Toxicoses and efficacy associated with administration of mitoxantrone to cats 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, Straw, Salmon, Atwater, Ciekot, LaRue, Withrow), School of Veterinary Medicine, Tufts University, 200 Westboro Rd, North Grafton, MA 01536 (Moore), the Animal Health Hospital, 2560 Harrison, Tuscon, AZ 85748 (Klein), and School of Veterinary Medicine, University of California, Davis, CA 95616 (Peaston).

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Antony 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, Straw, Salmon, Atwater, Ciekot, LaRue, Withrow), School of Veterinary Medicine, Tufts University, 200 Westboro Rd, North Grafton, MA 01536 (Moore), the Animal Health Hospital, 2560 Harrison, Tuscon, AZ 85748 (Klein), and School of Veterinary Medicine, University of California, Davis, CA 95616 (Peaston).

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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, Straw, Salmon, Atwater, Ciekot, LaRue, Withrow), School of Veterinary Medicine, Tufts University, 200 Westboro Rd, North Grafton, MA 01536 (Moore), the Animal Health Hospital, 2560 Harrison, Tuscon, AZ 85748 (Klein), and School of Veterinary Medicine, University of California, Davis, CA 95616 (Peaston).

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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, Straw, Salmon, Atwater, Ciekot, LaRue, Withrow), School of Veterinary Medicine, Tufts University, 200 Westboro Rd, North Grafton, MA 01536 (Moore), the Animal Health Hospital, 2560 Harrison, Tuscon, AZ 85748 (Klein), and School of Veterinary Medicine, University of California, Davis, CA 95616 (Peaston).

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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, Straw, Salmon, Atwater, Ciekot, LaRue, Withrow), School of Veterinary Medicine, Tufts University, 200 Westboro Rd, North Grafton, MA 01536 (Moore), the Animal Health Hospital, 2560 Harrison, Tuscon, AZ 85748 (Klein), and School of Veterinary Medicine, University of California, Davis, CA 95616 (Peaston).

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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, Straw, Salmon, Atwater, Ciekot, LaRue, Withrow), School of Veterinary Medicine, Tufts University, 200 Westboro Rd, North Grafton, MA 01536 (Moore), the Animal Health Hospital, 2560 Harrison, Tuscon, AZ 85748 (Klein), and School of Veterinary Medicine, University of California, Davis, CA 95616 (Peaston).

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M. D. Salmon 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, Straw, Salmon, Atwater, Ciekot, LaRue, Withrow), School of Veterinary Medicine, Tufts University, 200 Westboro Rd, North Grafton, MA 01536 (Moore), the Animal Health Hospital, 2560 Harrison, Tuscon, AZ 85748 (Klein), and School of Veterinary Medicine, University of California, Davis, CA 95616 (Peaston).

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M. K. Klein 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, Straw, Salmon, Atwater, Ciekot, LaRue, Withrow), School of Veterinary Medicine, Tufts University, 200 Westboro Rd, North Grafton, MA 01536 (Moore), the Animal Health Hospital, 2560 Harrison, Tuscon, AZ 85748 (Klein), and School of Veterinary Medicine, University of California, Davis, CA 95616 (Peaston).

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Stephen W. Atwater 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, Straw, Salmon, Atwater, Ciekot, LaRue, Withrow), School of Veterinary Medicine, Tufts University, 200 Westboro Rd, North Grafton, MA 01536 (Moore), the Animal Health Hospital, 2560 Harrison, Tuscon, AZ 85748 (Klein), and School of Veterinary Medicine, University of California, Davis, CA 95616 (Peaston).

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Phyllis E. Ciekot 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, Straw, Salmon, Atwater, Ciekot, LaRue, Withrow), School of Veterinary Medicine, Tufts University, 200 Westboro Rd, North Grafton, MA 01536 (Moore), the Animal Health Hospital, 2560 Harrison, Tuscon, AZ 85748 (Klein), and School of Veterinary Medicine, University of California, Davis, CA 95616 (Peaston).

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Susan M. LaRue 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, Straw, Salmon, Atwater, Ciekot, LaRue, Withrow), School of Veterinary Medicine, Tufts University, 200 Westboro Rd, North Grafton, MA 01536 (Moore), the Animal Health Hospital, 2560 Harrison, Tuscon, AZ 85748 (Klein), and School of Veterinary Medicine, University of California, Davis, CA 95616 (Peaston).

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Anne Peaston 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, Straw, Salmon, Atwater, Ciekot, LaRue, Withrow), School of Veterinary Medicine, Tufts University, 200 Westboro Rd, North Grafton, MA 01536 (Moore), the Animal Health Hospital, 2560 Harrison, Tuscon, AZ 85748 (Klein), and School of Veterinary Medicine, University of California, Davis, CA 95616 (Peaston).

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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, Straw, Salmon, Atwater, Ciekot, LaRue, Withrow), School of Veterinary Medicine, Tufts University, 200 Westboro Rd, North Grafton, MA 01536 (Moore), the Animal Health Hospital, 2560 Harrison, Tuscon, AZ 85748 (Klein), and School of Veterinary Medicine, University of California, Davis, CA 95616 (Peaston).

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Summary:

Eighty-seven cats with histologically confirmed malignant tumors were used in a prospective study to determine the toxicity of mitoxantrone, a dihydroxyquinone derivative of anthracene, which was administered at 21-day intervals at dosages ranging from 2.5 to 6.5 mg/m2 of body surface, iv. Eleven of these cats were treated concurrently with radiation but were evaluated separately. Each cat was evaluated for signs of toxicosis for 3 weeks after each dose was administered or until the cat developed progressive disease, or until the cat's quality of life diminished to an unacceptable level as determined by the owner or attending veterinarian. Although the primary purpose of this study was to determine a clinically useful dosage and to characterize the toxicoses associated with mitoxantrone administration, each cat was monitored for response to treatment. Forty-nine cats had been refractory to 1 or more treatment modalities prior to inclusion in this study.

The most common signs of toxicosis after treatment with mitoxantrone were vomiting, anorexia, diarrhea, lethargy, sepsis secondary to myelosuppression, and seizures. Two cats died of complications that may have been attributed to mitoxantrone: 1 of cardiomyopathy and the other of pulmonary edema of an undetermined cause. Older cats were more likely to develop signs of toxicosis after the third or fourth mitoxantrone treatment than younger cats (P ≤ 0.05). Cats with signs of toxicosis during the 21-day interval after administration of the first dose of mitoxantrone were significantly (P ≤ 0.05) more likely to develop signs of toxicosis during the 21-day interval between the second and third doses of mitoxantrone. Similarly, cats that became toxic during the 21-day interval between the second and third doses were significantly (P ≤ 0.05) more likely to become toxic during the 21-day interval between the third and fourth doses. Controlling for age, breed, and dose of mitoxantrone, cats that became toxic after the first treatment were 2.4 times more likely to have poor performance status than the non toxic cats. Tumor-bearing cats had some degree of myelosuppression 7 days after they were given mitoxantrone at 6.5 mg/m2, iv (median neutrophil count, 2,440 cells/μl; range, 1,595 to 6,300 cells/μl).

Complete or partial remission (> 50% reduction volume reduction) was obtained in 18.4% (14/76) of cats given mitoxantrone alone. Remission was recorded in 17.6% (9/51) of cats with carcinoma, 11.8% (2/17) of the cats with lymphoma, and 37.5% (3/8) of the cats with sarcoma.

Because the cats with squamous cell carcinoma had a poor response to mitoxantrone, an additional 11 cats with squamous cell carcinoma were treated concurrently with radiation (44 to 65 Gy, 10 to 15 fractions) over a 3-week period beginning at the time the first dose of mitoxantrone (2.5 to 6 mg/m2) was given. None of these 11 cats had any signs of toxicosis attributable to mitoxantrone chemotherapy. Eight cats had a complete remission (median, 170 days; range, 28 to 485 days), and 1 had a partial remission that lasted 60 days.

Summary:

Eighty-seven cats with histologically confirmed malignant tumors were used in a prospective study to determine the toxicity of mitoxantrone, a dihydroxyquinone derivative of anthracene, which was administered at 21-day intervals at dosages ranging from 2.5 to 6.5 mg/m2 of body surface, iv. Eleven of these cats were treated concurrently with radiation but were evaluated separately. Each cat was evaluated for signs of toxicosis for 3 weeks after each dose was administered or until the cat developed progressive disease, or until the cat's quality of life diminished to an unacceptable level as determined by the owner or attending veterinarian. Although the primary purpose of this study was to determine a clinically useful dosage and to characterize the toxicoses associated with mitoxantrone administration, each cat was monitored for response to treatment. Forty-nine cats had been refractory to 1 or more treatment modalities prior to inclusion in this study.

The most common signs of toxicosis after treatment with mitoxantrone were vomiting, anorexia, diarrhea, lethargy, sepsis secondary to myelosuppression, and seizures. Two cats died of complications that may have been attributed to mitoxantrone: 1 of cardiomyopathy and the other of pulmonary edema of an undetermined cause. Older cats were more likely to develop signs of toxicosis after the third or fourth mitoxantrone treatment than younger cats (P ≤ 0.05). Cats with signs of toxicosis during the 21-day interval after administration of the first dose of mitoxantrone were significantly (P ≤ 0.05) more likely to develop signs of toxicosis during the 21-day interval between the second and third doses of mitoxantrone. Similarly, cats that became toxic during the 21-day interval between the second and third doses were significantly (P ≤ 0.05) more likely to become toxic during the 21-day interval between the third and fourth doses. Controlling for age, breed, and dose of mitoxantrone, cats that became toxic after the first treatment were 2.4 times more likely to have poor performance status than the non toxic cats. Tumor-bearing cats had some degree of myelosuppression 7 days after they were given mitoxantrone at 6.5 mg/m2, iv (median neutrophil count, 2,440 cells/μl; range, 1,595 to 6,300 cells/μl).

Complete or partial remission (> 50% reduction volume reduction) was obtained in 18.4% (14/76) of cats given mitoxantrone alone. Remission was recorded in 17.6% (9/51) of cats with carcinoma, 11.8% (2/17) of the cats with lymphoma, and 37.5% (3/8) of the cats with sarcoma.

Because the cats with squamous cell carcinoma had a poor response to mitoxantrone, an additional 11 cats with squamous cell carcinoma were treated concurrently with radiation (44 to 65 Gy, 10 to 15 fractions) over a 3-week period beginning at the time the first dose of mitoxantrone (2.5 to 6 mg/m2) was given. None of these 11 cats had any signs of toxicosis attributable to mitoxantrone chemotherapy. Eight cats had a complete remission (median, 170 days; range, 28 to 485 days), and 1 had a partial remission that lasted 60 days.

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