Phase I and Pharmacological Studies of Adriamycin Administered Intraperitoneally to Patients with Ovarian Cancer

Abstract

Abstract A Phase I study of Adriamycin administered i.p. was performed in 10 ovarian cancer patients who were refractory to systemic chemotherapy. Adriamycin was infused in 2 liters of Inpersol via a semipermanent Tenckhoff dialysis catheter. Adriamycin was administered for a 4-hr dwell every 2 weeks with concentrations ranging from 9 to 54 µm. The dose-limiting toxicity of i.p. Adriamycin was a sterile peritonitis. Severe abdominal pain with ascites and adhesions was observed at concentrations greater than 36 µm. There were three objective responses, and two other patients had a marked reduction in ascites formation while on treatment. The objective responses were in patients who had small volume ( Adriamycin concentrations were measured by high-pressure liquid chromotography. A mean of 85% of the drug was absorbed over the 4-hr dwell time. The concentrations attained i.p. have been demonstrated previously to be cytotoxic to human ovarian cancer cells from untreated patients or from patients who had relapsed after treatment with a non-Adriamycin combination. Plasma levels peaked within the first hr after i.p. instillation. Plasma levels were markedly lower than corresponding peritoneal concentrations. The maximum pharmacological advantage (peak peritoneal concentration/peak plasma concentration) was 474, while the 4-hr peritoneal level was 166 times higher than the corresponding plasma level after an i.p. dose of 40 mg/2 liters (36 /µm). The peak plasma levels after a 60-mg/2 liters (54 µm) dose were 10 times lower than after a 60-mg i.v. dose. The recommended starting dose for a Phase II trial is 27 to 36 µm (30 to 40 mg Adriamycin per 2 liters Inpersol) with a 4-hr dwell every 2 to 3 weeks for six cycles.