Faculty Bibliography

The levels of 5-fluorouracil (5-FU) in plasma and peritoneal fluid were determined after the bolus administration of drug in 2 L of dialysis fluid through a Tenckhoff catheter into the peritoneal cavity of colon cancer patients. An increasing dose of intraperitoneal (i.p.) 5-FU resulted in an increased level of 5-FU in the blood. In 18 treatment cycles studied in four patients, the clearance of 5-FU from peritoneal fluid and the level of drug in the plasma were increased by day 5 of i.p. treatment. In one of these patients, the peritoneal clearance of 5-FU did not further increase between days 8 and 12. If ascites fluid was not removed prior to subsequent 5-FU administration, drug absorption from the peritoneal cavity was markedly decreased. These studies show that a dose of 5-FU given within a body compartment may profoundly affect the pharmacokinetics of subsequent doses of the same chemotherapy

Eighteen patients with non-small cell lung cancer were entered into a phase II protocol of oral 4-demethoxydaunorubicin. All were evaluable for toxicity and 17 for response. The major toxicity was hematologic with eight patients developing an ECOG grade 3 or 4 toxicity. There were no responses to the treatment

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

In order to test the possible cardiac-sparing effect of doxorubicin administered by six-hour intravenous infusion and to prospectively evaluate the role of resting left ventricular ejection fraction in monitoring these patients, 33 women with advanced breast cancer were treated with combination chemotherapy containing 5-fluorouracil, cyclophosphamide, and doxorubicin. Doxorubicin was administered via a femoral catheter as a six-hour infusion. Cardiac function was monitored prior to therapy and at intervals during therapy by history and physical examination and by measurement of resting left ventricular ejection fraction with gated pool radionuclide angiography. Twenty-six responses were observed (complete response, seven [21 percent]; partial response, 19 [57 percent]). Systemic toxicity included alopecia, myelosuppression, and nausea and vomiting. There was a progressive fall in resting left ventricular ejection fraction during treatment from a median baseline value of 0.63. Mean fall from baseline left ventricular ejection fraction at a cumulative doxorubicin dose of 200 to 300 mg/m2 was 0.06 (p less than 0.005); at 301 to 449 mg/m2 it was 0.09 (p less than 0.0005); and at 450 mg/m2 or greater it was 0.15 (p less than 0.0005). Clinical congestive heart failure developed in three patients. Even though the decrease in left ventricular ejection fraction was often within the 'normal range' (left ventricular ejection fraction 0.50 or greater), these changes were progressive and appeared to be part of a continuum of doxorubicin-induced myocardial damage. Steady-state infusion levels of doxorubicin in plasma ranged from 90 to 120 nM. They confirm the hypothesis that lower concentrations can be achieved by continuous infusion rather than by bolus infusion. In this study, however, administration of doxorubicin by six-hour infusion did not appear to have a major cardiac-sparing effect. Studies of anthracycline cardiac toxicity should include determination of baseline left ventricular ejection fraction and serial observations during therapy. Failure to include deteriorations in function above an arbitrary cutoff point or to make observations only at higher cumulative doses may underestimate drug-induced myocardial damage