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Unexpected Toxicity Associated with Use of Body Surface Area for Dosing Melphalan in the Dog¹

North Carolina State University, School of Veterinary Medicine, Raleigh, North Carolina 27606 [R. L. P., G. L. H., D. E. T.]; Colorado State University, Veterinary Teaching Hospital, Fort Collins, Colorado 80523 [D. W. M., S. L. A., M. L. M., E. L. G.]; Duke University Medical Center, Division of Radiation Oncology, Durham, North Carolina 27710 [M. W. D.]; and Robart Research Institute, London, Ontario, Canada N6A5K8 [D. A. S.]

A multiinstitutional Phase I study using i.v. melphalan was conducted in dogs with spontaneously occurring neoplasia. Melphalan was administered at 7.5, 10, 11.25, 12.5, and 20 mg/m² of body surface area. Disproportionately greater toxicity was observed in small dogs. Seven of the eight dogs (88%) weighing less than 14 kg experienced severe myelosuppression (neutropenia, <1500/mm³; and/or thrombocytopenia, <80,000/mm³), whereas only three of 13 dogs (23%) weighing greater than 14 kg developed severe myelosuppression (P = 0.016). We concluded that small dogs are at greater risk of developing bone marrow toxicity from i.v. melphalan than large dogs if body surface area is used to calculate the dose. Although both body surface area and weight were found to be significantly correlated with severity of toxicity, melphalan-induced toxicity in dogs can be more accurately estimated by body weight than by surface area, P = 0.008 versus P = 0.022, respectively.

It may be necessary to prescribe antineoplastic agents that are eliminated by processes not primarily under metabolic influence or that produce side effects on tissue not correlated to basal metabolic rate on a parameter other than body surface area. In dogs, melphalan should be dosed on a weight basis, and treatment groups should be stratified by weight in randomized clinical studies, particularly when the weight range of treated subjects is great.

¹ This work was supported by the State of North Carolina and USPHS Grant CA 29582 awarded by the National Cancer Institute, Department of Health and Human Services.

² To whom requests for reprints should be addressed.

Received 6/25/87. Revised 10/ 8/87. Accepted 10/14/87.