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National Collaborating Centre for Cancer (UK). Prostate Cancer: Diagnosis and Treatment. Cardiff (UK): National Collaborating Centre for Cancer (UK); 2014 Jan. (NICE Clinical Guidelines, No. 175.)

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Prostate Cancer: Diagnosis and Treatment.

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7Hormone therapy

7.1. Introduction

The function of hormone therapy is to stop testosterone feeding prostate cancer and encouraging growth. Treatment is long-term, usually continuous and is often for several years.

There are two main methods of achieving control of prostate cancer by hormonal manipulation: (i) androgen deprivation (using luteinising hormone-releasing hormone agonists (LHRHa) or bilateral orchidectomy), which removes the supply of endogenous hormone; or (ii) androgen receptor blockade (anti-androgens), which reduces the effect of endogenous hormones. Both forms of therapy have proven efficacy for different states of the disease. Each method has associated morbidity and potentially specific impacts on the individual’s quality of life.

7.2. Neoadjuvant and adjuvant hormone therapy

Recommendations on neoadjuvant and adjuvant hormone therapy can be found in section 6.2.1.

7.3. Hormone therapy in metastatic disease

Recommendations on hormone therapy in metastatic disease can be found in sections 8.28.5.

Uncertainty exists as to whether continuous hormone treatment is always required; if intermittent hormone therapy was at least as effective at controlling prostate cancer the side-effects might be less. However, despite this, there is concern about stopping continuous treatment for fear of a detrimental effect and allowing disease progression.

Clinical question: Is intermittent hormone therapy as effective as continuous hormone therapy in men receiving long-term hormonal therapy for prostate cancer?

Clinical evidence (see also full evidence review) (2014)

Evidence statements

The evidence for all pre-specified outcomes is summarised in Table 50.

Table 50. GRADE profile: is intermittent hormone therapy as effective as continuous hormone therapy in men receiving long-term hormonal therapy for prostate cancer?

Table 50

GRADE profile: is intermittent hormone therapy as effective as continuous hormone therapy in men receiving long-term hormonal therapy for prostate cancer?

Overall survival

Moderate quality evidence from six randomised trials shows no significant difference in overall survival between men treated with intermittent hormone therapy and those treated with continuous hormone therapy (p=0.17; only five included in meta-analysis).

Progression-free survival (not biochemical)

Low quality evidence from two randomised trials found no significant difference in progression-free survival between intermittent and continuous therapy. However, both trials included both clinical and biochemical progression in their definition of disease progression. Three studies also provided very low quality evidence of no significant difference in progression-free survival between intermittent and continuous treatment groups for clinical progression.

Adverse events

One moderate quality study found the incidence of treatment-emergent adverse events to be borderline significantly higher in the continuous treatment group (p=0.042) (Mottet et al. 2009, 2013). However, two further studies provided low quality evidence of no significant difference in the rates of adverse events between groups but provided no figures. Crook (2011, 2012) and Duncan (2011) also reported no significant difference between treatment arms in the rate of cardiovascular events or osteoporotic fractures (but did not provide figures). While Hering et al. (2000) observed fewer mild adverse events (gastrointestinal, gynaecomastia and fatigue) and severe adverse events (severe nausea/vomiting and oedema of the lower limb) with intermittent than with continuous therapy (relative risk (RR) 0.29 and 0.15 respectively).

Low quality evidence from two randomised trials suggests that hot flushes are significantly less likely with intermittent than with continuous hormone therapy. While both studies reported fewer hot flushes with intermittent therapy (RR 0.66 and 0.97 respectively) there is uncertainty about the size of the effect due to heterogeneity.

Moderate quality evidence from one randomised trial (Calais da Silva et al. 2009, 2003, 2011a, 2011b) shows gynaecomastia is less likely in men treated with intermittent than with continuous hormone therapy (RR 0.64 95% CI 0.43–0.93). The evidence suggests that for every 100 men treated with intermittent instead of continuous therapy there would be seven fewer cases of gynaecomastia. Crook (2011, 2012) and Duncan (2011) also reported patients receiving intermittent had significantly less gynaecomastia than those receiving continuous therapy but no effect size was reported (p<0.001).

Low quality evidence from one randomised trial (Calais da Silva et al. 2009, 2003, 2011a, 2011b) suggests sexual activity within the previous month was more likely during intermittent therapy than during continuous therapy (RR 2.90 95% CI 1.52–5.53). The evidence suggests for every 100 men treated with intermittent instead of continuous therapy there would be an additional 18 reporting sexual activity within the previous month. Low quality evidence from another randomised trial (Hering et al. 2000) found impotence was much less likely in men receiving intermittent than in those on continuous therapy (RR 0.06 95% CI 0.01–0.28). While Crook (2011, 2012) and Duncan (2011) reported that patients receiving intermittent had significantly greater desire for sexual activity and better erectile function than those receiving continuous therapy but no effect sizes reported (p<0.001). Miller et al. (2007) also found self-assessed sexual activity to be better with intermittent therapy (but no effect sizes were reported).

Health-related quality of life

Very low quality evidence from five randomised trials suggests better quality of life with intermittent than with continuous therapy. The studies reported that patients receiving intermittent therapy had significantly better physical function (p<0.001), overall self-assessed health (p<0.001), and physical and emotional scores, but did not report the actual figures. However, one moderate quality study did not find any significant difference between the treatment groups using the QLQ-C30 but did not provide figures (Mottet et al. 2009, 2013).

Another study found that those in the intermittent group were significantly less likely to report impotence (p<0.001) or poor mental health (p=0.003) at 3 months (Hussain et al. 2006, 2013). At 9 months patients in the intermittent group were more likely to report high libido (p=0.01) and less likely to report impotence (p<0.001). However, at 15 months there remained no significant difference between groups in any of the quality of life outcomes. While Salonen et al. (2006, 2008, 2012, 2013) found significant differences in sexual functioning but not activity limitation or physical capacity, favouring intermittent treatment at a median follow-up of 65 months, but did not report individual scores or outcomes of other domains.

Treatment-related morbidity and mortality, patient acceptability

These outcomes were not reported by any of the included studies.

Cost-effectiveness evidence (2014)

A literature review of published cost-effectiveness analyses did not identify any relevant papers. No further economic modelling was undertaken for this topic as it was not thought to be necessary because estimating the likely economic effects of the recommendation seemed relatively straightforward. Thus, other topics with more complex cost and benefit trade offs were prioritised for economic modelling.

RecommendationConsider intermittent therapy for men having long-term androgen deprivation therapy (not in the adjuvant setting), and include discussion with the man, and his partner, family or carers if he wishes, about:
  • the rationale for intermittent therapy and
  • the limited evidence for reduction in side effects from intermittent therapy and
  • the effect of intermittent therapy on progression of prostate cancer.
[new 2014]

For men who are having intermittent androgen deprivation therapy:
  • measure PSA every 3 months and
  • restart androgen deprivation therapy if PSA is 10 ng/ml or above, or if there is symptomatic progression.
[new 2014]
Relative value placed on the outcomes consideredThe GDG considered the outcomes of overall survival, progression free survival and reduction in adverse events to be the most important as these would indicate the effect of intermittent hormone therapy on both survival and quality of life. Patient acceptability and treatment-related morbidity were also considered important outcomes but were not reported by the evidence.
Quality of the evidenceThe evidence for this question was assessed by GRADE as being very low quality for health-related quality of life and progression free survival, low to moderate quality for reduction in adverse events and moderate quality for overall survival. The GDG noted that many of the included studies were only available in abstract form. However the data reported in these abstracts was consistent with that reported in full papers and so the GDG agreed it was appropriate to include these abstracts in the evidence base
Trade-off between clinical benefits and harmsThe GDG noted that the evidence had shown no difference in overall survival between intermittent and continuous hormone therapy. Also that intermittent hormone therapy had been associated with improvements in health-related quality of life and reduction in adverse events which could potentially lead to improved patient acceptability. However it was noted that this evidence was of very low to moderate quality. The GDG also acknowledged, based on their clinical experience, that it was possible for men receiving intermittent hormone therapy to be lost to follow-up and potentially undertreated. Nonetheless the GDG agreed that the potential benefits of receiving intermittent hormone therapy outweighed the harms.
Trade-off between net health benefits and resource useThe GDG noted that no relevant, published economic evaluations had been identified and no additional economic analysis had been undertaken in this area. The opinion of the GDG, based on their clinical experience, was that recommending intermittent hormone therapy, instead of continuous, would result in cost savings. However there would likely be additional costs associated with the requirement for increased PSA testing in follow-up. The GDG were unclear what the net effect of this would be.
Other considerationsThe GDG noted that clarification was needed on which men could be considered for intermittent hormone therapy – to avoid the potential for variation in practice. They agreed to recommend this treatment for those men maintaining a PSA <10, as this was the PSA level consistently reported in the studies that had been appraised. The GDG were also concerned that regular PSA monitoring, which was part of the trial protocols for intermittent hormone therapy, may not happen outside of the trial setting. They therefore agreed to recommend 3 monthly PSA monitoring as this was the maximum interval reported in the trials that comprised the evidence base for this topic.

Signalling through the androgen receptor remains critically important in hormone relapsed prostate cancer and several new drugs have been designed to disrupt this pathway. Recommendations on ‘Prostate cancer (metastatic, castration resistant) - abiraterone (following cytoxic therapy)’ can be found in NICE technology appraisal guidance 259.

7.4. Managing the complications of hormone therapy

Androgen deprivation decreases a mans testosterone levels over the long term, which can lead to adverse effects, including cardiovascular morbidity/mortality, hot flushes, sexual dysfunction, osteoporosis and fatigue.

Anti-androgen therapy is less likely to result in sexual dysfunction and/or lethargy. These agents however commonly cause breast enlargement (gynaecomastia) and breast pain (mastalgia).

7.4.1. Cardiovascular effects

It has been postulated that long term decrease in testosterone levels may lead to an increased risk of cardiovascular morbidity (including thromboembolic events and myocardial infarction) and mortality.

Clinical question: What are the adverse cardiovascular effects of long-term androgen deprivation and how prevalent are they?

Clinical evidence (see also full evidence review) (2014)

Evidence statements

The evidence for all pre-specified outcomes is summarised in Tables 51 to 55.

Table 51. GRADE profile: what are the adverse cardiovascular effects of long-term androgen deprivation and how prevalent are they?

Table 51

GRADE profile: what are the adverse cardiovascular effects of long-term androgen deprivation and how prevalent are they?

Table 52. GRADE profile: what are the adverse cardiovascular effects of long-term androgen deprivation and how prevalent are they?

Table 52

GRADE profile: what are the adverse cardiovascular effects of long-term androgen deprivation and how prevalent are they? Sub-group analyses: anti-androgen monotherapy versus other androgen deprivation therapy (ADT)

Table 53. GRADE profile: what are the adverse cardiovascular effects of long-term androgen deprivation and how prevalent are they?

Table 53

GRADE profile: what are the adverse cardiovascular effects of long-term androgen deprivation and how prevalent are they? Sub-group analyses: androgen deprivation therapy (ADT) of duration ≥ 6 months versus no ADT

Table 54. GRADE profile: what are the adverse cardiovascular effects of long-term androgen deprivation and how prevalent are they?

Table 54

GRADE profile: what are the adverse cardiovascular effects of long-term androgen deprivation and how prevalent are they? Sub-group analyses: studies including patients with comorbidities versus studies excluding patients with comorbidities

Table 55. GRADE profile: what are the adverse cardiovascular effects of long-term androgen deprivation and how prevalent are they?

Table 55

GRADE profile: what are the adverse cardiovascular effects of long-term androgen deprivation and how prevalent are they? Sub-group analyses: randomised controlled trials (RCTs) versus observational studies

Cardiovascular mortality

Eleven studies provided low quality evidence on cardiovascular mortality in patients receiving androgen deprivation therapy (ADT), though these varied in their definitions and results. The adjusted hazard ratios of receiving any ADT compared to a control without ADT ranged from 0.96 to 1.70. Adjusted hazard ratios for receiving ADT and radiotherapy compared to radiotherapy alone ranged from 0.7 to 1.2 and those for patients receiving both ADT and radical prostatectomy compared to prostatectomy alone ranged from 1.3 to 2.6. The standardised mortality ratio (SMR) for patients who received any form of ADT ranged from 0.38 to 1.29 in the studies. Only seven of the studies provided data in a format which could be included in a meta-analysis; this found no statistically significant difference in risk (RR 1.37 95% CI 0.90–2.07).

The sub-group analyses involving five studies showed no significant difference between patients receiving LHRH agonists alone or with anti-androgens and those receiving no ADT (p>0.05). In three of these studies ADT was given alongside radiotherapy. One study (McLeod et al. 2006) showed a borderline significant difference between those receiving anti-androgens and standard care (radical therapy or watchful waiting) compared to those receiving standard care alone (RR 1.3 95% CI 1.0–1.6). Another study (van Hemelrijck et al. 2010a) provided very low quality evidence of significantly fewer deaths due to myocardial infarction, arrthymia, ischemic heart disease (IHD), and heart failure in patients receiving anti-androgen monotherapy compared to other medical ADT (RRs: 0.57, 0.36, 0.54, and 0.26 respectively). The results suggest that for every 1,000 patients treated with anti-androgen monotherapy instead of another type or combined ADT, there would be 17 fewer deaths from myocardial infarction, four fewer from arrthymia, 32 fewer from IHD, and ten fewer from heart failure. No combined measure of cardiovascular mortality was reported by ADT type.

Following restriction of the meta-analysis to studies involving ≥ 6 months ADT, there remained no significant increase in the incidence of cardiovascular deaths between patients treated with ≥ 6 months of ADT and patients receiving no ADT, based on very low quality evidence from two studies. In a very low quality study not included in the meta-analysis Kim et al. (2011) found that incidence of cardiovascular death at 7 years was significantly higher at 1.4% in patients receiving > 6 months of ADT alongside EBRT, compared to 2.6% in patients receiving EBRT alone (p=0.001). Another low quality study by Alibhai et al. (2009) found that patients receiving > 24 months of ADT had a significantly lower risk of sudden cardiac death compared to patients receiving < 3 months (RR 0.81 95% CI 0.69–0.96), but patients receiving 3–6 months or 6–24 months ADT did not. In a moderate quality study D’Amico et al. (2007) reported that men aged ≥ 65 years who received 6 months of ADT experienced a shorter time to fatal myocardial infarction than men of the same age group who did not receive ADT (p=0.017). However, in their second study no significant difference in time to fatal myocardial infarction was found between patients aged ≥ 65 years receiving 6–8 months of ADT compared to patients receiving 3 months.

Upon exclusion of the only study reporting exclusion of patients with comorbidities (Tsai et al. 2007) from the meta-analysis, there remained no significant difference in cardiovascular mortality between patients receiving ADT and those not. The very low quality study which was excluded found a significant increase in cardiovascular mortality in patients receiving ADT compared to patients not receiving ADT. The relative risk of 2.44 (95% CI 1.73–3.44) suggests that for every 1,000 patients without comorbidities, treated with ADT, there would be 28 more cardiovascular deaths.

Four RCTs or analyses of multiple RCTs were included in a sub-group meta-analysis; there remained no significant difference in incidence of cardiovascular mortality between patients receiving ADT and those not. A sub-group analysis of the cohort studies provided very low quality evidence of a significant increase in risk in patients receiving ADT (RR 2.15 95% CI 1.33–3.46), suggesting that for every 1,000 patients there are 23 more cardiovascular deaths in patients treated with ADT.

Cardiovascular morbidity

Six studies provided very low quality evidence of cardiovascular morbidity in patients receiving hormone therapy. The studies varied in the type of events reported, with five reporting incidence of myocardial infarction, three reporting the incidence of coronary heart disease, two the incidence of heart failure, and one the incidence of arrhythmia. The incidence rate ranged widely between studies; between 10.2 and 61.3 cases per 1,000 person-years in those receiving hormone therapy, compared to between 7.4 and 29.7 per 1,000 person-years in the no-hormone therapy group. Studies also varied in whether the risk of cardiovascular disease was found to be lower in the hormone therapy or no-hormone therapy group, with the hazard ratio varying between 0.92 and 1.98. One study (van Hemelrijck 2010a and 2010b) reported the standardised incidence ratio (SIR) which was found to range between 1.12 and 1.47. Only two studies provided data which could be included in the meta-analysis, which found no significant difference in risk between those that received hormone therapy and those that did not.

One study provided very low quality evidence of significantly fewer overall cases of myocardial infarction, ischemic heart disease (IHD), and heart failure with anti-androgen monotherapy compared to other types of ADT (RRs: 0.79, 0.85, 0.54, and 0.85 respectively) (van Hemelrijck et al. 2010a). The results suggest that for every 1,000 patients treated with anti-androgen monotherapy instead of another or combined type of ADT, there would be 14 fewer cases of myocardial infarction, 15 fewer cases of IHD, and 33 fewer cases of heart failure. There was no significant difference in the risk of developing arrthymia for patients receiving anti-androgen monotherapy compared with any other type of ADT.

One study (Alibhai et al. 2009) provided low quality evidence of a borderline significant difference in the incidence of myocardial infarction between patients receiving ≥ 6 months ADT and patients receiving no ADT. The relative risk of 0.87 (95% CI 0.80–0.95) suggests that for every 1,000 patients treated with ≥ 6 months ADT there will be seven fewer myocardial infarctions. However, in their multivariate model Alibhai et al. (2009) found no significant difference in the risk of myocardial infarction for patients receiving 3–6 months, 6–24 months, or > 24 months ADT compared to patients receiving < 3 months. Alibhai et al. (2009) did find a significant difference in the incidence of congestive heart failure between patients treated with ≥6 months of ADT compared to patients receiving no ADT. The relative risk of 0.92 (95% CI 0.87–0.97) suggests that for every 1,000 patients 10 fewer would develop congestive heart failure if treated with ≥ 6 months of ADT. The multivariate model suggests that this different was only significant for the subgroup receiving > 24 months ADT (HR 0.81 95% CI 0.69–0.96) and not for the 3–6 or 6–24 month-subgroups.

None of the studies reported restricting their patients by comorbidities criteria. Three cohort studies reported on the incidence of cardiovascular events and found no significant difference between groups.

Cerebrovascular accident mortality

Two studies provided very low quality evidence of no significant increase in deaths from stroke in patients treated with hormone therapy compared to a control. A cohort study by van Hemelrijck et al. (2010a) found the SMR to range between 0.81 and 1.24 for different hormone therapies, compared to 0.99 and 1.01 for the curative therapy and surveillance control groups.

Following restriction of the meta-analysis to anti-androgen monotherapy versus no ADT there remained no statistically significant difference in the incidence of death due to stroke. One study (van Hemelrijck et al. 2010a) provided very low quality evidence of significantly fewer deaths due to stroke in patients receiving anti-androgen monotherapy compared to other medical ADT (RR 0.56 95% CI 0.40–0.79). The results suggest that for every 1,000 patients treated with anti-androgen monotherapy instead of another type or combined ADT, there would be eight fewer deaths from stroke.

Following restriction of the meta-analysis to studies involving ≥ 6 months ADT, there remained no significant increase in the incidence of deaths due to stroke between patients treated with ≥ 6 months of ADT and patients receiving no ADT, based on very low quality evidence from two studies.

None of the studies reported restricting their patients by comorbidities criteria. Only one RCT (McLeod et al. 2006) reported the incidence of deaths due to stroke and found no significant difference between patients treated with ADT and those not.

Cerebrovascular accident morbidity

Five studies provided very low quality evidence on incidence of stroke in patients treated with hormone therapy. The incidence rate ranged widely between studies; between 14.7 and 34.7 cases per 1,000 person-years in those receiving hormone therapy, compared to between 11.3 and 12 per 1,000 person-years in the no-hormone therapy group. One study reported incidence rates between 14.7 and 34.7 per 1,000 person-years in different hormone therapy sub-groups, compared with 11.3 per 1,000 person-years in the no-hormone therapy group (Keating et al. 2010). The adjusted hazard ratios reported for the hormone therapy group varied between 0.88 and 1.81 with studies results varying as to whether the risk was higher or lower in those treated with hormone therapy. Van Hemelrijck et al. (2010a) found the SIRs to range from 1.19 to 1.36 for the different hormone therapies, compared to 0.98 and 1.19 for the curative therapy and surveillance groups. Three of the studies provided data which could be included in a meta-analysis, which found no significant difference in risk between those that received hormone therapy and those that did not.

Following restriction of the meta-analysis to anti-androgen monotherapy versus no ADT there remained no statistically significant difference in the incidence of stroke. One study provided very low quality evidence of significantly fewer overall cases of stroke with anti-androgen monotherapy compared to other types of ADT (OR 0.85 95% CI 0.75–0.96) (van Hemelrijck et al. 2010a). The results suggest that for every 1,000 patients treated with anti-androgen monotherapy instead of another or combined type of ADT, there would be 12 fewer cases of stroke.

When the meta-analysis was restricted to studies comparing ≥ 6 months ADT with no ADT, only one study (Alibhai et al. 2009) providing low quality evidence was included. This study found a significant difference in the incidence of stroke between patients treated with ≥ 6 months of ADT compared to patients receiving no ADT (RR 0.84 95% CI 0.78–0.91), suggesting that for every 1,000 patients ten fewer would have a stroke if treated with ≥ 6 months of ADT.

Upon exclusion of the only study reporting exclusion of patients with comorbidities (Chung et al. 2012) from the meta-analysis, there remained no significant difference in the incidence of stroke between patients receiving ADT and those not. The very low quality excluded study found no significant difference in the incidence of stroke between patients receiving ADT and those not receiving ADT.

Four cohort studies reported on the incidence of stroke and found no significant difference between groups.

Thromboembolic events

Three studies provided very low quality evidence of the incidence of thromboembolic events in patients receiving hormone therapy. Two of these studies included any thromboembolic event, however their definitions varied. The third study (Hu et al. 2012) reported only the number of cases of deep venous thrombosis seen. The reported incidence rate ranged from 13.2 to 14.7 per 1,000 person years for patients receiving hormone therapy compared to 10.1 cases per 1,000 person-years in the no-hormone therapy group (where reported). The adjusted hazard ratio ranged from 1.10 to 1.56, suggesting an increased risk in patients receiving hormone therapy. The SIRs ranged from 1.56 to 2.81, also suggesting more cases than would be expected. However, where surveillance or curative therapy was used as a comparator, the SIRs ranged from 1.27 to 1.57 and from 1.73 to 2.03 respectively suggesting that these groups also saw more cases than expected.

One study provided very low quality evidence of significantly fewer overall cases of deep venous thrombosis and pulmonary embolism (RRs: 0.54 and 0.67 respectively) (van Hemelrijck et al. 2010b). The results suggest that for every 1,000 patients treated with anti-androgen monotherapy instead of another or combined type of ADT, there would be seven fewer cases of DVT and four fewer cases of pulmonary embolism.

No studies reporting thromboembolic events compared ≥ 6 months ADT with no ADT. However, a very low quality study by Ehdaie et al. (2012) found that risk of thromboembolic event was increased by 40% (95% CI 1.33–1.45) in patients receiving < 1 year of ADT, by 66% (95% CI 1.57–1.75) in patients receiving 1–3 years of ADT, and doubled in patients receiving > 3 years of ADT (95% CI 1.90–2.19) compared to patients receiving no ADT. Another low quality study (Hu et al. 2012) undertook subgroup analyses and found incidence of DVT to be significantly higher in patients receiving > 12 months of ADT compared to no ADT (HR 1.23 95% CI 1.11–1.36 for 13–24 months and HR 1.15 95% CI 1.04–1.27 for >25 months duration) but not for patients receiving ≤ 12 months of ADT.

None of the studies reported restricting their patients by comorbidities criteria. Two cohort studies reported on the incidence of thromboembolic events and found no significant difference between patients treated with ADT and those not.

Cost-effectiveness evidence (2014)

A literature review of published cost-effectiveness analyses did not identify any relevant papers. The limited clinical evidence base for this question made it unfeasible to undertake further economic modelling.

RecommendationNo recommendations made
Relative value placed on the outcomes consideredThe GDG considered the outcomes of cardiovascular mortality, cardiovascular morbidity, cerebrovascular accident mortality, cerebrovascular accident morbidity and thromboembolic events to be the most important to identifying what adverse cardiovascular effects were caused by long term androgen deprivation therapy in men with prostate cancer, and their prevalence.
Quality of the evidenceThe evidence was assessed by GRADE as very low quality for all outcomes, except cardiovascular morbidity which was assessed as low quality as much of the data was from cohort studies.
Trade-off between clinical benefits and harmsThe GDG noted from the evidence that adverse cardiovascular effects do occur with the use of long-term androgen deprivation therapy. It was also noted, following subgroup analyses according to type of androgen deprivation therapy, duration of androgen deprivation therapy and existence of co-morbidities, that the evidence indicated there was no significant difference in the occurrence of adverse cardiovascular effects in men receiving long-term androgen deprivation therapy. However, the GDG acknowledged there was considerable uncertainty around this result in addition to a high degree of heterogeneity in the evidence.

Given this uncertainty, the GDG were concerned that stating there was no increased risk of adverse cardiovascular effects could be falsely reassuring to patients, especially since the summary of product characteristics for some androgen deprivation therapies cites potential adverse cardiovascular effects as common. Equally, stating that there was an increased risk of adverse cardiovascular effects could cause unnecessary anxiety for patients because it is not clear from the evidence that this is the case.

The GDG also debated whether or not to recommend that the uncertainty over the risks of adverse cardiovascular effects be highlighted to men considering long-term androgen deprivation therapy. However, the patient members of the group cautioned that knowing this uncertainty would not be helpful in assisting a man to make this treatment decision. Therefore the GDG agreed not to make any recommendations on this issue.
Other considerationsThe GDG also decided not to make a recommendation for further research in this area because the GDG did not consider it a priority for the guideline.

7.4.2. Hot flushes

Hot flushes can be treated with anti-depressants, the α adrenergic agonist clonidine and hormone therapies such as medroxyprogesterone acetate, cyproterone acetate and diethylstilbestrol). Self-management (such as diet and lifestyle changes) may also be effective, as may complementary therapies.

Clinical question: What is the most effective intervention for hot flushes as a result of long term androgen suppression for prostate cancer?

Clinical evidence (see also full evidence review) (2014)

Evidence statements

The evidence for all pre-specified outcomes is summarised in Tables 56 to 66.

Table 56. GRADE profile: what is the most effective intervention for hot flushes as a result of long-term androgen suppression for prostate cancer?

Table 56

GRADE profile: what is the most effective intervention for hot flushes as a result of long-term androgen suppression for prostate cancer? Comparison: diethylstilbestrol versus control after bilateral orchidectomy

Table 57. GRADE profile: what is the most effective intervention for hot flushes as a result of long-term androgen suppression for prostate cancer?

Table 57

GRADE profile: what is the most effective intervention for hot flushes as a result of long-term androgen suppression for prostate cancer? Comparison: high dose versus low dose oestrogen patches after androgen deprivation therapy

Table 58. GRADE profile: what is the most effective intervention for hot flushes as a result of long-term androgen suppression for prostate cancer?

Table 58

GRADE profile: what is the most effective intervention for hot flushes as a result of long-term androgen suppression for prostate cancer? Comparison: megastrol acetate versus control after androgen deprivation therapy

Table 59. GRADE profile: what is the most effective intervention for hot flushes as a result of long-term androgen suppression for prostate cancer?

Table 59

GRADE profile: what is the most effective intervention for hot flushes as a result of long-term androgen suppression for prostate cancer? Comparison: medroxyprogesterone acetate (MA) versus venlafaxine (VF) versus cyproterone acetate (CA) after androgen (more...)

Table 60. GRADE profile: what is the most effective intervention for hot flushes as a result of long-term androgen suppression for prostate cancer?

Table 60

GRADE profile: what is the most effective intervention for hot flushes as a result of long-term androgen suppression for prostate cancer? Comparison: cyproterone acetate (CA) versus control after androgen deprivation therapy

Table 61. GRADE profile: what is the most effective intervention for hot flushes as a result of long-term androgen suppression for prostate cancer?

Table 61

GRADE profile: what is the most effective intervention for hot flushes as a result of long-term androgen suppression for prostate cancer? Comparison: transdermal clonidine versus control after androgen deprivation therapy

Table 62. GRADE profile: what is the most effective intervention for hot flushes as a result of long-term androgen suppression for prostate cancer?

Table 62

GRADE profile: what is the most effective intervention for hot flushes as a result of long-term androgen suppression for prostate cancer? Comparison: venlafaxine and soy protein versus control after androgen deprivation therapy

Table 63. GRADE profile: what is the most effective intervention for hot flushes as a result of long-term androgen suppression for prostate cancer?

Table 63

GRADE profile: what is the most effective intervention for hot flushes as a result of long-term androgen suppression for prostate cancer? Comparison: soy isoflavones versus control after androgen deprivation therapy

Table 64. GRADE profile: what is the most effective intervention for hot flushes as a result of long-term androgen suppression for prostate cancer?

Table 64

GRADE profile: what is the most effective intervention for hot flushes as a result of long-term androgen suppression for prostate cancer? Comparison: Dong Quai versus control after androgen deprivation therapy

Table 65. GRADE profile: what is the most effective intervention for hot flushes as a result of long-term androgen suppression for prostate cancer?

Table 65

GRADE profile: what is the most effective intervention for hot flushes as a result of long-term androgen suppression for prostate cancer? Comparison: electrostimulated acupuncture versus traditional acupuncture after androgen deprivation therapy

Table 66. GRADE profile: what is the most effective intervention for hot flushes as a result of long-term androgen suppression for prostate cancer?

Table 66

GRADE profile: what is the most effective intervention for hot flushes as a result of long-term androgen suppression for prostate cancer? Comparison: dietary and lifestyle changes after androgen deprivation therapy

Hot flushes

Very low quality evidence showed a complete resolution of hot flushes in 86% (12/14) of men treated with diethylstilbestrol compared with 0% (0/14) of those receiving placebo (RR 25 95% CI 1.62–385.09) (based on an RCT identified by the previous guideline; Atala et al. (1992). Low quality evidence from Gerber et al. (2000) compared the effect of low dose (0.05mg) and high dose (0.10mg) estradiol patches on hot flushes in 12 men with advanced prostate cancer receiving leuprolide injections. A moderate or major improvement in hot flushes was seen in 25% of the low dose estradiol group compared with 67% of the high dose group (RR in favour of high dose 2.67 95% CI 0.93–7.69).

One RCT (Loprinzi et al. 1994a) of low quality examined the effect of 20mg megestrol acetate on hot flushes in 66 men who had undergone surgical or medical androgen suppression. A significant reduction in both frequency and severity of hot flushes was found in favour of megestrol acetate. 79% of men in the megestrol acetate group and 12% of men in the placebo group reported at least 50% reduction in daily frequency of hot flushes (RR 6.50 95% CI 2.55–16.57). A high quality RCT found greater hot flush reduction was reported in a medroxyprogesterone and cyproterone acetate arm than was seen in a venlafaxine arm (Irani et al. 2010). Complete regression of hot flush symptoms was reported in 8% of the venlafaxine group, 37% of the cyproterone group, and 25% of the medroxyprogesterone group.

A low quality RCT of cyproterone acetate versus placebo found a mean number of hot flushes per day of around two during the treatment period compared to ten during the placebo phase (Eaton & McGuire 1983). The authors reported a significant reduction in incidence of hot flushes with cyproterone acetate. However, it is not specified whether this is versus baseline or placebo.

One RCT (Loprinzi et al. 1994b) found no significant difference between clonidine and placebo arms in terms of frequency or severity of hot flushes. Clonidine was associated with increased dry mouth and redness under the patch.

Another RCT of venlafaxine showed a 47% reduction in hot flush score (Irani et al. 2010). However, hormonal therapy with medroxyprogesterone and cyproterone had a significantly larger benefit than did venlafaxine. An unpublished study by Vitolins et al. (2011) compared four groups of treatment for hot flushes in androgen-deprived men: placebo pill plus casein protein, soy protein plus placebo pill, venlafaxine plus casein protein, or soy plus venlafaxine. All groups showed a reduction in hot flush score over time but there were no significant differences between groups.

One moderate quality placebo-controlled trial found no improvement in hot flushes for high dose isoflavones compared to placebo (Sharma et al. 2009). One RCT found no significant changes in the severity, frequency or duration of hot flashes among men receiving placebo or Dong Quai (a Chinese herbal compound) (Al-Bareeq et al. 2010). One trial (Frisk et al. 2009) of moderate quality compared electrostimulated acupuncture (EA) and traditional acupuncture (TA) in castrated men (via surgery or GnRH analogue). A decrease of hot flush frequency larger than 50% was reported in 57% of the EA group and 47% of the TA group at 12 weeks (RR 1.22 95% CI 0.60–2.48). At 12 months follow-up 18% of the EA group and 46% of the TA group still experienced a decrease in number of hot flushes of 50% or more (RR 0.26 95% CI 0.04–1.70). This study reported a 78% reduction of hot flush scores in the EA group and a 73% reduction in the TA group, without any statistical analysis.

Adverse events

Very low quality evidence showed diethylstilbestrol was associated with gynacomastia and breast tenderness, but the rates of adverse events were not reported (based on an RCT identified by the previous guideline; Atala et al. 1992). Low quality evidence from Gerber et al. (2000) compared the effect of low dose (0.05mg) and high dose (0.10mg) estradiol patches on hot flushes in 12 men with advanced prostate cancer receiving leuprolide injections. Painless breast swelling was reported by 4/12 men on high dose estradiol and 1/12 men on low dose estradiol (RR 4.00, CI 0.52 to 30.76).

A high quality RCT found higher adverse event rates in a cyproterone group (25%) compared to a medroxyprogesterone group (12%) and a venlafaxine group (20%) (Irani et al. 2010).

A low quality RCT of cyproterone acetate versus placebo found five out of 12 men complained of lethargy, severe enough to reduce dosage in one case (Eaton & McGuire 1983).

No adverse events were reported by a moderate quality placebo-controlled trial of isoflavones compared to placebo (Sharma et al. 2009) or an RCT comparing Dong Quai to placebo (Al-Bareeq et al. 2010). In a study comparing electrostimulated acupuncture (EA) and traditional acupuncture (TA) in castrated men (via surgery or GnRH analogue), three patients reported adverse events (one distress, one fatigue, one hematoma).

Cardiovascular events

None of the included studies reported this outcome.

Health-related quality of life

A high quality RCT found health-related quality of life scores to be high in cyproterone, medroxyprogesterone and venlafaxine groups over time (mean 85 out of 100) (Irani et al. 2010). Venlafaxine had the highest scores at 4 week and 8 week follow-up. One moderate quality placebo-controlled trial found no improvement in quality of life for high dose isoflavones compared to placebo (Sharma et al. 2009).

Cost-effectiveness evidence (2014)

A literature review of published cost-effectiveness analyses did not identify any relevant papers. No further economic modelling was undertaken due to the relatively insignificant cost implications.

RecommendationOffer medroxyprogesteroneaa (20mg per day), initially for 10 weeks, to manage troublesome hot flushes caused by long-term androgen suppression and evaluate the effect at the end of the treatment period. [new 2014]

Consider cyproterone acetate or megestrol acetatebb (20 mg twice a day for 4 weeks) to treat troublesome hot flushes if medroxyprogesterone is not effective or not tolerated. [new 2014]

Tell men that there is no good-quality evidence for the use of complementary therapies to treat troublesome hot flushes. [new 2014]
Relative value placed on the outcomes consideredThe GDG considered the outcomes of hot flushes, adverse events, cardiovascular events and health related quality of life to be the most relevant to this determining the most effective intervention for hot flushes.

The outcome of hot flushes was reported by the evidence for all interventions of interest with the exception of diet and lifestyle changes. The outcome of adverse events was reported for three interventions whilst health-related quality of life was reported for two interventions of interest.

The outcome of cardiovascular events was not reported for any of the interventions listed in the PICO for this topic.

The GDG also considered the additional outcome of duration of treatment because the recommendation on the use of synthetic progestogens as first-line therapy for the management of troublesome hot flushes in CG58 specified a time period for taking this therapy orally. The GDG were confident any evidence on duration of treatment would have been found by the search because the population for this topic included all drug interventions for hot flushes.
Quality of the evidenceThis evidence for hot flushes ranged from very low to high quality as assessed by GRADE. For adverse events it ranged from very low to moderate quality and for health-related quality of life the evidence ranged from low to high quality.

The GDG noted that some of the included studies had poor methodological quality, small population sizes and limited information on withdrawal/dropout rates.
Trade-off between clinical benefits and harmsThere was high quality evidence for the use of medroxyprogesterone to reduce the frequency and severity of hot flushes in men with prostate cancer treated with long term androgen suppression. Although both cyproterone and megestrol acetate were also shown be effective, the data was of low quality for both drugs. In addition the rate of adverse events was higher in men receiving cyproterone compared to medroxyprogesterone. Therefore the GDG decided to recommend the use of medroxyprogesterone as first-line therapy for the management of troublesome hot flushes and consider cyproterone acetate or megestrol acetate for second line management. The GDG decided not to make any recommendations on the use of diethylstilbestrol because even though it showed some level of effectiveness the evidence was drawn from one trial of very low quality.

The use of synthetic progestogens for the management of troublesome hot flushes in CG58 recommended they should be given for a period of two weeks. However the GDG agreed there was no evidence to support this length of treatment and it is not considered to be current practice. The evidence presented separately to the GDG on the treatment duration time for these hormone therapies indicated a time of 10 weeks. Therefore the GDG agreed to include this within the recommendation.

One study was identified that compared the use of transdermal clondine versus placebo and subsequently assessed the frequency and severity of hot flushes. No significant difference was found between either arm therefore the GDG decided not to make any statement on the use of clondine in this patient population.

There was poor quallity evidence of effect of reducing hot flushing frequency with acupuncture (these trials contained no non-acupuncture arm), and no evidence that either soy isoflavones or Dong Quai help reduced hot flushes compared to placebo. Therefore the GDG agreed that men should be advised there is no good quality evidence for the use of complementary therapies in the management of troublesome hot flushes.

No evidence was identified investigating the effects of diet or lifestyle on the frequency of hot flushes in men with prostate cancer treated with long term androgen suppression. Therefore the GDG were not able to make any recommendations for these interventions.

The GDG agreed that use of additional hormone therapies will lead to a significant reduction in hot flushes with minimal adverse events and improved quality of life. However they did note that the use of progestogens may have an effect on prostate cancer in patients with advanced disease. No other harms or benefits associated with these recommendations were identified by the GDG.
Trade-off between net health benefits and resource useThe GDG noted that no relevant, published economic evaluations had been identified and no additional economic analysis had been undertaken in this area. It was noted that all the drugs recommended are already being used but acknowledged there may be an additional cost incurred by increasing the treatment duration period from two to ten weeks.
aa

At the time of publication (January 2014), medroxyprogesterone did not have a UK marketing authorisation for this indication. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. Informed consent should be obtained and documented. See the General Medical Council’s Good practice in prescribing and managing medicines and devices for further information.

bb

At the time of publication (January 2014), megestrol acetate did not have a UK marketing authorisation for this indication. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. Informed consent should be obtained and documented. See the General Medical Council’s Good practice in prescribing and managing medicines and devices for further information.

7.4.3. Sexual function

Long term androgen suppression is often offered to men with non-localised disease. It functions to keep the disease under control by shrinking it, reducing its symptoms, or delaying its growth. In locally advanced and advanced cancer it can extend over months or years, or indefinitely. A range of methods for administering the treatment are used (injections, implants, tablets) on a regular, intermittent or ‘maximal blockage’ basis, and all act by stopping testosterone from reaching (prostate cancer cells).

Loss of sex drive (libido – total or reduced) and erectile problems (erectile dysfunction – ED) are very common side effects of long term androgen deprivation and can lead to physical, psychological, emotional and relationship difficulties. Therapeutic interventions are of two types; physical treatments (for example PDE5 inhibitors, prostaglandins, vacuum pumps and prostheses) and psychosexual counselling.

Clinical question: Which are the most effective interventions (singly or in combination) for sexual dysfunction as a result of long term androgen deprivation for prostate cancer?

Clinical evidence (see also full evidence review) (2014)

Evidence statements

The evidence for all pre-specified outcomes is summarised in Tables 67 to 71

Table 67. GRADE profile: which are the most effective interventions (singly or in combination) for sexual dysfunction as a result of long-term androgen suppression for prostate cancer?

Table 67

GRADE profile: which are the most effective interventions (singly or in combination) for sexual dysfunction as a result of long-term androgen suppression for prostate cancer? Comparison: PDE5 inhibitors versus placebo

Table 68. GRADE profile: which are the most effective interventions (singly or in combination) for sexual dysfunction as a result of long-term androgen suppression for prostate cancer?

Table 68

GRADE profile: which are the most effective interventions (singly or in combination) for sexual dysfunction as a result of long-term androgen suppression for prostate cancer? Comparison: prostaglandins versus placebo

Table 69. GRADE profile: which are the most effective interventions (singly or in combination) for sexual dysfunction as a result of long-term androgen suppression for prostate cancer?

Table 69

GRADE profile: which are the most effective interventions (singly or in combination) for sexual dysfunction as a result of long-term androgen suppression for prostate cancer? Comparison: psychosocial counselling versus control

Table 70. GRADE profile: which are the most effective interventions (singly or in combination) for sexual dysfunction as a result of long-term androgen suppression for prostate cancer?

Table 70

GRADE profile: which are the most effective interventions (singly or in combination) for sexual dysfunction as a result of long-term androgen suppression for prostate cancer? Comparison: vacuum devices versus control

Table 71. GRADE profile: which are the most effective interventions (singly or in combination) for sexual dysfunction as a result of long-term androgen suppression for prostate cancer?

Table 71

GRADE profile: which are the most effective interventions (singly or in combination) for sexual dysfunction as a result of long-term androgen suppression for prostate cancer? Comparison: prostheses versus control

Sexual function

A systematic review of the four RCTs reviewed in the previous guideline provided evidence that oral phosphodiesterase type 5 (PDE5) inhibitors are effective in the medium term (up to 4 months) when used to treat erectile dysfunction after EBRT or radical bilateral nerve-sparing or unilateral nerve-sparing retropubic prostatectomy (Miles et al. 2007). The combined results of the two parallel group RCTs for improvements in erections found a significant difference (OR 10.09 95% CI 6.20–16.43) in favour of PDE5 inhibitors. Three trials found significant improvements in successful vaginal intercourse in favour of PDE5 inhibitors. Overall, the PDE5 inhibitors led to improved erectile function in about two-thirds of patients. However, in a subgroup of men with more severe dysfunction at baseline (Brock et al., 2003), many fewer reported achieving successful sexual intercourse.

One new placebo-controlled crossover trial (Watkins-Bruner et al. 2011) in patients treated with radiotherapy (RT) and neoadjuvant and concurrent ADT found that, based on the improvement in erectile function (IIEF score of ≥4 out of a total possible score of 5), 21% responded to Sildenafil but not placebo; and 3% responded to placebo but not Sildenafil (66% did not respond to either placebo or Sildenafil and 10% responded to both). The mean improvement of those on Sildenafil compared to placebo using the IIEF erectile function domain was 4.03 (p< 0.001). There was no Sildenafil effect on the Sexual Adjustment Questionnaire (18% placebo only vs. 23% Sildenafil only). In the previous guideline, four RCTs demonstrated the effectiveness of Sildenafil, Tadalafil and Vardenafil for the treatment of erectile dysfunction (ED) after external beam radiotherapy and radical prostatectomy. All studies excluded men on ADT, except for Brock et al. (2003) who excluded men with low serum testosterone levels.

One prospective case-series study (Teloken et al. 2007) explored the effects of ADT on response to Sildenafil in patients with erectile dysfunction (ED) following radiotherapy. Mean erectile function domain score and percent of patients who experienced erectile function domain normalization at each time-point were lower in those with versus those without ADT. The percentage of men responding to Sildenafil at 24 months post-radiotherapy was 61% for those without ADT and 47% for those with ADT (p=0.032). This could be because tissue androgenisation is required for optimal response to PDE5 inhibitors. The duration of ADT treatment and testosterone recovery was not reported in this study. No trials which directly compared different PDE5 inhibitors were indentified.

No studies assessing the efficacy of prostaglandins on sexual dysfunction in men treated with ADT were found.

From the previous guideline, a review of placebo-controlled trials in patients with ED of mixed aetiology concluded that intraurethral alprostadil (prostaglandin E1) was beneficial in increasing the proportion of men achieving at least one successful attempt at sexual intercourse (OR 7.22 95% CI 5.68–9.18) (Urciuoli et al. 2004). It was not clear what proportion of patients had ED due to prostate cancer. All the trials included in the review preselected men who had a good response to alprostadil before randomisation.

No trials were indentified which assessed the efficacy of psychosexual counselling specific to men with sexual dysfunction following ADT. One systematic review was identified which evaluated the effectiveness of psychosocial interventions in improving sexual and/or relationship functioning for men with prostate cancer and their partners (Chisholm et al. 2012). Five out of 11 studies which used a measure of sexual functioning reported significant improvement for at least one arm of their intervention. Four out of these five studies had sexual functioning as a major focus of the intervention and used a face-to-face format run by psychologists/training psychologists. Specific intervention strategies that were unique to those interventions that had a positive effect on sexual functioning were the explicit use of sex therapy techniques, including taking a sexual history, teaching sensate focus, and challenging negative thoughts related to sexuality and masculinity. Of the six studies that found no impact of the intervention on sexual functioning, five had sexual functioning as a minor focus and five used supportive/educative strategies. Only two interventions were delivered face-to-face and nurses were more likely to deliver these interventions, with psychologists delivering two programs. Most studies included in the systematic review were of low methodological quality.

No studies were indentified which evaluated the use of vacuum devices for men with ED following ADT. In the systematic review by Miles et al. (2007) one trial was reported which evaluated the effectiveness of a vacuum constriction device (VCD) for inducing erection in 109 men with ED following retropubic prostatectomy (Raina et al. 2006). In the intervention group, 81% of those using the VCD successfully had sexual intercourse. At 9 months there was a significant difference in overall sexual function in favour of the intervention group (WMD 4.30 95% CI 2.53–6.07). There was no significant difference in erectile function between the two trial arms.

No studies were indentified which evaluated the use of penile prosthesis for men with ED following ADT. A systematic review by Khera & Goldstein (2011) found no systematic reviews or RCTs of penile prostheses in men with erectile dysfunction of any cause and state that prostheses are likely to be beneficial and are usually considered only after less invasive treatments have failed.

Cardiovascular events

In one trial of the PDE5 inhibitor Vardenafil (Brock et al. 2003) tachycardia and chest pain were reported in the intervention group. It is unclear if events occurred in the same individuals.

Localised pain/discomfort and localised bruising/swelling

From the previous guideline, a review of placebo-controlled trials in patients with ED of mixed aetiology found that increased penile pain was reported more frequently in the intraurethral alprostadil (prostaglandin E1) group compared to placebo (30% versus 3% respectively; OR 7.39 95% CI 5.40–10.12).

In a study evaluating the effectiveness of a vacuum constriction device (VCD) for inducing erection in 109 men with ED following retropubic prostatectomy, 23% in the intervention group discontinued treatment, mostly because of discomfort (55%) or penile bruising (20%) (Raina et al. 2006).

Infection/erosion and health-related quality of life

These outcomes were not reported by any of the included studies.

Cost-effectiveness evidence (2014)

A literature review of published cost-effectiveness analyses did not identify any relevant papers. No further economic modelling was undertaken due to the relatively insignificant cost implications.

RecommendationBefore starting androgen deprivation therapy, tell men and, if they wish, their partner, that long-term androgen deprivation will cause a reduction in libido and possible loss of sexual function. [new 2014]

Advise men and, if they wish, their partner, about the potential loss of ejaculation and fertility associated with long-term androgen deprivation and offer sperm storage. [new 2014]

Ensure that men starting androgen deprivation therapy have access to specialist erectile dysfunction services. [new 2014]

Consider referring men who are having long-term androgen deprivation therapy, and their partners, for psychosexual counselling. [new 2014]

Offer PDE5 inhibitors to men having long-term androgen deprivation therapy who experience loss of erectile function. [new 2014]

If PDE5 inhibitors fail to restore erectile function or are contraindicated, offer a choice of:
  • intraurethral inserts
  • penile injections
  • penile prostheses
  • vacuum devices.
[new 2014]
Relative value placed on the outcomes consideredThe GDG considered the outcomes of sexual function, cardiovascular events, localised pain/discomfort, localised bruising/swelling, infection/erosion and health related quality of life to be the most relevant to determining the most effective interventions (offered singly or in combination) for sexual dysfunction.

The outcome of sexual function was reported for four of the interventions of interest. The outcome of cardiovascular events was reported for only PDE5 inhibitors. The outcome of localised pain/discomfort was reported for two interventions and the outcome of localised bruising/swelling was reported for two interventions.

The outcomes of health related quality of life and infection/erosion were not reported in any of the evidence included in this topic.

The GDG noted that for the use of PDE5 inhibitors, headaches, moderate flushing and changes in vision were also reported as outcomes in the evidence but had not been listed in the PICO.
Quality of the evidenceBecause the initial search of the evidence (which focused on men being treated with long term androgen suppression) only yielded one relevant study the GDG agreed to broaden the search to include all men who had received treatment for prostate cancer. By doing this the GDG acknowledged that they would be updating the topic on effective interventions for managing sexual dysfunction as a side effect of treatment.

The evidence for sexual function ranged from very low to moderate quality as assessed by GRADE. For cardiovascular events the evidence was low quality. For localised pain/discomfort and localised bruising/swelling the evidence was very low quality.

The GDG noted that the evidence was in-direct, because it included all men who had received treatment for prostate cancer, and therefore the quality score had been downgraded in GRADE. No evidence on combination radiotherapy was identified.
Trade-off between clinical benefits and harmsThe GDG noted that the results from the one new study included in the evidence review for this topic supported the existing recommendations in CG58 on managing sexual dysfunction with PDE5 inhibitors. Although there was no evidence assessing the efficacy of the other interventions in men treated with long term ADT the GDG agreed to adopt the recommendations from CG58 and extrapolate them to make them specific to men receiving long term androgen deprivation.

Although the evidence on psychosexual counselling was drawn indirectly from a systematic review of men treated for prostate cancer it did report a significant improvement in sexual functioning following psychosocial interventions. As the GDG were concerned that current access to psychosexual counselling was variable they agreed to include a recommendation for healthcare professions to consider referring men being treated with long term androgen suppression, and their partners for psychosexual counselling. This would also make the provision to all patients and their partner more equitable.
Trade-off between net health benefits and resource useThe GDG noted that no relevant, published economic evaluations had been identified and no additional economic analysis had been undertaken in this area. It was the opinion of the GDG that no additional costs should be associated with the additional recommendation for psychosexual counselling as these services should already be in place.
OtherFor the purposes of this topic, ‘long term’ was defined as receiving androgen deprivation for greater than 6 months.

7.4.4. Osteoporosis

Osteoporosis is common in the ageing man and may be present in men about to commence androgen deprivation therapy. Such therapy may result in the development or worsening of osteoporosis. Interventions used to treat osteoporosis resulting from androgen deprivation therapy include calcium plus vitamin D supplementation, bisphosphonates, denosumab and exercise.

NICE has published guidance on the assessment of fracture risk from osteoporosis (NICE, 2012), which includes men on ADT.

RecommendationDo not routinely offer bisphosphonates to prevent osteoporosis in men with prostate cancer having androgen deprivation therapy. [2008]
Qualifying statementThis recommendation is based on a lack of evidence that the incidence of bone fractures is reduced.

Clinical evidence (2008)

There was consistent evidence from randomised trials (Diamond et al. 2001; Greenspan et al. 2007, 2008; Michaelson et al. 2007; Ryan 2006; Magno et al. 2005; Smith et al. 2001; Smith et al. 2003), that treatment with bisphosphonates increases the bone mineral density of the lumbar spine in men receiving hormonal therapy for prostate cancer. However, there was no evidence about the effect of bisphosphonates on the rate of symptomatic fractures: the single trial reporting this outcome had insufficient follow-up (Smith et al. 2003). There was no significant difference in the rate of severe adverse effects in bisphosphonate and placebo arms in three trials that reported this outcome (Ryan 2006; Greenspan et al. 2007, 2008; Smith et al. 2003).

Cost-effectiveness evidence (2008)

The literature review identified 153 potentially relevant papers, but none were obtained for appraisal as they did not include any economic evaluations. No economic modelling was undertaken as the GDG concluded evidence from one available RCT showed that bisphosphonates did not reduce or delay the development of symptomatic factures.

Clinical question: What is the most effective intervention for osteoporosis as a result of long term androgen deprivation for prostate cancer?

Clinical evidence (see also full evidence review) (2014)

Evidence statements

The evidence for all pre-specified outcomes is summarised in Tables 72 to 74.

Table 72. GRADE profile: what is the most effective intervention for osteoporosis as a result of long-term androgen suppression for prostate cancer?

Table 72

GRADE profile: what is the most effective intervention for osteoporosis as a result of long-term androgen suppression for prostate cancer? Comparison: bisphosphonates versus control

Table 73. GRADE profile: what is the most effective intervention for osteoporosis as a result of long-term androgen suppression for prostate cancer?

Table 73

GRADE profile: what is the most effective intervention for osteoporosis as a result of long-term androgen suppression for prostate cancer? Comparison: denosumab versus control

Table 74. GRADE profile: what is the most effective intervention for osteoporosis as a result of long-term androgen suppression for prostate cancer?

Table 74

GRADE profile: what is the most effective intervention for osteoporosis as a result of long-term androgen suppression for prostate cancer? Comparison: exercise versus control

Overall survival

One study (Rao et al. 2008) provided low quality evidence of no significant improvement in overall survival between patients receiving bisphosphonates compared to those receiving no intervention.

One study (Smith et al. 2012) provided moderate quality evidence of no significant improvement in overall survival between patients receiving denosumab, compared to no intervention (though the number of patients surviving was not reported). The study also reported no significant difference in median survival time between the two groups.

Fracture rate

One study (Klotz et al. 2013) provided low quality evidence of no significant difference in overall fracture rate between patients treated with alendronate and those receiving no intervention (p=0.43). Another study (Smith et al. 2009) provided moderate quality evidence of no significant difference in overall fracture rate between patients treated with denosumab and those receiving no intervention. However, this study did find a significant reduction in the occurrence of more than one fracture at any site in the denosumab group (p=0.006).

One study (Greenspan et al. 2007, 2008) provided low quality evidence of no significant difference in the rate of fragility fractures between patients receiving a bisphosphonate (alendronate) and those receiving no intervention.

Smith et al. (2003) found moderate quality evidence of no significant difference in the number of newly diagnosed or worsening vertebral fractures between patients receiving zoledronic acid or no intervention. One moderate quality study (Smith et al. 2009) also found a significant reduction in vertebral fractures in patients receiving denosumab compared to those receiving no intervention (RR 0.39 95% CI 0.20–0.78). The results suggest that for every 1,000 patients, 23 fewer vertebral fractures occur in those receiving denosumab alongside their ADT.

Osteonecrosis of the jaw

Seven studies, ranging from 12 to 24 months in follow-up, provided low quality evidence of no occurrence of osteonecrosis of the jaw (ONJ) in those receiving bisphosphonates or no intervention.

One study (Smith et al. 2012) provided very low quality evidence of an increased risk of ONJ in patients receiving denosumab compared to those receiving no intervention at 30 months (incidence of 2.3% compared to 0.0%). Another study (Smith et al. 2009) found no occurrence of ONJ in either the denosumab or no intervention group at 36 months.

Bone mineral density loss

Sixteen studies provided moderate quality evidence of a lower risk of bone mineral density (BMD) loss at the lumbar spine in patients receiving bisphosphonates than those receiving no intervention. There was a mean BMD increase of 4.1% in the bisphosphonates group and a mean decrease of 2.7% in the no intervention group. Seven of the studies contributed data to the meta-analysis which suggests a mean difference of 7.2% change (95% CI 5.7%–8.7%; p<0.0001) between those receiving bisphosphonates and those receiving no intervention. Six of the studies assessed the effect of zoledronic acid and found a significant mean difference of 7.7% (95% CI 6.1%–9.2%) compared to a no intervention group. The seventh study (Greenspan et al. 2007, 2008) assessed the effect of alendronate and found a significant mean difference of 5.1% (95% CI 3.5%–6.7%) compared to the no intervention group. One high quality study (Smith et al. 2009) reported a significant difference in lumbar spine BMD change between patients receiving denosumab and those receiving no intervention. A BMD increase of 5.6% was reported in the denosumab group compared to a decrease of 1.0% in the no intervention group (p<0.001).

Twelve studies provided low quality evidence of a lower risk of BMD loss at the hip in patients receiving bisphosphonates than those receiving no intervention. There was a mean BMD increase of 1.0% in the bisphosphonates group and a mean decrease of 1.6% in the no intervention group. Five of the studies contributed data to the meta-analysis which suggests a mean difference of 3.0% change (95% CI 2.0%–4.1%; p<0.0001) between those receiving bisphosphonates and those receiving no intervention. Four of these studies assessed the effect of zoledronic acid and found a significant mean difference of 3.6% (95% CI 2.9%–4.3%) compared to a no intervention group. The fifth study (Greenspan et al. 2007, 2008) assessed the effect of alendronate and found a significant mean difference of 1.4% (95% CI 0.4%–2.4%) compared to the no intervention group. One high quality study (Smith et al. 2009) also reported a significant difference in total hip BMD change between patients receiving denosumab and those receiving no intervention, but did not report the estimated percentage change.

Ten studies provided low quality evidence of a lower risk of BMD loss at the femoral neck in patients receiving bisphosphonates than those receiving no intervention. There was a mean BMD increase of 1.2% in the bisphosphonates group and a mean decrease of 2.1% in the no intervention group. Five of the studies contributed data to the meta-analysis which suggests a mean difference of 2.9% change (95% CI 2.1%–3.8%; p<0.0001) between those receiving bisphosphonates and those receiving no intervention. Four of the studies assessed the effect of zoledronic acid and found a significant mean difference of 3.3% (95% CI 2.2%–4.4%) compared to a no intervention group. The fifth study (Greenspan et al. 2007, 2008) assessed the effect of alendronate and found a significant mean difference of 2.3% (95% CI 0.9%–3.7%) compared to the no intervention group.

Three studies provided low quality evidence of a lower risk of BMD loss at the trochanter in patients receiving bisphosphonates than those receiving no intervention. Two of these studies (Smith et al. 2003; Michaelson et al. 2007) contributed data to the meta-analysis which suggests a mean difference of 4.0% change (95% CI 2.2%–5.8%; p<0.0001) between those receiving the bisphosphonate zoledronic acid and those receiving no intervention.

Health-related quality of life

One study (Galvao et al. 2010) provided moderate quality evidence of the impact of an exercise intervention on the health-related quality of life of prostate cancer patients undergoing ADT. The SF-36 was used to assess general quality of life status and found significantly better scores for general health, vitality and physical health in the exercise group. The QLQ C30 was also used to assess cancer specific quality of life and found the exercise group to have significantly better scores for role, cognitive, fatigue, nausea and dyspnea measures.

Skeletal-related events and change in FRAX score

These outcomes were not reported by any of the included studies.

Cost-effectiveness evidence (see also full evidence review) (2014)

A literature review of published economic evidence identified one relevant paper by Ito 2010. The paper was a cost-effectiveness analysis, which quantified health effects in terms of quality adjusted life years (QALYs) and thus can be considered a cost-utility analysis. The primary results of the analysis by Ito 2010 are summarised in Table 75.

Table 75. Modified GRADE table showing the included evidence (Ito 2010) comparing methods of managing and treating osteoporosis.

Table 75

Modified GRADE table showing the included evidence (Ito 2010) comparing methods of managing and treating osteoporosis.

No further health economic analysis was undertaken for this topic because other topics were deemed to be of greater economic importance and were thus given greater priority.

Study quality and results

The study was deemed only partially applicable to the guideline. This was mostly a result of the study considering a country other than the UK (analysis considered a U.S. setting). Minor limitations were identified with the study, with some minor concerns around the use of author assumptions and estimates. However, these were only used where no evidence could be sourced. Furthermore, there were no conflicts of interest identified so there is no reason to suspect that these assumptions were not made objectively.

Evidence statements

The base case results from Ito 2010 suggest that that the use of alendronate therapy in prostate cancer patients with osteoprosis improves effectiveness in QALY terms but that this comes at an increased cost. A strategy of selective alendronate therapy using BMD tests is shown to reduce the additional costs by reducing the number of patients that are treated unnecessarily (i.e. reducing ‘over-treatment’). In comparison to no alendronate therapy, selective alendronate therapy provided an additional QALY at a cost of $66,800.

Since the study is US based, it is difficult to draw firm conclusions from the analysis when applying it to the UK setting. However, it does show that selective alendronate therapy is more likely to be cost-effective than universal alendronate therapy.

In addition, the QALYs estimated in the study are potentially underestimates since they are based only on hip fractures. Including other fractures would potentially further increase incremental QALYs and thus improve the cost-effectiveness of selective alendronate therapy in comparison to no alendronate therapy.

RecommendationConsider assessing fracture risk in men with prostate cancer who are having androgen deprivation therapy, in line with Osteoporosis fragility fracture (NICE clinical guideline 146). [new 2014]

Offer bisphosphonates to men who are having androgen deprivation therapy and have osteoporosis. [new 2014]

Consider denosumab for men who are having androgen deprivation therapy and have osteoporosis if bisphosphonates are contraindicated or not tolerated. [new 2014]
Relative value placed on the outcomes consideredThe GDG considered the outcomes of bone mineral density loss and fracture rate to be the most important to identifying the most effective intervention to treat osteoporosis resulting from long-term androgen deprivation.

The outcomes of skeletal related events and change in fracture risk assessment tool (FRAX) score were not reported for any of the interventions of interest.

The GDG noted that whilst the evidence did report the outcome of health-related quality of life, it was not possible to determine if the effect on this outcome was a result of the intervention for osteoporosis. As a result the GDG did not consider this outcome when agreeing their recommendations.
Quality of the evidenceThe evidence on bone mineral density loss and fracture rate for bisphosphonates ranged from low to moderate quality as assessed by GRADE. The evidence on fracture rate and bone mineral density loss for denosumab was assessed by GRADE as moderate and high quality respectively. No evidence was found comparing calcium or vitamin D to patients not receiving these supplements.

The GDG noted that several studies lacked sufficient power to measure overall survival and fracture rate and that the number of participants was low. The GDG relied on the surrogate outcome of bone mineral density loss to correct for the weakness in the fracture rate data.
Trade-off between clinical benefits and harmsIt was noted that evidence had shown reduced fracture rates and improved bone mineral density with the use of bisphosphonates in men with osteoporosis resulting from long-term androgen deprivation. There was also evidence of no increase in the risk of osteonecrosis of the jaw.

The GDG noted there was high quality, limited evidence to show that denosumab has a positive impact on vertebral fractures. The GDG were also aware, based on their clinical experience that denosumab is the only treatment option available for men who have osteoporosis resulting from androgen deprivation therapy, but who have contraindications to using bisphosphonates. However the GDG were aware that the use of denosumab has potentially significant cost implications. They therefore recommended that this treatment be considered for men who are intolerant to or have contraindications to using bisphosphonates.

Due to the lack of evidence on the use of calcium and vitamin D to treat osteoporosis resulting from long term androgen deprivation, the GDG were not able to make any recommendations on these interventions.
Trade-off between net health benefits and resource useThe GDG noted that published cost effectiveness evidence had concluded that bone mineral density test followed by selective alendronate therapy had an ICER of $66,800/QALY (sterling equivalent = £48,238/QALYcc). The GDG were aware that this study was not UK based and that the quality of life data was often based on assumptions by clinical experts, rather than reported directly by patients. However they also noted that the clinical and cost effectiveness evidence came from trials which had given bisphosphonates to all men on androgen deprivation therapy, not just those with osteoporosis. The GDG considered that the clinical benefits and cost-effectiveness of using bisphosphonates in men with osteoporosis may have been underestimated because the study didn’t take into account all types of fractures and limited itself to hip fractures. In addition the calculation of reference costing may have been greater than that applicable in the UK. The GDG therefore agreed to recommend the use of bisphosphonates for treating osteoporosis resulting from long term androgen deprivation.
OtherThe GDG acknowledged that NICE guidance already existed about providing fracture risk assessment for men on androgen deprivation therapy. However they were concerned that consideration of such risk assessment is not yet embedded in clinical practice and therefore agreed to specifically highlight these recommendations from CG146.
cc

2008 US values converted to 2012 UK values using OECD price list from Cost conversion website: CCEMG – EPPI – Centre Cost Converter. Accessed at: http://eppi​.ioe.ac.uk​/costconversion/default.aspx

Research recommendationWhat is the clinical and cost effectiveness of standard care with bisphosphonates compared with denosumab to treat osteoporosis caused by long-term androgen deprivation therapy? [2014]
Why is this importantMen having long-term androgen deprivation therapy for prostate cancer have an increased fracture risk. Osteoporosis (NICE clinical guideline 146) recommends that fracture risk be assessed when starting long-term androgen deprivation therapy but the effectiveness of interventions such as bisphosphonates and denosumab in men with an increased fracture risk is not known.

7.4.5. Gynaecomastia

Gynaecomastia is a common, troublesome complication of long-term bicalutamide monotherapy. Randomised trials have studied the use of tamoxifen and of prophylactic radiotherapy to the breast buds. Although tamoxifen was shown to be an effective treatment of bicalutamide induced gynaecomastia, there is a theoretical concern that, as an anti-oestrogen, it could have an adverse effect on prostate cancer control.

RecommendationFor men starting long-term bicalutamide monotherapy (longer than 6 months), offer prophylactic radiotherapy to both breast buds within the first month of treatment. Choose a single fraction of 8 Gy using orthovoltage or electron beam radiotherapy. [2008]

If radiotherapy is unsuccessful in preventing gynaecomastia, weekly tamoxifendd should be considered. [2008]
Qualifying statementThese recommendations are based on GDG consensus, informed by several small RCTs.
dd

At the time of publication (January 2014), tamoxifen did not have a UK marketing authorisation for this indication. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. Informed consent should be obtained and documented. See the General Medical Council’s Good practice in prescribing and managing medicines and devices for further information.

Clinical evidence (2008)

Gynaecomastia

A systematic review (Di Lorenzo et al. 2005) considered evidence from randomised trials of radiotherapy or tamoxifen for the prevention and treatment of gynaecomastia and breast pain associated with anti-androgens. A narrative review of the evidence supported the effectiveness of both radiotherapy and tamoxifen, although there were theoretical concerns that, as an anti-oestrogen, tamoxifen could reduce the effectiveness of hormonal therapy.

Cost-effectiveness evidence (2008)

The GDG did not rate this topic as a health economic priority; therefore the cost-effectiveness literature on this topic has not been reviewed.

7.4.6. Fatigue

Androgen deprivation can cause fatigue and loss of muscle mass which can negatively affect quality of life. It has been suggested that exercise (e.g. resistance, aerobic) and counselling, in particular cognitive behavioural therapy, may be effective at reducing fatigue in men on long term androgren deprivation.

Clinical question: What is the most effective intervention for fatigue as a result of long term androgen suppression for prostate cancer?

Clinical evidence (see also full evidence review) (2014)

Evidence statements

The evidence for all pre-specified outcomes is summarised in Tables 76 to 78

Table 76. GRADE profile: what is the most effective intervention for fatigue as a result of long-term androgen suppression for prostate cancer?

Table 76

GRADE profile: what is the most effective intervention for fatigue as a result of long-term androgen suppression for prostate cancer? Comparison: interpersonal counselling versus health education

Table 77. GRADE profile: what is the most effective intervention for fatigue as a result of long-term androgen suppression for prostate cancer?

Table 77

GRADE profile: what is the most effective intervention for fatigue as a result of long-term androgen suppression for prostate cancer? Comparison: physical training plus information versus control

Table 78. GRADE profile: what is the most effective intervention for fatigue as a result of long-term androgen suppression for prostate cancer?

Table 78

GRADE profile: what is the most effective intervention for fatigue as a result of long-term androgen suppression for prostate cancer? Comparison: exercise versus control

Fatigue

One RCT compared interpersonal counselling with health education for men with prostate cancer (42% treated with hormone therapy) (Badger et al. 2011). Improvements in fatigue were higher for patients in the health education group than for those in the counselling group, although wide confidence intervals suggest there could be little difference between the two interventions (MD 5.12 95% CI −3.08–13.32).

Another study provided moderate quality evidence where men with prostate cancer were randomised to one of four groups (physical training; information; physical training plus information; or control) (Berglund et al. 2007). There was no significant effect of treatment on fatigue (scores for each group were not reported).

Of nine RCTs assessing the effectiveness of exercise, one did not provide details of the intervention (Oneill et al. 2012) but found a significant mean difference in fatigue between exercise interventions and the no intervention group of 0.38 (95% CI 0.11–0.66; p≤0.01). Two studies assessed a home-based exercise programme; one undertaken during radiotherapy and one undertaken whilst undergoing ADT. The remaining six studies investigated the effectiveness of supervised exercise during radiotherapy and ADT. The results of the studies were pooled for aerobic and resistance exercise separately; the pooled results for the home-based exercise studies showed a medium-sized, non-significant reduction in fatigue in favour of the exercise group (SMD 0.27 95% CI −0.04–0.57). The results from two studies after supervised aerobic exercise showed a large though non-significant reduction in fatigue in favour of the exercise group (SMD 0.75 95% CI −0.42–1.93). Because statistical heterogeneity was present (p=0.03) a sensitivity analysis was performed in which the outlying study (Monga et al. 2007) was excluded. This reduced the effect size to a small non-significant reduction in fatigue (SMD 0.23 95% CI −0.21–0.68). The pooled results for two studies of resistance exercise showed a small non-significant reduction in fatigue in favour of the exercise group (SMD 0.20 95% CI −0.07–0.47). The pooled results of two studies of combined aerobic and resistance exercise showed a large-sized significant reduction in fatigue in favour of the exercise group (SMD 0.96 95% CI 0.54.38).

Health-related quality of life

One moderate quality study found that health-related quality of life scores were higher in the health education group compared to interpersonal counselling, but this outcome lacked precision due to wide confidence intervals (MD −2.78 95% CI −6.60–12.16) (Badger et al. 2011).

The study providing moderate quality evidence on physical training versus information versus physical training plus information versus control, found no significant effect of treatment on quality of life (scores for each group were not reported) (Berglund et al. 2007).

One high quality study found a significant mean difference in health-related quality of life between exercise interventions and the no intervention group of 0.20 (95% CI 0.04–0.36; p≤0.01), but did not provide details of the exercise intervention (Oneill et al. 2012).

Cost-effectiveness evidence (2014)

A literature review of published cost-effectiveness analyses did not identify any relevant papers. No further economic modelling was undertaken due to the relatively insignificant cost implications.

RecommendationOffer men who are starting or having androgen deprivation therapy supervised resistance and aerobic exercise at least twice a week for 12 weeks to reduce fatigue and improve quality of life. [new 2014]

Tell men who are starting androgen deprivation therapy that fatigue is a recognised side effect of this therapy and not necessarily a result of prostate cancer. [new 2014]
Relative value placed on the outcomes consideredThe GDG considered the outcomes of fatigue and health related quality of life to be the most relevant to determining the most effective intervention for fatigue.

The GDG agreed to consider the additional outcome of intervention duration, as it was seen to be an important issue.
Quality of the evidenceThe evidence on both fatigue and health related quality of life ranged from moderate to high quality, as assessed by GRADE.

The GDG noted that in the majority of included studies, men were receiving androgen deprivation therapy at the same time as receiving the interventions. In addition, some of the studies which included interpersonal counselling as an intervention had wide confidence intervals associated with the data and the trial which assessed counselling as an intervention included all men with prostate cancer of which only 26% were reported as being on long term androgen deprivation therapy.
Trade-off between clinical benefits and harmsThe GDG noted that the evidence showed there was no significant effect of counselling on fatigue or quality of life. However the GDG agreed that some advice should be given to men starting androgen deprivation therapy about the likelihood of experiencing fatigue and that they should be made aware that fatigue is a recognised side effect of testosterone suppression and not necessarily of prostate cancer.

There was high quality evidence from a meta-analysis for the use of exercise in order to reduce the effects of fatigue and quality of life for men with prostate cancer starting or on androgen deprivation therapy. The results for home based exercise, supervised aerobic exercise alone and supervised resistance alone showed non-significant improvements in fatigue in favour of the intervention. However the pooled results of two studies of combined aerobic and resistance exercise showed a significant reduction in fatigue in favour of the exercise group. In addition six high quality studies assessed the effects of exercise on health related quality of life and showed that the intervention having the most beneficial effect was combined. Therefore the GDG agreed to recommend combined supervised aerobic and resistance exercise to reduce fatigue and improve quality of life.

The GDG noted that the recommendations in CG58 did not include any advice on the frequency or duration of regular resistance exercise to reduce fatigue. However the GDG noted that the invention duration for combined supervised aerobic and resistance exercise was twice weekly for 12 weeks in both trials where these interventions were assessed. Therefore the GDG decided to recommend that men starting or on androgen deprivation therapy should be offered supervised resistance and aerobic exercise for a minimum of 2 times per week for 12 weeks in order to reduce fatigue and improve quality of life.

The GDG agreed that the use of supervised resistance and aerobic classes will lead to a significant reduction in fatigue with minimal adverse events and improved quality of life. No harms associated with these recommendations were identified by the GDG.

Although the strength of evidence on the use of supervised resistance and aerobic exercise for men with prostate cancer on long term androgen suppression was moderate to high, the GDG were not certain whether a 12 week programme was sufficient. Therefore they agreed to include a research recommendation to assess whether combined supervised aerobic resistant exercise needs to be continued beyond 12 weeks in men receiving long term androgen suppression.
Trade-off between net health benefits and resource useThe GDG noted that no relevant, published economic evaluations had been identified and no additional economic analysis had been undertaken in this area. The GDG agreed there would be additional costs incurred by recommending supervised resistance and aerobic exercise programmes twice weekly for 12 weeks but were confident that the strength of the evidence for this intervention justified these costs.
OtherAs a result of the recommendations made, the GDG felt that some men (particularly those who were disabled) may have difficulty using these services due to their inability to attend exercise classes or because of poor or non-existent provision of facilities. The GDG agreed that service providers and commissioners should be aware of this issue when implementing these recommendations.
Research recommendationWhat is the effectiveness of 12 weeks of supervised aerobic resistance exercise compared with longer than 12 weeks in reducing fatigue in men receiving androgen deprivation therapy? [2014].
Why is this importantSupervised aerobic resistance exercise given for 12 weeks has been shown to improve quality of life and reduce side effects for men receiving androgen deprivation therapy for prostate cancer. It is not clear whether continuing the exercise program beyond 12 weeks will result in further improvements.

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