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

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monotherapy for low-to-intermediate risk prostate cancer. There are some institutional series using low-dose brachytherapy as a boost following external beam radiotherapy (EBRT) for locally advanced prostate cancer, but there are no randomised trials evaluating this approach and it is largely viewed as an experimental approach. Temporary implant brachytherapy. This involves the temporary insertion of a radioactive compound (usually Iridium-192) guided into various positions in the prostate via the placement of multiple catheters that have been placed under ultrasound guidance. It is usually performed in combination with external beam radiotherapy for patients with intermediate- and high-risk cancers. Occasionally lower activity compounds can be used in this way administering radiotherapy over longer time periods (e.g. 24-48 hours) There is a dearth of good randomised comparative trials to assist in assessing the place of brachytherapy in the treatment of locally advanced disease. There was only one randomised controlled trial that assessed the efficacy of temporary brachytherapy in addition to external beam radiotherapy for locally advanced disease. 88 It was a study of 104 T2-3 patients comparing the use of a temporary brachytherapy ‘boost’ with an iridium implant (35Gy given in 48 hours) in addition to a course of external beam treatment (40Gy) with external beam treatment alone (66Gy). In the brachytherapy plus EBRT arm, 17 patients (29%) experienced biochemical or clinical failure compared with 33 patients (61%) in the EBRT arm (hazard ratio=0.42; P=0.0024). While this study supported the concept that the addition of HDR like brachytherapy showed ‘efficacy’, the comparison was not useful to guide contemporary practice as the external beam radiation dose was 66Gy, which has been shown to be inferior to higher doses such as 74Gy. The results of this and other studies comparing brachytherapy with external radiation are difficult to generalise, since they are essentially comparing the same modality packaged in different ways. There are many other parameters in radiation treatment that affect the disease control probabilities, such as total dose, radiation technique and total treatment time, in addition to the modality of radiation, that is, brachytherapy versus external beam. There are no controls for these in many studies, including the randomised controlled trial, raising the question as to whether one of these other factors might account for any difference seen between the two arms. In addition, men with locally advanced disease in Australia are generally treated with the combination of androgen deprivation and radiation therapy. There may be interactions with this combination that further confound comparisons. Evidence summary Level References There is a paucity of high-quality randomised trial data comparing the use of brachytherapy to surgery for the treatment of locally advanced disease, or indeed comparing the use of brachytherapy radiation to external radiation. There is one medium-quality randomised trial. It provides little evidence to guide contemporary Australian practice, except to the extent it demonstrated evidence of effect of the high dose rate boost. As a result of the study’s design it is difficult to draw comparative conclusions from this study. 29 Locally advanced disease II 88
Recommendation 3D conformal dose escalated external beam radiotherapy alone, or reduced dose external beam radiation treatment in combination with high dose-rate brachytherapy, are wellrecognised radical treatments for locally advanced disease. There is no randomised evidence to suggest superiority or to recommend one modality over the other. Grade D 3.1.3 Radiotherapy and androgen deprivation therapy For the purpose of this chapter we have considered the evidence in terms of short-term (six months or less) and long-term (more than six months) androgen blockade. Long term androgen deprivation Four randomised controlled trials 6, 31, 68, 89, 90 and two meta-analyses 32, 91 fulfilled the eligibility criteria for inclusion in this review. The control arm in these trials was radiotherapy alone. Androgen deprivation consisted of oestrogen 90 , LHRH agonist 31,68, 89 ; and a non-steroidal anti-androgen. 6 Duration of ADT ranged from two years to indefinitely and was commenced with radiotherapy 68 or at completion of radiotherapy. The radiotherapy dose to the prostate in three of the trials ranged from 65 to 70 Gy. No data regarding radiotherapy were given in the fourth trial. 6 In two of the trials, pelvic lymph nodes were treated. 31, 68, 89 In all trials the endpoint of overall survival was examined. These studies showed a statistically significant improvement in overall survival with the exception of the study by Zagars 90 , which was a low-quality study using long-term oestrogens. While improved 31, 89, 90 biochemical disease-free survival was also observed, it should be noted that in two of the trials indefinite ADT was recommended. Biochemical failure in the context of indefinite androgen deprivation most likely represents castrate-resistant disease and these results should therefore be interpreted with caution. Short-term androgen deprivation Only one RCT, Trans Tasman Radiation Oncology Group (TROG) 96-01, fulfilled the eligibility criteria for inclusion in this review. 28 This was a three-arm study comparing external beam radiotherapy (EBRT) alone versus three months of hormones plus EBRT (commenced two months prior to radiotherapy) versus six months of hormones plus EBRT (commenced five months prior to radiotherapy). ADT consisted of an LHRH agonist (goserelin) and a non-steroidal anti-androgen (flutamide). The radiotherapy dose was 66Gy in 33 fractions, which is lower than the current standard dose used in Australia (typically 74Gy). Subgroup analysis of patients with T3–4 disease and patients with PSA>20 was only available for the comparison of EBRT alone versus six months of hormones plus EBRT, with disease-free survival and prostate-cancer-specific survival reported. This demonstrated a statistically significant improvement in disease-free survival with the addition of six months of hormones, but not in prostate-cancer-specific survival. It should be noted that radiation doses were lower than current standard doses used in Australia and target volumes varied, with several trials treating pelvic lymph nodes. There are no RCTs addressing the use of ADT in conjunction with brachytherapy and it remains unclear as to whether ADT provides a benefit in the era of higher-dose radiotherapy. On a final note, the Radiation Therapy Oncology Group (RTOG) 86–10 92 was not considered in this review as it did not meet inclusion criteria for survival outcomes. Clinical practice guidelines for the management of locally advanced and metastatic prostate cancer 30
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 42 and 43: Despite these reservations and the
Page 44 and 45: For non-metastatic disease there we
Page 46 and 47: Evidence summary Level References T
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
Page 92 and 93: trial. European Journal of Cancer 1
Page 94 and 95: 6 CASTRATION-RESISTANT PROSTATE CAN
Page 96 and 97: 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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