Adjuvant Thalidomide and Metronomic Chemotherapy for the Treatment of Canine Malignant Mammary Gland Neoplasms

Abstract

Background/Aim: The aim of the present study was to evaluate a multimodal approach for the treatment of canine malignant mammary gland neoplasms, including surgery, chemotherapy, thalidomide, and metronomic chemotherapy (MC). Materials and Methods: Fifty-eight female dogs were submitted to four different treatments: surgery; surgery with chemotherapy; surgery with chemotherapy and thalidomide; and surgery with chemotherapy and metronomic chemotherapy and overall survival was evaluated. Results: No statistical difference was found in the proliferative index and microvessel density of primary neoplasms and distant metastases following thalidomide treatment. Diffuse intense inflammatory infiltrate was predominant in primary tumors and diffuse moderate inflammatory infiltrate in metastatic lesions. No statistically significant difference was observed in median survival time (MST) between treatment groups when including all clinical stages (p=0.3177). However, animals diagnosed with distant metastasis treated with surgery and chemotherapy associated with thalidomide or MC presented longer MST when compared to animals treated only with surgery or surgery and chemotherapy (p<0.0001). Conclusion: The proposed multimodal therapy protocols including antiangiogenic and immunomodulatory therapies demonstrated a clinical benefit for patients in advanced clinical stages. Many mammalian species present mammary gland neoplasms similar to breast cancer in women, and the high incidence of spontaneous disease in domestic dogs and cats characterize them as pertinent comparative models (1). Human and canine breast cancer incidence present similar proportional distribution by age and sex (2), and resemblance in type, molecular transformative abnormalities, and behavior. This enables comparative studies involving carcinogenesis and the efficacy of novel therapies in mammary neoplasms in pets (1). Mammary gland neoplasms are the most common neoplasms that affect female dogs (3). Although the optimal extent remains unclear (4), surgery remains the most effective treatment for the disease. Adjuvant therapies may be required for high-risk, undifferentiated and advanced neoplasms (5, 6). Single-agent treatments have been considered less efficacious than combination therapies (7), and in solid tumors, angiogenesis has clearly been associated with metastasis and disease progression (8), and the combination of antiangiogenic strategies with conventional chemotherapy protocols will likely benefit the treatment of malignant tumors (9). In the late 1950s, thalidomide was marketed worldwide as a sedative and a hypnotic, and as an anti-emetic drug in early pregnancy (10). Thalidomide was associated with congenital deformities and peripheral neuropathy, and the drug was 1659 This article is freely accessible online.

Pharmacokinetics of thalidomide in dogs: can feeding affect it? A preliminary study

“…Steady-state plasma concentrations ranging from 5 to 7 μg/mL resulted in stable disease for up to 74 weeks in 12/31 glioma patients, however, similar concentrations (6.2 μg/mL) for 8 weeks in metastatic breast cancer patients showed no tumour response [ 39 40 ]. In a recent study in dogs, a similar TAL dose to that reported in the present study, was associated with equal or even longer survival times compared to intensive-dose chemotherapy in splenic hemangiosarcoma and mammary carcinomas [ 18 20 ]. The average plasma concentration computed at the steady state at 11.7 mg/kg TAL administration once-daily in fed dogs resulted in 3.7 μg/mL.…”

“…The dose of TAL administered in the present study (400 mg/dog, average 11.7 mg/kg) was selected based on clinical efficacy/adverse effects previously reported in dogs. A dose of 8.7 mg/kg/day and a 3-month daily-dose of 20 mg/kg followed by a 3-month daily-dose of 10 mg/kg were successfully used in the management of stage II–III splenic hemangiosarcomas [ 18 ] and canine mammary carcinomas [ 20 ], respectively, in dogs. This latter study showed adverse sedative effects in some dogs when given the higher dose (20 mg/kg), with symptom improvement when the dose was reduced to 10 mg/kg.…”

“…TAL has been used in canine chemotherapy for the treatment of hemangiosarcoma [ 17 18 ], pulmonary [ 19 ] and mammary carcinoma [ 20 ]. Equivalent or even longer survival times have been reported compared to traditional intensive-dose chemotherapy.…”

Deregulation of VEGFR-2 and PDGFR Expression and Microvascular Density in a Triple-Negative Model of Canine Malignant Mammary Tumors with Lymph Node or Lung Metastasis

“…Patients were classified as stage I–V [2]. Patients with at least stage III disease and at least tumor grade II received adjuvant chemotherapy with four cycles of 300 mg/m 2 carboplatin and 5 mg/kg of firocoxib every 24 h for six months according to the method of Bonolo et al [29]. Clinical follow-up was performed every three months in the first year with three-view thoracic radiographic examinations and complete blood counts.…”

Deregulation of VEGFR-2 and PGFR Expression and Microvascular Density in a Triple-Negative Model of Canine Malignant Mammary Tumors with Lymph Node or Lung Metastasis

“…Patients were classified as stage I-V [2]. Patients with at least stage III disease and at least tumor grade II received adjuvant chemotherapy with four cycles of 300 mg/m 2 carboplatin and 5 mg/kg of firocoxib every 4 hours for six months Bonolo et al [29]. Clinical follow-up was performed every three months in the first year with three-view thoracic radiographic examinations and complete blood counts.…”