Overtreatment and undertreatment Radical Prostatectomy: An Emerging Standard of Care for High Risk Prostate Cancer Matthew R. Cooperberg, MD,MPH UCSF Radiation Oncology Update San Francisco, CA April 2, 2011 Cooperberg et al. J Clin Oncol 2010; 28:1117 Natural history of high-risk disease Comparative Effectiveness Research Localized prostate cancer: IOM top 25 list for CER research No RCTs of surgery vs. radiation since 1982 Focus on prospectively-accrued registries with long-term followup to metastasis / mortality outcomes and robust risk adjustment Lu-Yao et al. JAMA 2009; 302:1202 1
CaPSURE: Patient characteristics Unadjusted outcomes RP N=5543 Age 61.5 ± 6.9 100-Kattan 19.1 ± 14.7 EBRT N=1294 70.6 ± 23.3 30.5 ± 22.5 All-cause mortality: n=1466 Mean time to death 6.8 ± 4.0 years Cancer-specific mortality: n=261 PADT N=1484 Total N=8321 73.1 ± 8.2 65.0 ± 8.7 36.6 ± 26.1 23.9 ± 19.9 CAPRA 2.7 ± 1.6 4.0 ± 2.1 4.4 ± 2.4 3.2 ± 2.0 Charlson 1.6 ± 1.2 2.0 ± 1.3 2.2 ± 1.3 1.7 ± 1.3 Results: Cancer-specific mortality Adjusted all-cause mortality Predictors of Cancer-Specific Mortality Variable HR p 95% CI Age 0.98 0.046 0.97 1.00 CAPRA 1.35 <0.001 1.28 1.43 RP Ref ERBT With By competing adjustment 1.96 risks by analysis: Kattan <0.001 rather than CAPRA: 1.28 2.78 PADT EBRT HR 2.2 2.1 (1.5 3.2); (1.4 3.1); PADT HR 3.2 2.6 (2.2-4.8) (1.7-4.2) 3.26 <0.001 2.27 4.67 PADT:EBRT HR 1.7 (1.3 2.1) Variable HR p 95% CI Age 0.98 0.046 0.97 1.00 CAPRA 1.10 <0.001 1.07 1.13 Charlson 1.11 <0.001 1.07 1.13 RP Ref EBRT 1.52 <0.001 1.30 1.78 PADT 2.29 <0.001 1.93 2.71 2
Predicted 10-year cancer-specific mortality Predicted 10-year cancer-specific mortality CAPRA RP EBRT PADT CAPRA 0 1.6 (1.0 2.6) 3.1 (1.8 5.2) 5.0 (3.0 8.4) CAPRA 1 2.2 (1.4 3.5) 4.2 (2.5 6.8) 6.8 (4.2 10.9) CAPRA 2 3.0 (2.0 4.7) 5.7 (3.5 9.0) 9.1 (5.8 14.3) CAPRA 3 4.1 (2.7 6.3) 7.6 (4.9 11.9) 12.3 (8.0 18.6) CAPRA 4 5.6 (3.7 8.4) 10.3 (6.7 15.8) 16.4 (11.0 24.2) CAPRA 5 7.6 (5.0 11.4) 13.8 (9.0 20.8) 21.8 (14.8 31.3) CAPRA 6 10.2 (6.7 15.4) 18.4 (12.1 27.4) 28.5 (19.8 40.0) CAPRA 7 13.7 (8.8 20.8) 24.3 (16.1 35.6) 36.8 (25.9 50.4) CAPRA 8 18.2 (11.7 27.8) 31.6 (21.1 45.7) 46.6 (33.4 62.0) CAPRA 9 24.0 (15.2 36.7) 40.5 (27.2 57.3) 57.6 (42.1 74.0) CAPRA 10 31.3 (19.6 47.5) 50.9 (34.5 69.7) 69.0 (51.9 84.8) Unmeasured confounding? Increase in Kattan score for RP patients HR for EBRT HR for PADT 0 2.21 (1.50-3.24) 3.22 (2.16-4.81) 5 1.95 (1.32-2.88) 2.84 (1.89-4.27) 10 1.72 (1.15-2.55) 2.50 (1.64-3.80) 15 1.51 (1.01-2.27) 2.20 (1.43-3.39) 20 1.33 (0.88-2.02) 1.94 (1.25-3.02) 25 1.17 (0.77-1.80) 1.71 (1.08-2.70) Example: an RP patient with GS 3+4, PSA 9, 30 ct2a would 1.03 have (0.67-1.61) to have the same 1.51 actual (0.94-2.41) risk as an EBRT patient with GS 3+3, PSA 4, ct1c 35 0.91 (0.58-1.44) 1.33 (0.81-2.16) Strength of registries Not an RCT, but several strengths Identical followup regardless of primary treatment Independent (3rd party) data analysis Consistent definitions Real world outcomes 3
Caveats Variation / trends in EBRT technique/dose Variation in NADT/AADT use/duration (adjustment made no difference use tracks with risk) Insufficient mortality events for brachytherapy / cryotherapy / watchful waiting analyses Mortality estimates may overestimate risk for contemporary patients with better staging and treatment Results from MSKCC and Baylor 1318 RP and 1062 EBRT patients All EBRT was IMRT 81 Gy Short-course NADT in 56% Predictor for metastasis HR 95% CI P-value Age 0.98 0.95-1.02 0.3 Year of treatment 0.97 0.87-1.07 0.5 NCCN risk (high vs low/int) 6.37 3.89-10.5 <0.001 Surgery vs. EBRT 0.35 0.19-0.63 0.001 Zelefsky et al. J Clin Oncol 2010; 28:1508 Results from MSKCC and Baylor Results from MSKCC and Baylor 81 to 86Gy of EBRT may be insufficient Favor combined brachy + IMRT or surgery + EBRT Need for a surgical arm in future trials in high-risk disease Zelefsky et al. J Clin Oncol 2010; 28:1508 Zelefsky et al. J Clin Oncol 2010; 28:1508 4
Results from Washington U 4656 localized CaP patients 3652 RP (16% ACM) 1004 EBRT (31% ACM) Results from Cleveland Clinic 4222 men with low-intermediate risk disease 1996-2005 tx ed RP, EBRT, brachy Control for age, PSA, Gleason score, BMI, stage, comorbidities 23 cancer-specific deaths (92 CAD deaths) Duan et al. AUA 2008 Ciezki et al. ASTRO 2009 Results from CCF / Wash U What about QOL? 10,472 men (6493 RP, 2260 EBRT, 1719 brachy) RT brachy + EBRT + NADT Lower-risk cohort overall than MSKCC or CaPSURE Cox and Fine & Gray analyses with age, race, risk, and comorbidity-based propensity score adjustment HR for ACM: 1.6 (95% CI 1.4-1.9) and 1.7 (95% CI 1.4-2.1), respectively, for EBRT and brachy relative to RP HR for CSM: 1.6 (95% CI 1.0-2.6) and 1.1 (95% CI 0.5-2.6) for EBRT and brachy relative to RP And don t forget about costs! Stephenson et al. AUA 2010 Wu et al. J Urol 2008; 180:2415 5
Conclusions Multiple studies in a variety of contexts with mature followup and robust risk-adjustment have shown a clear survival benefit for RP over EBRT (including IMRT). Magnitude of differences cannot be explained by variation in technique or ADT duration. Data re: brachy are less clear. RCTs between modalities in high-risk disease are needed Treatment for high-risk disease often must be multimodal, and should include surgery with greater frequency 6