Colorectal Cancer in Older - PowerPoint Presentation

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Colorectal Cancer

in Older PatientsKey Issues

Etienne GC Brain, MD PhDInstitut CurieSaint-Cloud, France

1

www.siog.org

etienne.brain@curie.fr

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Key issues (1)

Epidemiology and demographicsHow different are the considerations in older adults with CRC compared with other solid tumors?Cure versus controlToxicity and treatment-related mortalityHow does geriatric assessment inform decision-making?GA to select treatmentVulnerabilities and toxicityInterventions

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Key issues (2)

ScreeningValue > 70?SurgeryNeed for prehabilitation?Standard adjuvant systemic treatmentWhen and how to use chemotherapy? And which one?Challenges in metastatic settingMonochemo vs polychemoBiologicals (anti-VEGF, anti-EGF)

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Epidemiology

23-45% digestive tumours are diagnosed > 75 yo (FRANCIM 2010)CRC (INCa 2012)75-84 yo 14.7% of all cancers> 85 yo 18.7% of all cancers1st cancer any sex in elderly

30% new cases 75-84 yoMedian age at diagnosis 70 yoScreening > 75???

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Binder-

Foucard INCa report 2013

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SEER data on (A) incidence of new

CRC

cases and (B) colorectal

cancer–related deaths

Nadine J. McCleary et al. JCO 2014;32:2570-2580

©2014 by American Society of Clinical Oncology

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De Angelis Lancet

Oncol 2013

Relative survival accounts for mortality from causes other than the relevant cancer, which can vary widely between countries

Breast

Colon

Rectum

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Competing

causes of mortality

Deaths attributed to the primary cancer (solid dots) and those attributed to comorbidity (open circles)

Cumulative probability of death / time of diagnosis

Cumulative

probability

of death / attained

age

Log/log plot of probability of comorbid death vs corresponding probability for cancer-specific death

Prostate

NHL

Colorectal

Kendal Cancer 2008

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28

independent studies & 34 194 patientsOlder patientsIncreased frequency of comorbid conditionsMore later-stage diseaseMore emergency surgeryLess curative surgeryMore postoperative morbidity and mortalityWorse OS but less striking for CRC-specific survival

Lancet 2000

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Undertreatment

110 cases > 75 yo (1995-2000)Treatment according guidelines = 48% ptsSurgery 87% (R0 56%)ChemotherapyIII 26%IV 17%XRT (rectum) Early stage 17%Palliative 21%

Apparicio CROH 2009

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Doat Eur J Cancer 2014

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75+ vs < 75: median OS 8.4 months vs 22.3 months

(17.1 months in 75+ w/ chemo)

Doat Eur J Cancer 2014

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Doat Eur J Cancer 2014

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Adjuvant Setting

Sargent NEJM 2001

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Oxaliplatin

André ASCO 2012

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4,819

patients from NSABP C-08, XELOXA, X-ACT, and AVANT studies DFS/OS benefit was consistent for XELOX/FOLFOX vs. LV/5-FU, regardless of age or comorbidity Grade 3+ AE rates similar across cohorts and CCI scores, and higher in patients aged ≥ 70 Peripheral sensory neuropathy comparable across age and CCI scores Haller Ann Oncol 2015

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OS

Haller Ann Oncol 2015

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Haller Ann Oncol 2015

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Benefits of oxaliplatin beyond fluoropyrimidine in pts > 70 years is

uncertain Increased risk for AE’s with combination chemo (25% SAE w/ 15% neuropathy)Decision based on clinician’s clinical judgment Recurrence risk Fluoropyrimidine monotherapy is appropriate when oxaliplatin is felt to add excessive risk of toxicity for a patient

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Questions

Stratification on frailty/life expectancy for oxaliplatin vs none or chemo ves none (ADAGE/PRODIGE 34)Deficiency in mismatch repair & MSI (high frequency in older patients and improved

prognosis)?21

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Metastatic Setting

Most studies show similar benefit to systemic treatments as younger patients Few specific studies in older patients FOCUS 2, FFCD, AVEXChemoMono vs bi-therapy (oxaliplatin, irinotecan)! Capecitabine > 70Targeted treatmentsAnti-EGFR, anti-VEGF

! Bevacizumab with ATE history

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Irinotecan + 5-FU vs 5-FU alone

Gr 3+ toxicity

I + 5-FU < 70 5-FU < 70

I + 5-FU ≥ 70

5-FU

≥ 70

I + 5-FU

≥ 75

5-FU

≥ 75

Leukopenia

16.9

7.0

18.5

6.4

22.8

10.4

Neutropenia

28.9

16.1

29.7

19.9

25.0

24.3

Thrombocytopenia

1.5

0.7

1.2

0.7

4.7

2.2

Infx

w/o

neutropenia

1.2

1.1

2.4

2.6

8

0

Stomatitis

2.5

2.6

4.0

3.6

5.0

4.4

Diarrhea

20.5

11.4

23.4

12.6

29.8

11.3

Nausea

11.3

5.8

10.8

3.7

14.8

3.2

Vomiting

9.6

5.3

9.7

2.5

16.3

2.2

Handfoot syndrome

1.0

1.5

1.7

2.3

5.1

3.7

Thrombosis

4.9

4.2

4.3

4.5

7

15

Hepatic Toxicity

4.6

1.7

9.8

7.7

17

10

Folprecht JCO 2008

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Stratification: centre, PS,

surgery of primary, agePrimary objective: Overall Treatment

Utility = oxaliplatin and PFS (A vs B + C vs D), capecitabine and QoL (A vs C et B vs D)Secondary objectives: RR, toxicity, OSStatistics: 2x2, PFS 6 vs 9 mth, α 5%

β 20%, QoL 40% vs 60% improvement at 12w, α

5% β 10%, 460 patients

Dose

Initial: 80%

> 6 w: 100% if good tolerance

PS: FOCUS 1 (

Fluorouracil

,

Oxaliplatin

, CPT11 [

irinotecan

]: Use and

Sequencing

):

median

age

64

yo

(vs 60% deaths > 75+) (

Lancet 2007)Frail and elderlyA : LV5 FU2 q2wB : FOLFOX q2wR1:1:1:1

C : capecitabine q3w

D : XELOX q3w

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01/2004-07/2006

61 centres UK

Comprehensive health assessment (CHA)4 modules/IDEWalk 20 m, MNA, MMSE, comorbidities4 modules/patientADLSymptomsAnxiety/depressionQoL

/health ressources459 pts43% 75+13% 80+

LV5 FU2

FOLFOX

cape

XELOX

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LV5 FU2

FOLFOX

cape

XELOX

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Oxaliplatine

Median PFS 5.8 [3.3-7.5] vs 4.5 [2.8-6.4], HR 0.84 (0.69-1.01, p = 0.07)More RR 41-54% vs 35-37%)5 FU

QOL mprovement by 56% w/FU or capecitabineMore AE grade ≥ 3 ifOxaliplatin 39% vs 32% p = 0.17Cape 40% vs 30% p = 0.03

MultivariateLess

symptoms

Limited disease

Oxaliplatine



Better OTU

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FFCD 2001-02

123 patients with mCRC, first line of chemotherapy5-FU-based chemo ± irinotecanMedian age 80 yo (75-91)Charlson

index≤ 1 75%MMSE ≤ 27/30 31%IADL impairment 34%Toxicitygrade 3-4 toxicity71 patients (58%): IRI, MMSE, IADLDose-intensity reduction > 33%41 patients (33%): IRI, Alk phosph≥ 1 unexpected hospitalization (4 mth)54 patients (44%): MMSE, GDSCognitive function and autonomy impairment should be taken into account when choosing a regimen for chemotherapy

Aparicio J Clin Oncol 2013

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Critères

d’inclusionECOG PS 0-2CT adjuvante autorisée si terminée > 6 mois avant l’inclusionMauvais candidats pour une CT comprenant de l’irinotécan ou

de l’oxaliplatineCritères d’exclusionCT antérieure (CCRm) ou traitement anti-VEGF antérieur Maladie cardiovasculaire significative Traitement par aspirine (> 325 mg/j) ou autre

AINS actuel ou récentTraitement par anticoagulants à pleines doses ou par

antithrombotiques

AVEX

Cunningham Lancet

Oncol

2013

•

CCRm

•

Traitement

de 1

re

ligne

•

Âge

≥ 70

ans

(

n

= 280)Capécitabine 1 000 mg/m2 x 2/j J1-J14, tous les 21 joursCapécitabine 1 000 mg/m2 x 2/j J1-J14, tous les 21 jours

+

Bévacizumab

7,5 mg/kg

J1,

tous

les 21

jours

R

1:1

Stratification

• ECOG PS (0-1 versus 2)

•

Région

géographique

Schéma

de

l’étude

(phase III)

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Cunningham Lancet

Oncol 2013

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Cunningham Lancet

Oncol 2013

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AVEX

PFS: 9.1 vs 5.1 mos (HR 0.53, p<0.001) OS: 20.7 vs 16.8 mos (HR 0.79, p=0.182) [AVF2107g results: IFL+/- BEV 20.3 mos vs 15.6 mos (HR 0.66, p<0.001)] RR: 19.3% vs 10% p=0.042 Grade 3+ AEs: 59% vs 44.1% Conclusions: Cape + BEV could be a standard for selected elderly patients

Cunningham Lancet Oncol 2013

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Cunningham Lancet

Oncol

2013

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Safety of

bevacizumabPooled analysis of 3,007 patients enrolled in 4 mCRC studies (NO16966, AVF2107g, AVF2192g, and E3200) 1,864 were aged <65 years, 1,142 were ≥ 65 years, 712 patients were ≥ 70 years Bevacizumab statistically significantly improved PFS (HR 0.58; 95% CI 0.49–0.68) OS (HR 0.85; 95% CI 0.74–0.97) in patients aged ≥ 65 years and patients aged ≥70 years

Cassidy J Cancer Res Clin Oncol 2010

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Cassidy

J Cancer Res Clin Oncol 2010

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SEER database

3,039 patients ≥ 66, stage IV breast, lung, colon cancer, 2004-2007, bevacizumabContra-indication defined as 2 claims for thrombosis, cardiac disease, stroke, hemorrhage, hemoptysis, or GI perforationToxicity defined as 1st development of 1 condition > bevaBeva

use associated w/ white race, later year of diagnosis, tumor type, and decreased comorbid conditions35.5% had contra-indicationBlack race, increased age, comorbidity, later year of diagnosis, lower socioeconomic status, lung and CRCIf no contra-indication  30% complication (black race)Hershman J Clin Oncol 2013

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Cetuximab

Jehn

Br

J Cancer 2012

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Cetuximab

Folprecht ESMO 2010

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Cetuximab

Pooled analysis from KRAS wild-type pts CRYSTAL (FOLFIRI +/- cetuximab) OPUS (FOLFOX +/- cetuximab) OS, PFS and safety were all similar among older ( ≥ 70 years) and younger (<70 years) pts. Grade 3+ toxicity was increased in both treatment arms for elderly patients NO obvious interaction between age (< 70 vs ≥ 70 years) and the differences for treatment toxicity between the arms.

Folprecht ESMO 2010

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Panitumumab & regorafenib

Very limited amount of dataPanitumumabNo difference according to ageFirst line (Douillard JCO 2010)Second line (Peeters JCO 2010)RegorafenibNo difference according to age (Grothey

Lancet 2013)

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Refining the Chemo

Approach for CRC Older Patients

McLeary J Clin Oncol 2014

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Treatment

decisions should not be based on age alone Fit older patients can tolerate combination cytotoxic therapy as well and benefit as much as younger patients Same for biologics Consider less intense regimens for those who are not candidates for standard regimens Reduced dose FP + oxaliplatin Cape + BEV