Transcript The Oxford Overview - NCIC Clinical Trials Group

Third Annual Maria Ricci Lecture
Queen’s University and the
NCIC CTG Clinical Trials Group
Kingston, Ontario
Canada
The Oxford Overview:
Is it Still Relevant in 2010 ?
Presented by
KATHLEEN I. PRITCHARD, MD, FRCPC
Sunnybrook Odette Cancer Centre
University of Toronto
Toronto, Canada
The Oxford Overview
Early Breast Cancer Trialists’
Collaborative Group
(EBCTCG)
EBCTCG OVERVIEW
Steering Committee
K. Albain, S. Anderson, R. Arriagada, W. Barlow, J.
Bergh, J. Bliss, M. Buyse, D. Cameron, M. Clarke, A.
Coates, R. Collins, J. Costantino, J. Cuzick, S. Darby, N.
Davidson, C. Davies, A. Di Leo, M. Dowsett, M. Ewertz,
R. Gelber, C. Geyer, J. Godwin, A. Goldhirsch, R. Gray,
D. Hayes, C. Hill, J. Ingle, R. Jakesz, M. Kaufmann, P.
McGale, L. Norton, Y. Ohashi, S. Paik, E. Perez, R. Peto,
M. Piccart, L. Pierce, G. Pruneri, K. Pritchard, V. Raina,
P. Ravdin, J. Robertson, E. Rutgers, Y. F. Shao, S.
Swain, C. Taylor, P. Valagussa, G. Viale, T. Whelan, E.
Winer, Y. Wang, W. Wood.
EBCTCG OVERVIEW
Oxford Secretariat
Richard Peto
Sarah Darby
Mike Clarke
Christina Davies
Paul McGale
Richard Gray
Rory Collins
Jon Godwin
EBCTCG OVERVIEW
Steering Committee - Executive
Marc Buyse
Mike Clarke
Rory Collins
Sarah Darby
Christina Davies
Marianne Ewertz
Martine Piccart
Kathy Pritchard
Eric Winer
William Wood
EBCTCG OVERVIEW
Past Chairs
I. Craig Henderson
William Wood
Current Co-Chairs
Kathy Pritchard
Martine Piccart
EBCTCG September 2010.
Preliminary results
EBCTCG OVERVIEW
1984

First overview process





data sought from all randomized
trials of systemic adjuvant therapy
meta-analysis concept
collaboration sought built
sustained
Trialists
Secretariat
EBCTCG OVERVIEW
Methodology

Individual patient data

dates of randomization

treatment allocation

age

menopausal status

nodes

ER, PgR
EBCTCG OVERVIEW
Methodology

Data checked for internal
consistency

Data amended and updated by
correspondence
EBCTCG OVERVIEW
Methodology

Each trial analysed separately

Women in one trial are compared directly with
only the women in the same trial

One log rank statistic per trial

Stratified by age and nodal status

Combined to give an overall estimate of
the effect of different treatments
EBCTCG OVERVIEW
Outcomes

Recurrence

first reappearance of breast cancer

includes contralateral breast
cancer
EBCTCG OVERVIEW
Outcomes

Deaths

unknown causes included with deaths
from breast cancer unless specifically
stated otherwise

problem of death without recurrence
EBCTCG OVERVIEW
Outcomes

Breast Cancer Related Deaths

deaths of/with breast cancer
EBCTCG OVERVIEW
Outcomes
 Other Deaths



cardiac
stroke
other cancers
EBCTCG OVERVIEW
1984

Tamoxifen improved survival

CMF chemotherapy improved survival

Ovarian ablation improved survival
EBCTCG OVERVIEW
1990




longer tamoxifen seemed better
tamoxifen effects greater in ER+ve
women
tamoxifen reduced rate of contralateral
breast cancer
chemo effective in older and younger
women
EBCTCG OVERVIEW
1995




huge magnitude of effect of 5 years of
tamoxifen
5 years of tamoxifen clearly better than
1 or 2
tamoxifen prevented contralateral
breast cancer only in women with
ER+ve disease
anthracycline containing regimens
better than CMF
EBCTCG OVERVIEW
2000

15 year effects of chemo sustained in older
and younger women

chemo effect appears greater in ER negative
than in ER positive disease
But is this really true?
EBCTCG OVERVIEW
2000



15 year effects of 5 years of tamoxifen
sustained and of great magnitude
door opened to question of 5 years versus
longer tamoxifen
ovarian suppression/ablation effective but
not significantly so when added to
chemotherapy
EBCTG OVERVIEW
2005
 2000 Overview: Lancet, 2005
 Trialists meet: new Steering Committee
formed
 Many new trials added
 More women-years of follow-up for all major
questions
 But major trials still missing
EBCTCG OVERVIEW
2006
 Trialists met: new questions
 type of anthracycline-based regimen
 taxane trial status
 aromatase inhibitors
 trastuzumab
 chemoendocrine therapy (only in ER+,
pre- and postmenopausal subsets)
 Subcommittees of the SC formed
EBCTCG OVERVIEW
2010
 Tamoxifen
 AI’s
 Chemotherapy
 Locoregional therapy
2010 EBCTCG OVERVIEW
TAMOXIFEN
TAMOXIFEN VS NOT
No of women
1 yr vs not
2 yr vs not
5 yr vs not
LONGER VS SHORTER TAM
No of women
9126
23940
21457
2 – 4 vs 1 – 2 y 3200
5 vs 1 - 2 y 20000
10 vs 5 y
22000
54523
45200
Median follow-up = 15y
22% are ER- PR-
Median follow-up = 5y
50% are ER ?
2010 EBCTCG OVERVIEW
Tamoxifen for 5y vs same management but No Tam
Risks
Benefits
(all)
(ER+)
Absolute gain
at 15y
Proportional risk reductions
• Recurrence
38% (2p<0.00001) 13%
•BC mortality
30% (2p<0.00001) 9%
• All deaths
22% (2p<0.00001)
• Contralateral BC 39% (2p<0.00001)
Death w/o recurrence *
RR 1.05 (+ 0.07) 2p>0.1
Endometrial incidence
RR 2.33 (+ 0.25)
2p<0.00001
* Numerical excess of deaths due to stroke, pulmonary embolus, uterine cancer
(15 vs 13 ; 6 vs 0; 8 vs 1)
2010 EBCTCG OVERVIEW
Tamoxifen for 5y vs same management but no Tam
Learning more about Tam benefits
 On types of B.C. events…
 In subgroups
 In relation to chemotherapy administration
 Over time…
2010 EBCTCG OVERVIEW
Tamoxifen for 5y : Impact on BC events
2010 EBCTCG OVERVIEW
Tamoxifen for 5y: Benefits in subgroups
2010 EBCTCG OVERVIEW
Tamoxifen for 5y vs same management but no Tam
2010 EBCTCG OVERVIEW
Tamoxifen for 5y : Benefits in subgroups
AGE
Tumor
grade
Nodal
status
TAM for
5y :
BENEFITS
for whom ?
All do benefit !!
Tumor
diameter
2010
EBCTCG
OVERVIEW
2010
EBCTCG
OVERVIEW
2010 EBCTCG OVERVIEW
Tamoxifen for 5y: Benefits in subgroups
Yes
No
ER- PR-
ER levels
(fmol/mg prot)
ER- PR+
TAM for
5y :
BENEFITS
for whom ?
Uncertain
ER+ PR+
ER+ PR-
Yes
2010 EBCTCG OVERVIEW
Tamoxifen for 5y : Benefit over time
2010 EBCTCG OVERVIEW
Duration of adjuvant Tam and
outcome
2010 EBCTCG OVERVIEW
Impact of TAM duration
Even 1y only
provides
significant
benefit
10y provide
small benefit
which could ↑
over time
2010 EBCTCG OVERVIEW
Tamoxifen for 10y : Benefits vs risks at 10 y
Mean follow-up only 5y
Risks
Benefits
Absolute
Xcess
Absolute gain
Proportional risk reductions
• Recurrence
8% (2p=0.03) 1% (2p 0.03)
• BC mortality 3% (2p>0.1) 2,9% (2p 0.55)
• Contralateral
1.3% (2p 0.03)
BC
Death w/o recurrence *
+ 1,5% (2p=0.59)
Endometrial cancers
+ 0.7% (2p=0.00004)
*Numerical excess of deaths due to cerebrovascular events (42 vs 38 in y0-4;
27 vs 24 in y5-10), thrombo-embolic events (10 vs 56 in y0-4), end. cancers
(8 vs 6 in y0-4, 4 vs 2 in y5-10)
2010 EBCTCG OVERVIEW
TAMOXIFEN
 5y in ER+ disease
 reduces








recurrence by 38%,
BC death by 30%
all deaths by 22%
contralateral BC by 40%
benefits all women with ER+ disease
unclear benefits in ER-PgR+ disease
benefits women with ER very rich tumors more
increases endometrial cancer by 2.3 fold
2010 EBCTCG OVERVIEW
TAMOXIFEN
10 yrs vs 5 yrs of adjuvant TAMOXIFEN in ER+/?
Disease





absolute reduction in recurrence by 1% (2p=0.03)
reduces contralateral BC by 1.3% (2p=0.03)
increases endometrial cancer by 0.7% (2p=0.00004)
reduces BC mortality by 3% (2p=0.55)
increases death without recurrence by 1.5% (2p=0.59)
2010 EBCTCG OVERVIEW
TAMOXIFEN
Messages for clinical practice in 2010
 PgR does not predict for benefit of
adjuvant TAM
 For ER-PgR+ patients, the tumor should
be retested and if doubt remains, TAM
could be offered
 There is presently little incentive to
prescribe more than 5y of TAM, especially
in women with an uterus
Aromatase inhibitors
EBCTCG SEPTEMBER 2010
Data from 1st analysis
• No unplanned cross-over
• Cut-off 30 Sept 2006
• Cohort 1: 5yrs AI vs 5yrs tam
• Cohort 2: 2-3 yrs of AI vs 2-3 yrs of tam
after 2-3 yrs tam
5 years AI vs tamoxifen: trial-specific recurrence data
JCO, 2010, 28, 509-518
5 years AI vs tamoxifen: life table curve, recurrence
JCO, 2010, 28, 509-518
5 years AI vs tamoxifen: life table curves, br ca mortality
JCO, 2010, 28, 509-518
2-3yr AI vs tam after 2-3 yrs tam: life table curve, recurrence
JCO, 2010, 28, 509-518
2-3yr AI vs tam after 2-3 yrs tam: life table curve,
br ca mortality
JCO, 2010, 28, 509-518
2-3yr AI vs tam after 2-3 yrs tam: life table curve, mortality
(C) without recurrence, (D) all cause
JCO, 2010, 28, 509-518
2010 EBCTCG OVERVIEW
Aromatase Inhibitors
Message for Clinical Practice in 2010
 AIs > tamoxifen
 recurrence
 survival
 good given
 early
 after 2 yrs
2010 EBCTCG OVERVIEW
CHEMOTHERAPY
Polychemo vs NOT Anthracycline (A) vs CMF Taxane (+A) vs A
N = 23500
N ≈ 9500
N ≈ 14000
N = 22000
N ≈ 18000
N = 44000
N ≈ 11.000
N ≈ 23.000
N ≈ 10.000
CMF vs NOT
(only 5000 st CMF)
Anthrac vs NOT
(only 3000 of
Mas strenght)
Anthrac vs
st CMF
Tax + A vs lots of A
Tax + A vs more A
Tax + A vs same A
2010 EBCTCG OVERVIEW
Polychemotherapy versus
No chemotherapy
10y results in 23500 women
2010 EBCTCG OVERVIEW
Polychemotherapy vs NIL : 10y results
A
N
T
H
R
A
C
Y
C
L
I
N
E
C
M
F
S
T
A
N
D
A
R
D
S
2010 EBCTCG OVERVIEW
Polychemotherapy vs NO CTX : 10y results
CMF vs No CTX
Anthracycline vs No CTX
RR
Recurrence
1.0 A≥60 Lower All
E≥90 doses
BC mortality
A≥60 Lower All
E≥90 doses
0.76 0.73 0.72
0.68
0.5
RR
Recurrence
St
other
1.0 CMF CMF
0.82 0.79
0.70
0.5
All
BC mortality
St
other
CMF CMF
0.80 0.76 0.76
All
0.88 0.84
2010 EBCTCG OVERVIEW
Polychemotherapy vs NIL
Learning more about benefits
• Over time...
• In subgroups
2010 EBCTCG OVERVIEW
Polychemotherapy vs NO CTX :
Impact over time
Anthracycline vs No CTX
CMF vs No CTX
Strong, early effect... !
2010 EBCTCG OVERVIEW
Polychemotherapy vs NO CTX :
Impact on recurrence in subgroups
Anthracycline vs NO CTX
Standard CMF vs NO CTX
No indication of reduced
benefit !
No indication of reduced
benefit !
2010 EBCTCG OVERVIEW
Polychemotherapy vs NO CTX :
Benefits in subgroups
Concurrent
endocrine
AGE
diameter
therapy
ER poor,
+ or ?
Tumour
PolyCTX vs
No CTX
Who benefits
?
Tumour
Grade
All do benefit !
Nodal
Status
2010 EBCTCG OVERVIEW
Anthracycline regimens
vs
standard CMF
10y results in 22000 women
2010 EBCTCG OVERVIEW
A
C
X
4
M
O
R
E
A
N
T
H
R
A
C
Y
C
L
I
N
E
2010 EBCTCG OVERVIEW
Ratio of
annual
death
rates
1.0
Anthracycline vs standard CMF :
10 y results mortality with recurrence
Dose per cycle ≥ A60, E90
Any A
regimen
0.89
0.89
Cum
dose
A 360
E 720-800
0.78
0.5
Cum
dose
A 300
E 400-480
0.82
Cum
dose
A ≤ 360
0.98
Dose per cycle
< A60, E90
0.93
2010 EBCTCG OVERVIEW
Taxane + Anthracycline
regimens vs
Anthracycline regimens
5y results in 44000 women
2010 EBCTCG OVERVIEW
T
+
A
Vs
s
a
m
e
A
T
+
A
Vs
m
o
r
e
A
2010 EBCTCG OVERVIEW
Taxane + Anthracycline vs A :
5 y results in 44000 women
Ratio of
annual
event
rates
Mortality w/
recurrence
Recurrence
1.0
T+A
vs
int A
all
T+A
vs
T+A
same A vs
more A
all
T+A
vs
int A
T+A
T+A
vs
vs
same A
more A
0.75
2p<0.00001 2p=0.0001 2p<0.0001 2pNS
2p=0.00001 2p=0.001 2p=0.003 2pNS
2010 EBCTCG OVERVIEW:
Polychemotherapy :
Impact on recurrence over time
Anthracycline vs st CMF
EARLY IMPACT
Anthracycline (A) +
Taxane vs A
EARLY and LATE IMPACT
2010 EBCTCG OVERVIEW
Taxane + Anthracycline vs A :
Impact on recurrence in subgroups
No indication of reduced benefit !
2010 EBCTCG OVERVIEW
POLYCHEMOTHERAPY
Messages for clinical practice in 2010
 Taxane-based regimens
 Reduced in recurrence (2.8%)
 Reduced mortality with recurrence (1.3%)
 Except when compared to very well dosed
(total 2x2) anthracycline-based regimens
 Effect seems independent from the recorded
tumor characteristics (with lack on information
on HER2)
 Effect persists over 5 years
Effect of Radiotherapy after
Breast-conserving Surgery on
10-year Recurrence and 15-year Mortality
in Women with Early Breast Cancer
EBCTCG September 2010.
Preliminary results
Randomised trials of radiotherapy
following breast-conserving surgery (BCS ± RT)
that began before the year 2000
No of
trials
Years
trials
started
Lumpectomy
Sector resection
Low risk women
6
4
7
1976-86
1981-91
1989-96
All women
pN0
pN+
pN ?
17
Trial category
50% increase since EBCTCG (2005)
EBCTCG September 2010.
Preliminary results
No of women
4500
2400
4000
11,000
7300
1100
2500
Proportional effect of radiotherapy after breast-conserving
surgery (BCS ± RT) 11 000 women, pN0/pN+/pN?
Any recurrence
Breast cancer mortality
EBCTCG September 2010.
Preliminary results
Absolute effect of radiotherapy after breast conserving
surgery (BCS ± RT): 11 000 women pN0/pN+/pN?
Any recurrence
Breast cancer mortality
EBCTCG September 2010.
Preliminary results
Any death
Effect of radiotherapy after breast-conserving
surgery (BCS ± RT): 1100 pN+ women
Any recurrence
Breast cancer mortality
“One-in-four rule” one breast cancer death avoided for every 4 recurrences
avoided
EBCTCG September 2010.
Preliminary results
Absolute effect of radiotherapy after breastconserving surgery (BCS ± RT): 7300 pN0 women
Any recurrence
Breast cancer mortality
“One-in-four rule” one breast cancer death avoided for every 4 recurrences avoided
EBCTCG September 2010. Preliminary results
Conclusions
• Radiotherapy highly effective in reducing
recurrence in both pN0 and pN+ women
• Radiotherapy also reduces 15-year breast
cancer
• “One-in-four” rule applies for pN0 and
pN1 women
• Benefits not substantially reduced by fatal
side-effects
EBCTCG September 2010.
Preliminary results
The Oxford Overview:
Is it Still Relevant in 2010 ?
YES
EBCTCG OVERVIEW
Tamoxifen

5 +/- 5 years


30% - 40% in recurrence
25 in deaths
EBCTCG OVERVIEW
AIs

Better than Tam



for all subgroups
25% in recurrence
0 – 25%
in BC mortality
EBCTCG OVERVIEW
AIs

? Stronger effect after two
years of tamoxifen
EBCTCG OVERVIEW
Chemotherapy vs None

CMF/AC


20 – 30%
10 – 30%
A vs CMF
recurrence
BC mortality
EBCTCG OVERVIEW

Adriamycin vs Standard CMF


10 – 20%
10 – 20%
recurrence
mortality
EBCTCG OVERVIEW
Taxanes vs Non-Taxanes

10 – 20%

10%
recurrence
BC mortality
EBCTCG OVERVIEW

Natural History of Breast Cancer


ER/PgR +ve
ER and PgR -ve
EBCTCG OVERVIEW

By having all data




avoids publication bias
gives average effect size
clarifies time frames of effects
process / outcomes both useful
EBCTCG OVERVIEW


Future – Yes
Publications
 3 on radiation results
2010 - 2011
 one on chemotherapy
2011
 one on AIs
2011

Meet Again September 19-22, 2012
EBCTCG OVERVIEW


Future – Yes
Publications
 3 on radiation results
2010 - 2011
 one on chemotherapy
2011
 one on AIs
2011

Meet Again September 19-22, 2012