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OptimizingOptimizingOptimizingOptimizing the management of the management of the management of the management of

localizedlocalizedlocalizedlocalized prostate cancer prostate cancer prostate cancer prostate cancer in in in in

senior senior senior senior adultsadultsadultsadults

Nicolas MottetChairman EAU-ESTRO-SIOG prostate cancer guidelinesHead of Urology departmentJean-Monnet UniversitySaint-Étienne, France

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DisclosuresDisclosuresDisclosuresDisclosures

• Receipt of grants/research supports: • Astellas

• Pasteur

• Pierre Fabre

• Sanofi-Genzyme

• Takeda pharmaceutical / Millenium

• Receipt of honoraria or consultation fees: • Astellas

• Bayer

• BMS

• Ferring

• IPSEN

• Janssen

• Novartis

• Nuclétron

• Pierre Fabre

• Sanofi-Genzyme

• Takeda pharmaceutical / Millenium

• Zeneca

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Senior Senior Senior Senior adultsadultsadultsadults have highhave highhave highhave high----risk risk risk risk PCaPCaPCaPCa

Muralidhar V et al. Clin Genitourin Cancer 2015;13:525-30.e1-3

• SEER database (US): N=383,039

PCa: prostate cancer

Pe

rce

nta

ge

of

case

s

Age (years)

60%

50%

40%

30%

20%

10%

0%23-49 50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89 90-104

Prostate cancer diagnosed in 2004-2011 by age and NCCN risk group

High risk

Intermediate risk

Low risk

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HighHighHighHigh----risk risk risk risk PCaPCaPCaPCa ---- A A A A lethallethallethallethal diseasediseasediseasedisease????

Akre O et al. Eur Urol 2011;60:554-63

• Swedish national registry

• N=2,625 M0• T3-4, or

• T2 and PSA 50-99 ng/ml

• Non-curative intent treatment

27% 42%

PSA: prostate-specific antigen

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HighHighHighHigh----risk risk risk risk PCaPCaPCaPCa ---- LLLLocalocalocalocal therapytherapytherapytherapy andandandand ageageageage

• Irish Cancer Registry (2002-2008); N=5,456 pts with T1-T2 N0M0 PCa

De Camargo Cancela M et al. Br J Cancer 2013;109:272-9

91 87

52.6

6.3

0

20

40

60

80

100

40-59 60-69 70-79 80+

% w

ith

loca

lth

erap

y

Age (years)

Local therapy

Gleason <889

81

50

16

0

20

40

60

80

100

40-59 60-69 70-79 80+

% w

ith

loca

lth

erap

y

Age (years)

Local therapy

Gleason 8-10

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SPCG 4 SPCG 4 SPCG 4 SPCG 4 –––– SurgerySurgerySurgerySurgery improvesimprovesimprovesimproves survivalsurvivalsurvivalsurvival

• 695 men randomized to RP or WW• T2: >75%

• Mean PSA: 12.8 ng/ml

• Median follow-up: 23.2 years

• RP improves OS and CSS

Bill-Axelson A et al. N Engl J Med 2014;370:932-42

Population RR (CI 95%)

OSCSS

0.71 (0.59 – 0.86)

0.56 (0.41 – 0.77)

CI: confidence interval; CSS: cancer-specific survival;

OS: overal survival; RP: radical prostatectomy;

RR: relative risk; SPCG: Scandinavian Prostate Cancer Group;

WW: watchful waiting

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PIVOT PIVOT PIVOT PIVOT ---- SurgerySurgerySurgerySurgery does does does does notnotnotnot improveimproveimproveimprove survivalsurvivalsurvivalsurvival

• N=731 men randomized to RP or WW• T1c: 50%

• Gleason ≤6: 70%

• Low risk: 40%; intermediate risk: 34%

• Median follow-up: 10 years

Wilt TJ et al. N Engl J Med 2012;367:203-13

Cancer-specific deathOverall PSA >10 ng/ml

HR (95% CI) P HR (95% CI) P

Overall death 0.88 (0.71-1.08) 0.22 0.67 (0.48-0.94) NA

Cancer-specific death 0.63 (0.36-1.09) 0.09 0.36 (0.15-0.89) NA

HR: hazard ratio; NA: not available

Overall death

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ProtecTProtecTProtecTProtecT trial trial trial trial –––– Treatment Treatment Treatment Treatment vsvsvsvs activeactiveactiveactive monitoringmonitoringmonitoringmonitoring

• N=1,643 men• T1c: 76%

• Gleason 6: 77%

• Median PSA: 4.6 ng/ml

• Randomized to:• RP (RX discussed if R1 / pT3a / PSA >0.2)

• RX: 74 Gy + 3-6 months ADT(Neoadjuvant /concomitant)

• Active monitoring

Hamdy FC et al. N Engl J Med 2016;375:1415-24

ADT: androgen deprivation therapy;

ProtecT: Prostate Testing for Cancer and Treatment;

RX: radiotherapy

RP (n=553)Radiotherapy (n=545)Active monitoring (n=545)

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ComorbiditiesComorbiditiesComorbiditiesComorbidities ---- THE THE THE THE keykeykeykey driver for survivaldriver for survivaldriver for survivaldriver for survival

• N=19,639 (SEER database)

• No curative local treatment

Albertsen PC et al. J Clin Oncol 2011;29:1335-41

T2

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Life Life Life Life expectancyexpectancyexpectancyexpectancy, , , , ageageageage andandandand health statushealth statushealth statushealth status

Walter LC. JAMA 2001;285:2750-6; Updated to Walter LC. JAMA 2014;311:1336-47 (eAppendix 3) - Calculation from US 2010 Life Tables; update

20

16

12

9

6

4

15

11

8

54

3

9

6

43

21

0

5

10

15

20

25

70 years 75 years 80 years 85 years 90 years 95 years

Me

dia

n l

ife

exp

ect

an

cy (

ye

ars

)

Top 25th percentile

50th percentile

Lowest 25th percentile

Age

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HHHHealth status is ealth status is ealth status is ealth status is keykeykeykey in in in in localizedlocalizedlocalizedlocalized PCaPCaPCaPCa

• Predictors of non-PCa death:• Comorbidities: strongest predictor

• Age: less significant predictor

• Health status also affects the patient’s ability to tolerate therapies

• Screening to identify patients requiring health status assessment• Comorbidity• Nutritional status• Cognitive and physical functions

Droz JP et al. Lancet Oncol 2014;15:e404–14

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SurgerySurgerySurgerySurgery for highfor highfor highfor high----risk PCarisk PCarisk PCarisk PCa

• Multi-institutional cohort; N=3,828 with high-risk localized PCa

Briganti A et al. Eur Urol 2013;63:693-701

PCa death

Overall death

CCI: Charlson Comorbidity Index

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ComplicationsComplicationsComplicationsComplications of RPof RPof RPof RP ----

More More More More relatedrelatedrelatedrelated totototo comorbiditiescomorbiditiescomorbiditiescomorbidities thanthanthanthan ageageageage

Post-operative complications after RP are related

to comorbidities, not age

Alibhai SM et al. J Natl Cancer Inst 2005;97:1525-32

Number of comorbidities

Ra

te o

f co

mp

lica

tio

ns

70-79

60-69<60

0.4

0.3

0.2

0.1

0 1 2 3 4+

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ComplicationsComplicationsComplicationsComplications in 3,477 in 3,477 in 3,477 in 3,477 consecutiveconsecutiveconsecutiveconsecutive RPRPRPRP

Potency Return of

continenceAge

(years)All

Bilateral nerve sparing

Unilateral or partial nerve sparing

< 5050-5960-6970+

92%85%70%51%

93%85%71%52%

75%69%45%56%

95%96%93%86%

P <0.001 <0.001 <0.0001

Kundu SD et al. J Urol 2004;172:2227-31

Higher risk of erectile dysfunction and incontinence in senior adults treated by RP

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RT in senior RT in senior RT in senior RT in senior adultsadultsadultsadults ---- ToxicityToxicityToxicityToxicity

1Jani AB et al. Urology 2005;66:566-70; ²Hamilton AS et al. J Clin Oncol 2001;19:2517-26

0

5

10

15

20

25

30

35

40

45

Acute GU Acute GI Late GU Late GI

% o

f m

en

GU/GI toxicity1

(grade ≥2)

<60 yr 60-70 yr 70-74 yr ≥75 yr

P=0.10 P=0.19

P=0.22

P=0.09

70

59

41

63

32

18

0

10

20

30

40

50

60

70

80

<65 yr 65-74 yr ≥75 yr

% o

f m

en

Erection quality²

(firm enough for sexual intercourse)

Before treatment 24 months after treatment

GI: gastrointestinal; GU: genitourinary; RT: radiotherapy

N=527 consecutive men; RT in single institution N=497 localized PCa patients treated with RT randomly selected from SEER database

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RT + short course ADTRT + short course ADTRT + short course ADTRT + short course ADT

• N=206 localized unfavourable risk PCa• Post-hoc analysis; hypothesis generating only

D’Amico AV et al. JAMA 2008;299:289-95

Moderate or severe comorbidity

100

80

60

40

0

20

6 10820 41 3 5 7 9

N=49Log-rank P=0.08

RT+ADT

RT alone

Ove

rall

surv

ival

, %

Time after randomization, years

No or minimal comorbidity

Ove

rall

surv

ival

, %

100

80

60

40

0

20

RT alone

6 10820 41 3 5 7 9

N=157Log-rank P<0.001

RT+ADT

Time after randomization, years

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RT + ADT in locally advanced RT + ADT in locally advanced RT + ADT in locally advanced RT + ADT in locally advanced PCaPCaPCaPCa

1Pilepich MC et al. Int J Radiat Oncol Biol Phys 2005;61:1285-90; ²Bolla M et al. Lancet Oncol 2010;11:1066-73; ³Bolla M et al. N Eng J Med 2009;360;2516-27

100

75

50

25

0

P=0.002

%

RX + LHRH

RX

Years

ADT benefit RTOG 85-311 EORTC 228632 EORTC 229613

N 977 415 970

ADT duration Progression 3 years 6 months / 3 years

Patients T3 and/or N+ T1-2 grade 3 or T3-4 N0 (N1)

T1-4, N0-2 (or pN), M0

CSS YES YES YES

OS YES YES YES

RX + LHRH

RXP=0.0004

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Locally advanced Locally advanced Locally advanced Locally advanced PCaPCaPCaPCa

Local treatment is mandatoryLocal treatment is mandatoryLocal treatment is mandatoryLocal treatment is mandatory

1Engel J et al. Eur Urol 2010;57:754-61; ²Mason MD et al. J Clin Oncol 2015;33:2143-50

HR=2.04 if RP stopped

Surgery (Retrospective cohort N1)1

N=938 (45% T3)Radiotherapy (NCIC PR3 trial)²

N=1,205 (T3/T4 N0/Nx OR T2, PSA >40 µg/l OR T2, PSA >20 µg/ml, Gleason 8-10)

Ove

rall

surv

ival

(%

)

Time (years) Time (years)

HR=0.7

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OverusageOverusageOverusageOverusage of ADT monotherapy in senior adultsof ADT monotherapy in senior adultsof ADT monotherapy in senior adultsof ADT monotherapy in senior adults

• EORTC 30891 trial• N=985 with T1-4, N0-2 (unwilling /unfit for local therapy)

• 46% T3-4, 77% N0

• Median follow-up: 12.8 years

• 30% died without any ADT

• Benefit of immediate ADTonly in patients at high-risk of death 3-5 yrs after diagnosis (PSA >50 ng/ml, PSA DT <1 yr)

Studer UE et al. Eur Urol 2014;66:829-38

HR=1.21(95% CI 1.05-1.39)P=0.0085

Deferred ADT

Immediate ADT

DT: doubling time

All-causesmortality

Non-PCamortality

PCamortality

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ADT ADT ADT ADT monotherapymonotherapymonotherapymonotherapy in senior in senior in senior in senior adultsadultsadultsadults

BenefitsBenefitsBenefitsBenefits and and and and harmsharmsharmsharms shouldshouldshouldshould bebebebe carefullycarefullycarefullycarefully weightedweightedweightedweighted

• Increased risk of fracture1

• Increased risk of diabetes2

• Increased risk of thromboembolic events3

• Increased risk of dementia4

• Increased risk of all-cause morbidity in the following cases5-7:• Chronic heart failure

• History of myocardial infarction

• History of stroke

1.Shahinian VB et al. N Engl J Med 2005;352:154-64; 2Keating NL et al. J Clin Oncol 2006;27:4448-56; 3Ehdaie B et al. Cancer 2012;118: 3397-406; 4Nead KT et al. JAMA Oncol 2016; doi: 10.1001/jamaoncol.2016.3662; 5D‘Amico AV et al. J Clin Oncol 2007;25:2420-5; 6Hayes JH et al. BJU Int 2010;106:979-85; 7Nguyen PL et al. Int J RadiatOncol Biol Phys 2012;82:1411-6

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Vale CL et al. Lancet Oncol 2016;17:243-56

OS

PFS

PFS: progression-free survival

Docetaxel in M0: no placeDocetaxel in M0: no placeDocetaxel in M0: no placeDocetaxel in M0: no place

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EAUEAUEAUEAU----ESTROESTROESTROESTRO----SIOG guidelines SIOG guidelines SIOG guidelines SIOG guidelines 2016201620162016

Senior adultsSenior adultsSenior adultsSenior adults

www.uroweb.org

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Treatment decisions in localized diseaseTreatment decisions in localized diseaseTreatment decisions in localized diseaseTreatment decisions in localized disease

• Treatment decision should NOT be based on age

• Treatment decisions should consider:• The risk of dying from cancer (disease factors)

• The risk of dying from another cause (many related to comorbidities than age)

• Treatment-specific side effects / aggressiveness

• PCa-associated complications to interfere with comorbidity

• Patient's preferences