Drug Residues in Serum of Dogs Receiving Anticancer Chemotherapy

Background: The presence of drug residues in blood samples can represent an occupational hazard. However, studies on cytotoxic drug residues in serum of dogs are lacking in veterinary oncology. Objective: To evaluate possible occupational hazards associated with handling of blood samples from dogs receiving oncolytic drugs 7 days after treatment. Animals: Twenty‐seven client‐owned dogs treated for lymphoma or mast cell tumors with vincristine, vinblastine, cyclophosphamide, or doxorubicin. Methods: Prospective, observational study. Serum samples were either taken 7 days after administration of vincristine, cyclophosphamide, doxorubicin (lymphoma), and vinblastine (mast cell tumor), or 1–2 days after the last concurrent oral administration of cyclophosphamide (mast cell tumor). Additionally, serum was collected within 5 minutes of treatment. Measurement of drug residues in serum was performed by liquid chromatography tandem mass spectrometry (LC/MS/MS). Results: In 33 samples collected within 5 minute of treatment, the median serum concentrations were vincristine: 37 μg/L (range: 11–87 μg/L), vinblastine: 13 μg/L (range: 13–35 μg/L), cyclophosphamide: 2,484 μg/L (range: 1,209–2,778 μg/L), doxorubicin: 404 μg/L (range: 234–528 μg/L). In 81 serum samples collected 7 days after treatment vinblastine (7 μg/L) was detected in 1 sample, and cyclophosphamide (7 and 9 μg/L) in 2 samples collected 1–2 days after oral administration of cyclophosphamide. Medications were not detected in any of the other samples. Conclusions and Clinical Importance: Handling of blood samples from dogs receiving oncolytic chemotherapy 7 days after treatment with vincristine, vinblastine, cyclophosphamide, and doxorubicin should not present a health hazard.     

Cytotoxic Drug Residues in Urine of Dogs Receiving Anticancer Chemotherapy

The presence of cytotoxic drug residues in urine of dogs may represent an exposure risk for pet owners and other people as well as a potential environmental contaminant. However, studies on cytotoxic drug residues in excretions of clinical patients are lacking in veterinary oncology. Hypothesis: Variable concentrations of cytotoxic residues are present in urine samples, depending on sampling time and substance. Animals: Client‐owned dogs with lymphoma or mast cell tumors treated with standard chemotherapy protocols. Methods: Urine samples were collected before, directly after, and on days after administration of chemotherapy. Measurement of vincristine, vinblastine, cyclophosphamide, and doxorubicin residues in canine urine was performed by a quantitative liquid chromatography tandem mass spectrometry (LC/MS/MS) method. Results: Median cyclophosphamide residue concentration was 398.2 μg/L directly after treatment (d0) and was below the level of detection on days 1–3 (d1, d2, d3). Median vincristine residue concentration was 53.8 μg/L directly after treatment and was 20.2, 11.4, and 6.6 μg/L on days 1, 2, and 3. Median vinblastine residues were 144.9 (d0), 70.8 (d1), 35.6 (d2), and 18.7 μg/L (d3) with low concentrations detectable for 7 days after treatment. Median urine doxorubicin concentrations were 354.0 (d0), 165.6 (d1), 156.9 (d2), and 158.2 μg/L (d3). Low concentrations of doxorubicin were measurable up to 21 days after administration. Conclusions and Clinical Importance: Variable concentrations of chemotherapeutics were measured in urine samples, depending on sampling time point and drug. Findings may inform current chemoprotection guidelines and help minimize exposure risks.     

Efficacy and Toxicity of VAC Chemotherapy (Vincristine, Doxorubicin, and Cyclophosphamide) in Dogs with Hemangiosarcoma

Fifteen dogs with hemangiosarcoma were treated with a combination of vincristine, doxorubicin, and cyclophosphamide after incisional or excisional biopsy. The median survival for all fifteen dogs was 172 days (mean survival = 316 days). The median survival for those dogs with splenic hemangiosarcoma was 145 days (mean survival = 271 days) as compared with previously published median survival times in dogs with splenic hemangiosarcoma treated with surgery alone of 19 to 65 days. Toxicities included neutropenia (11/15), severe gastroenteritis (4/15), cardiotoxicity (3/15), and sepsis (2/15). The authors conclude that vincristine, doxorubicin, and cyclophosphamide chemotherapy may be an efficacious treatment modality in dogs with hemangiosarcoma and is associated with acceptable toxicity.     

Evaluation of a Multidrug Chemotherapy Protocol (ACOPA II) in Dogs With Lymphoma

A chemotherapeutic protocol using cyclophosphamide, vincristine, prednisone, doxorubicin, and L-asparaginase (ACOPA II) was evaluated in dogs with lymphoma. The response rate for 68 dogs treated with ACOPA II (complete remission [CR] 65%, partial remission [PR] 10%) was lower than that for 41 dogs treated with a related protocol previously evaluated (ACOPA I; CR 76%, PR 12%). Initial treatment with doxorubicin and prednisone did not decrease the prevalence or severity of toxicity during induction. The mortality during induction was 22%. The median duration of CR for dogs treated with ACOPA II was 9 months, with 40% still in remission at 1 year and 21% at 2 years. The rate of CR was lower for dogs with signs of illness at presentation (substage b ) and for dogs weighing less than 15 kg. Age was negatively correlated with survival time and duration of remission. Dogs with immunoblastic lymphoma had a more favorable prognosis than did those with lymphoblastic lymphoma. Survival times were also longer for dogs in substage a at presentation. Seven dogs in which treatment was discontinued while in remission had comparable remission duration to that achieved by dogs receiving long-term maintenance chemotherapy.     

Long‐Term Totally Implantable Venous Access Ports in Dogs and Cats Receiving Chemotherapy

Introduction:  We evaluated the totally implantable subcutaneous vascular access port (VAP) in 16 cancer patients undergoing intermittent chemotherapy for more than 30 months.
Methods:  Ports were surgically placed (The CompanionPort, Norfolk Vet Products, Skokie, Illinois 60076) in the jugular vein of 12 dogs and 4 cats between 1/2002 and 7/2004. Body weight determined polyurethane catheter size (4, 5, 7 fr.). The polysulfone port, surrounded by titanium, was anchored to subcutaneous tissue in the dorsolateral neck and confirmed with C‐arm fluoroscopy. All blood samples were obtained via VAP. Nine anticancer agents, other medications, crystalloids/colloids, and whole blood were administered. Ports were flushed every 4–5 weeks with heparinized saline solution (100 IU/ml). Removed catheters were submitted for bacteriology.
Results:  Seven of 16 animals are still alive. VAP were used for 1.5 to more than 30 months with 4–60 injections/port. Catheter tips were visualized from the left atrium distally into the caudal vena cava. Adverse events included post‐operative subcutaneous bruising and/or hematoma (4/16), difficult aspiration (4/16), catheter malposition (1/16), positional flushing (1/16), and occlusion requiring replacement (1/16). No thrombus formation or extravasation was evident. Bacterial colonization without signs of septicemia was observed in 3/4 catheters.
Conclusions:  VAP are an effective way of achieving long‐term venous access in the dog and cat. Complications are typically minor and infrequent.     

Pathology and Neurotoxicity in Dogs after Repeat Dose Exposure to a Serotonin 5-HT1B Inhibitor

AZD3783, a cationic amphiphilic drug and a potent inhibitor of the 5-hydroxytryptamine (5-HT_1B) receptor, was explored as a potential treatment for depression. To support clinical trials, repeat dose toxicity studies in rats and dogs were conducted. Here we report toxicity findings in dogs after dosing from 1 to 3 months. In the 1-month study, there were minimal neuronal vacuolation in the brain, a marked increase in liver enzymes accompanied by hepatocellular degeneration/necrosis and phospholipidosis (PLD), and PLD/cholecystitis in the gallbladder of animals dosed at 47 mg/kg/day. In the 3-month study, neurotoxicity resulted in euthanasia of one animal dosed at 30 mg/kg/day after 86 days. Extensive pathologic changes were seen in all animals in retina epithelium (inclusion bodies), brain (neuronal vacuolation, degeneration, or necrosis and nerve fiber degeneration), spinal ganglia (vacuolation, degeneration, or necrosis), as well as sciatic and optic nerves (degeneration). Pigment-laden macrophages were observed in the lung, kidney, liver, gallbladder, bone marrow, gastrointestinal tract, and lymphoid tissues. Also seen were vitrel and retinal hemorrhage in the eyes. A brain concentration and pathology study showed that the concentration of AZD3783 in the brain was approximately 4 times higher than in the plasma after 4 weeks of dosing, however, they were similar in all regions examined, and did not correlate with areas with pathologic findings. Our findings with AZD3783 in dogs have not been reported previously with other CNS compounds that effect through serotonergic pharmacology.     

Accidental 5-Fluorouracil Exposure in a Dog

objective: To demonstrate the range of toxicities with 5-Fluorouracil (5-FU).
Case Summary: A one-year-old male castrated Labrador Retriever presented to the University of Minnesota Veterinary Teaching Hospital Emergency Service following accidental ingestion of a 5% 5-Fluorouracil (5-FU) topical antineoplastic cream. The animal presented with status epilepticus and later demonstrated additional clinical signs consistent with 5-FU toxicosis including mucositis and diarrhea, profound but transient leukopenia, and thrombocytopenia.
New Information Provided: The calculated ingested dosage was 46 mg/kg. The dog responded well to intensive therapy, recovering uneventfully.     

Efficacy and Toxicity of Doxorubicin/Cyclophosphamide Maintenance Therapy in Dogs with Multicentric Lymphosarcoma

Doxorubicin/cyclophosphamide were evaluated as maintenance drugs for dogs with multicentric lymphosarcoma (n = 28). Median remission time of all dogs was 173 days. Remission duration was shorter, however, in dogs with stage IV/V disease, in dogs with pretreatment hypoalbuminemia, and in dogs that had received glucocorticoids before initiation of chemotherapy (P less than 0.04). Nineteen dogs were evaluable for toxicity. Dose-limiting gastrointestinal toxicosis was observed in three dogs, neutropenia was observed in three dogs, and cardiomyopathy was observed in three dogs. The doxorubicin/cyclophosphamide protocol described in this report is safe and effective in treating canine multicentric lymphosarcoma. Clinical stage, pretreatment steroid therapy, and hypoalbuminemia are prognostic factors for response to this protocol.     

Adverse Effects of Concurrent Carboplatin Chemotherapy and Radiation Therapy in Dogs

Background: Concurrent chemo- and radiotherapy improves outcome of certain human neoplasms but with increased signs of toxicity. Reports on adverse effects of concurrent chemo- and radiotherapy in the veterinary literature are scant.
Objective: To report adverse hematologic and gastrointestinal effects of combined carboplatin and radiation therapy in dogs.
Animals: Client-owned dogs with spontaneously occurring neoplasia.
Methods: Retrospective case study. Medical records of 65 dogs were reviewed. Criteria for inclusion were administration of radiation according to 1 of 3 fractionation schemes (19 × 3, 16 × 3, or 12 × 4 Gy) and administration of at least 1 concurrent carboplatin treatment at a dosage of 200–300 mg/m². Dog and treatment-related variables were analyzed for association with signs of intoxication.
Results: Median carboplatin dosage was 200 mg/m² (range, 200–250 mg/m²). Twelve of 58 dogs (21%) developed grade 3 or 4 neutropenia. Eleven of 56 dogs (20%) developed grade 3 or 4 thrombocytopenia. Six of 62 dogs (10%) developed grade 3, 4, or 5 gastrointestinal toxicosis. Analysis of association of dog and treatment-related variables with signs of intoxication was hampered by the small numbers of dogs in individual groups, and no statistically significant associations were found.
Conclusions and Clinical Importance: Combined modality therapy resulted in myelosuppression and gastrointestinal toxicosis. Future studies are needed to determine whether the potential benefit of combined modality therapy outweighs the risk of decreasing chemotherapy and radiation treatment intensity.     

Hemodynamic and Biochemical Alterations in Dogs with Lymphoma after Induction of Chemotherapy

Background

Doxorubicin is a common antineoplastic agent with dose‐dependent cardiotoxic adverse effects, and pre‐existing myocardial dysfunction is a contraindication to its use.

Objectives

To systematically define the hemodynamic and biochemical alterations in dogs undergoing chemotherapy for newly diagnosed lymphoma and assess the reversibility of these alterations with fluid administration.

Animals

Twenty‐one client‐owned dogs with newly diagnosed lymphoma were evaluated 1 week after induction of chemotherapy. Underlying degenerative valve disease was exclusionary. Eighteen healthy age‐ and weight‐matched dogs were used as controls.

Methods

Physical examination, blood pressure by Doppler, echocardiography, and biochemical evaluation (routine serum biochemistry, plasma renin activity and aldosterone concentrations, plasma and urine osmolalities, and urine electrolyte concentrations) were measured in dogs with lymphoma and compared to controls. Dogs with lymphoma received crystalloids IV at 6 mL/kg/h for 24 hours. All variables were reassessed at 4 and 24 hours. Deuterium oxide dilution and bromide dilution were used to determine total body water and extracellular water space, respectively.

Results

Baseline echocardiograms showed significantly smaller chamber dimensions in dogs with lymphoma compared to controls. These changes were reversed by fluid administration. Systolic blood pressure and urine sodium concentration were significantly increased, and bromide dilution space, PCV, urine specific gravity, and urine potassium concentration were significantly decreased compared to controls.

Conclusion and Clinical Importance

Echocardiographic and biochemical abnormalities in dogs with lymphoma appear consistent with volume depletion, and may be the result of systemic hypertension and subsequent pressure natriuresis.     

Cyclooxygenase Expression and Platelet Function in Healthy Dogs Receiving Low‐Dose Aspirin

Background

Low‐dose aspirin is used to prevent thromboembolic complications in dogs, but some animals are nonresponsive to the antiplatelet effects of aspirin (“aspirin resistance”).

Hypothesis/Objectives

That low‐dose aspirin would inhibit platelet function, decrease thromboxane synthesis, and alter platelet cyclooxygenase (COX) expression.

Animals

Twenty‐four healthy dogs.

Methods

A repeated measures study. Platelet function (PFA‐100 closure time, collagen/epinephrine), platelet COX‐1 and COX‐2 expression, and urine 11‐dehydro‐thromboxane B₂ (11‐dTXB₂) were evaluated before and during aspirin administration (1 mg/kg Q24 hours PO, 10 days). Based on prolongation of closure times after aspirin administration, dogs were divided into categories according to aspirin responsiveness: responders, nonresponders, and inconsistent responders.

Results

Low‐dose aspirin increased closure times significantly (62% by Day 10, P < .001), with an equal distribution among aspirin responsiveness categories, 8 dogs per group. Platelet COX‐1 mean fluorescent intensity (MFI) increased significantly during treatment, 13% on Day 3 (range, ?29.7–136.1%) (P = .047) and 72% on Day 10 (range, ?0.37–210%) (P < .001). Platelet COX‐2 MFI increased significantly by 34% (range, ?29.2–270%) on Day 3 (P = .003) and 74% (range, ?19.7–226%) on Day 10 (P < .001). Urinary 11‐dTXB₂ concentrations significantly (P = .005, P < .001) decreased at both time points. There was no difference between aspirin responsiveness and either platelet COX expression or thromboxane production.

Conclusions and Clinical Importance

Low‐dose aspirin consistently inhibits platelet function in approximately one‐third of healthy dogs, despite decreased thromboxane synthesis and increased platelet COX expression in most dogs. COX isoform expression before treatment did not predict aspirin resistance.

     

Basal and Glucagon-Stimulated Plasma C-PeDtide Concentrations in Healthy Dogs, Dogs With Diabetes Millitus, and Dogs With Hyperadrenocorticism

Serum glucose and plasma C-peptide response to IV glucagon administration was evaluated in 24 healthy dogs, 12 dogs with untreated diabetes mellitus, 30 dogs with insulin-treated diabetes mellitus, and 8 dogs with naturally acquired hyperadrenocorticism. Serum insulin response also was evaluated in all dogs, except 20 insulin-treated diabetic dogs. Blood samples for serum glucose, serum insulin, and plasma C-peptide determinations were collected immediately before and 5,10,20,30, and (for healthy dogs) 60 minutes after IV administration of 1 mg glucagon per dog. In healthy dogs, the patterns of glucagon-stimulated changes in plasma C-peptide and serum insulin concentrations were identical, with single peaks in plasma C-peptide and serum insulin concentrations observed approximately 15 minutes after IV glucagon administration. Mean plasma C-peptide and serum insulin concentrations in untreated diabetic dogs, and mean plasma C-peptide concentration in insulin-treated diabetic dogs did not increase significantly after IV glucagon administration. The validity of serum insulin concentration results was questionable in 10 insulin-treated diabetic dogs, possibly because of anti-insulin antibody interference with the insulin radioimmunoassay. Plasma C-peptide and serum insulin concentrations were significantly increased (P < .001) at all blood sarnplkg times after glucagon administration in dogs with hyperadrenocorticism, compared with healthy dogs, and untreated and insulin-treated diabetic dogs. Five-minute C-peptide increment, C-peptide peak response, total C-peptide secretion, and, for untreated diabetic dogs, insulin peak response and total insulin secretion were significantly lower (P < .001) in diabetic dogs, compared with healthy dogs, whereas these same parameters were significantly increased (P < .011 in dogs with hyperadrenocorticism, compared with healthy dogs, and untreated and insulin-treated diabetic dogs. Although not statistically significant, there was a trend for higher plasma C-peptide concentrations in untreated diabetic dogs compared with insulin-treated diabetic dogs during the glucagon stimulation test. Baseline C-peptide concentrations also were significantly higher (P < .05) in diabetic dogs treated with insulin for less than 6 months, compared with diabetic dogs treated for longer than 1 year. Finally, 7 of 42 diabetic dogs had baseline plasma C-peptide concentrations greater than 2 SD (ie, >0.29 pmol/mL) above the normal mean plasma C-peptide concentration; values that were significantly higher, compared with results in healthy dogs (P < .001) and with the other 35 diabetic dogs (P < .001). In summary, measurement of plasma C-peptide concentration during glucagon stimulation testing allowed differentiation among healthy dogs, dogs with impaired β-cell function (ie, diabetes mellitusl, and dogs with increased β-cell responsiveness to glucagon (ie, insulin resistance). Plasma C-peptide concentrations during glucagon stimulation testing were variable in diabetic dogs and may represent dogs with type-1 and type-2 diabetes or, more likely, differences in severity of β-cell loss in dogs with type-1 diabetes. J Vet Intern Med 1996;10:116–122. Copyright © 1996 by the American College of Veterinary Internal Medicine.     

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.     

Urinary and Plasma Catecholamines and Metanephrines in Dogs with Pheochromocytoma,Hypercortisolism, Nonadrenal Disease and in Healthy Dogs

Background

Diagnosis of pheochromocytoma (PC) is based on a combination of clinical suspicion, finding an adrenal mass, increased plasma, and urine concentrations of catecholamine metabolites and is finally confirmed with histopathology. In human medicine, it is controversial whether biochemically testing plasma is superior to testing urine.

Objectives

To measure urinary and plasma catecholamines and metanephrines in healthy dogs, dogs with PC, hypercortisolism (HC), and nonadrenal diseases (NAD) and to determine the test with the best diagnostic performance for dogs with PC.

Animals

Seven PC dogs, 10 dogs with HC, 14 dogs with NAD, 10 healthy dogs.

Methods

Prospective diagnostic clinical study. Urine and heparin plasma samples were collected and stored at −80°C before analysis using high‐pressure liquid chromatography (HPLC) coupled to electrochemical detection or tandem mass spectrometry were performed. Urinary variables were expressed as ratios to urinary creatinine concentration.

Results

Dogs with PC had significantly higher urinary normetanephrine and metanephrine : creatinine ratios and significantly higher plasma‐total and free normetanephrine and plasma‐free metanephrine concentrations compared to the 3 other groups. There were no overlapping results of urinary normetanephrine concentrations between PC and all other groups, and only one PC dog with a plasma normetanephrine concentration in the range of the dogs with HC and NAD disease. Performances of total and free plasma variables were similar. Overlap of epinephrine and norepinephrine results between the groups was large with both urine and plasma.

Conclusion and clinical importance

Measurement of normetanephrine is the preferred biochemical test for PC and urine was superior to plasma.