Faculty Bibliography

Doxorubicin provides the most consistent response rate in hepatocellular carcinoma. We therefore initiated a trial with its analog 4'epidoxorubicin. Eighteen patients, all without prior treatment, were given the drug as a single agent every 3 weeks with dose escalation whenever possible. Five patients were treated by six-hour infusion and 13 by intravenous (IV) bolus injection, with the median dose being 90 mg/m2. The patients were of diverse ethnic background and included some with underlying cirrhosis and hepatitis B surface antigenemia. Three patients had partial remissions (6, 12, 48 weeks) for a response rate of 17%. Four patients also had prolonged stable disease (14, 26, 27, 38 weeks). Toxicity was mild, although cardiac toxicity developed in three patients at 685, 825, and 1,460 mg/m2 cumulative dose. The response to 4'epidoxorubicin in this study appears to be equivalent to the reported response rates for doxorubicin, with decreased toxicity

With the rapid expansion of research programs examining intraperitoneal chemotherapy for ovarian cancer and other intraabdominal malignancies, there is a need for a reliable and safe access to the peritoneal cavity. The technical experience accumulated with either the Tenckhoff catheter or the Port-A-Cath in 288 patients treated at five institutions showed a low incidence of catheter-related peritonitis (5% and 8%, respectively), skin infection (6.6% and 0%), and bowel perforation following surgical implantation (3.5% and 1.3%). Postoperative leakage of intraabdominal fluid, bleeding, or ileus were uncommon and easily controlled. Drainage failure was the major problem with both systems; occurring in 45% of patients. Although both systems are workable, improved catheters for the administration of intraperitoneal chemotherapy are warranted

Local regional chemotherapy has yet to be proven superior to other methods of drug administration. While current studies are underway to assess the value of intraperitoneal chemotherapy in patients with gastrointestinal (GI) malignancies, many factors affect the success of such trials. Route of delivery and drug metabolism are all important. It is theorized that local exposure of liver with high concentrations of drug (even considering the limited efficacy of available agents) will result in improved tumor kill. In GI tumors, the putative route of spread is through the portal system to the liver. Intraperitoneal (IP) administration of drug offers an opportunity to deliver high concentrations of drug to local intraperitoneal surfaces, and, if there is sufficient hepatic extraction, IP administration also delivers a high concentration of drug to the liver. In a study of 5-fluorouracil (5-FU) in patients with metastatic colorectal carcinomas, high portal drug concentrations were achieved by this method of administration. It was concluded that IP therapy is an excellent method of delivering high concentrations of 5-FU and possibly other drugs to the hepatic parenchyma as well as to the intraperitoneal space. Since the effectiveness of such administration of still unclear, further clinical trials are indicated

No new chemotherapy agents have been developed in the recent past that present hope for improving survival in patients with colon or rectal cancer. This study was undertaken to investigate a new route of administering an old drug, 5-fluorouracil (5-FU). When 5-FU is delivered by the intraperitoneal (IP) route the tolerable dose of drug was markedly increased without an increase in adverse side effects. The natural history of surgically treated disease was changed by reducing the incidence of peritoneal carcinomatosis, but time to relapse and survival was not improved. Intraperitoneal 5-FU may be recommended for investigation in patients with perforated colon cancer, peritoneal implants, or as one part of a multimodality treatment protocol for colorectal cancer. If 5-FU is given to patients with gastrointestinal malignancy, the IP route should be strongly considered

A Phase I trial of intravenous bromodeoxyuridine (BUdR) and conventional fractionated radiation therapy was performed in 14 patients with glioblastoma multiforme and 7 patients with other poorly radioresponsive tumors. The BUdR was given as a constant intravenous infusion for 12 hr/day for up to 14 days. Thirteen patients received a second 14 day infusion following a 10 to 14 day interruption for bone marrow recovery. Local toxicity (within the radiation field) was minor, with 7 of the 21 patients requiring a brief treatment break for moist skin desquamation. There was no significant CNS toxicity noted clinically nor by autopsy examination. Additionally, no significant enhancement of radiation injury was noted to bowel or liver. However, one patient treated for multiple pulmonary metastases experienced a clinical and radiographic pattern consistent with radiation pneumonitis. Dose-dependent systemic toxicity occurred in bone marrow and skin. Moderate myelosuppression, especially thrombocytopenia, was found following a 14 day cycle of BUdR at and above 650 mg/m2/12 hr infusion. Approximately one-third of patients developed a maculo-papular erythematous rash to the scalp, neck and upper chest. In two patients, the rash became generalized with evidence of epidermolysis on skin biopsy. Pharmacology studies revealed steady-state arterial plasma levels of 2 X 10(-6) M/1 during the 12 hr infusion of 650 to 700 mg/m2. Radiosensitization was measured by a change in the D0 of radiation survival curves of human bone marrow CFUc prior to and following the 14 day infusion in 4 patients. A trend of increasing radiosensitization was noted in most patients as the infusion rate of BUdR was increased from 500 to 870 mg/m2/12 hr. We conclude that the maximum tolerable dose of BUdR is 650 to 700 mg/m2/12 hrs when given as a 2 week intermittent intravenous infusion. Local toxicity is acceptable. The major systemic toxicities are myelosuppression and a maculopapular skin rash.

Twenty-nine patients (two with small bowel cancer and 27 with colorectal cancer) were treated with a sequential 5-FU-hydroxyurea combination following the suggestion of schedule-dependent synergism in experimental systems. No enhanced toxicity was observed, but the response rate was only 4%. Seven additional patients manifested greater than or equal to 50% declines in CEA, but caution must be used in interpreting such changes as antitumor activity