Combined Gemcitabine and Carboplatin Therapy for Carcinomas in Dogs

Background: Response and adverse reactions to combined gemcitabine (GEM) and carboplatin (CARBO) therapy in dogs with carcinomas are not documented.
Hypothesis: GEM and CARBO are safe for the treatment of dogs with carcinomas.
Animals: Thirty-seven dogs with histologically or cytologically confirmed carcinomas.
Methods: Prospective clinical trial. Dogs were treated with GEM (2 mg/kg, 20–30-minute infusion IV) on Days 1 and 8 and 4 hours later, CARBO (10 mg/kg IV) on Day 1. The cycle was repeated on Day 22.
Results: Thirty-seven dogs (29 with measurable tumor) received a median of 2 cycles (range 0.5–6) for a total of 101 cycles administered. Twelve dogs (32%) developed neutropenia (3 Grade 3, and 5 Grade 4) and 9 (24%) thrombocytopenia (2 Grade 3, and 1 Grade 4). Dogs >20 kg were twice as likely to develop thrombocytopenia ( P = .023). Twenty-seven dogs (73%) had evidence of gastrointestinal (GI) toxicosis, but most signs were of mild to moderate severity and self-limiting. One dog died of treatment-related complications. Overall tumor response rate was 13%. One dog with metastatic prostatic carcinoma achieved a complete remission and 1 dog with intestinal adenocarcinoma and 1 with tonsillar squamous cell carcinoma achieved partial remission. Twelve dogs achieved stable disease for a median of 72 days.
Conclusion and Clinical Importance: GEM and CARBO combination causes mild to moderate hematologic and GI toxicosis in dogs with carcinoma. Response rate in this study was modest, and optimization of dosing of this combination is required.     

Hypofractionated Radiation Therapy of Brain Masses in Dogs: A Retrospective Analysis of Survival of 83 Cases (1991–1996)

There are few reports of radiation treatment for brain tumors in dogs, and the optimal treatment protocol has yet to be established. We completed a retrospective analysis of the survival times of a series of 83 dogs with intracranial masses that were treated by hypofractionated megavoltage radiation therapy. A total tumor dose of 38 Gray was given over 5 weeks as once weekly fractions via 3 perpendicular portals. The median survival time from the start of radiotherapy for the whole cohort was 43.7 weeks (range, 0.1-172 weeks). Extra-axial masses had a better survival time (49.7 weeks) than did other intracranial masses (intra-axial, 40.4 weeks; pituitary, 21.0 weeks). Delayed radiation toxicity was suspected as the cause of death or reason for euthanasia in 12 dogs. The hypofractionated radiation protocol resulted in survival times similar to those obtained using more conventional multifractionated regimens, and this protocol may be a useful, less intensive alternative treatment for brain tumors in dogs.     

Dacarbazine as Single-Agent Therapy for Relapsed Lymphoma in Dogs

Background: Multidrug resistance is the most common cause of treatment failure in dogs with multicentric lymphoma. 5-(3,3-Dimethyl-1-triazeno)-imidazole-4-carboxamide (DTIC) is an atypical alkylator used as standard treatment in human Hodgkin's lymphoma, and has been effective in combination treatment to treat resistant lymphoma in dogs. However, no data are available on the use of DTIC as a single agent in the treatment of relapsed canine lymphoma.
Hypothesis: Single-agent DTIC is effective and safe in treating dogs with lymphoma that relapsed or failed to respond to previous chemotherapy.
Animals: Forty client-owned dogs with relapsed lymphoma.
Methods: Dogs were eligible for the retrospective study if they had a histologically or cytologically confirmed diagnosis of lymphoma and had relapsed. Dogs received DTIC (800–1,000 mg/m² every 2–3 weeks as a 4–5-hour IV infusion) and were evaluated for response rate and duration. Hematologic and gastrointestinal toxicity was assessed.
Results: The overall response rate for dogs being treated with DTIC was 35% (14 dogs) with a median progression-free interval of 43 days. Thirteen dogs had a partial response and 1 dog had a complete response. Stable disease was achieved in 3 dogs. Mild gastrointestinal toxicity was reported in 3 dogs posttreatment. Thrombocytopenia was the principal toxicity observed 7–14 days after the treatment. Treatments were delayed because of thrombocytopenia.
Conclusions: DTIC, when used alone, is effective in the treatment of dogs with relapsed lymphoma.     

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.     

Retrospective study of orthovoltage radiation therapy for nasal tumors in 42 dogs

Megavoltage radiation therapy currently is the standard of care for dogs with nasal tumors. Some studies report that surgery and adjunctive orthovoltage radiation therapy result in longer control of these tumors than does megavoltage radiation therapy alone. This study reports less effective control of nasal tumors in dogs treated with surgery and orthovoltage radiation than previously observed, supporting the superiority of megavoltage radiation therapy for these tumors. In addition, this study suggests 2 new prognostic indicators for dogs with nasal tumors and describes toxicity associated with surgery and orthovoltage therapy. Forty-two dogs with nasal tumors were treated with surgical cytoreduction and 48 Gy orthovoltage radiation therapy administered in twelve 4-Gy fractions. Median survival was 7.4 months. One- and 2-year survival rates were 37% and 17%, respectively. Dogs with facial deformity had shorter survival than those without deformity (P = .005). Dogs with resolution of clinical signs after treatment had longer survival than those with chronic nasal signs (P = .0001). Acute radiation toxicity was moderate to severe for skin and eye and negligible for oral mucosa. Toxicity healed within 1 month after radiation therapy. Late toxicity was mild, but 70% of evaluable dogs experienced persistent ocular signs. Only 39% of dogs achieved a disease-free period.     

Cisplatin and doxorubicin toxicosis in dogs with osteosarcoma

Toxicosis associated with doxorubicin and cisplatin administration starting either 2 or 10 days after limb amputation for osteosarcoma was examined retrospectively in dogs. The purpose was to determine whether dosage and timing of chemotherapy affected rates of toxicosis after administration of the 1st treatment. Records of 100 dogs with appendicular osteosarcoma without evidence of metastases or concurrent disease were examined. Dogs received chemotherapy with doxorubicin and cisplatin every 3 weeks for 3 treatments starting 2 days (n = 51) or 10 days (n = 49) after amputation. The dosage of cisplatin was 60 mg/m2 and was given with 6-hour saline diuresis and butorphanol. Doxorubicin was given at 12.5-25 mg/ml during fluid administration. Hematologic data were collected before and weekly after treatment. Client interviews were conducted to assess gastrointestinal toxicosis during the interval between treatments. The reported toxicoses were graded on a scale of 0 to 4. Dogs receiving 25 mg/m2 of doxorubicin experienced greater rates of grade 4 toxicity (67%; n = 6) than dogs in groups receiving 12.5-20 mg/m2 of doxorubicin (< or = 25%; n = 94, P = .03). Dogs in the Day 2 group experienced greater rates (35%) of grade 4 toxicity than dogs in the Day 10 group (12%, P = .007). We concluded that chemotherapy administered 2 days after surgery produced an unacceptable level of toxicoses. except at greatly reduced dosages, and that even with a delay of treatment, 25 mg/m2 of doxorubicin, when given in combination with cisplatin at 60 mg/m2, was too toxic for routine use.     

Infrared Thermography in Dogs with Mammary Tumors and Healthy Dogs

Background

Infrared thermography is a painless, noninvasive, nonionizing diagnostic imaging exam used in human medicine as an auxiliary tool for breast cancer diagnosis in women.

Hypothesis/Objectives

Define thermographic mean temperatures of healthy mammary glands and compare these temperatures with those of mammary glands with tumors in dogs.

Animals

Fifty client‐owned female dogs were evaluated, including 20 with histopathologically confirmed mammary tumor and 30 clinically healthy (control).

Methods

A randomized study using infrared thermography analyzed each mammary gland of the animals from the control group and mammary glands with tumors from the tumor group, then the thermographic temperatures obtained were compared. Thermographic exam was performed in a temperature‐controlled room with a cooled thermographic camera—Flir E‐40 (Flir Systems^®)

Results

There was significantly a higher temperature in the caudal abdominal and inguinal mammary glands than the other glands in the healthy group (P < .05). Dogs with mammary tumors had significantly higher thermographic temperature compared with unaffected glands regardless of the tumor size and the location (P < .05).

Conclusions and clinical importance

The technique seems to be able to assess for the presence of neoplasia within the mammary tissue in bitches. Further investigation is necessary to determine the impact of this technique when adopted clinically.     

Decreased Ratio of CD8+ T Cells to Regulatory T Cells Associated with Decreased Survival in Dogs with Osteosarcoma

Background: Increased numbers of regulatory T cells (Treg) and decreased ratios of CD8+ T cells to Treg have been shown to correlate with decreased survival times (ST) in humans with certain malignancies. A possible connection between Treg and ST in dogs with cancer has not been investigated previously. Hypothesis: The purpose of this study was to compare numbers of Treg and T lymphocyte subsets in dogs with osteosarcoma (OSA) to those of healthy dogs and to determine whether pretreatment values were associated with disease‐free interval or with ST. We hypothesized that Treg numbers would be increased in dogs with cancer and that dogs with a high percentage of Treg would have a poorer prognosis. Animals: Twelve client‐owned dogs with appendicular OSA were entered into a prospective clinical trial. Twenty‐two healthy dogs were used as controls. Methods: The percentages and numbers of Treg and CD4+ and CD8+ T cells in blood, lymph nodes, and tumors were determined with flow cytometry and compared between dogs with OSA and control dogs. Results: Dogs with OSA had significantly fewer circulating CD8+ T cells and significantly more Treg compared with healthy dogs. The CD8/Treg ratio also was significantly lower in dogs with OSA compared with control dogs. In dogs with OSA, a decreased CD8/Treg ratio was associated with significantly shorter STs. Conclusions: These data support a role for Treg in the immune control of canine OSA and suggest that determination of the CD8/Treg ratio may be useful for assessing outcomes.     

Changes in Regulatory T Cells in Dogs with Cancer and Associations with Tumor Type

Background: Regulatory T cells (Treg) have been shown to suppress antitumor immunity and often are increased in humans and rodents with cancer. However, Tregs have not been well studied in dogs with cancer and it is not known if certain tumor types are associated with increased Tregs.
Hypothesis: We hypothesized that Treg percentages would be increased in dogs with cancer and that Treg percentages would be higher in dogs with certain types of cancer.
Animals: The percentages and numbers of Tregs and nonregulatory T cells and B cells were assessed in 34 dogs with cancer and 9 age-matched control dogs. Dogs evaluated included 14 dogs with sarcoma, 7 dogs with carcinoma, 7 dogs with lymphoma, and 6 dogs with mast cell tumor.
Methods: Numbers and percentages of Tregs, CD4⁺, and CD8⁺ T cells and B cells were determined using flow cytometry and compared between control dogs and dogs with cancer.
Results: The percentage of Tregs was significantly increased overall in dogs with cancer compared with control dogs. When tumor types were compared, Treg percentages were significantly increased in dogs with carcinoma. The Treg/CD8 T cell ratio was significantly higher in dogs with cancer compared with control dogs and was also significantly increased in 2 dogs with T-cell lymphoma.
Conclusions: Treg percentages in blood were increased in dogs with cancer, particularly in dogs with carcinoma. The Treg/CD8 ratio also identified tumor-specific abnormalities in dogs with cancer. These findings indicate that tumor-specific factors may affect Tregs in dogs.     

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.     

Concurrent Diseases and Conditions in Dogs with Splenic Vein Thrombosis

Background: Splenic venous thrombosis (SVT) is usually considered an incidental finding on abdominal ultrasound examination but can indicate the presence of underlying disease. Concurrent disease processes and conditions in dogs with SVT have not been identified previously. Objectives: To identify concurrent diseases and conditions in dogs with SVT. Animals: Eighty dogs with SVT. Methods: Retrospective review. Medical records from 1994 through 2008 were searched for dogs with SVT identified by ultrasound examination. These records were then reviewed for signalment, medical history, clinicopathologic testing, diagnostic imaging, and clinical diagnosis. Results: The most common concurrent conditions were neoplasia (54%), exogenous corticosteroid administration (43%), systemic inflammatory response syndrome (26%), disseminated intravascular coagulation (20%), pancreatitis (18%), and immune‐mediated disease (16%). The most common neoplastic disease was lymphoma, and the most common immune‐mediated disease was immune‐mediated hemolytic anemia. Protein‐losing nephropathy and naturally occurring hyperadrenocorticism were identified in <10% of the dogs. Concurrent splenic infarcts were identified in 33% of dogs, and concurrent portal vein thrombi were found in 18% of dogs. Conclusions: SVT is a sonographic finding of clinical importance, and dogs with SVT can have 1 or more coexisting diseases.     

Efficacy of Combination Chemotherapy for Treatment of Gastrointestinal Lymphoma in Dogs

Background: Chemotherapy for multicentric canine lymphoma has favorable results. The gastrointestinal (GI) tract is the most common extranodal site of canine lymphoma, but there have been no prospective studies to determine outcome when dogs with GI lymphoma are treated with chemotherapy.
Hypothesis: Treatment with a multiagent chemotherapy protocol is associated with a poor outcome in dogs with GI lymphoma.
Animals: Eighteen dogs with histologically confirmed GI lymphoma.
Methods: Prospective clinical trial in which dogs with GI lymphoma were treated with a 20-week combination chemotherapy protocol consisting of induction and consolidation phases.
Results: Thirteen dogs had primary GI lymphoma and 5 had multicentric lymphoma with GI involvement. The majority of the lymphomas (63%) were of T-cell origin. Overall remission rate was 56%; 9 dogs achieved a complete remission for a median of 86 days (range, 22–420 days) and 1 dog achieved a partial remission for 26 days. Overall median survival time was 77 days (range, 6–700 days). Dogs that failed to achieve a remission (10 versus 117 days; P = .002) or had diarrhea at initial presentation (70 versus 700 days; P < .001) had shorter survival times.
Conclusion and Clinical Importance: The response and survival of dogs with GI lymphoma treated with multiagent chemotherapy is poor but long-term survival is possible.     

Effects of Maropitant Citrate or Acepromazine on the Incidence of Adverse Events Associated with Hydromorphone Premedication in Dogs

Background

Vomiting is a common complication associated with the use of hydromorphine for pre‐emptive analgesia in dogs. The ideal anti‐emetic protocol for prevention of this complication has not been established.

Hypothesis

Maropitant administered concurrently or before hydromorphone would reduce the incidence of vomiting, signs of nausea, ptyalism, and increased panting compared to administration of acepromazine or a 0.9% saline control.

Animals

Sixty mixed‐breed female dogs scheduled for ovariohysterectomy.

Methods

Randomized, blinded, placebo‐controlled experimental study. Dogs were assigned to 4 experimental groups with 15 dogs per group. All groups received 0.2 mg/kg of hydromorphone IM. Group “Control” received 0.1 mL/kg saline SC 30–45 minutes before hydromorphone, group “Marop1” received 1 mg/kg maropitant SC 30–45 minutes before hydromorphone, group “Ace” received 0.02 mg/kg IM acepromazine 30–45 minutes before hydromorphone, and group “Marop2” received 1 mg/kg SC maropitant concurrently with hydromorphone. A trained and blinded observer documented adverse events from the time hydromorphone was administered until the time dogs were induced for surgery.

Results

Marop1 had significantly less vomiting (0%) compared to Control (87%; P < .01) and Ace (53%; P < .01). Marop2 had significantly less vomiting (27%) compared to Control (P < .01). Marop1 had significantly greater incidence of ptyalism (73%) compared to Ace (P < .01; 20%). Ace showed significantly less panting (33%) compared to Marop2 (93%; P < .01).

Conclusions and Clinical Importance

In healthy dogs, maropitant citrate administered before hydromorphone significantly decreases the incidence of vomiting in dogs but does not improve signs of nausea, ptyalism, or increased panting.     

Systematic Review of Nonsteroidal Anti‐Inflammatory Drug‐Induced Adverse Effects in Dogs

The aim of this systematic review was to identify, assess, and critically evaluate the quality of evidence of nonsteroidal anti‐inflammatory drug (NSAID)‐induced adverse effects in dogs. Original prospective studies published in peer‐reviewed journals in English (1990–2012) that reported data on the safety of NSAIDs administration in dogs were searched. For each study, design type (I, II, III, or IV) and assessment of quality (+, Ø, ?) were rated. For each drug, quantity and consistency rating (***, **, *) and strength of evidence (high, moderate, low, or extremely low) were identified and evaluated. The strength of evidence was defined in terms of how applicable and relevant the conclusions were to the target population. Sixty‐four studies met the inclusion criteria. Thirty‐five (55%) research studies and 29 (45%) clinical trials were identified. A high strength of evidence existed for carprofen, firocoxib, and meloxicam; moderate for deracoxib, ketoprofen, and robenacoxib; and low for etodolac. Quality and consistency rating were as follows: carprofen (***/***), deracoxib (**/***), etodolac (*/unable to rate), firocoxib (***/**), ketoprofen (**/***), meloxicam (***/***), and robenacoxib (**/**), respectively. Adverse effects were detected in 35 studies (55%) and commonly included vomiting, diarrhea, and anorexia. Three studies (5%) reported a power analysis related to adverse effects of ≥80%. In randomized, placebo‐controlled, blinded studies (n = 25, 39%), the incidence of adverse effects was not statistically different between treated and control dogs. Finally, most studies were not appropriately designed to determine the safety of NSAIDs, and involved a healthy nongeriatric population of research dogs.