Approximately 25% of patients with colorectal cancer will develop liver metastases as their initial site of disease recurrence and, at autopsy, the liver is involved in 50 to 80% of cases. Systemic chemotherapy response rates are generally between 15 and 25%. The response rates from regional infusion of chemotherapy are usually between 40 and 50%. Our laboratory has demonstrated a correlation between increased drug delivery to tumor and increased tumor response. We have developed an experimental protocol to determine tumor drug delivery by non- invasive methods. This institution has developed (and is currently employing) dynamic gamma scintigraphy to study blood flow and nutrient delivery to the liver and to colorectal hepatic metastases, using the short-lived isotope of nitrogen to label amino acids. We have developed a practical synthesis of 18F 5-fluoro-2'-deoxyuridine (FUdR), which will permit non-invasive measurements of tumor drug uptake by gamma scintigraphy. 18F2 is a cyclotron- generated isotope of F2; it is an indirect gamma emitter with a short half-life. The long-term objectives of this project are to characterized the distribution, extraction and retention of FUdR administered via the hepatic artery for treatment of patients with isolated unresectable colorectal hepatic metastases. Using 18P FUdR, patients can be studied non-invasively by dynamic scintigraphy over time. The etiology of gastroduodenal and hepatic toxicity will be examined. We will study the effect of infusion rate on tumor drug uptake and on systemic exposure. The efficacy of degradable starch microspheres (which increase drug uptake in model systems), and angiotensin II (which increases relative tumor blood flow) will be examined. Since the isotope half-life is only two hours, and only small amounts of radiation are involved, each patient may undergo repeated studies, acting as his own control.
