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2 predicting response to adt msk.eso 4.3.2011
1. Predicting Response to Hormonal Therapy and Survival in Men with Metastatic Prostate Cancer Maha Hussain, M.D., FACP Professor of Medicine & Urology Associate Director For Clinical Research Co-Leader, Prostate Cancer/GU Oncology Program University of Michigan Comprehensive Cancer Center
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3. PCa, prostate cancer; NR, not recorded; PFS, progression-free survival; MS, median survival; a Goserelin + flutamide arm superior in subjective and objective PFS, OS and rate of cancer deaths Selected Randomized Studies of Combined AD vs Monotherapy in M1 PCa Crawford ED et al. N Engl J Med 1989;321:419â24 Keuppens F et al. Cancer 1993;72(12 suppl):3863â9 Tyrrell C et al. Cancer 1993;72(12 suppl):3878â9 Eisenberger M et al. N Engl J Med 1998;339:1036â42 Author Treatment n PFS (months) OS (months) p Crawford, 1989 Leuprolide + placebo Leuprolide + flutamide 300 303 13.9 16.5 28.3 35.6 0.03 (PFS) 0.03 (OS) Keuppens, 1993 Orchidectomy Goserelin + flutamide a 163 161 Diff (subj) 8.1 Diff (obj) 11.0 Diff (ms) 7 Diff (c) 15 0.009 (PFS) 0.05 (OS) Tyrrell, 1993 Goserelin Goserelin + flutamide 282 287 NR NR 37.7 42.4 0.08 (PFS) 0.14 (OS) Eisenberger, 1998 Orchidectomy + placebo Orchidectomy + flutamide 687 700 18.6 20.4 29.9 33.5 0.26 (PFS) 0.16 (OS)
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7. Long Term Survival for S8894 Data as of 10/1/2008 Tangen et al, Clin Prostate Cancer, 2003
8. Clinical Predictors of Survival Multivariate Proportional Odds Model (n = 536) Tangen et al, Clin Prostate Cancer, 2003 Variable Estimated DR (95% CI) Ń Value Flutamide vs. Placebo 0.72 (0.47, 1.12) 0.14 Extensive vs. Minimal Disease 2.90 (1.78, 4.73) <0.0001 Performance Status (2/3 vs. 0/1) 1.22 (0.63,2.36) 0.56 Bone Pain (Yes vs. No) 2.61 (1.66, 4.12) <0.0001 Race (Black vs. Others) 1.19 (0.67, 2.10) 0.56 Gleason Score <7 1.0 (reference) - 7 1.84 (0.94, 3.60 0.076 >7 3.79 (2.00, 7.18) <0.0001 Log (PSA) 1.18 (1.03, 1.34) 0.016 Age 1.02 (1.00, 1.05) 0.082
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12. PSA (ng/mL) Patients (%) Q #1: Patients with Specified PSA Levels During or at the End of 7 Months ADT Induction (n=1395) Hussain M et al. J Clin Oncol 2006;24:3984â90
13. Multivariate Logistic Regression Model Predicting Lack of Achieving a PSA < 4.0 ng/ml During Induction Adjusted for Other Variables in the Model (n=1395) The results are similar for achieving PSA †4.0 ng/ml at any time during induction Significant (p<0.05) univariate predictors with < 15% missing are included in this model Lack of PSA †4.0 ng/ml at Months 6 &7 Predictor Odds Ratio (95% CI) P-value Age at Study Entry in 5 Year increments 0.93 (0.86, 1.00) 0.048 Prestudy PSA in 50 unit increments 1.02 (1.01, 1.03) <0.0001 Performance Status 2,3 vs. 0,1 1.88 (1.09, 3.25) 0.023 Gleason sum ℠8 1.97 (1.49, 2.60) <0.0001 Bone Pain Present 2.25 (1.70, 2.99) <0.0001
14. Q#2: Predictors of Risk of Death After 7 Months ADT, n=1,345 Predictor Univariate Hazard Ratio (95% CI) P-value Bone Pain Present 1.91 (1.63, 2.24) <.0001 Performance Status 2,3 vs. 0,1 1.83 (1.39, 2.41) <.0001 Gleason Sum 8 or higher 1.58 (1.34, 1.87) <.0001 Weight Change 1.57 (1.31, 1.88) <.0001 Positive Distant Nodes 1.34 (1.03, 1.73) 0.027 Prestudy PSA in 50 unit increments 1.01 (1.00, 1.01) 0.0024 Any PSA < 4ng/ml 0.26 (0.22, 0.31) <.0001 PSA < 4ng/ml at Months 6&7 0.20 (0.17, 0.23) <.0001 Any PSA < 0.2 ng/ml 0.34 (0.29, 0.40) <.0001 Any PSA < 0.2 ng/ml at Months 6&7 0.30 (0.26, 0.36) <.0001
15. Multivariate Proportional Hazards Model: Testing Effect of PSA < 4 ng/ml or < 0.2 at Months 6,7 on Subsequent Risk of Death (Estimates and p-values adjusted for other variables in the model) # comparison of these two estimates with a Wald chi-square, p <0.0001. Significant (p<0.05) univariate predictors with < 15% missing included in model Predictor Hazard Ratio (95% CI) P-value Performance Status 2 vs 0,1 1.86 (1.34, 2.60) <0.001 Bone Pain Present 1.50 (1.25, 1.80) <0.0001 Gleason sum â„8 1.35 (1.13, 1.62) 0.001 Prestudy PSA in 50 unit increments 0.99 (0.99, 1.00) 0.005 0.2 < PSA < 4 ng/ml at Months 6 & 7 0.30 # (0.24, 0.38) <0.0001 PSA †0.2 ng/ml at Months 6&7 0.17 # (0.13, 0.21) <0.0001
16. At Risk PSA †0.2 ng/ml 453 210 63 0.2 < PSA †4.0 219 77 20 PSA > 4.0 92 17 7 Hussain et al. J Clin Oncol 2006;24:3984â90 Overall Survival by By PSA Status at End of 7 month ADT Induction 0% 20% 40% 60% 80% 100% 0 24 48 72 96 120 Months After End of Induction PSA †0.2 0.2 < PSA †4.0 PSA > 4.0 At Risk 602 360 383 Deaths 199 166 322 Median in Months 75 44 13 P < .0001
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18. PSA-P as a Predictor of Overall Survival (Time Varying Analysis, Multivariate Cox Regression)
19. Landmark Analysis S9346 Overall Survival by PSA-P at 7 Months (PCWG 08: â„ 25% & â„ 2 ng/mL ) 0% 20% 40% 60% 80% 100% 7 31 55 79 103 127 151 Months After Registration No PSA Progression PSA Progression N 829 200 Events 465 191 Median in months 44 (51) 10 (17) P<.0001
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22. PSA -Based Personalized Therapy 2. Induce a response in suboptimal PSA â Responders About 30% of all registered patients to S9346 had a PSA > 4 at 7 months BUT not rising S1014: Abiraterone acetate for patients not achieving a PSA ïŁ 4 ng/mL after 7 months of CAD