Improving Flexibility and Quality of Life for Your Patients: A Must?

3.2.1. Side-effects of androgen deprivation therapy 

Although ADT has beneficial effects, it may also induce side-effects [7]. Until recently, most studies have focused on the short-term symptomatic side-effects such as hot flushes, loss of libido and erectile dysfunction, fatigue, and psychological effects such as emotional instability or depression [8], [9], [10]. Recently, however, it has become clear that a substantial part of ADT's related morbidity comes from long-term side-effects that are mostly hidden for the patient [8], including accelerated bone loss leading eventually to osteoporosis and potentially fractures [7]. In addition, ADT may lead to lipid changes, obesity or an increase in fatty tissue, loss of muscle mass, and many of the features of a metabolic syndrome such as increased subcutaneous mass, increased high-density lipoprotein (HDL) cholesterol, and increased adiponectin levels [7], [9]. One of the causes of these metabolic changes during ADT is the rapid induction of peripheral resistance to insulin, which may lead to type 2 diabetes mellitus [10], [11].

The metabolic changes associated with ADT may also have significant consequences for the cardiovascular health of ADT-treated men. Population-based studies have shown that ADT indeed increases the risk of diabetes and cardiovascular morbidity [12], [13], [14]. For instance, in an observational study including 73 196 men with locoregional PCa, it was shown that ADT-treated patients had statistically significantly higher rates of incident coronary heart disease, myocardial infarction (MI), and sudden cardiac death (SCD) than patients receiving no hormone treatment (Fig. 1) [12]. The rate of incident diabetes was also statistically significantly higher in ADT-treated men versus men receiving no ADT (29% vs 20.9%, respectively; p<0.001). However, a recent analysis of the phase 3 European Organisation for Research and Treatment of Cancer (EORTC) 22861 trial, which included 415 patients with locally advanced PCa, suggested that long-term adjuvant ADT to radiation therapy (RT) does not increase cardiovascular toxicity over RT alone [15]. Long-term ADT was given by means of an LHRH agonist over a period of 3 yr; the median follow-up was 9.1 yr. The 10-yr cumulative incidence of cardiovascular mortality was 11.1% for patients treated with RT alone and 8.2% for patients treated with RT and long-term adjuvant ADT (hazard ratio: 1.11; 95% confidence interval, 0.59–2.09; p=0.75). Although the difference in outcome between these two studies may be partly the result of the inclusion of different study populations, further research is needed to determine the effect of ADT on cardiovascular morbidity and to identify men at highest risk of these adverse events.

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Fig. 1. Rate of incident coronary heart disease, myocardial infarction, and sudden cardiac death in prostate cancer patients receiving androgen-deprivation therapy (ADT) or no treatment [12].

Next to the previously discussed side-effects, ADT may also affect cognitive function. Studies on older or hypogonadal men suggest that testosterone has a significant impact on cognitive performance, such as visuospatial abilities, verbal fluency, memory, and working memory [16]. A systematic literature review, including nine clinical trials evaluating the impact of ADT on cognitive function, showed that, overall, between 47% and 69% of ADT-treated patients declined in at least one cognitive area, most commonly in visuospatial abilities and executive functioning [16]. However, some studies reported contradictory results, with increased functioning in verbal memory. It should be noted that although these studies were designed relatively well, they generally only included a small number of patients.

3.2.2. Managing side-effects of androgen deprivation therapy 

Because the side-effects of ADT can not only be bothersome and seriously affect QoL but also potentially cause serious medical problems, they should be carefully monitored. In addition, appropriate actions need to be taken to prevent and manage side-effects, and in this regard, physicians should adopt a proactive attitude. Before initiation of ADT and also during ADT, the physician should assess the general risk on developing potential consequences of ADT, such as diabetes, cardiovascular disease, or osteoporosis. For example, before and during ADT, the physician should closely monitor the patient's bone mineral density (BMD) in order to assess the risk of osteoporosis and to be able to provide early treatment [17]. Early measurement of BMD can be done by dual energy x-ray absorptiometry. The spine is the preferred site for the serial measurement of bone mass to monitor changes in BMD. The hip can be used as an alternative when the spine is technically inaccessible. Interdisciplinary panels have attempted to provide recommendations for monitoring and treatment of osteoporosis [18]. These expert panels recommend BMD assessment of patients before initiation of ADT and regular follow-up during treatment. As ADT may also induce several endocrinologic and cardiovascular diseases, a colleague endocrinologist or internist can also be consulted to assist in the diagnosis and treatment of these problems.

Patients and their family should be informed about the potential side-effects of ADT as early as possible, which may help them recognise, prevent, and manage these effects. For example, explaining to the patient that he may experience problems with his memory may help him cope with this side-effect. Introducing the patient to some moderate, practical, and realistic beneficial dietary and lifestyle changes may promote general health during ADT and may moreover prevent some of the side-effects [17]. For example, dietary advice may help patients adopt a healthy diet to minimise ADT-related metabolic changes, cardiovascular side-effects, and osteoporosis. Physical exercise may prevent or minimise the decrease in BMD and increase in body mass. Furthermore, physical exercise may help fight fatigue, alleviate anxiety and depression, and improve QoL. For patients >65 yr, supplementation with calcium and vitamin D should be discussed to prevent osteoporosis [17].

One side-effect of ADT that may severely bother the patient are hot flushes, also referred to as hot flashes. Hot flushes are one of the most frequent side-effects of ADT, with up to 80% of patients describing it [10]. Mild to moderate hot flushes can in most cases be managed with lifestyle changes such as wearing loose clothing of natural fibres, avoiding food or beverages that trigger hot flushes, and avoiding large temperature changes [17]. However, in moderate-to-severe hot flushes, drug therapy may be required. A number of treatments have been used in the management of hot flushes, such as megestrol acetate, cyproterone acetate, and low-dose diethylstilbestrol. Unfortunately, many of these treatments have little evidence supporting their use, and many are based on the treatment of hot flushes in women [10]. An interesting recent development in the treatment of hot flushes comes from studies evaluating gabapentin, a drug originally developed to treat epilepsy but currently mainly used for the relief of pain. A 4-wk double-blind trial compared gabapentin (at doses of 300, 600, or 900mg/d) with placebo for treatment of hot flushes in 214 PCa patients on stable ADT experiencing bothersome hot flushes [19]. Frequency and severity of hot flushes were assessed by means of a questionnaire. A hot flush score was computed by assigning points (1, mild; 2, moderate; 3, severe; 4, very severe) to each hot flush based on reported severity, summing the points for each day, and averaging daily scores across each week of the study. Fig. 2 shows the median percent decrease from baseline in hot flush frequency and score after 4 wk of treatment with placebo and gabapentin. The change from baseline in hot flush frequency after 4 wk of treatment with the highest gabapentin dose (900mg/d) was statistically significantly different from that with placebo (p=0.02). The difference between placebo and 900mg/d of gabapentin in change from baseline in hot flush score approached statistical significance (p=0.10). Gabapentin may thus decrease hot flushes, to a moderate degree, in ADT-treated men.

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Fig. 2. The median percent decrease from baseline in hot flush frequency and hot flush score after 4 wk of treatment with placebo or gabapentin 300, 600, or 900mg/d [19].

Other recent developments in the prevention and treatment of some ADT side-effects are selective oestrogen receptor modulators, such as raloxifene and toremifene. In an ongoing 24-mo double-blind, randomised, placebo-controlled phase 3 trial, Smith et al evaluate whether toremifene (80mg/d) could prevent incident morphometric vertebral fractures in 1392 ADT-treated PCa patients [20]. An interim analysis of the first 197 subjects after 12 mo of treatment showed that toremifene statistically significantly increased the BMD of the hip and spine (Table 1). Although this conclusion needs to be confirmed by the final results of this trial, these interim results suggest that toremifene may decrease the risk of fractures in ADT-treated men. In the same study, the effect of toremifene on fasting serum lipids was assessed. An interim analysis at 12 mo in 188 patients showed that toremifene (80mg/d) improved lipid profiles in men receiving ADT compared to placebo. Toremifene statistically significantly decreased mean total cholesterol, low-density lipoprotein cholesterol, and triglycerides and increased HDL cholesterol versus placebo (Table 2) [21]. Although further research is required, toremifene may prevent the loss of bone mass and changes in lipid profile associated with ADT and may therefore prevent osteoporosis and cardiovascular disease.

Table 1. Toremifene (80mg/d) statistically significantly increases the bone mineral density of the lumbar spine, total hip, and femoral neck compared to placebo in men treated with androgen-deprivation therapy [20]

	Change (± SD) from baseline at 12 mo (%)	Toremifene (n=93)	Placebo (n=104)	p value
	Lumbar spine BMD	+1.6%±0.4%	−0.7%±0.3%	<0.001
	Total hip BMD	+0.7%±0.6%	−1.3%±0.3%	0.001
	Femoral neck BMD	+0.2%±0.4%	−1.3%±0.4%	0.009

SD=standard deviation; BMD=bone mineral density.

Table 2. Toremifene (80mg/d) statistically significantly improves the lipid profile of men treated with androgen deprivation therapy compared to placebo [21]

	Change (± SD) from baseline at 12 mo (%)	Toremifene (n=89)	Placebo (n=99)	p value
	Total cholesterol	−8.1%±1.4%	−1.0%±1.7%	0.001
	LDL cholesterol	−8.2%±2.5%	+0.8%±2.5%	0.003
	HDL cholesterol	+0.5%±2.2%	−4.9%±1.2%	0.018
	Triglycerides	−13.2%±3.6%	+6.9%±4.2%	0.003

SD=standard deviation; LDL=low-density lipoprotein; HDL=high-density lipoprotein.