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.
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.



To determine whether tailored dose-dense adjuvant chemotherapy improves the outcomes of early breast cancer compared with a standard 3-weekly chemotherapy schedule.



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.



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.



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.



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.



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.



clinicaltrials.gov Identifier: NCT00798070; isrctn.org Identifier: ISRCTN39017665.
Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Institutet and University Hospital, Stockholm, Sweden.
Theodoros
T
Foukakis
German Breast Group (GBG), Neu-Isenburg, Germany.
Gunter
G
von Minckwitz
Norrland University Hospital, Umeå, Sweden.
Nils-Olof
NO
Bengtsson
Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Institutet and University Hospital, Stockholm, Sweden.
Yvonne
Y
Brandberg
Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Institutet and University Hospital, Stockholm, Sweden.
Birgitta
B
Wallberg
Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Institutet and University Hospital, Stockholm, Sweden.
Tommy
T
Fornander
Landeskrankenhaus and Paracelsus Medical University, Salzburg, Austria.
Brigitte
B
Mlineritsch
Elisabeth Hospital, Kassel, Germany.
Sabine
S
Schmatloch
Department of Gynecology, Comprehensive Cancer Center, Medical University, Vienna, Austria.
Christian F
CF
Singer
Department of Internal Medicine, Comprehensive Cancer Center, Medical University, Vienna, Austria.
Günther
G
Steger
Department of Gynecology, Medical University, Innsbruck, Austria.
Daniel
D
Egle
Central Hospital, Karlstad, Sweden.
Eva
E
Karlsson
County Hospital, Sundsvall, Sweden.
Lena
L
Carlsson
German Breast Group (GBG), Neu-Isenburg, Germany.
Sibylle
S
Loibl
Helios Klinikum, Berlin-Buch, Germany.
Michael
M
Untch
Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Institutet and University Hospital, Stockholm, Sweden.
Mats
M
Hellström
Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Institutet and University Hospital, Stockholm, Sweden.
Hemming
H
Johansson
Department of Clinical Sciences, Cancer Epidemiology, Lund University, Lund, Sweden.
Harald
H
Anderson
Skåne University Hospital, Lund, Sweden.
Per
P
Malmström
Department of Surgery, Comprehensive Cancer Center, Medical University, Vienna, Austria.
Michael
M
Gnant
Landeskrankenhaus and Paracelsus Medical University, Salzburg, Austria.
Richard
R
Greil
Klinikum Frankfurt Höchst, Frankfurt, Germany.
Volker
V
Möbus
Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Institutet and University Hospital, Stockholm, Sweden.
Jonas
J
Bergh
D000328:Adult; D000368:Aged; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001317:Austria; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D017024:Chemotherapy, Adjuvant / Q000009:adverse effects / Q000379:methods; D003520:Cyclophosphamide / Q000008:administration & dosage; D018572:Disease-Free Survival; D000077143:Docetaxel; D004334:Drug Administration Schedule; D015251:Epirubicin / Q000008:administration & dosage; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D005858:Germany; D006801:Humans; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D011788:Quality of Life; D013548:Sweden; D043823:Taxoids / Q000008:administration & dosage
D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D043823:Taxoids; D000077143:Docetaxel; D015251:Epirubicin; D003520:Cyclophosphamide; D005472:Fluorouracil