Role of Radical Prostatectomy in metastatic Prostate Cancer The role of RP in metastatic cancer is very controversial. The topics I will focus on include rationale for local therapy in metastatic cancers, potential advantages of local treatment in pts with metastatic PCa, data from clinical studies and selection of patients for surgery.   Prof Vsevolod Matveev N.N.Blokhin Cancer Research Center Moscow, Russia

Topics for discussion Rationale for local therapy in metastatic cancers Potential advantages of local treatment in patients with metastatic PСa Data from clinical studies Patient selection for cytoreductive surgery

Surgery in metastatic cancer Surgery as palliation, for diagnosis Surgery as therapy? metastatic cancer is a systemic illness surgery is cytoreductive associated with morbidity/mortality risk/benefit ratio is high can improve survival ? bTraditionally, metastatic cancer is considered to be incurable, and the goals of treatment are the prolongation of life and improvement of its quality. Therefore, in metastatic setting Surgery is usually reserved for palliation of symptoms in patients with bleeding, intractable pain, What aout surgery as therapy? Metastatic cancer is a systemic disease and needs systemic treatment. Surgery in metastatic cancer is cytoreductive, it decrease tumor burden and is often associated with serious morbidity and mortality and risk to benefit ratio is high. Therefore, it is not surprising that local therapy is not routinely recommended for patients presenting with stage IV disease but the role of local treatment in metastatic cancer is gaining interest as some data indicate that it may improve survival.

The biological rationale for local therapy in stage IV cancer eliminates the source of cytokine signaling which may enhance metastatic seeding eliminates the source of circulating tumour cells eradicate self-renewing progenitor cells persisting after ADT that are capable of propagating adenocarcinoma Kim MY, et al. Cell 2009;139:1315–26. Psaila B Nat Rev Cancer 2009;9:285–93. Haffner MC, et al. J Clin Invest 2013;123:4918–22.

Solid tumors with survival benefit from cytoreductive surgery RCC Ovarian cancer Colon cancer Breast cancer melanoma

Surgery improved median survival by 9 months Phase III MF07-01 Trial: Impact of Initial Local Resection on Stage IV Breast Cancer Survival Survival Local Surgery (n = 138) Systemic Therapy (n = 136) HR (95% CI) P Value 3-yr survival, % 60 51 -- .10 5-yr survival, % 41.6 24.4 .005 Median OS, mos 46 37 0.66 (0.49-0.88) Surgery improved median survival by 9 months A. Soran et al. ASCO 2016

Number of metastasectomies Nationwide inpatient sample was used from 2000-2011 Role of surgery in metastatic cancer goes beyond local treatment of the primary tumor. In high-volume centers Number of metastasectomies is increasing dramatically for many cancers. High-volume centers are driving the trends in the performance of metastasectomy. Role of surgery in stage IV cancer is evolving. Apart from palliative indication surgery has become an integral part of multimodal approach in many solid tumors. Bartlett EK, et al. Cancer 2015;121(5):747-757

Surgery in stage IV cancer Role of surgery in stage IV cancer is evolving Surgery has become an integral part of multimodal approach in many solid tumors Pca patients differ from other tumors?

Metastatic Prostate Cancer standard of care in mPCa systemic ADT + chemotherapy with docetaxel 5-yr survival only 28% 1/3 of pts without treatment of the primary experience significant complications of the urinary tract due to local progression EAU guidelines 2016

Secondary analysis of SWOG 8894 1,286 men mPCa randomized to orchiectomy + placebo vs orchiectomy + flutamide RP prior to mPCa associated with a decreased risk of death compared with NLT 51% risk of death reduction for CSS 30% risk of death reduction for OS potential role for local therapy Potential benefit of local therapy in metastatic PCa was for the first time demonstrated in the SWOG 8894 trial which randomized 1,286 men with mPCA to orchiectomy plus placebo vs orchiectomy plus flutamide. RP before ADT had a significant impact on CSS with a 51% risk reduction and 30% risk of death reduction for overall survival compared with no earlier definitive treatment and implicated a potential role for local therapy. Previous radical prostatectomy (RP) prior to MPCa was associated with a decreased risk of death implicated a potential role for local therapy Thompson IM, et al. J Urol 2002; 168:1008.

8,185 pts with stage IV PCa treated with RP, brachy or NLT 5-year CSS after RP, Brachy and NLT 75.8% vs 61.3% vs 48.7% 5-yr overall survival 67.4% vs 52.6% vs 22.5% in pts RP vs Brachy vs NLT 8,185 patients with stage IV PCA from the SEER data bank who were treated with RP, brachytherapy or no surgery or radiation. The 5-yr OS and predicted DSS were each significantly higher in patients undergoing RP (67.4% and 75.8%, respectively) or BT (52.6 and 61.3%, respectively) compared with NSR patients (22.5% and 48.7%, respectively) ( p < 0.001). Undergoing RP or BT was each independently associated with decreased CSM ( p < 0.01). Culp et al. Eur Urol, 65 (2014) 1058-1066

4069 mPCa: RP (n=47), IMRT (n=88), CRT (n=107) versus NLT (n=3827) adjusted probability of all cause and PCa specific mortality after LT for treatment group, age, year of diagnosis, race, marital status, PSA, Gleason score, AJCC staging (TNM), Charlson Comorbidity Index, ADT, bone RT within 6 mos of diagnosis This registry-based observational study compared 4069 men receiving local therapy (LT) versus no LT for metastatic pros-tate cancer (mPCa), using (SEER)–Medicare data. Overall, 47 men underwent RP, 88 underwent IMRT, 107 underwent CRT, and 3827 had no LT. RP and IMRT were associated, respectively, with 57% (hazard ratio [HR]: 0.43; 95% confidence interval [CI], 0.26–0.70) and 55% (HR: 0.45; 95% CI, 0.31–0.65) reductions in all-cause mortality. CRT was not associated with reduced mortality. Satkunasivam et al. J Urol 2015;194:378–85.

RP and IMRT 57% and 55% lower risk of all cause mortality RP and IMRT 52% and 62% reduction in risk of PCa SM Competing risk analysis 42% and 57% reduction in risk of PCa SM After accounting for these and conventional risk factors, RP and IMRT were associated with IMRT 57% and 55% lower risk of all cause mortality and 52% and 62% reduction in the risk of PCa specific mortality, respectively. Competing risk analysis revealed a 42% and 57% decrease in the risk of prostate cancer specific mortality for radical prostatectomy and intensity modulated radiation therapy. Satkunasivam et al J.Urol 2015;194:378–85.

300 pts М+ , 192 (64%) local sypmtoms 72 received LT (56.9% TURP, 52.7% RT) LT more frequently in low V, (35.4% vs. 16.2%), PSA (75 vs 184 ng/ml) and local symptoms (34.2% vs. 4.8%) LT in multivariante analysis associated with improved OS (62.1 vs. 55.8 мес), Significant only for RT 69.4 vs. 55.1 ms No correlation with PSA, Gleason, n of bone mets and presence of symptoms In our study, although local treatment (LRT) overall conferred a survival advantage (62.1 vs. 55.8 months; HR, 0.74; P ј .044), this was almost entirely restricted to patients receiving RT (69.4 vs. 55.1 months; HR, 0.54; P ј .002) as opposed to those who received TURP (54.3 vs. 58.8 months; HR, 1.23; P ј .239). The survival benefit from local RT appeared to be independent of other known prognostic variables (age, Gleason Score, PSA, volume of disease, and presence of symptoms) included in multivariable Cox regression models. Importantly, the survival benefit was independent of the volume of bone metastases, suggesting that patients with a low as well as a high burden of metastases could potentially benefit from local RT. These results, although limited by the small number of patients and its retrospective nature, might indicate that the overall biological effect of TURP on OS is negligible whereas RT might instead have a favorable effect on OS. The different effect on OS between these 2 main local treatment modalities (RT or TURP) might be, in part, explained by the different rationale for treatment indication. Although TURP was generally carried out to resolve urinary symptoms such as urinary obstruction and/or urinary frequency, the rationale for administering RT in nearly half of the patients was primarily not to palliate local symptoms but rather to improve local control and prevent the subsequent development of local symptoms. Clinical Genitourinary Cancer DOI: (10.1016/j.clgc.2017.04.013)

Apart from possible benefit in survival CRP also results in significantly reduced complication rates of the lower and upper urinary tract. Won et al analyzed the outcome of 263 patients with castration resistant prostate cancer who underwent RP, EBRT or no local treatment before ADT. RP significantly reduced the incidence of local complications compared to that of patients who did not undergo local surgical therapy (20% vs54.3%, p¼0.001) or who did undergo EBRT (20% vs 46.7%, p¼0.007). Bladder outlet obstruction developed in 4.4%, 35.6% and 42.8% of patients who underwent RP, EBRT or no local treatment, respectively Won A.C. et al BJU Int 2013; 112:E250.

Selection of the right patients may be the most important factor in outcomes.

How to select pts for cPE? Tumor characteristics Extent of metastatic disease Gleason Score tumour doubling time (PSA DT) Response to neoadjuvant ADT/chemotherapy (PSA nadir, objective response) Patient characteristics Overall patient performance status comorbidities Selection of the right patients may be the single most important factor in outcomes. This is precisely what makes trials so difficult.

e 1470 (9.5%) of 15501 pts received LT 3-yr OM-free survival 69% in LT vs 54% in NLT Cox regression: NLT group, age, Charlson comorbidity index were predictors of OM (p 0.03) 3-yr improvement in OM-free survival after LT was 15.7% for pts with predicted OM risk 20% vs 0% for OM risk 72%. Pts with low tumor risk and good general health status benefit the most from local treatment The impact of LT on OM was highly influenced by tumor and patient characteristics. Overall, 9.5% (n = 1470) of patients received LT. In the postpro-pensity matched cohorts, 3-yr OM-free survival was higher in the LT group versus the NLT group (69% vs 54%; p < 0.001). In multivariable Cox regression, the NLT group, age, and Charlson comorbidity index were predictors of OM (all p 0.03). This model was used to predict the 3-yr OM risk. The interaction between predicted OM and LT status was significant (p < 0.001). The benefit of LT on OM decreased progressively as predicted OM risk increased. Specifically, the 3-yr absolute improvement in OM-free survival was 15.7%, for patients with predicted OM risk 20% versus 0% for those with predicted OM risk 72%. Conclusions: Men with mPCa at diagnosis benefit from LT in terms of OM. This is largely affected by baseline characteristics. Specifically, patients with a relatively low tumor risk and good general health status appear to benefit the most. Loppenberg et al., Eur Urol 2016

What is the risk of surgical morbidity in mPCa?

control group: 38 men treated with ADT CRP group: 23 pts with minimal osseous metastases (≤3 hot spots on bone scan), no visceral or extensive lymph node mts, PSA after neoadjuvant ADT < 1.0 ng/ml control group: 38 men treated with ADT Median follow-up 34.5 and 47 months in groups 1 and 2 In the case-control study Heidenreich explored the feasibility of a multimodality therapeutic approach in a well selected patients with PCA and low volume skeletal metastases, no visceral or extensive lymph node mts and PSA after neoadjuvant ADT less than 1. The control group included 38 treated with ADT. 23 patients with biopsy proven prostate cancer, minimal osseous metastases (3 or fewer hot spots on bone scan), absence of visceral or extensive lymph node metastases and prostate specific antigen decrease to less than 1.0 ng/ml after neoadjuvant androgen deprivation therapy were included in the feasibility study (group 1). A total of 38 men with metastatic prostate cancer who were treated with androgen deprivation therapy without local therapy served as the control group (group 2). Surgery related complications, time to castration resistance, and symptom-free, cancer specific and overall survival were analyzed using descriptive statistical analysis. Results: Mean patient age was 61 (range 42 to 69) and 64 (range 47 to 83) years in groups 1 and 2, respectively, with similar patient characteristics in terms of initial prostate specific antigen, biopsy Gleason score, clinical stage and extent of metastatic disease. Median followup was 34.5 months (range 7 to 75) and 47 months (range 28 to 96) in groups 1 and 2, respectively. Median time to castration resistant prostate cancer was 40 months (range 9 to 65) and 29 months (range 16 to 59) in groups 1 and 2, respectively (p¼0.04). Patients in group 1 experienced significantly better clinical progression-free survival (38.6 vs 26.5 months, p¼0.032) and cancer specific survival rates (95.6% vs 84.2%, p¼0.043), whereas overall survival was similar. Of the men in groups 1 and 2, 20% and 29%, respectively, underwent palliative surgical procedures for locally progressing prostate cancer. Heidenreich A, et al. J. Urol. 2014 , 193, 832-838

Results CSS rate 95.6% vs 84.2% (p=0.043) Clinical PFS 38.6 vs 26.5 months (p=0.032) Median time to CRPC 40 and 29 months (p=0.014) OS rate 93.3% vs 78.9% (p=0.048) 20% and 29% underwent palliative surgical procedures Heidenreich A, et al. J. Urol. 2014 , 193, 832-838

Complications and Functional Outcome of cytoreductive PE No Clavien grade 4 or 5 complications Of 23 pts 21 (91.3%) continent (0 -1 pads per day) 2 (8.7%) pts need 2 to 4 pads per day. CRP in mPCa can be performed with same high quality and safety outcome as routine RP Adoption of local treatment in MPCa must be judicious as the treatments themselves increase the risk of surgical morbidity and can be detrimental to health related quality of life. Also, the frequency and the seriousness of surgery related complications do not differ from RP in highrisk PCA.In Heidenreih study No Clavien grade 4 or 5 complications occurred. The functional outcome of CRP does not differ from the reported outcome of RP in high risk PCA in terms of postoperative continence recovery Of 23 patients 21 (91.3%) are continent with the use of 0 to 1 pads per day (13 patients [56.5%] 0 pads per day and 8 patients [34.8%] 1 pad per day) and 2 (8.7%) patients need 2 to 4 pads per day. Therefore, CRP can be performed with same high quality and safety outcome as routine RP. Heidenreich A, et al. J. Urol. 2014 , 193, 832-838

Conclusions There might be a role for cytoreductive prostatectomy in the multimodality management of prostate cancer Patient selection is the key CPE reduces the risk of locally recurrent prostate cancer and local complications. Future randomized studies are needed to provide better data

Without randomized trial we can only guess…

NCT02454543 Multicentric, Prospective, Randomized Controlled Trial Comparing Radical Prostatectomy Plus Neoadjuvant Hormones With Androgen Deprivation Therapy Alone in the Management of Men With Pauci-metastatic Prostate Cancer Estimated Enrollment: 452 Study Start Date: May 2015 Estimated Study Completion Date: April 2025 Estimated Primary Completion Date: April 2020 (Final data collection date for primary outcome measure)