Antony S. Moore

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.

Prognosis for dogs with stage I or II splenic hemangiosarcoma treated by splenectomy alone: 32 cases (1991-1993).

A retrospective analysis was performed on the case records of 32 dogs with Stage I or II splenic hemangiosarcoma that were treated by splenectomy alone and that survived the seven-day postoperative period. Median survival time for these 32 cases was 86 days (mean, 116 days; range, 14 to 470 days), and the one-year survival rate was estimated to be 6.25%. Survival was not influenced by signalment, presenting signs, stage of disease, or clinicopathological findings. The data provides a basis from which to evaluate adjuvant chemotherapy for splenic hemangiosarcoma that is confined to the spleen macroscopically.

Treatment of immune-mediated hemolytic anemia in dogs with cyclophosphamide.

A review of 60 cases of immune-mediated hemolytic anemia (IMHA) in the dog was performed in order to characterize the disease and to identify potential prognostic indicators. Dogs ranged in age from 1 to 13 years, with a mean age of 6.5 years. The 2 most commonly affected breeds were Cocker Spaniels and Labrador Retrievers. Fifty-two of the 60 dogs tested (87%) were autoagglutination positive and spherocytes were present in 45 (75%). Forty-one (89%) of 46 patients tested positive for the presence of immunoglobulin on the red blood cell surface (Coombs assay). The most common clinical signs at presentation were lethargy, weakness, pale mucous membranes, icterus, hemoglobinuria, and anorexia. PCV less than 25% was present in 59 (98%) dogs. At the time of presentation, 35 dogs (58%) had a nonregenerative anemia, whereas 25 patients (42%) had a regenerative response. Thrombocytopenia was seen in 41 (68%) dogs. Nine of 34 dogs (26%) had a prolonged prothrombin time, 19 of 34 (56%) had a prolonged activated partial thromboplastin clotting time, and 12 of 34 (35%) had abnormal fibrinogen concentrations. All dogs received prednisone at immunosuppressive doses (2.2-4.4 mg/kg PO as a single or divided dose every 24 hours) and cyclophosphamide as primary therapy. Forty-one dogs (63%) received cyclophosphamide at 50 mg/m2 q24h for 4 days, whereas 9 dogs (15%) received an initial high dose (200 mg/m2) followed by 3 days of a lower dose (50 mg/m2 q24h). No statistical difference in survival times was found for either protocol. Thirteen dogs were treated with azathioprine in addition to cyclophosphamide and prednisone. The median survival time of dogs that received all 3 drugs was 370 days as compared to 9 days for those dogs that were treated with cyclophosphamide and prednisone alone. Thirty-one (52%) dogs died from the disease, 13 (22%) dogs were alive, and 15 (25%) dogs were lost to follow-up. The median length of survival for all dogs was 21 days. Eight dogs that were discharged from the hospital suffered a relapse (PCV < 25%).

MOPP Chemotherapy for Treatment of Resistant Lymphoma in Dogs: A Retrospective Study of 117 Cases (1989–2000)

The purpose of this retrospective study was to evaluate the efficacy and toxicity of the MOPP chemotherapy protocol (mechlorethamine, vincristine, procarbazine, and prednisone) as a rescue regimen in dogs with lymphoma. One hundred seventeen dogs that had resistance to previously administered chemotherapy were evaluated. Before treatment with MOPP, all dogs received a median of 6 chemotherapy drugs for a median duration of 213 days. Thirty-one percent (36 of 117) had a complete response (CR) to MOPP for a median of 63 days, and 34% (40 of 117) had a partial response (PR) for a median of 47 days. Sixteen percent (19 of 117) had stable disease (SD) for a median of 33 days. Predictors for response to MOPP were not identified. Gastrointestinal (GI) toxicity occurred in 28% (33 of 117) of the dogs, and 13% (15 dogs) required hospitalization. Five dogs developed septicemia, and 2 died as a result. MOPP was an effective treatment for dogs with resistant lymphoma and was well tolerated by the majority of affected dogs.

A combination chemotherapy protocol with MOPP and CCNU consolidation (Tufts VELCAP-SC) for the treatment of canine lymphoma.

A chemotherapy protocol using a consolidation phase of alkylating agents was used for treating 94 dogs with lymphoma. Fifty-seven percent of dogs were in stage V, 63% were ill and 38% had T-cell lymphoma. The complete remission (CR) rate was 70% and is comparable to results achieved with previously published chemotherapy protocols. Anorexia predicted the remission; of the 40 dogs without anorexia, 35 (88%) achieved CR whereas of 52 dogs with anorexia, 30 (58%) achieved CR. Median first CR duration was 168 days and 1- and 2-year CR rates were 17.4 and 15.5%, respectively. Platelet count affected length of first CR, with a 53.2% reduced chance of coming out of remission with each log increase in platelet count. Median survival time was 302 days. One and 2-year survival rates were 44 and 13%, respectively. Anorexia and no dose reduction of any drug were independent negative variables. Of 93 dogs with toxicity data, 65 dogs (70%) required a dose reduction. Cyclophosphamide was most commonly reduced with reductions in 31 (38%) of 82 dogs. A dose reduction was significantly more likely in dogs with B-cell lymphoma than in those with T-cell lymphoma.

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.

Single Agent Chemotherapy with Doxorubicin for Feline Lymphoma: A Retrospective Study of 19 Cases (1994–1997)

Medical records of 21 cats with confirmed lymphoma treated with single-agent doxorubicin were reviewed. Nineteen cats met the inclusion criteria for this retrospective study. Doxorubicin was given at a dosage of 25 mg/m2 (n = 8) or 1 mg/kg (n = 11) IV, every 3 weeks for a total of 5 treatments. Four of 16 tested cats were positive for feline leukemia virus (FeLV) and all 16 cats tested negative for feline immunodeficiency virus. Eight of the 19 cats (42%) responded to doxorubicin for a median duration of 64 days (range, 35-575 days). Five cats (26%) achieved a complete response (CR) to doxorubicin for a median duration of 92 days (range, 54-575 days). Partial response was observed in 3 cats. Institution was the only significant prognostic indicator for response, with cats treated at Colorado State University being more likely to achieve CR than cats treated at Tufts University. Cats that achieved CR to doxorubicin and FeLV-negative cats had significantly longer survival times. Loss of appetite was the most common toxicity, observed in 9 cats (47%), and was severe in 5 cats (26%). Other toxicoses were less frequent and included vomiting, diarrhea, and myelosuppression. Doxorubicin was not very effective at inducing and maintaining remission in the cats in this study. Therefore, if doxorubicin is used for the treatment of feline lymphoma, it should be combined with other effective chemotherapeutic drugs in a combination protocol.

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.

A combination chemotherapy protocol with dose intensification and autologous bone marrow transplant (VELCAP-HDC) for canine lymphoma.

Twenty-eight dogs with lymphoma were treated with a 12-week, 5-drug chemotherapy protocol concluding with high-dose cyclophosphamide supported by autologous bone marrow transplants. A dose escalation design was used to determine the maximum tolerated cyclophosphamide dose (MTD) in this setting. Three cyclophosphamide dose levels were given: 300 mg/ m2 IV (groupl, 3 dogs), 400 mg/m2 IV (group 2, 12 dogs), and 500 mg/m2 IV (group 3, 13 dogs); and the MTD was 500 mg/m2 IV. Toxicity was common but mild, and the dose-limiting toxicity was myelosuppression, specifically neutropenia. No dog died as a result of treatment-related toxicity. One dog in group 3 developed fever, neutropenia, and presumed sepsis and responded promptly to routine management. No other dog required hospitalization. Lower stage and higher cyclophosphamide dose (both increasing dose [study groups 1-3], and the highest dose [group 3]) compared with the lower doses combined (groups 1 and 2) were significantly associated with longer remission duration (all P < .0001). Median remission duration for dogs in group 3 was 54 weeks, compared with 21 weeks for dogs in groups 1 and 2 combined. Factors associated with longer survival time were lower stage (P = .042) and higher cyclophosphamide dose (both increasing dose [study groups 1-3], and the highest dose [group 3] compared with the lower doses combined [groups 1 and 2]) (P = .027). Median survival time for dogs in group 3 was 139 weeks, compared with 43 weeks and 68 weeks for dogs in groups 1 and 2, respectively.

Phase I evaluation of CCNU (lomustine) in tumor-bearing cats.

1-(2-Chloroethyl)3-cyclohexyl-1-nitrosourea (CCNU) is an alkylating agent in the nitrosourea subclass. A prospective evaluation of CCNU was done to determine the maximally tolerated dosage of CCNU in tumor-bearing cats. Response data were obtained when available. Twenty-five cats were treated with CCNU at a dosage of 50-60 mg/m3 body surface area. Complete hematologic data were available for 13 cats. Neutropenia was the acute dose-limiting toxicity. The median neutrophil count at the nadir was 1,000 cells/microL (mean, 2,433 cells/microL; range, 0-9,694 cells/microL). The time of neutrophil nadir was variable, occurring 7-28 days after treatment, and counts sometimes did not return to normal for up to 14 days after the nadir. Based on these findings, a 6-week dosing interval and weekly hematologic monitoring after the 1st treatment with CCNU are recommended. The nadir of the platelet count may occur 14-21 days after treatment. The median platelet count at the nadir was 43,500 cells/microL. No gastrointestinal, renal, or hepatic toxicities were observed after a single CCNU treatment, and additional studies to evaluate the potential for cumulative toxicity should be performed. Five cats with lymphoma and 1 cat with mast cell tumor had measurable responses to CCNU. Phase II studies to evaluate antitumor activity should be completed with a dosing regimen of 50-60 mg/m3 every 6 weeks.