Oxaliplatin in colorectal cancer in senior adult · of CRC : Î. 60% . after 70 years ... Neutropenia Thrombocytopenia Fatigue Ra t e, G r a d e 3+ Age < 70 Age > 70 p = 0.08

Madrid Madrid -- VIII e SIOG VIII e SIOG --

OxaliplatinOxaliplatin in in ElderlyElderlycolorectal cancer patientscolorectal cancer patients

Dr Elisabeth Carola Dr Elisabeth Carola Centre Hospitalier de Senlis Centre Hospitalier de Senlis -- FranceFrance

GERCOR GERCOR -- GEPOGGEPOG


Acknowlegments:

Pr Pr AimeryAimery de Gramont de Gramont CHU St Antoine CHU St Antoine –– ParisParisDr Thomas Dr Thomas Aparicio Aparicio CHU Bichat CHU Bichat –– ParisParisDr Tristan Dr Tristan Cudennec Cudennec CHU Ambroise Paré CHU Ambroise Paré –– ParisParisPr Hervé Curé Pr Hervé Curé Institut Jean Institut Jean GodinotGodinot -- ReimsReimsDr Frédérique Dr Frédérique Maindrault Maindrault CHU St Antoine CHU St Antoine -- ParisParisDr François MorvanDr François MorvanCH Pontoise CH Pontoise -- Paris

Dr Nathalie PerezDr Nathalie PerezCHU St Antoine CHU St Antoine -- ParisParis

Dr Frédérique Rousseau Dr Frédérique Rousseau Centre Paoli Calmette Centre Paoli Calmette -- MarseilleMarseillePr Laurent Pr Laurent Teillet Teillet Hôpital Ste Perrine Hôpital Ste Perrine -- ParisParisDr Christophe Dr Christophe Tournigand Tournigand CHU St Antoine CHU St Antoine --ParisParisDr Florence Woerth Dr Florence Woerth CH SenlisCH Senlis

Paris


Colorectal cancer ( CRC) : an Colorectal cancer ( CRC) : an ElderlyElderly DiseaseDiseaseCRC is the third most common cancer in the world with 800 000 new cases/ year

In France, 36 000 new cases / In France, 36 000 new cases / yearyear of CRC :of CRC :60% 60% afterafter 70 70 years years 43% 43% afterafter 75 75 years years 11% 11% afterafter 85 85 yearsyears

Remontet L, Buemi A, Velten M et al. Evolution de l’incidence et de la mortalité par cancer en France de 1978 à 2000. Août 2003. p53-59. Site web de l’InVS : http://www.invs.sante.fr

Life Expectancy

70-75 80-85 85

+12-15 years +7-8 years +5-6 years

AGE


44,1% 44,1% 8%8%--MetastaticMetastatic diseasedisease

19881988--89 89 (2)(2)

47,3%47,3%

86,1%86,1%

4,9%4,9%

24,4%24,4%

Côte d’Or Côte d’Or departmentdepartment (1997(1997--1998)1998) (1)(1) ::

--Stade II CCRStade II CCR

--Stade III CCRStade III CCR

< 65 < 65 yearsyears> 75 > 75 yearsyears

% of patients % of patients treatedtreatedwithwith chemotherapychemotherapy

CRC in CRC in ElderlyElderly : : UndertreatedUndertreated !!

(1)Faivre-Finn C, Bouvier AM, Mitry E et al. Chemotherapy for colon cancer in a well-defined French population: is it under- or over-prescribed? Aliment Pharmacol Ther 2002;16(3):353-359.(2)Aparicio T Mitry E, Sa Cunha A et al. Management of colorectal cancer of elderly patients. Gastroenterol Clin Biol 2005;29(10):1014-23. .


LV5FU2 vs FOLFOX 4 : PFS

A de Gramont et al J Clin Oncol Vol18, No16,2000:2938-2947

Oxaliplatin : First Line Agent in Advanced Colorectal Cancer

0102030405060708090

100

0 5 10 15 20 25months

%

LV5FU2 n=210

sd

LV5FU2+oxaliplatin n=210

sd


Is Is itit TrueTrue In In ElderlyElderly Patient ?Patient ?


FOLFOX4 in Elderly Patients with FOLFOX4 in Elderly Patients with Colon Cancer : A Pooled AnalysisColon Cancer : A Pooled Analysis

Study Comparator regimen

Setting N

MOSAIC1 5-FU/LV Adjuvant 2246

N97412 IFL 1st Line 546

de Gramont3 5-FU/LV 1st Line 420

Rothenberg4 5-FU/LV 2nd Line 530

Total 3742

11André et al, NEJM 2004; André et al, NEJM 2004; 22Goldberg et al, JCO 2004; Goldberg et al, JCO 2004; 33dede GramontGramont et al, JCO 2000; et al, JCO 2000; 44Rothenberg et al, JCO 2003Rothenberg et al, JCO 2003


Progression or Progression or DiseaseDisease Free Free SurvivalSurvival


OverallOverall Survival Survival


Adverse Events (Gr > 3)

0

5

10

15

20

25

30

35

40

45

50

Neutropenia Thrombocytopenia Fatigue

Rat

e, G

rade

3+

Age < 70Age > 70

p = 0.08p = 0.04

p = 0.04

0

2

4

6

8

10

12

14

16

Neurotoxicity Diarrhea Nausea/Vomiting 60 Day Mortailty

Rat

e, G

rade

3+

Age < 70Age > 70

p = 0.37

p = 0.20

p = 0.38

p = 0.38


ConclusionsConclusions

Elderly patients benefit from FOLFOX4 treatment Elderly patients benefit from FOLFOX4 treatment to a similar degree to younger patientsto a similar degree to younger patientsElderly patients experience slightly more but Elderly patients experience slightly more but manageable toxicitymanageable toxicityAge alone should not be a criteria to exclude Age alone should not be a criteria to exclude elderly patients from FOLFOX4 chemotherapyelderly patients from FOLFOX4 chemotherapy

CautionCautionConclusions only applies to selected elderly Conclusions only applies to selected elderly patients for clinical trialspatients for clinical trials2 of 4 trials limited eligibility to patients 2 of 4 trials limited eligibility to patients << 75 75 yearsyears


Age A: MOSAIC B: de Gramont C: Goldberg D: Rothenberg

No. of Patients No. of Patients No. of Patients No. of Patients

≤ 39 126 12 28 35 40-49 262 49 64 86 50-59 628 99 154 157 60-69 915 174 170 170 70-75 290 71 70 60 75-79 25 15 37 31 ≥ 80 0 0 8 7

Patient Age by Decade and Trial


OPTIMOXOPTIMOX 11 StudyStudy designdesign

RRAANNDDOOMMIISSAATTIIOONN

FOLFOX4 until progression

FOLFOX7 x 6 cysLV5FU2 x 12 cyFOLFOX7 x6 cy

A

B


OptimoxOptimox 1 1 -- OverallOverall Survival Survival Patients >75 Patients >75 yearsyears vsvs Patients Patients ≤≤ 75 75 yearsyears

0 25 50 75 100 125 1500.0

0.2

0.4

0.6

0.8

1.0

> 75 years

≤ 75 years

weeks

Prop

ortio

n 20.7 months

20.2 months

p = 0,15


The Stop and GO StrategyOptimox 2 Study

Reintroduction of Folfox 7 if progression

BreakReintroduction of Folfox 7 if progression

A RANDOMIZED PHASE II TRIAL


The Stop and GO StrategyOptimox 2 Study

BreakMaintenance

(1)

(2)

Good PronosticPoor Pronostic

NA


Is Is itit TrueTrue in the Real Life ?in the Real Life ?


Four Questions ?Four Questions ?

WhatWhat isis the best the best StrategyStrategy : : MonotherapyMonotherapy or or Association?Association?

FolfoxFolfox or or XeloxXelox : : isis Oral Oral betterbetter thanthan all infusion ?all infusion ?

Is Is there there a place for a place for targetedtargeted therapiestherapies withwithoxaliplatinoxaliplatin in in elderlyelderly??

TreatmentTreatment for for whichwhich elderlyelderly populationpopulation??


MonotherapyMonotherapy or Association?or Association?

FFCD (2000FFCD (2000--05)05)-- PreliminaryPreliminary resultresult410 pts 410 pts 02/2002 02/2002 –– 02/200602/2006MedianMedian FollowFollow up : 25 up : 25 monthsmonthsAdvanced CRC Advanced CRC withwith non non resectableresectable metastasismetastasisArm A LV5FU2s Arm A LV5FU2s FOLFOX6FOLFOX6 FOLFIRIFOLFIRI

Vs Arm B FOLFOX6 Vs Arm B FOLFOX6 FOLFIRI FOLFIRI otherother treatmenttreatmentPFS 11.5 PFS 11.5 monthsmonths VS 12 VS 12 monthsmonthsOS 17 OS 17 monthsmonths vs 16 vs 16 monthsmonths

BouchBouchéé et al ASCO 2007 abstract 4069et al ASCO 2007 abstract 4069


MonotherapyMonotherapy or Association?or Association?

• FOCUS 2 a multicenter, 2×2 factorial randomized trial

• 460 patients

• Four arms : (A) LV5FU2s, (B) FOLFOX, (C) Capecitabineet (D) Capox

• Age : <70 ans (101), 70-75 ans (161), >75 ans (198)


FOCUS 2 Study

p<0,0001p<0,0001p=0,66p=0,6634%34%17%17%43%43%16%16%RR RR atat12wk12wk

P=0,09P=0,09P=0,008P=0,00839%39%36%36%26%26%24%24%ToxTox 33--44

P=0,02P=0,02P=0,14P=0,1431%31%41%41%37%37%51%51%↑↑ dose dose atat 6wk6wk

HR=0,87 HR=0,87 p=0,16p=0,16

HR=0,92 HR=0,92 p=0,41p=0,41

PFS PFS hazardhazardratioratio

62 vs 48% 62 vs 48% p=0,03p=0,03

56 vs 54% 56 vs 54% p=0,95p=0,95

45%45%64%64%51%51%60%60%↑↑ QOLQOL atat12wk12wk

+/+/-- oxalioxaliFU FU vsvs capcapCAPOXCAPOXCap.Cap.FOLFOXFOLFOXLV5FU2LV5FU2

AC vs BDAC vs BDAB vs CDAB vs CDDDCCBBAA

Seymour MT ASCO 2007 n°9030


The The BackboneBackbone of of treatmenttreatment forforAdvanced CRCAdvanced CRC

Single agent Single agent fluorouracilfluorouracil(+/(+/--bevacizumabbevacizumab ?)?)

Multiple Multiple metastasesmetastases and good to and good to moderatemoderate performance performance statusstatus and and lessless aggressiveaggressive diseasedisease or or comorbidcomorbid conditionsconditions

3 (or2) 3 (or2) drugdrug combinationcombinationPoorPoor perfomansperfomans statusstatus or or aggressiveaggressive diseasedisease or imminent or or imminent or presentpresent tumortumor relatedrelated symptomssymptoms

3 3 drugdrug combinationcombinationLiver and/or Liver and/or lunglung metastasesmetastases onlyonlyand and resectionresection mightmight bebe possible possible afterafter chemotherapychemotherapy

TreatmentTreatment strategystrategyCharacteristicsCharacteristics

HJ Schmoll and D Sargent –Lancet 2007;370-105-107


FolFoxFolFox or or XeloxXelox ??

GERICO II : Impact of GERICO II : Impact of XeloxXelox regimenregimen on on independanceindependance of of elderlyelderlypatients patients mesuredmesured by ADLby ADL60 patients >70 YEARS ( 60 patients >70 YEARS ( MedianMedian age : 78 age : 78 yearsyears oldold ))Advanced CCR first lineAdvanced CCR first lineTreatmentTreatment : : CapecitabineCapecitabine 750 mg/m² 750 mg/m² orallyorally bidbid d1d1--14 14

+ + oxaliplatinoxaliplatin 90 mg/m²IV q3w90 mg/m²IV q3wNo ADL No ADL decreasedecrease afterafter 3 courses3 coursesNo ADL No ADL decreasedecrease afterafter 6 courses in 96% of patients6 courses in 96% of patientsOR : 33%, stabilisation : 18% OR : 33%, stabilisation : 18% ToxicityToxicity grade 3grade 3--4 : 4 : haematologicalhaematological 12%, 12%, diarrheadiarrhea 13%, hand13%, hand--foot foot syndrome 0% (19% grade 1syndrome 0% (19% grade 1--2), 2), neurotoxicityneurotoxicity 2% (67% grade 12% (67% grade 1--2)2)

Viret F ASCO 2007 n°19513 (non sélectionné)


XeloxXelox as firstas first--Line Line treatmenttreatment for for elderlyelderly

Phase II Trial Phase II Trial –– 50 patients50 patientsFromFrom JanuaryJanuary 2003 to 2003 to SeptemberSeptember 20032003MeanMean age : 76 age : 76 yearsyears28 pts 28 pts hadhad comorbiditiescomorbiditiesORR: 36%ORR: 36%OS: 13.2 OS: 13.2 monthsmonths12 patients 12 patients receivedreceived a second linea second line«« A A goodgood therapeutictherapeutic option in option in thethe elderlyelderly »»

J J FeliuFeliu et al et al BrBr J of Cancer 2006;94,969J of Cancer 2006;94,969--975975


FUFOX vs CAPOXFUFOX vs CAPOXFromFrom August 2002 to August 2004 476 patients August 2002 to August 2004 476 patients werewere randomizedrandomized140 patients >70 140 patients >70 yearyear--oldoldCRC CRC metastaticmetastatic firstfirst--linelineOR : >70 OR : >70 yearsyears vsvs <70 <70 yearsyears : 49 : 49 vsvs 52%52%PFS : >70 PFS : >70 yearsyears vsvs <70 <70 yearsyears : 7,7 v: 7,7 vss 7,5 7,5 monthsmonths (OR: 1,07; IC95% 0,86(OR: 1,07; IC95% 0,86--1,34)1,34)OS : >70 OS : >70 yearsyears vsvs <70 <70 yearsyears : 14,4 : 14,4 vsvs 18,8 18,8 monthsmonths (OR: 1,37; IC95% 1,07(OR: 1,37; IC95% 1,07--1,76 p=0,013)1,76 p=0,013)ToxTox 33--4 : >70 4 : >70 yearsyears more GI adverse more GI adverse effectseffects and and lessless neurosensoryneurosensory toxicitytoxicity

ORRORR

OSOS

PFSPFS

46%46%54%54%> 70 > 70 yearsyears

1,06 IC95% [0,751,06 IC95% [0,75--1,51]1,51]

14,2 14,2 monthsmonths14,4 14,4 monthsmonths> 70 > 70 yearsyears

1,01 IC95% [0,741,01 IC95% [0,74--1,38]1,38]

7,6 7,6 monthsmonths7,9 7,9 monthsmonths> 70 > 70 yearsyears

OddOdd RatioRatioCAPOXCAPOXFUFOXFUFOX

Arkenau H ASCO-GI 2007 n°283


55--FU FU vsvs CapecitabineCapecitabine Preference TrialPreference Trial

R = ra n d o m isa tio n ; Q = q u e s tio n n a ire

R Pa tie n t c h o ic e

F irst tre a tm e n t c o u rse

C ap ecitabin e

i .v . 5-FU /L V C ap ecitabin e

i .v . 5-FU /L V

QQ

S e c o n d tre a tm e n tc o u rse

Gollins SW, Samuel L, Napier M and Twelves C. European Society of Medical Oncology Meeting 2004, Annals of Oncology 15, Sup 3, abst 347


Overall patient preference before and Overall patient preference before and after treatmentafter treatment

79

58

82

58

72

57

4

31

6

33

2

29

0

20

40

60

80

100

Before After Before After Before After

All patien ts(n=94)

O ral → i.v .(n=51)

i.v. → oral(n=43)

P atien ts (% )

P atien t g roup:

O ralI.V .


HOW MANY COLORECTAL CANCER (CRC) PATIENTS OLDER THAN 70 YEARS MAY BE SAFELY TREATED WITH

BEVACIZUMAB ?From January 2004 to December 2005

91 pts > 70 years - Median age 76 years old

65 pts had comorbidities : (CIRGS)

– 29/91 comorbidities grade>2

– 36/91 Comorbidities grade 1

– 26/91 no comorbidity

• Bevacizumab is contraindicated for 36% of pts

• It’s moot for 40% of patients

• 34% of patients could benefit of bevacizumab

L. M. Pasetto ASCO 2006, abstract 13589


BevacizumabBevacizumab afterafter 75 75 yearsyears oldold : Caution !: Caution !

212119192020nn

29%29%11%11%10%10%HypertensionHypertension

5%5%5%5%0%0%PerforationPerforation

11,6%11,6%VenousVenousthromboembolicthromboemboliceventsevents

19%19%11%11%10%10%ArterialArterialthromboembolicthromboemboliceventsevents

>>75757373

7070--74746565--6969MedianMedian ageage

ToxicityToxicity grade 3grade 3--44

Raman AK, ASCO 2007 n°14546Raman AK, ASCO 2007 n°14546


GERICOGERICO 08 :08 :XeloxXeloxBevacizumabBevacizumab in in ElderlyElderly

Dr Frédérique ROUSSEAU IPCDr Frédérique ROUSSEAU IPC--MarseilleMarseille

BECTBECT--FNCLCCFNCLCC

XELOX XELOX ––AvastinAvastin®® 6 cures6 cures

Capecitabine Capecitabine 750 mg/m² PO 750 mg/m² PO bidbid J1J1--1414OxaliplatinOxaliplatin 90 mg/m² IV J190 mg/m² IV J1

Bevacizumab Bevacizumab 7.5 mg/m² IV J17.5 mg/m² IV J1

Aims : Study the feasability of the combination WithXELOX-Avastin®®

ORRPFSOSToxicityImpact of independance mesured by ADL

70 patients70 patients


WhoWho cancan profit of the profit of the treatmenttreatment ??


CGA : Help for Oncologist

Vulnerability

Balducci L Cancer Control .2007;14:7-12


A Scale predictive of chemotherapiestoxicities in Elderly G

OLD 07-1

9. Vous sentez vous souvent triste ou d9. Vous sentez vous souvent triste ou dééprimpriméé ??10. Pr10. Préésence de lsence de l’’Entourage*Entourage*

*Aidant ou famille*Aidant ou famille

DepressionDepression and and helperhelper

7. Clairance de la cr7. Clairance de la crééatinine >30ml/mnatinine >30ml/mn8. Albumin8. Albuminéémie >30g/lmie >30g/lRenalRenal functionfunction and and

nutritialnutritial statusstatus

1.1. Hospitalisation dans lHospitalisation dans l’’annannéée pre prééccéédentedente6. Poly m6. Poly méédications > 5 dications > 5 ComorbiditiesComorbidities

3. 3. Aide pourAide pour ::--ttééllééphoner phoner --prendre les mprendre les méédicamentsdicaments--faire les courses faire les courses -- tenir ses comptestenir ses comptes--prprééparer les repas parer les repas -- conduire ou utiliser les conduire ou utiliser les --entretenir la maison transportsentretenir la maison transports

4.4. Appui Appui monopodalmonopodal 5s5s

DependanceDependance

1.1. Date du jour et nom de la ville de lDate du jour et nom de la ville de l’’HHôôpitalpital2.2. RRééppéétition de trois mots (cigare, fleur, porte ou tition de trois mots (cigare, fleur, porte ou

citron, clcitron, cléé, ballon) et apr, ballon) et aprèès quelques minutess quelques minutes

Cognitive Cognitive functionsfunctions


Documents

Oxaliplatin in colorectal cancer in senior adult · of CRC : Î. 60% . after 70 years ... Neutropenia Thrombocytopenia Fatigue Ra t e, G r a d e 3+ Age < 70 Age > 70 p = 0.08