Efficacy and Safety of the All-Oral Schedule of Metronomic Vinorelbine and Capecitabine in Locally Advanced or Metastatic Breast Cancer Patients: The Phase I-II VICTOR-1 Study
Background. Vinorelbine (VRB) and capecitabine (CAPE) are demonstrated to be active in pretreated metastatic breast cancer patients. Different studies have demonstrated that the metronomic treatment is active with an acceptable toxicity profile. We designed a Phases I-II study to define the MTD of oral metronomic, VRB, and CAPE. Patients and Methods. Phase I: fixed dose of CAPE was 500？mg thrice a day, continuously. Level I of VRB was 20？mg/tot thrice a week for 3 weeks (1 cycle). Subsequent levels were 30？mg/tot and 40？mg/tot (Level III), respectively, if no Grades 3-4 toxicity were observed in the previous level. Phase II: further 32 patients received the MTD of VRB plus CAPE for a total of 187 cycles to confirm toxicity profile. Results. 12 patients were enrolled in Phase I and 22 in Phase II. Phase I: the MTD of VRB was 40？mg. Phase II: 187 cycles were delivered, observing 5.9% of Grades 3-4 toxicity. 31 patients are evaluable for efficacy, obtaining a clinical benefit rate of 58.1%. Conclusion. MTD of VRB with fixed dose of CAPE was 40 mg thrice a week and was the recommended dose for the ongoing Phase II multicenter study. 1. Background Different studies in animal models have demonstrated that the combination of VRB and CAPE has a synergistic activity against breast cancer cells, due to their different mechanism of action [1]. These results have been subsequently confirmed in numerous studies conducted in metastatic breast cancer patients, heavily pretreated with taxanes and anthracyclines, in which VRB was administered as iv formulation [2]. Subsequent trials showed that there was a substantial equivalence between the iv and the oral formulations of VRB, even if this latter was characterized by a higher rate of haematological toxicity [3–5]. In all these studies, VRB and CAPE were administered on days 1 and 8, according to the approved standard schedule. Metronomic chemotherapy refers to the frequent, even daily, administration of drugs at doses significantly lower than the maximum tolerated dose (MTD), with no prolonged drug-free breaks [6]. A recent study by Dellapasqua et al. [7] showed that the metronomic combination of cyclophosphamide and CAPE with bevacizumab was effective and minimally toxic in advanced breast cancer patients. This study fixed the dose of CAPE as 500？mg thrice a day, continuously. Different studies have evaluated the possibility to administer VRB in a metronomic way [8, 9], trying to establish the MTD of the drug, both as single agent or as part of a multidrug regimen. These studies fixed the MTD of oral metronomic
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