Tailored Dose-Dense Chemo Fails to Show Benefit in Early Breast Cancer

Tailored dose-dense chemotherapy in high-risk early breast cancer patients did not show a significant improvement in recurrence-free survival compared with standard adjuvant chemotherapy, according to a new study. Adverse events were more frequent in the dose-dense group as well.

Results were published today in JAMA.

“Higher doses of anthracyclines increase the relative effectiveness of adjuvant chemotherapy,” wrote researchers led by Theodoros Foukakis, MD, of the Cancer Center Karolinska in Stockholm. “However, dose intensification of anthracyclines has been limited by the occurrence of cardiotoxic effects and secondary hematologic malignant neoplasms at high cumulative doses. Dose-dense therapy, defined as delivery of chemotherapy at shorter intervals without increasing the cumulative dose, was thus suggested as a means to improve efficacy.”

Body surface area is used to calculate the dosing of most chemotherapy agents, but this leads to large variability in both efficacy and adverse events among patients.

Following surgery, the international, multicenter, phase III PANTHER (Pan-European Tailored Chemotherapy) study randomized 2,017 patients to either standard adjuvant chemotherapy (n = 1,011) or tailored dose-dense chemotherapy (n = 1,006).

Women on trial were under 65 years of age (median, 51 years) and had high-risk node-negative or nonmetastatic node-positive breast cancer.

The primary endpoint of the trial was breast cancer recurrence–free survival. After a median follow-up of 5.3 years there were 269 breast cancer recurrences: 118 in patients receiving the tailored dose-dense therapy and 151 in patients on standard therapy, for a hazard ratio (HR) of 0.79 (95% CI, 0.61–1.01; log-rank P = .06; 88.7% vs 85% at 5 years).

At 5 years, overall survival in patients receiving dose-dense therapy was 92.1% compared with 90.2% in those who received standard chemotherapy (P = .09). The distant disease–free survival rate in the dose-dense therapy group was 89.4% vs 86.7% in the standard therapy group (P = .17), but neither of these secondary endpoints reached statistical significance.

Event-free survival was significantly better in patients who received the tailored dose-dense regimen (HR, 0.79; 95% CI, 0.63–0.99; P = .04; 86.7% vs 82.1% at 5 years).

Nonhematologic grade 3/4 adverse events occurred more frequently in patients treated with the tailored dose-dense chemotherapy (53% vs 37%). Fatigue, musculoskeletal pain, and neutropenic infection were the most common grade 3/4 adverse events in both groups.

The number of secondary cancers was similar between the two groups, with 18 in the tailored dose-dense group compared with 19 in the standard chemotherapy group. This included 5 cases of myelodysplastic syndrome or acute myeloid leukemia between the two groups.

Health-related quality of life was evaluated in 1,629 patients. There were no differences between the two patient groups at baseline, but significant differences in favor of the standard chemotherapy group were seen on EORTC QLQ-C30, in 13 of 15 variables, following treatment. Sexual functioning and adverse effects of chemotherapy were worse on EORTC QLQ-BR-23 in the tailored dose-dense group.

“Dose escalation led, as expected, to a worsening of health-related quality-of-life measures during treatment and an increase of grade 3 or 4 adverse effects, but no toxic deaths and no increase in secondary malignant neoplasms,” the authors wrote.

Study Details

The standard chemotherapy regimen consisted of 3 cycles of fluorouracil (500 mg/m²) plus epirubicin (100 mg/m²) and cyclophosphamide (500 mg/m²) every 3 weeks followed by 3 cycles of 100-mg/m² docetaxel every 3 weeks. The tailored dose-dense regimen consisted of 4 cycles of leukocyte nadir–based tailored and dose-dense epirubicin (38–120 mg/m²) and cyclophosphamide (450–1,200 mg/m²) every 2 weeks followed by 4 cycles of tailored dose-dense docetaxel (60–100 mg/m²) every 2 weeks.