Cisplatin Therapy in 41 Dogs With Malignant Tumors

Forty-one dogs with a variety of histopathologically diagnosed, measurable tumors were treated with cisplatin (cis-diamminedichloroplatinum, Platinol, Bristol Laboratories, Syracuse, NY 13221-4755) as a single agent at a dosage of 60 mg/m2 given intravenously at 3-week intervals. In an attempt to avoid renal toxicity of cisplatin, saline diuresis was induced and maintained for 4 hours before and 2 hours following cisplatin administration. The dogs received one to ten doses of cisplatin. To determine response to therapy and to monitor toxicity of the drug, the dogs were evaluated with physical examinations including tumor measurements, radiography, complete blood counts, platelet counts, urinalyses, serum urea nitrogen concentrations, and serum creatinine concentrations. An overall response rate of 19% was observed. Complete remission occurred in one of 11 dogs with squamous cell carcinomas and one of one dog with a mediastinal undifferentiated carcinoma. Partial remissions were documented in one of 11 dogs with squamous cell carcinomas, two of three dogs with metastatic osteosarcomas, one of three dogs with nasal adenocarcinomas, and one of one dog with a thyroid adenocarcinoma. Toxic side effects were primarily gastrointestinal in nature, with vomiting occurring 1-6 hours after cisplatin administration in 27 of 41 dogs. Severe anorexia occurred in three dogs, and hemorrhagic diarrhea was observed in one dog. One dog developed grand mal seizures and died 3 hours following therapy. Granulocytopenia was documented in six dogs, and thrombocytopenia was observed in four dogs. One dog showed an increase in serum urea nitrogen and creatinine concentrations, but this patient had known pre-existing renal disease.(ABSTRACT TRUNCATED AT 250 WORDS)     

Canine Ehrlichiosis in Six Dogs with Persistently Increased Antibody Titers

Chronic ehrlichiosis was diagnosed in six dogs on the basis of increased immunofluorescent antibody titers to Ehrlichia canis. Although clinical signs varied, all six dogs were anemic, hyperglobulinemic, and an IgG monoclonal gammopathy was documented in five dogs in which serum protein electrophoreses were performed. All dogs were treated with tetracycline for at least 14 days; four dogs also received immunosuppressive drugs. Clinical signs resolved within 1 week, hematologic abnormalities resolved in 1 to 5 months, and increased globulin concentrations normalized in 1 to 15 months; however, E. canis antibody titers remained increased for 15 to 31 months after initiation of treatment. Results of this study show that increased E. canis titers can persist in dogs with ehrlichiosis for many months after clinical recovery.     

Lameness Associated with Coxofemoral Soft Tissue Masses in Six Dogs

Six cases of mechanical lameness involving the coxofemoral joint are presented. All dogs had a history of chronic rear leg pain and lameness, and decreased range of motion of the hip. On physical examination, ventral subluxation of the coxofemoral joint during extension was present in three dogs. A radiographic diagnosis of subluxation was made in five dogs. In each dog, surgical exploration of the area caudal to the coxofemoral joint revealed a fibrous mass between the lesser or third trochanters and the ischium, diagnosed as a nonneoplastic fibrous reaction by microscopic examination. The clinical, radiographic, and histopathologic signs were similar to previously described cases of myositis ossificans. Five dogs returned to normal function after excision of the soft tissue mass, and one dog was normal when lost to follow-up 4 weeks postoperatively.     

Evaluation of Intracavitary Chemotherapy Delivery for the Treatment of Mammary Carcinoma

Introduction:  The purpose of this study was to evaluate tolerability and efficacy of local (intracavitary) delivery of paclitaxel from a gel polymer (poloxamer 407) following marginal (histologically incomplete) resection of mammary carcinoma in a mouse model
Methods:  In vitro sensitivity to paclitaxel as well as poloxamer‐taxol mixture (polotax) was determined for 4 human breast tumor cell lines using the MTS‐assay (Promega). Nude mice were then injected with MCF‐7/ADR (Adriamycin^R resistant) cells. Tumor growth was monitored by imaging of luciferase activity with a CCD camera (IVIS system, Xenogen). Primary tumors were allowed to grow to 3 different size ranges. At the time of primary tumor resection, animals were randomly assigned to treatment groups comparing intracavitary (in the wound) polotax to intravenous paclitaxel. Mice were imaged weekly to evaluate tumor regrowth and metastasis.
Results:  All cells lines demonstrated sensitivity to paclitaxel and three of the four cell lines demonstrated improved cytotoxicity with polotax compared to drug delivered alone. One of 9 mice treated with polotax had local regrowth (by 60 days) compared to 6 of 9 mice treated with intravenous paclitaxel. One of 9 mice treated with polotax had distant metastasis at 60 days compared to 5 of 8 mice treated with intravenous paclitaxel. These effects were seen with tumors of all sizes.
Discussion/Conclusions:  Poloxamer delivery of paclitaxel appears to result in improved efficacy compared to paclitaxel alone. Improved local and systemic control of mammary carcinoma is seen following intracavitary poloxamer delivery of paclitaxel compared to paclitaxel alone in this mouse model.     

A Combination Chemotherapy Protocol (VELCAP-L) for Dogs with Lymphoma

Ninety-eight dogs with lymphoma treated with a 5-drug combination chemotherapy regimen (vincristine, L-asparaginase. cyclophosphamide, doxorubicin, prednisone [VELCAP-L]) were evaluated for pretreatment characteristics predictive for response and remission duration. The complete remission rate was 69%, with a median remission duration of 55 weeks. Dogs with advanced stage of disease, constitutional signs, dogs that were older, and dogs that were dyspneic were less likely to achieve remission. Once in remission, small dogs and dogs without pretreatment thrombocytopenia were likely to have longer remission duration. Toxicoses were frequent, but rarely fatal, and no predictitive factors were found for a dog developing toxicoses. VELCAP-L is an effective treatment for dogs in stage I-III lymphoma, particularly in young, small animals.     

Increase in Regulatory T Cells in Dogs with Cancer Undergoing Chemotherapy

Introduction:  Regulatory T cells (Treg) are a naturally occurring population of T cells phenotypically identified by co‐expression of CD4 and the IL‐2 receptor (CD25). Theyplay a critical role in the control of tolerance and autoimmunity and have also been implicated in impairment of anti‐tumor responses. We hypothesized that levels of Treg would be higher in cancer‐bearing dogs than in normal dogs and that they would decrease with chemotherapy.
Methods:  Serial PBMC were isolated from twenty cancer‐bearing dogs receiving either single‐agent doxorubicin or the Madison‐Wisconsin protocol. The following time points were studied: pre‐treatment, day 2, week 1, week 3, 3 months and 6 months after initial treatment. Ten age‐matched, normal dogs were also studied. PBMC were immunostained with directly conjugated antibodies to CD4, CD8, CD44 and IL‐2 receptor and then evaluated by flow cytometry.
Results:  Low numbers of lymphocytes with the CD4+/IL‐2R+ phenotype were detectable in both normal and cancer‐bearing dogs. A statistically significant increase in the percentage of IL2‐R+/CD4+ T cells was observed in the cancer‐bearing dogs beginning two days after chemotherapy and persisting throughout treatment. The percentage of IL‐2R+/CD4+ T cells was also increased in pre‐treated cancer‐bearing dogs compared to control dogs.
Conclusion:  The percentage of IL‐2R+/CD4+ T cells was generally higher in dogs with cancer than in healthy dogs. Unexpectedly, the percentage of IL‐2R+/CD4+ cells increased during chemotherapy which suggests that chemotherapy may exert immunosuppressive effects through a previously undescribed mechanism. The identity of these CD4+/IL‐2R+ T cells as true Treg awaits additional characterization studies.     

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.     

Efficacy and Toxicity of Intracavitary Administration of Pegylated Liposomal Encapsulated Doxorubicin (DOXIL) in Dogs with Hemangiosarcoma

Introduction:  Canine hemangiosarcoma (HSA) is a fatal malignancy and most dogs die within 6–8 months of diagnosis. The spleen is a common primary site, representing 50% of all cases. These dogs typically present with clinical signs due to tumor rupture and intra‐abdominal dissemination; the abdomen is also the main site of disease progression when these patients fail. Direct delivery of chemotherapy into the abdominal cavity may therefore be a rational approach in this malignancy.
Methods:  14 dogs with stage 2 or 3 splenic HSA were recruited. Doxil at a dose of 1 mg/kg was diluted in saline and administered via ultrasound‐guidance into the abdominal cavity. The dogs were scheduled to receive 4 treatments every 3 weeks. Samples of plasma and abdominal fluid were collected for pharmacokinetic analysis. All dogs were monitored for recurrence and complete necropsies were requested at death.
Results:  8 dogs with stage 3 and 6 dogs with stage 2 HSA were enrolled. All 14 dogs have died, 12/14 due to tumor and 2 from other causes. There was no difference in median survival days between stages (stage 2: 244, stage 3: 125, p = .22). All 12 dogs that died due to tumor‐related causes failed with intra‐abdominal recurrence. Necropsies showed that the dogs in this study had relatively fewer extra‐abdominal metastasis compared to dogs treated with systemic chemotherapy. Pk analysis showed detectable plasma doxorubicin 1 and 2 weeks after treatment.
Conclusion:  Direct abdominal administration of Doxil did not prevent intra‐abdominal recurrence; however, it appeared to provide effective systemic coverage.     

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.     

Experience with Cyclosporin-A After Renal Allografting in Two Dogs Research Note

After renal allografting, cyclosporin-A was administered to one partially nonmatched dog that was followed for 79 days. Cyclosporin-A and prednisolone were administered to one nonmatched dog that was followed for 805 days. Side effects encountered with cyclosporin-A included lymphocytic dermatitis, papillomatosis, bacterial and fungal infections, and B lymphocyte hyperplasia.     

Kirschner-Ehmer Apparatus Immobilization Following Achilles Tendon Repair in Six Dogs

Postoperative immobilization is an essential part of the management of Achilles tendon injuries. Results are reported in six dogs managed with the Kirschner-Ehmer apparatus for immobilization of the tarsus as an alternative to the use of casts or splints. In all six dogs, good to excellent function was restored to the limbs after removal of the Kirschner-Ehmer apparatus. There were no immobilization or tenorraphy failures.     

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.     

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.     

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.     

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.     

Laparoscopic Cholecystectomy for Management of Uncomplicated Gall Bladder Mucocele in Six Dogs

Objectives— To describe a technique for, and outcome after, laparoscopic cholecystectomy (LC) for management of uncomplicated gall bladder mucocele (GBM) in dogs. Study Design— Case series. Animals— Dogs (n=6) with uncomplicated GBM. Methods— Dogs with ultrasonographic evidence of GBM but without imaging or laboratory signs of gall bladder rupture, peritonitis, or extra‐hepatic biliary tract rupture that had LC were included. A 4 portal technique was used. A fan retractor was used to retract the gall bladder to allow dissection around the cystic duct with 5 or 10 mm right‐angle dissecting forceps. The cystic duct was ligated using extracorporeally tied ligatures supplemented sometimes with hemostatic clips. A harmonic scalpel was used to dissect the gall bladder from its fossa. The gall bladder was placed into a specimen retrieval bag and after bile aspiration the bag was withdrawn through the 11 mm portal incision. Results— Five dogs had mild intermittent clinical signs including vomiting, inappetence, and lethargy. All dogs had successful LC without conversion to an open approach. All dogs with clinical signs had improvement or resolution of signs postoperatively. No important perioperative complications occurred and all dogs were alive at a median of 8 months postoperatively (range, 3–14 months). Conclusions— LC can be accomplished safely and effectively in dogs with uncomplicated GBM. Clinical Relevance— A minimally invasive approach for cholecystectomy can be used for the treatment of GBM in dogs.