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…
