Dose-dense Chemotherapy in Breast Cancer: Epirubicin-based Regimens Studied in German and UK Trials

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In the treatment of early breast cancer, dose-dense regimens (given every 2 weeks) have proven superior to conventionally dosed chemotherapy (given every 3 weeks), but data on long-term survival are lacking. Two studies presented at the San Antonio Breast Cancer Symposium evaluated the benefit of dose-dense epirubicin-based regimens, but they may have raised more questions than answers.

UK TACT2 Trial

The phase III UK TACT2 trial compared standard chemotherapy with epirubicin plus CMF (cyclophosphamide, methotrexate, fluorouracil) to accelerated (dose-dense) epirubicin in node-positive or high-risk node-negative early breast cancer.1 It tested the hypotheses that accelerated epirubicin improves outcomes, and that capecitabine (Xeloda) gives similar efficacy with better tolerability than CMF. The current report focused on the impact of accelerating epirubicin therapy.

David Cameron, MD, Professor of Oncology at the University of Edinburgh, Scotland, presented the first efficacy results of standard vs accelerated epirubicin. The capecitabine comparison is still awaited.

The study included 4,391 patients randomly assigned between 2005 and 2008 to epirubicin (100 mg/m2 × 4) every 3 weeks or accelerated epirubicin (100 mg/m2 × 4) plus pegfilgrastim (Neulasta) at 6 mg on day 2 every 2 weeks, followed by classical CMF every 4 weeks for four cycles or capecitabine (2,500 mg/m2/d × 14) every 3 weeks for four cycles. Other adjuvant treatment for HER2-positive or hormone receptor–positive disease was given as needed.

For patients whose HER2 and estrogen receptor status was known, 61% had estrogen receptor–positive/HER2-negative tumors, 19% were HER2-positive and 20% were estrogen receptor–negative/HER2-negative.

At a median follow-up time of 49 months, the primary endpoint—time to recurrence—was not significantly different for the two treatment strategies, Dr. Cameron reported. At 3 years, recurrence rates were 90.9% with standard chemotherapy and 91.0% with accelerated epirubicin; at 5 years, recurrence rates were 85.2% and 86.4%, respectively (P = .60).

Overall survival was similar as well, rates being 95.4% and 94.4%, respectively, at 3 years and 89.3% and 88.6%, respectively, at 5 years (P = .23).

“There was no evidence of any improvement in disease outcomes,” Dr. Cameron said. “The hazard ratio for time to recurrence was 0.96. And there was no differential effect by subgroup.”

The dose-dense approach was associated with less myelosuppression (growth factors were mandatory), but more hand-foot toxicity, he noted.

10-Year Follow-up of iddETC

On the other hand, the phase III German AGO Breast Study Group’s iddETC (intense dose-dense epirubicin, paclitaxel, cyclophosphamide) trial showed that a dose-dense and dose-intense regimen was superior to standard chemotherapy.2

“At 10 years, recurrence-free survival and overall survival continue to be significantly superior, with an absolute difference in overall survival of 10%,” said Volker J. Moebus, MD, Director of the Breast Center and Chief of the Department of Obstetrics and Gynecology at the Klinikum Frankfurt Höchst in Germany. “This is quite remarkable for a chemotherapy trial.”

The iddETC trial enrolled 1,284 patients with at least four positive lymph nodes (median, eight). In contrast to other dose-dense trials, the iddETC regimen is dose-dense and dose-intensified. In the experimental arm, patients received three courses each of epirubicin (150 mg/m2), paclitaxel (225 mg/m2) and cyclophosphamide (2,500 mg/m2) every 2 weeks with growth factor support. In the standard arm, they received four courses of conventionally dosed epirubicin/cyclophosphamide (90/600 mg/m2) followed by four courses of paclitaxel (175 mg/m2), all in 3-week intervals without growth factor support.

At a median follow-up of 122 months, time to relapse, which was the primary endpoint, was reduced by 26% in the iddETC arm (P = .00014). “We observed 604 disease-free survival events, 282 with iddETC and 322 with standard chemotherapy,” Dr. Moebus said. “We saw that iddETC improved disease-free survival irrespective of nodal status, HER2 status, and estrogen receptor status.”

Deaths were reduced by 28% in the iddETC arm, having occurred in 201 of those patients vs 245 in the conventional arm. This yielded 10-year overall survival rates of 69% and 59%, respectively (P = .0007).

In patients with four to nine positive nodes, deaths were reduced by 23% (P = .061), and 10-year survival rates were 74% and 66%, respectively. Greater benefit was observed in patients with ≥ 10 positive nodes, where mortality was reduced by 34% (P = .0016) and 10-year survival rates were 62% and 48%, respectively, Dr. Moebus said.

Epoetin Alfa Reduces Need for Transfusions but Increases Risk of Venous Thromboembolism

The trial also evaluated the safety of epoetin alfa as prophylaxis against anemia, and randomly assigned the iddETC cohort to epoetin alfa (n = 319) or not (n = 324). Dose-dense regimens with growth factor support require red blood cell transfusions in up to one-fourth of patients, Dr. Moebus pointed out.

In the second randomization to epoetin alfa or not, red blood cell transfusions were significantly less among patients who received epoetin alfa (13%) compared with those who received no prophylaxis (28%, P < .0001). This protection occurred without more recurrences or deaths.

Relapses occurred in 146 patients in the prophylaxis group and in 136 of patients not receiving epoetin alfa (P = .69). The 10-year relapse-free survival rates were 57% and 55%, respectively, and overall survival rates were 70% and 68%, respectively (P = .45).

The use of epoetin alfa, however, was associated with an increase in venous thromboembolism: 13% vs 7% (P = .029).

“Epoetin alfa diminished the percentage of red blood cell transfusions, and primary prophylaxis avoided a decline in hemoglobin values. Negative impacts on recurrence-free and overall survival were not found,” he said. “We also confirmed the known elevated risk for venous thrombotic events by [erythropoiesis-stimulating agent] use.”

In conclusion, Dr. Cameron noted that iddETC is a feasible regimen with a manageable toxicity profile. “We observed no therapy-related deaths or long-term toxicity such as congestive heart failure or peripheral neuropathy, and no increases in myelodysplastic syndrome or acute myeloid leukemia. The iddETC regimen should be considered a standard regimen for high-risk breast cancer patients with node-positive disease.” ■

Disclosure: Dr. Cameron reported no potential conflicts of interest. Dr. Moebus is a speaker for Amgen and Roche, has received research support from Johnson & Johnson and Amgen, and is a member of the advisory board for Sanofi-Aventis.


1. Cameron D, Barrett-Lee P, Canney P, et al: The UK TACT2 Trial: comparison of standard vs accelerated epirubicin in patients requiring chemotherapy for early breast cancer. 2012 San Antonio Breast Cancer Symposium. Abstract S3-3. Presented December 6, 2012.

2. Moebus V, Schneeweiss A, du Bois A, et al: Ten year follow-up analysis of intense dose-dense adjuvant ETC (epirubicin, paclitaxel and cyclophosphamide) confirms superior DFS and OS benefit in comparison to conventional dosed chemotherapy in high-risk breast cancer patients with ≥ 4 positive lymph nodes. 2012 San Antonio Breast Cancer Symposium. Abstract S3-4. Presented December 6, 2012.

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