Neal J. Meropol, MD

Olszewski and colleagues reviewpreclinical and clinicaldata regarding vascular endothelialgrowth factor (VEGF) inhibitors,with particular attention to thedevelopment of bevacizumab (Avastin)in patients with colorectal cancer.The translation from biologic conceptto clinical proof of concept has beenstriking in its rapidity. However, manyimportant questions remain, and thisstory is only beginning to unfold. Inthis commentary, we will highlightsome of those questions that bear onthe optimal use of VEGF inhibitors inpatients with colorectal cancer.

The epidermal growth factor receptor (EGFR) is commonly expressedin colorectal cancers but not in most normal tissues, raising the possibilitythat this receptor could serve as a target for highly selective therapy.Based on preclinical studies demonstrating that antagonists of EGFRresulted in the inhibition of tumor growth, the development of clinicalreagents has been aggressively pursued. Early clinical studies demonstratedantitumor activity of EGFR inhibitors in patients with advancedcolorectal cancer, with acceptable toxicity. This early success fueledrapid clinical development. In this article, we will review the currentstatus of EGFR inhibitors in the treatment of patients with colorectalcancer, in an effort to describe both how far we have come as well aswhere we need to go in optimizing this promising therapeutic approach.

The second edition of the Textbook of Uncommon Cancer is a useful resource for practicing oncologists who encounter unusual presentations of common tumors or esoteric subtypes of more common cancers. The text is laid out according to

Either alone or in combination with other antineoplastics, fluorouracil (5-FU) has been the mainstay of treatment of gastrointestinal, breast, and head and neck cancers for the past 40 years. Numerous active 5-FU schedules are in

There are many challenges facing those involved in chemotherapy drug development. In addition to identification of new agents, clinical investigators must address questions regarding the optimal methods of administration of established agents so as to maximize efficacy and minimize toxicity. Treatment toxicity affects not only morbidity and mortality but also issues of dose intensity, quality of life, and health-care costs. Therefore, there is great interest in preventing the side effects associated with chemotherapy.

Therapeutic options for patients with advanced colorectal cancer who have failed treatment with fluorouracil (5-FU) are limited. Responses have been reported in this setting with a protracted venous infusion of 5-FU. Daily oral therapy with tegafur and uracil (UFT) plus leucovorin (LV) has the potential to mimic the pharmacology of continuous infusion 5-FU. Therefore, we undertook a phase II study of a 28-day schedule of a combination chemotherapy regimen containing oral UFT/leucovorin in patients with measurable metastatic colorectal cancer who had failed treatment with bolus 5-FU. In addition, we sought to determine whether coadministration of UFT and leucovorin alters the bioavailability of these agents. In a pretreatment phase, each patient underwent sequential pharmacokinetic sampling following a single dose of UFT alone, leucovorin alone, and the combination of UFT plus leucovorin. The preliminary results of this trial suggest that tegafur pharmacokinetics are not affected by coadministration of leucovorin and that folate pharmacokinetics are not affected by UFT. [ONCOLOGY 11(Suppl 10):22-25, 1997]