Faculty Bibliography

We hypothesized that cyclophosphamide and cis-platinum, without adriamycin, which had been used in previous studies, may be equally efficacious, but less toxic. We treated 27 patients with non-small cell bronchogenic carcinoma with the combination of cyclophosphamide and cis-platinum. We report six responses (25% response rate), with median survival of 79 weeks as compared to 28 weeks in nonresponders (p less than 0.01). Our regimen had acceptable hematologic toxicity and tolerable gastrointestinal toxicity. However, cumulative nephrotoxicity and neurotoxicity were observed. We conclude that cyclophosphamide and cis-platinum may compare favorably to the cyclophosphamide, adriamycin and cis-platinum combination, with respect to response and toxicity

A phase II study of ip 5-FU was performed in 14 patients with ovarian cancer who were refractory to systemic chemotherapy including prior iv 5-FU in 12 of the patients. 5-FU was administered via a semipermanent Tenckhoff peritoneal dialysis catheter. The starting concentration of 5-FU in the dialysate was 4 mM. The patients received eight consecutive 2-L exchanges, each of 4-hour duration, for a total of 36 hours including time for instillation and drainage. Treatment courses were repeated every 2 weeks for six cycles or until disease progression occurred. A total of 69 cycles of ip 5-FU were administered to 14 patients. There was one complete response to therapy documented by second-look laparotomy. While the response rate was only 7%, in seven of eight (88%) patients with small volume disease (tumor masses less than 2.0 cm in diameter), there was no evidence for disease progression while receiving ip 5-FU therapy. In this phase II trial, the major toxic effect of ip 5-FU was abdominal pain. While there were no cases of documented bacterial peritonitis, all of the patients experienced some degree of abdominal discomfort while receiving therapy. Fifty percent of the patients had severe abdominal pain with at least one cycle of therapy. Other toxic effects included myelosuppression, mucositis, nausea and vomiting, and skin rash. The results of this study indicate that ip 5-FU should be further evaluated in patients with ovarian cancer who have a small volume of disease and who have not had prior therapy with 5-FU

A cannulation set has been designed for repeated short-term infusion of vesicant chemotherapeutic agents via the femoral vein. The major complication was thrombophlebitis in 2.1% of infusions. The procedure provides reliable venous access when therapeutic plans are changed or when the inability to provide catheter care makes an indwelling catheter unwarranted

The plasma pharmacokinetics of Adriamycin and adriamycinol following a 15-min infusion of 75 mg/sq m of Adriamycin were studied in ten patients previously untreated with Adriamycin. The disappearance kinetics of Adriamycin could adequately be described by a biexponential equation with an initial half-life of 8-min and a terminal half-life of 30 hr. The major drug exposure (area under the concentration-time curve) occurs during the terminal phase where drug concentrations are generally less than 10(-7) M (0.05 micrograms/ml). An improvement in the high-performance liquid chromatography sensitivity facilitated the determination of the terminal phase. The plasma kinetics of adriamycinol, the major and only known active metabolite of Adriamycin, show a rapid initial increase in plasma concentration followed by a slow decline which parallels that of Adriamycin during the terminal phase. The relative drug exposure of adriamycinol to Adriamycin was approximately 50%. The relationship between the measured plasma drug levels and free drug available for distribution into tissues was studied by comparing the plasma binding characteristics of Adriamycin and adriamycinol. A constant 20 to 25% of the total plasma concentrations of both Adriamycin and adriamycinol was freely diffusible over the whole range of observed concentrations, 20 nM to 2 microM. Thus, the free drug exposure (area under the concentration-time curve) of tumor and host tissues in vivo can be determined from these plasma measurements, since the free drug exposures in plasma and in extracellular fluid are equivalent. These results can also serve as a guide for the design of clinically relevant in vitro studies of Adriamycin and adriamycinol. The pharmacokinetic parameters determined in this study have been used to simulate plasma concentration-time courses for a variety of Adriamycin treatment schedules. Alternatives are suggested which reduce peak plasma Adriamycin concentration while antitumor area under the concentration-time curve is maintained