PubMed1989
An important subset of malignancies arising in the ovary or digestive organs remains confined to the peritoneal cavity throughout its natural course. These tumors constitute appropriate targets for loco-regional therapy. With this rationale a clinical phase I and pharmacokinetic study of intraperitoneally administered N, N', N'' triethylenethiophosphoramide (thiotepa), an alkylating agent with activity against ovarian carcinoma, was initiated with the objectives of determining the systemic and local toxicities, maximum-tolerated dose, and pharmacokinetic advantage associated with using the drug in this manner. A total of 13 patients received 15 courses of intraperitoneal thiotepa at doses ranging from 30 mg/m2 to 60 mg/m2. The only important systemic toxicity observed was myelosuppression. At 50 mg/m2 two patients developed Eastern Cooperative Oncology Group (ECOG) grade III myelosuppression. At 60 mg/m2, the maximum-tolerated dose, the mean nadir WBC and platelet counts were 2.7 X 10(3)/microliter and 110 X 10(3)/microliter, respectively. There were no instances of vomiting, stomatitis, or alopecia. Pharmacokinetic studies performed in nine patients revealed that thiotepa was rapidly lost from the peritoneal cavity in a biexponential fashion with a mean t1/2 alpha of 0.26 +/- 0.08 hour and a mean t1/2 beta of 2.13 +/- 0.52 hour. Concomitant with the rapid loss of drug from the peritoneal cavity was the rapid rise in drug levels in the plasma, with peak plasma values approaching those associated with intravenous administration. Peritoneal exposure to thiotepa expressed as the area under the curve (AUC)peritoneal fluid was 7 to 34 micrograms/mL X hour. Systemic exposure expressed as the AUCplasma ranged between 0.95 and 7.71 micrograms/mL X hour. The observed pharmacokinetic advantage of intraperitoneal administration calculated as AUCperitoneal fluid/AUCplasma was 4.3 +/- 0.6. This relatively small advantage, combined with our observation of rapid appearance of the active metabolite, tepa, into the plasma argue against an important role for intraperitoneal administration of thiotepa.