Dose-Dense Chemotherapy Benefits Persist for a Decade

Neil Osterweil

December 06, 2012

SAN ANTONIO, Texas — After 10 years, dose-dense dose-intensified chemotherapy continues to offer significantly better disease-free and overall survival than standard chemotherapy for women with breast cancer with axillary node involvement, according to a new study.

Ten-year overall survival rates were higher in women treated with an intensive dose-dense (IDD) regimen of epirubicin, paclitaxel, and cyclophosphamide than in those treated with standard-dose epirubicin and cyclophosphamide with sequential paclitaxel (69% vs 59%; P = .0007).

Volker Moebus, MD, from the Academic Hospital of the Goethe University in Frankfurt, Germany reported the study results here at the 35th Annual San Antonio Breast Cancer Symposium.

Disease-free survival was also better with the IDD regimen (hazard ratio [HR], 0.74; 95% confidence interval [CI], 0.63 - 0.87; P = .00014). This improvement occurred regardless of nodal, HER2, or estrogen-receptor status, Dr. Moebus said.

These findings extend those of a 5-year analysis of the data (J Clin Oncol. 2010;28:2874-2880), which showed better 5-year event-free survival rates with IDD chemotherapy than with conventional chemotherapy (70% vs 62%; P < .001). Overall survival rates were also better with IDD chemotherapy (82% vs 77%; P = .0295).

IDD "is a feasible regimen with manageable toxicity. We observed no therapy-related deaths or long-term toxicity like congestive heart failure or long-lasting peripheral neuropathy," Dr. Moebus said.

High Risk for Adverse Events

The survival advantages came at a cost, however; 9 patients (1.3%) in the IDD group developed myelodysplastic syndrome or acute myeloid leukemia, compared with 2 (0.3%) in the standard-dose group. That had a couple of clinicians who were not involved in the study worried.

Steven Vogl, MD, a private practitioner in the Bronx, New York, and a perennial gadfly and audience favorite at cancer meetings, said that "in the United States...most of us think that high-dose cyclophosphamide doesn't do any good, except in generating patients for leukemia doctors."

He suggested that the benefit they saw with the IDD regimen might be attributable to more frequent dosing with paclitaxel.

Michaela Higgins, MD, an instructor in medical oncology at the Massachusetts General Hospital Cancer Center in Boston, agrees. "The improved benefit seen in this study could be due to a number of factors," she told Medscape Medical News.

The dose of cyclophosphamide used in the IDD regimen, which is much higher than that used in the doxorubicin and cyclophosphamide regimen more commonly delivered in the United States, might have been influential. "It also may be a scheduling issue with [paclitaxel]. Several studies have shown that [paclitaxel], given either weekly or 2-weekly, improves outcomes over patients who were treated every 3 weeks," Dr. Higgins said.

She noted that the study reinforces the therapeutic benefits of more frequent dosing with an anthracycline-based regimen in women at high risk (some of the women in the study had as many as 10 lymph nodes involved). However, the increased risk for myelodysplastic syndrome and leukemia and the high rate of blood transfusions required in the IDD group (28% vs 13%) mitigated the adoption of a similar regimen.

Epoietin-Alfa Substudy

In this phase 3 trial, researchers from the German AGO Breast Study Group recruited 1284 patients younger than 65 years with breast cancer and the involvement of at least 4 axillary lymph nodes.

Patients were randomly assigned to either IDD or standard therapy. The IDD regimen consisted of 3 courses of epirubicin 150 mg/m², paclitaxel 225 mg/m², and cyclophosphamide 2500 mg/m² at 2-week intervals, with granulocyte-colony stimulating factor support administered at a dose of 5 µ/kg on days 3 through 10.

The standard regimen consisted of 4 courses of conventionally dosed epirubicin 90 mg/m² and cyclophosphamide 600 mg/m² followed by 4 courses of paclitaxel 175 mg/m²; all cycles were administered at 3-week intervals without growth-factor support.

The researchers conducted a substudy of patients in the IDD group to see whether subcutaneous epoetin alfa 150 IU/kg 3 times a week reduced red blood cell transfusions and/or had an effect on disease-free survival.

For 10-year overall survival, they found that the IDD regimen was especially beneficial in women with 10 or more lymph nodes involved, compared with the standard regimen (62% vs 48%; HR, 0.66; 95% CI, 0.51 - 0.86; P = .0016)

However, the addition of epoetin alfa in the IDD group did not make any difference in either disease-free or overall survival at 10 years.

The study was supported by Bristol-Myers Squibb Germany, Amgen Germany, Pharmacia Germany, and Johnson & Johnson Germany. Dr. Moebus reports receiving grant/research support from Amgen, GSK, sanofi-aventis, Pfizer, Roche, Novartis, and Johnson & Johnson. Dr. Higgins and Dr. Vogl have disclosed no relevant financial relationships.

35th Annual San Antonio Breast Cancer Symposium (SABCS): Abstract S3-4. Presented December 6, 2012.