Dose-Dense Chemotherapy Supported for Early Node-Positive Breast Cancer

Increasing chemotherapy dose density improves survival for early breast cancer patients with node-positive disease but there is no added survival gain with the inclusion of fluorouracil

medwireNews: Dose-dense epirubicin, cyclophosphamide and paclitaxel (EC-P) improves disease-free survival (DFS) in patients with early node-positive breast cancer compared with standard dosing, phase III results indicate.

However, the 2 x 2 factorial open-label trial also demonstrated that the addition of fluorouracil to either EC-P regimen (FEC-P) did not significantly improve survival and was associated with an increased risk of grade 3 or 4 adverse effects.

“This study strongly supports the notion that fluorouracil can be safely discarded from adjuvant regimens for early breast cancer”, write Gunter von Minckwitz and Sibylle Loibl, from the German Breast Group in Neu-Isenburg in an editorial accompanying the study in The Lancet.

The trial included 2091 patients who were randomly assigned to receive EC-P or FEC-P every 2 weeks with pegfilgrastim support (dose-dense) or at the standard interval of every 3 weeks, explain lead author Lucia Del Mastro, from Istituto Nazionale per la Ricerca sul Cancro in Genova, Italy, and team.

Over a median of 7.0 years, local or distant recurrence, contralateral or ipsilateral breast tumours, second primary malignancies, all-cause death or loss to study follow-up were reported for 22% and 23% of patients given dose-dense EC-P and FEC-P, respectively, and 26% and 29% of those given standard interval EC-P and FEC-P, respectively.

Five-year DFS was achieved by 81% of patients given either dose-dense regimen and 76% of standard interval patients, giving a significant hazard ratio (HR) of 0.77. Overall survival (OS) was 94% and 89% for the dose-dense and standard interval regimens, respectively, with a significant HR of 0.65.

EC-P and FEC-P patients had comparable DFS at 5 years, regardless of dose intensity, at 79% and 78%, respectively, and 5-year OS rates of 92% and 91%, respectively.

The researchers note that dose-intense chemotherapy was associated with a higher rate of grade 3 or 4 anaemia (1.4 vs 0.2%), transaminitis (1.9 vs 0.4%) and myalgia (3.1 vs 1.6%) than standard interval chemotherapy, albeit with lower rates of neutropenia (14.9 vs 44.0%).

Moreover, patients given fluorouracil had higher rates of grade 3 or 4 neutropenia (34.5 vs 24.2%), fever (0.9 vs 0.2%), nausea (4.6 vs 2.7%) and vomiting (3.1 vs 1.4%) than those given EC-P.

“Although, the role of fluorouracil in the adjuvant treatment of early breast cancer cannot be completely discarded, the lack of efficacy noted in our study raises a general question on the opportunity to include it in modern adjuvant chemotherapy regimens, especially if the increase in toxic effects associated with its use is taken into account”, the authors note.

The editorialists observe that paclitaxel is now given in weekly doses, as research has shown it to be equally effective but less toxic than dosing every 2 weeks. They therefore question what the difference in efficacy would be between dose-dense versus standard interval epirubicin (or an anthracycline) plus cyclophosphamide regimens if given followed by weekly paclitaxel.

“[T]his finding should be weighed against potential late toxic effects, especially cardiac toxic effects”, Gunter von Minckwitz and Sibylle Loibl comment.

“The… investigators are therefore encouraged to consolidate the results of their successful study by reporting long-term efficacy and toxic effects in the future.”

References

Del Mastro L, De Placido S, Bruzzi P, et al. Fluorouracil and dose-dense chemotherapy in adjuvant treatment of patients with early-stage breast cancer: an open-label, 2 x 2 factorial, randomised phase 3 trial. Lancet 2015; Advance online publication 1 March. doi: dx.doi.org/10.1016/S0140-6736(14)62048-1

von Minckwitz G, Loibl S. Evolution of adjuvant chemotherapy for breast cancer. Lancet 2015; Advance online publication 1 March. doi: dx.doi.org/10.1016/S0140-6736(14)62348-5

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