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Case Report · Volume 5, Issue 3, Pages 120–126, 23 March 2017 · Open Access

Thalidomide Treatment in a Canine Mammary Gland Carcinosarcoma Presenting Pulmonary Metastasis

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Journal:
Advances in Animal and Veterinary Sciences
Published:
23 March 2017
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From the article

  • Thalidomide Treatment in a Canine Mammary Gland Carcinosarcoma Presenting Pulmonary Metastasis.
  • The patient did not present any adverse events related to the thalidomide administration and thoracic radiographs demonstrated stable metastatic disease.
  • The present case report suggests that the drug provided clinical benefit in the treatment of distant metastasis.
  • However, clinical trials are necessary to confirm the benefit of thalidomide in canine mammary gland neoplasms, as well as in other malignant neoplasms in veterinary medicine.

Selected from the article's own text.

Abstract

Cecilia Bonolo de Campos; Gleidice Eunice Lavalle; Silvia Fialho Ligório; Lidianne Narducci Monteiro; Renee Laufer Amorim; Geovanni Dantas Cassali

1Department of Veterinary Clinic and Surgery, School of Agricultural and Veterinary Sciences of the Sao Paulo State University (FCAV/UNESP) – Jaboticabal Campus, Brazil; 2Laboratory of Comparative Pathology, Department of General Pathology, Federal University of Minas Gerais (UFMG), Brazil; 3Department of Veterinary Clinic and Surgery, Veterinary School, Federal University of Minas Gerais (UFMG), Brazil; 4Department of Pharmaceutical and Biotechnological Development, Fundação Ezequiel Dias, Brazil;5Department of Veterinary Clinics, College of Veterinary Medicine and Animal Science, Sao Paulo State University (FMVZ/UNESP) – Botucatu Campus, Brazil.
 
Abstract | Carcinosarcomas are uncommon in the dog and present an unfavorable prognosis. Thalidomide has been used in the investigational treatment of several diseases due to its known immunomodulatory and anti-angiogenic properties. A female dog underwent radical unilateral mastectomy, which enabled the diagnosis of a stage III and grade III carcinosarcoma, followed by chemotherapy treatment with doxorubicin and carboplatin. Twelve months after the mastectomy, thoracic radiographs revealed the presence of multiple nodules in the lung, and thalidomide administration was initiated at 20 mg/kg/day during three months and then 10 mg/kg/day without discontinuation. The patient did not present any adverse events related to the thalidomide administration and thoracic radiographs demonstrated stable metastatic disease. The patient was euthanized presenting metastasis in several other organs and overall survival was considered 963 days. The progression of distant metastasis in the studied patient was considered hindered by thalidomide.

Keywords | Adjuvant therapy, Dog, Metastasis, Neoplasm, Survival.

 

aPressurized Heat bWater Bath cHours dRoom Temperature

Three view TR are necessary for all dogs with malignant mammary gland neoplasms, which remains as the standard diagnostic method for the evaluation of thoracic metastatic disease in veterinary medicine. Conventional radiography can detect lesions ranging from 6-9 mm in diameter ; . Radiographic detection of lung masses depends on several intrinsic (location, size, mass opacity, normal thoracic and extrathoraric structures) and radiographic technique factors, as well as the interpretation of radiographs. The RLR projection is the most sensitive for detection of lung metastasis, followed by the LLR and the VD projection. The sensitivity for the three-view combination is nearly 100%, regardless of the number of readers .

Figure 5: A. Canine mammary gland presenting neoplastic Ki-67-immunoreactive epithelial cells stained in brown (nucleous). DAB immunohistochemistry, counterstained with Harris’s hematoxylin, x600. B. Canine mammary gland presenting neoplastic ER-immunoreactive epithelial cells stained in brown (nucleous). DAB immunohistochemistry, counterstained with Harris’s hematoxylin, x600. C. Canine mammary gland presenting neoplastic PR-immunoreactive epithelial cells stained in brown (nucleous).

DAB immunohistochemistry, counterstained with Harris’s hematoxylin, x600. D. Canine mammary gland presenting neoplastic Cox-2-immunoreactive epithelial cells stained in brown (cytoplasm). DAB immunohistochemistry, counterstained with Harris’s hematoxylin, x600. E. Canine mammary gland presenting neoplastic CD31-immunoreactive endothelial cells stained in brown (cytoplasm). DAB immunohistochemistry, counterstained with Harris’s hematoxylin, x600.





There are no established guidelines for the treatment of malignant mammary gland neoplasms beyond surgery. However, treatment recommendations generally intensify with advancing clinical stage and increasing seriousness of the prognostic factors . Carcinosarcomas present extremely variable histological characteristics and are uncommon in the dog (Misdorpet al., 1999) presenting very aggressive biological behavior and an unfavorable prognosis . The lungs are the most frequent site of metastasis, followed by regional lymph nodes. Carcinosarcoma metastasis are characterized by carcinomatous, sarcomatous, or mixed components. Other sites less frequently affected are heart, kidneys, liver, adrenal glands, brain, ovaries, hypophysis, bones, spleen, and pleura. The average time between detection and death in seven dogs was 18 months .

Thalidomide was described as a potent angiogenesis inhibitor in vivo . The discovery of thalidomide’s antiangiogenic properties coincided with the emerging importance of angiogenesis in tumor growth and progression . The anti-angiogenic activity of thalidomide suggest that the drug may present potential clinical benefit in the treatment of malignancies in which neoangiogenesis is present, including solid tumors ; ; . Antiangiogenic therapy is an appealing strategy for targeting resistant disease, and accumulating evidence suggests that the combination of cytotoxic chemotherapy and antiangiogenic therapy has greater antitumor effects than either strategy alone . Therefore, a novel treatment protocol option for advanced canine mammary gland tumors may consist of surgery, chemotherapy and thalidomide in association, although clinical trials are necessary to verify the clinical benefit of the proposed therapeutic protocol.

Thalidomide and its analogs exhibit a multitude of biologic effects on cytokine and cell-mediated responses . The effects of thalidomide on immune function are incompletely understood; however, anti-inflammatory and immunomodulatory activities have been described .

The antiangiogenic and immunomodulatory properties of thalidomide are implicated in the major activity of the drug in patients with multiple myeloma and holds promise in the treatment of other hematologic malignancies. Results in solid tumors are less encouraging, but patients with certain tumors, such as glioma, renal cell cancer, and prostate cancer, may benefit . Our results demonstrated an increase in the microvessel density at the metastatic site when compared to the primary neoplasm. The inflammatory infiltrate was similar in the primary and metastatic neoplasms. Therefore, the antiangiogenic and immunomodulatory properties of the drug were not demonstrated. However, the proliferative index of the primary neoplasm was higher than the metastatic proliferative index, which may suggest the antitumor effect of the drug. Direct cytotoxic effect of thalidomide on tumor cells was demonstrated on multiple myeloma cell lines, with inhibition of DNA synthesis in vitro .

In canines, the safety profile of thalidomide was evaluated and daily oral administration was considered well tolerated. The NOAEL (no-observed-adverse-effect levels) was 200 mg/kg . Two studies began to evaluate the clinical benefit of thalidomide in canine malignancies; however, the clinical trials were not completed ; . The present case report suggests that the drug provided clinical benefit in the treatment of distant metastasis. In addition, the patient maintained adequate quality of life during the thalidomide treatment, with an absence of adverse effects.

Gross metastatic disease at the time of diagnosis was associated to a poorer prognosis, with a median post-operative survival of 5 months, when compared to 28 months for animals diagnosed with mammary gland neoplasms that lacked evidence of metastasis at diagnosis . Another study found a 13.6% survival rates one year after mastectomy for animals diagnosed with distant metastasis . In veterinary oncology, there are insufficient options for the treatment of distant metastasis. However, the 20-month overall survival after the diagnosis of pulmonary nodules in the present case report was considered satisfying.

The progression of distant metastasis in the studied patient was considered hindered by thalidomide. However, clinical trials are necessary to confirm the benefit of thalidomide in canine mammary gland neoplasms, as well as in other malignant neoplasms in veterinary medicine.

Acknowledgements

This research was supported by the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP Grant 2014/01329-9) and the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq Grant 302449/2013-2).

Conflict of Interest

The authors declare they have no conflict of interest.

Authors Contribution

CBC, GEL, and GDC conceived the study. CBC performed data collection and wrote the manuscript. CBC and LDM performed data analysis. SLF aided in the obtainment of necessary resources. GDC, GEL, RLA, SLF supervised the work. All authors were involved in revising the manuscript.

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