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 Think differently

DOGMA Metastatic prostate cancer should not be operated on.

Pathologic Stage: 1990-2009

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

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

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)

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

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)

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

Before surgery (Hypothesis) 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

Removing the primary tumors and lymph nodes CTL Prostate Cancer CTL Treg Treg MDSC MDSC Prostate Cancer Secondary tumors 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.

Significance of RP in pN+ Disease IMPROVED SURVIVAL IN PATIENTS TREATED WITH RP Cadeddu et al, Urology, 1997 Yes Ghavamian R et al , J Urol 1999 MATCHED-CONTROLLED ANALYSIS Frohmuller et al, Eur Urol, 1995 Schmeller et al, Br J Urol, 1997 No (MEDIAN F-UP: 3.8 YRS) Grimm et al, Eur Urol, 2002 Steuber et al, BJU Int, 2011 Engel et al, Eur Urol, 2010

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

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 survival HR 2.04 (1.59-2.63) p<0.0001

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

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

65% vs 30%

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) Scandanavian PC group and Swedish assoc Urologic Oncology

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

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? Why? Speculation

Mayo Clinic: Single Series pTxN+ in PSA era

PATIENT DEMOGRAPHICS Feature No. patients (n=507) Median age at RP (range) 66.0 (47-79) Median total no. nodes removed (range) 11 (1-37) Preoperative PSA <10 10-19.9 ≥ 20 142 (28%) 150 (29.6%) 215 (42.4%) Pathological Gleason score ≤ 7 8-10 376 (74.2%) 131 (25.8%) Seminal vesicle invasion 337 (66.5%)

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

POSTOPERATIVE SURVIVAL LR free CSS SP free Survival for patients with positive 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

Cancer-specific survival (%) IMPACT OF No. (+) NODES 1 2 Cancer-specific survival (%) P<0.001 Years following RRP No. pos No. patients % 5-yr survival % 10-yr survival nodes 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

RISK FACTORS FOR DEATH FROM PROSTATE CANCER HR (95% CI, chi square p value) ≥ 2 vs. 1 positive node 2.2 (1.3-3.5, p=0.001) Stage (pT3/4 vs. pT2) 2.2 (0.7-7.1, p=0.20) Preoperative PSA 0.96 (0.8-1.2, p=0.66) Gleason score (8-10 vs ≤ 7) 2.0 (1.3-3.3, p=0.004) Non-diploid vs. diploid 1.8 (1.1-2.9, p=0.023) (+) surgical margin 2.1 (1.2-3.9, p=0.016) Total no. nodes removed 0.98 (0.94-1.0, p=0.50) Year of RRP 1.0 (0.94-1.1, p=0.50) AHT (vs. no AHT) 1.8 (0.42-7.5, p=0.43)

Lethal disease? Mayo; unpublished There are 1000 patients with prostatectomies at Mayo Clinic Rochester from 1987-2012 and positive nodes. First, we deleted 249 patients with prior treatment. Next, we removed 13 patients who did not want their records used in research. The final cohort has 738 patients.

Mayo; unpublished Median follow-up time in this cohort is 10.1 years

Transatlantic Collaboration- OVERALL SURVIVAL n=696 pN+ 2 4 6 8 10 12 14 0.0 0.2 0.4 0.6 0.8 1.0 Time (Years) Overall survival OVERALL SURVIVAL % 5- years (No at risk) 84% (577) % 8- years (No at risk) 74% (413) % 10- years (No at risk) 67% (324) ~65% Median follow-up: 112 months (mean: 113, range 4-243) Briganti, Karnes, et al, Eur Urol

CANCER SPECIFIC SURVIVAL ACCORDING Cancer-specific survival TO THE EXTENT OF LNI 2 4 6 8 10 12 14 0.0 0.2 0.4 0.6 0.8 1.0 Time (Years) Cancer specific survival ≤ 2 positive nodes > 2 positive nodes Cancer-specific survival % 5-yr (No at risk) % 8-yr %10-yr ≤ 2 positive nodes 93% (448) 89% (323) 85% (242) > 2 positive nodes 81% (133) 74% (92) 72% (83) Briganti, Karnes, et al, Eur Urol

CSS: Cox regression models UNI AND MULTIVARIABLE ANALYSES Univariable analysis Multivariable analysis HR; p value Predictive Accuracy Pre-operative PSA 1.012;<0.001 57.4% 1.006;0.06 Path Gleason score -;<0.001 65.7% 7 vs 2-6 2.3;0.01 1.8;0.10 8-10 vs 2-6 5.4;<0.001 4.1;<0.001 Pathological stage 60.7% -;0.19 pT3a vs pT2 2.0;0.22 1.3;0.61 pT3b vs pT2 3.8;0.009 2.0;0.17 pT4 vs pT2 7.4,<0.001 2.9;0.09 Number of positive nodes 1.17;<0.001 62.1% 1.1;<0.001 Surgical margin status 2.41;<0.001 58.7% 1.8;0.02 Adjuvant RT 0.71;0.18 52.6% 0.44;0.003

Briganti, Karnes Addition of Radiation? Local, Regional, or Both 20 40 60 80 100 120 0.2 0.4 0.6 0.8 1.0 Time (Months) Overall survival Adjuvant HT+RT (n=117) Adjuvant HT alone (n=247) Overall survival % 5-yr (No at risk) % 8-yr %10-yr Adjuvant HT+RT 87% (93) 79% (48) 74% (27) Adjuvant HT alone 75% (191) 61% (133) 50% (96) Italian radiated Briganti, Karnes

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

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

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

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

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

Role of adjuvant hormone therapy (HT)?

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

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

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

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 Slide Revision: 09-03-2002 pjs

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

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

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 -

What about “Bulky” Lymphadenopathy?

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

Clinical Positive Clinical Negative p-value No patients 34 168 Median age (range) 60 (42-74) 64 (47-77) 0.04 Median BMI (range) 27.7 (19.6-36.4) 27.6 (17.6-36.4) 0.58 Median ng/ml PSA 12.1 (0.1 - 248) 20.9 (1.6 – 388) 0.006 No. Gleason score (%) 6 2 (9) 29 (26) 0.06 7 13 (57) 55 (50) 8-10 8 (34) 34 (24) No. clinical stage (%) T1a-c 3 (9) 22 (13) 0.11 T2a 6 (19) 60 (35) T2b 5(16) 23(14) T3-4 18 (56) 63 (38) Limitations; numbers, retrospective, nonmatched

Neoadjuvant Treatment Clinical positive (n = 34) Clinical negative (n = 168) p-value No patients on androgen deprivation therapy (%) Yes 13 (38) 0 (0) <0.01 No 21 (62) 168 (100) No. patients with radiation (%) None N/A

Clinical Positive (n = 34) Clinical Negative (n = 168) Pathologic Findings Clinical Positive (n = 34) Clinical Negative (n = 168) p-value No + nodes (%) 34 (100) 168 (100) N/A No. + Margin (%) 17 (50) 106 (63) 0.15 No. + SV (%) 23 (68) 121 (72) 0.61 No. Gleason sum (%) 6 3 (10) 34 (21) 0.03 7 12 (41) 86 (53) 8-10 14 (48) 42 (26)

Clinical Positive (n = 34) Clinical Negative (n = 168) Adjuvant Treatment Clinical Positive (n = 34) Clinical Negative (n = 168) p-value No. patients on androgen deprivation therapy (%) Yes 29 (85) 153 (91) <0.35 No 5 (15) 15 (9) No. patients with radiation (%) 34 (6) 17 (10) <0.53 32 (94) 151 (90)

Negative Positive

Negative Positive

Should we always deny surgery to cN+? “No” Positive Negative Retrospective, limited #, not matched Should we always deny surgery to cN+? “No”

Conclusion Consider surgery in prostate cancer nodal metastasis Confers survival advantage How? pN+=Acceptable outcomes Adjuvant therapy Duration? To whom? Not always a systemic disease Node dissection potentially therapeutic THINK DIFFERENTLY; ADJUVANT HT ANDRT

Thank you karnes.r@mayo.edu