Abstract
Oral metronomic chemotherapy may target tumor cells indirectly via antiangiogenic activity, restoration of anticancer immune response, or induction of tumor dormancy. We initiated the single-center, randomized, open-label, phase II study to determine whether the addition of metronomic cyclophosphamide to docetaxel (T) (w/o trastuzumab) improves overall response rate (ORR) as first-line treatment among patients with non-triple-negative metastatic breast cancer (MBC). Eligible patients with previously untreated non-triple-negative MBC were randomly assigned (1:1) to receive 3-weekly cycles of Metro-TC (T 75mg/m2, d1 plus oral cyclophosphamide 50 mg daily) or T alone. All patients received treatment until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint was ORR. Finally, 35 patients were randomized to Metro-TC group while 31 to T group. Median treatment cycles of T for both groups were 8. ORR was not improved by addition of metronomic cyclophosphamide to T (71.4% vs. 51.6%; P = 0.09). There was no statistically significant difference with regard to progression free survival (median 18.5 vs. 11.7 months; P = 0.07) or overall survival (median 33.7 vs. 33.6 months; P = 0.84) between the two group. Grade 3/4 adverse events (eg. neutropenia [100% vs. 100%], febrile neutropenia [29% vs. 29%], and neurotoxicity [6% vs. 3%]) were also comparable. There were no treatment-related deaths. We conclude that concomitant administration of metronomic cyclophosphamide and T does not appear to be a significantly active schedule for first-line treatment of non-triple-negative MBC.
Highlights
Metastatic breast cancer (MBC) is essentially an incurable disease and the prognosis has changed little over the past decade with median overall survival of patients is still only 2–3 years [1,2,3]
Patients included in the study were required to meet the following criteria: at least 18 years of age; histologically confirmed non-triple-negative breast cancer with metastatic disease; measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria; a life expectancy of no less than 3 months; Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1; absolute neutrophil count (ANC) ≥ 1.5 × 109/L; platelet count ≥ 75 × 109/L; hemoglobin ≥ 9 g /dL; total serum bilirubin ≤ 1.5 × upper limit of normal (ULN); AST/ALT ≤ 2.5 × ULN (≤ 5 × ULN in case of liver metastases); serum creatinine ≤ 1.0 × ULN
Between Dec 2011 and Nov 2012, 66 patients with non-triple-negative metastatic breast cancer (MBC) were recruited, in which 35 patients were randomized to Metro-TC group while 31 to T group (Figure 1)
Summary
Metastatic breast cancer (MBC) is essentially an incurable disease and the prognosis has changed little over the past decade with median overall survival of patients is still only 2–3 years [1,2,3]. Metronomic chemotherapy, refers to treatment at regular, close intervals without prolonged breaks at doses significantly less than the maximum-tolerated dose [4]. This treatment modality may target tumor cells indirectly via inhibiting angiogenesis and vasculogenesis by continuously exposing the more slowly proliferating tumor endothelial cells to cytotoxic therapy [5,6,7,8]. Metronomic schedule of cyclophosphamide is effective in multiple tumor types, including ovarian cancer, [16, 17] prostate cancer, [18, 19] breast cancer, [6, 20,21,22,23] some refractory solid tumors, [24] and lymphomas [24, 25]
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