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

Richard Gray,Lucy Davies,Christian Jackisch,Pascal Piedbois,Bernd Gerber,Valentina Nekljudova,Georgia-Angeliki Koliou,Marianne Ewertz,Christina Bamia,Mario Giuliano,Philip Poortmans,Hirofumi Mukai,Elizabeth Mackinnon,Constance Cirrincione,Christina Davies,Gurdeep Mannu,Jack Cuzick,Rosie Bradley,Mitch Dowsett,Stella Dolci,John Yarnold,Yasuo Ohashi,Lucia Del Mastro,Harry Bartelink,Don Berry,Jon Godwin,Milvia Zambetti,Jeremy Braybrooke,Mohammad Sadoon,Xiang Wang,Carol Redmond,Yi Shan,David Dodwell,Joe Costantino,Paul Ellis,Stephen Chia,Eileen Rakovitch,Jan Bogaerts,Sam James,Claudia Bighin,Carolyn Taylor,Catherine Hill,Lucy Gettins,Dongsheng Tu,Elizabeth Bergsten Nordström,Angelo Di Leo,Sabino De Placido,Sibylle Loibl,Bernard Fisher,Binghe Xu,Denis Larsimont,Yong Fu Shao,Larry Norton,Francesco Boccardo,Dimitris Mavroudis,Reshma Jagsi,Mike Clarke,Michael Gnant,Philip Morris,Nadia Harbeck,Mark Levine,Gordon Bass,Judith Bliss,Hui Liu,Paolo Bruzzi,Nicholas Wilcken,Hongchao Pan,Eva Carrasco,Simon Read,Theresa Mchugh,Aron Goldhirsch,David Cameron,Zulian Liu,Lucy Kilburn,Nina Bijker,Jean Marie Nogaret,Martine Piccart,Vaughan Evans,Mario Roberto Sertoli,Paul Mcgale,Jonas Bergh,Gloria Broadwater,Vinod Raina,George Fountzilas,Cornelis Van De Velde,Zhe Wang,Michael Untch,Giuseppe Viale,Daniel Rea,Clare Boddington,Wolfgang Janni,Norman Wolmark,Petronella G M Peer ,Kathleen I Pritchard ,Tanja Čufer ,Joseph A Sparano ,Andrew N.j Tutt ,S.b Vliek ,S Pastorino ,Soon Young Paik ,Serban Dan Costa ,James N Ingle ,Lois E Shepherd ,Lisa A Carey ,Prudence A Francis ,John M.s Bartlett ,Dongbing Zhao ,John R Mackey ,Sandra M Swain ,Jean‐Pierre Julien ,Timothy J Whelan ,Nancy E Davidson ,Peter M Ravdin ,F Duane ,Peter A Fasching ,James J Dignam ,Jens U Blohmer ,Vivianne C G Tjan‐Heijnen ,Fátima Cardoso ,John F Forbes ,Roger A’hern ,Bingshu E Chen ,D Lawrence Wickerham ,Paolo Pronzato ,V Möbus ,Paul E Goss ,Stewart J Anderson ,Lori J Pierce ,Étienne Brain ,W C Wood ,Eleftherios P Mamounas ,A H Tulusan ,Guenther G Steger ,Theodoros Foukakis ,Hyman B Muss ,Sabine C Linn ,J F R Robertson ,Pamela J Goodwin ,Emiel J Rutgers ,R Arriagada ,Vivien Bramwell ,Charles E Geyer ,Kathy S Albain ,Richárd Pető ,Meredith M Regan ,Robert E Coleman ,Alan S Coates ,Julie Ann Burrett ,Karen A Gelmon ,Catherine Philippson ,Joseph L Pater ,Gϋnter Von Minckwitz ,M Venturini ,Wendy R Parulekar ,Miguel Àngel Seguí ,Raymond B Weiss ,Candace R Correa ,Michelino De Laurentiis ,Robert Kerrin Hills ,Miguel Martín ,William E Barlow ,Daniel F Hayes ,Dennis J Slamon ,Richard D Gelber ,Yao-Chen Wang ,James P Morden

doi:10.1016/s0140-6736(18)33137-4

Richard Gray, Lucy Davies + Show 164 more

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https://doi.org/10.1016/s0140-6736(18)33137-4

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Journal: The Lancet	Publication Date: Feb 8, 2019
Citations: 268	License type: cc-by

Affiliation: Cancer Research UK Edinburgh Centre

Abstract

SummaryBackgroundIncreasing 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.MethodsTo 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).FindingsIndividual 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.InterpretationIncreasing 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.FundingCancer Research UK, Medical Research Council.

Highlights

Among women with early breast cancer, standard combination chemotherapy that includes an anthrac ycline and taxane reduces breast cancer mortality by about a third compared with no chemotherapy.[1]
Evidence before this study Previous meta-analyses from the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) have shown that anthracycline and taxane-based combination chemotherapy reduces the risk of breast cancer mortality by about a third compared with no chemotherapy
Compliance was similar in both arms in the trials comparing 2-weekly versus 3-weekly chemotherapy using the same drugs, doses, and number of cycles. This meta-analysis demonstrates that increasing the dose intensity of anthracycline and taxane-based adjuvant chemotherapy regimens for early breast cancer, either by shortening the interval between cycles or by sequential administration of anthracyclines and taxanes, reduces the 10-year risk of recurrence and of death from breast cancer by about 10–15%

Summary

Introduction

Among women with early breast cancer, standard combination chemotherapy that includes an anthrac ycline and taxane reduces breast cancer mortality by about a third compared with no chemotherapy.[1]. Cell biology and cytokinetic modelling suggest that increasing dose intensity (ie, the amount of drug delivered per unit time)[5] could enhance tumour cell kill, reduce tumour regrowth between cycles, and thereby further improve the likelihood of cure.[6,7] studies comparing anthracycline doses have shown no apparent benefit from escalating beyond standard doses,[8] lesser benefit is seen with doses below this threshold,[9,10,11] suggesting that dose escalation alone cannot kill all tumour cells. 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

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