Mast cell tumours are the most common form of skin cancer in dogs, accounting for up to 21 percent of skin cancer cases (Blackwood et al., 2012). Surgery is the treatment of choice in areas amenable to wide excision. Multimodal treatment is often required for the effective local control of more surgically challenging mast cell tumours when it is not possible to achieve sufficient histological margins. Multimodal treatment involves a combination of cytoreductive surgery and multiple radiotherapy or chemotherapy treatments (Blackwood et al., 2012). Multimodal treatment is not always possible or desired for both client-related factors (eg concerns about finances, practicalities or health and safety) or patient-related factors (eg anaesthetic risk, risk of complications or adverse effects, patient comorbidities or age). Here we look at a case treated with the novel compound tigilanol tiglate, which offers a new medical option for treatment of mast cell tumours (De Ridder et al., 2020).
Tigilanol tiglate
Tigilanol tiglate offers a novel treatment modality for the local treatment of canine mast cell tumours. It has European approval for the treatment of non-resectable, non-metastatic (WHO staging; London and Thamm, 2019) subcutaneous MCTs located at or distal to the elbow or the hock, and non-resectable, non-metastatic cutaneous MCTs in dogs. It is licensed for the treatment of non-ulcerated MCTs less than or equal to 8cm3 in volume and accessible by intratumoural injection. Lack of metastasis should ideally be ascertained prior to treatment by cytology of local lymph nodes and imaging.
Tigilanol tiglate is a cell signalling molecule and works largely through specific protein kinase C (PKC) activation that induces a localised acute inflammation. PKC activation also elicits disruption of the tumour vasculature resulting in haemorrhagic necrosis and ultimately destruction of the tumour mass. Clinically, this is seen as tumour separation with blackening and shrinkage of the tumour and leaking of a thick discharge with a resulting tissue deficit that develops typically within seven days. Granulation tissue then rapidly fills the newly created wound bed, with the majority of patients achieving full wound closure within four to six weeks with minimal scarring.
In a study by De Ridder et al. (2020), complete remission (CR, RECIST criteria; Eisenhower et al., 2009) was achieved in 75 percent of cases within four weeks of the first treatment, and in an additional 44.4 percent of the remaining dogs when treated twice. Dogs should be adequately restrained during treatment to avoid self-injection, but sedation may not be required in all patients. In 65 of 74 dogs available for assessment 12 months after initial CR to tigilanol tiglate, there was no evidence of local MCT recurrence (Campbell et al., 2019).
Case study
The patient described in the case study below was one of the animals during the pivotal trial who was initially part of the control group and then received one dose of tigilanol tiglate (De Ridder et al., 2020).
Signalment
An 11-year-old female neutered Jack Russell Terrier weighing 6.6kg presented with a subcutaneous mass on the medial aspect of the left elbow which measured 1.7cm length, 1.6cm width and 0.6cm depth. The patient also had a mild tracheal collapse and had a history of multiple non-metastatic low-risk mast cell tumours in unrelated body regions. The owner was reluctant to consider further surgery given the risk of incomplete margins based on the anatomical location and did not want to pursue any adjuvant treatment.
Examination and diagnostic testing
A mast cell tumour was diagnosed by cytology performed at a commercial laboratory using May-Grunwald-Giemsa staining. The tumour was suspected to be subcutaneous based on physical assessment.
The tumour was assigned a “low” cytological grade (based on Scarpa et al., 2016). Lymph node aspiration was not performed as the sentinel prescapular and axillary lymph nodes were not palpable or accessible for sampling. Further staging was not performed and the tumour considered non-metastatic. Results of haematology, serum biochemistry and urinalysis performed before treatment showed no significant abnormalities.
Treatment
Premedication and concomitant medications were prescribed as per the datasheet before injection with tigilanol tiglate to reduce the risk of and for symptomatic treatment of potential treatment-induced mast cell degranulation. Corticosteroids (prednisolone 0.5mg/kg PO q12h) were given two days prior to treatment for mast cell stabilisation (day -2 and -1) and antihistamines against H1 and H2 receptors (diphenhydramine 3mg/kg q12h and famotidine 0.75mg/kg q12h respectively) were given on the day of injection (day 0) to counteract the local and systemic effects of histamine release. These three medications were continued for seven days post treatment.
The dose rate of tigilanol tiglate is 0.5 x tumour volume (cm3) with a minimum dose of 0.1ml and a maximum dose of 0.15mg/kg or 4ml in total per animal. On the day of treatment, the tumour had decreased in size under the influence of prednisolone and measured 1.6cm length x 1.6cm width x 0.4cm depth. A tumour volume of 0.5cm3 was determined with use of the modified ellipsoidal calculation represented by the following equation: tumour volume = 0.5 x length (cm) x width (cm) x depth (cm) (Celikoglu et al., 2008). A dose of 0.25mg was calculated (0.04mg/kg), but a total of 0.3mg (0.05mg/kg) was prescribed as the dose was rounded up to the nearest 0.1mg. The dose was delivered via an intratumoural injection fanned throughout the mass with an aseptic technique after clipping of the area to be treated. The dose was delivered uneventfully with the patient conscious although some patients may require sedation if there is poor collaboration or if sensitive tissues are treated.
Outcome
The outcome of treatment with tigilanol tiglate appears to follow four main steps. Within hours, local inflammation, oedema and bruising were noted at the treatment site. With further progression of local inflammation, the animal showed signs of discomfort so tramadol (3.8mg/kg q12h) was prescribed for additional analgesia starting 24 hours after injection for a seven-day course duration. Within four days, the area showed signs of haemorrhagic necrosis with the tumour softening and separating from the healthy skin surface. By day seven, there was eschar formation with presence of mild serous discharge and a maximum wound size of 3.2cm x 2.1cm; early granulation was also noticed. By day 14, there was full detachment of the necrotic tissue with healthy granulating tissue present and significant wound contracture (2.6cm x 1.5cm). Throughout this period the animal did not wear an Elizabethan collar and required no wound management (eg dressing or topical treatments). By day 28 a scab was covering the small residual wound (size 1mm x 10mm) that was completely re-epithelialised by day 42. Photos can be found in the paper by De Ridder et al. (2020).
Discussion
In this case, a complete remission was achieved with one single treatment of tigilanol tiglate. The expected development of the wound required minimal management with a hands-off approach. This case is a typical example of the expected outcome of treatment with tigilanol tiglate represented by a rapid onset of inflammation, haemorrhagic necrosis and wound formation with rapid healing at the treatment site. The quality of life of the patient was very good throughout treatment with moderate discomfort noted during the inflammatory and sloughing phase which was easily managed with symptomatic treatment and an expected mild adverse event. The tissue-sparing effect, the administration of a single treatment and possibility to perform this treatment without sedation or anaesthesia in most patients offers significant benefits to patients where surgery with wide margins or multimodal treatment are not possible or desired.
The administration of hazardous medications for chemotherapy treatment that may be required as part of multimodal therapy may carry health and safety concerns for the veterinary staff and owners. Tigilanol tiglate is a medicinal product and a cell signalling molecule, rather than a cytotoxic agent, which is derived from Fontainea picrosperma, commonly known as the blushwood tree. Simple personal protective equipment is recommended, to include gloves and goggles as the product is an irritant and potential skin sensitiser.
