MCO 2011 - Slide 3 - A. Horwich - First-line endocrine treatment

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MCO 2011 - Slide 3 - A. Horwich - First-line endocrine treatment

  1. 1. Firstline Hormone Therapy for Prostate Cancer<br />Alan Horwich<br />Institute of Cancer Research and Royal Marsden Hospital, Sutton, Surrey, UK<br />
  2. 2. Therapeutic Windows for Hormone Therapy in Prostate Cancer<br /><ul><li>PSA failure after local treatment
  3. 3. Locally advanced disease-neoadjuvant/adjuvant
  4. 4. Locally advanced disease-sole treatment
  5. 5. Firstline for metastases
  6. 6. 2,3,4-line for metastases </li></ul>CRPC concept= failure of firstline hormone therapy<br />
  7. 7. Hormone Therapies for Prostate Cancer<br /><ul><li>LHRH agonists……………egZoladex, Prostap
  8. 8. LHRH antagonists……….egDegarelix
  9. 9. Antiandrogens……………egCasodex, Flutamide, MDV 3100
  10. 10. Steroids…………………..egpredisone, dexamethasone
  11. 11. Oestrogens………………egStilboestrol
  12. 12. Cyp 17 antagonists……egAbiraterone, TAK-700</li></li></ul><li>
  13. 13. Androgen Suppression in Prostate Cancer<br />
  14. 14. Diabetes and cardiovascular disease during androgen deprivation for prostate cancerKeating JNCI 2010VA Study<br />
  15. 15. Efsathiou JCO 2009 2792-99<br />No. = 945 FU 8.1 yrs<br />CVD = 117<br />At 9 yrs CVD 8% vs 11%<br />With LOWER risk in LHRHagroup<br />
  16. 16. Osteoporosis and duration of LHRHa therapy Stage I-II Ca Prostate with PSA control<br />Morote Eur Urol 2003 44 661<br />Prostatectomy controls (57) Men treated with LHRHa (53)<br />Loss of bone mineral density particularly in first 6–12m (Daniell 2000, Mittan 2002)<br />Osteoporotic fracture rate increased. 4% 5yr, 20% 10yr (Oefelein 2001)<br />
  17. 17. What should we advise patients on androgen deprivation therapy?<br />Address risk factors<br />Diabetes , Cholesterol, Hypertension<br />Aspirin<br />Exercise<br />In the adjuvant setting duration of hormone therapy should be tailored to need<br />
  18. 18. Issues for Hormone Therapy in Prostate Cancer<br /><ul><li>Immediate vs Deferred?
  19. 19. Combined androgen blockade?
  20. 20. Intermittent or continuous
  21. 21. Adjuvant bisphosphonate?
  22. 22. Role with RT in localised disease</li></li></ul><li> Immediate Versus Deferred Hormonal Treatment for Patients With Prostate Cancer Who Are Not Suitable for Curative Local Treatment: Results of the Randomized Trial SAKK 08/88<br />Urs E. Studer et al 2004 JCO 22;4109-18<br />Overall survival<br />Time to post –orchx pain <br />No difference in CSS, confirmed in EORTC 30891 JCO 24;1868-76<br />N=985<br />
  23. 23. Samson et al 2002<br />“Modest benefit at 5 years probable outweighed by increased side-effects”<br />
  24. 24. Phase 3 RCT IAS vs Continuous AD –PSA progression after local Rx; NCIC PR07 Klotz abs 2011<br />
  25. 25. MRC Trial PR05 AD vs AD +Clodronate in Metastatic Prostate Cancer<br />Dearnaley D P et al. JNCI J Natl Cancer Inst 2003;95:1300-1311<br />overall survival time from randomization<br />symptomatic bone progression-free survival time <br />Also<br />STAMPEDE trial recruiting—looking at AD withzoledronate, celecoxib, docetaxel and will have an abiraterone arm<br />
  26. 26. What is the evidence that adding hormone therapy to radiotherapy improves outcome?<br />For how long should hormone therapy be continued?<br />Hormone deprivation or anti-androgen?<br />Should we add RT in patients on long term hormone therapy?<br />
  27. 27. Roach JCO 2008 26 585-591<br />N = 456 <br /> 1987-91 T2 (bulky) -T4 N+/-<br />MAB 4m pre and with RT vs RT alone<br />
  28. 28. Disease specific mortality<br />Roach JCO 2008 26 585-591<br />Overall survival<br />10yr OS 43% vs 34% p=0.12<br />10yr DSM 23% vs 36% p=0.01<br />Fatal cardiac events<br />Distant metastases<br />10 yr Dist Met 35% vs 47% p=0.006<br />10 yr Cardiac deaths 14% vs 10%<br />
  29. 29. Long term androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III randomised trial Bolla Lancet 2002 360 103<br />
  30. 30. Adjuvant trials of androgen suppression and radiotherapy<br />3 Phase III trials reported<br />EORTC 22866 (415 T3/4 or N+),RTOG 85-31 (977 T3 or N+),Swedish (105 LN+)<br /><ul><li>All trials show improvement in local control and delay of metastases
  31. 31. All trials show improvement in cause related and overall survival
  32. 32. RTOG 85-31 shows overall survival advantage for Gleason 8-10 only and Swedish trial for node positive</li></ul>Bolla Lancet 2002 360 103; Pilepich IJROBP 2005 61 1285; Granfors J Urol 2006 176 544<br />
  33. 33. Hormones + RT versus RT alone<br />Short course hormones markedly improve local control and disease free survival<br />For short course hormones most trials have not shown an improvement in overall survival<br />Long term hormones have markedly improved survival in patients with locally advanced high risk cancers.<br />Conclusions<br />
  34. 34. What is the evidence that adding hormone therapy to radiotherapy improves outcome?<br />For how long should hormone therapy be continued?<br />Hormone deprivation or anti-androgen?<br />Should we add RT in patients on long term hormone therapy?<br />
  35. 35. RTOG 92-02:Radiotherapy and duration of androgen suppression (4 vs 28 months)No. 1554 Follow up 56m<br />.<br />3% OS benefit only in Gl 8-10<br />Horwitz E M et al. JCO 2008;26:2497-2504<br />©2008 by American Society of Clinical Oncology<br />
  36. 36. 6months vs 3yrs concomitant and adjuvant hormonal treatment<br /> for locally advanced Ca Prostate EORTC 22961 Bolla et al 2009 N=970<br />Overall survival STAD 81% vs LTAD 84.8%<br />P Ca deaths STAD n=46 vs LTAD 28<br />CVD deaths STAD n= 31 vs LTAD 25<br />Overall STAD<br />Overall LTAD<br />P Ca STAD<br />P Ca LTAD<br />
  37. 37. Hormone duration?<br />Long term hormone therapy compared to short term improves progression free survival <br />Improved overall survival probably just in high risk patients<br />As yet unclear that intermediate risk patients gain from more than 3-6 months<br />Conclusions<br />
  38. 38. What is the evidence that adding hormone therapy to radiotherapy improves outcome?<br />For how long should hormone therapy be continued?<br />Hormone deprivation or anti-androgen?<br />Should we add RT in patients on long term hormone therapy?<br />
  39. 39. Bicalutamide 150mg plus standard care vs standard care alone for early prostate cancer.McleodBJU Int 2006 9 247<br />Dearnaley ECCO September 07<br />
  40. 40. What is the evidence that adding hormone therapy to radiotherapy improves outcome?<br />For how long should hormone therapy be continued?<br />Hormone deprivation or anti-androgen?<br />Should we add RT in patients on long term hormone therapy?<br />
  41. 41. NCRI PR3 / MRC PR07 TrialP.Warde ASCO 2010<br />Randomisation:<br />Hormone Treatment alone vs HT and RT to prostate +/- pelvis<br />No.1205 <br />Deaths 310 CaP deaths 140<br />7yr OS 66% vs 74% HR 0.77 p=0.03 NNT 12.5<br />7 yr CSS 79% vs 90 % HR 0.57 p=0.001 NNT 9<br />Same result as Widmark et al 2009<br />
  42. 42. CONCLUSIONS: Combined Modality Treatment<br />Neo/Adjuvant hormonal therapy should be used in all men with high risk or locally advanced prostate cancer treated with external beam radiotherapy<br />Short course (3-6m) NAD improves local control in intermediate/high risk localised and advanced localised prostate cancer<br />Long course androgen suppression reduces development of metastases and improves survival for men with advanced localisedand high grade prostate cancer<br />Optimal duration of ‘long term’ hormone therapy is at least 2 years for Gl ≥8 cancer, but may be shorter for more favourable disease<br />Comparisons of LHRHa with monotherapybicalutamide are needed<br />Men with locally advanced disease and good health should have RT as well as hormone therapy<br />

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