E.B. Neuwald; A.C. Tourrucôo; A. Faraon; L.O. Oliveira; S.T. Oliveira; N.R.C. Hlavac; L.A. Lacerda; C.S. Lasta; F.H.D. González
Doxorubicin is an anthracycline glycoside antimicrobial isolated from cultures of Streptomyces peucetius var. caesius. It is considered to be one of the most important antineoplastic agents because of its broad activity against several neoplasms in humans and domestic animals (Souza & Camacho 2006). However, the therapeutic usefulness of this agent has been limited by its toxicity, including hematological toxicity, gastrointestinal disturbances, cardiotoxicity, alopecia and severe local injury when extravasation occurs (Badylak et al. 1985, Ahaus et al. 2000). These doxorubicin toxicities in the dog have been well described and can be divided into acute, short-term and chronic effects. Acute doxorubicin toxicosis is uncommon and consists of head shaking, cutaneous hyperemia, anaphylaxis, vomiting, hypotension and cardiac arrhythmias (Davis 1983, Phillips et al. 1998). Short-term toxicities are those seen 1 to 2 weeks after the injection of doxorubicin and include weight loss, anorexia, diarrhea, bone marrow hypoplasia and alopecia. Chronic toxicosis includes hair loss, testicular atrophy and cardiac toxicity (Davis 1983). The purpose of this study was to evaluate the severity of doxorubicin toxicity in dogs with mammary neoplasms, including clinical signs, hematological and electrocardiographic alterations.
Materials and Methods
Sixteen dogs treated with single agent chemotherapy, consisting of doxorubicin, by the Oncology Service at the Veterinary Clinical Hospital of Federal University of Rio Grande do Sul and with cytopathologically or histopathologically confirmed malignant mammary tumors were evaluated in this study. Informed consent was obtained from all owners. All dogs were found to be free of cardiac disease on the basis of physical examination, thoracic radiographies and electrocardiography at the time of first chemotherapy. Doxorubicin was given over 40 minutes through an indwelling venous catheter at a dosage of 30 mg/m2 IV each 21 days for three treatments. Immediately before each infusion of the drug all animals were administered promethazine chloride (0.4 mg/kg IM) and metoclopramide chloridrate (0.4 mg/kg SC). After the administration, a 6-lead electrocardiogram (ECG) was performed during a period of one minute. The owners of all dogs were advised of the signs of doxorubicin toxicity and were oriented to return to hospital if they were moderate or severe. One week after the chemotherapy (nadir) all animals were evaluated by physical examination; an ECG was performed and blood samples were collected for hemograms and platelets count. Data evaluated included breed, tumor type, gender, weight, age and signs of acute, short term or chronic toxicities such as gastrointestinal, cutaneous or cardiac alterations. The hematologic toxicity was assigned by the presence of leucopenia (white blood count less than 4000/µL), neutropenia (neutrophils less than 2500/µL), thrombocytopenia (platelets less than 200 x 103/µL) and anemia (packed cell volume less than 37%). The granulocyte and platelets grade were assigned according to a standard hematological system (grade 0, neutrophil count > 2500 cells/µL and platelets > 200 x 103/µL; grade 1, 1500-2499 cells/μL and 100-200 x 103/μL; grade 2, 1000-1499 cells/μL and 50-100 x 103/µL; grade 3, 500-999 cells/μL and 25-50 x 103/μL; grade 4, < 500 cells/μL and < 25 x 103/μL) (Ahaus et al. 2000, Sonremo et al. 2004). All dogs that presented white blood cells (WBC) less than 3000 cell/μL in the nadir of doxorubicin were treated prophylactic with trimethoprim-sulfadiazine (15 mg/kg PO BID) during 10 days. Sepsis was defined as the coexistence of neutropenia, fever and clinical signs (i.e., anorexia, vomiting, lethargy and dehydration) requiring hospitalization. The signs of gastrointestinal toxicity were based on the presence of anorexia, vomiting and diarrhea and were graded as mild (anorexia < 3 days duration, nausea and soft stools), moderate (anorexia > 3 and < 5 days, 1-5 vomits episodes per day and watery stools) or severe (anorexia > 5 days, more than 5 vomits episodes per day and bloody stools). Cardiac toxicity was evaluated by the presence of congestive heart failure signs (i.e., cough, ascites and dyspnea), sudden death and arrhythmias detected on ECG. Cutaneous alterations were considered as hyperemia, especially at the local of catheter introduction, and hair loss. A delay in treatment was defined as a delay of one week or more; the decision to delay or suspend the treatment was based on the clinician's judgment and the owner request. A repeated-measures analysis was used and statistical calculations were performed by use a general linear model in a statistical program. Values of P < 0.05 were considered significant. Results: Sixteen dogs with mammary tumors were evaluated. Pure breed dogs (n = 13) and mixed breeds (n = 3) entered in this study. English Cocker Spaniel (n = 5) was the most commonly represented breed; others included Dachshund (n = 2), Poodle toy (n = 2), Collie, Bichon Frise, Pinscher and Miniature Schnauzer (n = 1 each). The tumors included adenocarcinoma (n = 8), carcinosarcoma (n = 4), complex (n = 2), solid (n = 1) and anaplastic (n = 1) carcinomas. All dogs were females; 6 spayed and 10 intact. The majority of dogs were middle-aged to older, ranged from 6 to 12 years, with a mean of 9.2. The median weight was 11kg, ranged from 3.5 to 32kg. Nine animals (56.25%) received three doses of doxorubicin and completed the treatment. Five dogs (31.25%) received two doses; four had moderate to severe hematological and/or gastrointestinal toxicities and their owners requested to stop the chemotherapy; and one was submitted to surgery after just two doses because of good response. Only two dogs (12.5%) received just one dose of doxorubicin; one died because of pulmonary metastasis and the other had chemotherapy discontinued because of severe toxicity. Acute doxorubicin reactions were observed in one animal (6.25%) that showed ventricular premature complexes at the ECG immediately after de drug administration. Short-term toxicities were frequently observed. Hematological toxicity was observed in 15 animals (93.75%) one week after the chemotherapy administration. Leucopenia and neutropenia were observed in 14 dogs (87.5%). Thrombocytopenia was detected in 11 animals (68.75%). Five dogs (31.25%) presented grade 1 hematological toxicity; one grade 2 (6.25%); two grade 3 (12.5%) and 7 animals (43.75%) grade 4. Anemia was observed in 6 dogs (37.5%); but of those two were anemic before the first dose of doxorubicin. A delay of one week in the treatment was performed in only one animal that was with packed cell volume (PCV) of 23%. Twelve animals (75%) presented gastrointestinal toxicosis; showing signs as anorexia, vomiting and diarrhea. It was severe in 7 dogs, moderate in 3 and mild in 2 dogs. Sepsis was observed in only one animal after the first dose and the chemotherapy was suspended. However, other two dogs required hospitalization because of dehydration. Chronic doxorubicin toxicities were observed in 3 dogs that had hair loss as cutaneous lesions. None animal showed clinical signs of cardiac toxicity; nevertheless, ECG alterations were observed in 7 dogs (43.75%). Ventricular premature complexes were observed in 3 animals; in one immediately after doxorubicin administration and in 2 they appear in ECG after the third dose and one month after the therapy. Two dogs developed Mobitz type II second degree atrioventricular block at the nadir that disappeared one month after the treatment. One dog developed first grade atrioventricular block that persisted until the last ECG and one dog showed sinusal bradycardia only detected one month after the chemotherapy. Of the 16 dogs included in this study, 11 were alive and did not have evidenced signs of metastasis or recurrence 18 to 74 weeks after the beginning of treatment. One dog was euthanatized because of tumor local recurrence; one dog developed hemangiosarcoma and died; and the other 3 dogs died or were euthanatized because of pulmonary metastasis.
Discussion and Conclusions
The chemotherapeutic protocol used in this study was associated with substantial toxicity. Five animals (31.25%) had their treatment suspended because of doxorubicin toxicity, especially hematological and gastrointestinal. However, no animal died because of therapy complications. Three of them required hospitalization to receive adequate treatment because of dehydration and/or sepsis. According with other study, hospitalization was required in 3.5% of the chemotherapeutic cycles (Ahaus et al. 2000). Acute toxic effects of doxorubicin are uncommon in dogs (Phillips et al. 1998) and were observed only in one animal in this study. This dog showed signs of acute doxorubicin-induced cardiotoxicosis, with ventricular premature complexes in the ECG, but without clinical signs such as hypotension or weakness. In dogs this toxicity, in most cases, is transient, develops within minutes after IV administration and is not dose-related event (Souza & Camacho 2006). In this case, the arrhythmias disappeared one month after the chemotherapy. The low frequency of acute reactions may be explained by the use of antihistaminic blockade, since important vasoactive substances, such as histamine, are released after IV administration of doxorubicin (Souza & Camacho 2006). Beside this, the slow velocity of drug administration may contribute to rare occurrence of this type of toxicity (Davis 1983). On the other way, short-term toxicities were frequently observed. Both hematological and gastrointestinal alterations were observed in the first week after the treatments. These data differ from others authors were hematological toxicity (especially neutropenia) was observed in 50% of dogs treated with doxorubicin at a dosage of 30 mg/m2 (Ahaus et al. 2000). In our study, leucopenia and neutropenia were observed in 87.5% of the animals at the nadir, however, at the day 21 all dogs were recovered of these alterations and were able to receive another dose. With doses of 30 mg/m2, hematological changes consisting of leucopenia and thrombocytopenia are seen about 7 to 14 days post-treatment and were usually resolved by about 17 to 20 days post-treatment (Davis 1983, Silva et al. 2004). Moreover, these animals presented signs of gastrointestinal toxicity, as anorexia, vomiting and diarrhea. There was a positive correlation evidencing that the animals with severe neutropenia showed the more severe gastrointestinal toxicity. A delay in the treatment was required in only one dog because of anemia (PCV 23%). Anemia is not a frequent alteration observed in dogs treated with doxorubicin because of the erythrocytes median live of 120 days (Silva et al. 2004), but it was observed in six animals in this work. However, anemia is very frequent in dogs with cancer due a multifactorial etiology (Cançado & Chiattone 2002), as evidenced in two animals in this study, that were anemic before the beginning of the treatment. Chronic toxicity of doxorubicin was detected in 3 animals as hair loss. No dog developed cardiomyopathy, probably because the total cumulative dose of doxorubicin was 90 mg/m2.
Although some authors evidenced that cardiac alterations may develop in dogs receiving less than 90 mg/m2 (Mauldin et al. 1992). In this work, ECG abnormalities were detected in 6 dogs and may indicate chronic cardiotoxicosis. However, clinical signs of cardiomyopathy usually begin with cumulative doses of 150 mg/m2 (Mauldin et al. 1992). The toxicity observed in this study may be explained by the fact that small dogs are significantly more likely than large dogs to develop toxicoses when doxorubicin is administered at a dosage of 30 mg/m2 (Berg et al. 1995). Some authors recommend the dose of 1mg/kg for dogs with less than 20kg (Phillips et al. 1998). Thus, this work demonstrated the importance of monitoring doxorubicin protocols in dogs, specially for hematological, gastrointestinal and cardiac toxicities.
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