Cancer du sein et sujet âgé - Longue Vie et Autonomie · 2015-03-25 · Cancer du sein et sujet...

1

Cancer du sein et sujet âgé

Docteur Etienne BrainOncologie Médicale

Hôpital René Huguenin / Institut CurieSaint-Cloud, France

[email protected]

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

7

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)

8

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


13

Trastuzumab use60-64 yo vs 85+

36% vs 6%p<.001


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


14

Présentation clinique

Freyer Ann Oncol 2006

Les traitements

15

En pratique…

• 1.009 MBC65-74A 500> 75A 509

• 107 oncologues


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)

16

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

18

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)

19

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)

20

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- !

24

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


CIRSG

QLQ-C30WillingnessTolerance


CIRSG


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: [email protected].

28

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: [email protected].

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

43

Screeningpour oncodage…

…ou "screenage"pour onco dingues !

G8

EB

Le G8

FR

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)[email protected]

[email protected]

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


CIRSG

QLQ-C30Willingness


CIRSG



CIRSG


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 ?


54

En 2015 ??

??

20%

40%

?

15th SIOG Conference - Prague, Czech Republic

Geriatric oncology and Supportive Care: A global Ap proach to Advance the Science

SAVE THE DATE - 12 to 14 November 2015

Cancer du sein et sujet âgé - Longue Vie et Autonomie · 2015-03-25 · Cancer du sein et sujet...

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Transcript of Cancer du sein et sujet âgé - Longue Vie et Autonomie · 2015-03-25 · Cancer du sein et sujet...