CLINICAL AND BIOLOGICAL DEFINITION OF ELDERLY

PATIENTS

Pr Claire FALANDRY

Unité d’Oncogériatrie, Service de Gériatrie

Centre Hospitalier Lyon Sud

Laboratoire CarMEN de l’Université de Lyon

Institut de Cancérologie des HCL

Photo CHLS

Outline

� The “negative” definition� The “usual” aging� Clinical definition(s) of frailty� Pragmatic definitions� Biomarkers of aging

THE « NEGATIVE » DEFINITION

« Not fit enough »

� = those who are not included in clinical trials� Age restrictions / Exclusion criteria

Hutchins, NEJM 1999

Where are we now ?

� Flowchart clinicaltrial.gouv� Cancer interventional studies, “young” versus “old”

Interventional studies, exclude unknown

01/01/2004 to 12/31/2013 N = 108 213

CancerN = 27305

Cancer and Geriatric, seniorN = 501

Other than cancerN = 80927

Cancer non geriatric, exclude senior

N = 26804

0

20

40

60

80

2004 2005 2006 2007 2008 2009 2010 2011 2012 2013

Cancer and geriatric

0,0%

0,5%

1,0%

1,5%

2,0%

2,5%

2004 2005 2006 2007 2008 2009 2010 2011 2012 2013

% Geriatric

With grateful thanks to Olivier Saint Jean

A big effort from hematology

N

Leukemia (all types) 123

Lymphoma (all types) 72

Lung 68

Breast 53

Colorectal 49

Prostate 22

Myeloma 20

Head and neck 19

Gastric, esophagal 19

Brain 10

Ovarian 9

Bladder 6

Uterus 5

Pancreatic 3

Liver 2

Melanoma 1

With grateful thanks to Olivier Saint Jean

Total cancer Cancer non geriatric Cancer and geriatric

N % N % N %

27305 26804 501

OVERALL SURVIVAL 7531 27,6% 7318 27,3% 213 42,5%

SURVIVAL WITHOUT PROGRESSION 7050 25,8% 6894 25,7% 156 31,1%

QUALITY OF LIFE 2789 10,2% 2699 10,1% 90 18,0%

AUTONOMY 302 1,1% 292 1,1% 10 2,0%

TOXICITY 6172 22,6% 6049 22,6% 123 24,6%

REMISSION 706 2,6% 655 2,4% 51 10,2%

RESPONSE 11751 43,0% 11519 43,0% 232 46,3%

With grateful thanks to Olivier Saint Jean

Functional aspects

• ≥ 80 years:• 28 % with at least one dependence on ADL• 4,5 % highly dependent• 72 % need help for house keeping• 11 % isolated • Age category with the lower incomes

Life expectancy in good healthDependence rate with age

Functional aspects

Usual aging 0 10Frailty FragileBedridden

Successful aging

• A continuum between normal versus pathological aging

Extend inclusion criteria

+/- specific trials

Extend inclusion criteriaSubgroup analysesShort and long term

toxicitiesImpact on autonomy and

QOL+/- specific trials

Specific trials

Impact on survival,

autonomy and QOL

Trial needs in oncology

A need for prediction

Treatment decision

Adjuvant

Metastatic

Feasibility

Toxicities

Benefit/risk ratio

Short term

Toxicities

Long term

Toxicities

Expected survival out of cancer

THE “USUAL” AGING

Aging concepts

� Aging is associated with a progressive decline of multiple organs and functions

� Functional reserves declineSkin

Kidney

Muscle

Nervoussystem

Sensoryorgans

Heart & vessels

Cartilages

Hematopoiesis

Bones

Metabolism

Gastro-intestinal system

Physiological agingPhysical deconditioningChronic diseasesPathological aging

The Bouchon theory

� 1 + 2 + 3 leads to decompensation

Physiological agingChronic diseasesAcute disease/stressor

Organ

Illustration 1: hematopoietic issues� Short term:

� Long term:� CALGB, 6642 pts, 3 trials

� 3 % > 70 ans

� Toxic deaths: 1.5 % > 65 ans vs 0.19 % < 50 ans

� Age correlated (multivariate analysis) with:� Grade 4 hematotoxicities

� Premature arrest

� AML & myelodysplasic syndroms (1.8 %)

Dees et al. Cancer Invest, 2000.

0

50

100

150

200

250

300

350

Course 1 Course 4

<65 years n = 32≥65 years, n = 11

ANC(/mm 3)

260

179

270

94

P = 0.28P < 0.01

Neutrophils nadir after AC

Muss HB et al. J Clin Oncol 25: 3699-704

Illustration 2: heart issues

� Adjuvant chemotherapy in breast cancer

� SEER 1992-2002 data: CHF risk at 10 years – generalpopulation

� SEER 2000-2007 data: anthracyclines +/- trastuzumab – 67 to 94 years

38,4% (RR=1,26) vs 32,5% vs 29,0%FR : age (HR=1.79 per 10 years;1.66-1.93), black, trastuzumab (HR=1.46;1.21-1.77),

HTA (HR=1.45;1.39-1.52), diabetes (HR=1.74;1.66-1.83), coronaropathy (HR, 1.58;1.39-1.79)

Pinder, JCO 2007: 25;3808-3815

41,9% (RR=1,26) vs 32,1% vs 18,1%

Chen, J Am Coll Card 2012: 60;2504-12

Illustration 3: pharmacologic issues

16

Absorption: � blood flows� secretion of digestive enzymesimpaired mucous membranes

Distribution: � weight ou � fat (15% à 30% weight), � intracellular fluids, � albumenia

Metabolism: � hepatic blood flow , � CYP P450 (20-30% F<H)� hepatocyte function

Excretion: � GFR

Interactions: � associated polymedication

Measure site

Distribution

Absorption

ADME System

Metabolism(liver,…)

Excretion

Fate of the drug

CLINICAL DEFINITION(S) OF FRAILTY

Aging and frailty: some « lapalissades »…

� A consensual definition: “physiological multisystem limitation limiting the adaptive capacities in response to stress.”

� No consensus for operational criteria..

Rolland, 2013

Aging and frailty: different concepts

Adapted from Gérard, Livre Blanc de la Gériatrie 2015

Linked conceptssSARCOPENIAMALNUTRITION

« Some » frailties :COGNITIVESENSORYTHYMICSOCIO-CULTURALENVIRONMENTALCOMORBIDITIESCOMEDICATIONS…

Physical phenotypeMotor

Fried phenotype

Multi-domain phenotypeMedico-Psycho-Cognitivo-Social

Rockwood frailty index

- A predefined phenotype theory

- At risk of dependence

- Cumulative deficits theory

- CGA- Includes dependent

patients

Fried’s phenotypic theory of frailty

Fried et al. J Gerontol Med Sci 2001: 56: M146-M156

The malnutrition / frailty /sarcopenia link

Xue et al, 2008

Different frailty approaches

Multi-domain (cumulative) Phenotypic (Fried)

Conceptual definition Frailty = accumulation of geriatric syndromes(dementia, dependences..)

Frailty = Reversible state, independent of comorbidities, precedes entry into dependence

Patients’ selection All At risk of incapacity

Evaluation model Comprehensive Geriatric Assessment

Evaluation of functional performances (sarcopenia ++++)

Advantages Identify domains of geriatric intervention

Homogeneous population, evaluable interventions

Limits Heterogeneouspopulations

Limitative

Adapted from Gérard, SOFOG 2015

Cancer & aging: like a thunderbolt

Cancer Host

Therapeutic index

Pharmacology

Main toxicities

HistologyLocal treatment

Systemictreatment

Treatmentobjectives ?

ComorbiditiesNutrition

Psycho-cognitive

SocialEnvironment

AdherenceComplianceFeasibility

Oncogeriatrics: historically a multidomainapproach

� Repetto, 2002 : EGS does better than PS…� Extermann, 2005 : SIOG recommendations for

a comprehensive geriatric assessment� Soubeyran, 2012 : screening test validation:

G8…� Towards a tailored oncogeriatric treatment

plan…

CGA & prognosis: is the phenotypicapproach the best fitting model (1) ?

� Le G8 : une « inspiration » issue du MNA…

CGA & prognosis: is the phenotypicapproach the best fitting model (2) ?

� ADL & IADL

� Gait speed

� SPPB

� Falls in the last 6 months

CGA & prognosis: is the phenotypicapproach the best fitting model (3) ?

� However: � According Fried criteria:

� Dependent people should be excluded � Most cancer patients are frail or prefrail (97% !!!)

� Frequently entangled symptoms…� Weight loose… Cancer ? Frailty ?� Fatigue… Cancer ? Frailty ?� ↘ physical activity Cancer ? Frailty ?� ↘ gait speed Cancer ? Frailty ?� Muscular weakness Cancer ? Frailty ?

Gérard, SOFOG 2015

THE PRAGMATIC APPROACH

� = impact of geriatric parameters on various patients' outcomes� Overall survival� Treatment decision� Treatment toxicity� Treatment feasibility

Mortality prediction

� Prognosis: eprognosis.org

� Lee score: 4-year mortality scoreTotal 4 ans mortality

0-56-910-13≥ 14

< 4 %15 %42 %64 %

Lee, JAMA 2006

NCHS 2000

� 1-year mortality: Walter score

� 100-days mortality: NCASS score

Walter, JAMA 2001

Boulahssass, JCO 2015

Toxicity prediction

Extermann, Cancer 2009

Hurria, JCO 2009

Treatment completion prediction

Falandry, Annals Oncol 2013

AGING BIOMARKERS ?

� Variation of the hemoglobin level with age and sex

Hawkins WW, Blood 1954

Anemia ?

Baltimore Longitudinal Study on Aging

Erschler WB, JAGS 2005

Aging and erythropoiesis

↓ Medullar cellularity

↓ Iron uptake

→ ou ↓ BFU-E et CFU-E progenitors

→ ou ↑ Epo plasmatic concentration

Price E, Blood Cells Mol Dis 2008

Anemia according OMS

Définition : not age-dependant�Males: Hb < 13 g/dL�Females: Hb < 12 g/dL

Prévalence :�~ 10% after 65 years�~ 20% after 80 years�~ 50% in patients living in nursing home

Anemia epidemiology

Gulranik JM, Blood 2004

Anemia ?

Culleton BF, Blood 2006

Cancer type Studies number Risque relatif

ajusté

NSCLC

VAS

Prostate

Lymphoma

Other

All

15

10

6

3

26

60

1,19 [1,10-1,29]

1,75 [1,37-2,23]

1,47 [1,21-1,78]

1,67 [1,30-2,13]

1, [1,40-4,47]

1,65 [1,54-1,77]

Caro, Cancer 2001

Potential biomarkers of aging

AG Pallis et al, JGO 2014

IL6 as a good candidate

The Immune Risk Profile

� OCTO/NONA study� CMV infection 100% (vs 85%)

� Ratio CD4/CD8 < 1: differenciated T cells accumulation CD27-CD28-CD57+CD8+ CMV Ag-specific

� Deleterious impact of high rates of anti-CMV Ab

Hadrup, 2006

Strandberg, 2010

Pawelec et al, J. Comp. Path, 2010

The telomere connection

� 1938-9 : Muller -McClintock : telomere « telos » « meros »

� 1961 : Hayflick Hypothesis (Mitotic clock)

� 1973 : Olovnikov – A theory of marginotomy – the end-replication problem

� 1987 : Telomerase gene discovery

� 1999 : Terc null mice display a premature aging phenotype

� 2009 : Nobel prize pour E. Blackburn, C. Greider et J. Scoztack

� 2011 : « telomere » : 13182 PubMed references

Homologous recombinationNon Homologous End Joining

Replication fork stalling

High sensitivity to oxydative stress

End-replicationproblem

Telomerase activation

ALT telomere lengtheningChromosomal recombinations –telomere healing

SenescenceTissue renewal loss

Pro-inflammatory secretory phenotype

Pro-tumorogenic potential

Measuring telomere health ?

Senescence

60

DNA damage response signaling

- loss of telomerase activity ?- Higher turn over ?- Inflammaging ? - Oxydative stress ?

PBMC length

� Mortality : controversial data:� Cawthon RM & al: Association between telomere length in blood and mortality in people aged 60

years or older. Lancet 2003;361:393-5

� Fitzpatrick AL, Kronmal RA, Kimura M, Gardner JP, Psaty BM, Jenny NS, Tracy RP, Hardikar S, Aviv A: Leukocyte telomere length and mortality in the cardiovascular health study. J Gerontol A Biol SciMed Sci 2011;66:421-9.

� Martin-Ruiz C & al: Assessment of a large panel of candidate biomarkers of ageing in the newcastle85+ study. Mech Ageing Dev 2011;132:496-502.

� Eisenberg DT & al: Substantial variation in qpcr measured mean blood telomere lengths in young men from eleven european countries. Am J Hum Biol 2011;23:228-31.

� Willeit P & al: Telomere length and risk of incident cancer and cancer mortality. Jama 2010;304:69-75.

� Degenerative diseases :� Brouilette SW & al: Telomere length, risk of coronary heart disease, and statin treatment in the West of

Scotland primary prevention study: a nested case-control study. Lancet 2007;369:107–114

� van der Harst P & al: Telomere length of circulating leukocytes is decreased in patients with chronicheart failure. J Am Coll Cardiol 2007;49:1459–1464

� van der Harst P & al: Possible association between telomere length and renal dysfunction in patients with chronic heart failure. Am J Cardiol 2008;102:207–210

Telomerase activity

� Epel ES & al: Accelerated telomere shortening in response to life stress . Proc Natl Acad Sci U S A 2004;101:17312-5.

� Atzmon G & al: Evolution in health and medicine sackler colloquium: Genetic variation in human telomerase is associated with telomerelength in ashkenazi centenarians . Proc Natl Acad Sci U S A 2010;1:1710-7.

� Ornish D & al: Increased telomerase activity and comprehensivelifestyle changes: A pilot study . Lancet Oncol 2008;9:1048-57.

Telomere-dysfunction Induced foci (TIFs)

� Measuring directly DNA damage response

Augereau et al, Blood 2011From Gilson et al, Nat Rev Mol Cell Biol 2007

DNA-damage biomarkers

� Proteins induced by telomere dysfunction and DNA damage represent biomarkers of human aging and disease

Jiang et al, PNAs 2008

Some data in oncology

� With a cut-off of 5770bp, TL discriminates 2 groups of patients with different TCr

Treatmentcompletion rate (TCr)

0%

20%

40%

60%

80%

100%

ST LT

p=0.02

n = 34

Short

n = 75

Long

59%

80%

Telomerelength Falandry, Aging 2015

event

ObservedRisk:

short/long telomere

group

95% confidence

interval P

Serious Adverse Events 2.69 1.17-6.19 .019

Unplanned hospital admissions 2.14 0.92-4.95 .070

Grade > 3 non-hematological toxicities

2.04 0.88-4.71 .095

� Severe toxicity increases with telomere shortening

Overall survival

Time

Sur

viva

l

0 10 20 30 40

0.0

0.2

0.4

0.6

0.8

1.0 IVvsIII=0, ST5999=0

IVvsIII=0, ST5999=1IVvsIII=1, ST5999=0IVvsIII=1, ST5999=1

Time (months)

Ove

rall

surv

ival

Stage III, telomere size ≥ 6000bpStage III, telomere size < 6000bpStage IV, telomere size ≥ 6000bpStage IV, telomere size < 6000bp

� Multivariate analysis :

� Stage (IV vs III) HR=2,53 [1.54-4.27]; p=0,0003

� Telomere < 6000bp HR=1,57 [0.98-2.51]; p=0,06

p16: modeling the gerontogenic impact of treatment

� p16 & ARF ARN accumulation 12 months afterchemotherapy Sanoff et al., JNCI 2014

THOMs

� Different ways to define an elderly population� A need for prospective evaluation considering

its heterogeneity� A need for some consensus about frailty…