Radical Prostatectomy in p N Prostate Cancer RJ

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Radical Prostatectomy in p. N+ Prostate Cancer RJ Karnes MD, FACS Vice-Chair Associate Professor

Radical Prostatectomy in p. N+ 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”

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

DOGMA • Metastatic prostate cancer should not be operated on.

DOGMA • Metastatic prostate cancer should not be operated on.

Pathologic Stage: 1990 -2009

Pathologic Stage: 1990 -2009

Background • Before PSA-25% presented with metastatic disease • With PSA screening-<5% • Reverse

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? •

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

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 Huggins, Ca Research, 1941

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

Why? • Control of primary-symptoms, … • Improve response to systemic therapy • HT

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. . )

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

Courtesy of Haidong Dong, Ph. D Before surgery (Hypothesis) CTL Prostate Cancer Treg MDS

Courtesy of Haidong Dong, Ph. D Before surgery (Hypothesis) CTL Prostate Cancer Treg MDS C Primary tumors Treg MDS C Tumor draining lymph nodes Prostate Cancer Secondary 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 MDS C

Removing the primary tumors and lymph nodes CTL Prostate Cancer CTL Treg MDS C Primary tumors Treg MDS C Tumor draining lymph nodes Prostate Cancer Secondary 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 p. N+ Disease Cadeddu et al, Urology, 1997 Ghavamian R

Significance of RP in p. N+ Disease Cadeddu et al, Urology, 1997 Ghavamian R et al , J Urol 1999 IMPROVED SURVIVAL IN PATIENTS TREATED WITH RP Yes MATCHED-CONTROLLED ANALYSIS Frohmuller et al, Eur Urol, 1995 Yes Schmeller et al, Br J Urol, 1997 No (MEDIAN F-UP: 3. 8 YRS) Grimm et al, Eur Urol, 2002 Yes Steuber et al, BJU Int, 2011 Yes MATCHED-CONTROLLED ANALYSIS Engel et al, Eur Urol, 2010 Yes

Mayo Clinic Study: p. Tx. N+ • Non-randomized: 1966 -1995 • Matched: Orchiectomy (n=79)

Mayo Clinic Study: p. Tx. N+ • 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: p. Tx. N+ • Non-randomized: 1988 -2007 • n=1, 413 (n=456

Munich Cancer Registry: p. Tx. N+ • 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: > 4 LNI (+RP 17%, -RP 28%) • Multi-variate analysis: RP as a predictor of survival HR 2. 04 (1. 59 -2. 63) p<0. 0001

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

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

Randomized Controlled Trials: p. Tx. N+ (Early vs. Delayed HT) • ECOG 3886: Immediate

Randomized Controlled Trials: p. Tx. N+ (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 (12 cc cancer remaining) • 10 yr. OS= Whole cohort ~30% • Schroeder F, J Urol 2004

65% vs 30%

65% vs 30%

Treatment of the “Primary”: SPCG-7/SFUO-3 (`96 -`02) • n=875 randomized to HT vs HT+EBRT

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 p. N+) • c. T 3= >75% • SVI=>20% • PSA>30=20% • 10 yr Mortality: • ~40% HT vs ~30% HT+EBRT • RR 0. 68 (0. 52 -0. 88)

No treatment of primary tumor: 10% improvement in OS Treatment of primary tumor: 30

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

The Abandoned Prostate/Nodes • Why is survival better when treated? • Premetastatic niche, etc….

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

Mayo Clinic: Single Series p. Tx. N+ in PSA era

Mayo Clinic: Single Series p. Tx. N+ in PSA era

PATIENT DEMOGRAPHICS Feature Median age at RP (range) Median total no. nodes removed (range)

PATIENT DEMOGRAPHICS Feature Median age at RP (range) Median total no. nodes removed (range) No. patients (n=507) 66. 0 (47 -79) 11 (1 -37) Preoperative PSA <10 142 (28%) 10 -19. 9 150 (29. 6%) ≥ 20 215 (42. 4%) Pathological Gleason score ≤ 7 376 (74. 2%) 8 -10 131 (25. 8%) Seminal vesicle invasion 337 (66. 5%)

POSTOPERATIVE EVENTS • Median follow-up of 10. 3 years: • 213 patients with BCR

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

Survival for patients with positive nodes (%) POSTOPERATIVE SURVIVAL LR free CSS SP free

Survival for patients with positive nodes (%) POSTOPERATIVE SURVIVAL LR free CSS SP free BCR free Years following RRP BCR free LR free SP free CSS % 5 -yr survival (no. at risk) 69. 0 (302) 94. 9 (397) 90. 1 (393) 94. 2 (412) % 10 -yr survival (no. at risk) 55. 9 (179) 89. 2 (248) 80. 1 (245) 85. 8 (263) CP 1267102 -9

IMPACT OF No. (+) NODES 0 1 Cancer-specific survival (%) 2 P<0. 001 Years

IMPACT OF No. (+) NODES 0 1 Cancer-specific survival (%) 2 P<0. 001 Years following RRP No. pos nodes 0 1 2 No. patients at risk 9, 754 290 217 % 5 -yr survival (no. at risk) 99 (7, 390) 97 (239) 90 (173) % 10 -yr survival (no. at risk) 98 (3, 748) 90 (154) 79 (109) CP 1267102 -11

RISK FACTORS FOR DEATH FROM PROSTATE CANCER Risk Factor HR (95% CI, chi square

RISK FACTORS FOR DEATH FROM PROSTATE CANCER Risk Factor HR (95% CI, chi square p value) ≥ 2 vs. 1 positive node 2. 2 (1. 3 -3. 5, p=0. 001) Stage (p. T 3/4 vs. p. T 2) 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

Lethal disease? Mayo; unpublished

Mayo; unpublished

Mayo; unpublished

Transatlantic Collaboration- OVERALL SURVIVAL 1. 0 n=696 p. N+ 0. 6 % 5 -

Transatlantic Collaboration- OVERALL SURVIVAL 1. 0 n=696 p. N+ 0. 6 % 5 - years (No at risk) % 8 - years (No at risk) % 10 - years (No at risk) 0. 4 Overall survival 0. 8 OVERALL SURVIVAL 84% (577) 74% (413) 0. 2 ~65% 67% (324) 0. 0 0 2 4 6 8 Time (Years) 10 12 14 Median follow-up: 112 months (mean: 113, range 4 -243) Briganti, Karnes, et al, Eur Urol

CANCER SPECIFIC SURVIVAL ACCORDING TO THE EXTENT OF LNI 1. 0 ≤ 2 positive

CANCER SPECIFIC SURVIVAL ACCORDING TO THE EXTENT OF LNI 1. 0 ≤ 2 positive nodes 0. 6 0. 4 ≤ 2 positive nodes > 2 positive nodes 0. 2 Cancer specific survival 0. 8 Cancer-specific survival 0. 0 0 2 % 5 -yr (No at risk) % 8 -yr (No at risk) %10 -yr (No at risk) 93% (448) 89% (323) 74% (92) 85% (242) 72% (83) 81% (133) 4 6 8 Time (Years) 10 > 2 positive nodes 12 14 Briganti, Karnes, et al, Eur Urol

CSS: Cox regression models UNI AND MULTIVARIABLE ANALYSES Univariable analysis Multivariable analysis HR; p

CSS: Cox regression models UNI AND MULTIVARIABLE ANALYSES Univariable analysis Multivariable analysis HR; p value Predictive Accuracy HR; p value Pre-operative PSA 1. 012; <0. 001 57. 4% 1. 006; 0. 06 Path Gleason score -; <0. 001 65. 7% -; <0. 001 7 vs 2 -6 2. 3; 0. 01 1. 8; 0. 10 5. 4; <0. 001 4. 1; <0. 001 8 -10 vs 2 -6 Pathological stage -; <0. 001 p. T 3 a vs p. T 2 2. 0; 0. 22 1. 3; 0. 61 p. T 3 b vs p. T 2 3. 8; 0. 009 2. 0; 0. 17 7. 4, <0. 001 2. 9; 0. 09 p. T 4 vs p. T 2 60. 7% -; 0. 19 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 0. 71; 0. 18 52. 6% 0. 44; 0. 003 Adjuvant RT

1. 0 Addition of Radiation? Local, Regional, or Both 0. 6 0. 4 Adjuvant

1. 0 Addition of Radiation? Local, Regional, or Both 0. 6 0. 4 Adjuvant HT alone (n=247) 0. 2 Overall survival 0. 8 Adjuvant HT+RT (n=117) Overall survival % 5 -yr (No at risk) % 8 -yr (No at risk) %10 -yr (No at risk) Adjuvant HT+RT 87% (93) 79% (48) 74% (27) Adjuvant HT alone 75% (191) 61% (133) 50% (96) 20 40 60 Time (Months) 80 100 120 Briganti, Karnes

NOMOGRAM PREDICTING CSS AT 5, 8 AND 10 YEARS AFTER SURGERY Points PSA PATHOLOGICAL

NOMOGRAM PREDICTING CSS AT 5, 8 AND 10 YEARS AFTER SURGERY Points PSA PATHOLOGICAL GLEASON PATHOLOGICAL T STAGE SURGICAL MARGINS TOTAL No POSITIVE NODES ADJUVANT RT Total Points CSS at 5 years 0 10 20 40 60 80 100 40 60 50 70 80 90 100 140 AUC: 72. 7% 7 ≤ 6 8 -10 p. T 3 a p. T 4 p. T 2 p. T 3 b Positive Negative 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 No Yes 0 20 40 60 0. 995 0. 97 CSS at 8 years CSS at 10 years 30 0. 97 0. 95 80 0. 95 100 0. 9 0. 8 120 0. 7 140 0. 7 160 0. 6 0. 5 0. 4 0. 3 0. 2 0. 1 180 200 0. 1 220 0. 001

MSKCC SERIES: 162 men without HT Van Bodman et al J Urol 184: 143

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

MSKCC series p. N+ without HT * BCR 28% (95% CI, 21%– 36%) European

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

MSKCC series p. N+ without HT 72% (95%CI 61%– 80%) 72 vs 85%?

MSKCC series p. N+ without HT 72% (95%CI 61%– 80%) 72 vs 85%?

MSKCC series p. N+ without HT 60% (95% [CI] 49%– 69%) vs 65%?

MSKCC series p. N+ without HT 60% (95% [CI] 49%– 69%) vs 65%?

Role of adjuvant hormone therapy (HT)?

Role of adjuvant hormone therapy (HT)?

Recapitulation: 1 st step-Isolation of CD 44 -positive stem-like cells from LAPC-4 Courtesy of

Recapitulation: 1 st step-Isolation of CD 44 -positive stem-like cells from LAPC-4 Courtesy of Haojie Huang, Ph. D

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

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

Hormonal Therapy • When to start in metastatic disease? • Turn on until stops

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 Ca. P(p. Tx N+) Free of

Progression-Free Survival ± HT for Lymph Node Positive Ca. P(p. Tx N+) Free of clinical progression (%) Yes P<0. 001 Number at risk Group No 58 Yes 231 No Years after RRP 23 189 13 145 RPMyers 7 64 3 5 CP 1076063 -1

Review: Outcome of p. Tx. N+ (CSS) 10 yr CSS= 50 to 85% (fxn

Review: Outcome of p. Tx. N+ (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,

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:

ECOG • 1988 -1993 • Median follow-up 12 years • Met ½ accrual goal: PSA screening • c. T 1 -2 (No c. T 3 nor c. N+) • N=80 had pre-op CT scans and all -

What about “Bulky” Lymphadenopathy?

What about “Bulky” Lymphadenopathy?

Methods • Lymph node metastasis 1988 -2003 • Subset with available imaging • Preoperative

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 No patients p-value 34 168 Median age (range) 60 (42

Clinical Positive Clinical Negative No patients p-value 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 6 2 (9) 29 (26) 7 13 (57) 55 (50) 8 -10 8 (34) 34 (24) T 1 a-c 3 (9) 22 (13) T 2 a 6 (19) 60 (35) T 2 b 5(16) 23(14) T 3 -4 18 (56) 63 (38) No. Gleason score (%) 0. 06 No. clinical stage (%) 0. 11

Neoadjuvant Treatment Clinical positive Clinical negative (n = 34) (n = 168) p-value No

Neoadjuvant Treatment Clinical positive Clinical negative (n = 34) (n = 168) p-value No patients on androgen deprivation therapy (%) Yes 13 (38) 0 (0) No 21 (62) 168 (100) <0. 01 No. patients with radiation (%) Yes None No None N/A

Pathologic Findings Clinical Positive Clinical Negative (n = 34) (n = 168) p-value No

Pathologic Findings Clinical Positive Clinical Negative (n = 34) (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 6 3 (10) 34 (21) 7 12 (41) 86 (53) 8 -10 14 (48) 42 (26) No. Gleason sum (%) 0. 03

Adjuvant Treatment Clinical Positive Clinical Negative (n = 34) (n = 168) p-value No.

Adjuvant Treatment Clinical Positive Clinical Negative (n = 34) (n = 168) p-value No. patients on androgen deprivation therapy (%) Yes 29 (85) 153 (91) No 5 (15) 15 (9) <0. 35 No. patients with radiation (%) Yes 34 (6) 17 (10) No 32 (94) 151 (90) <0. 53

Negative Positive

Negative Positive

Negative Positive

Negative Positive

Positive Negative Should we always deny surgery to c. N+? “No”

Positive Negative Should we always deny surgery to c. N+? “No”

Conclusion Consider surgery in prostate cancer nodal metastasis • Confers survival advantage • How?

Conclusion Consider surgery in prostate cancer nodal metastasis • Confers survival advantage • How? • p. N+=Acceptable outcomes • Adjuvant therapy • Duration? • To whom? • Not always a systemic disease • Node dissection potentially therapeutic

Thank you • karnes. r@mayo. edu

Thank you • karnes. [email protected] edu