Amputation and Carboplatin for Treatment of Dogs With Osteosarcoma: 48 Cases (1991 to 1993) zy Philip zyxwvutsr J. Bergman, E. Gregory MacEwen, Ilene D. Kurzman, Carolyn J. Henry, Alan S. Hammer, Deborah W. Knapp, Ann Hale, Stephen A. Kruth, Mary K. Klein, Jeffrey Klausner, Alan M. Norris, Dudley McCaw, Rodney C. Straw, and Stephen J. Withrow zyx Forty-eight dogs with histologically confirmed appendicular osteosarcoma (OSA) entered a prospective clinical trial eval- uating treatment with amputation and up to 4 doses of car- boplatin given every 21 days. The median disease-free inter- val (DFI) was 257 days, with 31.2% of the dogs disease-free at 1 year. The median survival time was 321 days, with 35.4% of the dogs alive at 1 year. Dogs with proximal humeral OSA had shorter DFI zyxwvutsrqp (P = .016) and survival (P = ,037) times than dogs with OSA at other locations. Dogs with lower body weights (<40 kg) had longer DFI zyxwvutsr (P = .0056) and survival (P zyxwvut anine appendicular osteosarcoma (OSA) is an aggres- C sive tumor that has a poor prognosis without treat- ment.1.2 This tumor has been estimated to affect 8,000 to 10,000 dogs annually in the United States, and accounts for 85% of all primary bone tumors in dogs.’.’ Amputation, which rarely results in a cure but relieves local discomfort, has traditionally been the standard treatment modality. Be- cause 80% to 90% of patients have microscopic occult meta- static disease at presentation, amputation is only a palliative pr~cedure.~.’ The median survival of dogs with OSA treated by amputation alone is 126 to 134 days, and only 10% to 12% of the dogs are alive at 1 year.’ Therefore, to improve survival, some form of systemic therapy is necessary. Recently, cis-diamminedichloroplatinum (cisplatin) has shown activity against OSA in dogs and people.’,7-” The median survival of dogs receiving cisplatin after surgery improved to 262 to 325 days, and 33% to 45% of the dogs zyxwvuts From the zyxwvutsrqpon Colorudo State University, Fort Collins, CO (Bergman, Straw, Withrow); the University qf Wisconsin, Madison, Wl (MucEwen, Kurzman); Auburn University, Auburn, AL (Henry); The Ohio Stute University, Columbus, OH (Hummer);Purdue University, West Lafayette, zyxwvutsrqpon IN (Knupp); Michigan State University, East Lan- sing, MI (Hule); Ontario Veterinary College, Univemity of Guelph, Guelph, Onturio, Canada (Kruth); Southwest Veterinunj Oncology, Tucson, A 2 (Klein); the University of Minnesota, St. Paul, MN (Klausner); Veterinury Referral Clinic, Toronto, Ontario, Canada (Norris); and the University of Missouri, Columbia, MO (McCaw). Accepted August 29, 1995. An ubstruct of this work wus presented at the 12th Annual Meeting ofthe Veterinury Cancer Society, Paci$c Grove, CA, October 1992. The authors acknowledge the manuscript assistance of Helen Muwhiney. Supported in purt by a Grunt,frvm the Bristol-Myers Corporution und by Grunt 2 POI CA29582 from the National Cancer Institute. Its contents ure solely the responsibility of the authors and do not nt.cessari1)) represent the oficial views of the National Cancer Insti- tute. Reprint requests: Philip J. Bergman, DVM, M.D. Anderson Cun- cer Center, Smith Reseurch Building-173, 151.5 Holcornbe Blvd, Houston, TX 77030. Copyright zyxwvutsrqp 0 I996 by the American College of Veterinury Internul Medicine 0891 -6640/96/1002-0005$3.00/0 = .007) times than larger dogs. Survival times for dogs that received carboplatin were statistically longer than those pre- viously reported for amputation alone (P < .001). DFI and survival times are similar to those previously reported for 2 to 4 doses of cisplatin. Carboplatin appears to be a well- tolerated chemotherapeutic drug that can be given safely every 21 days at a dose of 300 mg/m2. Neutropenia was the dose-limiting toxicity in this study. J Vet Intern Med 1996;10:76-81. Copyright 0 1996 by the American College of Veterinary Internal Medicine. were alive at 1 Cisplatin is nephrotoxic and requires intensive saline di~resis.l~-~‘ This complication must be con- sidered when one uses cisplatin in dogs with compromised renal function or congestive heart failure. Recently, a strong trend was found toward improved survival in dogs with OSA receiving higher doses of c is plat in.'^ The use of a non-neph- rotoxic agent of similar efficacy is very appealing and has been the impetus for development of cisplatin analogues. Cis -diammine- 1, 1 -cyclobutane dicarboxylate platinum (11) (carboplatin, CBDCA, JM-8, Paraplatin; Bristol-Myers, Squibb Laboratories, Evansville, IN) is a second-generation platinum compound that differs from cisplatin in its pharma- cological and toxic properties without reducing clinical effi- cacy.’*.’’ The dose-limiting toxicity of carboplatin in people is myelosuppression, most notably thrombocytopenia. ”-” In a phase I trial of carboplatin in dogs, the dose-limiting toxici- ties were neutropenia and thrombocyt~penia.~~ Recornmen- dations were made to use a dose of 300 mg/m2in future trials because dogs experienced marked myelotoxicity at doses of 350 to 400 mg/mz. Carboplatin is considered an alternative therapy to cisplatin in human patients with pre-existing con- ditions such as neurological or renal Similarly, it is considered useful in patients unable to undergo the vigorous diuresis associated with cisplatin.2’ The objectives of this study were to (1) perform a prospec- tive multi-institutional clinical trial for dogs with OSA; (2) define frequency and types of toxicity; (3) determine disease- free interval (DFI) and overall survival times for dogs treated with amputation and carboplatin; (4) compare DFI and sur- vival data with previously documented results; and (5) iden- tify prognostic factors. Materials and Methods From November 1991 to April 1993, 48 dogs with appendicular OSA were treated with amputation and postoperative IV carboplatin. Twenty-one dogs had treatment and follow-up evaluations at the Colorado State Univei-sity Veterinary Teaching Hospital (CSUVTH), 5 dogs at Michigan State University, 5 dogs at Auburn University, 4 dogs at Ohio State University, 4 dogs at Ontario Veterinary Col- lege, and 3 dogs at Purdue University. The remaining 6 dogs had treatment and follow-up evaluations at 4 other veterinary centers. Thirty-seven dogs received commercially available Paraplatin and 11 dogs received pharmaceutical grade carboplatin. Of the 1 I dogs 76 Journal of Veterinary internal Medicine, Vol 10, No 2 (March-April), 1996: pp 76-81