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Effect of tailored dose-dense chemotherapy vs standard 3-weekly adjuvant chemotherapy on recurrence-free survival among women with high-risk early breast cancer : A randomized clinical trial

Foukakis, Theodoros; Von Minckwitz, Gunter; Bengtsson, Nils Olof; Brandberg, Yvonne; Wallberg, Birgitta; Fornander, Tommy; Mlineritsch, Brigitte; Schmatloch, Sabine; Singer, Christian F. and Steger, Günther, et al. (2016) In JAMA: the journal of the American Medical Association 316(18). p.1888-1896
Abstract

IMPORTANCE Standard dosing of chemotherapy based on body surface area results in marked interpatient variation in pharmacokinetics, toxic effects, and efficacy.Whether tailored dosing can improve outcomes is unknown, as is the role of dose-dense adjuvant chemotherapy. OBJECTIVE To determine whether tailored dose-dense adjuvant chemotherapy improves the outcomes of early breast cancer compared with a standard 3-weekly chemotherapy schedule. DESIGN, SETTING, AND PARTICIPANTS A randomized, open-label, phase 3 trial ofwomen aged 65 years and younger who had surgery for nonmetastatic node-positive or high-risk node-negative breast cancer at 86 sites in Sweden, Germany, and Austria between February 20, 2007, and September 14, 2011.... (More)

IMPORTANCE Standard dosing of chemotherapy based on body surface area results in marked interpatient variation in pharmacokinetics, toxic effects, and efficacy.Whether tailored dosing can improve outcomes is unknown, as is the role of dose-dense adjuvant chemotherapy. OBJECTIVE To determine whether tailored dose-dense adjuvant chemotherapy improves the outcomes of early breast cancer compared with a standard 3-weekly chemotherapy schedule. DESIGN, SETTING, AND PARTICIPANTS A randomized, open-label, phase 3 trial ofwomen aged 65 years and younger who had surgery for nonmetastatic node-positive or high-risk node-negative breast cancer at 86 sites in Sweden, Germany, and Austria between February 20, 2007, and September 14, 2011. INTERVENTIONS Patients were randomized 1:1 either to 4 cycles of leukocyte nadir-based tailored and dose-dense adjuvant epirubicin and cyclophosphamide every 2 weeks followed by 4 cycles of tailored dose-dense docetaxel every 2 weeks, or to standard-interval chemotherapy with 3 cycles of fluorouracil and epirubicin-cyclophosphamide every 3 weeks followed by 3 cycles of docetaxel every 3 weeks. MAIN OUTCOMES AND MEASURES The primary end pointwas breast cancer recurrence-free survival (BCRFS). Secondary end points included 5-year event-free survival (EFS), distant disease-free survival (DDFS), overall survival (OS), and rates of grade 3 or 4 toxic effects. RESULTS Among 2017 randomized patients (1006 in the tailored dose-dense group and 1011 in the control group; median [IQR] age, 51 [45-58] years; 80% with hormone receptor-positive tumors; 97%with node-positive disease), 2000 received study treatment (1 cycle of chemotherapy; 1001 in the tailored dose-dense group and 999 in the control group). After a median follow-up of 5.3 years (IQR, 4.5-6.1 years), 269 BCRFS events were reported, 118 in the tailored dose-dense group and 151 in the control group (HR, 0.79; 95%CI, 0.61-1.01; log-rank P =.06; 5-year BCRFS, 88.7%vs 85.0%). The tailored dose-dense group had significantly better EFS than the control group (HR, 0.79; 95%CI, 0.63-0.99; P =.04; 5-year EFS, 86.7%vs 82.1%). The groups did not differ in OS (HR, 0.77; 95%CI, 0.57-1.05; P =.09; 5-year OS, 92.1% vs 90.2%) or DDFS (HR, 0.83; 95%CI, 0.64-1.08; P =.17; 5-year DDFS, 89.4%vs 86.7%). Grade 3 or 4 nonhematologic toxic effects occurred in 527 (52.6%) in the tailored dose-dense group and 366 (36.6%) in the control group. CONCLUSIONS AND RELEVANCE Among women with high-risk early breast cancer, the use of tailored dose-dense chemotherapy compared with standard adjuvant chemotherapy did not result in a statistically significant improvement in breast cancer recurrence-free survival. Nonhematologic toxic effects were more frequent in the tailored dose-dense group. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00798070; isrctn.org Identifier: ISRCTN39017665.

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JAMA: the journal of the American Medical Association
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316
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18
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1888 - 1896
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American Medical Association
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  • scopus:84995814981
  • wos:000387116500017
ISSN
0098-7484
DOI
10.1001/jama.2016.15865
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English
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2016-12-05 11:31:10
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@article{cf4eebcf-9fce-4e25-b55d-d068ea94052c,
  abstract     = {<p>IMPORTANCE Standard dosing of chemotherapy based on body surface area results in marked interpatient variation in pharmacokinetics, toxic effects, and efficacy.Whether tailored dosing can improve outcomes is unknown, as is the role of dose-dense adjuvant chemotherapy. OBJECTIVE To determine whether tailored dose-dense adjuvant chemotherapy improves the outcomes of early breast cancer compared with a standard 3-weekly chemotherapy schedule. DESIGN, SETTING, AND PARTICIPANTS A randomized, open-label, phase 3 trial ofwomen aged 65 years and younger who had surgery for nonmetastatic node-positive or high-risk node-negative breast cancer at 86 sites in Sweden, Germany, and Austria between February 20, 2007, and September 14, 2011. INTERVENTIONS Patients were randomized 1:1 either to 4 cycles of leukocyte nadir-based tailored and dose-dense adjuvant epirubicin and cyclophosphamide every 2 weeks followed by 4 cycles of tailored dose-dense docetaxel every 2 weeks, or to standard-interval chemotherapy with 3 cycles of fluorouracil and epirubicin-cyclophosphamide every 3 weeks followed by 3 cycles of docetaxel every 3 weeks. MAIN OUTCOMES AND MEASURES The primary end pointwas breast cancer recurrence-free survival (BCRFS). Secondary end points included 5-year event-free survival (EFS), distant disease-free survival (DDFS), overall survival (OS), and rates of grade 3 or 4 toxic effects. RESULTS Among 2017 randomized patients (1006 in the tailored dose-dense group and 1011 in the control group; median [IQR] age, 51 [45-58] years; 80% with hormone receptor-positive tumors; 97%with node-positive disease), 2000 received study treatment (1 cycle of chemotherapy; 1001 in the tailored dose-dense group and 999 in the control group). After a median follow-up of 5.3 years (IQR, 4.5-6.1 years), 269 BCRFS events were reported, 118 in the tailored dose-dense group and 151 in the control group (HR, 0.79; 95%CI, 0.61-1.01; log-rank P =.06; 5-year BCRFS, 88.7%vs 85.0%). The tailored dose-dense group had significantly better EFS than the control group (HR, 0.79; 95%CI, 0.63-0.99; P =.04; 5-year EFS, 86.7%vs 82.1%). The groups did not differ in OS (HR, 0.77; 95%CI, 0.57-1.05; P =.09; 5-year OS, 92.1% vs 90.2%) or DDFS (HR, 0.83; 95%CI, 0.64-1.08; P =.17; 5-year DDFS, 89.4%vs 86.7%). Grade 3 or 4 nonhematologic toxic effects occurred in 527 (52.6%) in the tailored dose-dense group and 366 (36.6%) in the control group. CONCLUSIONS AND RELEVANCE Among women with high-risk early breast cancer, the use of tailored dose-dense chemotherapy compared with standard adjuvant chemotherapy did not result in a statistically significant improvement in breast cancer recurrence-free survival. Nonhematologic toxic effects were more frequent in the tailored dose-dense group. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00798070; isrctn.org Identifier: ISRCTN39017665.</p>},
  author       = {Foukakis, Theodoros and Von Minckwitz, Gunter and Bengtsson, Nils Olof and Brandberg, Yvonne and Wallberg, Birgitta and Fornander, Tommy and Mlineritsch, Brigitte and Schmatloch, Sabine and Singer, Christian F. and Steger, Günther and Egle, Daniel and Karlsson, Eva and Carlsson, Lena and Loibl, Sibylle and Untch, Michael and Hellström, Mats and Johansson, Hemming and Anderson, Harald and Malmström, Per and Gnant, Michael and Greil, Richard and Möbus, Volker and Bergh, Jonas},
  issn         = {0098-7484},
  language     = {eng},
  month        = {11},
  number       = {18},
  pages        = {1888--1896},
  publisher    = {American Medical Association},
  series       = {JAMA: the journal of the American Medical Association},
  title        = {Effect of tailored dose-dense chemotherapy vs standard 3-weekly adjuvant chemotherapy on recurrence-free survival among women with high-risk early breast cancer : A randomized clinical trial},
  url          = {http://dx.doi.org/10.1001/jama.2016.15865},
  volume       = {316},
  year         = {2016},
}