Pilot clinical study of carmustine associated with a lipid nanoemulsion in combination with vincristine and prednisone for the treatment of canine lymphoma

A lipid nanoemulsion (LDE) resembling low‐density lipoprotein can target malignant tumours. In in vivo and clinical studies, association of chemotherapeutic agents to LDE decreased their toxicity and increased pharmacological action. Here, safety of LDE as carmustine carrier (50 mg m^?2, intravenous) combined with vincristine and prednisone for the treatment of dogs with lymphoma was tested and compared with commercial carmustine with vincristine and prednisone. In five dogs from LDE‐carmustine and six from commercial carmustine, complete remission was achieved (P > 0.05). Partial remission occurred in two dogs from each group. In both groups, the median progression‐free intervals (119 and 199 days) and overall survival times (207 and 247 days) were equal. Neutropenia was observed in both groups, but no other major toxicities occurred. Therefore, no difference was observed between the treatments. LDE‐carmustine was shown to be safe and effective in a drug combination protocol, which encourages larger studies to investigate the use of this novel formulation to treat canine lymphomas.     

Chemoimmunotherapy for canine lymphosarcoma

A total of 157 dogs with lymphosarcoma were available for study; 67 were treated. All of the treated dogs were given 4 drug combinations and 20 of them also were given autogenous vaccine. Sixty (90%) of the dogs treated with multiple drugs improved clinically. Of the dogs with clinical improvement, 48 (80%) had either complete or partial remission; of these, 32 (67%) had complete remission. Clinical staging proved useful in increasing the accuracy of prognosis, whereby dogs in less advanced stages of disease responded better to therapy, with a higher percentage of complete clinical remissions and longer survival. The mean survival time of the 47 dogs treated with drugs alone was 138 days, which compared with a mean survival time of 30 days for 34 nontreated dogs. Dogs subjected to chemotherapy and immunotherapy had a mean survival time of 341 days. Dogs in complete remission at time of vaccination survived significantly (P less than 0.01) longer than did dogs treated with drugs and vaccinated while not incomplete remission.     

Histologic classification as a prognostic criterion for canine lymphosarcoma

Neoplastic tissues from 72 dogs with lymphosarcoma were histologically classified according to the Rappaport schema to determine if the histologic features of the disease had any clinical or prognostic importance. Of 72 dogs, lymphosarcomas in 7 were classified as nodular (9.7%) and 65 were classified as diffuse (90.3%). The two principal cytologic types were lymphocytic, poorly differentiated, and histiocytic, which composed 39% and 56% of the lymphosarcomas, respectively; whereas lymphocytic, well differentiated, mixed, and undifferentiated composed 6%. Clinically, all of the dogs were stage III or IV, according to the accepted criteria for canine lymphosarcoma. The overall complete remission rate was 64% and was defined as no clinical evidence of disease after 9 weeks of chemotherapy. Median remission among nodular histiocytic, diffuse lymphocytic, poorly differentiated, and diffuse histiocytic (DH) groups of dogs was 42 days, 29 days, and 42 days (range, 0 to 1,095), respectively. Median survival for the same groups was 235 days, 190 days, and 173 days (range, 1 to 1,261), respectively. A logarithmic analysis of variance revealed no significant differences among nodular histiocytic, diffuse lymphocytic, poorly differentiated, and DH groups relative to days remission, as well as to days survival. It was observed that those dogs with neoplasms classified as DH had longer remission durations. It would appear that for any one animal, histologic classification according to the Rappaport schema cannot be used as a prognostic criterion in predicting therapeutic response, remission, or survival.     

Chemotherapy for canine lymphosarcoma.

Twenty dogs with naturally occurring lymphosarcoma were histologically diagnosed, clinically staged, and treated with combinations of drugs, including corticosteroids, alkylating agents, plant alkaloids and antimetabolities. Clinical response was categorized as complete, partial, or unsatisfactory. Of the 20 dogs, 17 responded to the chemotherapy completely or partially, with a mean objective remission duration of 104.8 days. The mean survival time for 19 dogs was 211.5 days, whereas the mean survival time for 16 dogs which responded completely or partially was 233.7 days.     

Serum concentrations of immunoglobulins G, A, and M in dogs with neoplastic disease

The concentrations of the three major classes of immunoglobulins (Ig) were determined in canine serum by single radial immunodiffusion against calibrated standards. Serum samples were collected from 121 dogs categorized into 3 groups: normal dogs (n = 34), those with lymphosarcoma (n =41), and those with malignant, solid neoplasms other than lymphosarcoma (n = 46). The mean value for serum IgM concentration in the group of dogs with lymphosarcoma was significantly (P less than or equal to 0.02) higher than was the mean IgM concentration of the normal dogs. Dogs with neoplasms other than lymphosarcoma had significantly increased serum concentrations of IgG and IgM antibodies. There was no significant difference in serum IgA concentration among the three groups. A wide range of Ig concentrations was in the serum of clinically normal dogs, as well as in dogs with neoplastic diseases. Although individual dogs with neoplasms had low serum Ig concentrations, the 81 dogs with neoplastic disease were generally able to synthesize Ig.     

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.     

Reevaluation of the University of Wisconsin 2-year protocol for treating canine lymphosarcoma

This retrospective study investigated a population of 96 dogs with newly diagnosed malignant lymphosarcoma that were treated with the commonly used University of Wisconsin-Madison (UW-M) chemotherapy protocol. Pretreatment characteristics were analyzed to determine prognostic factors. Dogs with higher World Health Organization (WHO) stages (including stage IV) and dogs with hypercalcemia were at significantly higher risk of relapse (P=0.018 and P=0.016, respectively). Dose reduction, treatment delays, and prior therapy with cortico-steroids were not associated with clinical outcome. First remission duration of 270 days was similar to historically reported data. Overall survival time of 218 days was much shorter than historical data.     

Doxorubicin-lnduced Cardiotoxicosis Clinical Features in 32 Dogs

Clinical cardiac abnormalities developed in 32 of 175 dogs that had various malignancies and were treated with doxorubicin: 31 dogs had electrocardiographic abnormalities including arrhythmias and nonspecific alterations in the R wave, ST segment, or QRS duration and 7 dogs had congestive heart failure. All seven dogs that had congestive heart failure died within 90 days. At necropsy, 13 of 32 affected dogs had noninflammatory myocardial degeneration, myocytolysis, vacuolation, and/or fibrosis and there was intramural coronary arteriosclerosis in all 13. Five dogs with lymphosarcoma were in complete clinical remission when they died of doxorubicin-induced cardiomyopathy, but the overall survival times of the lymphosarcoma subset was nevertheless longer than in previous studies. The clinical use of doxorubicin in the dog can cause cardiotoxicosis but the therapeutic benefit appears to outweigh risks in most dogs.     

Efficacy of doxorubicin as an induction agent for cats with lymphosarcoma

OBJECTIVE: To determine the efficacy of doxorubicin when used alone in inducing remission in cats with lymphosarcoma. DESIGN: Prospective multi-institutional study of naturally occurring disease. METHODS: Cases were accrued from veterinary institutions in Australia and New Zealand after obtaining consent from informed owners. Cats were treated with doxorubicin every 3 weeks for three treatments. If there was no response to the first dose of doxorubicin or if the cat relapsed during the doxorubicin regimen, the cat was withdrawn from the trial and either euthanased or treated with other agents. Age, breed, gender and anatomic site of the lymphosarcoma (multicentric, alimentary, mediastinal, extranodal) were recorded for each cat. Clinical remission was assessed before each treatment by physical examination, radiography, ultrasonography and computed tomography where appropriate. Complete remission was defined as the disappearance of all clinical signs and clinically detectable tumour. RESULTS: Twenty-one cases were accrued over a 2-year-period but only 19 were available for data analysis. Young Siamese cats were over-represented and all cats with mediastinal tumours were young Siamese. There was a significant difference between the mean ages of cats with mediastinal or multicentric lymphosarcoma (mean +/- SD: 3.5 +/- 3.0 and 4.3 +/- 2.6 years, respectively) and cats with alimentary or extranodal LSA (11.4 +/- 0.9 and 11.0 +/- 0.9 years, respectively). Of 19 cats treated with doxorubicin alone, 6 (32%) had complete remission, 6 (32%) had partial remission and 7 (36%) did not respond. CONCLUSIONS: The results suggest that doxorubicin cannot be recommended as a single agent for treatment of feline lymphosarcoma because of the rather poor remission rate achieved.     

CORRELATION BETWEEN THORACIC RADIOGRAPHIC CHANGES AND REMISSION/SURVIVAL DURATION IN 270 DOGS WITH LYMPHOSARCOMA

A retrospective study was undertaken wherein the medical records and thoracic radiographs of 270 dogs with lymphosarcoma were reviewed to determine the type and frequency of thoracic radiographic changes. Statistical evaluation of the relationship between radiographic, clinical and immunologic factors and the primary remission duration and survival times was performed using univariate and multivariate analysis. One hundred ninety-two dogs (71 %) had some type of thoracic radiographicabnormality, including 80 dogs (29.6%) with pulmonary infiltrates and 164 dogs (64.4%) with thoracic lymphadenomegaly. Only T-cell phenotype (p = 0.0056 for survival, p = 0.0045 for remission) and the presence of cranial mediastinal lymphadenomegaly (p = 0.0005 for survival, p = 0.0129 for remission) were identified as having a significant negative correlation to both primary remission and survival duration by multivariate analysis.     

Dexamethasone, melphalan, actinomycin D, cytosine arabinoside (DMAC) protocol for dogs with relapsed lymphoma

BACKGROUND: In general, treatment of relapsed lymphoma is associated with a lower probability of response and shorter duration of remission. The purpose of this study was to evaluate the efficacy of the combination chemotherapy protocol DMAC (dexamethasone, melphalan, actinomycin D, and cytosine arabinoside) for reinduction of remission in dogs with relapsed lymphoma. HYPOTHESIS: That DMAC would be an effective reinduction protocol for dogs with relapsed lymphoma. ANIMALS: Fifty-four dogs. RESULTS: Seventy-two percent of the dogs achieved remission (44% complete remission [CR] and 28% partial remission [PR]), 11% had stable disease (SD), and 17% had progressive disease (PD). The median remission duration was 61 days (range, 2-467+ days). The median remission durations for dogs with CR, PR, and SD were 112, 44, and 27 days, respectively. Factors that affected the response rate were previous treatment with doxorubicin and an inability to achieve remission with the previous protocol. Thrombocytopenia occurred in 56% of the dogs (grade 1 in 3 dogs, grade 2 in 6 dogs, grade 3 in 7 dogs, and grade 4 in 7 dogs) and neutropenia in 17% of the dogs (grade 2 in 1 dog, grade 3 in 2 dogs, and grade 4 in 4 dogs). Gastrointestinal toxicosis occurred in 22% of the dogs (grades 1 in 5 dogs, grade 2 in 3 dogs, and grade 3 in 1 dog). CONCLUSIONS AND CLINICAL IMPORTANCE: The DMAC protocol is an effective rescue protocol for dogs with relapsed multicentric lymphoma. Although thrombocytopenia is a common manifestation of toxicity, in general, the protocol is well tolerated.     

Follow-up studies by peroral gastric biopsies and necropsy in vomiting dogs.

The results of follow-up studies in 139 vomiting dogs are presented. Follow-up studies were performed by biopsies in 34 dogs, by biopsies and necropsy in six dogs and by necropsy only in 99 dogs. The times between the first and the last series of biopsies varied from three to 1042 days and from one to 656 days between the first series of biopsies and necropsy. From the 55 dogs with gastritis in the first series of biopsies, 35 also showed gastritis in the following biopsies or at necropsy. These were mainly severe types of gastritis such as diffuse, hypertrophic or atrophic. Ten dogs with superficial gastritis showed no gastric changes at necropsy, two dogs had edema only and three dogs had gastric changes other than gastritis, such as multiple polyps. In general, carcinoma and lymphosarcoma were found in the biopsies as well as at necropsy, but in three cases of terminal carcinoma only gastritis had been diagnosed initially. In 35 dogs the first series of gastric biopsies showed no pathological changes, but in 22 of these dogs gastritis, ulceration, fibrosis, atrophy, gastric dilation with local necrosis, and perforation or lymphosarcoma of the submucosa were found in the second series of biopsies or at necropsy. Several dogs which did not have gastric changes at necropsy had enteritis or intestinal lymphosarcoma.     

Etoposide (VP-16)

A retrospective analysis was performed of the effect of VP-16 (etoposide) in the treatment of 13 dogs with lymphoma. Twelve dogs had achieved partial (two) and complete (ten) responses to combination chemotherapy, but all were out of remission at the time of the trial. One dog had not previously had chemotherapy. There was minimal response to VP-16 chemotherapy in the 13 dogs studied, and only two of 13 dogs had some response to treatment. For one dog, complete and partial remission durations were one and three months, respectively. In another dog, there was partial remission of eight days. There were no responses in the other 11 dogs. The most serious adverse reaction after administration of VP-16 was an acute pruritic cutaneous reaction that occurred in 11 of the 13 dogs, which may have been associated with the vehicle of VP-16, polysorbate 80. Results showed that VP-16 has minimal activity for treatment of dogs with lymphoma that have experienced relapses after treatment with other anti-cancer drugs. More trials are needed with higher dosages and the oral form of the drug, which does not contain polysorbate 80.     

Single-Drug Chemotherapy of Canine Transmissible Venereal Tumor With Cyclophosphamide, Methotrexate, or Vincristine

During a 21-month period, 48 dogs with spontaneous canine transmissible venereal tumor (clinical stage, T1-T3) were presented to the Veterinary Teaching Hospital, Ahmadu Bello University, Zaria, Nigeria, and were divided into one control and four treatment groups to test the efficacy of single-agent chemotherapeutic drugs. The dogs were not randomly assigned to groups because each chemotherapeutic agent was not continuously available during the test period. Group I consisted of four dogs that received oral cyclophosphamide (50 mg/M2 body surface area [BSA]) on the first four days for six weeks. No therapeutic response was noted in any of the four dogs. Group II consisted of ten dogs that received intravenous (IV) cyclophosphamide (50 mg/M2 BSA) for four consecutive days per week for six weeks. Two of the ten had a partial remission. Group III consisted of eight dogs that received oral methotrexate (2.5 mg/M2 BSA) every other day for six weeks. No therapeutic response was noted in any of the eight dogs. Group IV consisted of 20 dogs that were administered IV vincristine sulfate (0.5 mg/M2 BSA) weekly until a response was noted. Complete remission occurred in each of the 20 dogs. One dog had recurrence within 12 months. Group V was the untreated control group, consisting of six dogs among which no spontaneous remission was seen. Instead, tumor progression was noted. Adverse responses to medication, anorexia, vomiting, diarrhea, and weight loss were seen only with dogs treated with cyclophosphamide and methotrexate.     

Evaluation of treatment with doxorubicin and piroxicam or doxorubicin alone for multicentric lymphoma in dogs

OBJECTIVE: To evaluate the antitumor and toxic effects of treatment with doxorubicin combined with piroxicam or doxorubicin alone for multicentric lymphoma in dogs. DESIGN: Nonrandomized clinical trial. ANIMALS: 75 dogs with multicentric lymphoma. PROCEDURE: 33 dogs were treated with doxorubicin (30 mg/m2, IV, q 21 d, for 3 doses) and piroxicam (0.3 mg/kg [0.14 mg/lb], PO, q 24 h); results were compared with a historical control group of 42 dogs treated with doxorubicin (30 mg/M2, IV, q 21 d, for 3 doses) alone. Results-The percentages of dogs that had remission with doxorubicin-piroxicam treatment (79%) or doxorubicin treatment alone (74%) were not significantly different. Median duration of first remission was 130 days with doxorubicin-piroxicam and 147 days with doxorubicin alone; these values were not significantly different. Severe toxicosis was observed in 22% of dogs treated with doxorubicin-piroxicam and 17% of dogs treated with doxorubicin alone. CONCLUSIONS AND CLINICAL RELEVANCE: Both treatment protocols were efficacious and well tolerated. The doxorubicin-piroxicam treatment was no more effective regarding response rate, remission duration, or survival duration, compared with the control group treated with doxorubicin alone.     

Chemotherapy followed by half-body radiation therapy for canine lymphoma

A protocol of induction chemotherapy followed by half-body radiation therapy for treatment of lymphoma was used in 94 dogs. Seventy-three (78%) dogs achieved complete remission. Substage (P = .011) and phenotype (P = .015) were identified as predictors of complete remission rate. Of these, 52 dogs received half-body irradiation. Cranial and caudal halves received a total dose of 8.0 Gy, given in 2 fractions of 4.0 Gy on consecutive days with cobalt-60 photons and a 3-week interval between halves. Median 1st remission for these dogs was 311 days. Anemia was identified as the only predictor for length of 1st remission (P = .024). Toxicoses after half-body irradiation generally were mild and infrequent and included myelosuppression and gastrointestinal signs. Thirty-one dogs relapsed and 20 resumed treatment with induction followed by maintenance chemotherapy. Seventeen (85%) dogs achieved a 2nd complete remission. Median overall remission for all 52 dogs was 486 days. Results of this study suggest that half-body radiation therapy after induction chemotherapy is well tolerated and might increase remission duration compared with conventional protocols that use chemotherapy alone, but this increase might not be long enough to be clinically relevant or to justify application of the method described herein.     

Comparison of the effects of asparaginase administered subcutaneously versus intramuscularly for treatment of multicentric lymphoma in dogs receiving doxorubicin

OBJECTIVE: To determine the effectiveness and safety of asparaginase administered s.c. versus i.m. for treatment of multicentric lymphoma in dogs receiving doxorubicin. DESIGN: Prospective study. ANIMALS: 49 dogs with multicentric lymphoma. PROCEDURE: Dogs were treated with doxorubicin every 3 weeks, for a total of 5 treatments, and were given 3 weekly treatments of asparaginase, s.c. or i.m. Using high-performance liquid chromatography, mean plasma asparagine, aspartic acid, glutamine, and glutamic acid concentrations were determined in dogs before and during treatment with asparaginase (10,000 U/m2 of body surface area, once a week for 3 weeks). Asparaginase was administered s.c. in 23 dogs and i.m. in 26 dogs. Variables evaluated included time to response to chemotherapy, remission and survival times, and clinical and serum biochemical indicators of toxicoses. RESULTS: Using the World Health Organization's staging system for lymphoma, 30 dogs were in clinical stage III and 19 were in clinical stage IV. One week after asparaginase treatment, plasma asparagine concentrations were low and plasma aspartic acid, glutamine, and glutamic acid concentrations were high. Differences in plasma amino acid concentrations were not found between s.c. and i.m. groups. For dogs in clinical stage IV, i.m. administration of asparaginase significantly decreased the number of days to complete remission, compared with s.c. administration (8 vs 17 days, respectively). For dogs in clinical stage III, i.m. administration favorably increased the duration of first remission (191 vs 103 days) and survival time (289 vs 209 days). Overall, dogs treated i.m. had a faster response to chemotherapy (9 vs 15 days), a longer remission (191 vs 109 days), and a longer survival time (286 vs 198 days), compared with all dogs treated s.c. Asparaginase toxicoses were not observed regardless of the route of administration. CLINICAL IMPLICATIONS: For dogs with multicentric lymphoma that are receiving doxorubicin, i.m. treatment with asparaginase is more effective than s.c. treatment.     

Treatment of dogs with lymphoma using a 12-week, maintenance-free combination chemotherapy protocol

BACKGROUND: Treatment of lymphoma in dogs by long-term chemotherapy has favorable results. However, the efficacy of short-term, maintenance-free treatment protocols on remission and survival times in dogs has not been determined. HYPOTHESIS: That treatment using a 12-week chemotherapy protocol would be associated with satisfactory treatment outcome in dogs with lymphoma. ANIMALS: 77 dogs with histologically or cytologically confirmed diagnosis of lymphoma. METHODS: Prospective clinical trial in which dogs were treated with a 12-week chemotherapy protocol consisting of L-asparaginase, vincristine, cyclophosphamide, doxorubicin, and prednisolone. RESULTS: Complete remission rate was 76.3%. Multivariate logistic regression analysis revealed that clinical substage (P = .006) and immunophenotype (P = .003) had a significant influence on the likelihood of a dog achieving complete remission. Median duration of first complete remission was 243 days (range 19-1,191 days). The 6-month, 1-year, and 2-year remission rates were 68%, 28%, and 16%, respectively. In the multivariate analysis of patient variables, immunophenotype (P = .022) revealed a significant influence on first remission duration. Toxicosis was mild with the exception of 1 treatment-associated death. CONCLUSIONS AND CLINICAL IMPORTANCE: In this group of dogs the 12-week maintenance-free chemotherapy protocol was well tolerated and had satisfactory results.     

Chemotherapeutic responses in dogs with lymphosarcoma and hypercalcemia

Twelve dogs with lymphosarcoma and hypercalcemia were treated over a period of 36 months. Signs and laboratory findings were referable to hypercalcemia and azotemia. All dogs were staged, classified histologically, and given cytoreductive chemotherapy, using 5 drugs (vincristine sulfate, cytosine arabinoside, cyclophosphamide, L-asparaginase and prednisone). For azotemia, symptomatic therapy (0.9% NaCl solution and furosemide) was given. Seven dogs responded completely, with marked reduction of lymphadenopathy and return of serum calcium concentration to normal. Median duration of remission in this group was 48 days (range, 14 to 93), and median survival time was 112 days (range, 85 to 153). Five nonresponding dogs had less than 50% reduction in measurable tumor mass, although serum calcium concentration returned to normal. The median survival time for this group was 34 days (range, 23 to 68). Two of the nonresponders died from sepsis and another from disseminated intravascular coagulation. Response to therapy did not appear to be influenced by age, breed, sex, initial calcium concentration, degree of azotemia, or histologic classification.