10/12/2008

1

Assessment of senior adultswith advanced prostate cancer for chemotherapy: SIOG guidelineschemotherapy: SIOG guidelines

Jean-Pierre Droz, MD, PhDProfessor of Medical Oncology

Claude-Bernard Lyon 1 University Centre Léon-Bérard, Lyon, France

Age distribution of men with prostate cancerat diagnosis in US - SEER (2000-2004)

ntag

e of

men

27.3%

36.7%

22.4%

n=258,707

20

25

30

35

40

Perc

en

Age at diagnosis

0.5%

8.4%4.7%

At diagnosis, 64% of men aged ≥ 65 years and 27% aged ≥ 75 yearsNational Cancer Institute website (www..cancer.gov)

0

5

10

15

35-44 45-54 55-64 65-74 75-84 85+

Number of men aged 70+ and 80+in US (1950 – 2050)

20

25

3070+ years

80+ yearsn m

en

0

5

10

15

1950 1960 1970 1980 1990 2000 2010 2020 2030 2040 2050

80+ years

Mill

ion

Baby boom generation: a LOT of prostate cancer!

US Census Bureau – International Data Base – United States Data from 2010 to 2050 are projections

Standard prostate cancer treatment

• Localized disease:– Prostatectomy– Radiation therapy– Brachytherapy / HIFU– Brachytherapy / HIFU– Surveillance

• Advanced disease:– Androgen deprivation– Chemotherapy– Palliative treatments

Top 25th percentile

Lowest 25th percentile

50th percentile

Healthy

Vulnerable(median)

Frail

18

14.215

20

25

ncy,

yea

rs

Life expectancy in senior adults: a largevariability reflecting health status variability

A question of population

Need for health

Walter LC et al. JAMA 2001, 285, 2750-2756

10.8

7.9

5.84.3

12.4

9.3

6.7

4.73.2

2.3

6.7

4.93.3

2.21.5 1

0

5

10

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

Life

exp

ecta

n

status evaluation

Chances of survival depends of health statusA question of individual

tion

surv

ivin

g

Independent

Frail

Vulnerable Vulnerable* and frail** senior adults are the majority and

Rockwood K et al. Lancet 1999, 353, 205-206

Prop

ort

Time to death (months)

IndependentIncontinence onlyVulnerable*Frail**

Frail are the majority and are at death risk !

*Vulnerable: need for assistance in ≥ 1 (or ≥ 2 if incontinence) activities of mobility or daily livingor cognitive impairment without dementia or bowel + urinary incontinence

**Frail: need for assistance in ≥ 2 (or ≥ 3 if incontinence) activities of mobility or daily livingor dementia or bowel + urinary incontinence

10/12/2008

2

Domains of expertise of health statusin senior adults:

Which have been our choices?Comorbidity is a key predictor

of life expectancy

1. Example of radical prostatectomy2. Example of radio-HT therapy

Assigned weight Condition1 (each) Myocardial infarction

Congestive heart failurePeripheral vascular diseaseCerebrovascular disease (except hemiplegia)DementiaChronic obstructive pulmonary diseaseConnective tissue diseaseUlcer diseaseMild li di

Charlson comorbidity index

Total score: [0–30]

Mild liver diseaseDiabetes (without complications)

2 (each) HemiplegiaModerate or severe renal diseaseDiabetes with end-stage organ damage2nd solid tumour (non metastatic)LeukaemiaLymphoma, multiple myeloma…

3 Moderate or severe liver disease

6 (each) 2nd metastatic solid tumorAIDS

Charlson et al. J Chronic Dis 1987;40:373-83

Comorbidity is the strongest predictor ofnon prostate cancer mortality (multivariate analysis)

All cause mortality

Prostate Cancermortality

Non-prostateCancer mortality

RR p RR p RR p

Radical prostatectomy

0.41 <0.00 0.35 0.001 0.44 <0.00

Radiationtherapy

0.90 ns 0.41 0.001 1.10 ns

A t di i 1 04 <0 00 1 04 0 14 1 05 <0 00Age at diagnosis 1.04 <0.00 1.04 0.14 1.05 <0.00

Charlson 2+ 2.63 <0.00 1.43 0.23 3.03 <0.00

Biopsy grade 1.28 0.005 2.08 <0.001 1.15 0.15

baseline PSA 1.55 <0.00 2.51 <0.00 1.22 0.10

Income $10,000(> versus <)

0.91 0.014 0.96 0.66 0.90 0.008

Tewari et al. J. Urol 2004;171:1513-15191611 men with clinically localised prostate cancer and4538 age, race and comorbidity matched controls

Radical prostatectomy complications:SEER-Medicare database

Begg N Engl J Med 2002;346:1138-1144

Romano-Charlson index is a strong and significantpredictor of post-operative and late urinary complications

urvi

val,

%

No or minimalcomorbidity*

Moderate or severecomorbidity*

No benefit of radiation therapy plus androgen deprivation if moderate/severe comorbidity

Ove

rall

su

Years after randomization Years after randomization

D‘Amico et al., JAMA. 2008, 299: 289-295*Adult comorbidity evaluation 27 (ACE-27)

RT+HT

10/12/2008

3

Cumulative Illness Rating Scale Geriatric (CIRS–G)

ScoreHeartVascularHematopoeiticRespiratoryEyes, ears, nose, throat & larynxU Gi

Rating strategy0 = no problem1 = current mild problem or

past significant problem2 = moderate disability or

morbidity, requires first-line therapy

Parmele PA, et al. J Am Geriatr Soc 1995;43:130–137

Upper GiLower GILiver RenalGenitourinaryMusculoskeletal/integumentNeurologicalEndocrine/metabolic & breastPsychiatric illness

3 = severe/constant significant disability/ uncontrollable chronic problems

4 = extremely severe/ immediate treatment required/ end organ failure / severe impairment in function

CISR-G & health status

FIT

• No problem [grade 0]• Current mild problem [grade 1]• Moderate disability/morbidity,

requires first-line therapy [2]

• At least 1 severe/constant

FRAIL

VULNERABLEsignificant disability or uncontrollable chronicproblem [grade 3]

• Several ‘grade 3’ problems• Or at least 1 extremely severe/

immediate treatment required/end organ failure/severe impairment in function [grade 4]

Evaluation of dependence statusin senior adults

IADL1 ADL2

Get place at walking distanceUse telephone

TransferContinenceGoing to toilet

1IADL: simplified Instrumental Activities of Daily Living (Lawton, Gerontologist 1969, 9: 179)2ADL: index of independence in Activities of Daily Living (Katz, JAMA 1963, 185: 914)

One abnormality is significant

Use telephoneTake medicationManage money

BathingDressingFeeding

• Nutrition:- Weight loss and body mass index- Serum albumin level

• Cognition:Screening for memory impairment

And also…

- Screening for memory impairment• Depression• Polypharmacy• Risk of falling

- Monopodal stay position• Caregiver

Chemotherapy in advancedprostate cancerprostate cancer

TAX 327: docetaxel shows a similar benefit in young and senior adults

All patientsAge ≤ 68 yearsAge ≥ 69 yearsNo painPain

FavorsDocetaxel q3w

FavorsMitoxantrone

0.5 0.7 0.9 1.0 1.1 1.3 1.5

PSA <115 ng/mLPSA ≥115 ng/mL

KPS ≤80%KPS ≥90%FACT-P <109FACT-P ≥109

Berthold D et al. J. Clin. Oncol. 2008; 26:242-45

No visceral diseaseVisceral disease

Berthold D et al. J. Clin. Oncol. 2008; 26:242-45

10/12/2008

4

Fizazi K et al. Eur. Urol. 2008; Epub ahead of print

• 175 senior adults (aged 75 to 90 years) treated withfirst line docetaxel-based therapy for metastatic HRPC:– 95 patients (54%) had "standard" docetaxel regimen

(70-75 mg/m² d1, q3w)– 80 patients (46%) had "adapted" docetaxel regimen

(30-35 mg/m² weekly)

Efficacy Adapted regimen(n=80)

Standard regimen(n=95)

p

Treatment response

PSA response* 68% 71% 0.79

Recist response 43% 40% 0.96

Fizazi K et al. Eur. Urol. 2008; Epub ahead of print

*PSA decrease of 50% or more from baseline under treatment

• Median progression-free survival: 7.4 months(25.5% at 1 years, 5.1% at 2 years)

• Median overall survival: 15 months(59.3% at 1 year, 28.7% at 2 years)

• No significant trend between standard and adapted regimen

Grade 3-4 adverse events

Fizazi K et al. Eur. Urol. 2008; Epub ahead of print

SR: standard docetaxel regimen; AR: adapted docetaxel regimen

Specific guidelines for management of senior adults with prostate cancer now ready for publication

• Systematic literature search • Specific aspects pertaining to geriatrics• The bibliographic material was reviewed and discussed

by a scientific panelJ.P. Droz(oncologist France)

M. Kattan(quantitative health sciences US)(oncologist, France)

L. Balducci(oncologist, USA)M. Bolla(radiation oncologist, France)M. Emberton(urologist, UK)John Fitzpatrick(urologist, Ireland)S. Joniau & H. van Poppel(urologists, Belgium)

(quantitative health sciences, US)S. Monfardini(oncologist, Italy)J. Moul(urologist, US)A. Naeim(oncologist, US)F. Saad(urologist, Canada)Cora Sternberg(oncologist, Italy)

SIU 2007 - ECCO 2007 - SIOG 2007 - ASCO GU 2008 EAU 2008

10/12/2008

5

SIOG proposed recommendations

• The urological approach in senior adults with prostate cancer should be the same as in younger patients

• Internationally accepted guidelines (EAU NCCN• Internationally accepted guidelines (EAU, NCCN, AUA, etc.) are valid, as well as scientifically established national guidelines

Localized prostate cancerSpecial considerations for senior adults

Only men within the high risk group havea significant 10-year mortality due to prostate cancer

and are likely to receive curative treatment

Group 1(Healthy)

Life expectancy evaluation

Group 2(Vulnerable, i.e.

reversible problem)

Group 3(Frail, i.e.

non-reversible problem)

Group 4(Terminal illness)

• Comorbidity (CISR-G): grade 0,1 or 2

• Independent in IADL*N l i i

• Comorbidity (CISR-G): at least one grade 3

• Dependent in ≥1 IADL*

• Comorbidity (CISR-G): several grade 3 or at least one grade 4D d t l t 1 ADL

• Terminal• Bedridden • Major comorbidities

Guideline: Localized prostate cancer

Standard treatmentas for younger patients except prostatectomy

Symptom management including specific

treatments (hormones, RTUP, etc.)

Readaptation

Standard treatment

as for youngerpatients

Only palliativetreatment

• No malnutrition • At risk of malnutrition • Dependency: at least 1 ADL impaired

• Cognitive impairment • Severe malnutrition

• Cognitive impairment

EAU 2008 – Abstracts 916

Advanced prostate cancerSpecial considerations for senior adults

• Hormone-sensitive prostate cancer:– Androgen deprivation is the standard but induces bone loss– Baseline evaluation: bone mineral density + dosage Ca &

Vitamine D3– Supplémentation with calcium & vitamine D– Previous ostéoporosis : biphosphonates

• Hormone-resistant prostate cancer:– Chemotherapy with docetaxel (75 mg/m2 q3w) is the standard

and shows the same efficacy in healthy senior adults as in younger patients.

– The tolerability of weekly docetaxel has not been specifically studied in vulnerable and frail senior adults. (The place of weekly docetaxel in this setting should be further evaluated)

– Palliative treatments as palliative surgery, radiopharmaceutics, radiotherapy, medical treatments for pain and symptoms

Life expectancy evaluation

Group 1(Healthy)

Group 2(Vulnerable, i.e.

reversible problem)

Group 3 (Frail, i.e.

non-reversible problem)

Group 4(Terminal illness)

• Comorbidity (CISR-G): grade 0,1 or 2

• Independent in IADL*• No malnutrition

• Comorbidity (CISR-G): at least one grade 3

• Dependent in ≥1 IADL*• At risk of malnutrition

• Comorbidity (CISR-G): several grade 3 or at least one grade 4

• Dependency: at least 1 ADL impaired

• Terminal• Bedridden • Major comorbidities• Cognitive impairment

Guideline: Advanced prostate cancer

Adapted (weekly?)chemotherapy

Standardchemotherapy

Symptomatictreatment

Standardchemotherapy

Hormonal treatment (first and second lines, anti-androgen withdrawal, biphosphonates)

ReadaptationEAU 2008 – Abstracts 644

No malnutrition At risk of malnutrition p y p• Cognitive impairment • Severe malnutrition

Cognitive impairment

Work still in progress ...• A set of references has been selected• A first draft has been written and has circulated in the

writing committee• Guideline proposals have been presented in various

meetings to obtain feed-back opinion• Extensive manuscript (a review) will be submitted this

month to Critical Review in Hemato-Oncology on behalfmonth to Critical Review in Hemato-Oncology on behalf of the SIOG Prostate Cancer Guidelines Task Force

• Abridged version will be submitted to BJU Int. this month

• Recommendations will be discussed in the setting of the different societies (ASCO, AUA, EAU, ASTRO, ESMO, ESTRO...). Production of consensus guidelines will be attempted. Validation to be proposed to the different national societies