Dose-Dense Chemotherapy in Breast Cancer

Audrey Andrews

March 2013, Highlights - Chemotherapy

Two studies presented in San Antonio reached conflicting conclusions regarding the value of dose-dense chemotherapy in patients with early breast cancer.

The phase 3 UK TACT2 trial compared standard chemotherapy with epirubicin plus CMF (cyclophosphamide/methotrexate/fluorouracil) with accelerated (dose-dense) epirubicin in node-positive or in high-risk, node-negative early breast cancer. The current report focused on the impact of accelerating epirubicin chemotherapy; the capecitabine/CMF comparison is premature.

The study included 4391 patients randomized between 2005 and 2008 to epirubicin (100 mg/m2 for 4 cycles) every 3 weeks or accelerated epirubicin (100 mg/m2 for 4 cycles plus peg­filgrastim 6 mg on day 2) every 2 weeks, followed by classical CMF every 4 weeks for 4 cycles or capecitabine (2500 mg/m2 daily for 14 days) every 3 weeks for 4 cycles. Other adjuvant treatment for HER2-positive or hormone receptor?positive disease was given as needed.

At a median follow-up of 49 months, the primary end point—time to recurrence (TTR)—was not significantly different for the 2 treatment strategies, reported David Cameron, MD, Pro­fessor of Oncology, University of Edinburgh, Scotland.

The TTR rates were 90.9% with standard chemotherapy and 91.0% with accelerated epirubicin at 3 years, and 85.2% and 86.4%, respectively (P = .60), at 5 years.

Overall survival (OS) rates were similar?95.4% with standard chemotherapy and 94.4% with accelerated epirubicin at 3 years, and 89.3% and 88.8%, respectively, at 5 years (P = .23). No subgroup benefited more from
the dose-dense regimen than any
other subgroup.

“There was no evidence of any improvement in disease outcomes,” Dr Cameron noted.

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

Dose-Dense/Dose-Intense Regimen Superior to Conventional Chemotherapy

In contrast, the phase 3 German AGO iddETC (intense dose-dense epirubicin/paclitaxel/cyclophosphamide) trial showed that an epirubicin-based regimen that was dose-dense and dose-intense was superior to standard chemotherapy.

Volker J. Möbus, PhD, Head, De­part­ment of Obstetrics and Gyne­cology, of the Klinikum Frankfurt Hoechst in Germany, reported, “At 10 years, recurrence-free survival and overall survival continue to be significantly superior, with an absolute difference in overall survival of 10%.”

The iddETC trial enrolled 1284 patients with ?4 positive lymph nodes (median, 8). In the experimental arm (iddETC), patients received 3 cycles each of epirubicin (150 mg/m2) every 2 weeks with growth factor support.

In the standard arm, they received 4 cycles of conventionally dosed epirubicin plus cyclophosphamide (90/600 mg/m2) followed by 4 cycles 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 end point, was reduced by 26% (P = .014) in the iddETC arm.

“We saw that iddETC improved disease-free survival irrespective of nodal status, HER2 status, and estrogen receptor status,” Dr Möbus said.

Deaths were reduced by 28% in the iddETC arm. The 10-year OS rates were 69% and 59%, respectively (P = .007). The most benefit was seen in patients with ?10 positive nodes, where mortality was reduced by 34% (P = .016) and 10-year survival rates were 62% and 48%, respectively, Dr Cameron explained.

Epoetin Alfa Reduces the Need for Transfusions

The iddETC arm was randomized to receive epoetin alfa as prophylaxis treatment against anemia, or no epoetin alfa, in an effort to determine the safety, efficacy, and the impact on clinical outcomes. Dose-dense regimens with growth factor support require red blood cell transfusions in up to 25% of patients, Dr Möbus noted.

Red blood cell transfusions were significantly lower among patients who received epoetin alfa (13% vs 28%; P <.001), and there was no increase in recurrences or deaths. There was no difference in relapse rates or OS; however, the use of epoetin alfa was as­sociated with an increase in venous thromboembolism?13% versus 7%—a known consequence of these drugs.

“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,” Dr Möbus pointed out.

Dr Cameron concluded 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.”