Toceranib Use in Dogs and Cats - Vet Education

What is Toceranib?

Toceranib is an anti-cancer drug, developed and registered for use in dogs initially for the treatment of mast cell neoplasia. It is an anti-angiogenic agent (inhibits blood vessel formation) and an anti-proliferative agent (inhibits cell growth and division).[1] It belongs to a class of anti-neoplastic drugs that inhibits the receptor sites of the enzyme tyrosine kinase. There are more than 58 different tyrosine kinase receptors known at present – and when bound, tyrosine kinase enhances such activities as cell growth, metabolism, and adhesion, among other processes. Mutated tyrosine kinases are implicated in unrelated cell growth of tumour cells. The blocking of tyrosine kinase enzyme binding sites with agents such as Toceranib are therefore utilized as effective cancer treatments.

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Mast Cell Neoplasia

Mast cell neoplasia is a cancer of a type of blood cell normally involved in the body’s response to allergens and inflammation. It is a common skin tumour in dogs, but can also affect other areas of the body, including the spleen, liver, gastrointestinal tract and bone marrow.

Most mast cell tumours in dogs (and some in cats) produce/express a tyrosine kinase growth factor receptor called KTS, and a significant number (up to 50%) have a mutation in the c-kit gene coding for the KIT protein, which results in cells in these mast cell tumours receiving signal to grow, when they normally would not, resulting in uncontrolled tumour growth

Toceranib has demonstrated good efficacy – both as a sole agent, and as part of combination chemotherapy in the treatment of mast cell tumours in dogs in several clinical studies:

  1. In a randomized clinical trial of 145 dogs with recurrent mast cell disease following surgical excision, the overall response rate was 42.8%, with complete remission observed in 14.5% of patients.[2]
  2. In another trial of 41 dogs with non-resectable mast cell tumours, treated with lomustine and toceranib, an overall response rate of 46% was achieved.[3]
  3. In a retrospective study of 50 cats with mast cell disease, clinical benefit was seen in 80% of cases, including 86% (19/22) with cutaneous, 80% (8/10) with visceral and 76% (13/17) with gastrointestinal involvement.[4]

It should be noted that response rates to traditional chemotherapy with lomustine (CCNU) are documented at 42% in dogs and 50% in cats.[5],[6]

Can Toceranib Be Used for Other Types of Cancer?

Since toceranib was released, several researchers have investigated the potential use of the drug either alone, or in combination with other treatment modalities – including chemotherapy, radiation therapy, and surgery – in a wide range of cancer types. A summary of some of these studies is included below:

Canine Tumours

Canine Osteosarcoma:

In a randomized study of 126 dogs with osteosarcoma, managed with limb amputation and a 4-dose schedule of carboplatin, dogs were compared in a trial of post-carboplatin cyclophosphamide and piroxicam, or carboplatin/piroxicam with addition of toceranib. Median survival time was not significantly different between the 2 groups. The results of this study showed that addition of toceranib did not improve survival in dogs with osteosarcoma.[7]

In another study of 22 dogs with pulmonary metastasis secondary to osteosarcoma, Toceranib was administered as an adjunct to limb amputation for control of primary disease. No difference in disease-free interval or survival time were noted over untreated historical controls. Overall, the results of this clinical trial do not support the use of Toceranib as single agent therapy for canine metastatic osteosarcoma.[8]

Canine Haemangiosarcoma:

In a prospective study of 43 dogs with haemangiosarcoma, dogs were initially administered doxorubicin for 10 weeks after surgery. Those without evidence of metastasis at that time received toceranib and monitored alongside dogs who had metastatic disease until time of death. Toceranib-treated dogs showed no improvement in median survival time, or disease-free interval over un-treated dogs.[9]

Canine Frontal Sinus Squamous Cell Carcinoma:

A case series of 3 dogs evaluated the use of toceranib in combination with piroxicam, versus piroxicam combined with carboplatin. All 3 dogs were treated with carboplatin and piroxicam. Dogs 1 and 2 achieved tumour remission. The third dog had a protocol changed from carboplatin/piroxicam to toceranib/piroxicam. Significant tumour reduction occurred in the latter dog, but relapse resulted in patient euthanasia after 195 days. This report suggests Toceranib may be an effective alternative to carboplatin in this tumour type.[10]

Insulinoma:

A case report of a dog with advanced (stage III) pancreatic insulinoma treated with toceranib and prednisolone was presented, with the patient having stable glycaemic control and survival for over 24 months. Historically, these tumours are associated with a median survival time of 6 months. There may be potential for the use of toceranib in the management of these tumours, based on future studies with larger case numbers.[11]

Transitional Cell Carcinoma:

A prospective study aimed to determine whether addition of toceranib to vinblastine treatment for transitional cell carcinoma was of benefit. Whilst tumour size did reduce over the course of treatment, overall survival time and clinical course was not altered over that of historical controls.[12]

Pheochromocytoma:

In a study of 5 dogs with the adrenal tumour pheochromocytoma, all 5 dogs in the study that received toceranib as therapy, experienced clinical improvement or stable disease, suggesting toceranib may be of benefit in the management of this tumour.[13]

Gastrointestinal stromal tumour:

A ten‐year‐old, female‐entire English springer spaniel with a stromal tumour of the caecum with widespread abdominal metastasis was treated with toceranib phosphate, and had complete response, despite the absence of exon‐8 or exon‐11 c‐kit mutation. There was no clinical evidence of tumour recurrence nine months after diagnosis.[14]

Feline Tumours

Feline Oral Squamous Cell Carcinoma:

A retrospective study of 46 cats with oral squamous cell carcinoma compared the use of toceranib to those cats who received no treatment following diagnosis (no radiation or other chemotherapy). Cats receiving toceranib had longer survival times (123 days vs. 45 days). Additionally, the concurrent use of NSAID medications also improved survival times in this study, over non-medicated controls.[15]

Feline Injection-Site Sarcomas:

In a prospective study of 18 cats with unresectable injection site sarcomas, toceranib resulted in no measurable positive effect on tumour size or patient disease.[16]

Other tumours

In a study of 85 dogs [17] with various tumours, toceranib was shown to produce either complete, or partial response to the following tumour types:

  1. Apocrine gland anal sac adenocarcinoma
  2. Metastatic osteosarcoma
  3. Thyroid carcinoma
  4. Head and neck carcinoma
  5. Nasal carcinoma

However, larger trials are considered necessary to elucidate the true nature of the effect of toceranib and any superiority over current treatment protocols, before firm recommendations can be made.

Conclusion

 To date, mast cell neoplasia – particularly those with KIT gene mutations – appear to be the most sensitive tumours to toceranib administration. There remains, however, a large body of work to be carried out to definitively determine if toceranib may be of significant use in the management of other tumour types, as much of the work in other tumour types has been carried out with small numbers of patients, which invariably result in data associated with less certainty.

References:

  • https://www.zoetisus.com/products/dogs/palladia/index.aspx DOA: 09/05/2019
  • London CA, Malpas PB, Wood-Follis SL, Boucher JF, Rusk AW, Rosenberg MP, Henry CJ, Mitchener KL, Klein MK, Hintermeister JG, Bergman PJ. 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. Clinical Cancer Research. 2009 Jun 1;15(11):3856-65.
  • Burton JH, Venable RO, Vail DM, Williams LE, Clifford CA, Axiak‐Bechtel SM, Avery AC, Thamm DH. Pulse‐administered toceranib phosphate plus lomustine for treatment of unresectable mast cell tumors in dogs. Journal of veterinary internal medicine. 2015 Jul;29(4):1098-104.
  • Berger EP, Johannes CM, Post GS, Rothchild G, Shiu KB, Wetzel S, Fox LE. Retrospective evaluation of toceranib phosphate (Palladia) use in cats with mast cell neoplasia. Journal of feline medicine and surgery. 2018 Feb;20(2):95-102.
  • Rassnick KM, Moore AS, Williams LE, London CA, Kintzer PP, Engler SJ, Cotter SM. Treatment of canine mast cell tumors with CCNU (lomustine). Journal of Veterinary Internal Medicine. 1999 Nov;13(6):601-5.
  • Rassnick KM, Williams LE, Kristal O, Al-Sarraf R, Baez JL, Zwahlen CH, Dank G. Lomustine for treatment of mast cell tumors in cats: 38 cases (1999–2005). Journal of the American Veterinary Medical Association. 2008 Apr 15;232(8):1200-5.
  • London CA, Gardner HL, Mathie T, Stingle N, Portela R, Pennell ML, Clifford CA, Rosenberg MP, Vail DM, Williams LE, Cronin KL. Impact of toceranib/piroxicam/cyclophosphamide maintenance therapy on outcome of dogs with appendicular osteosarcoma following amputation and carboplatin chemotherapy: a multi-institutional study. PLoS One. 2015 Apr 29;10(4)
  • Laver T, London CA, Vail DM, Biller BJ, Coy J, Thamm DH. Prospective evaluation of toceranib phosphate in metastatic canine osteosarcoma. Veterinary and comparative oncology. 2018 Mar;16(1)
  • Gardner HL, London CA, Portela RA, Nguyen S, Rosenberg MP, Klein MK, Clifford C, Thamm DH, Vail DM, Bergman P, Crawford-Jakubiak M. Maintenance therapy with toceranib following doxorubicin-based chemotherapy for canine splenic hemangiosarcoma. BMC veterinary research. 2015 Dec;11(1):131.
  • De Vos J, Ramos Vega S, Noorman E, De Vos P. Primary frontal sinus squamous cell carcinoma in three dogs treated with piroxicam combined with carboplatin or toceranib. Veterinary and comparative oncology. 2012 Sep;10(3):206-13.
  • Flesner BK, Fletcher JM, Smithee T, Boudreaux B. Long-Term Survival and Glycemic Control with Toceranib Phosphate and Prednisone for a Metastatic Canine Insulinoma. Journal of the American Animal Hospital Association. 2019 Jan;55(1): 551-05.
  • Rippy SB, Gardner HL, Nguyen SM, Warry EE, Portela RF, Drost WT, Hostnik ET, Green EM, Chew DJ, Peng J, London CA. A pilot study of toceranib/vinblastine therapy for canine transitional cell carcinoma. BMC veterinary research. 2016 Dec;12(1):257.
  • Musser ML, Taikowski KL, Johannes CM, Bergman PJ. Retrospective evaluation of toceranib phosphate (Palladia®) use in the treatment of inoperable, metastatic, or recurrent canine pheochromocytomas: 5 dogs (2014–2017). BMC veterinary research. 2018 Dec;14(1):272.
  • Elliott JW, Swinbourne F, Parry A, Baines L. Successful treatment of a metastatic, gastrointestinal stromal tumour in a dog with toceranib phosphate (Palladia). Journal of Small Animal Practice. 2017 Jul;58(7):416-8.
  • Wiles V, Hohenhaus A, Lamb K, Zaidi B, Camps-Palau M, Leibman N. Retrospective evaluation of toceranib phosphate (Palladia) in cats with oral squamous cell carcinoma. Journal of feline medicine and surgery. 2017 Feb;19(2):185-93.
  • Holtermann N, Kiupel M, Hirschberger J. The tyrosine kinase inhibitor toceranib in feline injection site sarcoma: efficacy and side effects. Veterinary and comparative oncology. 2017 Jun;15(2):632-40.
  • London C, Mathie T, Stingle N, Clifford C, Haney S, Klein MK, Beaver L, Vickery K, Vail DM, Hershey B, Ettinger S. Preliminary evidence for biologic activity of toceranib phosphate (Palladia®) in solid tumours. Veterinary and comparative oncology. 2012 Sep;10(3):194-205.

About the author

Dr. Philip Judge

BVSc MVS PG Cert Vet Stud MACVSc (VECC; Medicine of Dogs)

Director: Vet Education Pty Ltd

Consultant in Veterinary Emergency and Critical Care

Internationally renowned lecturer and published author

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Disclaimer: Every effort has been made to ensure that the information contained in this article is current and correct. No responsibility is assumed by the publisher for loss or injury resulting from any use or operation of methods described herein. Because of rapid advances in medical sciences, independent verification of drug doses and recommendations should be made.

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