Surgical Treatment in Locally Advanced Prostate Cancer Bertrand Guillonneau Paris, France

Surgical Treatment in Locally Advanced Prostate Cancer What is/are the definition/s of LAPCa ? How to diagnose pre-op LAPCa? What are the rationales for surgery? What are the surgical quality criteria? What are the results for surgery in LAPCa? Could surgery succeed alone?

Definitions Locally Advanced PCa includes: pT3ab pN0 M0 <pT4 pN1 M0 Very Heterogeneous definition not all pT3a are the same not all pT3b are the same not all PN1 are the same But they are all classified as “High risk” PCa Locally Advanced PCa excludes: pT4 pTx Nx M1

Definitions “High Risk PCa” is a too wide definition 1) biopsy Gleason score 8+ 2) preoperative PSA 20+ 3) TNM stage T3+ 4) PSA>=20 or clinical stage T2c+ or biopsy Gleason score 8+ 5) 5-year preoperative predicted probability of survival < 70% 6) PSA >=20 or clinical stage T3+ or Gleason score 8+ The definition is changing over the time1 And they are not all LAPCa: 22% are pT2N0 at DCSS 1. Foassati et al, BJU., 2015, in press

High Risk Prostate Cancer – Progression-Free Probability With good technique, surgery results in excellent long term control of hi risk cancers Yossepovitch O. et al, J Urol., 2007, 179, 493-9

High Risk Prostate Cancer – Progression-Free Probability With good technique, surgery results in excellent long term control of hi risk cancers Yossepovitch et al, J Urol, 2007, 179: 493-9

High Risk Prostate Cancer – Progression-Free Probability With good technique, surgery results in excellent long term control of hi risk cancers Yossepovitch et al, J Urol, 2007, 179: 493-9

The Specific Definition of High Risk Prostate Cancer Has Minimal Impact on Biochemical Relapse-Free Survival Carvell T et al, J Urol, 2009, 181: 75-80

Risks Akre et al, Eur Urol., 2011, 60: 555-63

Pre-op Diagnosis of LaPCa Based today on Clinical Stage: 43.8% of patients who had been previously staged as T3 actually had organ-confined tumors 1 PSA - level - velocity ? PBx - Gleason score - Ratio Pos. Cores / Neg. cores - Infiltration / core length - Ratio cancer length / overall core length Negative Bone Scan 1.Van Poppel et al, Eur J Cancer, 2006,42: 1062-67

Pre-op Diagnosis of LaPCa What is the place today of MRI PET-Choline CT… Proteinomics? Genomics? CTC?

MRI Diagnosis of LaPCa Sensitivity (95%CI) Specificity (95%CI) Review of 75 studies, 9796 patients : Sensitivity (95%CI) Specificity (95%CI) ECE 0.57 (0.49-0.64) 0.91 (0.88-0.93) SVI 0.58 (0.47-0.68) 0.96 (0.95-0.97) overall T3 0.61 (0.54-0.67) 0.88 (0.85-0.91) De Rooij et al, Eur Urol, 2015, epub

Rationale for surgery 1. Avoid late local events related to primary tumor Retention Hematuria Bladder invasion Ureteral invasion Rectal invasion

Surgery increases OS and CSS Zelefski et al, JCO, 2010, 28: 1508-13

Surgery increases OS and CSS Zelefski et al, JCO, 2010, 28: 1508-13

Surgery increases OS and CSS Zelefski et al, JCO, 2010, 28: 1508-13

Surgery deletes primary site Kim. et al, Cell., 2009, 139: 1315-26

Surgical Quality Criteria 1. Surgical approach 2. Surgical margin status 2. Extended Pelvic Lymph Node Dissection

KM curve for BCR following radical prostatectomy for laparoscopic (black line) or open (gray line) : Surgical approach doesn’t matter. PSA>=20, clinical stage T2C+ or biopsy Gleason grade 8+

Positive Surgical Margins at Radical Prostatectomy Predict Prostate Cancer Specific Mortality Wright et al, JUrol, 2010, 183: 2213-18

Positive Surgical Margins at Radical Prostatectomy Predict Prostate Cancer Specific Mortality Wright et al, JUrol, 2010, 183: 2213-18

Surgical Results at DCSS pT3a +SM = 29% pT3b +SM = 55%

Surgical Results at DCSS Variable p (95% CI) pT3b stage 0.68 (0.51-2.78) Positive margins 0.025 (1.12-5.43) PSA 0.028 (1.03-1) N° positive biopsies 0.64 (1.02-0.93) GS ≤6 7 (referral) ≥8 0.9 (0-6.17) 0.005 0.9 (0-1.74)

Pelvic Lymph Node Dissection

Surgical Results at DCSS PLND performed for LNI risk >2% Number of nodes removed: median = 12; mean = 13

+PLN and Locally Advanced PCa at DCSS %NX pT2 67 33 pT3 63 25 12 pT3a 72 16 pT3b 36 62 2

Surgical Results at DCSS

Long-term outcomes of patients with lymph node metastasis treated with radical prostatectomy without adjuvant androgen-deprivation therapy. Touijer et al, EurUrol, 2014, 65:20-5

Long-term outcomes of patients with lymph node metastasis treated with radical prostatectomy without adjuvant androgen-deprivation therapy. Touijer et al, EurUrol, 2014, 65:20-5

Long-term outcomes of patients with lymph node metastasis treated with radical prostatectomy without adjuvant androgen-deprivation therapy. Touijer et al, Eur Urol, 2014, 65:20-5

Could Surgery alone succeed? Role of aduvant EBRT Role of aduvant HT+EBRT Role of neo-adjuvant treatment What is the population in which surgery is sufficient

Surgery + Adjuvant EBRT Patients pT2-4 pN+ M0 Briganti et al, Eur Urol, 2011, 59: 832-40

Surgery + Adjuvant EBRT 536 pT3aN0/NX R1 with the required follow-up data Karl et al, Radiot Oncol, 2015, 116: 119-24

Neo-adjuvant HT + Surgery Long-term follow-up of 3-month neoadjuvant hormone therapy before radical prostatectomy in a randomized trial Yee, BJU, 2010, 105: 185-90

Neo-adjuvant Trt + Surgery 1. A Phase 2 Open-Label, Randomized, Multi-center Study of Neoadjuvant Abiraterone Acetate (CB7630) Plus Leuprolide Acetate and Prednisone Versus Leuprolide Acetate Alone in Men With Localized High Risk Prostate Cancer.(NCT00924469) Closed, March 2012 Primary Outcome Measures: Testosterone Concentration in Prostate Tissue …/… 2. A Randomized, Open-Label, Phase 2 Study of MDV3100 as a Neoadjuvant Therapy for Patients Undergoing Prostatectomy for Localized Prostate Cancer (NCT01547299) Primary Outcome Measures: Pathologic Complete Response Rate [ Time Frame: 6 months ] [ Designated as safety issue: No ]Pathologic complete response rate following triplet therapy (enzalutamide in combination with leuprolide and dutasteride) and enzalutamide alone when administered as neoadjuvant therapy for 6 months prior to prostatectomy in patients with localized prostate cancer. Pathologic complete response is defined as the absence of morphologically identifiable carcinoma in the prostatectomy specimen, as evaluated by the site pathologist using standard methods …/…

Surgery in LAPCa Surgery has a premium role Quality of Surgery matters control of local tumor control of positive node(s) Surgery alone can not do all for all Diagnosis of LAPCa is still lacking