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Cancer du sein et sujet âgé
Docteur Etienne Brain
Oncologie Médicale
Hôpital René Huguenin / Institut Curie
Saint-Cloud, France
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
… 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)
Current dilemna and extreme positions
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
2009
2050
http://www.un.org/esa/population/publications/ageing/ageing2009chart.pdf
We live in an era of unprecedented,
rapid and inexorable global ageing
China has the largest elderly population (92 million)… but
this is only 7% of the Chinese population!!!
www.worldmapper.org
Projected number of cancer cases for 2000–2050 by age group (<45, 45–64, 65–84, 85+) based on projected census population estimates and delay-adjusted 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
Binder-Foucard INCa report 2013
De Angelis Lancet Oncol 2013
Relative survival accounts for
mortality from causes other than
the relevant cancer, which can
vary widely between countries
Breast
Ovary
2007 1991 2002
2013 2015
• 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
Phénotype
Plus de formes hormonosensibles (RH+)
Moins de formes agressives (triple négatif, HER2+++)
0
10
20
30
40
50
60
70
80
90
100
20 - 29 30 - 39 40 - 49 50 - 59 60 - 69 70 - 79 > 80
ER+
PgR+
ER-PgR-
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)
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 ; Sotiriou, PNAS 2003
Reis 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
Dépistage
Pas d’indication d’extension du dépistage de masse > 74A (stades plus précoces dépistés mais aucun bénéfice démontré sur survie)
Mais dépistage individuel à poursuivre selon état de santé
Aucune étude conduite spécifiquement sur cette population
Breast-cancer screening > 70?
19
Warner NEJM 2011; Royce JAMA 2014; Gross JAMA 2014
Age
(yr)
Nb of trial(s) Relative risk
of death (95%CI)
60-69 Malmö &
Ostergöland
0.68 (0.54-0.87)
70-79 Ostergöland 1.12 (0.73- 1.72)
75+: YES YOU CAN, but
– No mass screening
– Depends on life expectancy
Prise en charge initiale
Retard fréquent… d’où des stades plus tardifs
Des standards fréquemment non respectés (sous-traitement)
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)
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
Trastuzumab use
60-64 yo vs 85+
36% vs 6%
p<.001
Moran, EBCC-9, abstract 415
Trastuzumab use
60-64 yo vs 85+
36% vs 6%
p<.001 0
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 disease and a Charlson score of 0 who underwent surgery (n=850)
p <0.001
Moran, EBCC-9, abstract 415
Radiothérapie
Hughes J Clin Oncol 2013
After BCS: TAM vs XRT + TAM (CALGB 9343)
334/636 deaths
(21 i.e 6.3% due to BC)
Radiotherapy
• Omission if pT1 ER+? (NCCN)
– According to life expectancy
– > 80 yo, multi-morbidities, good compliance to endocrine treatment?
• Low risk patients
– Once-per-week fraction schedule (Whelan regimen)
– Accelerated partial breast irradiation (APBI)
• Larger radiation doses given to the localized tumour bed (instead of to the
entire breast)
Spare extensive and burdensome transportations
But don’t neglect the psychological burden of recurrence!
Khan Semin Radiat Oncol 2012
Les traitements
En pratique…
• 1.009 MBC
65-74A 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, anastrozole/ARIMIDEX,
exemestane/AROMASINE et anti-oestrogène (tamoxifène),
la question de l’observance est majeure (et donc l’ajustement à la
tolérance)
En contexte adjuvant/précoce, l’hormonothérapie se donne 5 ans en
général (discussion sur les extensions au delà)
En contexte métastatique, l’hormonothérapie est le traitement
généralement de première intention (phénotype RH+ fréquent)
SERM = Anti-oestrogènes Selective Estrogen Receptor Modulators
• > 35 ans d’utilisation
• Standard
Déplétion en oestrogènes au mieux
réalisée par une inhibition spécifique
de l’aromatase qui convertit les
précurseurs des oestrogènes
en oestradiol et oestrone
Analogues de
la LHRH
Progestatifs
Castration
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 / mortalité
EBCTCG Lancet 1998 & 2005
Leçons des méta-analyses
• TAM / 0
15 10 5
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 1-98 0,82 (0,67-0,99) 0,04 5143 65
0,79 (0,64-0,97) 0,02 2867 65
65 5137
65 4229
ITA
0,20
65 nr nr
65 nr nr
0,63 (0,40-1,00) 0,05 1265
60 0,58 (0,39-0,87) 0,08 1959 ABCSG / ARNO
60
nr nr
nr nr
nr
nr
No analysis according age in IES and ABCSG-6
TAM superior AI superior
HR (CI 95%) p N
Bénéfice des IA selon l’âge
COMPLIANCE
is the issue!!!
TAM AI
Neurocognition
Sexuality
Hot flushes
Thrombosis & embolism
Uterus cancer
Gynecological tractus
Vaginal discharge
Cataract
Arthralgias & myalgias
Osteoporosis
Fractures
Dryness
Cardiovascular
Lipid profile
?
Fractures
Etude
Suivi
(m)
Années
sous
TAM
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 95
ABCSG 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)
Copyright © American Society of Clinical Oncology
Morales, L. et al. J Clin Oncol; 26:3147-3152 2008
Getting a grip on aromatase inhibitor–associated arthralgias
Dawn L. Hershman
La chimiothérapie, c’est plus
compliqué…
Car index thérapeutique plus étroit que l’hormonothérapie
Des doses généralement ajustées (inférieures)
Physiological variations x PK & PD
Mechanism Consequences
Absorption Gastric dumping and
secretions
Absorption of proteins, vitamins
and drugs
Metabolism
Hepatocytes, 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
Excretion GFR, tubular filtration
Biliary excretion
Renal elimination of drugs
excreted by kidney
Biliary elimination
Balducci. Oncologist 2000; Wildiers. Clin Pharmacokinet 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
41
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 2005
Del Mastro Ann Oncol 2005, ten Tije JCO 2005
La chimiothérapie adjuvante
« marche » si on est attentif aux
effets secondaires…
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 cancer All
All
≤50
≤50
≥65
≥65 51-64
51-64
Muss, JAMA 2005
0
0.2
0.4
Cumulative proportion with event
0.6
0.8
1.0 Hazard ratio (>65:5) = 2.25
95% CI of (>65: 65) = (1.04–4.86)
Log rank p-value = 0.029
Wilcoxon p-value = 0.78
0 200 300 400 700 800 900 1000
Cumulative dose of doxorubicin (mg/m2)
600 500 100
468 172
345 110
296 92
103 28
6 1
4 1
20 3
59 12
431 !51
65* >65*
*Patients at risk
65
65
Doxorubicine, 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
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
AC N = 4,712
Other chemo N = 3,921
No chemo N = 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)
Meta-analysis
2012
EBCTCG Lancet 2012
• Decrease of BC mortality ~ 33% – 4 anthra + 4 taxanes > 4 anthra
• RR 0·86, SE 0·04, 2p=0·0005
– 4 anthra + 4 taxanes ~ 8 anthra • RR 0·94, SE 0·06, 2p=0·33
– 4 AC = 6 CMF • RR 0·98, SE 0·05, 2p=0·67
– FAC ou FEC > CMF • RR 0·78, SE 0·06, 2p=0·0004
– 4 FAC > 4 AC ou CMF (vs no CT) • RR 0·64, SE 0·09, 2p<0·0001
• RR 0·78, SE 0·09, 2p=0·01
• RR 0·76, SE 0·05, 2p<0·0001
• No influence – Age (but mostly < 70 yo)
– pT, pN
– Differentiation, ER
– TAM
• Impact varies according to risk – Low risk reduced absolute
benefit
… mais principalement si ER- !
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 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
> 65A
6 CMF or 4 AC
6 capecitabine
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
Copyright © American Society of Clinical Oncology
Jones, S. et al. J Clin Oncol; 27:1177-1183 2009
Fig 1. Disease-free survival (DFS) and overall survival (OS) (A) DFS by treatment; (B) DFS by treatment and age; (C) OS by treatment: 1 day; (D) OS by treatment and age
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
1. Neutropénie fébrile 15%
2. Risque dénutrition 15% vs 38%
3. Impact QoL (social & role
functioning)
4. Tolérance cardiaque du
trastuzumab
5. Pas d’EPP
6. 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].
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: CMF
Blue bars: weekly docetaxel
Targeted treatments
Lack of specific data!
But clinical evidence for benefit
Tyrosine
kinase
domain
Ligand-
binding
domain
Erb-B1
EGFR
HER1
Erb-B2
HER2/neu
Erb-B3
HER3 Erb-B4
HER4
Trans-
membrane
TGF-α
EGF
Epiregulin
Betacellulin
HB-EGF
Amphiregulin
Heregulin
(neuregulin-1)
Heregulin
(neuregulin-1)
Epiregulin
HB-EGF
Neuregulins-2,3,4
Trastuzumab
Piccart NEJM 2005
> 60 yo 16%
The incidence of CHF from the Finnish Herceptin Study (FINHER), Herceptin Adjuvant trial (HERA), Breast
Cancer International Collaborative Group trial 006 (006) with TCH and AC-TH analyzed separately, the North 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
- 2 gr 3 LVSD (0.5%) (95% CI, 0.1%-1.8%)
- 13 significant asymptomatic LVEF decline
(3.2%) (95% CI, 1.9%-5.4%)
Tolaney NEJM 2015
BCIRG 006: Mean LVEF and Cardiac
Safety
No cardiac related deaths on any arm
Slamon D, et al. SABCS 2015. Abstract S5-04. Slide credit: clinicaloptions.com
66
65
64
63
62
61
60
59
58
LV
EF
po
ints
%
0 12 24 36 48 60 72 84
Mos since randomization
AC -> T (N = 1019)
AC -> TH (n = 1043)
TCH (n = 1032)
(N = 1019)
(N = 1043)
(N = 1032)
NEOSPHERE
417 EBC HER2+, randomized phase II 1:1:1:1
1. Docetaxel + trastuzumab
2. Docetaxel + trastuzumab + pertuzumab
3. Trastuzumab + pertuzumab
4. Docetaxel + pertuzumab
Gianni, Lancet Oncol 2012
pCR increased if double HER2
blockade
General recommendations for adjuvant
chemo & tratsuzumab in elderly
• Focus on ER-
• Regimen
– Validated 4 AC, 6 CMF
– Option 4 TC
– Capecitabine no
– Docetaxel qw no
– Sequential regimen no data
– Liposomal doxorubicin ?
• Primary prophylaxis of febrile neutropenia w/ G-CSF
• No restriction on trastuzumab if chemo indicated
– 4 TC + trastuzumab
– Paclitaxel qw x 12 + trastuzumab
– TCH x 6??? (carboplatin AUC 6!)
Miles Breast Cancer Res Treat 2013
Pertuzumab
Verma N Engl J Med 2013
Dieras J Clin Oncol 2014
Barrios ASCO 2015
T-DM1
Kamilla 194 pts 65-69, 78 pts 70-74, 120 pts 75+
Bevacizumab
(Avastin®)
Miller N Engl J Med 2007
> 65 yo 20%
MBC L1
ATE events Chemo 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)
% < 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+
Signatures ?
40 %
15 %
Mammaprint®
25,000 genes, 78 tumours, 70 genes, 17 pN0, all < 55 yo
van’t Veer, Nature 2002; van de Vijver, NEJM 2002
295 pts < 53 yo
MINDACT
• 6,600 pts < 70
– FEB 2007-AUG 2011
– 11,291 registered pts
– 6,673 enrolled (59.1%)
Biganzoli, Lancet Oncol 2012
Problème
démographique
Recherche
clinique
peu
représentée
Mortalité
spécifique
et effets
secondaires
significatifs
Phénomène
hétérogène
Espérance de vie
ou
pronostic « hors
cancer »
?
• 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 & CGA
CGA versus
or + ?
Two worlds confronting one another?
Genomic defect
targeted therapy
CGA defect
targeted geriatric
intervention
Definition of “old” x ageing heterogeneity
Age
Top 25th%
Fit
50th%
Intermediate
Lowest 25th%
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
Multimorbidities across age
Piccirillo Critical Rev Oncol Haematol 2008
dementia CHF
solid tumour AIDS
diabetes HBP
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
Competing
HR of death
Kendal Cancer 2008
Prostate NHL Breast
Comprehensive Geriatric Assessment CGA Assessment Instrument Administration Prognosis
Dependency,
functional
status
PS, Activity of Daily Living (ADL), Instrumental
ADL Self administered +
Comorbidity
Charlson Comorbidity Index (CCI),
Cumulative Illness rating Scale-Geriatric
(CIRS-G)
Self- or interviewer-
administered or
chart-based
+
Economic /
social support Life conditions, relatives, care-givers
Interviewer-
administered or
chart-based
?
Cognition Folstein Mini-mental State Examination
(MMSE)
Interviewer-
administered
+
functional status
Depression Geriatric Depression Scale (GDS) Self administered +
Polypharmacy List
Interviewer-
administered or
chart-based
?
Nutrition Mini Nutritional Assessment (MNA), BMI Interviewer-
administered +
Geriatric
syndromes Dementia, delirium, falls
interviewer-
administered or
chart-based
+
functional status
Mobility/falls Timed-up-and-go test, Tinetti, gait speed Performance-tests ?
http://www.eprognosis.org/
Lee. JAMA 2006
4-year mortality score in general elderly population
Health retirement study
• > 50 yo (40% > 70 yo)
− Construction 11,701 subjects
− Validation 8,009 subjects
CGA impact on treament decision & interventions
• Systematic review (Medline & Embase)
– 1,654 reports 10 studies
• 3 w/ CGA performed by geriatrician
• 7 w/ GA performed by cancer specialist, healthcare worker or (research) nurse
• Change in oncologic treatment: 6 studies
– Modification of initial treatment plan: 39% patients
• 2/3 w/ less intensive treatment (irrespective of performer)
• High role of functional & nutritional status
• Implementation of non-oncologic interventions defined
according to CGA: 7 studies
– All but one: interventions suggested for > 70% patients
• Social 38%, medication 37%, nutritional 26%
• Psychological, cognitive impairment, mobility and falls risk, previously
unidentified comorbid conditions: all ~ 20%
Hamaker Acta Oncol 2014
≥ 75 yo 1st visit
New cancer or relapse
G8
Physician
± nurse
≤ 14/17 > 14/17
Primary focus on*: systemic treatment?
Decision 1
YES NO
Standard health cares vigilance and geriatrician
sought according to needs
CGA
* But not exclusively
Adjusted health cares ± MDTB 2 and decision 2
Geriatric interventions
1. Streamlining geriatrician time
2. Involvement of oncologists
3. Impact - Decisions 1 and 2
- Geriatric interventions
- Day hospital in geriatric oncology
MDTB 1
Adapted recommendations for patient’s referral for CGA at Institut Curie
MDTB: multi disciplinary tumor board
6 key messages for elderly BC patients
1. Age and standard approach upfront influence treatment decision
– In 40% cases: but not always in the right direction!
2. Under and over-treament are frequent
3. Access to innovation is unbalanced
4. Comprehensive Geriatric Assessment = enforceable & not opposable
– Brings to clinicians new information in > 2/3 cases
– Modifies clinical decision in 20-25% cases (function & nutrition)
5. Geriatric problems are far more frequent than usually believed
– 2/3 impaired G8, +50% functional dependence or risk of malnutrition, +40% significant comorbidities, 20% depression, +10% cognitive dysfunctions, polypharmacy, etc.
6. Competing risks for mortality
– Call for some degree of assessment of life expectancy to balance treatment decision
Need for specific research
8842 studies found for:
Open Studies | Interventional Studies | cancer | Adult, Senior | Phase 1, 2, 3
www.clinicaltrials.gov
298 studies found for:
older OR elderly | Open Studies | Interventional Studies | cancer | Senior | Phase 1, 2, 3
www.clinicaltrials.gov
3.4%!!!
GERICO (UNICANCER)
GERICO ≥ 2,000 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 Faisabilité
Qualité 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
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 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)
897/1,080
1,671/2,000
Biomarkers
Cost, Will Poster, oral
2012 ELAN (PAIR ORL, GORTEC/GERICO) 70+ Multiple OS 380 NA Poster
SHS (cognition, acceptability, etc.) 70+ SHS Qualitative res NA Poster
2013 Frail lung (GFPC/GERICO), poly vs mono 70+ III OS + QoL 252 NA NA
2014 UCGI-30 (G-12) XRT/CTneo vs XRT rectum
OSAGE (Besançon) 75+
III
I/II
R0 + IADL
MTD, RR EOT
420
54
2014 Pain (intergroupe soins support AFSOS) 70+ Cohorte Description > 1,000
2015 ASTER 2/3 + EORTC/BIG 70+ III Outcome + QoL 1,200/2,500
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
Microarray
qRT-PCR CGA
EUDRACT N° 2011-004744-22, PHRC national 2011, NCT01564056
R** 1:1
All patients Lee Score
G8, CCI
Polymedications
Genomic Grade
(GG)
evaluation
CCI
Polymedications Events
Group II
Low 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 yr XRT
XRT
baseline 16 weeks 1, 2, 3 & 4 year
1, 2, 3 & 4 year
MMSE, IADL
QLQ C30 & ELD15
LVEF
Socioeconomic
Standard Lab
1 blood + serum
Polymedications
MMSE, IADL
QLQ C30 & ELD15
LVEF
Socioeconomic
Willingness
Standard Lab
1 blood + serum
G8, CCI
Polymedications
MMSE, IADL
QLQ C30 & ELD15
LVEF
Socioeconomic
Willingness
Standard Lab every year
1 blood + serum (M12 & M48)
Events
Chemo tolerance
Standard Lab
Complete
curative
surgery
Sc
ree
nin
g
** 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, NCT01564056)
2,000
1,100
900
Hypothesis B > A +7.5% (A 80% vs B 87.5%) HR 0.60 5% 10%
Inclusions on February 29th, 2016 (FR + BE) (47 months)
1,914
1,033
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, anti-PDL1, anti-PD1, CMF, 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, etc.
Charlson, CIRSG, CGA, 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.
FEC, FAC, SoFOG, ADL, IADL, CMF, DXR, PK/PD, CEX, G8, EORTC, 5FU CDDP, Calvert and Chatelut AUC,
GDS, population PK, FOLFIRI, MMS, FOLFOX, CPA, CRASH, DFS, OS, TTP, NCI, GERICO, TILs, CARG, anti-PDL1,
anti-PD1, EORTC TFE, JCO, JNCI, Charlson, JGO, CIRSG, ctDNA, EGS, EGA, MNA, GFI, Unicancer, Lee’s
score, JAGS, etc.
Let us make together hear the voice of
elderly!
Join our unique CME accredited training programme lead by international experts in the field of
geriatrics AND oncology designed to provide specific skills in assessment, care pathways and
therapeutic choices about the elderly patients with cancer in order to provide the basis of the
assessment and the multi-dimensional approach that should be applied to elderly cancer
patients.
Find out more at www.siog.org
This course is an ESO recommended
activity and is held with the support of
Under the auspices of / endorsed by:
Course director: Silvio Monfardini (IT)
Course coordinator: Giuseppe Colloca (IT)
“Geriatric oncology:
a multidisciplinary approach in a global environment”
SAVE THE DATE & JOIN US IN MILAN | www.siog.org
