"Chemotherapy dosage" Special Double Issue: TUMOR TIDBITS, A BIWEEKLY EMAIL NEWSLETTER FROM GULF COAST VETERINARY ONCOLOGY Number 78; November 15, 2002. ======================================================================= THIS WEEK'S TUMOR TIDBIT: Why Meter Squared? ======================================================================= Because the differences between the effective and toxic doses of most cancer chemotherapeutics is slight, it is important to achieve therapeutic concentrations in tumor tissues at the same time that concentrations in nontarget tissues (bone marrow, intestine) are minimized. In order to determine the dosage regimen that will most likely accomplish these goals, similar drug concentrations must be achieved in all patients dosed according to a specific regimen. Body surface area (BSA) was introduced into medical oncology in order to derive a safe starting dose for phase I studies of anticancer drugs in human beings derived from preclinical animal toxicology data. It is not clear however, as to why dosing by BSA was extended to the routine dosing of antineoplastic agents in both species. Several formulas exist to estimate BSA, but the formula in current veterinary use was derived on data from only nine human patients; subsequent attempts to validate the formula have found the formula to either over or underestimate the actual determined BSA. While cardiac output does correlate with BSA, the relationship between BSA and other physiologic measures relevant for drug metabolism and disposition, such as, renal and hepatic function, is weak or nonexistent. Further only adriamycin and cisplatin have been studied in dogs to determine if dosing by BSA would reduce interpatient variability, and none of these drugs were found to have significant relationships between their pharmacokinetics and BSA. Results to date suggest that canine BSA estimates may be inaccurate because the values for the constant (K) and exponent (a) in the formulae (BSA = K.Wa) are incorrect or because a linear parameter such as body length is lacking from the formulae. Results also suggest the relationship between BSA and the physiologic/pharmacologic factors that influence drug exposure may not be closely correlated. To illustrate the problem with BSA dosing in dogs, a 30 kg (66 lb) dog has a BSA of 1 meter squared. If this dog were to be given Adriamycin at the 'standard' dosage of 30 mg/m2, this dog would be given a 30 mg total delivered dose, or the equivalent to 1 mg/kg. However, a 5 kg (11 lb) dog has a BSA of 0.30 meter squared and would thus be given a dosage of 9 mg (30 mg/m2 times 0.30 m2) equivalent to 1.8 mg/kg (9 mg divided by 5 kg) or an 80% overdosage of Adriamycin when based upon body weight. Adriamycin does not fit the BSA model yet studies have not yet been completed to determine the appropriate dosage based upon body weight. The conclusion - until such studies are conducted in dogs of vary body size, shape, weight and length, chemotherapeutic drug dose selection in human and veterinary medicine remains anecdotal. Some suggested reading about dosing and chemotherapy is listed below. ======================================================================= We hope this info helps and don't hesitate to call us Gulf Coast Veterinary Oncology! Kevin A. Hahn, DVM, Phd, Diplomate ACVIM (Oncology), drhahn@gcvs.com Janet K. Carreras, VMD, Diplomate ACVIM (Oncology), drcarreras@gcvs.com Glen K. King, DVM, MS, Diplomate ACVR (Radiology & Radiation Therapy), drking@gcvs.com Gulf Coast Veterinary Diagnostic Imaging & Oncology 1111 West Loop South, Suite 150, Houston, TX 77027 P: 713.693.1166 F: 713.693.1167 W: www.gcvs.com ======================================================================= SUGGESTED READING Arrington KA, Frazier DL, Tabeling GS, Hahn KA, Legendre AM. The comparison of pharmacokinetics, hematologic parameters, and clinical signs of doxorubicin administration in small and large dogs. Proc Vet Cancer Soc 1992:36-37. Bravo L, Hahn KA, Legendre AM, Daniel GB, Frazier DL, Rohrbach BW. Evaluation of pre- and post-cisplatin renal function in 23 tumor-bearing dogs. Proc Vet Cancer Soc 1992:39-40. Ausmus P, Hahn KA, Avenell JS, Barbaro G, Bravo L, Legendre AM, Frazier DL. Pharmacokinetics of cisplatin (2 mg/kg v. 60 mg/m2) in 31 dogs. Proc Vet Cancer Soc 1994:43-44. Hahn KA, Frazier DL, Cox S, Legendre AM, Bravo L, Avenell JS, Barbaro G. Pharmacokinetics of adriamycin (1 mg/kg v. 25 mg/m2) in 9 cats. Proc Amer College Vet Internal Med 1995:824. Daniel GB, Hahn KA, Bravo L, Legendre AM. The effect of a single therapeutic dose of cisplatin on GFR in dogs. Oncology Reports 1997;4:153-156. Hahn KA, Rohrbach BW, Legendre AM, Frazier DL, Nolan ML. Hematologic changes associated with weekly low-dose cisplatin administration in dogs. Vet Clin Path 1997; 26:29-31. Hahn KA, Nolan ML, McEntee MF, Daniel GB, Legendre AM. Hematologic and systemic toxicoses associated with carboplatin administration in cats. Amer J Vet Res 1997;58:677-679. Hahn KA, Fields MA, Hultgren JL, Nolan ML, Legendre AM. Dose-response and time-course of carboplatin-induced micronucleated polychromatic erythrocytes in the cat: implications for combination carboplatin chemotherapy. Chemotherapy 1997;43:282-287. Hahn KA, Frazier DL, Cox SK, Legendre AM. Effect of infusion regime on doxorubicin pharmacokinetics in the cat. J Amer Anim Hosp 1997;33:427-433. Price GS, Frazier DL. Use of body surface area (BSA)-based dosages to calculate chemotherapeutic drug dose in dogs: I. Potential problems with current BSA formulae. J Vet Intern Med 1998 Jul-Aug;12(4):267-71. Frazier DL, Price GS. Use of body surface area to calculate chemotherapeutic drug dose in dogs: II. Limitations imposed by pharmacokinetic factors. J Vet Intern Med 1998 Jul- Aug;12(4):272-8. ======================================================================= We hope this info helps and don't hesitate to call us Gulf Coast Veterinary Oncology! Kevin A. Hahn, DVM, Phd, Diplomate ACVIM (Oncology), drhahn@gcvs.com Janet K. Carreras, VMD, Diplomate ACVIM (Oncology), drcarreras@gcvs.com Glen K. King, DVM, MS, Diplomate ACVR (Radiology & Radiation Therapy), drking@gcvs.com Gulf Coast Veterinary Diagnostic Imaging & Oncology 1111 West Loop South, Suite 150, Houston, TX 77027 P: 713.693.1166 F: 713.693.1167 W: www.gcvs.com