Introduction
Over the past few decades, survival rates for pediatric cancer have markedly improved. However, certain high-risk or refractory/relapsed tumors show resistance to cytotoxic chemotherapy, resulting in a very poor prognosis. Moreover, conventional chemotherapy imposes side effects that limit dosing and impair quality of life (QOL). Angiogenesis, thought to be involved in all tissue growth, has gained the status of a key driver in the local and distant growth of cancer. Therefore, antiangiogenic therapy, an alternative approach to cancer treatment, is less likely to develop drug resistance.1
The term metronomic chemotherapy (MC), first coined by Hanahan in 2000, is defined as the continuous or frequent administration of chemotherapy at doses below the maximum tolerated dose without prolonged drug-free breaks.2 In contrast to conventional chemotherapeutic regimens based on maximum-tolerated doses with periods for recovery, MCs mainly target endothelial cells within the tumor microenvironment and induce angiogenic dormancy in tumors.
One MC strategy is the combination of low-dose oral etoposide with or without differentiating and anti-angiogenic agents.3,4Another strategy is based on low-dose oral cyclophosphamide, sometimes combined with weekly vinblastine, vincristine, and oral methotrexate.5,6 In response to trial results, combination therapies named Combined Oral Metronomic Biodifferentiating Antiangiogenic Treatment (COMBAT), including etoposide and temozolomide or cyclophosphamide for relapsed pediatric solid tumors, have been published.7,8 More recently, another combination therapy that included alternating 21-day cycles of low-dose oral cyclophosphamide and etoposide was developed.9,10These combination therapies also include antiangiogenic agents, such as retinoic acids, vitamin D3, thalidomide, celecoxib, fenofibrate, and bevacizumab.
Previous reports have shown that MC is an attractive option (i) as a palliative treatment for patients with measurable, resistant, progressive, and/or relapsed tumors, or (ii) as consolidation or maintenance therapy for patients with no measurable disease but with high-risk tumors, who are in first or second complete remission but have a very low probability of maintaining a long-term disease-free status.4–13 In our institute, MC has been provided for patients with refractory/relapsed solid tumors.