The Anti-Angiogenic Basis of Metronomic Chemotherapy

Robert S. Kerbel; Barton A. Kamen

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Abstract and Introduction

Abstract

In addition to proliferating cancer cells and various types of normal cells, such as those of the bone marrow, conventional cytotoxic chemotherapeutics affect the endothelium of the growing tumour vasculature. The anti-angiogenic efficacy of chemotherapy seems to be optimized by administering comparatively low doses of drug on a frequent or continuous schedule, with no extended interruptions — sometimes referred to as 'metronomic' chemotherapy. In addition to reduced acute toxicity, the efficacy of metronomic chemotherapy seems to increase when administered in combination with specific anti-angiogenic drugs. Gaining better insight into the mechanisms of these effects could lessen or even eliminate the empiricism used to determine the optimal dose and schedule for metronomic chemotherapy regimens.

Introduction

For almost half a century, systemic therapy of cancer has been dominated by the use of cytotoxic chemotherapeutics. Most of these drugs are DNA-damaging agents or microtubule inhibitors that are designed to inhibit or kill rapidly dividing cells. They are often administered in single doses or short courses of therapy at the highest doses possible without causing life-threatening levels of toxicity — this is referred to as the 'maximum tolerated dose' (MTD). MTD therapy requires prolonged breaks (generally of 2-3 weeks in duration) between successive cycles of therapy. Despite the number of such chemotherapeutics and the huge number of clinical trials that have been undertaken to test them, progress has been modest in terms of curing or significantly prolonging the lives of patients with cancer — particularly those with advanced-stage or metastatic disease.[1,2] Moreover, the progress that has been made in treating certain types of malignancy often comes at a high price, given the toxic side effects that are frequently associated with MTD-based chemotherapy. These include acute myelosuppression, hair loss, damage to the intestinal mucosa, nausea and mucositis, as well as the long-term cardiac, renal, neurological and reproductive consequences. Indeed, many of the recent pharmacological advances in oncology treatment involve growth factors and anti-nausea drugs, which are administered to patients with cancer to minimize the severity of, or accelerate recovery from, chemotherapy-induced toxicities. Such 'supportive-care drugs' can significantly add to the financial burden of cancer chemotherapy, and have their own side effects.

A reappraisal of the best ways of administering chemotherapy is underway. Instead of only using short bursts of toxic MTD chemotherapy interspersed with long breaks to allow recovery from the harmful side effects, there is now a shift in thinking towards the view that more compressed or accelerated schedules of drug administration using much smaller individual doses than the MTD would be more effective — not only in terms of reducing certain toxicities, but perhaps even improving antitumour effects as well.[3,4,5,6] Moreover, some of these dosing/scheduling strategies are ideally suited to combining chemotherapeutics with many of the new targeted and relatively non-toxic anticancer drugs that have been or are being developed. The most recent refinement of this concept is called 'metronomic' chemotherapy,[3] which refers to the frequent, even daily, administration of chemotherapeutics at doses significantly below the MTD, with no prolonged drug-free breaks.

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