Quimioterapia metronómica em cães e gatos: um estudo retrospetivo
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2022-03-31
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A oncologia veterinária sofreu uma evolução significativa ao longo das últimas décadas. A quimioterapia tem sido aplicada com sucesso em inúmeras neoplasias, na qual domina a quimioterapia com agentes antineoplásicos clássicos, baseando-se no conceito de dose máxima tolerada. No entanto, devido à sua elevada toxidade e ao aparecimento de resistências, têm surgido várias alternativas terapêuticas. De entre elas, destaca-se a quimioterapia metronómica, que consiste na administração de baixas doses de compostos quimioterápicos, de forma contínua e por um longo período. Recentemente ainda foi sugerido combinar os protocolos metronómicos com os protocolos convencionais como uma estratégia sinérgica, emergindo assim um novo regime dentro da quimioterapia metronómica e o qual foi denominado de “chemo-switch”. O estudo retrospetivo teve como objetivos descrever o uso da quimioterapia metronómica na prática clínica de pequenos animais, relativamente aos fármacos citotóxicos e combinações utilizadas, tumores mais comuns, resposta clínica e efeitos secundários manifestados e comparar os resultados obtidos com os da bibliografia atualmente disponível. Também se procedeu à análise de relações estatisticamente significativas entre algumas variáveis clínicas com a espécie essencialmente. No total, foram avaliados 48 cães e 30 gatos diagnosticados com neoplasias malignas espontâneas, submetidos a quimioterapia metronómica com ciclofosfamida (10 a 15 mg/m2 ) ou clorambucilo (4 mg/m2 ), tanto em monoterapia como em terapia combinada (inibidores da cicloxigenase-2, toceranib), no Hospital Veterinário do Porto e no Hospital Veterinário Berna, entre maio de 2016 e agosto de 2021. Observaram-se algumas diferenças estatísticas significativas no que respeita à espécie (cão e gato). Assim, revelaram diferenças o género (p=0,010), o tipo de tumor diagnosticado (p=0,003), o inibidor da cicloxigenase-2 utilizado (p<0,001), , o modo em que foi empregue o tratamento (p=0,004), a realização de cirurgias prévias (p=0,009) e a resposta tumoral ao sexto mês de tratamento (p=0,007). Nos cães, os tumores mais comuns foram: carcinoma prostático (n=6 [12,5%]), carcinoma mamário (n=6 [12,5%]), hemangiossarcoma (n=5 [10,4%]), osteossarcoma (n=5 [10,4%]), melanoma oral (n=4 [8,3%]), fibrossarcoma (n=3 [6,3%]), carcinoma adrenal (n=3 [6,3%]) e carcinoma hepatocelular (n=3 [6,3%]). Na espécie felina, o carcinoma mamário destacou-se consideravelmente (n=22 [73,3%]), seguindo-se o osteossarcoma (n=2 [6,7%]) e o fibrossarcoma (n=2 [6,7%]). A quimioterapia metronómica foi empregue em quatro regimes: adjuvante, paliativo, neoadjuvante e chemo-switch. Após seis meses, 6 (15,8%) cães e 1 (3,7%) gato apresentaram doença estável e 2 (5,3%) cães e 9 (33,3%) %) gatos estavam livres da doença. 30 (78,9%) cães e 17 (63%) gatos tinham doença progressiva. O tempo médio de sobrevivência total em cães e gatos foi de 368 e 511 dias, respectivamente. A toxicidade foi observada em 54,3% dos cães e 63,3% de gatos, de grau leve a moderado na sua generalidade. Em geral, a quimioterapia metronómica foi bem tolerada em cães e gatos com cancro. Porém, não demonstrou eficácia na estabilização da doença neoplásica. Estes achados sugerem que uma avaliação mais aprofundada desta abordagem é necessária em pequenos animais, a fim de elucidar a vantagem do seu uso em termos clínicos e definir diretrizes terapêuticas, tornando o seu uso mais frequente, metódico e seguro.
Veterinary oncology has undergone significant evolution over the past few decades. Chemotherapy has been successfully applied to numerous neoplasms, in which chemotherapy with classical antineoplastic agents dominates, based on the maximum tolerated dose concept. However, due to its high toxicity and the emergence of resistance, several therapeutic alternatives have emerged, introducing a new paradigm in cancer treatment. Among them, metronomic chemotherapy stands out, which consists of administering low doses of chemotherapeutic compounds, continuously and for a long period of time. Recently, it was even suggested to combine metronomic protocols with conventional protocols as a synergistic strategy, thus emerging a new regimen within metronomic chemotherapy, which was called “chemo-switch”. The retrospective study aimed to describe the use of metronomic chemotherapy in small animal clinical practice, describing the cytotoxic drugs and combinations used, the most common tumors, evaluating the clinical response and side effects and to compare the results obtained with those of the currently available literature. We also analyzed the statistically significant relationships between some clinical variables with the species essentially. In total, were evaluated 48 dogs and 30 cats diagnosed with spontaneous malignant neoplasms, undergoing metronomic chemotherapy with cyclophosphamide (10 to 15 mg/m2 ) or chlorambucil (4 mg/m2 ), both in monotherapy and in combination therapy (cyclooxygenase-2 inhibitors, toceranib), at the Hospital Veterinário do Porto and at the Hospital Veterinário Berna, from May 2016 to August 2021. Some statistically significant differences were observed with respect to species (dog and cat). Thus, differences were revealed by gender (p=0.010), type of tumor diagnosed (p=0.003), adjuvant non-steroidal anti-inflammatory cyclooxygenase-2 inhibitor used (p<0.001), the way in which the treatment was used (p=0.004), previous surgeries (p=0.009) and tumor response in the first month (p=0.004) and sixth month of treatment (p=0.007). In dogs, the most common tumors were: prostatic carcinoma (n=6 [12.5%]), mammary carcinoma (n=6 [12.5%]), hemangiosarcoma (n=5 [10.4%]), osteosarcoma (n=5 [10.4%]), oral melanoma (n=4 [8.3%]), fibrosarcoma (n=3 [6.3%]), adrenal carcinoma (n=3 [6.3%]) and hepatocellular carcinoma (n=3 [6.3%]). In the feline species, mammary carcinoma stood out considerably (n=22 [73.3%]), followed by osteosarcoma (n=2 [6.7%]) and fibrosarcoma (n=2 XII [6.7%]). Metronomic chemotherapy was used in four regimens: adjuvant, palliative, neoadjuvant and chemo-switch. After six months, 6 (15.8%) dogs and 1 (3.7%) cat had stable disease and 2 (5.3%) dogs and 9 (33.3%) cats were disease free. 30 (78.9%) dogs and 17 (63%) cats had progressive disease. The median overall survival time in dogs and cats was 368 and 511 days, respectively. Toxicity was observed in 54.3% of dogs and 63.3% of cats, degree mild to moderate in general. In general, metronomic chemotherapy was well tolerated in dogs and cats with cancer. However, it did not demonstrate efficacy in stabilizing the neoplastic disease. These findings suggest that further evaluation of this approach is needed in small animals, to elucidate the advantage of its use in clinical terms and to define therapeutic guidelines, making its use more frequent, methodical and safe.
Veterinary oncology has undergone significant evolution over the past few decades. Chemotherapy has been successfully applied to numerous neoplasms, in which chemotherapy with classical antineoplastic agents dominates, based on the maximum tolerated dose concept. However, due to its high toxicity and the emergence of resistance, several therapeutic alternatives have emerged, introducing a new paradigm in cancer treatment. Among them, metronomic chemotherapy stands out, which consists of administering low doses of chemotherapeutic compounds, continuously and for a long period of time. Recently, it was even suggested to combine metronomic protocols with conventional protocols as a synergistic strategy, thus emerging a new regimen within metronomic chemotherapy, which was called “chemo-switch”. The retrospective study aimed to describe the use of metronomic chemotherapy in small animal clinical practice, describing the cytotoxic drugs and combinations used, the most common tumors, evaluating the clinical response and side effects and to compare the results obtained with those of the currently available literature. We also analyzed the statistically significant relationships between some clinical variables with the species essentially. In total, were evaluated 48 dogs and 30 cats diagnosed with spontaneous malignant neoplasms, undergoing metronomic chemotherapy with cyclophosphamide (10 to 15 mg/m2 ) or chlorambucil (4 mg/m2 ), both in monotherapy and in combination therapy (cyclooxygenase-2 inhibitors, toceranib), at the Hospital Veterinário do Porto and at the Hospital Veterinário Berna, from May 2016 to August 2021. Some statistically significant differences were observed with respect to species (dog and cat). Thus, differences were revealed by gender (p=0.010), type of tumor diagnosed (p=0.003), adjuvant non-steroidal anti-inflammatory cyclooxygenase-2 inhibitor used (p<0.001), the way in which the treatment was used (p=0.004), previous surgeries (p=0.009) and tumor response in the first month (p=0.004) and sixth month of treatment (p=0.007). In dogs, the most common tumors were: prostatic carcinoma (n=6 [12.5%]), mammary carcinoma (n=6 [12.5%]), hemangiosarcoma (n=5 [10.4%]), osteosarcoma (n=5 [10.4%]), oral melanoma (n=4 [8.3%]), fibrosarcoma (n=3 [6.3%]), adrenal carcinoma (n=3 [6.3%]) and hepatocellular carcinoma (n=3 [6.3%]). In the feline species, mammary carcinoma stood out considerably (n=22 [73.3%]), followed by osteosarcoma (n=2 [6.7%]) and fibrosarcoma (n=2 XII [6.7%]). Metronomic chemotherapy was used in four regimens: adjuvant, palliative, neoadjuvant and chemo-switch. After six months, 6 (15.8%) dogs and 1 (3.7%) cat had stable disease and 2 (5.3%) dogs and 9 (33.3%) cats were disease free. 30 (78.9%) dogs and 17 (63%) cats had progressive disease. The median overall survival time in dogs and cats was 368 and 511 days, respectively. Toxicity was observed in 54.3% of dogs and 63.3% of cats, degree mild to moderate in general. In general, metronomic chemotherapy was well tolerated in dogs and cats with cancer. However, it did not demonstrate efficacy in stabilizing the neoplastic disease. These findings suggest that further evaluation of this approach is needed in small animals, to elucidate the advantage of its use in clinical terms and to define therapeutic guidelines, making its use more frequent, methodical and safe.
Descrição
Dissertação de Mestrado em Medicina Veterinária
Palavras-chave
oncologia , quimioterapia metronómica