Metronomic Chemotherapy for Palliative Treatment of Malignant Oral Tumors in Dogs

Abstract

The aim of this study was to evaluate the efficacy of metronomic chemotherapy in the palliative treatment of various malignant oral tumors in dogs. Our focus was to determine the effect of treatment on local disease control and to assess the tolerability and safety of the treatment in dogs with various oral malignancies. Metronomic chemotherapy with cyclophosphamide was used to treat 12 dogs and was combined with non-steroidal anti-inflammatory drugs in 6/12 (50%) of dogs. A clinical benefit was observed in 6/12 (50%) patients 1 month and in 4/12 (33%) 3 months after treatment initiation. The median survival time of the dogs was 155 days (range 21–529 days). At the end of the observation period, the disease had progressed in 10/12 (83.3%) of the patients. Sterile hemorrhagic cystitis was the most commonly reported side effect of treatment, occurring in 4/12 (33.3%) dogs. The results of our study suggest that metronomic chemotherapy with cyclophosphamide can be, in a subset of dogs, beneficial in the palliation of malignant oral tumors.

Metronomic chemotherapy: bridging theory to clinical application in canine and feline oncology

“…Since then, this modality has been increasingly applied to veterinary patients due to the fewer side effects, less need for supportive medications, generally low cost, less stressful administration, convenience to pet owners, and possible combination with other therapies ( 14 ). Although initially it was arguably considered by some authors as a merely palliative treatment, it is currently known that MC has greater therapeutic potential, whether in combination with surgery ( 57–66 ), radiotherapy ( 67 , 68 ) or electrochemotherapy ( 66 ), or even as first-line treatment for advanced, metastatic or incurable disease ( 69 , 70 ). Furthermore, its use in combination with MTD chemotherapy (MTDC) has also been reported, either simultaneously or after the latter for maintenance therapy (chemo-switch regimen) ( 57 , 60 , 62 , 71–76 ).…”

“…Although less frequently, oral chlorambucil has been described as the main drug at the dose of 4 mg/m 2 daily in dogs ( 58 , 62 , 83–85 ) and 0.4 to 0.6 mg/kg or 4 mg/m 2 every other day in cats ( 79 , 82 ) for the treatment of some neoplasms in these two species. It has also been used as a substitute for cyclophosphamide when sterile haemorrhagic cystitis occurs ( 57 , 70 , 73 , 74 , 76 , 80 ). In turn, metronomic prescription of lomustine ( 68 , 86 ), temozolomide ( 42 ), and etoposide ( 55 , 57 , 87 ) has also been described in the oncological treatment of some canine patients at daily doses of 2.84 mg/m 2 , 6.6 mg/m 2 and 50 mg/m 2 , respectively.…”

“…Regarding non-cytotoxic agents, non-steroidal anti-inflammatory drugs (NSAIDs) are the most prescribed in association with MC, due to their ability to inhibit cyclooxygenase isoform-2 (COX-2), whose expression is considered a negative prognostic factor in various types of canine and feline tumours ( 91 ). This inhibitory effect compromises endothelial cell tube formation and VEGF expression, preventing tumour progression ( 73 , 78 , 80 ) Thus, several COX-2 inhibitors have been included in MC protocols, such as piroxicam ( 55 , 56 , 61 , 62 , 67 , 69–71 , 73–75 , 77 , 79–81 , 86 , 90 ), meloxicam ( 56 , 61–63 , 70 , 73–76 , 82 , 85 , 86 , 90 ), firocoxib ( 56 , 59 , 62 , 65 , 73 , 76 , 86 , 90 ), carprofen ( 68 , 70 , 86 ), deracoxib ( 74 , 75 , 86 ), celecoxib ( 78 ), and cimicoxib ( 65 ). Amongst these, piroxicam, an oxicam derivate, is the NSAID whose efficacy as anticancer drug has been most recognised, at a recommended dose of 0.3 mg/kg per day or every other day ( 69 , 79 , 92 ).…”

“…In turn, sterile haemorrhagic cystitis has been described in dogs treated with oral metronomic cyclophosphamide, due to the formation of acrolein through liver metabolism, which accumulates and causes irritation in the bladder mucosa ( 55 , 76 , 90 ). This toxicity can affect up to 58% of canine patients ( 55 , 59 , 61 , 62 , 70 , 73 , 75–77 , 81 , 90 ) and must be prevented by administering it in the morning and encouraging water intake and frequent urination, in order to reduce urinary stasis. In line with this, the concomitant use of diuretics, such as furosemide, has also been advised ( 90 , 102 ).…”

“…In line with this, the concomitant use of diuretics, such as furosemide, has also been advised ( 90 , 102 ). Furthermore, if this urinary AE occurs, cyclophosphamide is generally replaced by chlorambucil ( 57 , 70 , 73 , 74 , 76 , 80 ). The time required for its development differs depending on the dose of cyclophosphamide.…”