EORTC-AMAROS-trial临床试验课件

Radiotherapyorsurgery

of

the

axillaafter

a

positive

sentinel

node

inbreast

cancer

patients:

final

analysisof

the

EORTC

AMAROS

trialBy

the

EORTC

Breast

Cancer

Group

andRadiation

Oncology

GroupIn

collaboration

with

the

Dutch

BOOG

Groupand

ALMANAC

Trialists’

GroupEmiel

J.T.

RutgersThe

Netherlands

Cancer

Institute,

AmsterdamClinical

trial

information:

NCT00014612Background

Sentinel

node

(SN)

biopsy

has

replaced

theaxillary

lymph

node

dissection

(ALND)

if

cN0If

axillary

SN+

(AxSN+)

and

indication

for

axillatreatment,

ALND

is

standard

of

careALND

is

associated

with

high

rates

of

side

effect

Axillary

radiotherapy

(AxRT)

provides

goodregional

control

with

limited

side

effects

in

cN0Deutschet

al,

IJROBP

2008Hoebers

et

al,

Cancer

2000Fisher

et

al,

NEJM

2002Louis-Sylvestre

et

al,

JCO

2004HypothesisAxillary

radiotherapy

provideslocal

control

and

survivalcomparable

to

ALND

with

fewerside

effects

in

women

with

apositive

axillary

SNEligibility

CriteriaInclusion

Invasive

breast

cancer0.5-5cmClinically

N0BCT

or

mastectomyAny

ageInformed

consentExclusionMulticentric

disease

Neoadjuvantsystemic

treatment

Previous

axillarytreatmentPrior

malignancyTrial

designcT1-2N0RSNBStratification:

institutionAdjuvant

systemic

therapy

by

choiceALNDAxRTAxSN+AxSN-ObjectivesPrimary:

To

demonstrate

non-inferiority

in

axillaryrecurrence

rateSecondary:To

compare

overall

survival

(OS)

and

disease-free

survival

(DFS)To

compare

lymphedema,

shoulder

function

andQuality

of

Life

(QoL)Endpoints

and

statistical

designPrimary:

5-years

axillary

recurrence

free

rateNon

inferiority

hypothesis

(design):assumption:

ALND

98%;

AxRT

>96%one-sided

log-rank;

alpha

=

0.05; power

=

80%52events

neededSecondary:Efficacy:

OS

and

DFSSafety:

shoulder

function,

lymphedema,

QoLAxRTTiming:Start

<12weeksafter

SNBExtent:level

I

+

II

+

III

+

medial

SCDose

&

schedule:25x

2Gy

or

equivalent

Quality

control:dummy

runHurkmans

et

al,

Radiother

Oncol

2003Timing:<12

weeksafter

SNBExtent:Level

I

+

II

mandatoryLevel

III

optionalAdditional

AxRT:≥

4

positive

nodesALNDRESULTS2001-

2010:

4806

patients

enrolled

(4766

required)All

included

patientsn

=

4806SNB

negative

N

=

3131

(65.1%)ALND

N

=

744ALND

N

=

598AxRT

N

=

681AxRT

N

=

535ExcludedN

=

146Intent-to-treat

(ITT)sampleAxSNB

positiveN

=

1425

(29.7%)SNB

not

identifiedN

=

132

(2.7%)SNB

otherN

=

120

(2.5%)ExcludedN

=

146Per

Protocol

(PP)sample10 not

eligible

885 ITC

only

(

before

amendment)

6751Non-

compliance71Efficacy

analyses

(OS

andDFS):per

protocol

(PP)by

intent-to-treat

(ITT)Both

PP

and

ITT

analyses

gave

similar

resultsIntent-to-treat

analysis

reportedTreatment

complianceRandomized

treatmentBoth

treatmentsCross-overNo

axillary

treatment631

(84.8

%)590(86.6

%)41(5.5

%)1(0.1

%)46(6.2

%)68(10.0

%)24(3.2

%)22(3.2

%)ALND(744

pts)AxRT(681

pts)Median

age

(Q1-Q3)Menopausal

stagepre-menopausalpost-menopausalMedian

tumor

size

(Q1-Q3)Grade123Pre-operative

ultrasound

ax5i9l.l2a%ALNDAxRT(744

pts)(681

pts)56

(48

-

64)55

(48

-

63)38.1

%42.5

%57.7

%54.5

%17

mm

(13

-

22)18

mm

(13

-

23)24.1

%22.6

%47.8

%45.7

%25.8

%29.4

%Baseline

clinical61.5

%Breast

surgeryBCS81.9

%81.8

%Mastectomy17.1

%17.8

%Systemic

treatmentchemotherapy60.9

%61.3

%hormonal

therapy78.6

%77.1

%immunotherapy6.0

%6.4

%no

systemic

treatment9.0

%9.4

%84.8

%RT

breast/chest

wall87.7

%ALND(744

pts)AxRT(681

pts)Baseline

treatmentSN

resultsALND(744

pts)AxRT(681

pts)Median

number

of

SNremoved

(Q1-Q3)Size

of

metastases

in

SNmacrometastasesmicrometastasesITC59.4

%61.5

%28.9

%28.6

%11.7

%9.8

%2

(1-3)2

(1-3)Straver

et

al,

Ann

Surg

Oncol

2010ALND

results01-3≥

467.1

%25.0

%7.8

%ALND(744

pts)Median

number

of

all

nodes

removed

(Q1-Q3)

15

(12-20)Number

of

additional

positive

nodes

(besides

SN)5-years

axillary

recurrence

rate:ALND

0.43%AxRT

1.19%(4

/

744

events

(0.54%))(7

/

681

events

(1.03%))<<

hypothesis

(2%)Consequence:

planned

comparison

is

underpoweredAxillaryrecurrence

rateAxillary

recurrencerate

SN-5-years

axillary

recurrence

rate:0.72%

(25/3131

events

(0.80%))Disease-free

survivalHR:1.17;

95%CI:

0.93-1.51P

=

0.18Overall

survivalHR:1.17;

95%CI:

0.85-1.62P

=

0.34Breast

cancerspecific

deaths:ALND:

53

(7

.1

%)Ax

RT:

54

(7

.9

%)Results

side

effects50-70%

form

compliance

at

all

time

pointsLymphedema

of

the

armMeasured:

1,

3

and

5

years

after

treatmentItems:Clinical

observationTreatment

for

edema:sleeve

garmentlymph

drainage

therapycompression

therapy2440.0%29.8%21.7%16.7%13.6%Years

after

randomization%Lymphedema:

clinical

observationand/ortreatmentP

<

0

.

0001P

<

0

.

0001P

<

0

.

0001Lymphedema:

clinical

observationP

<

0

.

0001P

=

0

.

002727.8%22.5%23.2%15.1%13.8%10.8%%P

<

0

.

0001Years

after

randomizationLymphedema:

treatment31.5%20.9%16.8%16.1%9.7%6.6%Years

after

randomization%P

<

0

.

0001P

<

0

.

0001P

=

0

.

0001Shoulder

function1

8

0

°9

0

°2

0

°-4

0

°Measured:

1,

3

and

5

years

after

treatmentItems:Ante/retroversionAb/adductionShoulder

functionResults:No

significant

differences

in

all

4

excursionsTrend

towards

impaired

movement

after

AxRT

in

first

year

onlyRelative

movement:Excursion

treated

armExcursion

untreated

armYears

after

randomizationMultivariateANOVA:

p

=

0.29Measured:

1,

2,

3

and

5

years

after

treatmentQuestionnaire:EORTC-QLQ-C30

(core

questionnaire

version

3)QLQ-BR23

(breast

cancer

module)Results:

No

significant

differencesSelected

scales:arm

symptoms,

pain

&

body

imageQuality

of

LifesResults:Trend

towards

more

difficultieto

move

the

arm

after

ARTTrend

towards

more

swellingafter

ALNDQuality

of

LifeAx

RTALNDAx

RTALNDDiscussion

The

axillary

recurrence

rate

was

far

belowhypothesized,

hence,

the

trial

was

underpoweredAxRT:

level

I

+

II

+

III

+

SCImbalance

in

AxSN+

patients

per

arm-

independent

committee:

no

explanationIndication

for

axillary

treatment?ConclusionBoth

ALND

and

AxRT

provide

excellent

andcomparable

locoregional

control

in

AxSN+patientsSignificantly

less

lymphedema

after

AxRTAxRT

can

be

considered

standardAcknowledgementWe

are

very

grateful

to

all

the

patients

who

participated

in

this

trialAcknowledgementResearch

fellows:

Mila

Donker,MariekeStraver,

Philip

MeiPrincipal

investigators:

Cornelis

vandeVelde,

Robert

ManGeertjan

van

TienhovenEORTC

headquarters:

Nicole

Duez,Leen

Slaets,

JanBogaerts,

Carlo

Messina,

Corneel

Coens,

the

IDMCEORTC

Breast

Cancer

Group

EORTC

Radiation

Oncology

GroupDutch

BOOG

GroupALMANAC

Trialists’

GroupParticipating

institutesArnhem,

ZH

Rijnstate,

the

NetherlandsHardewijk,

St

Jansdal

ZH,

the

NetherlandsAmsterdam,

NKI-AVL,

the

NetherlandsFirenze,

UnivHosp

Careggi,

ItalyDrachten,

ZH

Nij

Smellinghe,

the

NetherlandsUtrecht,

Diakonessenhuis,

the

NetherlandsLeiden,

LUMC,

the

NetherlandsAmsterdam,

AMC,

the

NetherlandsDen

Haag,

MCH

Westeinde,

the

NetherlandsLjubljana,

Univ

Hosp,SloveniaLille,

Centre

Oscar

Lambret,FranceGeneva,

Hosp

Cantonal,

SwissNijmegen,

UMC

St

Radbout,

the

NetherlandsGrenoble,

CHUG

Grenoble,

FranceGdansk,

Medical

Univ,

PolandRoermond,

Laurentius

ZH,

the

NetherlandsDen

Haag,

Bronovo

ZH,

the

NetherlandsGroningen,

UMCG,

the

NetherlandsHardenberg,

Röpcke-Zweers

ZH,

the

NetherlandsDen

Haag,

Haga

ZH,

the

NetherlandsCardiff,

UnivHosp

Wales,

United

KingdomManchester,

Manchester

Univ

Hosp,

UnitedKingdomTorino,

San

Giovanni

Battista

Hosp,

ItalyApeldoorn,

Gelre

ZH,

the

NetherlandsEindhoven,

Catharina

ZH,

the

NetherlandsAmstelveen,

Amstelland

ZH,

the

NetherlandsDelft,

R

de

Graaf

GH,

the

NetherlandsHaarlem,

Kennemer

GH,

the

NetherlandsIstanbul,

Marmara

Univ

Hosp,

TurkeyHaifa,

Rambam

Med

Center,

IsraelParis,

Inst

Curie,

FranceThankyouForm

compli