Phase II Trial of a Metronomic Schedule of Docetaxel and Capecitabine with Concurrent Celecoxib in Patients with Prior Anthracycline Exposure for Metastatic Breast Cancer

Abstract

Background: This phase II clinical trial examined the activity of a metronomic dosing schedule of docetaxel and capecitabine chemotherapy in patients with advanced breast cancer. Patients also received daily oral celecoxib in an effort to improve outcome measures and to ameliorate some of the common side effects of chemotherapy. Methods: Patients received docetaxel at a starting dose of 15 mg/m2 weekly, oral capecitabine 1250 mg/m2 once daily, and oral celecoxib 200 mg twice daily. The primary endpoint was clinical benefit: percentage of patients experiencing either an objective response or stable disease (SD) for more than 6 months. In the absence of significant neutropenia, the dose of docetaxel was escalated after 4 and 8 weeks of treatment. Therapy was given until disease progression or development of unacceptable toxicity. The level of thymidine phosphorylase expression in peripheral white blood cells of patients was measured before and during treatment to determine the effect on this capecitabine-activating enzyme. Results: Of 47 patients enrolled, 38 (81%) completed treatment to a disease endpoint. No complete responses were achieved, but 13 of the 38 patients (34%) experienced a partial response, and another 3 patients (8%) experienced SD for more than 6 months. The clinical benefit rate was therefore 42% (95% confidence interval: 27% to 57%). The median time to disease progression for all evaluable patients was 3.6 months (range: 0.9–21.7 months). The most common nonhematologic toxicities were diarrhea, plantar– palmar erythrodysesthesia, fatigue, mucositis, and vomiting. Most patients (89%) received combination chemotherapy until disease progression. Conclusions: The present study demonstrates that metronomic docetaxel–capecitabine chemotherapy with daily celecoxib can produce significant anticancer activity, with predictable toxicity. Efficacy fell short of expectations, with outcome measures being similar to those obtained when the study agents are given in conventional dosing. Furthermore, there is mounting evidence to indicate that a low dose of taxanes fails to induce thymidine phosphorylase expression, an effect believed to be important in achieving therapeutic synergism when taxanes are given concurrently with capecitabine.

Metastatic breast cancer patients treated with low-dose metronomic chemotherapy with cyclophosphamide and celecoxib: clinical outcomes and biomarkers of response

“…Cyclophosphamide (Cy), is one of the most used drugs in cancer treatment and is one of the earliest cytotoxic drugs used in MCT [13]. Celecoxib (Cel), a selective Cyclooxygenase 2 inhibitor, has shown antitumor activity for breast cancer cell lines, not only in-vitro but also in-vivo [14], and its use has been translated to the clinic [15].…”

Phase II Trial of Fulvestrant With Metronomic Capecitabine for Postmenopausal Women With Hormone Receptor-Positive, HER2-Negative Metastatic Breast Cancer

“…Other trials have used other approaches. [26][27][28][29][30] The fulvestrant arm in the Evaluation of Faslodex versus Exemestane Clinical Trial (EFECT) trial reported by Chia and colleagues was comparable to the fulvestrant schedule in this study. 4 Chia et al reported a median TTP of 3.7 months, 4 compared with 26.94 months (95% CI, 7.26 months-upper limit not estimated) for the current sample.…”

Clinical overview of metronomic chemotherapy in breast cancer

“…In this trial, the outcome measures were similar to those obtained when the study agents are dosed in a c onventional manner. 106 Metronomic chemotherapy was investigated in combination with endocrine therapy. The activity of fulvestrant (250 mg given by intramuscular injection every 28 days) in combination with oral metronomic chemotherapy was evaluated in two cohorts of 33 postmenopausal patients with heavily pre-treated ER-positive advancedstage breast cancer.…”