The Evolving Definition of Advanced Prostate Cancer

The Evolving Definition of Advanced Prostate Cancer Judd W. Moul, MD Professor and Chief Division of Urologic Surgery Duke University Durham, North Carolina First… a “Poster-Boy” for Contemporary “Advanced” Disease  Hormonal therapy (HT)  Brachytherapy  External beam radiotherapy  “MULTIMODAL THERAPY” Bumiller E. “Guiliani opts for hormones for cancer.” New York Times. August 2, 2000:A24. …Another Poster Boy for Contemporary “Advanced” Disease…  Arnold Palmer – Radical prostatectomy and PSA recurrence The Evolving Face of Prostate Cancer  Many younger, healthier men: risk vs benefit of Rx more important  Rx based on risk stratification  Neoadjuvant/adjuvant HT use  Risk stratified early Rx in biochemical recurrence  Earlier use of HT in advanced PC  Traditional vs non-traditional HT: LHRH vs antiandrogen monotherapy vs IHT The Evolving Definition of Advanced Prostate Cancer  Younger, healthier, better informed patients  Stage migration – less D2 disease  Broadened definition of advanced disease with longer survival expected  Potential for longer-term use of HT  Less blanket acceptance of traditional HT side-effects, especially over many years  More need to balance risk vs benefit of Rx decisions Age Migration: More Patients Diagnosed at Younger Age (DoD CPDR National Database) 50 >70 Constituent Age Ratio (%) 40 30 65 ~ 70 20 60 ~ 65 10 55 ~ 60 <55 0 Diagnosis Year Stage Migration: Marked by Fewer Patients Presenting with Clinical Metastasis (Stage D1/D2) at Diagnosis (DoD CPDR National Database) Rate of Bone Metastasis at Diagnosis 12 8 4 0 Diagnosis Year (N=10686) Risk Stratification in Clinically Localized Disease LOW RISK PSA < 10 ng/mL and biopsy Gleason ≤ 6 and 1992 AJCC T1c, 2a PSA > 10 - 20 ng/mL or biopsy Gleason 7 or 1992 AJCC T2b PSA > 20 ng/mL or biopsy Gleason ≥ 8 or 1992 AJCC ≥ T2c INT RISK HIGH RISK D’Amico AV, Whittington R, Malkowicz, et al. J Clin Oncol. 2000;18:1164–1172. HIGH RP HIGH XRT “Rising PSA”= PSA Only or Biochemical Recurrence... …most common stage of “advanced” disease PSA Relapse  New CaP cases/year 231,000  3/4 who receive localized disease treatment annually  35% who may experience PSA-only recurrence/yr 173,250 60,600 More men are younger and healthier at time of PSA-only recurrence *Based on SEER statistics. 2004. PSA Relapse: Arguments for Early HT  Most common presentation of “advanced” prostate cancer  Relatively easy to define clinical condition  Likely to impact natural lifespan for many contemporary patients  Survival advantage to early hormonal therapy for advanced disease becoming more clear  “Watchful waiting” not acceptable for many men PSA Relapse: Arguments Against Early HT  Long natural history of rising PSA before clinical metastases and death for most men  No randomized controlled clinical trials to address this issue  Side effects of hormonal therapy  Cost of hormonal therapy PSA Relapse: Natural History of Untreated Men Radical prostatectomy (N=1997 between 1982 and 1997) PSA-only recurrence (N=315; 15%) 8 years median Clinical metastases 5 years median Death from prostate cancer Pound CR et al. JAMA. 1999;281:1591-1597. Study Cohort Diagram Illustrating Exclusion and Inclusion of Patients Primary Radical Prostatectomy Patients Overall n = 5,382 Primary RP Patients Diagnosed in PSA-Era (1988-2002) n = 4,967 Primary RP Patients Diagnosed in PSA-Era with Follow-up n = 528 Excluded due to post RP follow-up < 6 months n = 363 Excluded due to a salvage XRT after PSAR n = 49 Excluded due to no follow-up after PSAR PSA Recurrences (Study Cohort) n = 1,352 Recurrence 1st Year* n = 544 44 (8.1%) Clinical Metastases Moul JW et al. J Urol. 2004;171:1141-1147. GL > 7, or PSA-DT < 12 months* n = 343 62 (18.1%) Clinical Metastases Non-Curable* n = 664 103 (7.6%) Clinical Metastases *Groups not mutually exclusive PSA Only Recurrence Cohort to Illustrate PSA at Initiation of HT PSA Recurrence Patients n = 1,352 Started HT > 0.2 – 2.5 ng/mL n = 221 (16.3%) Started HT > 2.6 – 5.0 ng/mL n = 47 (3.5%) Started HT > 5.1 – 10.0 ng/mL n = 39 (2.9%) Started HT PSA > 10.0 ng/mL n = 48 (3.6%) No HT (Median/mean follow-up 5.2/4.7 years after radical prostatectomy) n = 997 (73.7%) Moul JW et al. J Urol. 2004;171:1141-1147. Early HT Administered at PSA >5 ng/mL Affects Clinical Metastasis-Free Survival  Patients with pathological Gleason sum > 7 or PSA-DT < 12 Months Moul JW et al. J Urol. 2004;171:1141-1147. Early HT Administered at PSA <10 ng/mL Affects Clinical Metastasis-Free Survival  Patients with pathological Gleason sum > 7 or PSA-DT < 12 Months Moul JW et al. J Urol. 2004;171:1141-1147. Early HT Administered at <5 ng/mL Did Not Affect Clinical Metastasis-Free Survival  Overall cohort with PSAR at current follow-up Moul JW et al. J Urol. 2004;171:1141-1147.  Good News: – First study to show clinical DFS benefit to early HT for PSAR – Emphasizes the importance of “risk stratification” in PSA relapse – Supports that men with high-grade disease (Gleason 8-10) and quick PSA-DT (<12 months) are high risk of clinical failure  Bad News: – Not a randomized controlled trial – Overall, there was no benefit to early HT – Database study is a “moving target” and results may change over time – Follow-up too short to determine overall survival impact CPDR/CaPSURE/Harvard PSA-DT Study 100 Prostate Cancer–Specific Survival 80 60 40 20 0 0 1 2 3 4 5 6 7 95 65 10 18 Surgery, PSA DT 3 months Radiation, PSA DT 3 months Surgery, PSA DT <3 months Radiation, PSA DT <3 months 8 52 34 6 10 9 26 18 2 4 10 12 8 1 1 Time (Years) Following PSA Failure 537 509 433 358 282 206 144 668 635 536 430 306 200 130 74 62 49 41 33 22 15 172 154 127 99 75 54 33 Number at Risk D’Amico AV, et al. J Natl Cancer Inst. 2003;95:1376-1383. Take-Home Messages  Changing face of advanced prostate cancer is profound  High-risk localized and PSA recurrence: most common “advanced” prostate cancer  No randomized controlled trials to guide our clinical decisions in PSA recurrence  Our recent work* emphasizes that we take a “risk stratified” approach to PSA relapse  Men with high grade disease (Gleason 8-10) and those with short PSA-DT (<12 months) have delayed clinical metastases if they receive early HT  Unknown if early HT for PSA relapse will improve cancer-specific or overall survival *Moul et al. J. Urol. March 2004.