The concept of metronomic chemotherapy began in the

The concept of metronomic chemotherapy began in the 1990s, when Kerbel showed chemotherapeutic agents may be able to target tumor vessel endothelial cells. In 2000, Browder et al demonstrated a more frequent, lower dose of cyclophosphamide, i.e. anti-angiogenic schedule, could induce response in tumors refractory to conventional dosing. Since then, metronomic chemotherapy was defined as frequent or continuous administration of chemotherapeutic agents at low doses without prolonged drug-free breaks, aiming to minimize toxicity and increase efficacy via inhibition of tumor angiogenesis. Subsequent trials were performed in various tumor types testing different drug combinations, doses and schedules of administration. Oral daily cyclophosphamide 50 mg daily has been studied extensively in advanced breast cancer, in combination with capecitabine, methotrexate, or other targeted agents – trastuzumab or bevacizumab. In one study of heavily pretreated metastatic breast cancer patients, treatment with metronomic cyclophosphamide and methotrexate resulted in an overall response rate of 19%, with an overall clinical benefit of 31.7%. The effect of metronomic UFT was demonstrated prospectively in a large phase III trial, increasing overall survival of operated lung cancer patients. A recent retrospective study found adjuvant metronomic UFT can reduce distant failure and improve overall survival in NPC patients with persistently detectable TAPI-1 EBV DNA after curative treatment. Treatment with metronomic cyclophosphamide and UFT were generally well-tolerated. Most common treatment-related adverse events were grade 1 nausea and/or vomiting, grade 1 and 2 anemia, neutropenia and low grade fatigue. In contrast, myelosuppression is a great concern when giving oral etoposide. One reason is that early pharmacokinetic studies showed a mean bioavailability within the range of 40–90%, with wide inter-patient variation, making it difficult to predict the AUC for any individual oral dose of drug. In an early phase I study covering 21 days of oral Etoposide by Hainsworth et al, they found the maximal tolerated dose to be 50 mg/m2/day. Further phase II studies using 50 mg/m2 once or twice daily for 14 or 21 days were conducted in previously treated and untreated patients with different types of cancer, including lung cancer, lymphoma, ovarian and breast cancer. Biweekly bevacizumab and oral etoposide 50 mg/m2 daily for 21 consecutive days every four weeks were given to patients with recurrent malignant gliomas. Although treatment efficacy was encouraging, 23% of patients were found with grade 3/4 neutropenia. Patients with platinum-resistant epithelial ovarian cancer were given a lower dosage of etoposide 50 mg/m2 daily for 14 consecutive days every four weeks. Grade 3/4 neutropenia was found in 27.2% patients. Patients with advanced non-small cell lung cancer were given etoposide at a dose of 100 mg once daily for 7 consecutive days, and subsequently using the same dose every other day for another 14 days. The regimen was repeated every four weeks. Partial response was observed in 28% of patients and stable disease in 34% of the patients. However, 65% of patients developed grade 1/2 leukopenia and 15% of the patients suffered from grade 3/4 leukopenia. A lower dose of metronomic oral etoposide (50 mg daily for 5 days every three weeks) in combination with cyclophosphamide (50 mg daily) was given to patients with postoperative macroscopic residual disease or recurrent advanced ovarian cancer. Only 7% of patients had grade 3/4 toxicity. In our patient, oral metronomic etoposide (50 mg daily for 7 days every 4 weeks) was added after the patient progressed on metronomic UFT and cyclophosphamide. After stabilization of disease, the dosage of oral etoposide was further lowered to 50 mg daily for 3 days every four weeks due to grade 2 neutropenia and grade 1 fatigue. The patient continued to remain stable under low dose etoposide-based combination metronomic chemotherapy. Currently, there is Shuttle vector no standard schedule of administration for metronomic etoposide. Due to increased hematologic toxicities seen after treatment with higher doses of etoposide, even as a single agent, further study is warranted to evaluate the efficacy and toxicity of low dose etoposide-based combination metronomic chemotherapy.