A Feasibility Trial of Antiangiogenic (Metronomic) Chemotherapy in Pediatric Patients With Recurrent or Progressive Cancer

Abstract

Standard chemotherapeutic drugs, when modified by the frequency and dose of administration, can target angiogenesis. This approach is referred to as antiangiogenic chemotherapy, low-dose chemotherapy, or metronomic chemotherapy. This study evaluated the feasibility of 6 months of metronomic chemotherapy, its toxicity and tolerability, surrogate markers of activity, and preliminary evidence of activity in children with recurrent or progressive cancer. Twenty consecutive children were enrolled and received continuous oral thalidomide and celecoxib with alternating oral etoposide and cyclophosphamide every 21 days for a planned duration of 6 months using antiangiogenic doses of all four drugs. Surrogate markers including bFGF, VEGF, endostatin, and thrombospondin were also evaluated. Therapy was well tolerated in this heavily pretreated population. Toxicities (predominantly reversible bone marrow suppression) responded to dose modifications. Sixty percent of the patients received less than the prescribed 6 months of therapy due to toxicity (one case of deep vein thrombosis), personal choice (1 patient), or disease progression (10 patients). Forty percent of the patients completed the 6 months of therapy, resulting in prolonged or persistent disease-free status. One quarter of all patients continue to be progression free more than 123 weeks from starting therapy. Sixteen percent of patients showed a radiographic partial response. Only elevated thrombospondin-1 levels appeared to correlate with prolonged response. This oral antiangiogenic chemotherapy regimen was well tolerated in this heavily pretreated pediatric population, which showed prolonged or persistent disease-free status, supporting the continued study of antiangiogenic/metronomic chemotherapy in human clinical trials.

Phase I trial of docetaxel and thalidomide: a regimen based on metronomic therapeutic principles

“…In contrast to our study which showed benefit of docetaxel with thalidomide in solid tumors, Colleoni found that the addition of thalidomide to metronomic chemotherapy in advanced breast cancer patients did not improve the response rate compared to chemotherapy alone [40]. However, other studies showed favorable results with combination metronomic chemotherapy and thalidomide in malignancies [41][42][43]. Few trials have evaluated the docetaxel and thalidomide combination, although with slightly different dosing than in our trial.…”

Pharmacodynamic and pharmacokinetic study of chronic low-dose metronomic cyclophosphamide therapy in mice

“…If so, from a pharmacologic point of view, there may be no need to switch between CPA and other cytotoxic drugs (e.g., etoposide) to delay resistance as has been suggested by others (41). Moreover, stopping LDM CPA because of tumor recurrence due to reduced vascular dependence might fuel an unchecked ''proangiogenic rebound'' and consequently resumption of more rapid tumor growth as recently observed after termination of antitumor treatment using antiangiogenic receptor tyrosine kinase inhibitors (42).…”

A review of Judah Folkman's remarkable achievements in biomedicine

“…Others (17) subsequently called it ''metronomic therapy.'' His work showed that tumors that had become completely resistant to conventional cytotoxic therapy administered at maximum tolerated doses followed by off-therapy intervals could, in contrast, be significantly inhibited or permanently regressed by antiangiogenic chemotherapy (18).…”