Increasing the dose intensity of chemotherapy by more frequent administration or sequential scheduling: a patient-level meta-analysis of 37 298 women with early breast cancer in 26 randomised trials

Early Breast Cancer Trialists' Collaborative Group (EBCTCG)

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Background: Increasing the dose intensity of cytotoxic therapy by shortening the intervals between cycles, or by giving individual drugs sequentially at full dose rather than in lower-dose concurrent treatment schedules, might enhance efficacy. Methods: To clarify the relative benefits and risks of dose-intense and standard-schedule chemotherapy in early breast cancer, we did an individual patient-level meta-analysis of trials comparing 2-weekly versus standard 3-weekly schedules, and of trials comparing sequential versus concurrent administration of anthracycline and taxane chemotherapy. The primary outcomes were recurrence and breast cancer mortality. Standard intention-to-treat log-rank analyses, stratified by age, nodal status, and trial, yielded dose-intense versus standard-schedule first-event rate ratios (RRs). Findings: Individual patient data were provided for 26 of 33 relevant trials identified, comprising 37 298 (93%) of 40 070 women randomised. Most women were aged younger than 70 years and had node-positive disease. Total cytotoxic drug usage was broadly comparable in the two treatment arms; colony-stimulating factor was generally used in the more dose-intense arm. Combining data from all 26 trials, fewer breast cancer recurrences were seen with dose-intense than with standard-schedule chemotherapy (10-year recurrence risk 28·0% vs 31·4%; RR 0·86, 95% CI 0·82–0·89; p<0·0001). 10-year breast cancer mortality was similarly reduced (18·9% vs 21·3%; RR 0·87, 95% CI 0·83–0·92; p<0·0001), as was all-cause mortality (22·1% vs 24·8%; RR 0·87, 95% CI 0·83–0·91; p<0·0001). Death without recurrence was, if anything, lower with dose-intense than with standard-schedule chemotherapy (10-year risk 4·1% vs 4·6%; RR 0·88, 95% CI 0·78–0·99; p=0·034). Recurrence reductions were similar in the seven trials (n=10 004) that compared 2-weekly chemotherapy with the same chemotherapy given 3-weekly (10-year risk 24·0% vs 28·3%; RR 0·83, 95% CI 0·76–0·91; p<0·0001), in the six trials (n=11 028) of sequential versus concurrent anthracycline plus taxane chemotherapy (28·1% vs 31·3%; RR 0·87, 95% CI 0·80–0·94; p=0·0006), and in the six trials (n=6532) testing both shorter intervals and sequential administration (30·4% vs 35·0%; RR 0·82, 95% CI 0·74–0·90; p<0·0001). The proportional reductions in recurrence with dose-intense chemotherapy were similar and highly significant (p<0·0001) in oestrogen receptor (ER)-positive and ER-negative disease and did not differ significantly by other patient or tumour characteristics. Interpretation: Increasing the dose intensity of adjuvant chemotherapy by shortening the interval between treatment cycles, or by giving individual drugs sequentially rather than giving the same drugs concurrently, moderately reduces the 10-year risk of recurrence and death from breast cancer without increasing mortality from other causes. Funding: Cancer Research UK, Medical Research Council.

Original languageEnglish (US)
Pages (from-to)1440-1452
Number of pages13
JournalThe Lancet
Volume393
Issue number10179
DOIs
StatePublished - Apr 6 2019

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Meta-Analysis
Breast Neoplasms
Drug Therapy
Appointments and Schedules
Recurrence
Mortality
Anthracyclines
Pharmaceutical Preparations
Colony-Stimulating Factors
Therapeutics
Adjuvant Chemotherapy
Estrogen Receptors
Biomedical Research
Neoplasms
Research

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Increasing the dose intensity of chemotherapy by more frequent administration or sequential scheduling : a patient-level meta-analysis of 37 298 women with early breast cancer in 26 randomised trials. / Early Breast Cancer Trialists' Collaborative Group (EBCTCG).

In: The Lancet, Vol. 393, No. 10179, 06.04.2019, p. 1440-1452.

Research output: Contribution to journalArticle

@article{b65ddecb32284446ba85b750611a6b2b,
title = "Increasing the dose intensity of chemotherapy by more frequent administration or sequential scheduling: a patient-level meta-analysis of 37 298 women with early breast cancer in 26 randomised trials",
abstract = "Background: Increasing the dose intensity of cytotoxic therapy by shortening the intervals between cycles, or by giving individual drugs sequentially at full dose rather than in lower-dose concurrent treatment schedules, might enhance efficacy. Methods: To clarify the relative benefits and risks of dose-intense and standard-schedule chemotherapy in early breast cancer, we did an individual patient-level meta-analysis of trials comparing 2-weekly versus standard 3-weekly schedules, and of trials comparing sequential versus concurrent administration of anthracycline and taxane chemotherapy. The primary outcomes were recurrence and breast cancer mortality. Standard intention-to-treat log-rank analyses, stratified by age, nodal status, and trial, yielded dose-intense versus standard-schedule first-event rate ratios (RRs). Findings: Individual patient data were provided for 26 of 33 relevant trials identified, comprising 37 298 (93{\%}) of 40 070 women randomised. Most women were aged younger than 70 years and had node-positive disease. Total cytotoxic drug usage was broadly comparable in the two treatment arms; colony-stimulating factor was generally used in the more dose-intense arm. Combining data from all 26 trials, fewer breast cancer recurrences were seen with dose-intense than with standard-schedule chemotherapy (10-year recurrence risk 28·0{\%} vs 31·4{\%}; RR 0·86, 95{\%} CI 0·82–0·89; p<0·0001). 10-year breast cancer mortality was similarly reduced (18·9{\%} vs 21·3{\%}; RR 0·87, 95{\%} CI 0·83–0·92; p<0·0001), as was all-cause mortality (22·1{\%} vs 24·8{\%}; RR 0·87, 95{\%} CI 0·83–0·91; p<0·0001). Death without recurrence was, if anything, lower with dose-intense than with standard-schedule chemotherapy (10-year risk 4·1{\%} vs 4·6{\%}; RR 0·88, 95{\%} CI 0·78–0·99; p=0·034). Recurrence reductions were similar in the seven trials (n=10 004) that compared 2-weekly chemotherapy with the same chemotherapy given 3-weekly (10-year risk 24·0{\%} vs 28·3{\%}; RR 0·83, 95{\%} CI 0·76–0·91; p<0·0001), in the six trials (n=11 028) of sequential versus concurrent anthracycline plus taxane chemotherapy (28·1{\%} vs 31·3{\%}; RR 0·87, 95{\%} CI 0·80–0·94; p=0·0006), and in the six trials (n=6532) testing both shorter intervals and sequential administration (30·4{\%} vs 35·0{\%}; RR 0·82, 95{\%} CI 0·74–0·90; p<0·0001). The proportional reductions in recurrence with dose-intense chemotherapy were similar and highly significant (p<0·0001) in oestrogen receptor (ER)-positive and ER-negative disease and did not differ significantly by other patient or tumour characteristics. Interpretation: Increasing the dose intensity of adjuvant chemotherapy by shortening the interval between treatment cycles, or by giving individual drugs sequentially rather than giving the same drugs concurrently, moderately reduces the 10-year risk of recurrence and death from breast cancer without increasing mortality from other causes. Funding: Cancer Research UK, Medical Research Council.",
author = "{Early Breast Cancer Trialists' Collaborative Group (EBCTCG)} and Richard Gray and Rosie Bradley and Jeremy Braybrooke and Zulian Liu and Richard Peto and Lucy Davies and David Dodwell and Paul McGale and Hongchao Pan and Carolyn Taylor and William Barlow and Judith Bliss and Paolo Bruzzi and David Cameron and George Fountzilas and Sibylle Loibl and John Mackey and Miguel Martin and {Del Mastro}, Lucia and Volker M{\"o}bus and Valentina Nekljudova and {De Placido}, Sabino and Sandra Swain and Michael Untch and Pritchard, {Kathleen I.} and Jonas Bergh and Larry Norton and Clare Boddington and Julie Burrett and Mike Clarke and Christina Davies and Fran Duane and Vaughan Evans and Lucy Gettins and Jon Godwin and Robert Hills and Sam James and Hui Liu and Elizabeth MacKinnon and Gurdeep Mannu and Theresa McHugh and Philip Morris and Simon Read and Yaochen Wang and Zhe Wang and Peter Fasching and Nadia Harbeck and Pascal Piedbois and Michael Gnant and Sparano, {Joseph A.}",
year = "2019",
month = "4",
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doi = "10.1016/S0140-6736(18)33137-4",
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volume = "393",
pages = "1440--1452",
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TY - JOUR

T1 - Increasing the dose intensity of chemotherapy by more frequent administration or sequential scheduling

T2 - a patient-level meta-analysis of 37 298 women with early breast cancer in 26 randomised trials

AU - Early Breast Cancer Trialists' Collaborative Group (EBCTCG)

AU - Gray, Richard

AU - Bradley, Rosie

AU - Braybrooke, Jeremy

AU - Liu, Zulian

AU - Peto, Richard

AU - Davies, Lucy

AU - Dodwell, David

AU - McGale, Paul

AU - Pan, Hongchao

AU - Taylor, Carolyn

AU - Barlow, William

AU - Bliss, Judith

AU - Bruzzi, Paolo

AU - Cameron, David

AU - Fountzilas, George

AU - Loibl, Sibylle

AU - Mackey, John

AU - Martin, Miguel

AU - Del Mastro, Lucia

AU - Möbus, Volker

AU - Nekljudova, Valentina

AU - De Placido, Sabino

AU - Swain, Sandra

AU - Untch, Michael

AU - Pritchard, Kathleen I.

AU - Bergh, Jonas

AU - Norton, Larry

AU - Boddington, Clare

AU - Burrett, Julie

AU - Clarke, Mike

AU - Davies, Christina

AU - Duane, Fran

AU - Evans, Vaughan

AU - Gettins, Lucy

AU - Godwin, Jon

AU - Hills, Robert

AU - James, Sam

AU - Liu, Hui

AU - MacKinnon, Elizabeth

AU - Mannu, Gurdeep

AU - McHugh, Theresa

AU - Morris, Philip

AU - Read, Simon

AU - Wang, Yaochen

AU - Wang, Zhe

AU - Fasching, Peter

AU - Harbeck, Nadia

AU - Piedbois, Pascal

AU - Gnant, Michael

AU - Sparano, Joseph A.

PY - 2019/4/6

Y1 - 2019/4/6

N2 - Background: Increasing the dose intensity of cytotoxic therapy by shortening the intervals between cycles, or by giving individual drugs sequentially at full dose rather than in lower-dose concurrent treatment schedules, might enhance efficacy. Methods: To clarify the relative benefits and risks of dose-intense and standard-schedule chemotherapy in early breast cancer, we did an individual patient-level meta-analysis of trials comparing 2-weekly versus standard 3-weekly schedules, and of trials comparing sequential versus concurrent administration of anthracycline and taxane chemotherapy. The primary outcomes were recurrence and breast cancer mortality. Standard intention-to-treat log-rank analyses, stratified by age, nodal status, and trial, yielded dose-intense versus standard-schedule first-event rate ratios (RRs). Findings: Individual patient data were provided for 26 of 33 relevant trials identified, comprising 37 298 (93%) of 40 070 women randomised. Most women were aged younger than 70 years and had node-positive disease. Total cytotoxic drug usage was broadly comparable in the two treatment arms; colony-stimulating factor was generally used in the more dose-intense arm. Combining data from all 26 trials, fewer breast cancer recurrences were seen with dose-intense than with standard-schedule chemotherapy (10-year recurrence risk 28·0% vs 31·4%; RR 0·86, 95% CI 0·82–0·89; p<0·0001). 10-year breast cancer mortality was similarly reduced (18·9% vs 21·3%; RR 0·87, 95% CI 0·83–0·92; p<0·0001), as was all-cause mortality (22·1% vs 24·8%; RR 0·87, 95% CI 0·83–0·91; p<0·0001). Death without recurrence was, if anything, lower with dose-intense than with standard-schedule chemotherapy (10-year risk 4·1% vs 4·6%; RR 0·88, 95% CI 0·78–0·99; p=0·034). Recurrence reductions were similar in the seven trials (n=10 004) that compared 2-weekly chemotherapy with the same chemotherapy given 3-weekly (10-year risk 24·0% vs 28·3%; RR 0·83, 95% CI 0·76–0·91; p<0·0001), in the six trials (n=11 028) of sequential versus concurrent anthracycline plus taxane chemotherapy (28·1% vs 31·3%; RR 0·87, 95% CI 0·80–0·94; p=0·0006), and in the six trials (n=6532) testing both shorter intervals and sequential administration (30·4% vs 35·0%; RR 0·82, 95% CI 0·74–0·90; p<0·0001). The proportional reductions in recurrence with dose-intense chemotherapy were similar and highly significant (p<0·0001) in oestrogen receptor (ER)-positive and ER-negative disease and did not differ significantly by other patient or tumour characteristics. Interpretation: Increasing the dose intensity of adjuvant chemotherapy by shortening the interval between treatment cycles, or by giving individual drugs sequentially rather than giving the same drugs concurrently, moderately reduces the 10-year risk of recurrence and death from breast cancer without increasing mortality from other causes. Funding: Cancer Research UK, Medical Research Council.

AB - Background: Increasing the dose intensity of cytotoxic therapy by shortening the intervals between cycles, or by giving individual drugs sequentially at full dose rather than in lower-dose concurrent treatment schedules, might enhance efficacy. Methods: To clarify the relative benefits and risks of dose-intense and standard-schedule chemotherapy in early breast cancer, we did an individual patient-level meta-analysis of trials comparing 2-weekly versus standard 3-weekly schedules, and of trials comparing sequential versus concurrent administration of anthracycline and taxane chemotherapy. The primary outcomes were recurrence and breast cancer mortality. Standard intention-to-treat log-rank analyses, stratified by age, nodal status, and trial, yielded dose-intense versus standard-schedule first-event rate ratios (RRs). Findings: Individual patient data were provided for 26 of 33 relevant trials identified, comprising 37 298 (93%) of 40 070 women randomised. Most women were aged younger than 70 years and had node-positive disease. Total cytotoxic drug usage was broadly comparable in the two treatment arms; colony-stimulating factor was generally used in the more dose-intense arm. Combining data from all 26 trials, fewer breast cancer recurrences were seen with dose-intense than with standard-schedule chemotherapy (10-year recurrence risk 28·0% vs 31·4%; RR 0·86, 95% CI 0·82–0·89; p<0·0001). 10-year breast cancer mortality was similarly reduced (18·9% vs 21·3%; RR 0·87, 95% CI 0·83–0·92; p<0·0001), as was all-cause mortality (22·1% vs 24·8%; RR 0·87, 95% CI 0·83–0·91; p<0·0001). Death without recurrence was, if anything, lower with dose-intense than with standard-schedule chemotherapy (10-year risk 4·1% vs 4·6%; RR 0·88, 95% CI 0·78–0·99; p=0·034). Recurrence reductions were similar in the seven trials (n=10 004) that compared 2-weekly chemotherapy with the same chemotherapy given 3-weekly (10-year risk 24·0% vs 28·3%; RR 0·83, 95% CI 0·76–0·91; p<0·0001), in the six trials (n=11 028) of sequential versus concurrent anthracycline plus taxane chemotherapy (28·1% vs 31·3%; RR 0·87, 95% CI 0·80–0·94; p=0·0006), and in the six trials (n=6532) testing both shorter intervals and sequential administration (30·4% vs 35·0%; RR 0·82, 95% CI 0·74–0·90; p<0·0001). The proportional reductions in recurrence with dose-intense chemotherapy were similar and highly significant (p<0·0001) in oestrogen receptor (ER)-positive and ER-negative disease and did not differ significantly by other patient or tumour characteristics. Interpretation: Increasing the dose intensity of adjuvant chemotherapy by shortening the interval between treatment cycles, or by giving individual drugs sequentially rather than giving the same drugs concurrently, moderately reduces the 10-year risk of recurrence and death from breast cancer without increasing mortality from other causes. Funding: Cancer Research UK, Medical Research Council.

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UR - http://www.scopus.com/inward/citedby.url?scp=85063678346&partnerID=8YFLogxK

U2 - 10.1016/S0140-6736(18)33137-4

DO - 10.1016/S0140-6736(18)33137-4

M3 - Article

C2 - 30739743

AN - SCOPUS:85063678346

VL - 393

SP - 1440

EP - 1452

JO - The Lancet

JF - The Lancet

SN - 0140-6736

IS - 10179

ER -