador C Spain 2013 Prospective 33 Locally et al. 17 advanced or metastatic GnRH agonists with or without bicalutamide 12 months 73 +3.8 +7.6 +0.9 14.7 Cheung AS Australia 2016 Prospective 34 Non-metastatic NA 12 months 68 +5.0% 3.40 1.7 et al. 18 2017 The Japanese Urological Association 47

K MITSUZUKA AND Y ARAI 40% 30% 20% 10% 0% 0 3 6 Months 9 12 Fig. 2 Mean increase in total, LDL and HDL cholesterol, and in triglycerides during 1 year of ADT. 14, Total cholesterol;, HDL cholesterol;, LDL cholesterol;, Triglyceride. 10.0% 8.0% 6.0% 4.0% 2.0% 0.0% 0 3 6 Months 9 12 Fig. 3 Mean increase in fasting blood sugar and hemoglobin A1c during 1 year of ADT. 14, Fasting blood sugar;, Hemoglobin A1c. respectively (P = 0.028). 14 Cheung et al. reported that ADT increased fat mass, but visceral fat was unchanged after 12 months of ADT using dual-energy X-ray. 18 Although a predominant increase in subcutaneous fat compared with visceral fat was not seen in all studies, and methods of measuring fat or lean mass were not consistent among the studies, the mechanisms of ADT-related obesity might be different from those of usual obesity. Sarcopenia caused by ADT has not been as well studied as weight gain, but several studies reported the effect of ADT on lean mass. In 2004, Smith et al. reported that the percent lean mass deceased by 3.8% after 1 year of ADT using dualenergy X-ray. 7 In another study, they compared changes in thigh muscle area using CT between patients treated with leuprolide and patients treated with bicalutamide monotherapy, and they showed that thigh muscle area decreased 2.7% in the leuprolide group and 2.2% in the bicalutamide group. 22 Recently, Chang et al. studied muscle attenuation in 39 men using CT measurement of the rectus femoris, sartorius and quadriceps muscles. There was a significant decrease in the muscle cross-sectional area of the sartorius, quadriceps and rectus femoris muscles, with decreases of 21.8%, 15.4% and 16.6%, respectively. 31 The skeletal changes caused by ADT lead to impairments in physical function or QOL. Alibhai et al. showed that endurance, upper extremity strength and physical components of QOL were affected within 3 months of starting ADT. 32 Furthermore, these changes in body compositions (sarcopenic obesity) as a result of ADT might be related to an increase of risk of fall or frailty. Wu et al. reported that the incidence rates of falls were significantly higher in patients treated with ADT (13.37 per 1000 person-years) than those without ADT (6.44 per 1000 person-years). 33 Winters-Stone et al. examined the prevalence of falls and frailty in prostate cancer survivors who were current, past or never users of ADT. 34 Current or past ADT users had twice as many recurrent falls (P < 0.001) and more fall-related injuries than unexposed men (P = 0.01). Furthermore, current (43%) or past (40%) ADT users were more likely to be classified as prefrail or frail than never users (15%; P < 0.001). Incidence of cardiovascular disease These metabolic changes might lead to cardiovascular events, but the association between ADT and cardiovascular disease is controversial. In 2006, Keating et al. reported that ADT increased the risks of coronary heart disease, myocardial infarction and sudden death in patients aged >65 years with prostate cancer in 2006. 35 In 2010, they again showed that ADT was associated with an increased risk of diabetes and cardiovascular disease in men of all ages with prostate cancer in an observational study of 37 443 population-based men who were diagnosed with local or regional prostate cancer in the Veterans Healthcare Administration. 19 In 2013, they examined the influence of comorbidities on CVD risk in a population-based observational study of 185 106 USA men aged 66 years diagnosed with local/regional prostate cancer from 1992 to 2007, including 49.9% of patients who were treated with ADT and 50.1% of patients who were treated without ADT. 36 Among men with no comorbidities, ADT was associated with an increase in myocardial infarction (adjusted hazard ratio 1.09), whereas among patients with comorbidities, such as previous myocardial infarction, congestive heart failure, peripheral arterial disease, stroke, hypertension, chronic obstructive pulmonary disease and renal disease, CVD risks increased similarly regardless of ADT use. Several recent studies also showed relationships between CVD risks and comorbidities in patients treated with ADT. In a trial of 206 men with localized but unfavorable-risk prostate cancer randomized to radiation therapy or to radiation therapy plus 6 months of ADT, cardiac death occurred in 13 patients in each treatment group. In those who received ADT, most cardiac deaths occurred among those with moderate-to-severe comorbidities. 37 In contrast, other groups did not find an association between ADT and CVD risks. Alibhai et al. carried out a matched-cohort study comparing patients aged 66 years with prostate cancer given 48 2017 The Japanese Urological Association

Metabolic changes by androgen deprivation therapy Table 2 Changes in body composition by androgen deprivation therapy Region Year Study design No. patients Indications Methods of ADT ADT duration Age, years (mean or median) Methods Visceral fat Subcutaneous fat Lean mass Smith JC UK 2001 Prospective 22 Non-metastatic GnRH agonists (21) et al. 5 Orchiectomy (1) Smith MR et al. 6 metastasis USA 2002 Prospective 32 No bone GnRH agonists with bicalutamide Smith MR USA 2004 Prospective 52 Non-metastatic Leuprolide (50%) et al. 29 Bicalutamide (50%) Lee H USA 2005 Prospective 65 Including et al. 30 previous ADT (35%) Smith MR 7 USA 2004 Prospective 79 Non-metastatic GnRH agonists or orchiectomy with or without antiandrogen Smith MR et al. 9 bicalutamide USA 2006 Prospective 25 Non-metastatic GnRH agonists with Torimoto K Japan 2011 Prospective 39 Any stage GnRH agonists with et al. 10 3 months 67 Bioelectrical impedance analysis +8.4% (fat mass) 2.7% (lean mass) 48 weeks 66 CT (L4 level) 0.3% +11.1% 3.2% (paraspinal muscle) 12 months 52 Dual-energy X-ray GnRH agonist 12 months 66 Dual-energy X-ray or without bicalutamide 48 weeks 71 Dual-energy X-ray 12 weeks 68 Dual-energy X-ray 12 months 74 Bioelectrical impedance analysis Leuprolide +11.2% (fat mass) Bicalutamide +6.4% (fat mass) Leuprolide 3.6% (lean mass) Bicalutamide 2.4% (lean mass) +6.6% (fat mass) 2.0% (lean mass) +11.0% (fat mass) 3.8% (lean mass) +4.3% (fat mass) 1.4% (lean mass) +2.08 kg (fat mass) +17.24 cm 2 (visceral fat) Hamilton EL Australia 2011 Prospective 26 Non-metastatic NA 12 months 71 CT (L4-5) +22% +13% et al. 11 0.57 kg (lean mass) Mitsuzuka K Japan 2016 Prospective 177 Any stage GnRH agonists with et al. 14 or without bicalutamide Dual-energy X-ray 12 months 75 CT (umbilical level) Cheung AS Australia 2016 Prospective 34 Non-metastatic NA 12 months 68 Dual-energy X-ray et al. 18 +14% (fat mass) 3-6% (lean mass) +21.2% +29.8% 8.0% (psoas muscle) +3.5 kg (fat mass) Unchanged (visceral fat) 1.49 kg (lean mass) Data not published. 2017 The Japanese Urological Association 49

K MITSUZUKA AND Y ARAI continuous ADT for at least 6 months or who underwent bilateral orchiectomy with patients with prostate cancer who had never received ADT. They showed that, although ADT treatment was associated with an increased risk of diabetes mellitus (hazard ratio 1.16), neither use of ADT nor duration of ADT treatment was associated with an increased risk of myocardial infarction or sudden cardiac death. 38 Thus, metabolic changes by ADT were confirmed in many previous studies, but whether these changes lead to CVD events has not yet been determined, probably because of differences in patient populations, study design or selection bias in men offered ADT among the studies. 39 Interestingly, Jespersen et al. reported that ADT increased the risk of myocardial infarction and stroke, but orchiectomy did not increase these risks. 40 GnRH agonists might have a direct role on the cardiac receptors regulating cardiac contractile function and lead to a dysfunction of this system. 41 Impacts of ADT on metabolic status in Asian men Weight gain/lipid and glucose metabolism Onozawa et al. investigated the initial therapy of 8291 newly diagnosed prostate cancer patients in 2010 who were registered in a Japanese multi-institutional observation study. 3 ADT was most frequently used as the initial therapy (40.2%) for newly diagnosed prostate cancer patients, but information about ADT-related adverse effects is sparse in Japanese patients. Metabolic changes caused by ADT were considered to be lower in Japanese patients than in Caucasian patients, possibly because the prevalence of severe obesity or metabolic syndrome is lower in Asian countries than in Western countries. 42 However, some Japanese studies showed that significant changes in metabolism can occur in Japanese patients. Nishiyama et al. described metabolic changes among 49 Japanese patients who received 6 months of ADT in 2005. 8 In that study, the mean increase in weight was 0.8%, and the mean increases in total cholesterol, HDL cholesterol, triglycerides, and fasting blood sugar were 6.1%, 5.0%, 8.2% and 3.5%, respectively. Torimoto et al. described the effects of ADT on lipid metabolism and body composition as measured by bioelectrical impedance analysis among 32 Japanese patients who received 1 year of ADT. 10 In that study, the weight increase was 1.37 kg, and increases in total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides were 4.1%, 14.8%, 3.2% and 14.1%, respectively. We recently carried out a prospective observational study that examined changes in lipid and glucose metabolism and body composition in Japanese patients with prostate cancer. 14 In that study, patients with prostate cancer who were hormone-naive and scheduled to receive long-term ADT were recruited between 2011 and 2013. Of 177 patients who completed 1 year of ADT, mean increases in bodyweight and abdominal circumference were 2.9% and 3.0%, respectively. Mean increases in total, LDL cholesterol, HDL cholesterol, and triglycerides were 10.6%, 14.3%, 7.8% and 16.2%, respectively. Mean increases in fasting blood sugar and hemoglobin A1c were 3.9% and 2.7%, respectively. Lipid alterations were noted in patients without comorbidities, whereas changes in hemoglobin A1c were noted in patients with diabetes mellitus at baseline. These lipid and glucose alterations were prominent in the early ADT period. Both visceral and subcutaneous fat, as measured by CT, increased by >20%. The increase was significantly greater in subcutaneous fat than in visceral fat (P = 0.028). These studies showed that metabolic changes caused by ADT could be similar in Japanese patients and Caucasian patients, but the incidence of diabetes mellitus or cardiovascular events in Japanese patients might not always be similar to that in Caucasian patients, because the possible risks of diabetes mellitus or cardiovascular events including insulin sensitivity, prevalence of obesity, metabolic syndrome and diabetes mellitus among the general population or genetic status might differ between Japanese and Caucasian populations. 43 Bone metabolism In 2004, Miyaji et al. showed that bone mineral density significantly decreased from 0.966 to 0.937 g/cm 2 (P = 0.047) after 2 years of ADT in 27 patients with prostate cancer without bone metastasis. 44 Two Japanese cross-sectional studies showed a prevalence of osteoporosis in patients treated with ADT. Wang et al. measured the bone mineral density in the lumbar spine, total hip, and femoral neck in the hormone-naive and ADT-treated prostate cancer patients. 45 The rate of osteoporosis in the hormone-na ıve and ADT-treated prostate cancer patients was 2.3% (1/43) and 8.6% (5/58), respectively (P = 0.294). Yuasa et al. reported that the rate of osteoporosis in patients who were hormone-naive, ADT-treated for <2 years, and ADT-treated for >2 years was 4.5% (4/88), 12.1% (4/33) and 10.8% (4/37), respectively. 46 They showed that the ADT-treated patients had significantly lower bone mineral density, T-scores and Z-scores than the hormone-naive patients, but there was no concomitant significant increase in the prevalence of osteoporosis in the ADT-treated patients who had been treated with ADT for an average of 30.7 months. Future studies are expected to clarify whether the incidence of osteoporosis, fracture, diabetes mellitus or CVD in Japanese patients treated with ADT are similar to those of Caucasian patients. Differences between GnRH agonist and antagonist Several studies examined the differences in clinical outcomes between GnRH agonist and antagonist, but the differences have not been clearly elucidated. Albertsen et al. analyzed the six phase III prospective randomized trials and concluded that the risk of cardiac events within 1 year of initiating therapy was significantly lower for treatments with GnRH antagonists than for treatments with GnRH agonists in patients with preexisting CVD. 47 However, the study was a post-hoc analysis of the six phase III trials, and did not provide convincing evidence to show a clear superiority of GnRH antagonist, because the inclusion criteria and the intervention dosage was heterogenous, and the primary end-point was not the incidence of CVD. 48 A few basic studies showed possibilities of mechanisms of differences between GnRH agonists and antagonists; 50 2017 The Japanese Urological Association

Metabolic changes by androgen deprivation therapy GnRH receptors that exist on T cells or in the urinary tract might play significant roles. 49,50 One interesting study using a mouse model showed that fat accumulation, decreased glucose tolerance and formation of aortic atherosclerotic plaque were less noticeable in mice treated with GnRH antagonists than in those treated with orchiectomy or GnRH agonists. 51 Management of metabolic changes during ADT (metabolic health) Overuse of ADT Adverse effects of ADT have been widely recognized by physicians, and now interest regarding the adverse effects of ADT is moving to how we can decrease them. The most important issue is to select appropriate patients who really need ADT. As previously described, approximately 40% of Japanese patients with newly diagnosed prostate cancer underwent primary ADT. 3 Furthermore, the percentage of primary ADT in patients aged >80 years and with low-risk prostate cancer was 59%. Such overuse of ADT for patients who might not need ADT should be reconsidered when considering ADT-related adverse effects. Intermittent ADT Intermittent ADT might have some merits compared with continuous ADT. In 2000, Egawa et al. performed a pilot study of intermittent ADT in Japanese men with advanced prostate cancer. 52 They showed that bone mineral density was normal for age in 10 of 17 patients at 23 months following intermittent ADT. Calais et al. showed that intermittent ADT did not decrease overall survival and caused no clinical impairment in QOL, and patients had better sexual activity and considerable economic benefit. 53 Crook et al. assessed overall survival and QOL in patients who had prostate-specific antigen recurrence after radiotherapy and received intermittent or continuous ADT. Although median overall survival was not significantly different between patients treated with intermittent and continuous ADT, QOL factors including physical function, fatigue, urinary symptoms, hot flashes, sexual activity and erections improved with intermittent therapy. 54 Recently, Rezaei et al. reported that the incidence of metabolic syndrome in patients treated with 12 months of intermittent ADT was 14.7%, which was lower than the incidence in previous studies of continuous ADT. 55 Although no studies have directly compared the effects of intermittent ADT on metabolic changes with those of continuous ADT, intermittent ADT could be an option for patients with undesirable QOL impairment with continuous ADT. Instruction or education before initiating ADT Instruction or education for patients treated with ADT is also very important to avoid unfavorable metabolic changes or events during ADT. Metabolic changes by ADT are noticeable in the early period of ADT, and the Swedish group recently showed that the risk of cardiovascular events was highest in the first 6 months. 56 Therefore, such instruction or education should be carried out before initiating ADT, especially for patients who have risk factors, such as diabetes mellitus or previous CVD. Several studies showed the utility of exercise to decrease or prevent the metabolic changes as a result of ADT. In 2003, Segal et al. carried out a randomized trial that studied the effects of 12 weeks of resistance exercise on ADT-related adverse effects. They showed that resistance exercise reduced fatigue and improved QOL and muscular fitness in patients treated with ADT compared with no exercise intervention. 57 Recently, Cormie et al. also carried out a randomized trial to determine if supervised exercise minimizes treatment toxicity as a result of ADT. They showed that a 3-month exercise program prevented gains in fat mass, and maintained cardiovascular fitness, muscular strength, lower body function or serum cholesterol level compared with usual care. 58 Thus, exercise intervention seems to be effective to reduce adverse effects derived from ADT, but exercise type, intensity, frequency and duration differed among the studies, and need to be further examined in future studies. 59 Monitoring or intervention during ADT Monitoring or intervention for metabolic changes during ADT is, of course, essential. Routine measurements of weight, laboratory data including lipid or sugar levels, blood pressure and bone mineral density are necessary to avoid unfavorable events. If the metabolic changes are significant, repeat instructions including diet or exercise and intervention using medications should be considered. Regarding bone loss, denosumab has been shown to increase the lumbar bone mineral density by 5.6% and reduce vertebral fracture using a 60-mg regimen every 6 months. 60 Bisphosphonate has been also shown to increase bone mineral density, but an optimal regimen or effectiveness in prevention of a skeletal-related event in a hormone-sensitive prostate cancer has not been determined. 61,62 Conclusions The use of ADT might be expected to continue in the future despite the appearance of new-generation androgen receptor targeting drugs or chemotherapy agents. Many existing studies have shown that ADT has non-negligible changes through suppressing testosterone almost completely. Prostate cancer has a relatively better prognosis than other malignancies, and it also has aspects of chronic disease even when metastatic. We physicians need to be conscious of metabolic health, which means avoiding unfavorable results as a result of ADT, as well as maintaining cancer control. Metabolic changes can occur in Japanese patients with prostate cancer treated with ADT, but subsequent events, such as diabetes mellitus, cardiovascular events, sarcopenia or fracture, need to be further investigated. Future studies should be planned to elucidate the associations between ADT and such events in Japanese patients with prostate cancer. Conflict of interest None declared. 2017 The Japanese Urological Association 51

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