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Initial Androgen Treatment for Progressive, Metastatic or Recurrent Prostate Cancer

Initial Androgen Treatment for Progressive, Metastatic or Recurrent Prostate Cancer. Andrew Loblaw BSc, MD, MSc, FRCPC, CIP Department of Radiation Oncology Sunnybrook Health Sciences Centre January 28, 2011. Objectives.

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Initial Androgen Treatment for Progressive, Metastatic or Recurrent Prostate Cancer

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  1. Initial Androgen Treatment for Progressive, Metastatic or Recurrent Prostate Cancer Andrew LoblawBSc, MD, MSc, FRCPC, CIP Department of Radiation Oncology Sunnybrook Health Sciences Centre January 28, 2011

  2. Objectives • To review the standard initial hormonal interventions for prostate cancer • To discuss the evidence behind the use of AA monotherapy • To review the published literature on the benefit of combined androgen blockade • To review emerging evidence on the benefit of bicalutamide CAB for prostate cancer • To review the evidence behind the timing of ADT • To review the pros/cons of intermittent androgen blockade

  3. Standard ADT

  4. Standard ADT* * * * (aberelix) * Seidenfeld J Ann Int Med 2002; 132(7):566-77

  5. Combined Androgen Blockade

  6. PCTCGIndiv Pt DataMeta-Analysis 8275 men, 27 trials 88% D2 Overall Death Rate 70.4 vs 72.4% ARR 2% NSAA Death Rate 72.4 vs 75.3% ARR 2.9% (p<0.005) PCTCG. Lancet 2000;355:1491-8

  7. Schmitt et al Meta-Analysis • 20 RCTs, 6320 men with prostate cancer • Efficacy • 2 y OS: OR 1.16 (95% CI 1.00 – 1.33) • 5 y OS: OR 1.29 (95% CI 1.11 – 1.50) • Toxicity • diarrhea (10% v 2%) • gastrointestinal pain (7% v 2%) • non-specific ophthalmologic events (29% v 5%) Schmitt et al Urology 57:727-32, 2001

  8. Anti-androgen Use Today • Steroidal Antiandrogens • Ketoconazole • Cyproterone acetate • Non-steroidal Antiandrogens • Flutamide • Nilutamide • Bicalutamide

  9. CCO MAB Guideline

  10. SideEffects

  11. Patient Decision Making n = 10 men with prostate cancer on RT “What potential survival advantage (at 5 years) would you expect to justify these additional side effects and the inconvenience of taking a daily pill” 1 (10%) < 1 % survival benefit at 5 y 5 (50%) 1-5% survival benefit at 5 y 3 (30%) 5-10% survival benefit at 5 y 1 (10%) 10-15% survival benefit at 5 y

  12. New Data • Klotz et al. • Combined data from PCTCG and Schellhammer’s RCT of bicalutamide + LHRH vs flutamide + LHRH • Same methods used to get FDA approval of capecitabine in colon CA RHR = HR (PCTCG) * HR (Schell) = HR(flut vs castration) * HR (bical vs flut) = HR (bical vs castration) = .80 (95% CI 0.66 - 0.98) Klotz L, Schellhammer P. Clin Prostate Cancer. 2005 Mar;3(4):215-9.

  13. Docetaxel for HR Prostate Cancer Tannock NEJM 2004 Petrylak NEJM 2004 HR 0.80 HR 0.76 18.9 mo 16.5 mo

  14. Relative Benefit vs Accepted Treatments Potential benefit of bicalutamide CAB • Pound Series 5 year median survival from diagnosis of metastatic disease • Bicalutamide CAB would increase median OS 1.25y over castrate therapies alone (with HR 0.80) Potential Costs • CAB pack $(3900) per 6 months • Docetaxel $20 000 per 6 months

  15. ASCO 2006 Update An interim analysis of an RCT2 and a study that combined data from an individual patient data metaanalysis and a randomized active control study,3 were published since the last guideline. Overall survival is greater with the addition of an NSAA to medical or surgical castration, but increased adverse effects may occur as a result. Loblaw DA et al., JCO April 2007

  16. Akaza update • Double-blind RCT, N=205, 40% D2 • CAB vs LHRHa (or CAB at progression) • Median F/U 5.2y HR 0.78 (0.60 – 0.99)p=0.0498 or 0.042 5y OS 75 vs 63%CSS HR 0.79 (.55 – 1.11) Akaza H et alCancer 115: 3437-45; 2009

  17. Summary CAB • Several meta-analyses have shown small to moderate improvements in overall survival with CAB • Two recent clinical practice guidelines recognize these improvements but are concerned about additive toxicity • All studies in MA used older AA which are rarely used today • Bicalutamide CAB has very tolerable side effects and has a large OS benefit

  18. Clinical Practice “I think there is a compelling survival advantage with bicalutamide CAB and I will speak to my patients about that option” or “I am not convinced that there is a compelling survival advantage with bicalutamide CAB and a clinical trial should be designed to address the issue”

  19. Timing of ADT i) Watchful Waiting Patients

  20. VACURG I Study • 1960-1975, n=954 locally advanced or metastatic disease • Randomized to one of four arms: placebo, orch+placebo, DES (5mg), or orch+DES • Patients with metastatic disease in the placebo arm were allowed active treatment upon progression 12 year survival P Orch+P DES Orch+DES Cause specific (%) Overall (%) 65 10 70 12 77 13 76 13 Jordan WP. South Med J 1977;70(12):1411-1413

  21. Outcomes • Distant Progression • Overall survival • Cause specific survival • Pain-free survival • TURP • Ureteric obstruction • Metastatic complication MRC Study Schema R A N D O M I Z E Immediate ADT T3/4 or M1Prostate Cancer n=469 Deferred ADT (at symptom onset) n=934 n=465 MRC Prostate Cancer Working Party Investigators Group Br J Urol 1997;79:235-246

  22. MRC Study Outcomes n =934, T3/4 or M1 Immediate (%) Deferred (%) 2p Distant progression Painful metastases TURP Urinary obstruction 5 yr OS 5 yr CSS 38 47 26 7 42 58 59 86 45 12 37 46 <0.001 <0.001 <0.001 <0.025 0.02 0.001 Minimum follow-up of 2.7 years MRC Prostate Cancer Working Party Investigators Group Br J Urol 1997;79:235-246

  23. MRC Study Outcomes n =934, T3/4 or M1 Immediate (%) Deferred (%) 2p Overall survival Extraskeletal metastases Urinary obstruction 7 42 58 12 37 46 0.09 0.25 0.26 Minimum follow-up of 9.5 years Kirk, 2004

  24. MRC Criticisms • No standardized follow-up schedule - 29 patients (6.2%) randomized to deferred arm died of prostate cancer before receiving treatment • Minority of patients had PSA measured on follow-up • Generalizability? - Results from locally advanced or M1 tumors may not reflect biology of biochemical failures post-RT

  25. Outcomes • Cause specific survival • Overall survival • First pain • Symptom-free survival • Ureteric obstruction • New metastases SAKK 08/88 Study Schema R A N D O M I Z E Immediate Orchiectomy • LocalizedProstate Cancer • Too unwell for radical therapy n=96 Deferred Orchiectomy (at symptom onset) n=197 n=92 Studer et al. J Clin Oncol 2004;22:4109-4118

  26. SAKK 08/88 Results Cause Specific Survival Overall Survival Time to Hormone Resistant Disease

  27. EORTC 30891 Study Schema Too unwell for radical therapy Outcomes R A N D O M I Z E Immediate ADT • Overall survival • Cause specific survival • Non-PC survival • Symptom-free survival • Time to Dist Mets • Symptomatic AIPC • Castrate Metastases • TURP T0-4 N0-2 M0Prostate Cancer n=493 Deferred ADT (at symptom onset) n=985 Excluded Age > 80 yr Other CA (non-BCC) Symptomatic Pr CA “juxtaregional LN” n=492 Studer UE et al. J Clin Oncol 2006;24:1868-76

  28. 68% 36% 61% 25% p = 0.44 p = 0.062 SURVIVAL Overall Hazard Ratio 1.25 (1.05-1.48) Non-inferiority p = 0.47 Cause specific Mortality Immediate (%) Deferred (%) 5 yr 10 yr 9 25 13 26 All cause Mortality Immediate (%) Deferred (%) 5 yr 10 yr 23 39 26 46

  29. Immediate Arm By PSAdt in deferred arm Deferred Arm Cause-Specific Mortality Studer UE et al. Eur Urol 2008;53:914-9

  30. Timing of ADT iii) N+ Post-Radical Prostatectomy Patients

  31. ECOG 3886N+ post rP Messing E et al. N Engl J Med 1999;341:1781-8

  32. EORTC 30846N+, no rP OS HR 1.23 [0.88-1.71] medOS 7.8 vs 6.2 y CSS no difference • Difference w/ ECOG 3886 • More T3 (66%) • No local treatment

  33. Timing of ADT iii) Recurrent Cancer Post-RT

  34. Dose Escalated Radiation Therapy Pollack IJROBP 2002 Zeitman JAMA 2005 n=305 Sathya JCO 2005 Peeters JCO 2006

  35. Burden of Problem Extent of disease Incidence Localized 17,225 (85%) Metastatic 3,151 (15%) Skarsgard D, Tonita J. Ca Cause Control 2000; Cdn Cancer Stats 2006

  36. 5391 4852 6982 (31%) (28%) (41%) Burden of Problem 5 yr Biochemical Failure At risk (n) Post-RT (n) Incidence Localized disease Low risk Intermediate High risk 970 1941 1745 485 970 873 30% overall (2570 post-RT) Skarsgard D, Tonita J. Ca Cause Control 2000; Cdn Cancer Stats 2006

  37. Post-Radiotherapy Failure • Local therapies • Radical prostatectomy • Cryotherapy • HiFU • Seed brachytherapy* • ANDROGEN DEPRIVATION THERAPY • ASCO Androgen Sensitive Guideline 2006 Update available Jan 29th, 2007

  38. RCTs Timing of ADT Post Radical RT • TROG Timing of Androgen Deprivation (TOAD) • ongoing

  39. Patterns of Care Survey Oncologists Survey (%) Trigger PSA (ng/mL) for starting ADT 1994 Canada 2000 USA 2004 Canada <10 10-20 20-50 >50 20 18 32 24 28 50 20 2 53 36 11 0 Skarsgard D, Tonita J. Ca Cause Control 2000; Cdn Cancer Stats 2006

  40. ASCO Guidelines Hormone-Sensitive Prostate Cancer (2004) • Timing of ADT • Systematic review of literature • 1 meta-analysis • 1 Markov model Loblaw DA et al. J Clin Oncol 2004;14:2927-41

  41. ASCO Guidelines “...antiandrogen in addition to castrate therapy. Until data from studies using modern medical diagnostic/biochemical tests and standardized follow-up schedules become available, no specific recommendations can be issued regarding the question of early versus deferred ADT. A discussion about the pros and cons of early versus deferred ADT should occur.” Loblaw DA et al J Clin Oncol 2004;14:2927- 41

  42. Meta-Analysis of Literature • Literature search • Medline 1966 – Mar 2006 • Cochrane Database of Systemic Reviews • Inclusion criteria • RCTs on patients with metastatic or untreated localized prostate cancer • ADT Intervention • Exclusion Criteria • Patients previously treated with ADT • Patients undergoing primary RT with ADT

  43. Meta-Analysis of Literature • Methods of analysis • Outcomes: all cause death, prostate cancer mortality • RevMan 4.2.8 • Visual and statistical evaluation of heterogeneity • Combined Relative Ratio, 95% confidence intervals • Sensitivity analyses performed for methodological weakness, heterogeneity

  44. Prostate Cancer Mortality

  45. Overall Mortality

  46. ASCO Guidelines “Until data from studies using modern medical diagnostic/ biochemical tests and standardized follow-up schedules become available, no specific recommendations can be issued regarding the question of early versus deferred ADT. A discussion about the pros and cons of early versus deferred ADT should occur.” Loblaw DA et al J Clin Oncol 2004;14:2927- 41 “In metastatic or progressive PCa, immediate versus symptom-onset institution of ADT results in a moderate decrease (17%) in relative risk (RR) for PCa-specific mortality, a moderate increase (15%) in RR for non–PCa-specific mortality, and no overall survival advantage. Therefore, the Panel cannot make a strong recommendation for early ADT initiation.… For patients electing to wait until symptoms for ADT, regular monitoring visits are indicated.” Loblaw DA et al J Clin Oncol April 2006

  47. Unanswered Questions • What are the benefits of immediate ADT following radiation therapy • Can we extrapolate from Watchful Waiting / Metastatic patient data? 2. What is the magnitude of detriment on QOL?

  48. ADT Side Effects • Vasomotor symptoms • Decreased libido  erectile dysfunction • Decreased muscle mass • Decreased energy • Metabolic syndrome • Osteopenic effects

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