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Cytoreductive Prostatectomy Mark L. Gonzalgo, M.D., Ph.D. Professor & Chief of Urology University of Miami Hospital Associate Director for Clinical Affairs Sylvester Comprehensive Cancer Center University of Miami Miller School of Medicine Locally Advanced and Metastatic Prostate Cancer 5-15% of newly diagnosed prostate cancers are locally advanced or metastatic Survival rates for metastatic prostate cancer remain poor Standard of care for metastatic prostate cancer is systemic treatment, but is there a role for local therapy? Role of Local Treatment of Primary Tumor Survival benefit shown for other malignancies: Renal Cell Colorectal Intracranial Glioma Ovarian Breast Proposed Rationale for Cytoreductive Prostatectomy Reasonable mechanistic theories with some basic science data exist: Tumor debulking Removing tumor-promoting factors and immunosuppressive cytokines increased response to ADT after RP “Seed and soil” hypothesis Receptive microenvironment may be driven by factors secreted by the primary tumor. Development of individual metastases is dependent on an intact primary tumor focus Tumor self-seeding Circulating tumor cells return to and grow in primary tumor sites from derived metastases What is Oligometastatic? No consensus definition ≤ 3 lesions outside of the treated primary tumor Randomized phase II trials SABR-COMET in Canada = 5 oligometastasis STOMP in Belgium = 3 oligometastasis CORE in the UK (includes prostate, breast, and lung cancer with 3 oligometastasis) Locally Advanced and Metastatic Prostate Cancer No clinical trial has assessed the role of RT in patients with node-positive N+M0 disease STAMPEDE Trial – Control Arm Exploratory multivariate analysis of the impact of RT on survival and failure-free survival Control arm of the STAMPEDE Trial 721 men with newly diagnosed M0 disease were included: Radiotherapy encouraged but not mandated for N0M0 patients only (since November 2011) Failure-free survival outcomes favored use of RT for patients with both N0M0 (HR, 0.33 [95% CI, 0.18-0.61]) and N+M0 disease (HR, 0.48 [95% CI, 0.29-0.79]). Data suggest that benefits of RT extend to men with N+M0 disease James et al., JAMA Oncol, 2016 James et al., JAMA Oncol, 2016 3,540 patients with cN+ prostate cancer without distant metastases between 2004 and 2011 32.2% men treated with ADT alone 51.4% received ADT+RT Propensity score matching: 318 patients in each group Statistically significant overall survival benefit for patients with cN+ prostate cancer treated with ADT+RT compared to ADT alone Lin et al., JNCI 2015 Lin et al., JNCI 2015 Retrospective study 0f SEER data 2004 – 2010 8,185 patients Stage IV (M1a-c) PC Radical prostatectomy (RP) vs. Brachytherapy (BT) vs. No surgery or radiation therapy (NSR) 38% of men died from prostate cancer with median follow-up of 16 months 5-yr OS RP 67.4% BT 52.6% NSR 22.5% RP and BT were independently associated with better overall survival compared to no surgery or radiation Cumulative incidence of cancer-specific mortality RP and BT were associated with decreased cancer-specific mortality compared to no surgery or radiation Subgroup Analysis Factors independently associated with increased mortality in localized therapy: age ≥ 70 yr cT4 high grade disease PSA ≥ 20 ng/ml pelvic lymphadenopathy 5 year OS: ≤ 1 factor - 77.3% 2 factors- 53.1% ≥ 3 factors - 38.2% - similar to NSR Culp et al., Eur Urol, 2014 Limitations Selection bias No No data on comorbidities data about adjuvant ADT or chemotherapy No data on extent of bony metastasis Patients treated with RP were 10 years younger than the NSR group (62 vs 72) RP patients had a higher proportion of those with PSA < 20 No discussion on the impact on quality of life or complications of treatment Examined perioperative outcomes and short- term complications after radical prostatectomy for locally resectable, distant metastatic prostate cancer Retrospective case series from 2007 to 2014: 106 patients with newly diagnosed metastatic (M1) prostate cancer from USA, Germany, Italy, and Sweden Outcome measures: margin status, continence, readmission, reoperation, and overall complication rates at 90 days 79.2% of patients had no complications Positive-margin rate = 53.8% 94/106 (88.7%) men were alive at a median follow-up of 22.8 months Multi-institutional Analysis of Perioperative Outcomes in 106 Men Who Underwent Radical Prostatectomy for Distant Metastatic Prostate Cancer at Presentation (Sooriakumaran, et al.) Retrospective. Comparison to meta-analysis of prostatectomy for standard indications. (Tewari, et al.) Overall complications ~ 20.8% (8.2 -19.4) Readmission ~ 3.8% (3.0) Reoperation ~ 1.9% (2.3) Transfusion rates ~ 14.2% (16.5) Mean length of stay ~ 3.1 days (3.0) Wound infections ~ 4.7% (2.8) Positive margin rate ~ 54% (42.6) Take home message: Radical prostatectomy is technically feasible and safe in men with metastatic prostate cancer Developed a predictive model for 3 year cancer specific mortality risk based on: Age at diagnosis PSA level Gleason score T stage N stage M stage LT compared with NLT conferred higher CSM-free survival rate in patients with a predicted CSM risk < 40% LT did not provide a survival benefit when the predicted CSM risk > 50% 11 patients with oligometastatic disease treated with RP and extendend PLND Oligometastatic: ≤ 5 bone lesions at bone scan with or without suspicious nodal involvement 10 patients had LN invasion 8 patients had positive SM ADT was administered to 10 patients CSM-free survival = 82% 7 year clinical progression-free survival = 45% Conclusions Data for support of cytoreductive prostatectomy remains limited Clinical Trials are necessary: Some evidence exists for safety in perioperative period and technically feasibility Little evidence for long term safety/morbidity Reasonable mechanistic theories Prospective cohort studies for other cancers lend credibility Future Directions TRoMbone: 5 year OS of radical prostatectomy plus usual treatment vs. usual treatment alone in oligometastatic PC STAMPEDE (NCT00268476): ADT vs multiple arms including ADT+RP NCT01751438: Systemic + local (radiation or surgery) vs systemic alone in M1 mPC NCT00924469 and NCT01547299: Neoadjuvant androgen deprivation therapy to RP