Canine Hepatocellular Carcinoma and Multicentric Lymphoma - Treatment with Metronomic Cyclophosphamide

Abstract

Background: Hepatocellular carcinomas (HCC) represent approximately 50% of primary liver neoplasms and can be localized or distributed throughout the parenchyma. Lymphoma is the clonal proliferation of lymphocytes, with the multicentric form being the most common in dogs. Metronomic chemotherapy consists of the administration of low-dose antineoplastic agents at short, regular intervals. However, no effective treatment for nodular or disseminated HCC nor reports of metronomic chemotherapy in dogs with lymphoma exist. Thus, this study aimed to report the use of antineoplastic therapies in 2 dogs diagnosed with inoperable nodular HCC and multicentric lymphoma.
Cases: The 1 st patient was a 16-year-old bitch mixed breed weighing 7.4 kg that was treated at the Veterinary Hospital of the Federal University of Santa Maria (HVU-UFSM). Ultrasound examination revealed nodular structures measuring approximately 1 cm throughout the hepatic parenchyma, with the largest one measuring approximately 4.48 x 3.07 cm located in the left lateral lobe. An increased uterine volume was also observed. Exploratory celiotomy showed pyometra and hepatic nodules. Liver biopsy confirmed the diagnosis of HCC. Owing to the impossibility of surgical resection, the treatment of choice was metronomic chemotherapy with cyclophosphamide at 15 mg/mm2 every 48 h with follow-up imaging and blood tests. Nine months after diagnosis, a nodular area of approximately 1.5 x 1.3 cm was identified in the greater curvature of the stomach. The patient remained clinically stable, with stable neoplasm progression. However, at
the age of 19 years, the bitch died 2 years and 5 months after the metronomic administration of cyclophosphamide, and
the causa mortis was elderliness. The 2 nd patient was a 10-year-old bitch Shih Tzu weighing 3.7 kg, referred for suspected lymphoma and also examined at the HVU-UFSM. The patient manifested with enlarged mandibular and popliteal lymph nodes and lymphocytic leukocytosis. A multicentric lymphoma was confirmed via fine-needle aspiration cytology (FNAC) and through clinical signs and blood tests. Chemotherapy treatment was initiated with the CHOP regimen, which included cyclophosphamide [200 mg/m² ], vincristine [0.6 mg/m² ], doxorubicin [25 mg/m²], and prednisone [5 mg/kg]. However, this regimen was not effective and changed to chlorambucil [3 mg/m² ), VO, SID, for 4 days] and prednisone [1 mg/kg, VO, SID]. However, this protocol was not feasible due to the unavailability of the drug on the market; therefore, metronomic chemotherapy was initiated. The bitch received cyclophosphamide 15 mg/m2 every 48 h, showing clinical improvement
in the lymphocytic leukocytosis. Chronic anemia, weight loss, leukemia, and chronic kidney disease occurred as compli-
cations and were treated accordingly. The bitch lived for 3 years and 6 months after the diagnosis and eventually died due to years of treatment and worsening general condition due to the acquired complications.
Discussion: Veterinary Medicine is faced with several challenges in designing effective metronomic chemotherapy regi-
mens, including the selection of appropriate drugs and the establishment of effective doses. Both patients in this report
received cyclophosphamide [15 mg/m 2, every 48 h]. In human medicine, metronomic chemotherapy is considered a safe
and potentially useful treatment, which was observed in the reported patients since it presented few side effects and an
increased survival period of 880 days in the patient with HCC and 1,275 days in the patient with multicentric lymphoma.
This regimen can be considered for inoperable tumors and in cases of refractory to conventional regimens.

Keywords: antineoplastic agents, lymphosarcoma, chemotherapy, survival.

Título: Carcinoma hepatocelular e linfoma multicêntrico canino - tratamento com ciclofosfamida metronômica

Descritores: antineoplásicos, linfossarcoma, quimioterapia, sobrevida