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.