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Medical Oncology
04/19/23
University of Toronto Province-Wide Oncology Rounds
May 18, 2012
The EBCTCG Overview: Is it still relevant in 2012?
ByDr. Kathleen I. Pritchard
Department Division Director, Medical Oncology
Professor, Department of MedicineFaculty of Medicine, University of Toronto
Medical Oncology
The Oxford Overview
Early Breast Cancer Trialists’ Collaborative Group
(EBCTCG)
Medical Oncology
EBCTCG OVERVIEWK. 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.
Medical Oncology
EBCTCG OVERVIEWOxford Secretariat
Richard PetoSarah DarbyMike ClarkeChristina DaviesPaul McGaleRichard GrayRory CollinsJon Godwin
Medical Oncology
EBCTCG OVERVIEWSteering Committee - Executive
Marc Buyse
Mike ClarkeRory CollinsSarah DarbyChristina DaviesMarianne EwertzMartine PiccartKathy PritchardEric WinerWilliam Wood
Medical Oncology
EBCTCG OVERVIEW
Past ChairsI. Craig HendersonWilliam Wood
Current Co-ChairsKathy PritchardMartine Piccart
Medical Oncology
EBCTCG September 2010. Preliminary results
Medical Oncology
EBCTCG OVERVIEW1984
First overview process
data sought from all randomized
trials of systemic adjuvant therapy
meta-analysis concept collaboration sought built
sustained Trialists Secretariat
Medical Oncology
EBCTCG OVERVIEW
Methodology Individual patient data
dates of randomization treatment allocation age menopausal status nodes ER, PgR
Medical Oncology
EBCTCG OVERVIEW
Methodology
Data checked for internal consistency
Data amended and updated by
correspondence
Medical Oncology
EBCTCG OVERVIEWMethodology
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 ofthe effect of different treatments
Medical Oncology
EBCTCG OVERVIEW
Outcomes
Recurrence
first reappearance of breast cancer
includes contralateral breast cancer
Medical Oncology
EBCTCG OVERVIEW
Outcomes
Deaths
unknown causes included with deaths from breast cancer
unless specifically stated otherwise
problem of death without recurrence
Medical Oncology
EBCTCG OVERVIEW
Outcomes
Breast Cancer Related Deaths
deaths of/with breast cancer
Medical Oncology
EBCTCG OVERVIEW
Outcomes Other Deaths
cardiac stroke other cancers
Medical Oncology
EBCTCG OVERVIEW
1984
Tamoxifen improved survival
CMF chemotherapy improved survival
Ovarian ablation improved survival
Medical Oncology
EBCTCG OVERVIEW
1990
longer tamoxifen seemed better tamoxifen effects greater in ER+vewomen tamoxifen reduced rate of contralateral breast cancer chemo effective in older and younger women
Medical Oncology
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
Medical Oncology
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?
Medical Oncology
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
Medical Oncology
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
Medical Oncology
EBCTCG OVERVIEW2006 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
Medical Oncology
EBCTCG OVERVIEW2010
Tamoxifen
AI’s
Chemotherapy
Locoregional therapy
Medical Oncology
2010 EBCTCG OVERVIEWTAMOXIFEN
TAMOXIFEN VS NOT LONGER VS SHORTER TAMNo of women No of women
1 yr vs not2 yr vs not 5 yr vs not
91262394021457
2 – 4 vs 1 – 2 y 5 vs 1 - 2 y 10 vs 5 y
32002000022000
54523 45200
Median follow-up = 15y22% are ER- PR-
Median follow-up = 5y50% are ER ?
Medical Oncology
Medical Oncology
2010 EBCTCG OVERVIEWTamoxifen for 5y vs same management but No Tam
Benefits(ER+)
Risks(all)
Proportional risk reductions• Recurrence 38% (2p<0.00001)•BC mortality 30% (2p<0.00001)• All deaths 22% (2p<0.00001)• Contralateral BC 39% (2p<0.00001)
Death w/o recurrence * RR 1.05 (+ 0.07) 2p>0.1Endometrial 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)
Absolute gainat 15y
13%9%
Medical Oncology
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…
Medical Oncology
2010 EBCTCG OVERVIEWTamoxifen for 5y : Impact on BC events
Medical Oncology
2010 EBCTCG OVERVIEWTamoxifen for 5y: Benefits in subgroups
Medical Oncology
2010 EBCTCG OVERVIEWTamoxifen for 5y vs same management
but no Tam
Medical Oncology
TAM for5y :BENEFITSfor whom ?
AGENodal status
Tumor grade
Tumor diameter
2010 EBCTCG OVERVIEWTamoxifen for 5y : Benefits in
subgroups
All do benefit !!
Medical Oncology
2010EBCTCG
OVERVIEW
Medical Oncology
2010EBCTCGOVERVIEW
Medical Oncology
2010 EBCTCG OVERVIEWTamoxifen for 5y: Benefits in
subgroups
TAM for5y :BENEFITSfor whom ?
ER levels(fmol/mg prot)ER- PR-
ER- PR+
ER+ PR+
ER+ PR-
No
Uncertain
Yes
Yes
Medical Oncology
2010 EBCTCG OVERVIEWTamoxifen for 5y : Benefit over time
Medical Oncology
Medical Oncology
2010 EBCTCG OVERVIEW
Duration of adjuvant Tam and outcome
Medical Oncology
2010 EBCTCG OVERVIEWImpact of TAM duration
Even 1y onlyprovides
significantbenefit
10y providesmall benefitwhich could ↑ over time
Medical Oncology
2010 EBCTCG OVERVIEWTamoxifen for 10y : Benefits vs risks at 10
yMean follow-up only 5yBenefits Risks
Proportional risk reductions• Recurrence 8% (2p=0.03)• BC mortality 10% (2p>0.1)• Contralateral 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)
Absolute gain
1% (2p 0.03)2.9% (2p 0.55)1.3% (2p 0.03)
Absolute Xcess
Medical Oncology
2010 EBCTCG OVERVIEWTAMOXIFEN
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
Medical Oncology
2010 EBCTCG OVERVIEWTAMOXIFEN
10 yrs vs 5 yrs of adjuvant TAMOXIFEN in ER+/? Disease
absolute reduction in recurrence by 8% (2p=0.03) reduces contralateral BC by 10% (2p=0.03) increases endometrial cancer by 4 fold reduces BC mortality by 3% (2p=0.55) increases death without recurrence by 1.5% (2p=0.59)
Medical Oncology
2010 EBCTCG OVERVIEWTAMOXIFEN
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
Medical Oncology
2010 EBCTCG OVERVIEWTAMOXIFEN
Messages for clinical practice in 2010
There is presently little incentive to prescribe more than 5y of TAM, in postmenopausal women More than 5y of TAM may be useful at least for DFS in premenopausal women especially those without a uterus
Medical OncologyEBCTCG
SEPTEMBER 2010
Aromatase inhibitors
Medical Oncology
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 tamafter 2-3 yrs tam
Medical Oncology
JCO, 2010, 28, 509-518
5 years AI vs tamoxifen: life table curve, recurrence
Medical Oncology
JCO, 2010, 28, 509-518
5 years AI vs tamoxifen: subgroup analysis, recurrence
Medical Oncology
JCO, 2010, 28, 509-518
5 years AI vs tamoxifen: life table curves, br ca mortality
Medical Oncology
JCO, 2010, 28, 509-518
2-3yr AI vs tam after 2-3 yrs tam: life table curve, recurrence
Medical Oncology
JCO, 2010, 28, 509-518
2-3yr AI vs tam after 2-3 yrs tam:subgroup analysis, recurrence
Medical Oncology
JCO, 2010, 28, 509-518
2-3yr AI vs tam after 2-3 yrs tam: life table curve, br ca mortality
Medical Oncology
2010 EBCTCG OVERVIEWAromatase InhibitorsMessage for Clinical Practice in 2010
AIs > tamoxifen recurrence survival good given
early after 2 yrs
Medical Oncology
Comparisons between different polychemo-
therapy regimens for early breast cancer:
meta-analyses of long-term outcome among100,000 women in 123 randomised trials
Early Breast Cancer Trialists’ Collaborative Group (EBCTCG)
Published online December 6, 2011 in The Lancet
DOI:10.1016/S0140-6736(11)61625-5
EBCTCG, Lancet 2011
Medical Oncology
Direct and indirect comparisons between different polychemotherapy regimens,
based on ~100,000 randomised women
45,000 taxane vs no taxane*(44,000 with anthracycline in both arms)
22,000 anthracycline vs CMF(18,000 vs “standard” CMF)
5,000 more vs less anthracycline(2000 comparing currently relevant doses)
31,000 polychemotherapy vs no adjuvant chemo(13,000 CMF vs Nil; 10,000 anthr.-based regimen vs Nil)
* Excludes trials of one taxane regimen vs anotherEBCTCG, Lancet 2011
Medical Oncology
Trials of chemotherapy vs no adjuvant chemotherapy
- Any anthracycline-based regimen (eg, standard 4AC) vs nil
- Standard CMF vs nil
EBCTCG, Lancet 2011
Medical Oncology
Chemotherapy vs no adjuvant chemotherapyL: anthracycline-based regimen (eg, standard 4AC), R: standard CMF
EBCTCG, Lancet 2011
Medical Oncology
Chemotherapy vs no adjuvant chemotherapyL: anthracycline-based regimen (eg, standard 4AC), R: standard CMF
EBCTCG, Lancet 2011
Medical Oncology
Chemotherapy vs no adjuvant chemotherapyL: anthracycline-based regimen (eg, standard 4AC), R: standard CMF
EBCTCG, Lancet 2011
Medical Oncology
Breast cancer mortality ratio: anthracycline-based regimen(eg, standard 4AC) or standard CMF vs no chemotherapy,
by TYPE of treatment comparison
EBCTCG, Lancet 2011
Medical Oncology
Chemotherapy (anthracycline-based regimen or standard CMF) +5 year endocrine therapy vs 5 year endocrine therapy only,
ER+ disease only: by ENTRY AGE
EBCTCG, Lancet 2011
Medical Oncology
Trials of any anthracycline-based regimen (eg, standard 4AC) vs
no adjuvant chemotherapy:
Subgroup analyses byage, stage and ER status,
and by subsets of ER+ disease
EBCTCG, Lancet 2011
Medical Oncology
Any anthracycline-based regimen (eg, standard 4AC) vs no adjuvant chemotherapy,
by ENTRY AGE
EBCTCG, Lancet 2011
Medical Oncology
Any anthracycline-based regimen (eg, standard 4AC) vs no adjuvant chemotherapy,
by NODAL STATUS
EBCTCG, Lancet 2011
Medical Oncology
Breast cancer mortality ratio: any anthracycline-based regimen (eg, standard 4AC) vs no adjuvant chemotherapy,
by AGE and STAGE
EBCTCG, Lancet 2011
Medical Oncology
Any anthracycline-based regimen (eg, standard 4AC) vs no adjuvant chemotherapy,
by ER STATUS
EBCTCG, Lancet 2011
Medical Oncology
Breast cancer mortality ratio: any anthracycline-based regimen (eg, standard 4AC) vs no adjuvant chemotherapy,
by ER STATUS and subsets of ER+
EBCTCG, Lancet 2011
Medical Oncology
Any anthracycline-based regimen (eg, standard 4AC) vs no adjuvant chemotherapy,
ER+ disease only: by ENTRY AGE
EBCTCG, Lancet 2011
Medical Oncology
Trials of any anthracycline-based regimen* vs standard CMF
*Standard 4AC, standard 4EC, or higher-cumulative-dosage
regimens (eg, CAF or CEF)
EBCTCG, Lancet 2011
Medical Oncology
Definitions of “standard” CMF and 4AC (mg/m2 x frequency/cycle)
Standard CMF: Six 4-weekly cycles of C100x14 oral M40x2 iv F600x2 iv
Standard 4AC: Four 3-weekly cycles of A60 iv C600 iv
Approximate equivalence: in the trials of standard AC vs standard CMF,both appeared to be of comparable efficacy
EBCTCG, Lancet 2011
Medical Oncology
Standard 4AC vs standard CMF: approximate equivalence
EBCTCG, Lancet 2011
Medical Oncology
Examples of higher-cumulative-dosage* anthracycline-based regimens
(mg/m2 x frequency/cycle)
CAF:
Six 4-weekly cycles of C100x14 oral A40x2 iv F500x2 iv
CEF: Six 4-weekly cycles of C75x14 oral E60x2 iv F500x2 iv
* Higher dosage than standard 4AC not only of anthracycline but also of other cytotoxic drugs;
scheduled dosages could be reduced for toxicity
EBCTCG, Lancet 2011
Medical Oncology
Anthracycline-based regimens with higher cumulative dosage (eg CAF/CEF) vs standard CMF
EBCTCG, Lancet 2011
Medical Oncology
Breast cancer mortality ratio: anthracycline-based regimen vs standard CMF,
by TYPE of treatment comparison
EBCTCG, Lancet 2011
Medical Oncology
Trials of any anthracycline-based regimen vs standard CMF:
subgroup analysesby age, stage and ER status
EBCTCG, Lancet 2011
Medical Oncology
Breast cancer mortality ratio: anthracycline-based regimen vs standard CMF,
by AGE and STAGE
EBCTCG, Lancet 2011
Medical Oncology
Breast cancer mortality ratio: anthracycline-based regimen vs standard CMF,
by ER STATUS and subsets of ER+
EBCTCG, Lancet 2011
Medical Oncology
Taxane trials
Data on 44,000 women in randomised trials of a
taxane-plus-anthracycline-based regimen vs the
SAME, or MORE, non-taxane chemotherapy
11,000 in trials where the non-taxane regimen was the SAME, and 33,000 in trials where it was MORE
[15% node-negative; mean follow-up only 5 years;
mean recurrence rate about 5% per year]
EBCTCG, Lancet 2011
Medical Oncology
Taxane-plus-anthracycline-based regimens vs (L) the SAME, or (R) MORE, non-taxane chemo.
EBCTCG, Lancet 2011
Medical Oncology
Taxane-plus-anthracycline-based regimens vs (L) the SAME, or (R) MORE, non-taxane chemo.
EBCTCG, Lancet 2011
Medical Oncology
Taxane-plus-anthracycline-based regimens vs (L) the SAME, or (R) MORE, non-taxane chemo.
EBCTCG, Lancet 2011
Medical Oncology
Taxane comparisons, subdivided according to:
(a) how the non-taxane treatments compare
(active = control, active = ½ control, or an intermediate ratio), and
(b) whether the cycles of taxane are given concurrently (©) with the anthracycline, or whether taxanes are given alone (†).
EBCTCG, Lancet 2011
Medical Oncology
Breast cancer mortality ratio in taxane trials,by TYPE of treatment comparison
EBCTCG, Lancet 2011
Medical Oncology
Taxane trials: subgroup analysesby age, stage and ER status
Taxane-plus-anthracycline-based regimenvs
an anthracycline-based control regimenwith the SAME, or MORE, of each
non-taxane cytotoxic drug
EBCTCG, Lancet 2011
Medical Oncology
EBCTCG, Lancet 2011
Taxane-plus-anthracycline-based regimen vs the SAME, or MORE, non-taxane chemo,
by ENTRY AGE
Medical Oncology
EBCTCG, Lancet 2011
Taxane-plus-anthracycline-based regimen vs the SAME, or MORE, non-taxane chemo,
by NODAL STATUS before chemotherapy
Medical Oncology
Breast cancer mortality ratio in taxane trials,by AGE and STAGE
EBCTCG, Lancet 2011
Medical Oncology
EBCTCG, Lancet 2011
Taxane-plus-anthracycline-based regimen vs the SAME, or MORE, non-taxane chemo,
by ER STATUS
Medical Oncology
Breast cancer mortality ratio in taxane trials,by ER STATUS and subsets of ER+
EBCTCG, Lancet 2011
Medical Oncology
Halving big risks and halving
small risks by chemotherapy • Proportional risk reduction does not
depend much on age, ER status or nodal status (or on tumour grade or tumour diameter)
• Absolute risk reduction, however, depends on the prognosis – and, for ER+ disease, this is the prognosis with endocrine therapy
• Information lacking on tumour gene expression and on quantitative immunohistochemistry
EBCTCG, Lancet 2011
Medical Oncology
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
Medical OncologyEBCTCG September
2010. Preliminary results
Proportional effect of radiotherapy after breast-conserving surgery (BCS ± RT) 11 000 women, pN0/pN+/pN?
Any recurrence Breast cancer mortality
Medical OncologyEBCTCG 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 Any death
“One-in-four rule” one breast cancer death avoided for every 4 recurrences avoided
Medical OncologyEBCTCG September
2010. Preliminary results
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
Medical OncologyEBCTCG September 2010. Preliminary
results
Absolute effect of radiotherapy after breast-conserving 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
Medical Oncology
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
Medical Oncology
The Oxford Overview:Is it Still Relevant in 2010 ?
Medical Oncology
YES
Medical Oncology
EBCTCG OVERVIEW
Tamoxifen
5 +/- 5 years
30% - 40% in recurrence
25 in deaths
Medical Oncology
EBCTCG OVERVIEW
AIs Better than Tam
for all subgroups 25% in
recurrence 0 – 25% in BC
mortality
Medical Oncology
EBCTCG OVERVIEW
AIs
? Stronger effect after two
years of tamoxifen
Medical Oncology
EBCTCG OVERVIEW
Chemotherapy vs None
CMF/AC
20 – 30% recurrence 10 – 30% BC
mortality
A vs CMF
Medical Oncology
EBCTCG OVERVIEW
Adriamycin vs Standard CMF
10 – 20% recurrence
10 – 20% mortality
Medical Oncology
EBCTCG OVERVIEW
Taxanes vs Non-Taxanes
10 – 20% recurrence
10% BC mortality
Medical Oncology
EBCTCG OVERVIEW
Natural History of Breast Cancer
ER/PgR +ve
ER and PgR -ve
Medical Oncology
EBCTCG OVERVIEW
By having all data
avoids publication bias gives average effect size clarifies time frames of effects process / outcomes both
useful
Medical Oncology
EBCTCG OVERVIEW Future – Yes
Publications 2 on radiation results
2010 - 2011 one on chemotherapy
2011 one on tamoxifen
2011 one on AIs
2011 Meet Again September 19-22, 2012
Medical Oncology
Medical Oncology
Medical Oncology
Medical Oncology
Medical Oncology
EBCTCG OVERVIEW Future – Yes
Publications 2 on radiation results
2010 - 2011 one on chemotherapy
2011 one on tamoxifen
2011 one on AIs
2011 Meet Again September 19-22, 2012
Medical Oncology
EBCTCG September 2010. Preliminary results