Toxicoses associated with administration of mitoxantrone to dogs with malignant tumors

Gregory K. Ogilvie From the Comparative Oncology Unit, Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO 80523 (Ogilvie, Obradovich, Elmslie, Vail, Curtis, Straw, Dickinson, Cooper, Withrow), and Tufts University School of Veterinary Medicine, 200 Westboro Rd, North Grafton, MA 01536 (Moore).

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Joyce E. Obradovich From the Comparative Oncology Unit, Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO 80523 (Ogilvie, Obradovich, Elmslie, Vail, Curtis, Straw, Dickinson, Cooper, Withrow), and Tufts University School of Veterinary Medicine, 200 Westboro Rd, North Grafton, MA 01536 (Moore).

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Robyn E. Elmslie From the Comparative Oncology Unit, Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO 80523 (Ogilvie, Obradovich, Elmslie, Vail, Curtis, Straw, Dickinson, Cooper, Withrow), and Tufts University School of Veterinary Medicine, 200 Westboro Rd, North Grafton, MA 01536 (Moore).

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David M. Vail From the Comparative Oncology Unit, Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO 80523 (Ogilvie, Obradovich, Elmslie, Vail, Curtis, Straw, Dickinson, Cooper, Withrow), and Tufts University School of Veterinary Medicine, 200 Westboro Rd, North Grafton, MA 01536 (Moore).

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A. S. Moore From the Comparative Oncology Unit, Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO 80523 (Ogilvie, Obradovich, Elmslie, Vail, Curtis, Straw, Dickinson, Cooper, Withrow), and Tufts University School of Veterinary Medicine, 200 Westboro Rd, North Grafton, MA 01536 (Moore).

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Charles R. Curtis
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Rodney C. Straw From the Comparative Oncology Unit, Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO 80523 (Ogilvie, Obradovich, Elmslie, Vail, Curtis, Straw, Dickinson, Cooper, Withrow), and Tufts University School of Veterinary Medicine, 200 Westboro Rd, North Grafton, MA 01536 (Moore).

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Krista Dickinson From the Comparative Oncology Unit, Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO 80523 (Ogilvie, Obradovich, Elmslie, Vail, Curtis, Straw, Dickinson, Cooper, Withrow), and Tufts University School of Veterinary Medicine, 200 Westboro Rd, North Grafton, MA 01536 (Moore).

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Mary F. Cooper From the Comparative Oncology Unit, Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO 80523 (Ogilvie, Obradovich, Elmslie, Vail, Curtis, Straw, Dickinson, Cooper, Withrow), and Tufts University School of Veterinary Medicine, 200 Westboro Rd, North Grafton, MA 01536 (Moore).

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Stephen J. Withrow From the Comparative Oncology Unit, Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO 80523 (Ogilvie, Obradovich, Elmslie, Vail, Curtis, Straw, Dickinson, Cooper, Withrow), and Tufts University School of Veterinary Medicine, 200 Westboro Rd, North Grafton, MA 01536 (Moore).

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Summary

One hundred twenty-nine dogs with histologically confirmed malignant tumors were used in a prospective study to determine the toxicity of the new dihydroxyquinone derivative of anthracene, mitoxantrone, which was administered iv at 21-day intervals at dosages ranging from 2.5 to 5 mg/m2 body surface area. Each dog was evaluated for signs of toxicosis for 3 weeks after each dose was administered or until the dog died, whichever came first. The number of dogs in each evaluation period were as follows: 1 dose (n = 129), 2 doses (n = 82), 3 doses (n = 43), 4 doses (n = 26), 5 doses (n = 19), 6 doses (n = 9), 7 doses (n = 6), 8 doses (n = 5), 9 doses (n = 3), and 10 doses (n = 1). The most common signs of toxicosis were vomiting, diarrhea, anorexia, and sepsis secondary to myelosuppression. None of the dogs died of complications resulting from mitoxantrone treatment. Dogs with signs of toxicosis during the 21-day interval from administration of the first dose of mitoxantrone were 95 times (P = 0.003) more likely to develop signs of toxicosis during the 21-day interval from the second dose of mitoxantrone. Similarly, dogs that developed signs of toxicosis during the 21-day interval from the administration of the second dose were 34 times (P < 0.001) more likely to develop signs of toxicosis during the 21-day interval from the administration of the third dose. With each 1 mg/m2 increase in mitoxantrone, the odds of developing signs of toxicosis increased by 5.9 fold (P < 0.001). The performance status (modified Karnofsky performance scheme) of each dog was not adversely affected to a significant extent by mitoxantrone-induced toxicosis until the fifth dose (P = 0.0008). Cardiac toxicosis was not detected. Mitoxantrone was also administered iv to 4 clinically normal dogs, at a dosage of 5 mg/m2 of body surface area, a decrease in the neutrophil count was seen, with the nadir occurring on day 10 (mean ± sem: 1,159 ± 253 cells/μl; range, 480 to 1,680 cells/μl). Tumor-bearing dogs did not seem to have the same degree of myelosuppression (mean ± sem, 6,263 ± 1,230 cells/μl; range, 228 to 18,600 cells/μl).

Summary

One hundred twenty-nine dogs with histologically confirmed malignant tumors were used in a prospective study to determine the toxicity of the new dihydroxyquinone derivative of anthracene, mitoxantrone, which was administered iv at 21-day intervals at dosages ranging from 2.5 to 5 mg/m2 body surface area. Each dog was evaluated for signs of toxicosis for 3 weeks after each dose was administered or until the dog died, whichever came first. The number of dogs in each evaluation period were as follows: 1 dose (n = 129), 2 doses (n = 82), 3 doses (n = 43), 4 doses (n = 26), 5 doses (n = 19), 6 doses (n = 9), 7 doses (n = 6), 8 doses (n = 5), 9 doses (n = 3), and 10 doses (n = 1). The most common signs of toxicosis were vomiting, diarrhea, anorexia, and sepsis secondary to myelosuppression. None of the dogs died of complications resulting from mitoxantrone treatment. Dogs with signs of toxicosis during the 21-day interval from administration of the first dose of mitoxantrone were 95 times (P = 0.003) more likely to develop signs of toxicosis during the 21-day interval from the second dose of mitoxantrone. Similarly, dogs that developed signs of toxicosis during the 21-day interval from the administration of the second dose were 34 times (P < 0.001) more likely to develop signs of toxicosis during the 21-day interval from the administration of the third dose. With each 1 mg/m2 increase in mitoxantrone, the odds of developing signs of toxicosis increased by 5.9 fold (P < 0.001). The performance status (modified Karnofsky performance scheme) of each dog was not adversely affected to a significant extent by mitoxantrone-induced toxicosis until the fifth dose (P = 0.0008). Cardiac toxicosis was not detected. Mitoxantrone was also administered iv to 4 clinically normal dogs, at a dosage of 5 mg/m2 of body surface area, a decrease in the neutrophil count was seen, with the nadir occurring on day 10 (mean ± sem: 1,159 ± 253 cells/μl; range, 480 to 1,680 cells/μl). Tumor-bearing dogs did not seem to have the same degree of myelosuppression (mean ± sem, 6,263 ± 1,230 cells/μl; range, 228 to 18,600 cells/μl).

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