Cancer du sein et sujet âgé - Longue Vie et Autonomie · Cancer du sein et sujet âgé Docteur...

Cancer du sein et sujet âgé

Docteur Etienne Brain

Oncologie Médicale

Hôpital René Huguenin / Institut Curie

Saint-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

… 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: journals.permissions@oup.com.

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: 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)

c-orsini@unicancer.fr

e.brain@curie.fr

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