Adverse effects of androgendeprivation therapy ... - Wiley Online Library

Adverse effects of androgen-deprivation therapy in prostate cancer and their management Handoo Rhee*†, Jennifer H. Gunter†, Peter Heathcote*†, Ken Ho‡, Phillip Stricker§, Niall M. Corcoran¶ and Colleen C. Nelson† *Department of Urology and ‡Centre for Health Research, Princess Alexandra Hospital, †Australian Prostate Cancer Research Centre, Institute of Health and Biomedical Innovation, Queensland University of Technology, Princess Alexandra Hospital, Translational Research Institute, QLD, §Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, NSW, and ¶Epworth Prostate Centre, Epworth Healthcare, Melbourne, Australia

Objective To provide an up-to-date summary of current literature on the management of adverse effects of androgen-deprivation therapy (ADT).

Patients and Methods All relevant medical literature on men with prostate cancer treated with ADT from 2005 to 2014, and older relevant papers, were reviewed. Recent health advisory statements from the Australian government, societies and advocacy groups have been incorporated to the document.

cardiovascular disease, diabetes and osteoporosis, to depression, cognitive decline and sexual dysfunction, the range of adverse effects is wide. Baseline assessment, monitoring, prevention and consultation from a multidisciplinary team are important in minimising the harm from ADT.

Conclusions This review provides a series of practical recommendations to assist with managing the adverse effects of ADT.

Results

Keywords

There are numerous adverse effects of ADT that require pro-active prevention and treatment. Ranging from

androgen-deprivation therapy, prostate cancer, adverse effect

Introduction

This review provides an up-to-date summary of current literature that aims to assist clinicians, with a particular focus on Australian practice. Our aim is to provide a quick reference guide, and to highlight and make practical recommendations for potential adverse events. It is beyond the scope of this review to discuss in detail the controversies in indications for ADT, types or strategies of ADT, secondary hormonal manipulation, management of CRPC, and non-standard treatments for adverse events. There are more comprehensive reviews and commissioned societal guidelines such as the Clinical Practice Guidelines for the Management of Locally Advanced and Metastatic Prostate Cancer by the Cancer Council Australia and Australian Cancer Network [2], which have been referred to within the present article.

Prostate cancer is a highly prevalent malignancy affecting a significant proportion of men in the western world. Androgen-deprivation therapy (ADT), in the form of surgical or chemical castration, plays an integral part in the management of prostate cancer. It is clearly beneficial in men with symptomatic advanced prostate cancer or as a neoadjuvant therapy in those receiving radiotherapy. In patients with metastatic disease, the treatment is initially efficacious with the mean expected response duration of ≈3 years [1]. The end-stage prostate cancer termed ‘castrate-resistant prostate cancer’ (CRPC), then follows with the mean life-expectancy of 1–2 years [1]. In patients with biochemical recurrence after primary treatment without obvious metastatic disease, and in those with asymptomatic locally invasive or occult metastatic disease, the role and the timing of ADT are much more controversial. Unfortunately, these challenging groups of patients may be subjected to ADT and its morbidities for substantially longer periods than patients with widespread metastatic disease. As patients live for increasingly extended periods, awareness of the adverse effects related to drug induced hypogonadism and subsequent changes are important. © 2014 The Authors BJU International © 2014 BJU International | doi:10.1111/bju.12964 Published by John Wiley & Sons Ltd. www.bjui.org

Strategies for Using ADT Indications It has recently become clear that in the absence of curative intent therapy, ADT as monotherapy is unlikely to benefit patients unless they are at high risk of dying from prostate cancer (Table 1) [2–4]. A prospective European Organisation for the Research and Treatment of Cancer trial (EORTC)

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Table 1 Indications for ADT. Mx Neoadjuvant/adjuvant with curative-intent therapy M0

Palliative/not suitable for curative-intent therapy M0

Categories

Duration

Localised S0, low risk Intermediate risk High risk

Not advised as primary, neoadjuvant or adjuvant therapy with surgery or RT Neoadjuvant with RT Neoadjuvant with RT

Not applicable 4–6 months 2–3 years

Locally advanced

Primary immediate if PSA level of >50 ng/L, doubling time 50–75 nmol/L ○ Assess for risk of fractures (http://shef.ac.uk/FRAX/tool.aspx) Ë Treat if 10 year hip fracture risk ≥3% or major osteoporosis related fracture risk ≥20% • Refer to endocrinologist/oncologist • Pharmaceutical Benefits Scheme prescription: ○ Bisphosphonate – Alendronate 70 mg weekly, Risedronate 35 mg weekly, Zoledronic acid 4 mg 6 monthly Ë Indication – Osteoporotic men aged >70 years or those who have had fracture due to minimal trauma ○ Denusumab 60 mg 6 monthly Ë Indication – 4 mg given 6 monthly is subsidised for patients aged >70 years with T score of ≤–3.0, or established osteoporosis with fracture from minimal trauma ○ Pre-treatment dental assessment and follow-up to reduce risk of osteonecrosis of jaw

osteoporosis, as trabecular numbers also decline with the actual density of the bone [33]. This underscores the importance of preventing the initial loss early. BMD is a surrogate for fracture risk, which in turn is associated with increased risk of mortality. In a large observational study, ADT was associated with increased rate of fracture (hazard ratio, 1.34), and mortality risk doubled after a fracture [35]. Bisphosphonate diminishes the activity of osteoclasts to reduce BMD loss. Weekly oral alendronate dosage appears to be enough to maintain BMD in non-metastatic population [36]. Intravenous (i.v.) zoledronic acid in general appears to be more potent, as administration once a year was enough to increase BMD by 4% [37]. Yet, despite the positive effects on BMD, it does not appear to decrease fracture rate, increase overall survival, nor change time to metastasis [38]. Interestingly, this is in contrast to the effects in a CRPC cohort where i.v. bisphosphonate has been found to reduce fracture risk [39]. Therefore, selective use of bisphosphonate seems sensible in patients with end-stage prostate cancer. However, the medication given in high doses is associated with devastating drug reactions, such as hypocalcaemia (6%) and osteonecrosis of jaw (2%), which warrant pre-treatment assessment and follow-up [40]. Denosumab is a monoclonal antibody against receptor activator of nuclear factor κ B (RANK) ligand, an essential mediator of osteoclast function and proliferation [41]. Inhibition of the ligand impedes the bone resorbing function and survival of osteoclasts. Denosumab has been shown increase BMD (5.6% vs –1%) and decrease fracture rates (1.5% vs 3.9%) when given 6 monthly (60 mg) in patients with non-metastatic prostate cancer over 24 months [41]. Encouragingly, a high dosage with short interval regimen (120 mg, 4 weekly) increased time to skeletal-related events (3.6 months), as well as bone metastasis-free survival (4.2 months) in patients with CRPC [40,42]. As with bisphosphonate, denosumab was also associated with hypocalcaemia (2%) and osteonecrosis of jaw (5%) [43]. Recommendations are summarised in Table 6 [44].

Cardiovascular Disease (CVD) Almost all observational/retrospective studies demonstrate an association between ADT and CVD and sudden cardiac death. The largest of the observational studies, published by Keating et al. [45] showed that ADT was associated with an increased risk of myocardial infarct with hazard ratio of 1.09. The risk of death from CVD increased with particular risk factors (see below in recommendations, Table 7 [31,45,46]). Similarly, a recent Canadian review associated ADT with a 31% increase in the risk of myocardial infarct and 16% increase in the risk of cerebrovascular disease [47]. Interestingly, in post hoc analysis of RCTs, no statistically significant increase in CVD could be identified [46]. Such discrepancies may be explained by the fact that the use of ADT is skewed towards those who are not deemed fit for treatment with intention to cure. Moreover, the patients in the RCTs may be of better health than the general population. The truth is likely to be somewhere in-between, as CVD is still the most common cause of death in men diagnosed with prostate cancer. As Nguyen [48] points out, there is likely to be a subset of patients who are very susceptible to CVD from ADT and close monitoring of those with risk factors for CVD is recommended. In 2010, a science advisory statement from the American Heart Association published in Circulation [46] stated ‘It is reasonable, on the basis of the above data, to state that there may be a relation between ADT and cardiovascular events and death’. This position statement allowed the USA Food and Drug Administration to issue a warning on the class of LHRH analogues in 2010. Recommendations are summarised in Table 7. Risk Factors for CVD: Metabolic Syndrome, Diabetes and Sarcopaenic Obesity Metabolic syndrome Metabolic syndrome is common in men, even before starting ADT [11]. One of the most commonly accepted definitions of metabolic syndrome includes a constellation of biochemical © 2014 The Authors BJU International © 2014 BJU International

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Table 7 Recommendations – CVD. • Identify patients at risk of CVD such as [45]: ○ History of myocardial infarction ○ History of cerebrovascular events ○ Congestive heart failure ○ Peripheral arterial disease • Follow ‘National Vascular Disease Prevention Alliance’ guideline [31]: ○ Manage individual risk factors- see below ○ Stop smoking ○ Follow ‘Dietary Guidelines for Australian Adult’ (NHMRC)/’Benefits of Healthy Diet and Physical Activity for Cancer Survivors’ (CCA) Ë Diet rich in vegetables and fruit Ë Diet low in salt and saturated and trans fats ○ Follow ‘Australian Guidelines to Reduce Health Risks from Drinking Alcohol’ (NHMRC) Ë Minimise or avoid alcohol ○ At least 30 min of moderate intensity physical activity 5 days a week 2 ○ Maintain waist