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Radical Prostatectomy in pN+ Prostate Cancer

Radical Prostatectomy in pN+ Prostate Cancer. RJ Karnes MD, FACS Vice-Chair Associate Professor and Consultant Dept. of Urology/Urologic Oncology Mayo Clinic-Rochester. “The dogmas of the quiet past are inadequate to the stormy present” Lincoln. DOGMA.

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Radical Prostatectomy in pN+ Prostate Cancer

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  1. Radical Prostatectomy in pN+ Prostate Cancer RJ Karnes MD, FACS Vice-Chair Associate Professor and Consultant Dept. of Urology/Urologic Oncology Mayo Clinic-Rochester

  2. “The dogmas of the quiet past are inadequate to the stormy present” Lincoln

  3. DOGMA Metastatic prostate cancer should not be operated on.

  4. Pathologic Stage: 1990-2009

  5. Background • Before PSA-25% presented with metastatic disease • With PSA screening-<5% • Reverse stage shift with USPSTF Grade D PSA recommendation?

  6. Question? • Should the prostate be removed/treated in the setting of metastatic disease? • No high-level evidence

  7. Background • Controversial= Radical Prostatectomy (RP) and PLND in the setting of positive lymph nodes • Argue for resection • Lymph node positive prostate cancer does not always equal “systemic” non-curative disease • Debulking/Cytoreduction: Other disease states (colon, ovary, kidney)

  8. Hormonal therapy (HT): Lull in progress until recently Huggins, Ca Research, 1941

  9. Why? • Control of primary-symptoms, … • Improve response to systemic therapy • HT more effective against smaller tumor quantity (debulk/cytoreduce) • Isaacs, Cancer Res 1989 • Remove persistent source of future metastasis • “Factories” • “Late wave” in RT (radiation therapy) • Local control still important (PSM/RT) • Lower risk of death –RP=HR 0.77 (SWOG 8894; JUrol 2002)

  10. Cytoreducing these factories…(autocrine, genetic instabilities..)

  11. Courtesy of Haidong Dong, PhD Before surgery (Hypothesis) CTL Prostate Cancer Treg Treg MDSC MDSC Prostate Cancer Secondary tumors Tumor draining lymph nodes Primary tumors Immunosuppressive cells, like Treg cells and myeloid-derived suppressor cells, accumulated within prostate cancers. These cells poised at draining lymph nodes or circulating in the peripheral blood, to suppress antitumor activity of CTLs that are capable of rejecting secondary or metastatic tumors Miller, J immuno, 2006 Brusa, Int J Urology, 2013

  12. Removing the primary tumors and lymph nodes CTL Prostate Cancer CTL Treg Treg MDSC MDSC Secondary tumors Prostate Cancer Tumor draining lymph nodes Primary tumors When both primary prostate tumors and tumor draining lymph nodes were removed totally, Treg cells and MDSCs were either deleted or stop circulating to secondary ( metastatic) prostate tumor sites. Thus, the antitumor activity of cytotoxic lymphocytes (CTLs) was restored to attack tumors.

  13. Significance of RP in pN+ Disease

  14. Mayo Clinic Study: pTxN+ • Non-randomized:1966-1995 • Matched: Orchiectomy (n=79) vs RP+Orchiectomy (n=79) • CSS (cancer-specific) • 80% vs 40% • OS (overall survival) @ 10 years= • ~30% vs ~65% • p<0.001, RR 0.36, 95%CI 0.2-0.66 J Urol 1999

  15. Munich Cancer Registry: pTxN+ • Non-randomized: 1988-2007 • n=1,413 (n=456 aborted/n=957 RP) • n=938 complete data • Median F/U: 5.6 yrs • Non-matched: > 4LNI (+RP 17%,-RP 28%) • Multi-variate analysis: RP as a predictor of survivalHR 2.04 (1.59-2.63) p<0.0001

  16. 85% 95% 86% 65% 70% 60% 40% 30% Engel et al, Eur Urol 2010

  17. Randomized Controlled Trials: pTxN+ (Early vs. Delayed HT) • ECOG 3886: Immediate HT beneficial • RP done • 10 yr. OS= RP+Immediate HT~65% • Messing E, Lancet Oncology 2006 • EORTC 30846: Immediate HT not beneficial • RP not done (12cc cancer remaining) • 10 yr. OS= Whole cohort ~30% • Schroeder F, J Urol 2004

  18. 65% vs 30%

  19. Treatment of the “Primary”:SPCG-7/SFUO-3 (`96-`02) • n=875 randomized to HT vs HT+EBRT • Median F/U 7.6 yrs • Advanced cancers (high chance of occult pN+) • cT3= >75% • SVI=>20% • PSA>30=20% • 10 yr Mortality: • ~40% HT vs ~30% HT+EBRT • RR 0.68 (0.52-0.88)

  20. No treatment of primary tumor: 10% improvement in OS Treatment of primary tumor: 30-46% improvement in OS Verhagen et al Eur Urol,58:261-9,2010

  21. The Abandoned Prostate/Nodes • Why is survival better when treated? • Premetastatic niche, etc….. • New research focusing on Androgen Axis= • CRPC-Intraprostatic/intratumoral androgens persist and androgen regulated gene expression does as well • New drugs are an advancement • Selection= Morbidity “balance”-left in or removed?

  22. Mayo Clinic: Single Series pTxN+ in PSA era

  23. PATIENT DEMOGRAPHICS

  24. POSTOPERATIVE EVENTS • Median follow-up of 10.3 years: • 213 patients with BCR • 51 patients with local recurrence • 97 patients with systemic relapse • 200 deaths, 72 from prostate cancer

  25. POSTOPERATIVE SURVIVAL LR free CSS SP free Survival for patients withpositive nodes (%) BCR free Years following RRP % 5-yr survival % 10-yr survival (no. at risk) (no. at risk) BCR free 69.0 (302) 55.9 (179) LR free 94.9 (397) 89.2 (248) SP free 90.1 (393) 80.1 (245) CSS 94.2 (412) 85.8 (263) CP1267102-9

  26. IMPACT OF No. (+) NODES 0 1 2 Cancer-specificsurvival (%) P<0.001 Years following RRP No. pos No. patients % 5-yr survival % 10-yr survivalnodes at risk (no. at risk) (no. at risk) 0 9,754 99 (7,390) 98 (3,748) 1 290 97 (239) 90 (154) 2 217 90 (173) 79 (109) CP1267102-11

  27. RISK FACTORS FOR DEATH FROM PROSTATE CANCER

  28. Lethal disease? Mayo; unpublished

  29. Mayo; unpublished

  30. Transatlantic Collaboration- OVERALL SURVIVAL 1.0 0.8 0.6 Overall survival 0.4 0.2 0.0 0 2 4 6 8 10 12 14 Time (Years) n=696 pN+ ~65% Median follow-up: 112 months (mean: 113, range 4-243) Briganti, Karnes, et al, Eur Urol

  31. 1.0 ≤ 2 positive nodes 0.8 0.6 > 2 positive nodes Cancer specific survival 0.4 0.2 0.0 0 2 4 6 8 10 12 14 Time (Years) CANCER SPECIFIC SURVIVAL ACCORDING TO THE EXTENT OF LNI Briganti, Karnes, et al, Eur Urol

  32. CSS: Cox regression models UNI AND MULTIVARIABLE ANALYSES

  33. 1.0 0.8 0.6 Overall survival 0.4 0.2 20 40 60 80 100 120 Time(Months) Addition of Radiation? Local, Regional, or Both Adjuvant HT+RT (n=117) Adjuvant HT alone (n=247) Briganti, Karnes

  34. NOMOGRAM PREDICTING CSS AT 5,8 AND 10 YEARS AFTER SURGERY 60 0 10 20 30 40 50 70 80 90 100 Points PSA 0 20 40 60 80 100 140 7 PATHOLOGICAL GLEASON ≤6 8-10 pT3a pT4 PATHOLOGICAL T STAGE pT2 pT3b Positive SURGICAL MARGINS Negative TOTAL No POSITIVE NODES 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 No ADJUVANT RT Yes Total Points 0 20 40 60 80 100 120 140 160 180 200 220 CSS at 5 years 0.995 0.97 0.95 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.001 CSS at 8 years 0.97 0.95 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.001 CSS at 10 years 0.97 0.95 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.001 AUC: 72.7%

  35. MSKCC SERIES: 162 men without HT Van Bodman et al J Urol 184:143-48,2010

  36. MSKCC series pN+ without HT * BCR 28% (95% CI, 21%–36%) European Urology, Toujier

  37. MSKCC series pN+ without HT 72% (95%CI 61%–80%) 72vs85%?

  38. MSKCC series pN+ without HT 60% (95% [CI] 49%–69%) vs65%?

  39. Role of adjuvant hormone therapy (HT)?

  40. Recapitulation: 1st step-Isolation of CD44-positive stem-like cells from LAPC-4 Courtesy of Haojie Huang, PhD

  41. Impact of surgical removal of tumors on mouse survival ADT=Enzalutamide

  42. Hormonal Therapy • When to start in metastatic disease? • Turn on until stops working but then keep on? • Long-term morbidity • Quality of life • Patients want something different

  43. Progression-Free Survival ± HT for Lymph Node Positive CaP(pTx N+) Free of clinical progression (%) Yes P<0.001 No Number at risk Group No 58 23 13 7 3 Yes 231 189 145 64 5 Years after RRP RPMyers CP1076063-1

  44. Review: Outcome of pTxN+ (CSS) 10 yr CSS= 50 to 85% (fxn of HT?)

  45. ECOG/Messing trial: Role of Adjuvant Hormonal tx(HT) @PSA? Primary endpoint N Eng J Med, Vol 341, No 24

  46. ECOG • 1988-1993 • Median follow-up 12 years • Met ½ accrual goal: PSA screening • cT1-2 (No cT3 nor cN+) • N=80 had pre-op CT scans and all -

  47. What about “Bulky” Lymphadenopathy?

  48. Methods • Lymph node metastasis 1988-2003 • Subset with available imaging • Preoperative radiology reviewed • Clinically positive by CT or MRI (> 1 cm) • Clinically negative by CT or MRI • Clinical outcomes compared (All had RP+EPLND+HT) • Clinically positive versus negative

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