HERCULES STUDY

J Clin Oncol. 2010 Feb 22. [Epub ahead of print]

First-Line Trastuzumab Plus Epirubicin and Cyclophosphamide Therapy in Patients With Human Epidermal Growth Factor Receptor 2-Positive Metastatic Breast Cancer: Cardiac Safety and Efficacy Data From the Herceptin, Cyclophosphamide, and Epirubicin (HERCULES) Trial.

Untch M, Muscholl M, Tjulandin S, Jonat W, Meerpohl HG, Lichinitser M, Manikhas AG, Coumbos A, Kreienberg R, du Bois A, Harbeck N, Jackisch C, Müller V, Pauschinger M, Thomssen C, Lehle M, Catalani O, Lück HJ.

HELIOS Klinikum Berlin-Buch, Frauenheilkunde mit Geburtshilfe; Praxis für Gynäkologie und Geburtshilfe mit Schwerpunkt Onkologie, Berlin; Praxis für Kardiologie, Munich; Klinik für Gynäkologie und Geburtshilfe, Christian-Albrechts-Universität, Kiel; Frauenklinik der St-Vincentius-Krankenhauser, Karlsruhe; Universitätsklinikum Ulm Frauenklinik, Ulm; Department of Gynecology and Gynecologic Oncology, Dr Horst Schmidt Klinik, Wiesbaden; Breast Center Cologne/Frechen, University of Cologne, Cologne; Klinikum Offenbach, Offenbach; Klinik und Poliklinik für Gynäkologie, Universitätsklinikum Hamburg-Eppendorf, Hamburg; Klinik und Poliklinik für Gynäkologie, Martin-Luther-Universität Halle-Wittenberg, Halle (Saale); Medizinische Klinik 8-Kardiologie, Nürnberg; Gynäkologisch-Onkologische Praxis, Hannover, Germany; Russian Cancer Research Center, Moscow; Breast Cancer Department, St Petersburg City Oncology Hospital, St Petersburg, Russian Federation; and F. Hoffmann-La Roche, Basel, Switzerland.

PURPOSE: A high incidence of congestive heart failure (CHF) has been observed in patients with metastatic breast cancer (MBC) receiving doxorubicin-based chemotherapy and trastuzumab. The Herceptin, Cyclophosphamide, and Epirubicin (HERCULES) trial evaluated trastuzumab plus cyclophosphamide and the less cardiotoxic anthracycline epirubicin. PATIENTS AND METHODS: This prospective trial combined a phase I dose-finding stage with a phase II randomized stage. In total, 120 patients with human epidermal growth factor receptor 2 (HER2) -positive MBC and adequate cardiac function received first-line trastuzumab (4 mg/kg intravenous loading dose, then 2 mg/kg every week) plus cyclophosphamide (600 mg/m(2)) and either epirubicin 60 mg/m(2) (HEC-60) or 90 mg/m(2) (HEC-90) for six cycles, followed by trastuzumab monotherapy until progression. Sixty patients with HER2-negative disease received epirubicin (90 mg/m(2)) and cyclophosphamide (EC-90) alone. The primary end point was dose-limiting cardiotoxicity (DLC). RESULTS: Incidence of DLC was 5.0%, 1.7%, and 0% in the HEC-90, HEC-60, and EC-90 arms, respectively. All DLC events were manageable. There were no cardiac-related deaths. Other adverse-event profiles were comparable across the three arms, except febrile neutropenia, which was reported in 10% of the HEC-90 arm compared with 3% of the other arms. Tumor response rates were 57%, 60%, and 25% in the HEC-60, HEC-90, and EC-90 arms, respectively; median time to progression was 12.5, 10.1, and 7.6 months, respectively. CONCLUSION: The HEC regimen is a promising treatment option for patients with HER2-positive MBC. The lower incidence of DLC with HEC, compared with the historic incidence associated with trastuzumab plus doxorubicin, supports further evaluation of the regimen, especially in adjuvant or neoadjuvant settings.