Incorporation of 5-bromo-2'-deoxyuridine into colorectal liver metastases and liver in patients receiving a 7-day hepatic arterial infusion

Abstract

Preclinical and clinical data suggest that the combination of hepatic arterial bromodeoxyuridine (BrdUrd), a thymidine analogue radiation sensitizer, and high-dose three-dimensional conformal radiation therapy offer a high potential for improving the local control of intrahepatic cancers. A key step in the design of a successful protocol is to determine in patients the conditions for BrdUrd administration that would be expected to produce selective radiosensitization of the tumor. Therefore, we designed a clinical trial to assess BrdUrd incorporation into the DNA of hepatic colorectal metastases and normal liver after a 7-day continuous BrdUrd infusion at a dose rate of 25 mg/kg/day (the maximal tolerated dose for a 14-day infusion) for patients undergoing laparotomy for either resection of liver metastases or hepatic arterial catheter and pump placement. Thirteen patients were entered into this study. We found that the average replacement of thymidine by BrdUrd in the tumor and normal liver were 11.6 +/- 1.2% and 1.1 +/- 0.2%, respectively. This extent of incorporation would be expected to produce a single fraction radiation enhancement of 1.5 in the tumor without detectable sensitization of the normal liver. Immunohistochemical staining for BrdUrd revealed heterogeneity of incorporation with a range of approximately 60-80% of the cells labeled in different regions of the specimens. These findings suggest that hepatic arterial BrdUrd given at this dose and schedule has a high likelihood of producing clinically significant radiosensitization for patients with hepatic metastases from colorectal cancer. Furthermore, the demonstrated selectivity of tumor perfusion that can be obtained with hepatic arterial infusion combined with the high proliferative rate of colorectal metastases (versus normal liver) suggests that these patients may be good candidates for tumor-directed gene transfer therapy by using regionally delivered retroviral vectors.