Morbidity)and)Quality)of)Life:) …grandroundsinurology.com/wp-content/uploads/2017/03/1015...pT3 14% 35% 55% Margins)posiAve) 15% 19% 32% Louis)etal)CUAJ)2013) 60% recurrence free

Morbidity and Quality of Life: Brachytherapy or Prostatectomy?

Juanita Crook MD FRCPC Professor RadiaAon Oncology University of BriAsh Columbia

IntroducAon •   Trifecta goal of treatment

–   Absence of cancer –   Urinary conAnence and urinary QOL –   Sexual preservaAon

•   Many opAons available •   Many factors effect outcome

–   Oncologic presentaAon –   Baseline funcAon –   Age –   Prostate size –   Co-‐morbidiAes (BMI, DM, CVD, etc)

•   ORen comparing very dissimilar populaAons

ONCOLOGIC EFFICACY The worst toxicity is recurrence….

Oncologic Efficacy

•   ORen enhanced by mulAmodality treatment, either planned up front, or sequenAal as needed

•   Toxicity and QOL need to be evaluated by the whole package of treatment, not just one part of it –  Brachytherapy + EBRT +/-‐ ADT –  RP +/-‐ EBRT +/-‐ ADT

MORE AGGRESSIVE AND ADVANCED DISEASE

In North America, both Ac9ve Surveillance and reduced PSA screening are shi@ing the balance towards:

•   Prior to surgery –   Clinical stage > T3 –   Biopsy Gleason score 8-‐10 –   PSA > 20 ng/ml

•   A@er radical prostatectomy –  High Gleason (8-‐10) –   PosiAve surgical margins –   Seminal vesical invasion –   Extra-‐prostaAc extension

DefiniAon of High Risk

Risk of recurrence > 60% by 5 years

> Gleason 4+3

15 yr bNED post RP: Mullins et al, J Urol 2012:

3+3 3+4 > 4+3 Organ-‐confined 99% 86% 79%

EPE-‐, M+ 94% 75% 67% EPE, M-‐ 89% 72% 41% EPE, M+ 75% 45% 27% SVI 39% 39% 15%

4,478 RP 1982-2011, no ADT or EBRT

Gleason 3+4

15 year BNED

Oncologic outcomes of RP in the acAve surveillance era Louis et al, CUAJ 2013

•   TerAary care Canadian university center •   2643 paAents 2002-‐2012 •   Median age 61 years (38-‐77) •   Mean PSA 7.6 (SD 7.9) •   Clinical stage 70% T1/30% T2 •   Risk group: 35% favourable 54% intermediate 11% high risk

Surgical outcomes Louis et al, CUAJ 2013 Low risk Intermediate High Risk

Gleason score: 6 58% 10% 5% 7 41% 85% 55% >7 1% 5% 40% T stage pT2 85% 63% 36% pT3 14% 35% 55% Margins posiAve 15% 19% 32%

Louis et al CUAJ 2013

60% recurrence free at 5 years

40% recurrence free at 5 years

IdenAcal to results by Zumsteg et al, Prostate 2017 for favorable and unfavorable IR in SEARCH data base

Clinical and pathologic outcomes aRer RP for pre-‐op Gleason 8-‐10 BasAan et al Cancer 2006

•   Surgical monotherapy •   Johns Hopkins and mulAple shared equal-‐access regional centers (SEARCH)

•   n=220 (JH) and 149 (SEARCH) •   1982-‐2004 •   5 and 10-‐year biochemical recurrence free rates 40% and 27%

•   Favorable pathology : –   10-‐year recurrence-‐free rate 50%

Surgical outcomes

•   PosiAve margins: 29% (47% community) •   Extra-‐prostaAc: 75% •   Seminal vesicle invasion: 25% •   Lymph node involvement: 17% •   Higher PSA and higher clinical stage predict for worse outcome

•   Recommends mul9-‐modality treatment for high risk disease

BasAan et al cancer 2006

Surgical results for high risk Author Year n Follow up BNED LocaAon details BasAen 2006 220 2-‐22 yrs 27%@ 10 yrs Hopkins All 8-‐10

No Tx unGl fail

BriganA 2011 1366 2-‐22 yrs 54%@ 10 yrs MulA Europe

Diaz et al7 2014 36 Min 10 yrs 43%@ 10 yrs Detroit/Cleveland/NY

All roboGc

Isbarn 2013 4391 1-‐21 yrs pT3a: 53%@10 PSA>20:32%@10 pT3b: 10% @ 10

Germany +/-‐ RT 18% +/-‐ ADT 14%

Loeb 2010 175 8 yrs 68% @ 10 yrs Hopkins +/-‐ ADT 30% 1992-‐2008 D’Amico HR

Louis 2013 258 40% @ 5 yrs Univ Toronto Masson-‐Lecompte

2011 138 4.5 yrs 40% @ 5 yrs Univ Paris

Mullins 2012 120 10 yrs 60% @ 15 yrs Hopkins 30 yr report 1992-‐2011 Adj NS (no diff)

Roder 2011 166 Med. 4 yrs (to 15 yrs)

39% @ 10 yrs Denmark No tx unAl BF

Yamamoto 2012 189 8.1 yrs 48% @ 10 yrs Japan 52% neo adj ADT

Author Year n Median follow up

BNED treatment Failure definiAon

Dapoli et al4 2010 164 10.5 yrs 74%@16 yrs LDR+RT+/-‐ADT PSA>0.2

Fang et al16 Merrick W Virginia

2011 174 6.6 yrs 86%noADT@10 yr 92% (ADT)@10yrs

LDR+RT+/-‐ADT GS 8-‐10, PSA < 15

PSA>0.4

Marshall et al32 Stock/Stone NY

2014 421 6 yrs 73%@8 yrs 64%@ 12 yrs

LDR+RT+/-‐ADT

Morris et al ASCENDE RT

2016 390 8 yrs 82% @ 8 yrs ADT 12 mo EBRT + BT

PSA > 0.2

Ohashi et al37 2014 206 85%@5 yrs LDR+RT

Taira et al17 merrick

2011 473 7.2 yrs 91%@ 12 yrs LDR+RT+/-‐ADT All HR

PSA>0.4

Brachytherapy-‐based regimens for high risk

Comparing results across modaliAes difficult and potenAally misleading

•   Differences in paAent selecAon •   Different definiAon of failure •   Treatment specifics

–  Dose of radiotherapy (Quality of implant: D90) –   Type of surgery

•   Philosophy of treatment –  Upfront combinaAon (hormones, radiotherapy, brachytherapy)

–   Stepwise uAlizaAon of modaliAes (surgery +/-‐ radiaAon +/-‐ hormones)

THE TRI-‐MODALITY APPROACH (HORMONES FOR 9-‐12 MONTHS,

EXTERNAL RADIATION + BRACHYTHERAPY)

OpAmal radiaAon, opAmal hormone use

Tri-‐modality treatment for High Risk prostate cancer Stock 2006 IJROBP

•   1994-‐2006 •   n=360 (high risk or > 1 intermediate feature) •   45 with posiAve Seminal Vesical biopsy included •   Follow up 2-‐10 years (median 4.25) •   3 mo hormones + brachytherapy (Pd 103) + radiaAon (45 Gy: 39.6 -‐ 59.6 depending on implant quality)

•   Total hormones: 9 months •   97% negaAve post radiaAon biopsy (68/70 weighted to

those with ↑ PSA)

7-‐yr freedom from PSA failure: 83% Stock et al 2006

86% PSA < 0.1 8% PSA 0.1-‐0.2 3% PSA 0.2-‐0.5 3% PSA >0.5

PSA > 20 ng/ml predicts for biochem failure p=0.04

ASCENDE-‐RT (ANDROGEN SUPPRESSION COMBINED WITH ELECTIVE

NODAL DOSE ESCALATED RADIOTHERAPY)

The New York Mount Sinai experience by Stock and Stone was the basis for the defini9ve Canadian randomized trial

Level One Evidence for benefit of Brachytherapy Canadian ASCENDE-‐RT WJ Morris et al

–   Phase 3: 78 Gy vs. 46 Gy + LDR Brachytherapy –   n=398: follow up 5-‐11 years –   High risk and high Aer intermediate risk –   1 year ADT (8 month neoadj + 4 month concurrent/adjuvant)

Whole pelvis 4600/23

I125 Brachytherapy boost: 115 Gy

Pelvic IMRT 4600/23

Prostate boost 3200/16

PrognosGc features: summary 398 pts -‐ Well balanced with no significant differences between arms

•   Median age: 68 years •   NCCN High-‐risk: 69% •   Gleason sum ≥8: 40% •   iPSA >20 ng/mL: 19% •   cT3a: 29%

MVA analysis of biochemical failure: (Backwards: CondiAonal Cox model, Intent-‐to-‐treat, N=398 Factors on UVA with p< 0.3 included)

Variable HR 95% CI P-value

Randomization arm (DE-‐EBRT vs LDR-PB) 2.04 1.25 – 3.33 0.004

PPC (unit = 1%) 1.01 1.00 – 1.02 0.006

Clinical T stage (T3a vs T1-T2) 1.97 1.24 – 3.13 0.004

Log iPSA (unit = 1 log) 1.62 1.11 – 2.36 0.01

Gleason Sum (8-10 vs ≤ 7) 1.38 0.87 – 2.19 0.17

Results: Biochemical PFS all paAents Intent-‐to-‐treat analysis of the primary endpoint

121086420time since first LHRH injection (yrs)

1.0

0.8

0.6

0.4

0.2

0.0

prop

ortio

n free

of re

curre

nce

LDR-PB ARM

DE-EBRT ARM Kaplan-Meier

(95% CI)

Randomization (N=398)

DE-EBRT LDR-PB

PFS

5 yr 83.8 (±5.6) 88.7 (±4.8)

7 yr 75.0 (±7.2) 86.2 (±5.4)

9 yr 62.4 (±9.8) 83.3 (±6.6)

Absolute difference 5y – 4.9% 7y – 11.2% 9y – 20.95%

p=0.004

9-year PSA Relapse Free Survival:70% vs.94% p<0.001

9-year PSA Relapse Free Survival 58% vs.78%; p=0.05

b-‐PFS using a >0.2 ng/mL threshold (by treatment received N= 383)

LDR-‐PB ARM N=188

DE-‐EBRT ARM N=195

Kaplan-Meier (95% CI)

DE-EBRT (N=195)

LDR-PB (N=188)

b-PFS 5 yr 46.5 (±7.6) 87.9 (±5.0) 7 yr 37.7 (±8.0) 86.0 (±5.6) 9 yr 31.5 (±8.8) 82.2 (±7.0)

B-‐PFS using nadir + 2 vs. PSA > 0.2 ng/ml


1.0

0.8

0.6

0.4

0.2

0.0

pro

po

rtio

n f

ree

of

recu

rren

ce

DE-‐EBRT (n=195)

nadir+2ng/mL

>0.2 ng/mL log rank P value <0.001


1.0

0.8

0.6

0.4

0.2

0.0

pro

po

rtio

n f

ree

of

recu

rren

ce

LDR-‐PB (n=188)

nadir+2ng/mL

>0.2 ng/mL

log rank P value = 0.32

9-‐year K-‐M PFS = 82% using >0.2 ng/mL 9-‐year K-‐M PFS = 32% using >0.2 ng/mL


1.0

0.8

0.6

0.4

0.2

0.0

prop

ortio

n al

ive

Log rank p =0.09

LDR-‐PB ARM N=188

DE-‐EBRT ARM N=195

Overall Survival by treatment received

Other N=15

Not powered for survival endpoint

Local control

•   46% of PSA recurrence events were metastaAc •   Majority (86%) found to be metastaAc within 2 years of BF (median interval:4 mo) –  17 LDR –  18 DE-‐EBRT

•   80% of biochemical relapses not associated with early metastaAc relapse were in the DE-‐EBRT arm

Distributed evenly by randomizaAon

Ascende toxicity

•   398 pts accrued 2002-‐2011 •   Implants by 16 radiaAon oncologists •   Prior to incorporaAon of MRI in QA •   CumulaAve grade 3 GU toxicity 19% vs. 5% @ 5 years (p<0.001), GI 9% vs. 4% (NS)

•   BUT @ 6 years persistent grade 3 GU toxicity is 6.3%

•   GI: 95% of paAents in both arms grade 0-‐1

URINARY FUNCTION Single modality

Single insAtuAon comparison

Johnson et al, Can J Urol, 2016

2001-‐2012 (n=3515) Fox Chase: NCI-‐comprehensive Ca Center No combined Tx except post RP EBRT Evaluated by IPSS and SHIM

2371 308 441 425

Urinary funcAon post treatment by modality (IPSS doesn’t capture inconAnence)


Urinary QOL score: change from baseline


Change from post RP

Effect of treatment by baseline IPSS

IPSS 0-‐7

IPSS 22-‐25


•   IPSS does not reflect inconAnence •   Acute irritaAve and obstrucAve urinary symptoms well documented with LDR BT •   By 20 months, no difference

All pa9ents with severe symptoms at baseline improve with treatment

QuanAfying urinary complicaAons aRer RP Sujenthiran, BJUI, 2017

•   NHS hospitals in England, Hospital Episodes StaAsAcs database

•   2008-‐2012 •   18,761 men had RP, 17,299 had data •   Examined all re-‐admissions within 2 years •   Excluded pa9ents who had adj/salvage EBRT •   15.6% experienced at least one severe urinary complicaAon (3,609 re-‐admissions) –   Bladder outlet obstrucAon –  ArAficial urinary sphincter

QuanAfying urinary complicaAons aRer RP

Sujenthiran, BJUI, 2017

Kaplan Meier curve All severe urinary complicaAons

According to type

SEXUAL FUNCTION

Sexual funcAon at baseline


1 23

4

Sexual funcAon by modality


EF recovery aRer roboAc RP Alenizi, 2016 •   214 men with baseline funcAon recorded •   Divided by SHIM score: 22-‐25, 17-‐21, 12-‐16, <11 •   Potency = ability to penetrate +/-‐ PDE-‐5’s •   Evaluated q 3 months •   @ 12/24 months overall potency rate 43%/49%:

Group % 12mo EF 24 mo EF Med SHIM-‐24

22-‐25 39% 73% 83% 20

17-‐21 28% 48% 55% 12

12-‐16 12% 33% 50% 9

<12 16% 14% 21% 2

EF recovery aRer roboAc-‐assisted RP Alenizi, 2016

Age and BMI lower in men with higher SHIM p=0.02, p=0.05 More nerve preservaAon in men with higher SHIM p<0.001 PSA, p-‐stage, prostate volume NS

Problems in reporAng Sexual funcAon aRer prostate cancer treatment

•   Need an accurate denominator –  Not everyone treated was potent at baseline –  Not a binary funcAon –   “Fair”, “good” and “very good” oRen lumped together as “potent”

•   Very age dependent –   ExpectaAons very different for a 50 year old compared to a 75 year old

•   Need to account for natural decline with age –  What are the chances of being potent 10 years later, even without brachytherapy?

ReporAng of potency aRer an intervenAon •   ORen a crude percentage of subjects at Ame “x” •   Example: “52% of paAents were potent 5 years aRer treatment” Int J Clin Oncol 2013 –   Are the odds the same for a 55 year old man with full potency as for a 72 year old man who has sa9sfactory func9on half the 9me?

•   Beper to report according to baseline funcAon –   If full potency prior, then 74% potent at 5 years –   If impaired potency prior, then 52% potent at 5 years

–  Or, to report results by age: Snyder et al BJUI 2012 –   < 60 years at treatment: 87% at 5 years –   60-‐70 years: 68% at 5 years; > 70 years: 42%

71%

43% 48%

55% 57% 56% 52% 51%

46% 42%

35% 37% 37%

8%

8%

11%

7% 10% 9%

8% 7% 8% 14%

17% 16% 13%

21%

49% 41% 38%

33% 36% 40% 43%

46% 45% 48% 47% 50%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Baseline 6 wks 6 mths 12 mths 24 mths 36 mths 48 mths 60 mths 72 mths 84 mths 96 mths 108 mths 120 mths

Post Im

plan

t EF (%

)

follow up in months

Baseline and post implant EF

Impotent (%)

ParAal (%)

Potent (%)

Baseline 1.5 6 12 24 36 48 60 72 84 96 108 120

LDR BT global result: nadir funcAon (51%) @ 6 wks Improves to 67% by 24 mo: Suggests needle trauma eAology

Keyes et al, Brachytherapy 2015

LET’S SEE WHAT HAPPENS WHEN YOU COMBINE MODALITIES

EF PreservaGon ader BT by Age Group and ADT use: 7-‐ year follow-‐up

79%

66% 62%

50% 42%

92% 85%

77% 74%

57%

0% 10% 20% 30% 40% 50% 60% 70% 80% 90%

100%

age <60 60-‐64 65-‐69 70-‐74 >=75

Potent ADT Potent NO ADT

With longer follow up: there is a minimal decline in EF

Decline rates are similar to rates expected from aging process

Single fracAon HDR BT + EBRT Shahid, Morton et al Clin Oncol 2017

•   Intermediate risk PCa, n=125 •   15 Gy + 37.5/15 EBRT •   EPIC, IPSS, IIEF, CTCAE v3 •   Median follow up 5.2 yrs •   EPIC change from baseline to year 5:

–  Urinary: 91è 85 p=0.0028 (late grade 3: 4%) –  Bowel: 98 è96 p=0.03 (late grade 3: 0) –  Sexual: 63 è35 p< 0.0001 (59% potent at 1 year, 46% at 5 years)

Effect of EBRT + HDR 15 Gy on sexual funcAon

Shahid, Morton et al, Clin Oncol 2017

Majority of decline in first year, then fairly stable

Effect of HDR 15 Gy boost on EPIC QOL

Shahid, Morton et al, Clin Oncol 2017

HOW DOES ADDITION OF EBRT OR ADT EFFECT QOL AFTER SURGERY?

So high risk disease (+m, GS 8-‐10, + SV) has 60%+ failure rate by 10-‐15 years…

ConAnence recovery depends on RT •   n= 2190, open or RA-‐RP •   ConAnence= pad free •   15% received RT; 9.8%

salvage, 5.8% adjuvant •   3-‐yr conAnence

•   71% (no RT), •   59% (salvage), •   42% (adjuvant)

Zafueo, Montorsi, Brigan9, et al, J Urol 2016

ErecAle FuncAon recovery and EBRT

Zafueo, Montorsi, Brigan9, et al, J Urol 2016

•   2190 paAents, open or RA-‐RP •   Median age 62 •   EF: IIEF > 22 •   3-‐year EF recovery

•   No RT: 35% •   Salvage RT: 29% •   Adjuvant RT: 12%

•   3-‐year EF recovery (nerve sparing) •   No RT: 56% •   Adjuvant: 35%

QOL aRer RP alone vs. RP + EBRT +/-‐ ADT •   n=13,150 (1992-‐2013) •   Evaluated annually by self-‐administered quesAonnaires (IIEF, EORTC QOL c-‐30)

•   EBRT dose 66.6 Gy, 3D conformal •   Median Ame to adjuvant 3.3 months, 16.4 months for salvage

•   ConAnence evaluated by # of pads •   ErecAons by response to Q2 of IIEF (> 3)

Adam et al, European Urology, 2017

QOL aRer RP alone vs. RP + EBRT +/-‐ ADT

•   Propensity score matching: –  688 pairs for RP vs. RP+EBRT –  371 pairs for RP vs. RP+EBRT+ADT –  335 pairs for RP+EBRT vs. RP+EBRT+ADT

•   RP + EBRT è4% éinconAnence @ 3 yrs •   RP + EBRT + ADT further 4% éinconAnence and 3% é severe inconAnence

•   RP + EBRT è18%êpotency •   RP+ EBRT + ADT èfurther 17% êpotency


Effect of addiAonal treatment on inconAnence


RP____ vs. RP+EBRT -‐ -‐ -‐ -‐ RP_____ vs.

RP+EBRT+ADT-‐-‐-‐-‐-‐-‐

Effect of addiAonal treatment on potency


RP____ vs. RP+EBRT -‐ -‐ -‐ -‐

RP_____ vs. RP+EBRT+ADT-‐-‐-‐-‐-‐-‐

Effect of addiAonal treatment on QOL aRer RP


83-‐100

58-‐75

< 50

83-‐100

58-‐75

< 50

RP____ vs. RP+EBRT -‐ -‐ -‐ -‐

RP_____ vs. RP+EBRT+ADT-‐-‐-‐-‐-‐-‐

At 3 years probability of QOL score > 83 is 68% for RP alone, 57% for RP+ EBRT, and 48% for RP + EBRT + ADT

Summary •   All treatments have side effects •   The worst toxicity is recurrence •   Potency is beper preserved in younger men with good funcAon (RP good funcAon 83% @ 2 yrs, LDR age < 60 92%/ 60-‐65: 85% @ 7 years)

•   InconAnence is worse aRer surgery (3 years 71% fully conAnent, no EBRT)

•   Severe urinary complicaAons aRer RP in NHS 16% •   Add other treatments and things get worse

–  HDR +EBRT potency 46% @ 5 years (all comers)/Late grade 3 GU: 4%

–  Ascende 6% late grade 3 GU at 6 years (mostly strictures)

Summary cont’d •   No sense arguing about BT alone or RP alone if the majority of the paAents we treat now are going to need combined modality –   BT + EBRT –   BT + EBRT + ADT (triple modality à la ASCENDE) –   RP + adjuvant/salvage EBRT +/-‐ ADT

•   If 50-‐60% chance of needing addiAonal treatment aRer RP, should factor that in and evaluate the package

•   Maybe QOL will be beper without the surgery (can’t argue with the ASCENDE cure rates!)

Documents

Morbidity)and)Quality)of)Life:) …grandroundsinurology.com/wp-content/uploads/2017/03/1015...pT3 14% 35% 55% Margins)posiAve) 15% 19% 32% Louis)etal)CUAJ)2013) 60% recurrence free