Unexpected toxicity in patients treated with iphosphamide.

Abstract

A derivative of cyclophosphamide, 2,3-( N,N 1-bis(2-chloroethyl)diamido-1,3,2-oxazaphosphoridinoxyd (Iphosphamide), was less toxic in experimental systems than cyclophosphamide, while it had a broader antitumor spectrum. We studied this agent in a clinical trial of 37 patients with histologically proved, far-advanced malignant disease. The study was designed mainly to determine toxicity and dosimetry of Iphosphamide. Curative effect of Iphosphamide in experimental animals depends on concentration rather than on total dose; therefore, single large doses of the agent were investigated in the first 31 patients. Side effects include nausea, vomiting, alopecia, uremia, hematuria, dysuria and frequency, urinary incontinence, hemopoietic suppression, elevated alkaline phosphatase and transaminase, and mental confusion. Because of nephrotoxicity at high single doses, a further 6 patients received smaller daily doses; however, at the small daily dose levels tubular damage also occurred, as evidenced by granular cylinders in the urine of all 6 patients. At the smaller dose range, nephrotoxicity was the only toxic manifestation. Therapeutic benefit was obtained only with high doses. In view of kidney toxicity at all dosage levels, attention should be given to urine microscopy and other kidney function tests in all patients being treated with Iphosphamide.