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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

2019; Elsevier BV; Volume: 393; Issue: 10179 Linguagem: Inglês

10.1016/s0140-6736(18)33137-4

1474-547X

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

Cancer Genomics and Diagnostics

BackgroundIncreasing 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.