Lomustine (CCNU) for the Treatment of Resistant Lymphoma in Dogs

Forty-three dogs with lymphoma that had relapsed or had failed to achieve complete remission to previous chemotherapy were treated with lomustine (1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea [CCNU]) at a dosage of 90-100 mg/m2 body surface area p.o. every 3 weeks. Durable complete or partial responses occurred in 11 dogs for a median of 86 days. The acutely dose-limiting toxicosis was neutropenia 7 days after administration, resulting in a recommended dosage of 90 mg/m2. Cumulative thrombocytopenia occurred in dogs receiving continued CCNU treatment, and a dose interval of 3 weeks may be too short for continued administration of this drug. Toxicoses evident as fever or central nervous system signs or renal damage were uncommon or rare. CCNU is effective in the treatment of relapsed lymphoma.     

Antioxidant Status and Biomarkers of Oxidative Stress in Dogs with Lymphoma

Background: Oxidative stress might play a role in carcinogenesis, as well as impacting morbidity and mortality of veterinary cancer patients. The purpose of this study was to evaluate antioxidant concentrations and biomarkers of oxidative stress in dogs with newly diagnosed lymphoma before treatment and once in remission, with comparison with healthy controls.
Hypothesis: Dogs with lymphoma have increased oxidant and reduced antioxidant concentrations compared with healthy controls, and that these abnormalities normalize once remission is achieved.
Animals: Seventeen dogs with lymphoma and 10 healthy controls.
Methods: Prospective, observational study. Measures of oxidative stress [malondialdehyde and total isoprostanes (isoP)] and antioxidants [α-tocopherol, γ-tocopherol, oxygen radical absorbance capacity (ORAC), and glutathione peroxidase (GSHPx)] were assessed in dogs with newly diagnosed lymphoma before treatment compared with healthy control dogs. The same parameters were measured in the dogs with lymphoma on week 7 of the chemotherapy protocol when all dogs were in remission.
Results: At baseline, dogs with lymphoma had significantly lower α-tocopherol ( P <.001) and γ-tocopherol ( P = .003) but higher GSHPx ( P = .05), ORAC ( P = .001), and isoP ( P < .001) compared with healthy controls. In the dogs with lymphoma, α-tocopherol concentrations were higher ( P = .005) and ascorbic acid were lower ( P = .04) after treatment.
Conclusions and Clinical Importance: Results suggest that dogs with lymphoma have alterations in oxidant and antioxidant concentrations and that the status of some of these biomarkers normalize after remission. Further studies are warranted to determine whether antioxidant interventions to correct these are beneficial in the treatment of canine lymphoma.     

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.     

Prognostic Factors in Dogs with Lymphoma and Associated Hypercalcemia

Lymphoma and hypercalcemia were diagnosed in 37 dogs. Twenty-six of the dogs received chemotherapy. The association between some prognostic factors including clinical stage of disease, illness status, presence of bone marrow involvement, and presence of an anterior mediastinal mass and remission duration and survival time was evaluated. Statistical analysis of the prognostic factors showed that the presence of an anterior mediastinal mass had an adverse effect on remission duration (P less than 0.03). Calcium concentration was not significantly related to any of the prognostic factors evaluated. Dogs that received chemotherapy were more likely to be self-supporting than the dogs that were not treated (P less than 0.005). However, initial illness status was not significantly related to remission duration or survival time in the 26 dogs that were treated. Six dogs (25% of dogs treated) survived longer than 14 months. Five of these dogs were female. Overall mean and median remission times were 10.4 and 6 months, respectively.     

Early Tumor Response to Intraarterial or Intravenous Administration of Carboplatin to Treat Naturally Occurring Lower Urinary Tract Carcinoma in Dogs

Background

Survival times and tumor responses associated with malignant neoplasia of the lower urinary tract are poor despite the vast array of current treatments. Therefore, the evaluation of alternative treatments, such as intraarterial administration of chemotherapy (IAC) should be considered.

Objective

To describe a technique for superselective catheterization for IAC and to evaluate initial tumor response by ultrasonography after both IAC and intravenous administration of chemotherapy (IVC).

Animals

Client‐owned dogs with lower urinary tract neoplasia treated with either IVC (n = 15) or IAC (n = 11).

Methods

Retrospective study. An arterial approach via the carotid or femoral artery was utilized to obtain superselective access and administer chemotherapy in the IAC cases. Medical record review was performed, data were recorded, and recorded variables were evaluated statistically.

Results

Intraarterial chemotherapy was successfully administered in all cases. There was a significantly greater decrease in longest unidimensional measurement in the IAC group as compared to the IVC group (P = .013). The IAC group was also significantly more likely to have a tumor response as assessed by modified RECIST guidelines (P = .049). Dogs in the IAC group were significantly less likely to develop anemia (P = .001), lethargy (P = .010) and anorexia (P = .024).

Conclusion and Clinical Importance

This study demonstrated the feasibility and efficacy of performing IAC for lower urinary tract neoplasia. Further investigation is necessary as the follow‐up time was short and the impact on long‐term outcome and survival was not determined.     

Anemia Is Associated with Decreased Survival Time in Dogs with Lymphoma

Background: Anemia is a common complication in human patients with neoplasia and has been associated with decreased survival time and a poorer quality of life.
Hypothesis: The presence of anemia at diagnosis is negatively associated with survival and remission times in dogs with lymphoma, but not in dogs with osteosarcoma.
Animals: Eighty-four dogs with lymphoma and 91 dogs with osteosarcoma that presented for treatment at the Animal Cancer Center, Colorado State University.
Methods: Retrospective, case-control study. Medical records were reviewed to determine the presence or absence of anemia (PCV < 40) at initial presentation. Median survival and remission times were identified by the Kaplan-Meier product limit method and the association between anemia and survival was determined by a multivariable Cox proportional hazard regression analysis.
Results: Cancer-related anemia is more frequent in dogs with lymphoma than in control dogs or dogs with osteosarcoma. Dogs with lymphoma and anemia had a significantly decreased survival time compared with dogs without anemia. There was no effect of anemia on remission time in dogs with lymphoma. Anemic dogs with osteosarcoma did not have decreased survival or remission time compared with nonanemic dogs with osteosarcoma.
Conclusions and Clinical Importance: Shortened survival time in dogs with lymphoma and anemia at initial presentation has important prognostic significance. Understanding cancer-related anemia in dogs might offer new opportunities to improve quality of life and survival times in these patients.     

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.     

Phase I Evaluation of Doxorubicin and Whole-body Hyperthermia in Dogs with Lymphoma

Fifteen previously untreated dogs with histologically confirmed, high-grade multicentric lymphoma were entered into a phase I study to evaluate combined doxorubicin and whole-body hyperthermia (DOX/WBH). Groups of three, four, and eight dogs were treated with whole-body hyperthermia and concurrent doxorubicin at 12 mg/m2, 24 mg/m2 and 30 mg/m2, respectively, after one doxorubicin induction dose at 30 mg/m2. Plateau temperature (42 +/- 0.1 degree C) was maintained for 90 minutes using a radiant heating device. A total of five DOX/WBH treatments per dog were planned, and these were given every 21 days. Treatment-related toxicity was not seen in the 12-mg/m2 doxorubicin dose group. Tumor progression prohibited administration of more than three DOX/WBH treatments to any dog in the 12-mg/m2 group. Premature ventricular contractions developed after the fifth treatment in one of the four dogs treated with 24 mg/m2 of doxorubicin. Two dogs (25%) in the 30-mg/m2 dose group had treatment-related toxicity. One dog experienced acute serious myelosuppression 1 week after the third treatment. This dog received all planned DOX/WBH treatments. Asymptomatic cardiac toxicosis consisting of decreased ejection fraction and fractional shortening developed in the second dog. This dog received only two DOX/WBH treatments. The three dogs treated at 12 mg/m2 had partial responses of short duration (60-83 days). Four dogs treated at 24 mg/m2 had complete responses for 150, 164, 186, and 200 days. Eight dogs treated at 30 mg/m2 had complete responses with a mean and median duration of 241 and 190 days, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

Platelet Aggregation and Adenosine Triphosphate Secretion in Dogs with Untreated Multicentric Lymphoma

Whole-blood platelet aggregation and adenosine triphosphate secretion were measured in 15 dogs with untreated multicentric lymphoma and 10 normal control dogs to determine if dogs with lymphoma have altered platelet function. Dogs with quantitative platelet disorders (ie, thrombocytopenia or thrombocytosis) or with clinical evidence of a bleeding disorder were excluded from the study. Platelets from affected dogs had significantly greater maximum aggregation than those from control dogs, suggesting that platelets from dogs with lymphoma are hyperactive. Platelet hyperactivity may play a role in the development of hemostatic disorders (eg, disseminated intravascular coagulation) or in tumor metastasis. Further investigation is needed to determine if modification of platelet function in patients with lymphoma affects disease progression or outcome.     

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.     

Pulse‐Administered Toceranib Phosphate Plus Lomustine for Treatment of Unresectable Mast Cell Tumors in Dogs

Background

Nonresectable mast cell tumors (MCT) in dogs remain a therapeutic challenge, and investigation of novel combination therapies is warranted. Intermittent administration of tyrosine kinase inhibitors (TKI) combined with cytotoxic chemotherapy may effectively chemosensitize canine MCT while decreasing cost and adverse effects associated with either agent administered as monotherapy.

Hypothesis/Objectives

The primary study objectives were to (1) identify the maximally tolerated dose (MTD), (2) determine the objective response rate (ORR) and (3) describe the adverse event profile of pulse‐administered toceranib phosphate (TOC) combined with lomustine.

Animals

Forty‐seven client‐owned dogs with measurable MCT.

Methods

Toceranib phosphate was given PO on days 1, 3 and 5 of a 21‐day cycle at a target dosage of 2.75 mg/kg. Lomustine was given PO on day 3 of each cycle at a starting dosage of 50 mg/m². All dogs were concurrently treated with diphenhydramine, omeprazole, and prednisone.

Results

The MTD of lomustine was established at 50 mg/m² when combined with pulse‐administered TOC; the dose‐limiting toxicity was neutropenia. Forty‐one dogs treated at the MTD were evaluable for outcome assessment. The ORR was 46% (4 complete response, 15 partial response) and the overall median progression‐free survival (PFS) was 53 days (1 to >752 days). On multivariate analysis, variables significantly associated with improved PFS included response to treatment, absence of metastasis, and no previous chemotherapy.

Conclusions and clinical importance

Combined treatment with pulse‐administered TOC and lomustine generally is well tolerated and may be a reasonable treatment option for dogs with unresectable or metastatic MCT.