Accepted Article
Adverse Effects of Androgen Deprivation Therapy in Prostate Cancer and Their Management 1
H. Rhee1,2, J.H. Gunter2, P. Heathcote1,2, K. Ho3, P. Stricker4, N.M. Corcoran5, C.C. Nelson2
1
Department of Urology, Princess Alexandra Hospital, Brisbane, Australia
2
Australian Prostate Cancer Research Centre, Queensland Branch, Brisbane, Australia
3
Centre for Health Research, Princess Alexandra Hospital, Brisbane, Australia
4
Australian Prostate Cancer Research Centre, New South Wales Branch, Sydney, Australia
5
Australian Prostate Cancer Research Centre, Victorian Branch, Melbourne, Australia
Corresponding author: Handoo Rhee
Australian Prostate Cancer Research Centre Queensland Branch Translational Research Institute Ipswich Road, Woolloongabba, Brisbane QLD 4102 Australia
Email: [email protected] Phone: +61 7 3176 6946
ABSTRACT
OBJECTIVE: To provide an up-to-date summary of current literature on the management of adverse effects of androgen deprivation therapy (ADT).
SUBJECTS: All men suffering from prostate cancer who are treated with androgen deprivation therapy.
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/bju.12964 This article is protected by copyright. All rights reserved.
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METHODS: All relevant medical literature from 2005 to 2014 and older relevant papers were reviewed to formulate this article. Recent health advisory statements from the Australian government, societies and advocacy groups have been incorporated to the document.
RESULTS: There are numerous adverse effects of ADT that require pro-active prevention and treatment. Ranging from 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 minimizing the harm from ADT.
CONCLUSIONS: This review provides series of practical recommendations to assist with managing adverse effects of ADT.
Key Words: Androgen deprivation therapy, prostate cancer, adverse effect
Word Count: 4766
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 approximately 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 post 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 of time, awareness of the adverse effects related to drug induced hypogonadism and subsequent changes are important. 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 This article is protected by copyright. All rights reserved.
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Cancer Council Australia and Australian Cancer Network (2) which have been referred to within this article.
STRATEGIES FOR USING ANDROGEN DEPRIVATION THERAPY 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). A prospective trial EORTC 30981(3), recently reported that in patients who are unsuitable for local treatments due to metastatic disease or significant comorbidities, the only subgroups of patients that benefited from primary ADT were those with baseline prostate specific antigen (PSA) >50ng/mL and or when PSA doubling time was 1cm shortening of penile length in 93% (23). An ADT Survivorship Working Group published a sexual health focused paper that described the implications of sexual dysfunction including relationship changes and cognitive and affective disorders such as depression. A series of recommendations have been made ranging from counselling to erectile dysfunction medications, and even penile prosthesis in this population of patients (24). Quality of life recommendations are summarised in Table 3. Gynaecomastia/Mastalgia: Gynaecomastia is defined as proliferation of subareolar gland and ductal tissue, which may be associated with mastalgia. It is an irreversible and embarrassing side effect. Antiandrogen agents such as bicalutamide are significantly more likely to cause gynaecomastia and or mastalgia (up to 90% incidence) (23) and treatments with LHRH agonists have approximately 30% breast event rate (23). Both radiotherapy and tamoxifen has been shown to effectively reduce the risk of development when used as a prophylaxis, however, these strategies are not commonly adopted (25); tamoxifen is not PBS subsidized for this purpose. Otherwise, symptomatic relief using simple analgesia is usually employed. Hot flushes: Hot flushes are some of the most commonly experienced complaints affecting up to 80% of patients and described as sudden diaphoresis and facial discomfort (23). It is debilitating to some, and remains one of the leading causes of non-compliance. Lifestyle advice such as avoidance of triggers (e.g. heating or spicy foods) has a role in managing the reaction. Numerous medications are available and all demonstrate reasonable efficacy. In a randomized controlled trial, venlafaxine (selective serotonin re-uptake inhibitor, 75mg), cyproterone acetate (100mg) and medroxyprogestrone (20mg) all demonstrated improvements within 1 month (symptom scores: -47.2%, -94.5% and -83.7% respectively) (26). Unfortunately, none of the medications is available under the PBS, and are used offlabel in Australia. Again, the toxicity of cyproterone acetate needs to be noted prior to its use. Recommendations are summarised in Table 4. Quality of Life: Physical Function and Exercise Until recently, supervised exercise was not considered a serious contender in the management of the adverse effects of ADT. This was mostly due to the fact that the optimal exercise prescription was difficult to define and therefore, the outcomes of studies varied according to the exercise programmes implemented. Recent pioneering work in the field by exercise physiologists such as Galvao and Newton has managed to define supervised exercise programmes, which are becoming an important component of prescribing ADT. This article is protected by copyright. All rights reserved.
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As an exercise triggers anabolic and stimulating physiological changes to multiple organ systems in a body, the effects are broad and promising. In a recent randomized controlled trial by Cormie et al, early exercise intervention with ADT resulted in the preservation of total body weight, lean body mass, fat mass, as well as BMD and cholesterol levels (27). This is in contrast to the non-interventional arm developing adiposity, sarcopaenia, loss of BMD and dyslipidaemia. Further, physical function and quality of life components such as sexual health, fatigue and psychological distress also improved significantly. In recognition of the emerging benefits of exercise in combating ADT side effects, leuprolide users in Australia are entitled to a heavily discounted exercise programme. Kim et al recently reviewed the outcomes of the programme in Australia and found that it preserved patients’ body habitus, fitness and muscle strength (28). Results are less impressive for patients enrolling in exercise intervention programmes months to years after starting ADT, such as those in the Trans-Tasman Radiation Oncology Group trial (29). Although exercise improved fitness, physical function, muscle strength and mental health, the range of benefits were not as impressive as in those who started exercise intervention immediately with ADT. In a recent meta-analysis by Gardiner et al, the authors concluded that despite the varying outcomes from the randomized controlled trials, clinically meaningful benefits to the patients were observed during the periods of exercise. With continuation of exercises at home, beneficial outcomes were maintained even at 6 months post supervised intervention (30). Recommendations are summarised in Table 5. Bone Health The prevalence of osteopaenia and osteoporosis are high in patients newly diagnosed with prostate cancer (39% and 41% respectively) (32). Within the first year of ADT, absolute bone mineral density (BMD) loss is approximately 5% (33). The temporal relationship of ADT and incidence of osteoporosis is demonstrated over 4 and 10 years at 49.2% and 80.6% respectively (34). Further, dual energy X-ray absorptiometry (DEXA) scans underestimate osteoporosis, as trabecular numbers also decline with the actual density of the bone (33). This underscores the importance of preventing the initial loss early. Bone mineral density 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 (IV) 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 IV bisphosphonate has been found to reduce fracture risk (39). Therefore, selective use of bisphosphonate seems sensible in end stage prostate cancer patients. 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). This article is protected by copyright. All rights reserved.
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Denosumab is a monoclonal antibody against receptor activator of nuclear factor – kappa 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 (60mg) in patients with non-metastatic prostate cancer over 24 months (41). Encouragingly, a high dosage with short interval regimen (120mg 4 weekly) increased time to skeletal related events (3.6 months) as well as bone metastasis free survival (4.2 months) in CRPC patients (40, 42). As with bisphosphonate, denosumab was also associated with hypocalcaemia and (2%) osteonecrosis of jaw (5%) (43). Recommendations are summarised in Table 6.
Cardiovascular disease
Almost all observational/retrospective studies demonstrate association between ADT and cardiovascular disease (CVD) and sudden cardiac death (SCD). The largest of the observational studies, published by Keating et al demonstrated that ADT was associated with an increased risk of myocardial infarct with hazard ratio of 1.09 (45). The risk of death from CVD increased with particular risk factors (see below in recommendations, Table 7). 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 (46). Interestingly, in post hoc analysis of randomized controlled trials, no statistically significant increase in CVD could be identified (47). 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 randomized controlled trials 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 cardiovascular disease 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 (47) 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 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 cardiovascular disease: Metabolic syndrome, diabetes and sarcopaenic obesity Metabolic syndrome: Metabolic syndrome (MS) is common in men, even before starting ADT (9). One of the most commonly accepted definitions of MS includes a constellation of biochemical and clinical variables such as dyslipidaemia, hypertension and diabetes (Table 8). Interestingly, men treated with ADT classically exhibit higher high-density-lipoprotein (HDL) and preferentially increase subcutaneous fat, a phenotype different to the standard This article is protected by copyright. All rights reserved.
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metabolic syndrome. Although its implications are unknown, cautious approach with close follow up seems reasonable given such substantial association of MS with CVD (49). Hypercholesterolaemia: A rise in fasting cholesterol is an independent risk factor for cardiovascular mortality especially in the middle aged and elderly. ADT has been shown to increase total cholesterol by 10.6%, triglyceride by 26.9%, low density lipoprotein (LDL) cholesterol by 7.3% and increase in HDL cholesterol by 10% within 6 months of ADT from baseline measurements (51). Although the rise in HDL cholesterol may be cardiac protective, the subsequent rise in total cholesterol, triglyceride and LDL cholesterol may adversely affect patients overall.
Obesity: Sarcopenic obesity is a term used to describe a phenomenon of reduction in muscle mass and gain of adiposity. It ultimately affects up to 70% of patients on ADT (52), with significant changes to the body: lean mass decreases by 2.7%, total body fat increases by 9.4% and total body weight by 2.4% (51). Increased total body fat was attributed to a substantial increase in subcutaneous fat, especially near the waist. Sarcopaenia can in itself lead to the loss of strength, fatigue, lower quality of life and potential increase in falls (53). Diabetes Mellitus: Large cohort studies have associated diabetes to ADT with hazard ratios of up to 1.44 (54). Such data is supported by prospective trials that demonstrate substantial increase in fasting insulin (13.5 mU/L baseline vs 17mU/L at 3 months) and insulin resistance in most men on the treatment (55). Further, in those with pre-existing diabetes, glycosylated haemoglobin levels increased over the observational period with associated worsening of glycaemic control and increased use of diabetic medications (56). Recommendations summarised in Table 5.
Acute Kidney Injury: Recently, a potential for ADT to induce renal impairment requiring hospitalization was highlighted by Gandaglia et al (57) and Lapi et al (58). Some would argue that such findings are in keeping with ureteric and outlet obstructions from advanced prostate cancer usually necessitating ADT. Further, patients with CRPC on ADT may be treated with zoledronic acid, which is known to cause AKI. This is a new and controversial finding and is likely to be an area of interest in future research. Chronic renal impairment is associated with CVD and will add further fuel to arguments regarding the causal relationship of ADT to cardiovascular morbidity and mortality. Recommendations summarised in Table
EMERGING THERAPIES Enzalutamide, a potent androgen receptor antagonist is undergoing a phase II study to assess its efficacy as a first line treatment in conjunction with ADT in metastatic prostate cancer patients. It binds to androgen receptors and co-activators potently, whilst inhibiting nuclear translocation of the receptors (59). It has demonstrated 4 months survival advantage post docetaxel failure in CRPC patients and is expected to demonstrate significantly improved survival as a primary treatment. In a recent update on the progress, the reported adverse effects of the drug included gynaecomastia (36%), fatigue (34%), nipple pain (19%), hot flushes (18%) and seizures (1%) (60). This article is protected by copyright. All rights reserved.
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Abiraterone, a specific inhibitor of CYP17, has also demonstrated improved overall survival post docetaxel (61). It is a novel multi-organ, multi-step inhibitor of androgen synthesis. . In the recent update of COU-AA-302 trial, some of the reported complaints from ADT with abiraterone and prednisolone included fatigue (39%), arthralgia (32%), back pain (28%), peripheral oedema (28%), gastrointestinal side effects (22%), hot flush (22%) and hypertension (22%) (62). Twenty percent of patients reported cardiac disorders such as arrhythmias, ischaemic heart disease and heart failure. Further, 10mg prednisone is given concomitantly to counteract mineralocorticoid excess. Long term high dose prednisone may necessitate the help of endocrinologists to combat the challenges of Cushing’s syndrome such as osteoporosis, obesity and diabetes. DISCUSSION The general principle of managing adverse effects of long term ADT is: 1) to recognize that they are almost universal; 2) to discuss the potential complications with patients and partners prior to initiating the treatment; and 3) to proactively prevent, reduce and address the problems (Table 14). The initial discussions may be aided by education packages such as “Advanced Prostate Cancer: a guide for men and their families, Cancer Council Australia”, “Factsheet: Androgen Deprivation Therapy, Andrology Australia” or “Advanced Prostate Cancer Pack, Prostate Cancer Foundation of Australia”. Armed with the latest research in this field, clinicians can provide leadership to a multi-disciplinary team consisting of endocrinologist, cardiologist, geriatrician, dietician, exercise physiologist/physiotherapist and psychologist (Table 15).
A Men’s Health Clinic established in Austin, Australia, is a prime example of wellestablished and efficacious clinical system where all men commenced on ADT are referred for follow up and management by a multidisciplinary team. Unfortunately, without an established centre such as the Men’s Health Clinic, the reality of our health care system means that whilst oncological clinicians can provide leadership, most screening and follow up will have to be performed by themselves in conjunction with general practitioners. Currently, it is highly unlikely that older patients will be assessed by physicians prior to initiating ADT. In a recent review, Shore et al discussed the challenges of adopting novel agents for increasingly complicated advanced prostate cancer sufferers. The authors advised that a multidisciplinary team was necessary to keep up with modern emerging medicine (63).
There are two prospective studies that discuss the impacts of implementing management guidelines. Grossmann et al from Men’s Health Clinic described a bone and metabolic health clinic set up specifically to maintain well-being of patients treated with ADT by close monitoring and follow up. Patients were initially assessed with a battery of screening tests, and new onset of conditions such as osteoporosis, dyslipidaemia or diabetes was treated appropriately. The authors went further to recommend routine bisphosphonate therapy in men with T score below or equal to -2.0 (outside the PBS criteria). After 2 years, 113 men boasted reductions in total cholesterol, blood pressure, increased vitamin D level, maintenance of BMD and fewer cardiovascular events (n=3) (9). In another prospective trial, This article is protected by copyright. All rights reserved.
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Zhumkhawala et al (64) described an osteoporosis management plan using regular follow up and active management of T scores (number of standard deviations below the average BMD for a young adult) less than -2.5. Patients were treated with bisphosphonate, calcium (1200mg) and vitamin D (400-800IU). During 2-5 years of follow up, there was a 70% reduction in hip fracture rate. Although the impact on survival was not assessed, given the evidence above, it is likely to be significant CONCLUSION Androgen deprivation therapy plays a pivotal role in managing prostate cancer. As more patients are diagnosed with prostate cancer, early identification and management of adverse effects of ADT have become more important than ever. Moreover, as the use of novel androgen targeted therapies become more prevalent and patients survive longer, the duration of ADT is expected to increase. In this review, attempts have been made to provide summary of up-to-date information on ADT induced co-morbidities and current treatment recommendations. CONFLICTS OF INTEREST
None declared.
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39. Serpa Neto A, Tobias-Machado M, Esteves MA, et al. Bisphosphonate therapy in patients under androgen deprivation therapy for prostate cancer: a systematic review and meta-analysis. Prostate cancer and prostatic diseases. 2012 Mar;15(1):36-44. PubMed PMID: 21894175. Epub 2011/09/07. eng. 40. Fizazi K, Carducci M, Smith M, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet. 2011 Mar 5;377(9768):813-22. PubMed PMID: 21353695. Pubmed Central PMCID: PMC3090685. Epub 2011/03/01. eng. 41. Smith MR, Egerdie B, Hernandez Toriz N, et al. Denosumab in men receiving androgendeprivation therapy for prostate cancer. The New England journal of medicine. 2009 Aug 20;361(8):745-55. PubMed PMID: 19671656. Pubmed Central PMCID: PMC3038121. Epub 2009/08/13. eng. 42. Smith MR, Saad F, Coleman R, et al. Denosumab and bone-metastasis-free survival in men with castration-resistant prostate cancer: results of a phase 3, randomised, placebo-controlled trial. Lancet. 2012 Jan 7;379(9810):39-46. PubMed PMID: 22093187. Pubmed Central PMCID: PMC3671878. Epub 2011/11/19. eng. 43. Smith MR, Saad F, Oudard S, et al. Denosumab and bone metastasis-free survival in men with nonmetastatic castration-resistant prostate cancer: exploratory analyses by baseline prostatespecific antigen doubling time. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2013 Oct 20;31(30):3800-6. PubMed PMID: 24043751. Pubmed Central PMCID: PMC3795889. Epub 2013/09/18. eng. 44. Grossmann M, Hamilton EJ, Gilfillan C, et al. Bone and metabolic health in patients with nonmetastatic prostate cancer who are receiving androgen deprivation therapy. The Medical journal of Australia. 2011 Mar 21;194(6):301-6. PubMed PMID: 21426285. Epub 2011/03/24. eng. 45. Keating NL, O'Malley AJ, Freedland SJ, Smith MR. Does comorbidity influence the risk of myocardial infarction or diabetes during androgen-deprivation therapy for prostate cancer? Eur Urol. 2013 Jul;64(1):159-66. PubMed PMID: 22537796. Pubmed Central PMCID: PMC3683550. Epub 2012/04/28. eng. 46. Jespersen CG, Norgaard M, Borre M. Androgen-deprivation therapy in treatment of prostate cancer and risk of myocardial infarction and stroke: a nationwide Danish population-based cohort study. Eur Urol. 2014 Apr;65(4):704-9. PubMed PMID: 23433805. Epub 2013/02/26. eng. 47. Levine GN, D'Amico AV, Berger P, et al. Androgen-deprivation therapy in prostate cancer and cardiovascular risk: a science advisory from the American Heart Association, American Cancer Society, and American Urological Association: endorsed by the American Society for Radiation Oncology. Circulation. 2010 Feb 16;121(6):833-40. PubMed PMID: 20124128. Pubmed Central PMCID: PMC3023973. Epub 2010/02/04. eng. 48. Nguyen PL. Androgen-deprivation therapy and cardiovascular harm: let's not throw out the baby with the bathwater. Eur Urol. 2014 Apr;65(4):710-2. PubMed PMID: 23498063. Epub 2013/03/19. eng. 49. Tsai HK, D'Amico AV, Sadetsky N, Chen MH, Carroll PR. Androgen deprivation therapy for localized prostate cancer and the risk of cardiovascular mortality. J Natl Cancer Inst. 2007 Oct 17;99(20):1516-24. PubMed PMID: 17925537. Epub 2007/10/11. eng. 50. WHO. Obesity and Overweight. Fact Sheet. 2012;#311. 51. Smith MR, Finkelstein JS, McGovern FJ, et al. Changes in body composition during androgen deprivation therapy for prostate cancer. The Journal of clinical endocrinology and metabolism. 2002 Feb;87(2):599-603. PubMed PMID: 11836291. Epub 2002/02/12. eng. 52. Kim HS, Freedland SJ. Androgen deprivation therapy in prostate cancer: anticipated sideeffects and their management. Current opinion in supportive and palliative care. 2010 Sep;4(3):14752. PubMed PMID: 20592607. Epub 2010/07/02. eng. 53. Potosky AL, Knopf K, Clegg LX, et al. Quality-of-life outcomes after primary androgen deprivation therapy: results from the Prostate Cancer Outcomes Study. Journal of clinical oncology :
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official journal of the American Society of Clinical Oncology. 2001 Sep 1;19(17):3750-7. PubMed PMID: 11533098. Epub 2001/09/05. eng. 54. Keating NL, O'Malley AJ, Smith MR. Diabetes and cardiovascular disease during androgen deprivation therapy for prostate cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2006 Sep 20;24(27):4448-56. PubMed PMID: 16983113. Epub 2006/09/20. eng. 55. Smith MR, Lee H, Nathan DM. Insulin sensitivity during combined androgen blockade for prostate cancer. The Journal of clinical endocrinology and metabolism. 2006 Apr;91(4):1305-8. PubMed PMID: 16434464. Epub 2006/01/26. eng. 56. Keating NL, Liu PH, O'Malley AJ, Freedland SJ, Smith MR. Androgen-deprivation therapy and diabetes control among diabetic men with prostate cancer. Eur Urol. 2014 Apr;65(4):816-24. PubMed PMID: 23453420. Pubmed Central PMCID: PMC3779484. Epub 2013/03/05. eng. 57. Gandaglia G, Sun M, Hu JC, et al. Gonadotropin-releasing Hormone Agonists and Acute Kidney Injury in Patients with Prostate Cancer. Eur Urol. 2014 Jan 28. PubMed PMID: 24495466. Epub 2014/02/06. Eng. 58. Lapi F, Azoulay L, Niazi MT, et al. Androgen deprivation therapy and risk of acute kidney injury in patients with prostate cancer. JAMA : the journal of the American Medical Association. 2013 Jul 17;310(3):289-96. PubMed PMID: 23860987. Epub 2013/07/19. eng. 59. Tran C, Ouk S, Clegg NJ, et al. Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science (New York, NY). 2009 May 8;324(5928):787-90. PubMed PMID: 19359544. Pubmed Central PMCID: PMC2981508. Epub 2009/04/11. eng. 60. Tombal B, Borre M, Rathenborg P, et al. Enzalutamide monotherpy in hormone-naive prostate cancer: primary analysis of an open-label, single-arm, phase 2 study. The lancet oncology. 2014 Apr 11. PubMed PMID: 24739897. Epub 2014/04/18. Eng. 61. de Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and Increased Survival in Metastatic Prostate Cancer. New England Journal of Medicine. 2011;364(21):1995-2005. PubMed PMID: 21612468. 62. Rathkopf DE, Smith MR, de Bono JS, et al. Updated Interim Efficacy Analysis and Long-term Safety of Abiraterone Acetate in Metastatic Castration-resistant Prostate Cancer Patients Without Prior Chemotherapy (COU-AA-302). Eur Urol. 2014 Mar 6. PubMed PMID: 24647231. Epub 2014/03/22. Eng. 63. Shore ND, Karsh L, Gomella LG, et al. Avoiding obsolescence in advanced prostate cancer management: a guide for urologists. BJU International. 2014:n/a-n/a. 64. Zhumkhawala AA, Gleason JM, Cheetham TC, et al. Osteoporosis management program decreases incidence of hip fracture in patients with prostate cancer receiving androgen deprivation therapy. Urology. 2013 May;81(5):1010-5. PubMed PMID: 23490521. Epub 2013/03/16. eng.
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Table 1 – Indications for Androgen Deprivation Therapy Neoadjuvant/Adjuvant with Curative Intent Therapy Mx
Categories
Androgen Deprivation Therapy
Duration
Localized S0, low risk
Not advised as primary, neoadjuvant or adjuvant therapy with surgery or RT
Not applicable
Intermediate risk
Neoadjuvant with RT
4-6 months
High risk
Neoadjuvant with RT
2-3 years
M0
Palliative/Not suitable for Curative Intent Therapy Mx
Categories
Androgen Deprivation Therapy
Duration
Locally advanced
Primary immediate if PSA >50 ng/L, doubling time less than 12 months, or symptomatic
Indefinitely
M0
PSA recurrence
Neoadjuvant with palliative RT Indefinitely Primary immediate if PSA doubling time less than 12 months or symptomatic
Inconclusive
Primary deferred Indefinitely
M1
N positive post surgery
Adjuvant
Inconclusive
S1
Primary immediate
Indefinitely
S0
Primary deferred
Inconclusive
Primary immediate if PSA >50 ng/L, doubling time less than 12 months, or symptomatic
Indefinitely
Primary with chemotherapy/ATT
Indefinitely
CRPC
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ATT = androgen targeted therapy, CRPC = castrate resistant prostate cancer, M = metastasis, N = lymph node, PSA = prostate specific antigen, RT = radiotherapy, S0 = asymptomatic, S1 = symptomatic. Adopted and modified from Pagliaruol et al (6), Cancer Council Australia (2) and European Association of Urology (7).
Table 2. Recommendations – Indications for ADT The prevalence of adverse effects of ADT is high in elderly. Comorbidities should be considered in determining the need for ADT (7) Fragility screening methods are useful in determining the appropriateness of recommending treatments or to trigger a referral to a geriatrics team (7) IADT may be suitable in selective patients, especially if the adverse effects are significant (2, 12, 16, 17) Monitoring liver function prior and during cyproterone acetate use is recommended as a part of combined androgen blockade regimen (17) Table 3. Recommendations – Quality of Life Refer to psychiatrists or psychologists who specialize in the field (24) Psychosocial interventions (2) o o
Education packages Support groups
Prostate Cancer Foundation of Australia (www.pcfa.org.au, 1800 220 099) and Cancer Australia (www.canceraustralia.gov.au, 13 11 20) provide information and contact details for support groups, educational books and DVDs. Beyondblue provides information and support for those with depression (www.behondblue.org.au, 1300 224 636) Erectile dysfunction (24) o o o
o
Provide patients with PCFA fact sheet Non PBS medications: Phosphodiesterase inhibitors or intracavernosal injections Devices and prosthesis: Vacuum devices or penile implants Referral to a sexual health expert
PCFA = Prostate Cancer Foundation of Australia
Table 4. Recommendations – Hot Flushes Lifestyle changes: avoidance of triggers such as heating and spices. Implementation of relaxation techniques Non-PBS prescriptions (7) o o
Hormonal – Medroxyprogestrone, magestrol acetate, transdermal oestradiol or cyproterone acetate Non-hormonal - Selective serotonin re-uptake inhibitors
Complimentary medicine (2) o o
o
There is no overwhelming evidence to recommend any particular agent Open discussion and acceptance of patient’s decision is advised Acupuncture and phyto-oestrogen based products may be helpful
PBS = pharmaceutical benefits scheme
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Table 5. Recommendations – Physical Function and Exercise 30 minutes of moderate intensity activity on most days for patients who are able (31) In motivated patients, consider referral to exercise physiologists or physiotherapists Refer to industry lead programmes such as AbbVie’s “The Man Plan” ™ Trigger “Chronic Disease Management Programme” run by the Department of Health o
Initiated by “General Practitioner Management Plan”, where patients are entitled to five funded allied health services per year
Refer to clinical trials (www.anztr.org.au)
Table 6. Recommendations – Bone Health Follow Osteoporosis Australia guideline (44): o o o o o
Baseline and follow up BMD scan 1-2 yearly Lifestyle changes: Regular weight bearing exercise, smoking cessation, limitation of alcohol Calcium 600-1200mg per day diet or supplements Vitamin D 400-800IU per day supplements with target level >50-75nmol/L Assess for risk of fractures (http://shef.ac.uk/FRAX/tool.aspx) Treat if 10 year hip fracture risk ≥3% or major osteoporosis related fracture risk ≥20%
Refer to endocrinologist/oncologist PBS prescription: o
Bisphosphonate - Alendronate 70mg weekly, Risedronate 35mg weekly, Zoledronic acid 4mg 6 monthly Indication- Osteoporotic men older than 70 years or those who have had fracture due to minimal trauma o Denusumab 60mg 6 monthly Indication- 4mg given 6 monthly is subsidized for >70 year old patients with T score of -3.0 or less, or established osteoporosis with fracture from minimal trauma o Pre-treatment dental assessment and follow up to reduce risk of osteonecrosis of jaw BMD= bone mineral density, PBS = pharmaceutical benefits scheme, T score = number of standard deviations below the average BMD for a young adult, WHO = world health organization
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Table 7. Recommendations – Cardiovascular Disease Identify patients at risk of CVD such as (45): o o o
o
Follow “National Vascular Disease Prevention Alliance” guideline (31): o o o
o o o o
o Hypertension o Chronic Obstructive Airway Disease o Renal impairment
History of Myocardial Infarction History of Cerebrovascular Events Congestive Heart Failure Peripheral Arterial Disease
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) Diet rich in vegetables and fruit Diet low in salt and saturated and trans fats Follow “Australian Guidelines to Reduce Health Risks from Drinking Alcohol” (NHMRC) Minimize or avoid alcohol At least 30 minutes of moderate intensity physical activity 5 days a week Maintain waist
Adverse Effects of Androgen Deprivation Therapy in Prostate Cancer and Their Management 1
H. Rhee1,2, J.H. Gunter2, P. Heathcote1,2, K. Ho3, P. Stricker4, N.M. Corcoran5, C.C. Nelson2
1
Department of Urology, Princess Alexandra Hospital, Brisbane, Australia
2
Australian Prostate Cancer Research Centre, Queensland Branch, Brisbane, Australia
3
Centre for Health Research, Princess Alexandra Hospital, Brisbane, Australia
4
Australian Prostate Cancer Research Centre, New South Wales Branch, Sydney, Australia
5
Australian Prostate Cancer Research Centre, Victorian Branch, Melbourne, Australia
Corresponding author: Handoo Rhee
Australian Prostate Cancer Research Centre Queensland Branch Translational Research Institute Ipswich Road, Woolloongabba, Brisbane QLD 4102 Australia
Email: [email protected] Phone: +61 7 3176 6946
ABSTRACT
OBJECTIVE: To provide an up-to-date summary of current literature on the management of adverse effects of androgen deprivation therapy (ADT).
SUBJECTS: All men suffering from prostate cancer who are treated with androgen deprivation therapy.
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/bju.12964 This article is protected by copyright. All rights reserved.
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METHODS: All relevant medical literature from 2005 to 2014 and older relevant papers were reviewed to formulate this article. Recent health advisory statements from the Australian government, societies and advocacy groups have been incorporated to the document.
RESULTS: There are numerous adverse effects of ADT that require pro-active prevention and treatment. Ranging from 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 minimizing the harm from ADT.
CONCLUSIONS: This review provides series of practical recommendations to assist with managing adverse effects of ADT.
Key Words: Androgen deprivation therapy, prostate cancer, adverse effect
Word Count: 4766
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 approximately 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 post 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 of time, awareness of the adverse effects related to drug induced hypogonadism and subsequent changes are important. 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 This article is protected by copyright. All rights reserved.
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Cancer Council Australia and Australian Cancer Network (2) which have been referred to within this article.
STRATEGIES FOR USING ANDROGEN DEPRIVATION THERAPY 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). A prospective trial EORTC 30981(3), recently reported that in patients who are unsuitable for local treatments due to metastatic disease or significant comorbidities, the only subgroups of patients that benefited from primary ADT were those with baseline prostate specific antigen (PSA) >50ng/mL and or when PSA doubling time was 1cm shortening of penile length in 93% (23). An ADT Survivorship Working Group published a sexual health focused paper that described the implications of sexual dysfunction including relationship changes and cognitive and affective disorders such as depression. A series of recommendations have been made ranging from counselling to erectile dysfunction medications, and even penile prosthesis in this population of patients (24). Quality of life recommendations are summarised in Table 3. Gynaecomastia/Mastalgia: Gynaecomastia is defined as proliferation of subareolar gland and ductal tissue, which may be associated with mastalgia. It is an irreversible and embarrassing side effect. Antiandrogen agents such as bicalutamide are significantly more likely to cause gynaecomastia and or mastalgia (up to 90% incidence) (23) and treatments with LHRH agonists have approximately 30% breast event rate (23). Both radiotherapy and tamoxifen has been shown to effectively reduce the risk of development when used as a prophylaxis, however, these strategies are not commonly adopted (25); tamoxifen is not PBS subsidized for this purpose. Otherwise, symptomatic relief using simple analgesia is usually employed. Hot flushes: Hot flushes are some of the most commonly experienced complaints affecting up to 80% of patients and described as sudden diaphoresis and facial discomfort (23). It is debilitating to some, and remains one of the leading causes of non-compliance. Lifestyle advice such as avoidance of triggers (e.g. heating or spicy foods) has a role in managing the reaction. Numerous medications are available and all demonstrate reasonable efficacy. In a randomized controlled trial, venlafaxine (selective serotonin re-uptake inhibitor, 75mg), cyproterone acetate (100mg) and medroxyprogestrone (20mg) all demonstrated improvements within 1 month (symptom scores: -47.2%, -94.5% and -83.7% respectively) (26). Unfortunately, none of the medications is available under the PBS, and are used offlabel in Australia. Again, the toxicity of cyproterone acetate needs to be noted prior to its use. Recommendations are summarised in Table 4. Quality of Life: Physical Function and Exercise Until recently, supervised exercise was not considered a serious contender in the management of the adverse effects of ADT. This was mostly due to the fact that the optimal exercise prescription was difficult to define and therefore, the outcomes of studies varied according to the exercise programmes implemented. Recent pioneering work in the field by exercise physiologists such as Galvao and Newton has managed to define supervised exercise programmes, which are becoming an important component of prescribing ADT. This article is protected by copyright. All rights reserved.
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As an exercise triggers anabolic and stimulating physiological changes to multiple organ systems in a body, the effects are broad and promising. In a recent randomized controlled trial by Cormie et al, early exercise intervention with ADT resulted in the preservation of total body weight, lean body mass, fat mass, as well as BMD and cholesterol levels (27). This is in contrast to the non-interventional arm developing adiposity, sarcopaenia, loss of BMD and dyslipidaemia. Further, physical function and quality of life components such as sexual health, fatigue and psychological distress also improved significantly. In recognition of the emerging benefits of exercise in combating ADT side effects, leuprolide users in Australia are entitled to a heavily discounted exercise programme. Kim et al recently reviewed the outcomes of the programme in Australia and found that it preserved patients’ body habitus, fitness and muscle strength (28). Results are less impressive for patients enrolling in exercise intervention programmes months to years after starting ADT, such as those in the Trans-Tasman Radiation Oncology Group trial (29). Although exercise improved fitness, physical function, muscle strength and mental health, the range of benefits were not as impressive as in those who started exercise intervention immediately with ADT. In a recent meta-analysis by Gardiner et al, the authors concluded that despite the varying outcomes from the randomized controlled trials, clinically meaningful benefits to the patients were observed during the periods of exercise. With continuation of exercises at home, beneficial outcomes were maintained even at 6 months post supervised intervention (30). Recommendations are summarised in Table 5. Bone Health The prevalence of osteopaenia and osteoporosis are high in patients newly diagnosed with prostate cancer (39% and 41% respectively) (32). Within the first year of ADT, absolute bone mineral density (BMD) loss is approximately 5% (33). The temporal relationship of ADT and incidence of osteoporosis is demonstrated over 4 and 10 years at 49.2% and 80.6% respectively (34). Further, dual energy X-ray absorptiometry (DEXA) scans underestimate osteoporosis, as trabecular numbers also decline with the actual density of the bone (33). This underscores the importance of preventing the initial loss early. Bone mineral density 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 (IV) 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 IV bisphosphonate has been found to reduce fracture risk (39). Therefore, selective use of bisphosphonate seems sensible in end stage prostate cancer patients. 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). This article is protected by copyright. All rights reserved.
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Denosumab is a monoclonal antibody against receptor activator of nuclear factor – kappa 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 (60mg) in patients with non-metastatic prostate cancer over 24 months (41). Encouragingly, a high dosage with short interval regimen (120mg 4 weekly) increased time to skeletal related events (3.6 months) as well as bone metastasis free survival (4.2 months) in CRPC patients (40, 42). As with bisphosphonate, denosumab was also associated with hypocalcaemia and (2%) osteonecrosis of jaw (5%) (43). Recommendations are summarised in Table 6.
Cardiovascular disease
Almost all observational/retrospective studies demonstrate association between ADT and cardiovascular disease (CVD) and sudden cardiac death (SCD). The largest of the observational studies, published by Keating et al demonstrated that ADT was associated with an increased risk of myocardial infarct with hazard ratio of 1.09 (45). The risk of death from CVD increased with particular risk factors (see below in recommendations, Table 7). 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 (46). Interestingly, in post hoc analysis of randomized controlled trials, no statistically significant increase in CVD could be identified (47). 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 randomized controlled trials 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 cardiovascular disease 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 (47) 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 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 cardiovascular disease: Metabolic syndrome, diabetes and sarcopaenic obesity Metabolic syndrome: Metabolic syndrome (MS) is common in men, even before starting ADT (9). One of the most commonly accepted definitions of MS includes a constellation of biochemical and clinical variables such as dyslipidaemia, hypertension and diabetes (Table 8). Interestingly, men treated with ADT classically exhibit higher high-density-lipoprotein (HDL) and preferentially increase subcutaneous fat, a phenotype different to the standard This article is protected by copyright. All rights reserved.
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metabolic syndrome. Although its implications are unknown, cautious approach with close follow up seems reasonable given such substantial association of MS with CVD (49). Hypercholesterolaemia: A rise in fasting cholesterol is an independent risk factor for cardiovascular mortality especially in the middle aged and elderly. ADT has been shown to increase total cholesterol by 10.6%, triglyceride by 26.9%, low density lipoprotein (LDL) cholesterol by 7.3% and increase in HDL cholesterol by 10% within 6 months of ADT from baseline measurements (51). Although the rise in HDL cholesterol may be cardiac protective, the subsequent rise in total cholesterol, triglyceride and LDL cholesterol may adversely affect patients overall.
Obesity: Sarcopenic obesity is a term used to describe a phenomenon of reduction in muscle mass and gain of adiposity. It ultimately affects up to 70% of patients on ADT (52), with significant changes to the body: lean mass decreases by 2.7%, total body fat increases by 9.4% and total body weight by 2.4% (51). Increased total body fat was attributed to a substantial increase in subcutaneous fat, especially near the waist. Sarcopaenia can in itself lead to the loss of strength, fatigue, lower quality of life and potential increase in falls (53). Diabetes Mellitus: Large cohort studies have associated diabetes to ADT with hazard ratios of up to 1.44 (54). Such data is supported by prospective trials that demonstrate substantial increase in fasting insulin (13.5 mU/L baseline vs 17mU/L at 3 months) and insulin resistance in most men on the treatment (55). Further, in those with pre-existing diabetes, glycosylated haemoglobin levels increased over the observational period with associated worsening of glycaemic control and increased use of diabetic medications (56). Recommendations summarised in Table 5.
Acute Kidney Injury: Recently, a potential for ADT to induce renal impairment requiring hospitalization was highlighted by Gandaglia et al (57) and Lapi et al (58). Some would argue that such findings are in keeping with ureteric and outlet obstructions from advanced prostate cancer usually necessitating ADT. Further, patients with CRPC on ADT may be treated with zoledronic acid, which is known to cause AKI. This is a new and controversial finding and is likely to be an area of interest in future research. Chronic renal impairment is associated with CVD and will add further fuel to arguments regarding the causal relationship of ADT to cardiovascular morbidity and mortality. Recommendations summarised in Table
EMERGING THERAPIES Enzalutamide, a potent androgen receptor antagonist is undergoing a phase II study to assess its efficacy as a first line treatment in conjunction with ADT in metastatic prostate cancer patients. It binds to androgen receptors and co-activators potently, whilst inhibiting nuclear translocation of the receptors (59). It has demonstrated 4 months survival advantage post docetaxel failure in CRPC patients and is expected to demonstrate significantly improved survival as a primary treatment. In a recent update on the progress, the reported adverse effects of the drug included gynaecomastia (36%), fatigue (34%), nipple pain (19%), hot flushes (18%) and seizures (1%) (60). This article is protected by copyright. All rights reserved.
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Abiraterone, a specific inhibitor of CYP17, has also demonstrated improved overall survival post docetaxel (61). It is a novel multi-organ, multi-step inhibitor of androgen synthesis. . In the recent update of COU-AA-302 trial, some of the reported complaints from ADT with abiraterone and prednisolone included fatigue (39%), arthralgia (32%), back pain (28%), peripheral oedema (28%), gastrointestinal side effects (22%), hot flush (22%) and hypertension (22%) (62). Twenty percent of patients reported cardiac disorders such as arrhythmias, ischaemic heart disease and heart failure. Further, 10mg prednisone is given concomitantly to counteract mineralocorticoid excess. Long term high dose prednisone may necessitate the help of endocrinologists to combat the challenges of Cushing’s syndrome such as osteoporosis, obesity and diabetes. DISCUSSION The general principle of managing adverse effects of long term ADT is: 1) to recognize that they are almost universal; 2) to discuss the potential complications with patients and partners prior to initiating the treatment; and 3) to proactively prevent, reduce and address the problems (Table 14). The initial discussions may be aided by education packages such as “Advanced Prostate Cancer: a guide for men and their families, Cancer Council Australia”, “Factsheet: Androgen Deprivation Therapy, Andrology Australia” or “Advanced Prostate Cancer Pack, Prostate Cancer Foundation of Australia”. Armed with the latest research in this field, clinicians can provide leadership to a multi-disciplinary team consisting of endocrinologist, cardiologist, geriatrician, dietician, exercise physiologist/physiotherapist and psychologist (Table 15).
A Men’s Health Clinic established in Austin, Australia, is a prime example of wellestablished and efficacious clinical system where all men commenced on ADT are referred for follow up and management by a multidisciplinary team. Unfortunately, without an established centre such as the Men’s Health Clinic, the reality of our health care system means that whilst oncological clinicians can provide leadership, most screening and follow up will have to be performed by themselves in conjunction with general practitioners. Currently, it is highly unlikely that older patients will be assessed by physicians prior to initiating ADT. In a recent review, Shore et al discussed the challenges of adopting novel agents for increasingly complicated advanced prostate cancer sufferers. The authors advised that a multidisciplinary team was necessary to keep up with modern emerging medicine (63).
There are two prospective studies that discuss the impacts of implementing management guidelines. Grossmann et al from Men’s Health Clinic described a bone and metabolic health clinic set up specifically to maintain well-being of patients treated with ADT by close monitoring and follow up. Patients were initially assessed with a battery of screening tests, and new onset of conditions such as osteoporosis, dyslipidaemia or diabetes was treated appropriately. The authors went further to recommend routine bisphosphonate therapy in men with T score below or equal to -2.0 (outside the PBS criteria). After 2 years, 113 men boasted reductions in total cholesterol, blood pressure, increased vitamin D level, maintenance of BMD and fewer cardiovascular events (n=3) (9). In another prospective trial, This article is protected by copyright. All rights reserved.
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Zhumkhawala et al (64) described an osteoporosis management plan using regular follow up and active management of T scores (number of standard deviations below the average BMD for a young adult) less than -2.5. Patients were treated with bisphosphonate, calcium (1200mg) and vitamin D (400-800IU). During 2-5 years of follow up, there was a 70% reduction in hip fracture rate. Although the impact on survival was not assessed, given the evidence above, it is likely to be significant CONCLUSION Androgen deprivation therapy plays a pivotal role in managing prostate cancer. As more patients are diagnosed with prostate cancer, early identification and management of adverse effects of ADT have become more important than ever. Moreover, as the use of novel androgen targeted therapies become more prevalent and patients survive longer, the duration of ADT is expected to increase. In this review, attempts have been made to provide summary of up-to-date information on ADT induced co-morbidities and current treatment recommendations. CONFLICTS OF INTEREST
None declared.
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Table 1 – Indications for Androgen Deprivation Therapy Neoadjuvant/Adjuvant with Curative Intent Therapy Mx
Categories
Androgen Deprivation Therapy
Duration
Localized S0, low risk
Not advised as primary, neoadjuvant or adjuvant therapy with surgery or RT
Not applicable
Intermediate risk
Neoadjuvant with RT
4-6 months
High risk
Neoadjuvant with RT
2-3 years
M0
Palliative/Not suitable for Curative Intent Therapy Mx
Categories
Androgen Deprivation Therapy
Duration
Locally advanced
Primary immediate if PSA >50 ng/L, doubling time less than 12 months, or symptomatic
Indefinitely
M0
PSA recurrence
Neoadjuvant with palliative RT Indefinitely Primary immediate if PSA doubling time less than 12 months or symptomatic
Inconclusive
Primary deferred Indefinitely
M1
N positive post surgery
Adjuvant
Inconclusive
S1
Primary immediate
Indefinitely
S0
Primary deferred
Inconclusive
Primary immediate if PSA >50 ng/L, doubling time less than 12 months, or symptomatic
Indefinitely
Primary with chemotherapy/ATT
Indefinitely
CRPC
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ATT = androgen targeted therapy, CRPC = castrate resistant prostate cancer, M = metastasis, N = lymph node, PSA = prostate specific antigen, RT = radiotherapy, S0 = asymptomatic, S1 = symptomatic. Adopted and modified from Pagliaruol et al (6), Cancer Council Australia (2) and European Association of Urology (7).
Table 2. Recommendations – Indications for ADT The prevalence of adverse effects of ADT is high in elderly. Comorbidities should be considered in determining the need for ADT (7) Fragility screening methods are useful in determining the appropriateness of recommending treatments or to trigger a referral to a geriatrics team (7) IADT may be suitable in selective patients, especially if the adverse effects are significant (2, 12, 16, 17) Monitoring liver function prior and during cyproterone acetate use is recommended as a part of combined androgen blockade regimen (17) Table 3. Recommendations – Quality of Life Refer to psychiatrists or psychologists who specialize in the field (24) Psychosocial interventions (2) o o
Education packages Support groups
Prostate Cancer Foundation of Australia (www.pcfa.org.au, 1800 220 099) and Cancer Australia (www.canceraustralia.gov.au, 13 11 20) provide information and contact details for support groups, educational books and DVDs. Beyondblue provides information and support for those with depression (www.behondblue.org.au, 1300 224 636) Erectile dysfunction (24) o o o
o
Provide patients with PCFA fact sheet Non PBS medications: Phosphodiesterase inhibitors or intracavernosal injections Devices and prosthesis: Vacuum devices or penile implants Referral to a sexual health expert
PCFA = Prostate Cancer Foundation of Australia
Table 4. Recommendations – Hot Flushes Lifestyle changes: avoidance of triggers such as heating and spices. Implementation of relaxation techniques Non-PBS prescriptions (7) o o
Hormonal – Medroxyprogestrone, magestrol acetate, transdermal oestradiol or cyproterone acetate Non-hormonal - Selective serotonin re-uptake inhibitors
Complimentary medicine (2) o o
o
There is no overwhelming evidence to recommend any particular agent Open discussion and acceptance of patient’s decision is advised Acupuncture and phyto-oestrogen based products may be helpful
PBS = pharmaceutical benefits scheme
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Table 5. Recommendations – Physical Function and Exercise 30 minutes of moderate intensity activity on most days for patients who are able (31) In motivated patients, consider referral to exercise physiologists or physiotherapists Refer to industry lead programmes such as AbbVie’s “The Man Plan” ™ Trigger “Chronic Disease Management Programme” run by the Department of Health o
Initiated by “General Practitioner Management Plan”, where patients are entitled to five funded allied health services per year
Refer to clinical trials (www.anztr.org.au)
Table 6. Recommendations – Bone Health Follow Osteoporosis Australia guideline (44): o o o o o
Baseline and follow up BMD scan 1-2 yearly Lifestyle changes: Regular weight bearing exercise, smoking cessation, limitation of alcohol Calcium 600-1200mg per day diet or supplements Vitamin D 400-800IU per day supplements with target level >50-75nmol/L Assess for risk of fractures (http://shef.ac.uk/FRAX/tool.aspx) Treat if 10 year hip fracture risk ≥3% or major osteoporosis related fracture risk ≥20%
Refer to endocrinologist/oncologist PBS prescription: o
Bisphosphonate - Alendronate 70mg weekly, Risedronate 35mg weekly, Zoledronic acid 4mg 6 monthly Indication- Osteoporotic men older than 70 years or those who have had fracture due to minimal trauma o Denusumab 60mg 6 monthly Indication- 4mg given 6 monthly is subsidized for >70 year old patients with T score of -3.0 or less, or established osteoporosis with fracture from minimal trauma o Pre-treatment dental assessment and follow up to reduce risk of osteonecrosis of jaw BMD= bone mineral density, PBS = pharmaceutical benefits scheme, T score = number of standard deviations below the average BMD for a young adult, WHO = world health organization
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Table 7. Recommendations – Cardiovascular Disease Identify patients at risk of CVD such as (45): o o o
o
Follow “National Vascular Disease Prevention Alliance” guideline (31): o o o
o o o o
o Hypertension o Chronic Obstructive Airway Disease o Renal impairment
History of Myocardial Infarction History of Cerebrovascular Events Congestive Heart Failure Peripheral Arterial Disease
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) Diet rich in vegetables and fruit Diet low in salt and saturated and trans fats Follow “Australian Guidelines to Reduce Health Risks from Drinking Alcohol” (NHMRC) Minimize or avoid alcohol At least 30 minutes of moderate intensity physical activity 5 days a week Maintain waist
