Maintenance therapy with toceranib following doxorubicin-based chemotherapy for canine splenic hemangiosarcoma

BMC Veterinary Research

Laura D. Garrett⁷  Jennifer Locke^1,11  Carolyn Henry⁸  Martin Crawford-Jakubiak^1,12  Phil Bergman⁵  David M. Vail^1,10  Douglas H. Thamm²  Craig Clifford⁶  Mary K. Klein³  Mona P. Rosenberg⁹  Sandra Nguyen⁴  Roberta A. Portela⁷  Cheryl A. London¹  Heather L. Gardner¹ 

[1]Departments of Veterinary Biosciences and Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, 1925 Coffey Rd, Columbus, 43210, OH, USA

[2]Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, USA

[3]Southwest Veterinary Oncology, Tucson, AZ, USA

[4]Animal Referral Hospital, Sydney, Australia

[5]VCA Katonah Bedford Veterinary Center, Bedford Hill, NY, USA

[6]Hope Veterinary Specialists, Malvern, PA, USA

[7]Department of Veterinary Clinical Medicine, University of Illinois at Urbana-Champaign, College of Veterinary Medicine, Champaign, IL, USA

[8]Department of Veterinary Medicine and Surgery, College of Veterinary Medicine, University of Missouri, Columbia, MO, USA

[9]Veterinary Cancer Group, Tustin, CA, USA

[10]Department of Medical Sciences, School of Veterinary Medicine, University of Wisconsin, Madison, WI, USA

[11]Southeast Veterinary Oncology and Medicine, Orange Park, FL, USA

[12]Sage Centers for Veterinary Specialty and Emergency Care, Concord, CA, USA

关键词: Chemotherapy;    Dog;    Toceranib;    Hemangiosarcoma;   

Others  :  1213745
DOI  :  10.1186/s12917-015-0446-1

 received in 2014-10-23, accepted in 2015-05-28,  发布年份 2015

【 摘 要 】

Background

Spenic hemangiosarcoma (HSA) in dogs treated with surgery alone is associated with short survival times, and the addition of doxorubicin (DOX) chemotherapy only modestly improves outcome. The purpose of this study was to evaluate the impact of toceranib administration on progression free survival in dogs with stage I or II HSA following splenectomy and single agent DOX chemotherapy. We hypothesized that dogs with splenic HSA treated with adjuvant DOX followed by toceranib would have prolonged disease-free interval (DFI) and overall survival time (OS) when compared to historical dogs treated with DOX-based chemotherapy alone.

Results

Dogs with stage I or II splenic HSA were administered 5 cycles of single-agent DOX every 2 weeks beginning within 14 days of splenectomy. Dogs were restaged 2 weeks after completing DOX, and those without evidence of metastatic disease began toceranib therapy at 3.25 mg/kg every other day. Forty-three dogs were enrolled in this clinical trial. Seven dogs had evidence of metastatic disease either before or at re-staging, and an additional 3 dogs were found to have metastatic disease within 1 week of toceranib administration. Therefore 31 dogs went on to receive toceranib following completion of doxorubicin treatment. Twenty-five dogs that received toceranib developed metastatic disease. The median disease free interval for all dogs enrolled in this study (n = 43) was 138 days, and the median disease free interval for those dogs that went on to receive toceranib (n = 31) was 161 days. The median survival time for all dogs enrolled in this study was 169 days, and the median survival time for those dogs that went on to receive toceranib was 172 days.

Conclusions

The use of toceranib following DOX chemotherapy does not improve either disease free interval or overall survival in dogs with stage I or II HSA.

【 授权许可】

   
2015 Gardner et al.

【 图 表 】

Fig. 1.

Fig. 2.

【 参考文献 】

• [1]Dorn CR, Taylor DO, Schneider R, Hibbard HH, Klauber MR. Survey of animal neoplasms in Alameda and Contra Costa Counties, California. II. Cancer morbidity in dogs and cats from Alameda County. J Natl Cancer Inst. 1968; 40:307-18.
• [2]Thamm DH, Miscellaneous T. Withrow and MacEwen's Small Animal Clinical Oncology. 4th ed. Withrow SJ, Vail DM, editors. W B Saunders Co, St. Louis; 2007: p.785-795. [Hemangiosarcoma]
• [3]Brown NO, Patnaik AK, MacEwen EG. Canine hemangiosarcoma: retrospective analysis of 104 cases. J Am Vet Med Assoc. 1985; 186:56-8.
• [4]Spangler WL, Spangler WL, Kass PH, Kass PH. Pathologic factors affecting postsplenectomy survival in dogs. J Vet Intern Med. 1997; 11:166-71.
• [5]Wood CA, Moore AS, Gliatto JM, Ablin LA, Berg RJ, Rand WM. Prognosis for dogs with stage I or II splenic hemangiosarcoma treated by splenectomy alone: 32 cases (1991–1993). J Am Anim Hosp Assoc. 1998; 34:417-21.
• [6]Hammer AS, Couto CG, Filppi J, Getzy D, Shank K. Efficacy and toxicity of VAC chemotherapy (vincristine, doxorubicin, and cyclophosphamide) in dogs with hemangiosarcoma. J Vet Intern Med. 1991; 5:160-6.
• [7]Kahn SA, Mullin CM, de Lorimier L-P, Burgess KE, Risbon RE, Fred RM et al.. Doxorubicin and deracoxib adjuvant therapy for canine splenic hemangiosarcoma: a pilot study. Canadian Veterinary J. 2013; 54:237-42.
• [8]Ogilvie GK, Powers BE, Mallinckrodt CH, Withrow SJ. Surgery and doxorubicin in dogs with hemangiosarcoma. J Vet Intern Med. 1996; 10:379-84.
• [9]Sorenmo K, Duda L, Barber L, Cronin K, Sammarco C, Usborne A et al.. Canine hemangiosarcoma treated with standard chemotherapy and minocycline. J Vet Intern Med. 2000; 14:395-8.
• [10]Sorenmo KU, Baez JL, Clifford CA, Mauldin E, Overley B, Skorupski K et al.. Efficacy and toxicity of a dose-intensified doxorubicin protocol in canine hemangiosarcoma. J Vet Intern Med. 2004; 18:209-13.
• [11]Sorenmo KU, Jeglum KA, Helfand SC. Chemotherapy of canine hemangiosarcoma with doxorubicin and cyclophosphamide. J Vet Intern Med. 1993; 7:370-6.
• [12]Vail DM, MacEwen EG, Kurzman ID, Dubielzig RR, Helfand SC, Kisseberth WC et al.. Liposome-encapsulated muramyl tripeptide phosphatidylethanolamine adjuvant immunotherapy for splenic hemangiosarcoma in the dog: a randomized multi-institutional clinical trial. Clin Cancer Res. 1995; 1:1165-70.
• [13]U’Ren LW, Biller BJ, Elmslie RE, Thamm DH, Dow SW. Evaluation of a novel tumor vaccine in dogs with hemangiosarcoma. J Vet Intern Med. 2007; 21:113-20.
• [14]Lana S, U’ren L, Plaza S, Elmslie R, Gustafson D, Morley P et al.. Continuous low-dose oral chemotherapy for adjuvant therapy of splenic hemangiosarcoma in dogs. J Vet Intern Med. 2007; 21:764-9.
• [15]Sorenmo K, Samluk M, Clifford C, Baez J, Barrett JS, Poppenga R et al.. Clinical and pharmacokinetic characteristics of intracavitary administration of pegylated liposomal encapsulated doxorubicin in dogs with splenic hemangiosarcoma. J Vet Intern Med. 2007; 21:1347-54.
• [16]Dickerson EB, Marley K, Edris W, Tyner JW, Schalk V, Macdonald V et al.. Imatinib and Dasatinib Inhibit Hemangiosarcoma and Implicate PDGFR-β and Src in Tumor Growth. Transl Oncol. 2013; 6:158-68.
• [17]Fosmire SP, Dickerson EB, Scott AM, Bianco SR, Pettengill MJ, Meylemans H et al.. Canine malignant hemangiosarcoma as a model of primitive angiogenic endothelium. Lab Invest. 2004; 84:562-72.
• [18]Kodama A, Sakai H, Matsuura S, Murakami M, Murai A, Mori T et al.. Establishment of canine hemangiosarcoma xenograft models expressing endothelial growth factors, their receptors, and angiogenesis-associated homeobox genes. BMC Cancer. 2009; 9:363. BioMed Central Full Text
• [19]Lyles SE, Milner RJ, Kow K, Salute ME. In vitro effects of the tyrosine kinase inhibitor, masitinib mesylate, on canine hemangiosarcoma cell lines. Vet Comp Oncol. 2012; 10:223-35.
• [20]Tamburini BA, Phang TL, Fosmire SP, Scott MC, Trapp SC, Duckett MM et al.. Gene expression profiling identifies inflammation and angiogenesis as distinguishing features of canine hemangiosarcoma. BMC Cancer. 2010; 10:619. BioMed Central Full Text
• [21]Tamburini BA, Trapp S, Phang TL, Schappa JT, Hunter LE, Modiano JF. Gene expression profiles of sporadic canine hemangiosarcoma are uniquely associated with breed. PLoS One. 2009; 4:e5549.
• [22]Thamm DH, Dickerson EB, Akhtar N, Lewis R, Auerbach R, Helfand SC et al.. Biological and molecular characterization of a canine hemangiosarcoma-derived cell line. Res Vet Sci. 2006; 81:76-86.
• [23]Yonemaru K, Sakai H, Murakami M, Yanai T, Masegi T. Expression of vascular endothelial growth factor, basic fibroblast growth factor, and their receptors (flt-1, flk-1, and flg-1) in canine vascular tumors. Vet Pathol. 2006; 43:971-80.
• [24]Andersen NJ, Nickoloff BJ, Dykema KJ, Boguslawski EA, Krivochenitser RI, Froman RE et al.. Pharmacologic inhibition of MEK signaling prevents growth of canine hemangiosarcoma. Mol Cancer Ther. 2013; 12:1701-14.
• [25]Marley K, Maier CS, Helfand SC. Phosphotyrosine enrichment identifies focal adhesion kinase and other tyrosine kinases for targeting in canine hemangiosarcoma. Vet Comp Oncol. 2012; 10:214-22.
• [26]Murai A, Asa SA, Kodama A, Hirata A, Yanai T, Sakai H. Constitutive phosphorylation of the mTORC2/Akt/4E-BP1 pathway in newly derived canine hemangiosarcoma cell lines. BMC Vet Res. 2012; 8:128. BioMed Central Full Text
• [27]Hahn KA, Oglivie G, Rusk T, Devauchelle P, Leblanc A, Legendre A et al.. Masitinib is Safe and Effective for the Treatment of Canine Mast Cell Tumors. J Vet Intern Med. 2008; 22:1301-9.
• [28]London CA, Hannah AL, Zadovoskaya R, Chien MB, Kollias-Baker C, Rosenberg M et al.. Phase I dose-escalating study of SU11654, a small molecule receptor tyrosine kinase inhibitor, in dogs with spontaneous malignancies. Clin Cancer Res. 2003; 9:2755-68.
• [29]London C, Mathie T, Stingle N, Clifford C, Haney S, Klein MK et al.. Preliminary evidence for biologic activity of toceranib phosphate (Palladia(®)) in solid tumours. Vet Comp Oncol. 2012; 10:194-205.
• [30]London CA, Malpas PB, Wood-Follis SL, Boucher JF, Rusk AW, Rosenberg MP et al.. Multi-center, placebo-controlled, double-blind, randomized study of oral toceranib phosphate (SU11654), a receptor tyrosine kinase inhibitor, for the treatment of dogs with recurrent (either local or distant) mast cell tumor following surgical excision. Clin Cancer Res. 2009; 15:3856-65.
• [31]Veterinary Co-operative Oncology Group - Common Terminology Criteria for Adverse Events (VCOG-CTCAE) following chemotherapy or biological antineoplastic therapy in dogs and cats v1.0. Vet Comp Oncol. 2004; 2:195-213.
• [32]Göritz M, Müller K, Krastel D, Staudacher G, Schmidt P, Kühn M et al.. Canine splenic haemangiosarcoma: influence of metastases, chemotherapy and growth pattern on post-splenectomy survival and expression of angiogenic factors. J Comp Pathol. 2013; 149:30-9.
• [33]Abou Asa S, Mori T, Maruo K, Khater A, sawak El A, Abd el Aziz E, Yanai T, Sakai H: Analysis of genomic mutation and immunohistochemistry of platelet‐derived growth factor receptors in canine vascular tumours. Veterinary and Comparative Oncology 2013. doi:10.1111/vco.12035.
• [34]Pàez-Ribes M, Allen E, Hudock J, Takeda T, Okuyama H, Viñals F et al.. Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell. 2009; 15:220-31.
• [35]Ebos JML, Lee CR, Cruz-Munoz W, Bjarnason GA, Christensen JG, Kerbel RS. Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis. Cancer Cell. 2009; 15:232-9.
• [36]Singh M, Couto SS, Forrest WF, Lima A, Cheng JH, Molina R et al.. Anti-VEGF antibody therapy does not promote metastasis in genetically engineered mouse tumour models. J Pathol. 2012; 227:417-30.
• [37]Blagoev KB, Wilkerson J, Stein WD, Motzer RJ, Bates SE, Fojo AT. Sunitinib does not accelerate tumor growth in patients with metastatic renal cell carcinoma. Cell Rep. 2013; 3:277-81.
• [38]Kadenhe-Chiweshe A, Papa J, McCrudden KW, Frischer J, Bae J-O, Huang J et al.. Sustained VEGF blockade results in microenvironmental sequestration of VEGF by tumors and persistent VEGF receptor-2 activation. Mol Cancer Res. 2008; 6:1-9.
• [39]Inai T, Mancuso M, Hashizume H, Baffert F, Haskell A, Baluk P et al.. Inhibition of vascular endothelial growth factor (VEGF) signaling in cancer causes loss of endothelial fenestrations, regression of tumor vessels, and appearance of basement membrane ghosts. Am J Pathol. 2004; 165:35-52.
• [40]Mancuso MR, Davis R, Norberg SM, O’Brien S, Sennino B, Nakahara T et al.. Rapid vascular regrowth in tumors after reversal of VEGF inhibition. J Clin Invest. 2006; 116:2610-21.
• [41]Chung AS, Wu X, Zhuang G, Ngu H, Kasman I, Zhang J et al.. An interleukin-17-mediated paracrine network promotes tumor resistance to anti-angiogenic therapy. Nat Med. 2013; 19:1114-23.
• [42]Seghezzi G, Patel S, Ren CJ, Gualandris A, Pintucci G, Robbins ES et al.. Fibroblast growth factor-2 (FGF-2) induces vascular endothelial growth factor (VEGF) expression in the endothelial cells of forming capillaries: an autocrine mechanism contributing to angiogenesis. J Cell Biol. 1998; 141:1659-73.
• [43]Bernabe LF, Portela R, Nguyen S, Kisseberth WC, Pennell M, Yancey MF et al.. Evaluation of the adverse event profile and pharmacodynamics of toceranib phosphate administered to dogs with solid tumors at doses below the maximum tolerated dose. BMC Vet Res. 2013; 9:190. BioMed Central Full Text
• [44]Lee K, Qian DZ, Rey S, Wei H, Liu JO, Semenza GL. Anthracycline chemotherapy inhibits HIF-1 transcriptional activity and tumor-induced mobilization of circulating angiogenic cells. Proc Natl Acad Sci U S A. 2009; 106:2353-8.
• [45]Pan X, Tsimbas K, Kurzman ID, Vail DM: Safety evaluation of combination CCNU and continuous toceranib phosphate (Palladia(®)) in tumour-bearing dogs: a phase I dose-finding study. Veterinary and Comparative Oncology 2014. doi:10.1111/vco.12091.
• [46]Robat C, London C, Bunting L, McCartan L, Stingle N, Selting K et al.. Safety evaluation of combination vinblastine and toceranib phosphate (Palladia®) in dogs: a phase I dose-finding study. Vet Comp Oncol. 2012; 10:174-83.