Elsevier

The Lancet Oncology

Volume 2, Issue 12, December 2001, Pages 733-740
The Lancet Oncology

Review
Metronomic scheduling: the future of chemotherapy?

https://doi.org/10.1016/S1470-2045(01)00587-3Get rights and content

Summary

Tumour endothelium is a new target for anticancer treatments. Proliferating endothelial cells from the tumour, even if qualitatively different from those of blood vessels in the normal tissue of origin, remain putatively normal and genetically stable cells. The results of recent experimental studies have suggested that frequent administration of certain cytotoxic agents at low doses (a tenth to a third of the maximum tolerated dose), known as ‘metronomic’ chemotherapy, increases the antiangiogenic activity of the drugs. The effects of these metronomic schedules of cytotoxic agents may be further enhanced by concurrent administration of novel, selective, treatments that inhibit, at a molecular level, the processes of tumour formation and growth eg angiogenesis, growth factor pathways, and other signal transduction cascades. The need to treat patients for long periods also supports the use of metronomic scheduling for chemotherapy, to minimise toxicity and to target both proliferating tumour cells and endothelial cells. This review describes the experimental studies involving metronomic schedules of chemotherapy, alone and in combination with angiogenesis inhibitors, and suggests a new therapeutic anticancer paradigm for controlling cancer by long-term therapy, based on the development of combinations of metronomic cytotoxic agents with individually tailored compounds designed to target specific molecules.

Section snippets

The angiogenesis–chemotherapy model

Angiogenesis is necessary to sustain the growth of both the primary tumour and the development of metastases.12 Therapeutic targeting of tumour angiogenesis was first proposed by Folkman 30 years ago, at a time when the molecular mechanisms underlying abnormal neovascularisation were unknown.14 Progress in our understanding of the cellular and molecular basis of this biological process allowed the identification of several molecular targets and different selective approaches for inhibiting

Experimental studies on the antiangiogenic activity of metronomic chemotherapy

O'Leary and colleagues24 found that camptothecin analogues, which target the enzyme topoisomerase I, also cause significant suppression of angiogenesis in an in vivo mouse corneal model, at a dose of 359 nmol/kg (210 mg/kg) delivered over 6 days. This frequency of treatment prevented tumour and endothelial cell regrowth, and was active against tumour microvasculature.

Clements and coworkers25 used low (nanomolar), noncytotoxic concentrations of camptothecin and topotecan (50 nmol) to confirm the

Metronomic versus dose-density scheduling

Proof of the concept of metronomic scheduling requires the development of appropriate intermediate surrogate markers, which can be monitored before and after therapy; any quantitative or qualitative changes in the proliferation of endothelial cells also needs to be monitored. The concept of ‘high-time’ chemotherapy, defined as the longest possible period of drug exposure at a given desired drug concentration, is very useful for long-term therapy, but requires careful assessment of the

Metronomic schedules of chemotherapy in combination with antiangiogenic inhibitors and other molecular-targeted treatments

Significant antiangiogenic and antitumour effects are unlikely to be achieved in the clinical setting with a single chemotherapeutic agent at metronomic doses. The ability of metronomic chemotherapy to block angiogenesis, compared with that of selective angiogenesis inhibitors, remains to be proven, at least in terms of effective prolongation of survival.

Pioneering studies by Kakeji and Teicher39 showed potentiation or synergism when angiogenesis inhibitors were combined with standard schedules

Clinical studies

There are currently no published clinical studies in which metronomic scheduling of chemotherapy was compared with conventional schedules, nor are there any that describe appropriate in vitro or in vivo methods of monitoring antiangiogenic activity. However, a few trials have involved metronomic-like chemotherapy schedules. For example, the phase I study by Retain and colleagues55 involved continuous infusion of low doses of vinblastine for up to 36 weeks. The researchers found that 0·7 mg/m2

Future directions

There are several theoretical advantages and opportunities to be explored with regard to metronomic chemotherapy in combination regimens (Table 3). However, these regimens also present potential problems and challenges in terms of appropriate experimental study design and clinical testing. First, combined metronomic chemotherapy regimens should be further tested in experimental studies, in orthotopic and metastatic tumour models, as suggested by Fidler and Ellis,4 before proceeding to clinical

Search strategy and selection criteria

Published data for this review were identified by searches of MEDLINE, CANCERLIT, and Dematel databases. MeSH terms used were ‘antiangiogenic cancer chemotherapy’, ‘cytotoxic agents’, ‘inhibitors of angiogenesis’, and ‘metronomic chemotherapy’. Additional references were selected from relevant articles. Only papers in English, published up to July 2001, were chosen.

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