Clinical Practice Guidelines for the management of locally advanced ...

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Despite these reservations and the variety of sites at which BMD was measured, the results were consistent in terms of BMD being reduced with LHRH agonists and bilateral orchidectomy, increasingly so over time, but maintained (or slightly increased) with bicalutamide monotherapy. Non-metastatic disease: For men with non-metastatic disease, most studies showed a decline in bone mineral density in the 12 months following initiation of castration therapies. Total hip BMD decreased on average by 3.3 % in a group of 15 men after 12 months of LHRH agonist treatment. 36 This was significantly different from the rise in total hip BMD seen in aged-matched controls (n = 13). In this small study, at least 20% of men were osteopenic at baseline. Declines appeared to continue after 12 months with a 1.95 % decrease in proximal femoral bone mineral density reported for the 12 months after at least 18 months of LHRH agonist treatment. 37 A small case series suggest that combined androgen blockade also results in bone mineral density decreases and that its temporary cessation may induce a temporary stabilisation of bone loss. 38 In contrast oestrogen monotherapy may preserve BMD 39 and there is evidence from two RCTs that the anti-androgen bicalutamide, unlike castration therapies, maintains or increases hip and lumbar spine bone mineral density. 24, 25 These data are consistent with the known biology of testosterone depletion and its consequent decrease in oestrogen, and bone mineral depletion. Metastatic disease: Studies that included men with metastatic disease reported mean decreases in femoral neck bone density of 2.4 – 4.5% in the first 12 months of castration therapies 40, 41 and 10% at two years 41 , with declines continuing to occur after three or more years of treatment. 41 In a case series of 50 men, the prevalence of osteoporosis in the lumbar spine rose from 24% at baseline to 48% within six months of starting castration therapies. 42 After 12 men with metastatic disease started CAB, femoral neck BMD reportedly decreased on average by 6.5% and lumbar spine BMD by 6.6% at six months. 43 Osteopaenia, osteoporosis and fractures: The significant clinical impact of BMD changes is based on reports of a considerable background of osteopaenia in patients at baseline, and the reasonable presumption that continuing reductions in BMD predispose patients to clinically meaningful outcomes of osteoporosis and associated pathological fractures. Other risk factors for osteoporotic fractures include decreased muscle strength and frailty, which also may be influenced by androgen deficiency. It is also worth noting that the clinical significance of osteoporotic fracture is greater for hip than for vertebral bodies because of the high mortality rate related to the former. The data showed an increased likelihood of fractures over time with LHRH agonist therapy and bilateral orchidectomy although likelihood estimates varied, reflecting differences in study designs, type of fractures assessed and criteria used. In studies including men with both metastatic and non-metastatic disease, those who underwent orchidectomy had a significantly higher five-year cumulative incidence of osteoporotic fractures (12%) when compared with prostate patients who had not (1%) 44 and a significantly higher risk of an osteoporotic fracture than the age-specific general population, with a standardised incidence ratio of 3.50. 45 Fractures in non-metastatic disease patients: For men with non-metastatic disease, in a small case series 21% of 81 men receiving castration therapies experienced a non-metastatic fracture over a median follow-up period of 52 months 46 . In two large prospective studies, those who had received LHRH agonists had a significantly higher risk of hip or femur osteoporotic or traumatic fractures (risk ratios reported of 1.76 for a maximum of five years follow-up and 1.36 for a maximum of seven years follow-up) 47, 48 and a significantly higher risk (risk ratio = 1.50) of vertebral fractures for seven years maximal follow-up 48 when compared with those who had not taken LHRH agonists. These findings are of particular clinical significance as these men without metastatic disease may be destined to live for many years. The findings are directly applicable to the Australian population to the extent that LHRH agonists and, to a lesser extent, bilateral orchidectomy are the only primary forms of androgen therapy available on the PBS for locally advanced and metastatic disease either as monotherapy or part of 23 Locally advanced disease
CAB. The evidence provided in favour of bicalutamide monotherapy having a BMD-protective property is not relevant as this agent (and class of drug) is not approved for use as monotherapy in Australia. Evidence summary Level References For men with prostate cancer, both LHRH agonists and bilateral orchidectomy significantly reduce bone mineral density, continuing to do so over time, resulting in an increased likelihood of pathological fracture of vertebral bodies and hips from osteoporosis. There is insufficient evidence to make a definite comment on intermittent androgen deprivation. There is insufficient evidence to comment on whether there is a worse or diminished effect on BMD with combined androgen blockade (CAB) versus castration monotherapy. Bicalutamide monotherapy is not associated with reductions in BMD. Recommendation III-2, III- 3, IV II 24,25 39, 40, 44, 47, 49, 50 36, 37, 41, 43, 45, 51, 42, 52- 55,56,46,38 Before commencing patients on androgen deprivation therapy, consider the likely duration of that treatment and the risk–benefit analysis for the indication for treatment, and take into account the effects on bone mineral density and risks of pathological fractures from osteoporosis. Grade C In addition, consider BMD measurements at baseline and subsequently during treatment with the possibility of instituting preventative measures (calcium, vitamin D and exercise) as appropriate for good musculoskeletal health, as well as the use of bisphosphonates as indicated by the Pharmaceutical Benefits Scheme for osteoporosis. Effects on quality of life Only three randomised controlled trials comparing different hormone therapies and including men with locally advanced non-metastatic disease examined quality of life outcomes using validated questionnaires. 11, 21, 57-60 One trial used the EORTC QLQ C-30 instrument with the prostate cancer supplementary module and the Depression Anxiety Stress Scales, and two trials used the healthrelated QLQ instrument published by Cleary et al. 61 The longest follow-up was only 12 months. 57, 58 None of the instruments used directly assessed the impact of ADT-related symptoms such gynaecomastia and hot flushes on quality of life. Overall the evidence was limited. There were variations (albeit with a degree of overlapping commonality) in the types of ADTs employed, the instruments used and the numbers of domains assessed and reported. There were also variations in the way in which quality-of-life changes were reported and analysed. Quality of life was not a primary outcome in virtually all of these studies. All were of low quality, with attrition greater than 20% or unclear in two of the three studies. Different risk and benefit analyses apply to men being treated with long-term adjuvant ADT for locally advanced disease and men being treated with ADT for metastatic disease. One study included patients with metastatic disease as well as locally advanced disease. Clinical practice guidelines for the management of locally advanced and metastatic prostate cancer 11, 21, 24
Page 1: Clinical Practice Guidelines for th
Page 4 and 5: 4 Biochemical relapse .............
Page 6 and 7: FOREWORD The management of prostate
Page 8 and 9: SUMMARY OF CLINICAL PRACTICE RECOMM
Page 10 and 11: SUMMARY OF RECOMMENDATIONS Chapter
Page 12 and 13: Chapter Recommendations Grade Refs
Page 20 and 21: 1 INTRODUCTION 1.1 Natural history
Page 22 and 23: 2 PSYCHOSOCIAL CARE The diagnosis a
Page 24 and 25: 2.2 Effect of psychological and cog
Page 26 and 27: Evidence summary Level References T
Page 28 and 29: Recommendation Men with advanced pr
Page 30 and 31: An Australian cross-sectional study
Page 32 and 33: 10. Dunn J, et al. A review of peer
Page 34 and 35: 41. Sharpley CF, Christie DRH. An a
Page 36 and 37: different treatments from different
Page 38 and 39: Evidence summary Level References I
Page 40 and 41: Evidence summary Level References F
Page 44 and 45: For non-metastatic disease there we
Page 46 and 47: Evidence summary Level References T
Page 48 and 49: monotherapy for low-to-intermediate
Page 50 and 51: Evidence summary Level References M
Page 52 and 53: for surgery, suggesting that surger
Page 54 and 55: Microscopic fully resected node pos
Page 56 and 57: All three trials demonstrated impro
Page 58 and 59: Evidence summary Level References B
Page 60 and 61: of an international multicentre ran
Page 62 and 63: 45. Melton LJ, III, Alothman KI, Kh
Page 64 and 65: 76. Little DJ, Kuban DA, Levy LB, Z
Page 66 and 67: 105. Thompson IM, Tangen CM, Parade
Page 68 and 69: 4.2 Androgen deprivation therapy (e
Page 70 and 71: Evidence summary Level References F
Page 72 and 73: therapy since such studies would be
Page 74 and 75: apparent in trials comparing CAB wi
Page 76 and 77: QLQ instrument published by Cleary
Page 78 and 79: Note: Larger well-powered studies h
Page 80 and 81: Eight trials examined acute toxicit
Page 82 and 83: half of patients experienced pain r
Page 84 and 85: olus) in addition to radiotherapy a
Page 86 and 87: References 1. Seidenfeld J, Samson
Page 88 and 89: Cooperative Group. Scandinavian Jou
Page 90 and 91: Oncology Group, TROG 96.05). Radiot
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trial. European Journal of Cancer 1
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6 CASTRATION-RESISTANT PROSTATE CAN
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the median overall survival for pat
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There are two points regarding bisp
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with bone pain at study entry. At n
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Recently, there have been reports o
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of these studies 56, 58 and in the
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Side effects (toxicity) As these ra
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hydrocortisone respectively. Tannoc
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5. Manikandan R, Srirangam SJ, Pear
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33. Elomaa I, Kylmala T, Tammela T
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60. Janknegt RA, Abbou CC, Bartolet
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physiotherapists, occupational ther
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7.5 Q2: Symptom control There was e
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Informal or family caregivers deriv
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8. Hughes SL, Weaver FM, Giobbie-Hu
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8 COMPLEMENTARY AND ALTERNATIVE (UN
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corresponding benefit in obstructiv
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3. Eisenberg DM, Kessler RC, Van Ro
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areas of the state were more likely
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8 Miller DC, Litwin MS, Bergman J,
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10 EMERGING THERAPIES It is impossi
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APPENDIX 1 GUIDELINE DEVELOPMENT PR
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study type. Studies published befor
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Grade of recommendation Description
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2. National Health and Research Cou
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Dr Carole Pinnock AM Principal rese
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Surgery Professor Villis Marshall A
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APPENDIX 3 TNM CLASSIFICATION OF PR
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Summary Prostate T1 T2 T3 T4 N1 M1a
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APPENDIX 4 ABBREVIATIONS AND GLOSSA
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Glossary Actuarial survival A metho
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Effectiveness The extent to which a
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Lymph nodes Small, generally pea-si
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Each stage is divided into subgroup
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APPENDIX 6 - ORGANISATIONS WHICH PR
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Consultant Urologist, Royal Brisban
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No conflict of interest to declare.
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Index to Clinical practice guidelin
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cardiovascular mortality 19, 54, 55
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androgen deprivation therapy (ADT)
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and surgery 32-34 survival 18 toxic
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and chemotherapy 89-90 see also bon
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spinal cord compression 62-63 see a
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systemic 141 Tasmania Association f
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