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Original Investigation
November 8, 2016

Effect of Tailored Dose-Dense Chemotherapy vs Standard 3-Weekly Adjuvant Chemotherapy on Recurrence-Free Survival Among Women With High-Risk Early Breast CancerA Randomized Clinical Trial

Author Affiliations
  • 1Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Institutet and University Hospital, Stockholm, Sweden
  • 2German Breast Group (GBG), Neu-Isenburg, Germany
  • 3Norrland University Hospital, Umeå, Sweden
  • 4Landeskrankenhaus and Paracelsus Medical University, Salzburg, Austria
  • 5Elisabeth Hospital, Kassel, Germany
  • 6Department of Gynecology, Comprehensive Cancer Center, Medical University, Vienna, Austria
  • 7Department of Internal Medicine, Comprehensive Cancer Center, Medical University, Vienna, Austria
  • 8Department of Gynecology, Medical University, Innsbruck, Austria
  • 9Central Hospital, Karlstad, Sweden
  • 10County Hospital, Sundsvall, Sweden
  • 11Helios Klinikum, Berlin-Buch, Germany
  • 12Department of Clinical Sciences, Cancer Epidemiology, Lund University, Lund, Sweden
  • 13Skåne University Hospital, Lund, Sweden
  • 14Department of Surgery, Comprehensive Cancer Center, Medical University, Vienna, Austria
  • 15Klinikum Frankfurt Höchst, Frankfurt, Germany
JAMA. 2016;316(18):1888-1896. doi:10.1001/jama.2016.15865
Key Points

Question  Does administration of adjuvant systemic chemotherapy for women with early-stage breast cancer using a tailored dose-dense algorithm improve breast cancer recurrence–free survival compared with standard dosing algorithms?

Findings  In this randomized clinical trial of 2017 women with high-risk early breast cancer aged 65 years and younger, breast cancer recurrence–free survival rates were 88.7% for tailored dose-dense chemotherapy and 85.0% for standard chemotherapy over a median of 5.3 years, a difference that was not statistically significant.

Meaning  A tailored dose-dense algorithm did not significantly improve breast cancer recurrence–free survival for women with high-risk early-stage breast cancer.


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 of women 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 point was 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