Is Radical Prostatectomy Is Radical Prostatectomy Adequate For High Risk Prostate Adequate For High Risk Prostate

Cancer?Cancer?

Dr Manish PatelDr Manish Patel Urological Cancer Surgeon Urological Cancer Surgeon

Westmead HospitalWestmead HospitalUniversity of SydneyUniversity of Sydney

What is High RiskWhat is High RiskHigh Risk For Recurrence and Progression following Definitive Therapy.

Localised High Risk

Gleason score 8-10

PSA >20ng/ml

Locally Advanced

Clinical T3

Lymph node positive

Excluded:

Clinical T4

N2 or distant metastatic disease

GuidelinesGuidelines

Option: Although active surveillance, interstitial prostate brachytherapy, externalbeam radiotherapy, and radical prostatectomy are options for the management ofpatients with high-risk localized prostate cancer, recurrence rates are high.

For: cT3a or Gleason 8-10 or PSA>20ng/ml•Radical prostatectomy (selected patients with no fixation, low volume, + plevic lymph node dissection.)•ADT + XRT (3 years)

EAUEAU

AUA

NCCN

High Risk- Localised Prostate CancerHigh Risk- Localised Prostate CancerDown Grading is CommonDown Grading is Common

Donohue et.al. –MSKCC

238 Men had biopsy Gleason score 8-10.

45% had Gleason score <7 in prostate specimen.

Manoharan et.al- 31% down grading

Grossfeld et.al. -38% down grading

High Risk- Localised Prostate CancerHigh Risk- Localised Prostate Cancer

Very significant BFS in men down graded compared to Gleason 8-10.

• Also Bastian et.al.

• A 1/3 of men with A 1/3 of men with biopsy GS 8-10, may biopsy GS 8-10, may actually have less actually have less aggressive disease.aggressive disease.

Outcomes of High Risk Localised CaP-RRPOutcomes of High Risk Localised CaP-RRPPathological OutcomesPathological Outcomes

Study No. pT3 SVI Lymph node mets

Positive margins

Donohue et.al. (MSKCC)

238 33% 27% 20% 32%

Mian et.al. (MD Andersen)

188 24% 9% 6% 9%

Manoharen et.al (Uni Miami)

79 43% 29% 2% 46%

Serni et.al. (Uni of Florence)

116 39% 15%

Outcomes of High Risk Localised CaP-RRPOutcomes of High Risk Localised CaP-RRP

Study No. 5 yr BFS 10 yr BFS

Donohue et.al. (MSKCC) 238 51% 39%

Mian et.al. (MD Andersen) 188 71% 55% (7 years)

Manoharen et.al (Uni Miami) 79 68%

Serni et.al. (Uni of Florence) 116 78%

• Mian et.al.

Organ confined disease has good outcome

Outcomes of High Risk Localised CaP-RRPOutcomes of High Risk Localised CaP-RRP

High Risk Localised CaP-RRPHigh Risk Localised CaP-RRP

All patients

Low Charlson Score

High Charlson Score

453 PatientsHenry Ford Health SystemAll Prostate cancer- Gleason Score >7Analyses survivalPropensity score analysis

Surgery is better for all co-morbidities.Median OSRRP: 9.7 yrsRT: 6.7 yrsCons: 5.2yrs

Disease Specific SurvivalDisease Specific Survival

Treatment No. 10 year %DSS (95%CI)

Radical Prostatectomy 4154 76 (71-80)

Radiation Therapy 2977 52 (46-57)

Watchful Waiting 2834 43 (38-48)

SEER database of prostate Cancer TreatmentsPopulation based approach.9965 with Localised Gleason Score 8-10 prostate Cancer

Lu et.al.

Multimodality TherapyMultimodality TherapyNeoadjuvant Hormone TherapyNeoadjuvant Hormone Therapy

• Cytoreduction (2 trials with 3 month NHT)

– More organ confine disease

– Fewer positive margins

– No PSA PFS benefit.

• (Not powered for it, not enriched with high risk)

– Klotz et.al. did find PSA prgression benefit for men with PSA>20ng/ml.

Neoadjuvant Chemo

• Small phase II trials only

• No PSA progression or survival advantage

• Ongoing CALGB trial of Docetaxel and Estramustin.

Adjuvant RadiationAdjuvant Radiation

Bolla Et.al.

Biochemical PFS•2 Randomised Trials of higher risk Patients randomised to observation or adjuvant XRT

•Eligible patients were: SM+, ECE, SVI

•Results:BPFS and clinical progression were significantly lower in XRT•No survival benefit demonstrated

•No data on adjuvant vs EARLY Salvage XRT

Hazard Ratio for XRT treatmentSVI: 0.48SM+ 0.40ECE 0.50

Adjuvant Hormone TherapyAdjuvant Hormone Therapy• EPC studies

• 150 mg Bicalutamide

• 3 randomised studies through the world.

• Significant PSA PFS if 150 mg Bicalutamide added after RRP for lacally advanced or high risk CaP.

• No difference with localised CaP

• Survival is not altered.

Risk Group No. HR (95% CI)

Locally advanced 1719 0.42 (0.35-0.50)

N+ 74 0.11 (0.04- 0.30)

GS 7-10 1959 0.48 (0.40-0.58)

PSA>10ng/ml 1636 0.40 (0.33-0.49)

Adjuvant ChemotherapyAdjuvant Chemotherapy• Adjuvant Taxotere +LHRH in High risk CaP after RRP

– Closed- poor accrual

• Adjuvant Taxotere following High risk CaP after RRP- VA study

– Accruing.

Locally Advanced Prostate CancerLocally Advanced Prostate Cancer

176 with cT3 CaP

Pathology

Down staging is common.24% pathological down staging (pT2)with monotherapy41% with NHT

Stage PSA Gleason Score

T3a (85%)SVI (15%)

Median (12.7ng/ml)25% (2.6ng/ml)75% (26ng/ml)

<6 (47%)7 (38%)8-10 (15%)

Organ Confined

ECE SVI LNI SM+

30% 61% 34% 19% 27%

• Clinical failure only in 36% of BCR.

• 10 year freedom from clinical failure= 76%

Locally Advanced Prostate CancerLocally Advanced Prostate Cancer

48%44%

6%15%

24%

BCR Death

•Median follow up 4.6 years.•77% with BCR Tx with HT

Study Selection No. 5 yr CSS 10yr CSS

5 yrs OS 10 yr OS

Carver et.al. All 176 94% 85% 88% 75%

Gerber et.al All 345 57%

GS<7 73%

GS 7 67%

Van Den Oouden et.al.

GS<8 83 85% 72% 75% 60%

Gontero et.al All 51 93% 76%

Locally Advanced Prostate CancerLocally Advanced Prostate CancerResults From Other Centers-MonotherapyResults From Other Centers-Monotherapy

Morbidity of RRP for advanced diseaseMorbidity of RRP for advanced diseaseNo Worse Than clinically Localised DiseaseNo Worse Than clinically Localised Disease

Outcome Clinically OC (n=152)

Locally Advanced (n=51)

Sig

Transfusion (mean per Pt) 2.5 1 0.02

OT time (min) 140 168 0.001

Lymphocele % 3 12 0.04

Bladder Neck Contracture % 18 27 0.21

Full continence 78% 80% 0.91

Severe incontinence 10% 16% 0.2

Gontero et.al.

The Value of Extended LymphadenectomyThe Value of Extended LymphadenectomyIn High Risk Disease.In High Risk Disease.

• Nomograms have limited use.

• CT and MRI only sensitive in 10-30%

• Sentinal node biopsy with radiolabelling and gamma probe has problems

– Unable to detect nodes in area unexplored.

• SPECT imaging after intraprostatic injection under evaluation.

• high resolution MRI with lymphotrophic superpara-magentic nanoparticles has promise but not routinely available.

• Heidenreich et.al reported ePLND detects 24% vs 12% positive LNs.• Wowroshek et.al. gain an additional 35% LN+ pts with ePLND.• Studer et.al. 24% LN+ with ePLND.

– 58% along Internal I Artery– 19% only in IIA

ePLND is therapueticePLND is therapuetic

• All patients who have greater than 4 LN removed benefit.• Similar Result observed by MSKCC series

All patients LN- Patients

Konety et.all (SEER Data

RRP is adequate for High Risk CancerRRP is adequate for High Risk Cancer• High Risk

• Better with Organ confined

• Low PSA

• ePLND

• SM-

• Locally Advanced

• Better with lower GS

• Lower PSA

Surgery+ Hormones vs XRT+HormonesSurgery+ Hormones vs XRT+Hormones

Messing et.al. Bolla et.alN=91 LN+ after RRP High Risk (GS>8 or pT3)

89%79%

• 5yrs CSS of all patients with LN+ was 74%BCR

CSS