• 1

    Gobar GM, Kass PH. World Wide Web-based survey of vaccination practices, postvaccinal reactions, and vaccine site-associated sarcomas in cats. J Am Vet Med Assoc 2002;220:14771482.

    • Search Google Scholar
    • Export Citation
  • 2

    Coyne MJ, Postorino Reeves NC, Rosen DK. Estimated prevalence of injection-site sarcomas in cats during 1992. J Am Vet Med Assoc 1997;210:249251.

    • Search Google Scholar
    • Export Citation
  • 3

    Kass PH, Spangler WL, Hendrick MJ, et al.Multicenter case-control study of risk factors associated with development of vaccine-associated sarcomas in cats. J Am Vet Med Assoc 2003;223:12831292.

    • Search Google Scholar
    • Export Citation
  • 4

    Hendrick MJ, Shofer FS, Goldschmidt MH, et al.Comparison of fibrosarcomas that developed at vaccination sites and at nonvaccination sites in cats: 239 cases (1991–1992). J Am Vet Med Assoc 1994;205:14251429.

    • Search Google Scholar
    • Export Citation
  • 5

    Hendrick MJ, Goldschmidt MH, Shofer FS, et al.Postvaccinal sarcomas in the cat: epidemiology and electron probe microanalytical identification of aluminum. Cancer Res 1992;52:53915394.

    • Search Google Scholar
    • Export Citation
  • 6

    Doddy FD, Glickman LT, Glickman NW, et al.Feline fibrosarcomas at vaccination sites and non-vaccination sites. J Comp Pathol 1996;114:165174.

    • Search Google Scholar
    • Export Citation
  • 7

    Kass PH, Barnes WG Jr, Spangler WL, et al.Epidemiologic evidence for a causal relation between vaccination and fibrosarcoma tumorigenesis in cats. J Am Vet Med Assoc 1993;203:396405.

    • Search Google Scholar
    • Export Citation
  • 8

    Nieto A, Sanchez MA, Martinez E, et al.Immunohistochemical expression of p53, fibroblast growth factor-b, and transforming growth factor-α-in feline vaccine-associated sarcomas. Vet Pathol 2003;40:651658.

    • Search Google Scholar
    • Export Citation
  • 9

    Davidson EB, Gregory CR, Kass PH. Surgical excision of soft tissue fibrosarcomas in cats. Vet Surg 1997;26:265269.

  • 10

    Hershey AE, Sorenmo KU, Hendrick MJ, et al.Prognosis for presumed feline vaccine-associated sarcoma after excision: 61 cases (1986–1996). J Am Vet Med Assoc 2000;216:5861.

    • Search Google Scholar
    • Export Citation
  • 11

    Bregazzi VS, LaRue SM, McNiel E, et al.Treatment with a combination of doxorubicin, surgery, and radiation versus surgery and radiation alone for cats with vaccine-associated sarcomas: 25 cases (1995–2000). J Am Vet Med Assoc 2001;218:547550.

    • Search Google Scholar
    • Export Citation
  • 12

    Cohen M. Use of surgery and electron beam irradiation, with or without chemotherapy, for treatment of vaccine-associated sarcomas in cats: 78 cases (1996–2000). J Am Vet Med Assoc 2001;219:15821589.

    • Search Google Scholar
    • Export Citation
  • 13

    Kobayashi T, Hauck ML, Dodge R, et al.Preoperative radiotherapy for vaccine associated sarcoma in 92 cats. Vet Radiol Ultrasound 2002;43:473479.

    • Search Google Scholar
    • Export Citation
  • 14

    Barber LG, Sorenmo KU, Cronin KL, et al.Combined doxorubicin and cyclophosphamide chemotherapy for nonresectable feline fibrosarcoma. J Am Anim Hosp Assoc 2000;36:416421.

    • Search Google Scholar
    • Export Citation
  • 15

    Poirier VJ, Thamm DH, Kurzman ID, et al.Liposome-encap-sulated doxorubicin (Doxil) and doxorubicin in the treatment of vaccine-associated sarcoma in cats. J Vet Intern Med 2002;16:726731.

    • Search Google Scholar
    • Export Citation
  • 16

    Furlanut M, Franceschi L. Pharmacology of ifosfamide. Oncology 2003; 65(suppl 2): 26.

  • 17

    Carli M, Passone E, Perilongo G, et al.Ifosfamide in pediatric solid tumors. Oncology 2003; 65(suppl 2): 99104.

  • 18

    Cartei G. ed.Ifosfamide: a milestone drug. International Meeting, Padua, February 17–18, 2003. Oncology 2003;65(suppl 2):1105.

  • 19

    Rassnick KM, Moore AS, Northrup NC, et al.Phase I trial and pharmacokinetic analysis of ifosfamide in cats with sarcomas. Am J Vet Res 2006;67:510516.

    • Search Google Scholar
    • Export Citation
  • 20

    Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials 1989;10:110.

  • 21

    Newcombe RG. Two-sided confidence intervals for the single proportion: comparison of seven methods. Stat Med 1998;17:857872.

  • 22

    Simon R, Lee YJ. Nonparametric confidence limits for survival probabilities and median survival time. Cancer Treat Rep 1982;66:3742.

  • 23

    Dawson B, Trapp RG. Research questions about one group. In: Basic and clinical biostatistics. 3rd ed. New York: Lange Medical Books/McGraw-Hill Book Co, 2001;92131.

    • Search Google Scholar
    • Export Citation
  • 24

    Williams LE, Banerji N, Klausner JS, et al.Establishment of two vaccine-associated feline sarcoma cell lines and determination of in vitro chemosensitivity to doxorubicin and mitoxantrone. Am J Vet Res 2001;62:13541357.

    • Search Google Scholar
    • Export Citation
  • 25

    Bailey DB, Rassnick KM, Erb HN, et al.Effect of glomerular filtration rate on clearance and myelotoxicity of carboplatin in cats with tumors. Am J Vet Res 2004;65:15021507.

    • Search Google Scholar
    • Export Citation
  • 26

    Martano M, Morello E, Ughetto M, et al.Surgery alone versus surgery and doxorubicin for the treatment of feline injection-site sarcomas: a report on 69 cases. Vet J 2005;170:8490.

    • Search Google Scholar
    • Export Citation
  • 27

    Klastersky J. Side effects of ifosfamide. Oncology 2003;65(suppl 2):710.

  • 28

    Rassnick KM, Frimberger AE, Wood CA, et al.Evaluation of ifosfamide for treatment of various canine neoplasms. J Vet Intern Med 2000;14:271276.

    • Search Google Scholar
    • Export Citation
  • 29

    Payne SE, Rassnick KM, Northrup NC, et al.Treatment of vascular and soft-tissue sarcomas in dogs using an alternating protocol of ifosfamide and doxorubicin. Vet Comp Oncol 2003;1:171179.

    • Search Google Scholar
    • Export Citation
  • 30

    Loebstein R, Atanackovic G, Bishai R, et al.Risk factors for long-term outcome of ifosfamide-induced nephrotoxicity in children. J Clin Pharmacol 1999;39:454461.

    • Search Google Scholar
    • Export Citation
  • 31

    Zielinska E, Zubowska M, Bodalski J. Polymorphism at the glutathione S-transferase pi locus as a risk factor for ifosfamide nephrotoxicity in children. Pol Merkuriusz Lek 2003;14:295298.

    • Search Google Scholar
    • Export Citation
  • 32

    McCune JS, Friedman DL, Schuetze S, et al.Influence of age upon ifosfamide-induced nephrotoxicity. Pediatr Blood Cancer 2004;42:427432.

  • 33

    Loehrer PJ Sr. The history of ifosfamide. Semin Oncol 1992;19:26.

  • 34

    Aleksa K, Ito S, Koren G. Renal-tubule metabolism of ifosfamide to the nephrotoxic chloroacetaldehyde: pharmacokinetic modeling for estimation of intracellular levels. J Lab Clin Med 2004;143:159162.

    • Search Google Scholar
    • Export Citation
  • 35

    Marthaler NP, Visarius T, Kupfer A, et al.Increased urinary losses of carnitine during ifosfamide chemotherapy. Cancer Chemother Pharmacol 1999;44:170172.

    • Search Google Scholar
    • Export Citation
  • 36

    Karle P, Renner M, Salmons B, et al.Necrotic, rather than apoptotic, cell death caused by cytochrome P450-activated ifosfamide. Cancer Gene Ther 2001;8:220230.

    • Search Google Scholar
    • Export Citation
  • 37

    Kaijser GP, Beijnen JH, Bult A, et al.Ifosfamide metabolism and pharmacokinetics (review). Anticancer Res 1994;14:517531.

Advertisement

Results of a phase II clinical trial on the use of ifosfamide for treatment of cats with vaccine-associated sarcomas

View More View Less
  • 1 Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853.
  • | 2 San Francisco Veterinary Specialists, 600 Alabama St, San Francisco, CA 94110.
  • | 3 Animal Cancer Institute at Friendship Hospital for Animals, 4105 Brandywine St, Washington, DC 20016.
  • | 4 Veterinary Cancer Referral Group, 2965 Edinger Ave, Tustin, CA 92780.
  • | 5 Animal Cancer Specialists, 11536 Lake City Way NE, Seattle, WA 98125.
  • | 6 Animal Diagnostic Clinic, 4444 Trinity Mills Rd, Dallas, TX 75287.
  • | 7 Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853.

Abstract

Objective—To determine clinical activity and toxic effects of ifosfamide when used to treat cats with vaccine-associated sarcoma (VAS).

Animals—27 cats with a nonresectable, recurrent, or metastatic VAS.

Procedure—Each cat received ifosfamide (900 mg/m2 of body surface area) as an IV infusion during a 30-minute period. Diuresis by infusion of saline (0.9% NaCl) solution and administration of mesna were used to prevent urothelial toxicosis. Treatments were administered every 3 weeks, and tumor response was assessed after the second treatment. All ifos-famide-associated toxic effects were graded in accordance with predetermined criteria.

Results—61 treatments were administered to 27 cats (median, 2 treatments/cat; range, 1 to 4 treat-ments/cat). After ifosfamide treatment, 1 cat had a complete response and 10 had partial responses for an overall response rate of 11 of 27 (41%; 95% confidence interval [CI], 25% to 59%). Responses lasted from 21 to 133 days (median, 70 days; 95% CI, 60 to 113 days). The acute dose-limiting toxicosis was neutropenia, which was detected 5 to 28 days (median, 7 days) after treatment. Median nadir neutrophil count was 1,600 cells/μL (range, 200 to 5,382 cells/μL). Nine (33%) cats had adverse gastrointestinal effects (primarily salivation during the ifosfamide infusion and inappetence after treatment). Two cats were euthanatized because of severe nephrotoxicosis, and 1 cat developed pulmonary edema during diuresis.

Conclusions and Clinical Relevance—Ifosfamide has antitumor activity against VAS in cats and is tolerated well by most cats. Ifosfamide should be evaluated as an adjuvant treatment for cats with VAS.

Contributor Notes

Supported by the Vaccine-Associated Feline Sarcoma Task Force.

Presented in part at the 21st Annual American College of Veterinary Internal Medicine Forum, Charlotte, NC, June 2003.

The authors thank Drs. Dennis Bailey, Cheryl Balkman, Sue Downing, Karri Meleo, Tony Rusk, and Courtney Zwahlen for assistance with management of patients during the study.

Dr. Rassnick.