Post on 11-Aug-2018
1
Cancer du sein et sujet âgé
Docteur Etienne BrainOncologie Médicale
Hôpital René Huguenin / Institut CurieSaint-Cloud, France
etienne.brain@curie.fr
A frailty revealed…
• 2006: Mrs BON… IR… 84 yo– No previous medical history (high blood sugar?)– Husband: 86 yo w/ severe advanced Parkinson, 2 children– Breast self exam � T1c N0 M0 left breast– 54 kg/167 cm
• Conservative surgery + axillary lymph node dissection– Invasive ductal carcinoma, 17 mm, SBR II, 8 N-– ER- PgR-, Ki 67 40%, HER2-
• Adjuvant strategy– Chemotherapy with anthracylines (GERICO 06)? + XRT
• Scoring– Oncologist: PS 0 � “Easy! Go for it“– Geriatrician
• Functional status, cognition, nutrition, GDS � OK• However! 3 falls < 1 year
2
… treatment decision process
• LVEF by MUGA scan normal• Not in GERICO 06 trial, but OK for the oncology staff!• The lady “accepted”….
… treatment decision process & respect
• LVEF by MUGA scan normal• Not in GERICO 06 trial, but OK for the oncology staff!• The lady “accepted”…. but DID she?
• Central venous access + 1 cycle of AC-like chemo �febrile neutropenia + severe stroke (cardiac arythmia?)– Chemotherapy stopped
– Husband placed in nursing home
– Delayed XRT
– Recovered with neurological sequelae
– Seniors residence
– No relapse so far (last visit early 2015)
3
Pelike from Attica480–470 BC
Musée du Louvre
Pourquoi cette question ?
1. Le nihilisme thérapeutique : les sujets âgés ne reçoivent pas de traitement
2. La nuance : les sujets âgés peuvent bénéficier des traitements
3. L’enthousiasme thérapeutique aveugle : les sujets âgés reçoivent un traitement « futile »
� � � Places du gériatre et de l’oncologue
4
2009
2050
http://www.un.org/esa/population/publications/ageing/ageing2009chart.pdf
Démographie et Cancer
• Augmentation de l'espérance de vie & vieillissement de la population
• Augmentation du cancer avec l’âge> 65A
• Incidence x 11
• Mortalité x 15
EV (A) 2000 2035
H 60A 20.2 25.3
F 60A 25.3 34.0
Millions Hb (%) 2000 2050
Population totale 60.4 64.0
> 65A 9.5 (15.8) 19 (29.2)
> 75A 3.8 (6.4) 11.6 (18)
> 85A 1.2 (2.0) 4.8 (7.6)
Brutel INSEE Première 2004, Walter JAMA 2001
5
Projected number of cancer cases for 2000–2050 by a ge group (<45, 45–64, 65–84, 85+) based on projected census population estimates and delay-adj usted SEER-17 cancer incidence rates
Hayat The Oncologist 2007;12:20-37©2007 by AlphaMed Press
Incidence of cancer from 2010 to 2030 (Smith JCO 2009)• +11% < 65 yo• +67% > 65 yo
de Vathaire FRANCIM/INSERM 1996, IVS 2003
Cancer du sein - Incidence
Age 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75+ Total63.3 119.7 187.3 177.3 182.8 211.3 220 231.1 220.4 89.2
40% ou 25% x 1.5 en 2030 ?
6
De Angelis. Lancet Oncol 2013
Relative survival accounts for mortality from causes other than the relevant cancer, which can vary widely between countries
• Most common shortcut in statistics
“1 in 8 women will develop BC in their lifetime”instead of
“If everyone lived beyond the age of 70, 1 in 8 of those women would get or have had BC”
• Since BC risk increases w/ age, lifetime risk changes depending on age
– Age 20-29 1 in 2,000– Age 30-39 1 in 229– Age 40-49 1 in 68– Age 50-59 1 in 37– Age 60-69 1 in 26– Ever 1 in 8
Worldwidebreastcancer.com/breast-cancer-statistics- worldwide
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Phénotype
Plus de formes hormonosensibles (RH+)Moins de formes agressives (triple négatif, HER2+++)
Age
Grann Cancer 2005
• 205.736 femmes, cancers du sein > 20A• SEER 1990-2000• Récepteurs hormonaux (RH)
� Aux oestrogènes (RO ou RE, ou ER en anglais) et à la progestérone (RP ou PgR en anglais)� Négatifs (RH-) si tous les 2 sont absents� Positifs (RH+) si l’un ou l’autre est présent (RO ou RP)
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RO RP HER2 CK5-6/EGFR Ki67
Luminal A ++ ++ - - -
Luminal B ++ +/- - - +
Basal-like = triple négatif - - - + +
HER2 +/- +/- + -/+ +
Normal breast-like + + - -/+ -/+
Claudin-low +/- +/- -/+ +/- +/-
Apocrine - - +/- -/+ +
Perou, Nature 2000 ; Sorlie, PNAS 2001 & 2003 ; Sot iriou, PNAS 2003Reis Filho, Lancet 2011
La « nouvelle » classification
Cheang, Clin Cancer Res 2008; Durbecq, CROH 2008
• British Columbia Cancer Agency• 1986-1992• 4,046 pts
• Jules Bordet• 2,723 pts
9
Penault-Llorca et al. Bull Cancer 2010 (in press)
HER2 selon âge
Dépistage
Pas d’indication d’extension du dépistage de masse > 7 4A(stades plus précoces dépistés mais aucun bénéfice démont ré sur survie)
Mais dépistage individuel à poursuivre selon état de sant é
Aucune étude conduite spécifiquement sur cette population
10
Breast cancer screeningNEJM september 15,2011, Ellen Warnerno real benefit of screening after 70 years
Age N0 of trial(s) Relative risk of death
(95 CI)
60-69 yr 2 Malmö ans Ostergöland 0,68 (0,54-0,87)
70-79 1 Ostergöland 1,12 (0,73- 1,72)
19
Age limits for BC screening
• France: 50-74 ans• Europe : idem• USA : idem• Recommandations for elderly : YES YOU
CAN…but it’s not included in THE national program
• A few ( very few) continue
• The majority stops after 2 or 3 years
20
11
Prise en charge initiale
Retard fréquent… d’où des stades plus tardifsDes standards fréquemment non respectés (sous-traitem ent)
Prise en charge initiale• Registre Genève 1989-1999 : 407 sujets > 80A• Résultats
– Diagnostic tardif & bilan initial incomplet– Traitement spécifique suboptimal dans > 50% cas
Bouchardy JCO 2003
Traitement % DFS5A HR (95% CI)
Aucun 12 46 1
Tamoxifène 32 51 0.4 (0.2-0.7)
Tumorectomie 7 63 0.4 (0.1-1.4)
Mastectomie 33 82 0.2 (0.1-0.7)
Tumorectomie + adjuvant 14 90 0.1 (0.03-0.4)
Divers 2 42 0.8 (0.2-2.5)
12
A Population Based Study of the Management of Older Women with Breast Cancer taking into account
levels of Comorbidity
Tony Moran, Saiqa Tabasum, Christine Connor, Brian Magee, Vanessa Pope, Riccardo Audisio, Chris Holcombe, Nigel Bundred
Moran, EBCC-9, abstract 415
Methods
� Women diagnosed in Gr Manchester, Merseyside and Cheshire in 2009 aged 60 and older
� Data collected from cancer registry and hospital notes
� Tumour characteristics, management and Charlson comorbidity score
� 1888 women (82% of those on registry) in study
Moran, EBCC-9, abstract 415
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Trastuzumab use60-64 yo vs 85+
36% vs 6%p<.001
Moran, EBCC-9, abstract 415
Trastuzumab use60-64 yo vs 85+
36% vs 6%p<.0010
20
40
60
80
100
60-64 65-69 70-74 75-79 80-84 85+
(%)
Figure 2: Percentage of women with stage 1 or 2 dis ease and a Charlson score of 0 who underwent surgery (n=850)
p <0.001
Moran, EBCC-9, abstract 415
15
En pratique…
• 1.009 MBC65-74A 500> 75A 509
• 107 oncologues
Freyer Ann Oncol 2006
Le cancer du sein de la femme âgée se prête volontiers à
l’hormonothérapie car il est plus souvent RH+
Mais entre anti-aromatase (letrozole/FEMARA, anastro zole/ARIMIDEX, exemestane/AROMASINE et anti-oestrogène (tamoxifène) ,
la question de l’observance est majeure (et donc l’aju stement à la tolérance)
En contexte adjuvant/précoce, l’hormonothérapie se do nne 5 ans en général (discussion sur les extensions au delà)
En contexte métastatique, l’hormonothérapie est le tra itementgénéralement de première intention (phénotype RH+ fré quent)
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SERM = Anti-oestrogènesSelective Estrogen Receptor Modulators
• 35 ans d’utilisation• Standard
Déplétion en oestrogènes au mieuxréalisée par une inhibition spécifiquede l’aromatase qui convertit lesprécurseurs des oestrogènesen oestradiol et oestrone
Analogues dela LHRH
Progestatifs
Age Tamoxifène vs 0 Chimiothérapie vs 0
Rechute Mortalité Rechute Mortalité
< 40 44±10 39±12 40±6 29±7
40-49 29±7 24±9 36±4 30±5
50-59 34±5 24±7 23±3 15±4
60-69 45±5 35±6 13±3 9±4
≥ 70 51±12 37±15 12±11 13±12
Réduction (%) des risques annuels de rechute / mort alité
EBCTCG Lancet 1998 & 2005
Leçons des méta-analyses
17
• TAM / 0
15105
60 %
50 %
40 %
30 %
20 %
10 %
rech
ute
26,5
38,3
45,0
24,7
15,1
33,2
contrôle
TAM 5A
• IA / TAM
Réduction du risque de rechute
Bénéfice absolu à 10 ans
RO+ 41 % 13,6 %
Réduction du risque de rechute
Bénéfice absolu à 10 ans
RO+ Post-MP
20 % 5 %
AI 5A
ATAC
0,30 0,50 0,60 0,80 1,00 1,25 1,50 2,00
BIG 1-980,82 (0,67-0,99) 0,045143<<<< 65
0,79 (0,64-0,97) 0,022867≥≥≥≥ 65
<<<< 65 5137
≥≥≥≥ 65 4229
ITA
0,20
≤≤≤≤ 65 nr nr
>>>> 65 nr nr
0,63 (0,40-1,00) 0,051265
≥≥≥≥ 60 0,58 (0,39-0,87) 0,081959ABCSG / ARNO
<<<< 60
nr nr
nr nr
nr
nr
No analysis according age in IES and ABCSG-6
TAM superiorAI superior
HR (CI 95%) pN
Bénéfice des IA selon l’âge
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Cancer controlatéral
Ostéoporose
Myalgies
Hyperlipidémie
TAM IA
Cancer controlatéral
Thromboses
K endomètre
Bouffées de chaleurNeurocognition
Fonction sexuelle
Hyperlipidémie
Cardiovasculaire
Bouffées de chaleur
Thromboembolies
K endomètre
Signes génitourinaires
Arthralgies/myalgies
Ostéoporose
?
Fractures
Etude Suivi(m)
AnnéessousTAM
IA(%)
Comparateur(%)
p
ATAC 68 0 ANA (11.0) TAM (7.7) < 0.0001
ATAC 33 0 ANA (5.9) TAM (3.7) < 0.0001
ARNO 95ABCSG 8
28 2-3 ANA (2) TAM (1) 0.015
BIG 1-98 25.8 0 LET (5.6) TAM (4.0) < 0.001
IES 55.7 2-3 EXE (7.0) TAM (4.9) 0.003
MA.17 30 4-6 LET(5.3) Placebo (4.6) 0.25
Et jusqu’à 80% d’arthralgies en plus….(20.3% vs 12.3%, p < 0.001 BIG 1-98)
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Morales, L. et al. J Clin Oncol; 26:3147-3152 2008
Getting a grip on aromatase inhibitor–associated arthr algiasDawn L. Hershman
La chimiothérapie, c’est plus compliqué…
Car index thérapeutique plus étroit que l’hormonothéra pie
Des doses généralement ajustées (inférieures)
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Physiological variations x PK & PD
Mechanism Consequences
AbsorptionGastric dumping and secretions �
Absorption of proteins, vitaminsand drugs �
MetabolismHepatocytes, blood flow, CYP P450 activity �Interactions (CYP P450)
Protein synthesis, (de-) activation of drugs and carcinogens �
Distribution H2O, albumin, Hb �Vd hydrosolubles drugs �
Vd liposolubles drugs �
ExcretionGFR, tubular filtration �Biliary excretion �
Renal elimination of drugsexcreted by kidney �
Biliary elimination �
Balducci. Oncologist 2000; Wildiers. Clin Pharmacoki net 2003; http://www.ema.europa.eu
Les grands médicaments
• Anthracyclines (adriamycine, épirubicine, schémas FEC 100 ou AC)– Myélotoxicité– Cardiotoxicité
• Alkylants (cyclophosphamide/Endoxan®, schéma FEC 100 ou AC)– Myélotoxicité– Attention à la fonction rénale
• Taxanes (docetaxel/Taxotère®, paclitaxel/Taxol®)– Myélotoxicité– Neuropathie– Onycholyse– Rétention hydrique
• Antimétabolites (5-flurorouracile, forme orale = capecitabine/Xeloda®)– Syndrome mains pieds– Diarrhée
40
21
Chimiothérapie
• Des doses spécifiques– CMF et adaptation du CPA à la fonction rénale– Xeloda® 1000 mg/m² x 2/J– Taxol® < 80 mg/m²/s– Taxotère® : PK identique mais risque accru de
neutropénie ± fièvre > 65A• q3w 75 mg/m² 63% et 16% vs 30% et 0%• qw 35 mg/m² > 50% grade ≥ 3 (RD : 26 mg/m²)• q2w 50 mg/m² GERICO-04
Gelman JCO 1984, Crivellari JCO 2000, Bajetta JCO 2005Del Mastro Ann Oncol 2005, ten Tije JCO 2005
La chimiothérapie adjuvante « marche » si on est attentif aux
effets secondaires…
22
DFS
OS
• CALGB (1975-1999)
• 4 randomized trials
• 6487 pts> 65 yo 542 (8%)> 70 yo 159 (2%)
• Results– Benefit identical– Toxicity careful!!
• Toxic deaths 1.5%
Adjuvant chemo for breast cancerAll
All
≤50
≤50
≥65
≥6551-64
51-64
Muss, JAMA 2005
0
0.2
0.4
Cumulative proportion with event
0.6
0.8
1.0Hazard ratio (>65: ≤6≤6≤6≤65) = 2.2595% CI of (>65: ≤≤≤≤65) = (1.04–4.86)Log rank p-value = 0.029Wilcoxon p-value = 0.78
0 200 300 400 700 800 900 1000Cumulative dose of doxorubicin (mg/m 2)
600500100
468172
345110
29692
10328
61
41
203
5912
431!51
≤≤≤≤65*>65*
*Patients at risk
≤≤≤≤65
>>>>65
Doxorubicine, cardiac heart failure(CHF) and ageDoxorubicine, cardiac heart failure(CHF) and age
• 630 patients (3 phase III) with 32 CHF– 26% >550 mg/m²– >50%: reduction of LVEF <30% w/CT
• HRage 2.25 (1.04–4.86) vs 3.28 (1.4–7.65) if >400 mg/m²
Swain. Cancer 2003
23
Doxorubicin, CHF and age
• SEER 1992-2002: 43,338 women 66-80 years, no CHF history– stage I to III BC, chemotherapy vs no– AC: younger, fewer comorbidities, advanced (p=.001)– CHF10 years (%)
Pinder. J Clin Oncol 2007
ACN = 4,712
Other chemoN = 3,921
No chemoN = 34,705
38.4 32.5 29
• 66-70 years HR 1.26 (95% CI, 1.12-1.42) if AC• 71-80 years no impact of CT type
Baseline HR (95%CI)
Age (decade) 1.79 (1.66-1.93)
Black 1.40 (1.30-1.50)
Trastuzumab 1.46 (1.21-1.77)
Hypertension 1.45 (1.39-1.52)
Diabetes 1.74 (1.66-1.83)
Coronary 1.58 (1.39-1.79)
Left XRT 1.04 (0.98-1.11)
… mais principalement si ER- !
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Giordano* Elkin
No. total
No. w/CT
I-III, ∀∀∀∀ ER , 65+41,390
4,500
I-III, ER-, 66+5,081
1,711
pN ER HR (95% IC) HR (95% IC)pN0 ∀∀∀∀ 1.05 (0.85-1.31) NA
pN+ + 1.05 (0.85-1.31) NA
both - NA 0.85 (0.77-0.95)
pN+ - 0.72 (0.54-0.96) 0.76 (0.65-0.88)
pN+ > 70 yo - 0.74 (0.56-0.97)
Giordano & Elkin. J Clin Oncol 2006
Adjuvant chemotherapy and mortality
Adjuvant chemo is useful FIRST
in ER-, pN0 or pN+, even > 70 yo
*: BC specific mortality
CALGB / CTSU 49907CALGB / CTSU 49907
• 9/2001-12/2006
• 633 pts ≥ 65 yo
– 65% 70+
– 55% pT > 2 cm
– 71% pN+
– 68% ER+
• Non-inferiority trial
• Median folow up 2.4 years
• Capecitabine vs standard
– RFS3A 68% vs 85%
– OS3A 86% vs 91%
– Toxicity 33% vs 64%
• Capecitabine
– 76% compliance (> 80%)
• AC & CMF > capecitabine
– Interaction +++ if ER-
– HRRFS 4.39 (95% CI: 2.9-6.7)
– HROS 3.76 (95% CI: 2.23-6.34)j
Muss NEJM 2009
> 65A6 CMF or 4 AC
6 capecitabine
25
All
ER-
ER+
DFS OS
Muss, NEJM 2009
CALGB / CTSU 49907 (AC or CMF vs X)
We may try to avoid the risk of cardiotoxicity induced by
anthracyclines: TC & liposomal doxorubicin
26
Jones, S. et al. J Clin Oncol; 27:1177-1183 2009
Fig 1. Disease-free survival (DFS) and overall surv ival (OS) (A) DFS by treatment; (B) DFS by treatmen t and age; (C) OS by treatment: 1 day; (D) OS by trea tment and age
GERICO 06 (EUDRACT N°2005-000069-20, PHRC national 2005)
MC MC MC MC XRT
ADLTolerance
CGAADL + MNA +MMS + GDS +
CIRSG
QLQ-C30Willingness
CGAADL + MNA +MMS + GDS +
CIRSG
QLQ-C30WillingnessTolerance
CGAADL + MNA +MMS + GDS +
CIRSG
QLQ-C30WillingnessTolerance
1 & 2 yearDFS & OS
ADLTolerance
ADLTolerance
± trastuzumab
if HER2+++
trastuzumabif HER2+
q3w q3w q3w
4 cycles of “AC-like” chemoIn MC, M stands for liposomal non pegylated doxorubic in
27
1. Neutropénie fébrile 15%2. Risque dénutrition 15% vs 38%3. Impact QoL (social & role
functioning)4. Tolérance cardiaque du
trastuzumab5. Pas d’EPP6. DFS3A 85%
Kaplan–Meier survival analysis.
F. Perrone et al. Ann Oncol 2015;annonc.mdu564
© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.
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Mean differences in QoL scores of items presenting statistically significant differences at one or more time-points.
F. Perrone et al. Ann Oncol 2015;annonc.mdu564
© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.
Green bars: CMFBlue bars: weekly docetaxel
Chimiothérapie
� Rappel des recommandations précédentes pour ER- prin cipalement�Schémas validés
� 4 AC 1A� 6 CMF 1A
�Schéma optionnel : TC� 4 TC > 4 AC 2B
– Analyse post hoc de sous-groupe d’un essai randomisé, n ~ 80�! Capecitabine 2A
� Schéma séquentiel�Pas de données
� Analyse de toxicité rassurante�TC 2B�MC 4C
� Discuter systématiquement prophylaxie primaire GCSFAccord professionnel
� Pas de restriction sur trastuzumab si chimiothérapie indiquée
Brain, Oncologie 2011
29
Biganzoli, Lancet Oncol 2012
Targeted treatments
Lack of specific data!But clinical evidence for benefit
30
Tyrosinekinase
domain
Ligand-bindingdomain
Erb-B1EGFRHER1
Erb-B2HER2/neu
Erb-B3HER3
Erb-B4HER4
Trans-membrane
TGF-αEGFEpiregulinBetacellulinHB-EGFAmphiregulin
Heregulin(neuregulin-1)
Heregulin(neuregulin-1)EpiregulinHB-EGFNeuregulins-2,3,4
Trastuzumab
Piccart NEJM 2005
> 60 yo ≤≤≤≤ 16%
31
The incidence of CHF from the Finnish Herceptin Stud y (FINHER), Herceptin Adjuvant trial (HERA), Breast Cancer International Collaborative Group trial 006 (006) with TCH and AC-TH analyzed separately, the No rth
Central Cancer Treatment Group trial 9831 (N9831), and NSABP B-31 (B-31).
Bird B R H , Swain S M Clin Cancer Res 2008;14:14-24
©2008 by American Association for Cancer Research
• NSABP B31– Age
– 2% < 50 yo vs 5.4% > 60 yo– LVEF > 4 AC
– 12% if LVEF < 55%– Concomitant > sequential– Hypertension comedications
• B31/N9831– 6.7% pts who had completed AC had a lower LVEF or
developed cardiac symptoms preventing the initiation of TZT
– 1/3 pts who started TZT discontinued it: 4.7% with symptomatic CHF, 14.2% with confirmed asymptomatic decline in LVEF, and the rest for noncardiac reasons
• SEER database• 2,028 patients ≥ 66, stage I-III, 2005-2009, trastuzumab
– 71.2% < 76
– 66.8% w/o comorbidities (Charlson)
– 85.2% w/ chemotherapy
– 81.7% w/ complete trastuzumab treatment (> 9 months)
– Factors correlated w/ incomplete treatment• Age 80+ vs 66-70 OR 0.40 (0.30-0.55)• Comorbidities 2 vs 0 OR 0.65 (0.49-0.88)
Vaz-Luiz. J Clin Oncol 2014
32
Bevacizumab(Avastin®)
Miller N Engl J Med 2007
> 65 yo ≤ 20%
MBC L1
ATE eventsChemo only
N = 782
Chemo + beva
N = 963
Global 1.7 3.8
No risk factor 1.0 1.8
< 65 yo 1.4 2.1
≥≥≥≥ 65 yo (N = 279) 2.5 7.1
Previous history of ATE 3.4 15.7
≥≥≥≥ 65 yo and previous history 2.2 17.9
Scappaticci. J Natl Cancer Inst 2007
ATE and bevacizumab (various cancers)(ATE = arterial thrombo embolism)
33
%< 70
N = 2018
70+
N = 233*
HTN grade ≥ 3 4.2 6.9
Proteinuria grade ≥ 3 1.5 4.0
ATE (A or V) 3.3 2.9
Stop for toxicity
ATE
CHF
15
1.8
0.3
23
2.9
0.6
HTN 1.8 2.9
Biganzoli. Annals Oncol 2011
ATHENA: CT wo/anthracyclines + beva(breast cancer only)
*175 (7.8%) 70+, 51 (2.3%) 75+, 7 (0.3%) 80+
34
Signatures ?
40 %
15 %
Mammaprint®
25,000 genes, 78 tumours, 70 genes, 17 pN0, all < 5 5 yo
van’t Veer, Nature 2002; van de Vijver, NEJM 2002
295 pts < 53 yo
35
MINDACT
• 6,600 pts < 70
– FEB 2007-AUG 2011– 11,291 registered pts– 6,673 enrolled (59.1%)
Radiothérapie
37
XRT
• Pathologie faible risque– Schémas hypofractionés– Irradiation partielle accélérée� Amélioration logistique/accès aux soins
• Omission si pT1 ER+ ?– Surtout si > 80A, comorbidités, bonne observance HT
• CALGB 9343 Hughes ASCO 2010 et NEJM 2004
Khan, Semin Radiat Oncol 2012
Problèmedémographique
Rechercheclinique
peureprésentée
Mortalitéspécifique
et effetssecondairessignificatifs
Phénomène hétérogène
Espérance de vie ou
pronostic « hors cancer »
?
38
Traitement avant et après un certain âge…
• Sujet jeune– Obligations sociales et
familiales (enfants)– Quantité de vie
• Oncologue– Thérapeutique et innovation– Toxicité, réponse, survie
• RECIST• NCI CTC v4.0• Survie
– DFS, PFS, DDFS– OS
– Rapidité– « Portrait moléculaire » de la
tumeur & signatures
• Sujet âgé– QoL+++, indépendance,
cognition– Rester à la maison
• Gériatre– Séméiologie, diagnostic– Qualité de survie, quantité de
vie de qualité• Cognition• Indépendance• Statut fonctionnel• QoL
– Temps– « Portrait global » du patient &
EGA
EGA
Definition of “old” x ageing heterogeneity
Age Top 25 th%Fit
50th%Intermediate
Lowest 25 th%Sick
50 40 33 24.5
70 21.3 15.7 9.5
75 17 11.9 6.8
80 13 8.6 4.6
85 9.6 5.9 2.9
90 6.8 3.9 1.8
95 4.8 2.7 1.1
Women life expectancy
Walter. JAMA 2001
39
Comorbidity across ageComorbidity across age
Piccirillo. Critical Rev Oncol Haematol 2008
dementia CHF
solid tumour AIDS
diabetes hypertension
Co-morbidity @ AgeingStats.Gov
http://www.agingstats.gov/Agingstatsdotnet/Main_Sit e/Data/2008_Documents/Health_Status.aspx
40
Competing causes of mortality
Deaths attributed to the primary cancer (solid dots) and those attributed to comorbidity (open circles)
Cumulative probability of
death
Cumulative probability of
death vs attained age
CompetingHR of death
Kendal. Cancer 2008
Breast NHL
Quels outils ??
41
Comprehensive Geriatric AssessmentEvaluation Gériatrique Approfondie
Balducci Oncology 2006
Paramètres Outils Impact
AutonomiePS, Activity of Daily Living Scale (ADL), Instrumental Activity of Daily Living Scale (IADL)
Espérance de vie, dépendance, stress
Comorbidités Nombre, sévérité (Index de comorbidités)Espérance de vie, stress (pronostic ?)
Socio-économique Conditions de vie, aidants, soignants
Cognition Folstein Mini-mental status (MMS)Espérance de vie, dépendance
Emotion Echelle de dépression gériatrique (GDS)Survie (motivation au traitement ?)
Médicaments N, indications, interactions Interactions
Nutrition Mini Nutritional Assessment Scale (MNA) Réversible (survie ?)
Syndromes gériatriques Démence, délire, chutes Survie, dépendance
Impact of CGA on treatment decisions?YES and feasible!
ELCAPA 01 Créteil, France
• 375 patients ≥ 70 yo w/CGA– Age 79.6±5.6– 53% women, 59% GI tumours– Number of comorbidities 4.2±2.7,
CIRSG 11.8±5.3
• Modification of the initial therapeutic decision > CGA– 21% (95%CI 16.8-25.3) of which
81% with de-escalation– Univariate/multivariate analysis
• PS ≥ 2 (73% vs 41%)• ADL (59% vs 24%)• Malnutrition (82% vs 51%)• Cognitive defects (39% vs 25%)• Depression (53% vs 22%)• Comorbidities (4.8±2.9 vs 4.0±2.6)
Leuven
• 1,967 patients ≥ 70 yo, 10 hospitals– G8 + CGA if impaired (≤14/17)– 70.7% abnormal G8 score
warranting a CGA– 51.2% unknown geriatric
problems
• Physicians aware of the GA results at the time of treatment decision in 1,115 patients (61.3%)– Treatment decision influenced
282 patients (25.3%)– Geriatric interventions :
286 patients (25.7%)
• Feasible
Caillet, J Clin Oncol 2011; Kenis, Ann Oncol 2013
42
5 key messages for elderly BC patients
1. Under and over-treament are frequent2. Access to innovation is unbalanced3. Geriatric problems are far more frequent than usually
believed– 2/3 impaired G8, > 50% functional dependence, >10% cognitive
dysfunctions, 20% depression, > 40% significant comorbidities, > 50% risk of malnutrition, polypharmacy, etc.
4. ���� Comprehensive Geriatric Assessment CGA– Brings to clinicians new information in > 2/3 cases– Modifies clinical decision in 20-25% cases (function & nutrition)
5. Competing risks for mortality� call for a certain degree of assessment of life
expectancy to balance treatment decision
Caillet. J Clin Oncol 2011; Kenis. Ann Oncol 2013Bode. EBCC9 2014, abstract 414
Mieux utiliser l’EGA = dépister
44
G8 - Oncodage
• G8 vs VES 13– Sensibilité 76.6 vs 68.7%– Spécificité 64.4 vs 74.3%– Les 2 2 ~ 4’
• ~ 2/3 des patients 70+ ont un G8 ≤ 14/17
Recommandations INCa 2011/2012(UPCOG/UCOG)
���� patients 75+ avec score ≤≤≤≤ 14
EB
Recherche
Il faut des essais spécifiques !!
45
Sous-représentation dans les essais
• SWOG– 164 études (1993-1996)– 16.000 sujets
• FDA– 55 études AMM– 29000 sujets
> 65A
> 65A 59% cancers vs 33% inclusions> 75A 30% cancers vs 10% inclusions
Hutchins NEJM 1999; Talarico J Clin Oncol 2004Scher & Hurria J Clin Oncol 2012
GERICO (UNICANCER)c-orsini@unicancer.fr
e.brain@curie.fr
46
GERICO ≥ 1,500 patients2002 Création (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: XRT interst per op breast < 3 cm pN0 70+ IIFaisabilité
Qualité40 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 RH- 70+ II ADL 40 Accept CROH 2010
2008 G-07 : validation CRASH 70+ Cohorte Composite NA NA NA
Sarcoma Aegide + G-CSF 70+ II R Composite NA NA NA
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 Poster
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+ II R / III Composite 102 CTC/RX
2011 ASTER 70s/G-11/PACS 10 : CT adj breastRH+ HER2- GGI
70+ IIIOS
(competing risks)651/700
582/1,300Biomarkers
CostPoster, Oral
2012 ELAN (PAIR ORL, GORTEC/GERICO) 70+ Multiple OS 380
SHS (cognition, acceptability, etc.) 70+ SHS Poster
2013 Project frail lung (GFPC/GERICO) 70+ III OS ND
2014 UCGI-30 (G-12) XRT/CTneo vs XRT rectum 75+ III R0 + IADL 400
2014 ASTER 2 (G-13) + EORTC/int’l HER2 70+ III Outcome + QoL 1,200
2014 Pain (intergroupe soins support AFSOS) 70+ Cohorte Description > 1,000
GERICO 06 (EUDRACT N°2005-000069-20, PHRC national 2005)
MC MC MC MC XRT
ADLTolerance
CGAADL + MNA +MMS + GDS +
CIRSG
QLQ-C30Willingness
CGAADL + MNA +MMS + GDS +
CIRSG
QLQ-C30WillingnessTolerance
CGAADL + MNA +MMS + GDS +
CIRSG
QLQ-C30WillingnessTolerance
1 & 2 yearDFS & OS
ADLTolerance
ADLTolerance
± trastuzumab
if HER2+++
trastuzumabif HER2+
q3w q3w q3w
4 cycles of “AC-like” chemoIn MC, M stands for liposomal non pegylated doxorubic in
47
1. Neutropénie fébrile 15%2. Risque dénutrition 15% vs 38%3. Impact QoL (social & role
functioning)4. Tolérance cardiaque du
trastuzumab5. Pas d’EPP6. DFS3A 85%
Priorités ?
1. CGA : impact pronostique sur le cancer2. Traitements anti-cancéreux chez les sujets âgés « plus
vieux » (75+, octogénaires, nonagénaires, centenaires)3. Traitements anti-cancéreux chez les sujets
fragiles/vulnérables (à tout âge ?)4. Score gériatrique minimal5. Critères principaux de jugements spécifiques (extraits
de l’EGA, critères composites/co-critères)6. Biologie de transfert (cancer et vieillissement)
Intergroupe GERICO/UCOG(recherche clinique en oncogériatrie)
labelisé par l’INCa en 2014
48
To demonstrate the impact of geriatric assessment o n cancer prognosis in the elderly cancer population?
• PREPARE program (French PHRC 2013-2014)– Initial cares with first or second line chemotherapy
• L1: breast, CRC, gastric, lung, prostate, bladder, ovarian, myeloma, NHL
• L2: breast, CRC, prostate, myeloma, NHL
– Primary endpoint: 1-yr OS (+10%) & HrQoL (+10 points)
P Soubeyran
> 14 ���� Standard treatment
≤14
Standard treatment
Case management ("G8-guided", nurse, geriatrician, etc.)
> 70AL1 or L2
Soubeyran. PHRC 2013-2014
R1:1
G8
Protocol ASTER 70s
GERICO 11 / PACS10
Adjuvant systemic treatment for oestrogen-receptor (ER)-positive HER2-negative breast carcinoma in women over 70 according to
Genomic Grade (GG): chemotherapy + endocrine treatment versus endocrine treatment. A French UNICANCER Geriatric Oncology Group
(GERICO) and Breast Group (UCBG) multicentre phase III trial
MicroarrayqRT-PCR
CGA
EUDRACT N 2011-004744-22, PHRC national 2011, NCT015 64056
49
Toussaint, BMC Genomics 2009
8 genes (4 reporter + 4 reference)9 genes (6 reporter + 3 reference)
http://www.eprognosis.org/
50
Lee. JAMA 2006
4-year mortality score in general elderly populatio n
Health retirement study
• > 50 yo (40% > 70 yo)
− Construction 11,701 subjects
− Validation 8,009 subjects
R**
1:1
All patientsLee ScoreG8, CCI
Polymedications
Genomic Grade(GG)
evaluation
CCIPolymedications
Events
Group IILow GG
NO CHEMOTHERAPY IS RECOMMENDED - Follow up
Cy1+ GCSF
Cy2+ GCSF
Cy3+ GCSF
Cy4+ GCSF
q3w q3w q3w
HT 5 yr
Group I**High GG
Arm B = CT + HT
Arm A = HT HT 5 yrXRT
XRT
baseline 16 weeks 1, 2, 3 & 4 year
1, 2, 3 & 4 year
MMSE, IADLQLQ C30 & ELD15LVEFSocioeconomicStandard Lab
1 blood + serum
PolymedicationsMMSE, IADLQLQ C30 & ELD15LVEFSocioeconomicWillingnessStandard Lab1 blood + serum
G8, CCIPolymedicationsMMSE, IADLQLQ C30 & ELD15LVEFSocioeconomicWillingness
Standard Lab every year
1 blood + serum (M12 & M48)
Events
Chemo toleranceStandard Lab
Completecurativesurgery
Screening
** Group I include both high and equivocal GG cases
*Randomization stratified on pN, G8 and centre
time
GERICO 11 (EUDRACT N°2011-004744-22, PHRC national 2011, NCT0 1564056)
2,000
1,100
900
51
August 31st 2014
1391
738
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
< 65AN (%)
> 65AN (%)
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)
52
A frailty revealed… and assessed
• 2006: Mrs BON… IR… 84 yo– No previous medical history (high blood sugar?)– Husband: 86 yo w/ severe advanced Parkinson, 2 children– Breast self exam � T1c N0 M0 left breast– 54 kg/167 cm, BMI 19.4 (<25)
• Conservative surgery + axillary lymph node dissection– Invasive ductal carcinoma, 17 mm, SBR II, 8 N-– ER- PgR-, Ki 67 40%, HER2-
• Adjuvant strategy– Chemotherapy with anthracylines (GERICO 06)? + XRT
• Scoring– Oncologist: PS 0 � “Easy! Go for it“– Geriatrician
• Functional status, cognition, nutrition, GDS � OK• However! 3 falls < 1 year
+5
+1
+1
���� Lee 7 ~ 50% 4-yr mortality
FEC, AACR, FAC, ASCO, CMF, DXR, PK/PD, CEX, 5FU CDDP, Calvert AUC, ESMO, Chatelut
AUC, CTC, population PK, FOLFIRI, FOLFOX 7, CPA, DFS, DDFS, OS, TTP, NCI, CYP P450, JCO, JNCI, HER2, PI3K, mTOR, Phase 0, ECCO, ib and ab…etc.
Charlson, CIRSG, CGA, MNA, GDS, MMS, ADL,
IADL, GFI, CMR2, JAGS, G8, Oncodage, VES-13,
TRFs, JGO, NIA, Walter’s score, Lee’s
score…etc.
53
FEC, FAC, ADL, IADL, CMF, DXR, PK/PD, CEX, 5FU CDDP, Calvert and Chatelut AUC, GDS, population PK, FOLFIRI, MMS, FOLFOX, CPA, DFS, OS, TTP, NCI, GERICO, EORTC TFE, JCO, JNCI, Charlson, JGO, CIRSG, EGS, EGA, MNA, GFI, Lee’sscore, JAGS…etc.
Multidisciplinarité en 2006 ?
Freyer Ann Oncol 2006