Noninvasive monitoring of doxorubicin cardiotoxicity: a pilot study of two dogs

The cardiotoxicity of anthracycline anticancer agents, most notably doxorubicin, limits their use in treating a wide variety of cancers. Currently available methods for assessment of anthracycline‐induced cardiotoxicity (AIC) often lack specificity and sensitivity. The purpose of this pilot investigation was to determine noninvasive diagnostic methods that are predictive for AIC. Two mongrel dogs were anesthetized for injection of doxorubicin (22.5 mg) directly into the left coronary artery. Doxorubicin injection was repeated 2 weeks later. Dogs were followed for 12 weeks or until heart failure was documented. Dogs were monitored before and at serial time points after doxorubicin using echocardiography and signal‐averaged electrocardiography as well as ambulatory ECG monitoring. Blood was also collected for measurement of cardiac troponin I and T concentrations. Doxorubicin was readministered at 6 and 12 weeks after the second injection, as interim data analysis did not reveal adequate evidence of cardiomyopathy. Dog‐1 appeared to be more sensitive than Dog‐2 to AIC based upon gradual changes in variables of cardiac function and earlier time to failure (113 days). In contrast, Dog‐2 had inconsistent changes in cardiac function and a longer time to failure (139 days). Dog‐1 also had greater peak plasma cardiac troponin I levels (17.96 ng/ml) as compared to peak levels in Dog‐2 (4.08 ng/ml). In addition, Dog‐1 had increased ventricular extrasystolic contractions (VE)(0/day at baseline, 443/day one week prior to death), whereas dog‐2 showed very few VE's throughout. Spectral analysis of ECG data also revealed a significant decrease over time in total spectral power in Dog‐1 from 37,148 at baseline to 603 msec²/Hz one week prior to death, indicating decreased parasympathetic tone. Endomyocardial biopsies revealed minor changes despite significant clinical abnormalities. These data indicate differences in susceptibility to AIC between Dog‐1 and Dog‐2, and suggest a role for these noninvasive measures in monitoring the heart during chemotherapy.     

Cardiac troponin I in canine patients with lymphoma and osteosarcoma receiving doxorubicin: comparison with clinical heart disease in a retrospective analysis

The cumulative cardiotoxicity that occurs as a result of doxorubicin chemotherapy is irreversible and can affect both quality and quantity of life for the cancer patient. Cardiac troponin I (cTnI) is a sensitive and specific marker of cardiomyocyte death. The purpose of this retrospective study was to evaluate serum concentrations of cTnI in dogs with lymphoma or osteosarcoma given doxorubicin chemotherapy, and with known cardiac outcome, based on a minimum assessment by physical examination and thoracic radiography. Serum samples were also available for cTnI measurement from seven healthy dogs given intracoronary doxorubicin. Serial serum samples obtained before, during and after doxorubicin chemotherapy showed increased cTnI concentrations in some clinical patients following chemotherapy (P = 0.0083 compared to baseline), but this did not correlate with clinical signs of cardiomyopathy. In dogs that subsequently developed cardiomyopathy however, serum cTnI concentrations were elevated before clinical signs became evident (confirmed with echocardiography).     

Clinical Evaluation of Tavocept to Decrease Diuresis Time and Volume in Dogs with Bladder Cancer Receiving Cisplatin

Background

Transitional cell carcinoma is the most common bladder cancer of dogs. Cisplatin combined with piroxicam provides superior response rates, but unacceptable rates of nephrotoxicity. Tavocept is a chemoprotectant that has mitigated cisplatin toxicity and decreased the required infusion/diuresis volume in clinical trials in humans.

Hypothesis/Objectives

We hypothesized that Tavocept would decrease diuresis volume and time and facilitate safe administration of a cisplatin/piroxicam protocol to dogs with bladder cancer. Secondary objectives were to compare response rate and survival times to an historical comparator group treated without Tavocept.

Animals

Fourteen client‐owned dogs were prospectively enrolled.

Methods

Tumor volume was measured by computed tomography at days 0, 42, and 84. Dogs received combination Tavocept/cisplatin with a shortened diuresis protocol. A total of 4 doses was planned, with concurrent administration of piroxicam. Serial biochemical analyses were evaluated for azotemia.

Results

A 90‐minute infusion/diuresis time was used for all dogs. Three dogs (21%) had concurrent increases in serum creatinine (>2.0 mg/dL) and BUN (>42 mg/dL) concentrations; 2 of these dogs were isosthenuric. This frequency of nephrotoxicity is significantly less (P = 0.0406) than that of an historical control group treated without Tavocept. Overall response rate was 27%. Median survival time was comparable to historical controls (253 vs. 246 days).

Conclusions and Clinical Importance

Tavocept decreased the required diuresis time with cisplatin from > 6 hours to 90 minutes, while also decreasing occurrence of azotemia. Survival time was comparable, but the response rate was inferior to an historical comparator group. Further evaluation in other tumors susceptible to platinum agents is warranted.     

Outcome of 19 dogs with parathyroid carcinoma after surgical excision

Parathyroid carcinoma (PTC) is rare in dogs and there is little information documenting its treatment and prognosis. The objective of this study was to describe the outcome of dogs with PTC treated with surgical excision. Medical records of 19 dogs undergoing surgical excision of PTC between 1990 and 2010 were reviewed retrospectively. Dogs were presented for clinical hypercalcaemia or incidental hypercalcaemia noted by referring veterinarians on routine serum chemistry profiles. A parathyroid nodule was identified with cervical ultrasound in 17/17 dogs. Hypercalcaemia resolved in 18/19 dogs within 4 days postoperatively. Nine developed hypocalcaemia. None were confirmed to develop recurrent or metastatic PTC. The only death associated with PTC was a dog that was euthanized for intractable hypocalcaemia 9 days after surgery. Estimated 1-, 2- and 3-year survival rates were 72, 37 and 30%, respectively. Excision of PTC results in resolution of hypercalcaemia and excellent tumour control.     

Treatment of a malignant pheochromocytoma in a dog using 131I metaiodobenzylguanidine

A 12 yr old castrated male Yorkshire terrier was presented with a history of an inoperable pheochromocytoma. Physical examination revealed a large, midabdominal mass. Neurologic examination was normal at presentation. An abdominal computed tomography scan revealed a 215 cm(3) mass in the region of the right kidney. Forty-eight hours after IV injection of 370 megabecquerels (MBq, equivalent to10 millicuries [mCi]) of metaiodobenzylguanidine labeled with radioactive iodine ([(131)I]MIBG), standard planar scintigraphy was performed. A diffuse area of moderate uptake was noted in the midabdominal region. The dog experienced stable disease for 1.5 mo after injection based on a follow-up computed tomography (CT) scan; however, 5 mo after injection, repeat CT imaging revealed progression of the tumor, and a second IV injection of 370 MBq (10 mCi) of [(131)I]MIBG was administered. The dog died 3 wk after the second injection as a result of gastrointestinal blood loss that was believed to be caused by compression-induced bowel ischemia by the mass. A full necropsy was not performed, but the mass was removed for histologic evaluation, which confirmed the diagnosis of pheochromocytoma. This report is the first to document the treatment of canine pheochromocytoma using [(131)I]MIBG.     

Intraarticular injection of a Tin‐117 m radiosynoviorthesis agent in normal canine elbows causes no adverse effects

This longitudinal prospective exploratory study used serial measurements in five dogs to evaluate safety and retention of a tin‐117 m (^117mSn) colloid after intra‐articular injection in normal elbow joints. Each dog was deemed healthy based on physical examination, laboratory results, and radiographic evaluation of both elbows. While anesthetized, each received an MRI of both elbows, followed by fluorine‐18 fluorodeoxyglucose positron emission tomography scans of both elbow joints and associated lymph nodes. Joint fluid (0.5‐1.0 mL) was withdrawn aseptically from the left elbow joint, followed by intra‐articular injection of ^117mSn colloid (92.5 MBq; 1‐1.5 ml). Post‐injection assessments included blood counts, serum chemistry panels, urinalyses, radiographs, joint fluid analyses, MRI/positron emission tomography scans, scintigraphy, and biodistribution scans. On day 45‐47, each dog was euthanized and a complete postmortem examination was performed. Tissue samples were submitted for histopathology and radioisotope retention studies. Left elbow joints were decalcified and sectioned for future autoradiography. Scintigraphy, 1 day after injection, indicated slight radioisotope escape from the joint to regional lymph nodes. Serial blood, urine, feces, and organ counts indicated >99.1% of the ^117mSn activity was retained in the joint for 45‐47 days. Radiation output levels were below patient release levels the day following injection. Maximum standard uptake value for the injected joint decreased. Joint fluid cytology was unchanged. No dog exhibited lameness during the study. Absence of joint damage and lack of systemic effects after injection of the ^117mSn colloid in normal canine elbow joints indicate that this agent may be safely used for radiosynoviorthesis in dogs with osteoarthritis.     

Safety evaluation of combination vinblastine and toceranib phosphate (Palladia®) in dogs: a phase I dose-finding study

Combining drugs with known single-agent activity that lack overlapping dose-limiting toxicities (DLT) and exert antitumour activity through different mechanisms could improve clinical outcome. As toceranib and vinblastine meet these requisites, a phase I trial was performed in combination in dogs with mast cell tumours. The DLT for the simultaneous combination was neutropenia and the maximally tolerated dose was vinblastine (1.6 mg m(-2) every other week) concurrent with toceranib (3.25 mg kg(-1) PO, every other day). This represents greater than a 50% reduction in dose intensity for vinblastine (compared with single-agent use) and as such does not support this combination based on current drug combination paradigms. Although a strict adherence to dose paradigms speaks against the combination, evidence of significant activity (71% objective response) and enhanced myelosuppression suggest additive or synergistic activity. A prospective randomized evaluation comparing this combination with standard single-agent treatments would seem prudent to interrogate this potential.     

Serum alhpa 1-acid glycoprotein concentrations in healthy and tumor-bearing cats

The purpose of this study was to evaluate alpha 1-acid glycoprotein (AGP) concentrations in tumor-bearing and healthy cats. The hypothesis of the present study was that AGP concentrations would be significantly increased in tumor-bearing cats. Serum from 51 healthy and 97 tumor-bearing, client-owned cats was harvested at the time of presentation and stored at -80 degrees C until assayed. Cats with measurable, histologically confirmed malignancies, and healthy cats of similar ages were included. Serum was assayed for AGP concentration by using a radial immunodiffusion method. AGP concentrations were significantly (P = .0051) higher in tumor-bearing (763 +/- 595 microg/mL; mean +/- SD) when compared to healthy cats (501 +/- 377 microg/mL; mean +/- SD). Of the tumor-bearing cats, 35 had carcinomas, 33 had sarcomas, and 26 had discrete, round cell tumors. AGP concentrations were 645 +/- 62 microg/mL, 660 +/- 540 microg/mL, and 967 +/- 860 microg/mL, respectively, and there were no significant differences among the groups.