Medical Oncology 8/10/2015 University of Toronto Province-Wide Oncology Rounds May 18, 2012 The...

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


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


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


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


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

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


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


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


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


by AGE and STAGE

EBCTCG, Lancet 2011

Medical Oncology


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 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


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


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



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



Effect of radiotherapy after breast-conserving surgery (BCS ± RT): 1100 pN+ women Any recurrence Breast cancer mortality


Medical OncologyEBCTCG September 2010. Preliminary

results

Absolute effect of radiotherapy after breast-conserving surgery (BCS ± RT): 7300 pN0 women Any recurrence Breast cancer mortality


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


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

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 8/10/2015 University of Toronto Province-Wide Oncology Rounds May 18, 2012 The...

Documents

Transcript of Medical Oncology 8/10/2015 University of Toronto Province-Wide Oncology Rounds May 18, 2012 The...