Toceranib: a weapon against apocrine gland anal sac tumors in dogs?

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Apocrine gland anal sac adenocarcinomas (AGASACAs) are locally invasive and, in 50% to 90% of canine cases, have metastasized by the time of diagnosis.^1-3 With single or multimodal therapies, including surgery, chemotherapy and radiation, the median survival time is one to two years.^4-6

Toceranib phosphate, which is FDA-approved for the treatment of high-grade cutaneous mast cell tumors in dogs,⁷ is a receptor tyrosine kinase inhibitor that kills tumor cells and decreases blood supply to tumors.⁸ Toceranib’s anti-angiogenic and antitumor effects confer potential therapeutic activity against a wide range of tumor types, as both primary and adjuvant therapy.^9,10

What they did

In a retrospective study recently published in the Journal of Veterinary Internal Medicine,¹¹ investigators at the University of Wisconsin School of Veterinary Medicine reviewed their hospital medical records (2009-2019) for dogs receiving toceranib as either sole or adjuvant treatment (with surgery or non-concurring chemotherapy) for cytologically or histologically diagnosed AGASACA.

The study subjects consisted of 36 dogs: 25 males and 11 females of 19 different breeds. A total of 29 dogs had macroscopic (gross) disease; seven had microscopic disease. Median age at diagnosis was 10 years, and median primary tumor size was 3 cm.

Most dogs (63.9%) underwent surgical excision of the primary tumor before treatment with toceranib. Incomplete surgical margins and/or regional lymph node metastasis was noted in over half of these. Of the 36 dogs in the study, chemotherapy (including carboplatin, doxorubicin, melphalan, mitoxantrone, metronomic cyclophosphamide, lomustine and GS074) was used in 10 dogs prior to toceranib treatment, in three dogs after treatment with toceranib, and in eight dogs both before and after toceranib.

Metastatic disease, mainly to regional lymph nodes, was present at start of toceranib treatment in 86.1% of dogs, and hypercalcemia was detected in 38.9% of cases.

Toceranib dosages ranged from 2.1 to 3.8 mg/kg every 48 hours; five dogs were placed on a Monday-Wednesday-Friday schedule. The median dose was 2.7 mg/kg, and the median toceranib treatment duration was 190 days. Altered dosing was employed at the clinician’s discretion in the case of adverse events, which occurred in 52.7% of cases and consisted mainly of mild diarrhea and anorexia.

If toceranib was demonstrated to be well tolerated via blood work and other diagnostics performed within a month of initiating treatments, dogs were restaged every two to three months on the drug.

Survival times were recorded for the total population, for patients with macroscopic disease, and for those with post-resection microscopic disease. These intervals were calculated in three different ways:

• Overall survival time: time of disease diagnosis to time of death (from any cause)
• Time of initiation of toceranib treatment to time of death (from any cause)
• Progression-free survival: time of initiation of toceranib treatment to time of progressive disease or death (from any cause)

What they found

For the 29 patients with macroscopic disease, investigators performed tumor response assessments, which consisted of tumor caliper measurement, thoracic radiographs, ultrasonography or computed tomography. Responses were rated as follows:

• Complete regression
• Partial regression: ≥ 30% decrease in sum of longest diameters of target lesions, no progression of nontarget lesions or no new lesions
• Progressive disease: > 20% increase in sum of longest diameters of target lesions, progression of nontarget lesions or appearance of new lesion(s)
• Stable disease: absence of any of the above for ≥ 10 weeks
• Clinical benefit: complete or partial regression at any point in time, or stable disease for ≥ 10 weeks

Median overall survival, toceranib treatment–associated overall survival and progression-free survival times were, respectively, 827, 434 and 313 days. Of dogs with macroscopic disease, a clinical benefit from toceranib treatment was observed in 69%, with 20.7% manifesting partial response and 48.3% showing stable disease.

The toceranib dose did not significantly impact survival times among these dogs. This finding, as well as potentially higher likelihood and severity of adverse events as dose increases, suggests that lower doses might be optimal.

Study limitations and future work

The findings in this study are confounded by a number of variables, including the fact that many of the subjects received multiple additional treatment modalities, including surgery and chemotherapy. Of the dogs receiving chemotherapy, a variety of drugs and protocols were used. Furthermore, no control population was included.

Despite these limitations, the authors concluded that most dogs in the study received clinical benefit from toceranib, primarily in the form of disease stabilization versus regression. Prospective, controlled clinical trials are needed to further assess the efficacy of toceranib compared with other treatments in affected dogs.

Dr. Joan Capuzzi is a small animal veterinarian and journalist based in the Philadelphia area.

References

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2. Bennett PF, DeNicola DB, Bonney P, et al. Canine anal sac adenocarcinomas: clinical presentation and response to therapy. J Vet Intern Med 2002;16:100‐104.

3. Williams LE, Gliatto JM, Dodge RK, et al. Carcinoma of the apocrine glands of the anal sac in dogs: 113 cases (1985‐1995). J Am Vet Med Assoc 2003;223:825‐831

4. Turek MM, Forrest LJ, Adams WM, et al. Postoperative radiotherapy and mitoxantrone for anal sac adenocarcinoma in the dog: 15 cases (1991‐2001). Vet Comp Oncol 2003;1:94‐104.

5. Emms SG. Anal sac tumours of the dog and their response to cytoreductive surgery and chemotherapy. Aust Vet J 2005;83:340‐343.

6. Wouda RM, Borrego J, Keuler NS, et al. Evaluation of adjuvant carboplatin chemotherapy in the management of surgically excised anal sac apocrine gland adenocarcinoma in dogs. Vet Comp Oncol 2016;14:67‐80.

7. London CA, Malpas PB, Wood‐Follis SL, 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;15:3856‐3865.

8. Lemmon MA, Schlessinger J. Cell signaling by receptor tyrosine kinases. Cell 2010;141:1117‐1134.

9. Millanta F, Caneschi V, Ressel L, et al. Expression of vascular endothelial growth factor in canine inflammatory and non‐inflammatory mammary carcinoma. J Comp Pathol 2010;142:36‐42.

10. Maiolino P, De Vico G, Restucci B. Expression of vascular endothelial growth factor in basal cell tumours and in squamous cell carcinomas of canine skin. J Comp Pathol 2000;123:141‐145.

11. Heaton CM, Fernandes AF, Jark PC, Pan X. Evaluation of toceranib for treatment of apocrine gland anal sac adenocarcinoma in dogs. J Vet Intern Med 2020;34(2):873-881.