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Tailored dose-dense therapy fails to improve RFS in early breast cancer
Tailored dose-dense chemotherapy did not significantly improve breast cancer RFS compared with standard adjuvant chemotherapy among women with high-risk early breast cancer, according to results of a randomized, open-label, phase 3 trial published in JAMA.
In fact, nonhematologic toxic effects occurred more frequently in patients given tailored dose-dense chemotherapy.
“Although the total treatment time was similar, patients in the tailored dose-dense group underwent more therapy courses and subsequently had more toxic effects, more hospital visits and frequent blood draws,” Jonas Bergh, MD, professor and senior physician in the department of oncology–pathology at Cancer Center Karolinska of Karolinska Institutet and University Hospital in Stockholm, Sweden, and colleagues wrote.
Standard dosing of chemotherapy is calculated based on body surface area and leads to great interpatient variability in pharmacokinetics, toxicity and efficacy. Dose-dense therapy — or chemotherapy delivered at shorter intervals without increasing the cumulative dose — has been suggested as a means to improve efficacy of chemotherapy for early breast cancer.
Bergh and colleagues evaluated data from 2,017 women aged younger than 65 years (median age, 51 years; interquartile range [IQR], 45-58) who had surgery for nonmetastatic node-positive or high-risk node-negative breast cancer at 86 sites in Sweden, Germany and Austria. Researchers randomly assigned patients to receive tailored dose-dense adjuvant chemotherapy (n = 1,006) or standard chemotherapy (n = 1,011).
Tailored dose-dense chemotherapy included four cycles of leukocyte nadir–based tailored and dose-dense adjuvant epirubicin and cyclophosphamide every 2 weeks, followed by four cycles of tailored dose-dense docetaxel every 2 weeks.
Standard-interval chemotherapy consisted of three cycles of fluorouracil and epirubicin–cyclophosphamide every 3 weeks, followed by three cycles of docetaxel every 3 weeks.
Breast cancer RFS served as the study’s primary endpoint. Secondary endpoints included 5-year EFS, distant DFS, OS, and rate of grade 3 or grade 4 toxicity.
After a median follow-up of 5.3 years (IQR, 4.5-6.1), breast cancer RFS events occurred in 118 women in the tailored dose-dense group and 151 women in the control group. The 5-year breast cancer RFS rate was 88.7% in the tailored dose-dense group, which was not significantly better than the 85% rate in the control group (HR = 0.79; 95% CI, 0.61-1.01).
However, the tailored dose-dense group had a significantly better 5-year EFS than the standard-interval group (86.7% vs. 82.1%; HR = 0.79; 95% CI, 0.63-0.99).
Researchers observed comparable 5-year OS (92.1% vs. 90.2%; HR = 0.77; 95% CI, 0.57-1.05) and 5-year distant DFS (89.4% vs. 86.7%; HR = 0.83; 95% CI, 0.64-1.08) between the groups.
Grade 3 or grade 4 nonhematologic toxic effects occurred in 52.6% of those in the tailored dose-dense group and 36.6% in the standard chemotherapy group. The most common of these events included fatigue, musculoskeletal pain, and neutropenic infection in both groups.
“Hematologic toxic effects were increased in the tailored dose-dense group, as was expected, owing to dose tailoring, mainly for the epirubicin and cyclophosphamide treatment,” Bergh and colleagues wrote.
by Chuck Gormley
Disclosure: Bergh reports fees to Asklepios Medicin HB from UpToDate and grants to Karolinska Institutet and University Hospital from Amgen, AstraZeneca, Bayer, Merck, Pfizer, Roche and Sanofi-Aventis. Please see the study for a list of all other researchers’ relevant financial disclosures.