Recherche Clinique en Onco Gériatrie
Dr Etienne BRAIN
Institut Curie / Hôpital René Huguenin
Saint-Cloud, France
[email protected] & www.siog.org 1
Agent Name Approval N Age ≥ 65 N Age ≥ 75
Palbociclib 2/2015 37 44% 8 10%
86 25% --
Everolimus 7/2012 290 40% 109 15%
Pertuzumab 6/2012 60 15% 5 1%
Eribulin mesylate 11/2010 121 15% 17 2%
Lapatinib 1/2010 34 17% 2 1%
282 44% 77 12%
Ixabepilone 10/2007 45 10% 3 <1%
32 13% 6 2.5%
Package Insert, “Geriatric Usage” section
Few older adults included in registration studies!
Breast cancer as an example
Courtesy to Arti Hurria (adapted) 2
3
Distribution par tranche d’âges des patientes incluses dans le National Cancer Institute3
Cependant, mise en place d’essais dédiés aux personnes âgées
3: Hurria, JCO 14
Peu d’amélioration ces dernières années…
In standard trials
- Younger
- Less comorbidities
- Less organ dysfunctions
- Fitter
Trial Population versus Real-Life Data
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• SEER database
• 3,039 patients ≥ 66, stage IV breast, lung, colon cancer, 2004-2007,
bevacizumab
– Contra-indication defined as 2 claims for thrombosis, cardiac disease, stroke,
hemorrhage, hemoptysis, or GI perforation
– Toxicity defined as 1st development of 1 condition > beva
– Beva use associated w/ white race, later year of diagnosis, tumor type, and decreased
comorbid conditions
– 35.5% had contra-indication
• Black race, increased age, comorbidity, later year of diagnosis, lower socioeconomic status, lung and CRC
– If no contra-indication 30% complication (black race)
Hershman J Clin Oncol 2013 5
1. Therapeutic nihilism – Elderly patients do not receive any treatment
2. The intermediate position? – Elderly patients may benefit from treatments
3. Blind therapeutic enthusiasm – Elderly patients receive futile/non beneficial treatments
Place and role of geriatrician and oncologist Pelike from Attica 480–470 BC
Musée du Louvre
Current Dilemna & Extreme Positions
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Need for Distinction between…
1. Non-eligibility
– Upper age limit & stringent inclusion/exclusion criteria
• Under-representation and misrepresentativeness
2. Non-invitation (physician’s reluctance)
– To avoid toxicity & drop out rate; long accrual time; difficulty to handle elderly
in trials; belief of less adhesion of elderly to trials; cost increased; institutional
support lacking; informed consent
3. Non-inclusion (patient’s decline)
– Distrust/mistrust; randomization; fear for toxicity, uncertainty; QoL; logistics
(cost, transportations); dependence; understanding; fear from patient’s circle
of family and friends
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National Call for Coordinating Units
in GO (UCOG) - 2011
• Aims: To support national development of GO according to health care
mapping, including French overseas departments and territories to
cover the whole French territory
1. To better adjust treatments for elderly cancer patients, emphasizing on
shared decision making process between oncologists and
geriatricians
2. To promote access to all in all regions
3. To strenghten specific research (clinical & translational)
4. To support teaching and general information
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• « Action 2.16 : Améliorer la prise en charge des personnes âgées atteintes
de cancer et la prise en compte de leurs besoins spécifiques, notamment en
s’appuyant sur une recherche clinique renforcée pour cette population. La
prise en charge des personnes âgées, caractérisées par plusieurs éléments
de fragilité dans la prise en charge du cancer (polypathologies fréquentes,
difficultés de mobilité), est une priorité »
Research
GERICO
= To use geriatric parameters & items
in methods & design
Adding & integrating
Predicting
Screening
Interventions
Real life
Population
Specific criteria
Translational
Ethics
GERICO (UNICANCER) [email protected] (chair)
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GERICO ≥ 2,500 patients 2002 Creation (F Pein & AC Braud) Age Phase Primary endpoint N Ancillary Publication
2002 G-01: X+VNR PO breast, lung, prostate 70+ II ADL 80 PK CROH 2010
G-02: CT XELOX CCR M+ 70+ II ADL 60 PK JGO 2011
2004 G-03: per op brachyXRT breast < 3 cm pN0 70+ II Feasibility, QoL 40 Cost Brachy 2013
2005 G-04: CT TxT q2w breast M+ 70+ II IADL 27/60 NA Poster
G-05: CT TxT q2w NSCLC M+ 70+ II IADL 5/60 NA Poster
2006 G-06: CT adjuvant anthra (MC) breast ER- 70+ II ADL 40 Will CROH 2010
2009 G-09: breast M+ HER2+++ X + lapatinib 70+ II Composite 4/52 NA Poster
Retrospective L1 CT M+ breast (Bergonié) 75+ Cohorte Description 500 NA CROH 2001
DOGMES L1 DXR lipos (GINECO) 70+ II RR 60 NA EJC 2012
2010 G-10/GETUG P-03: CT TxT prostate + PK 75+ II R Composite 66/60 :144 PK Poster
PRODIGE 20 (G-08): CT ± beva CCR M+ 75+ IIR/III Composite 102 CTC/RX Pending
2011 ASTER 70s/G-11/PACS 10: CT adj breast RH+ HER2- GGI 70+ III OS (competing risks) 1,080/2,000 TR, cost, acc Poster, oral
2012 ELAN (PAIR ORL, GORTEC/GERICO) 70+ II/III OS 446 NA Poster
SHS (cognition, acceptability, etc.) 70+ SHS Qualitative res NA Poster
2014 UCGI-30 (G-12) XRT/CTneo vs XRT rectum
OSAGE (Besançon) 75+
III
I/II
R0 + IADL
MTD, RR EOT
420
54 acc
2016 ASTER 2/3 + EORTC/BIG 70+ III Outcome + QoL 1,200/2,500 Acc
2017 MBC, SCSC, STS, palliative XRT 11
The importance of patient-centred priorities in science cannot be understated
w/ multifarious factors Race
Culture Socioeconomic background
Diet Life-style choices
Immunity Access to cares Transportation
Insurance systems Family unit
Health economics Stage of development Access to innovation
Spirituality Political support
Acceptability 12
Ce qui compte hors cancer
0
20
40
60
80
100
Mobilité Tenue Courses Ménage Hobbies Conduite Religion Confiance Famille Douleur Travail
31 patients 75+
Dempster & Donnelly. Qual Life Res 2000 13
Fried. NEJM 2002
226 patients 60+
Limited life expectancy No treatment resulting in death
= due to cancer, congestive heart failure, or chronic obstructive pulmonary disease
Burden of treatment
= length of the hospital stay, extent of testing, and invasiveness of interventions
Scenario 1
Low-burden treatment restoring participant's current state of health
98.7% accept treatment
Scenario 2
High-burden treatment restoring participant's current state of health
11% rate of acceptance
Scenarios 3 & 4
Low- or high-burden treatment with survival
but severe functional or cognitive impairment
74-89% rate of acceptance
West Haven Veterans Affairs
1
2
3
4
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Co-primary & Composite endpoints
• Co-primary: combine ≥ 2
primary endpoints (i.e.
hierarchy) w/ dimensions
potentially equally/closely
weighted
– Toxicity/efficacy
– Efficacy/functional status
• But
– Correlation between events not
always known and measurable
– sample size
• Composite: combine several criteria in 1
– Cardiology: angor, MI or death
– Oncology: death, M+ or LR relapse (DFS)
– Treatment success (efficacy/toxicity & compliance) • % pts w/ response w/o major AE > n Cy chemo at dose planned
and w/o delay
• But
– Mix of events • Each event should have the same clinical importance for treatment
decision making & describe same clinical issue
– Threshold?
– N events and sample size
– Difficult conclusion if divergent criteria
Time to treatment failure
Treatment failure-free survival
Time w/o symptoms or toxicity
Overall treatment utility
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GERICO 06 (EUDRACT N° 2005-000069-20, PHRC national 2005)
MC MC MC MC XRT
ADL
Tolerance CGA
ADL + MNA +
MMS + GDS +
CIRSG
QLQ-C30
Willingness
CGA ADL + MNA +
MMS + GDS +
CIRSG
QLQ-C30
Willingness
Tolerance
CGA ADL + MNA +
MMS + GDS +
CIRSG
QLQ-C30
Willingness
Tolerance
1 & 2 year
DFS & OS
ADL
Tolerance
ADL
Tolerance
± trastuzumab
if HER2+++
trastuzumab
if HER2+
q3w q3w q3w
4 cycles of “AC-like” chemo In MC, M stands for liposomal non pegylated doxorubicin
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1. Febrile neutropenia 15%
2. Risk of denutrition 15% vs 38%
3. Impact on QoL (social & role functioning)
4. Cardiac tolerance of trastuzumab
5. No palmar plantar erythrodysesthesia
6. DFS3A 85%
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ASTER 70s (EUDRACT N° 2011-004744-22, PHRC national 2011, NCT01564056)
Adjuvant chemotherapy for ER+ HER2- BC in 70+ patients
CGA Microarray
qRT-PCR
screened
randomized
Chemo = 4 TC or 4 AC or4 MC
4-yr OS 19
Hurria J Clin Oncol 2016
1. 58% grade ≥ 3 toxicity
2. Risk increased w/
increasing risk score
3. AUC/ROC 0.65 (95%CI
0.58-0.71) ~ development
cohort 0.72 (95%CI 0.68-
0.77) (P = .09)
4. No association between
PS and chemo toxicity (P
= .25)
A true predictive model for
chemo-related grade 3-5 toxicity
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6/2013-01/2018
592 pts screened
342/592 (58%) in trials
II 81/80 III 181/202 III 80/164
H&N program
GORTEC / GERICO
ONCOVAL / ELAN
FIT definition
• GDS 4 = 0/4
• MMSE > 23/30
• Caregiver
• No fall
• TGUG < 20’
• ADL = 6/6
• CCI ≤2 if 80+
• CCI ≤3 if 75-80
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GA
Frail
Vulnerable Docatexel q3w
Docetaxel qw
Docatexel q3w
Docetaxel qw
randomization
Feasibility defined as 1. 6 cycles of docetaxel (qw or q3w) 2. w/o • Treatment stop > 2 w • Need for dose reduction > 25% • Febrile neuropenia or grade 3-4 non haematological toxicity • Loss of ADL 2 points
Simon Optimum 2-step design
α=5%, 1-β=90%
p0=0.70 & p1=0.90
1. 15 pts/arm (>11)
2. 36 pts/arm ( 30)
Total 60-144 pts
GERICO 10 (treatment x frailty level design)
CRPC
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GERICO 10 results
• 12/2010-08/2012
– 66 patients (45+21) --> per protocol = 49 patients (30+19)
– Group vulnerable (N = 30) • No deaths
• But not feasible (7/15 & 10/15)
– Group frail (N = 19) • 5 toxic deaths
Standard docetaxel
qw or q3w
is not feasible
in most frequent
CRPC elderly patients 23
GA: 1 for all or all for 1?
• For whom?
– Curative vs palliative
– Adjuvant vs metastatic
– Agressive vs chronic
– 65+, 70+, 75+? Etc.
• Screening tool?
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G8 & Oncodage
• G8 vs VES 13
– Sensitivity 76.6 vs 68.7%
– Specificity 64.4 vs 74.3%
– Both 2 ~ 4’
• ~ 2/3 of patients 70+ have a G8 score 14/17
• Strong 1-yr prognosis impact (w/ stage, PS, but not age)
– HR 2.72 (95%CI 1.66-4.47)
2011/2012 INCa recommandations
(UPCOG/UCOG)
Patients 75+ with G8 score 14
Soubeyran PLOS 2014 25
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Treatment failure-free survival
- Standard 3.2 mths
- GA 3.1 mths (HR 0.91; 95%CI 0.76-1.1)
Corre J Clin Oncol 2016
Treatment STD
(%)
CGA
(%) P
All grade toxicity 93.4 85.6 .015
Treatment failure
related to toxicity 11.8 4.8 .007
There is more to life
than survival!
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Nutritional vs standard: 1-yr mortality
70+ w/ MNA 17–23.5
341 patients enrolled/820 planned power!
CRC (22.4%), NHL (14.9%), lung (10.4%), pancreas (17.0%)
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Demonstrate the impact of GA on cancer prognosis in elderly patients
• PREPARE program (Pierre Soubeyran, French PHRC 2013-2014)
Initial cares with first or second line chemotherapy
L1: breast, colorectal gastric, lung, prostate, bladder, ovarian, myeloma, NHL
L2: breast, colorectal, prostate, myeloma, NHL
Co-primary endpoints: 1-yr OS (+10%) & HrQoL (+10 points)
P Soubeyran
> 14 Standard treatment
≤14
Standard treatment
Case management ("G8-guided", nurse, geriatrician, etc.)
> 70 yo
L1 or L2 R
1:1
G8
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Research challenges in GO
1. Address frailty (vulnerable/frail patients are more frequent than fit ones!)
2. Older elderly patients (octogenarians, nonagenarians, centenarians, etc.)
3. Specific co-primary or composite endpoints (weighing QoL + cancer-related targets)
4. Dose-escalation strategies (from doses lower than those approved in younger and fit
adults, based on PK and assessment of functional reserves)
5. De-escalation strategies (targeted therapies vs conventional treatment)
6. GA & case management: impact on cancer prognosis
7. Consensual minimal set of geriatric data to share across groups and countries
8. Translational research (ageing biology and cancer)
9. Pharmaco-economic issues
10. International collaboration
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1. Social environment: Q1 “do you live alone?” + Q2 “do you have a person or caregiver able to provide care and support?”
2. Autonomy: Activities of Daily Living (ADL) (abnormal if <6/6) and 4-Instrumental ADL (IADL) (abnormal if <4/4)
3. Mobility: Time Get Up and Go test (TGUG) (abnormal if >20 sec) 4. Nutrition: unintentional weight loss (>10% in 6 months) and BMI (< 21) 5. Cognitive status: Mini-Cog (abnormal if <4/5) 6. Mood: Mini-Geriatric Depression Scale (Mini-GDS) (abnormal if ≥ 1/4) 7. Comorbidities: updated Charlson index score
National & International validation
Geriatric COre DatasEt (G-CODE) (Delphi/RAND + Consensus Methods)
DIALOG = GERICO + UCOG = intergroup of clinical research in GO labeled by INCa in 2014 & 2017 34
• Review 2005-2012 (National Call PHRC)
– Number of projects
• 27/479 (6%)
– 400 patients 2,400 patients
– 1% of eligible population (vs 7.5% for the rest of the population)
– Funding
• 7,5/139 M€ (6%)
• All calls include GO since 2005!!!
• Young patient
– Social and family obligations (children)
– Quantity of life +++
• Elderly patient
– QoL+++
– Independence
– Staying at home
• Oncology
– Therapies and innovation
– Toxicity, response, survival
• RECIST
• NCI CTC v4.0
• Survival (DFS, PFS, DDFS, OS)
– Fast-moving world
– "Molecular portrait" of tumour & GEP
• Geriatrics
– Symptoms, diagnosis
– Quality of survival, i.e. amount of life
with good QoL
• Cognition
• Functional status
• QoL
• Nutrition, etc.
– Requiring time
– "Global portrait" of patient & GA
GA versus
or + ?
Genomic defects
targeted therapy
GA defects
targeted geriatric
intervention
Two Worlds Confronting One Another?
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From a "prejudice-based" to…
….an "evidence-based" medicine…
• 10 institutions CALGB
– 77 « paires » cancer du sein (< 65A vs > 65A)
– Etude des cas de propositions d’essai
– Analyse multifactorielle : stade, âge (comorbidités contrôlées)
– Aucune différence de participation si proposition +++ : 56% vs 50%
Kemeny JCO 2003
< 65A
N (%)
> 65A
N (%) p
I 11/35 (31) 13/40 (33)
II 22/34 (68) 11/29 (38) 0.0004
IV 2/2 (100) 1/2 (50)
Total 36/71 (51) 25/71 (35)
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FEC, AACR, FAC, ASCO, anti-PDL1, anti-PD1, CMF, SABCS, PD-1, PDL1, DXR, PK/PD, CEX, 5FU CDDP, Calvert AUC, ESMO, Chatelut AUC, CTC, TILs,
population PK, EORTC, FOLFIRI, ctDNA, FOLFOX 7, CPA, DFS, CALGB, DDFS, OS, TTP, NCI, CYP P450, JCO, JNCI, HER2, PI3K, mTOR, Phase 0,
ECCO, ib and ab, Unicancer, EORTC, SWOG, CALGB, etc.
Charlson, CIRSG, CGA, AD, MCI, MNA, GDS, MMS, ADL,
IADL, GFI, CMR2, JAGS, EUGMS, G8, CARG,
Oncodage, VES-13, TRFs, JGO, NIA, SoFOG, Walter’s score, Lee’s score, CRASH,
etc.
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FEC, FAC, SoFOG, ADL, IADL, CMF, SABCS, DXR, PK/PD, CEX, G8, EORTC, 5FU CDDP, MCI, Calvert and Chatelut AUC, CARG, GDS, population PK, AD, FOLFIRI, MMS, FOLFOX, CPA, CRASH,
SWOG, DFS, OS, TTP, NCI, GERICO, TILs, CARG, anti-PDL1, anti-PD1, EORTC TFE, JCO, JNCI, Charlson, JGO, CIRSG, PD-1, PDL-1, ctDNA, EGS, EGA, MNA, GFI,
Unicancer, Lee’s score, JAGS, etc.
To be practice changing, let us be practice sharing!
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