Evaluation of a Multidrug Chemotherapy Protocol (ACOPA II) in Dogs With Lymphoma

A chemotherapeutic protocol using cyclophosphamide, vincristine, prednisone, doxorubicin, and L-asparaginase (ACOPA II) was evaluated in dogs with lymphoma. The response rate for 68 dogs treated with ACOPA II (complete remission [CR] 65%, partial remission [PR] 10%) was lower than that for 41 dogs treated with a related protocol previously evaluated (ACOPA I; CR 76%, PR 12%). Initial treatment with doxorubicin and prednisone did not decrease the prevalence or severity of toxicity during induction. The mortality during induction was 22%. The median duration of CR for dogs treated with ACOPA II was 9 months, with 40% still in remission at 1 year and 21% at 2 years. The rate of CR was lower for dogs with signs of illness at presentation (substage b ) and for dogs weighing less than 15 kg. Age was negatively correlated with survival time and duration of remission. Dogs with immunoblastic lymphoma had a more favorable prognosis than did those with lymphoblastic lymphoma. Survival times were also longer for dogs in substage a at presentation. Seven dogs in which treatment was discontinued while in remission had comparable remission duration to that achieved by dogs receiving long-term maintenance chemotherapy.     

Is Maintenance Chemotherapy Appropriate for the Management of Canine Malignant Lymphoma?

A retrospective study was conducted between two groups of dogs with histopathologically diagnosed multicentric malignant lymphoma to determine if treatment with either short-term or continuous chemotherapy resulted in a significant difference in first-remission length or survival time. One group was treated with single agent, short-term (three cycles) of doxorubicin. Dogs obtaining complete remission while receiving doxorubicin were given no further chemotherapy. The other group received combination agent, long-term chemotherapy consisting of cyclophosphamide, vincristine sulfate, and prednisone (COP). Dogs obtaining complete remission on COP by the end of 6 weeks were given maintenance chemotherapy of cyclophosphamide, prednisone and methotrexate. One hundred and five dogs were treated. Thirty-eight dogs received doxorubicin and 67 received COP. All dogs were evaluated at 6 weeks for response to chemotherapy and followed until death. No significant differences were observed in first-remission length or survival time when comparing dogs treated with either short-term doxorubicin or long-term COP (P greater than 0.05). Sex, weight, age, clinical stage, performance status, histopathologic cell type, and grade were not significant factors for determining the responsiveness to either chemotherapy protocol. However, within either treatment group, significant differences in first-remission length were observed in dogs evaluated histopathologically by the Keil and NCI working formulation and in survival time when evaluated by performance status (P less than 0.05).     

Evaluation of Prognostic Factors and Sequential Combination Chemotherapy With Doxorubicin for Canine Lymphoma

Fifty-five dogs with lymphoma were treated using a doxorubicin-based sequential combination chemotherapy protocol. Complete response, partial response, and no response were seen in 46, 4, and 5 dogs, respectively. The overall median remission duration and survival times were 36 and 51 weeks, respectively. Age, sex, weight, World Health Organization stage, World Health Organization substage (i.e., a = not ill, b = ill), serum calcium concentration, blood urea nitrogen concentration, breed, and protocol alteration secondary to toxicity were evaluated for prognostic significance. Univariate analysis of prognostic factors identified sex, World Health Organization substage, and serum calcium as statistically significant ( P ≤ .05) variables for both survival and remission duration. Upon multivariate analysis, only substage ( P = .036) was a significant prognostic factor for remission duration, whereas, both substage ( P = .006) and sex ( P = .005) were significant prognostic factors for survival. (Journal of Veterinary Internal Medicine 1993; 7:289–295. Copyright © 1993 by the American College of Veterinary Internal Medicine.)     

Principles of treatment for feline lymphoma

Lymphoma is the most commonly diagnosed neoplasm in cats. As feline leukemia virus antigenemia has decreased over the past 15 years, there has been a profound shift in the presence, signalment, and frequency of sites of feline lymphoma in North America. There is variation in anatomic classification systems, but most studies have divided lymphoma into four groups: alimentary, mediastinal, multicentric, or extranodal. Clinical signs and common differential diagnoses for each of the forms are described. Staging allows for evaluation of the extent of disease. As in the dog, lymphoma is a systemic disease in the cat, and chemotherapy is the treatment of choice for most forms. Exceptions are described. In contrast to canine lymphoma, feline lymphoma is generally more challenging and frustrating to treat than canine lymphoma. Response rates are lower, and remission duration is shorter. Fortunately, cats treated with chemotherapy tend to have less toxicity than dogs. Positive prognostic factors are feline leukemia virus-negative, clinically well at time of diagnosis, and response to therapy. Achieving a complete remission is prognostic for survival. Unfortunately, response cannot be predicted before treatment.     

Prognostic factors for tumor remission and survival in dogs after surgery for primary lung tumor: 76 cases (1975-1985)

The association of various prognostic factors with remission and survival after the excision of lung tumors was evaluated in 76 dogs. Overall, the median survival time of treated dogs was 120 days; 72% had tumor that underwent remission (median duration of remission, 120 days). Dogs with tumors that underwent remission had significantly (P = 0.001) increased survival time (median, 330 days vs 28 days for dogs with tumors that did not undergo remission). The finding of normal-sized lymph nodes at the time of therapeutic thoracotomy was significantly (P = 0.001) correlated with increased remission probability (85.4% remission rate vs 43.6% in dogs with large lymph nodes). Use of various diagnostic methods to find normal regional lymph nodes before surgery indicated that such finding was significantly (P less than or equal to 0.01) correlated with increased remission duration (median remission duration, 365 days, vs 60 days for tumors in dogs with large lymph nodes), and the finding of normal lymph nodes at the time of surgery was significantly (P less than or equal to 0.01) correlated with increased survival time (median, 345 days, vs 60 days for dogs with large lymph nodes).     

Chemotherapy of lymphoma in 75 cats

Seventy-five cats with lymphoma were treated with combination sequential chemotherapy consisting of vincristine, cyclophosphamide, and methotrexate. Thirty-nine cats had mediastinal, 16 had multicentric, 14 had alimentary, and 6 had renal lymphoma. The median survival time of the 75 cats was 8 weeks, with a mean of 32 weeks. Sixty-two cats had follow-up evaluation until death or cure and had a median survival time of 7 weeks, with a mean of 37 weeks. Of the 62 cats, 32 (52%) attained complete remission, with a median remission duration of 16 weeks and a mean of 46 weeks. The addition of prednisolone and/or L-asparaginase to the protocol did not improve the results. Sixteen cats with multicentric lymphoma had the longest survival times (median, 18 months) and remission durations (median, 25 months). Prognostic factors were evaluated in each anatomic form of lymphoma.     

Evaluation of a discontinuous treatment protocol (VELCAP-S) for canine lymphoma

Eighty-two dogs with lymphoma received a single 15-week course of chemotherapy, after which treatment was ceased until relapse. Fifty-six dogs (68%) achieved complete remission for a median 1st remission duration of 20 weeks. Forty-eight dogs relapsed, of which 30 repeated the induction cycle. In 22 of these dogs, 1st remission had been short, and they received maintenance chemotherapy; the other 8 dogs received 2 or 3 cycles of induction chemotherapy. Second remission rate for these 30 dogs was 87% (26 dogs). Overall disease control for the 38 dogs that remained on protocol was 44 weeks, which was not markedly shorter than for dogs treated with a previously reported protocol in which maintenance chemotherapy was instituted in all dogs after an identical 1st induction (VELCAP-L). Dogs that were febrile and dogs that were dyspneic were less likely to achieve a complete remission to induction chemotherapy. Of dogs that achieved a complete remission, those that were thrombocytopenic at entry had a shorter 1st remission, and dogs that were anorexic at entry had shorter overall disease control. There was a correlation between 1st remission duration and length of any subsequent remission obtained. The incidence of toxicity was high, particularly after the combination of doxorubicin and vincristine. Dose reductions because of toxicity did not markedly reduce remission duration. We conclude that discontinuous chemotherapy may reduce patient visits in a small number of patients because of long-term disease control. Delaying maintenance chemotherapy until after 2nd remission is achieved does not markedly affect overall disease control.     

CHOP chemotherapy for the treatment of canine multicentric T-cell lymphoma

Dogs with multicentric T-cell lymphoma are commonly treated with CHOP chemotherapy protocols that include cyclophosphamide, doxorubicin, vincristine and prednisone. The purpose of this study was to evaluate the use of CHOP chemotherapy for dogs with multicentric T-cell lymphoma. Identification of prognostic factors in this specific subset of dogs was of secondary interest. Twenty-three out of 24 dogs responded to CHOP chemotherapy and these dogs remained on the protocol for a median of 146 days. No variable was associated with progression free survival (PFS) including stage, substage, hypercalcemia or radiographic evidence of a cranial mediastinal mass. The median overall survival time (OST) for all dogs was 235 days. Dogs that were thrombocytopenic at presentation experienced a significantly longer OST (323 versus 212 days, P=0.01).     

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.     

Evaluation of the use of chemotherapy and other prognostic variables for surgically excised canine thyroid carcinoma with and without metastasis

This retrospective study compared the efficacy of surgery alone versus surgery in combination with chemotherapy in the treatment of canine thyroid carcinoma; potential prognostic factors were evaluated. Forty-four dogs with biopsy-confirmed thyroid carcinoma met the inclusion criteria. Twenty-eight dogs were treated with surgery alone and 16 with surgery and chemotherapy. The median survival of dogs treated with surgery and chemotherapy was 518 d, which was not statistically different from that of the dogs treated with surgery alone. The number of thyroid lobes removed at surgery was prognostic with respect to survival. Despite an overall metastatic rate of 48%, the addition of chemotherapy to surgical excision did not improve survival; however, this finding may be due to inadequate power to demonstrate a difference.     

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.     

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.     

Biologic behavior and prognostic factors for mast cell tumors of the canine muzzle: 24 cases (1990-2001)

The medical records of 24 dogs with histologically confirmed mast cell tumors (MCT) of the muzzle were retrospectively evaluated to determine their biologic behavior and prognostic factors. Information on signalment, tumor grade and stage, treatment methods, and pattern of and time to failure and death was obtained from the medical record. Twenty-three dogs were treated with combinations of radiotherapy, surgery, and chemotherapy; 1 dog received no treatment. There were 2 Grade 1, 15 Grade 11, and 7 Grade III tumors. Tumors were stage 0 (n = 8), stage 1 (5), stage 2 (6), stage 3 (4), and stage 4 (1). Mean and median survival times of treated dogs were 36 and 30 months, respectively. Prognostic factors affecting survival time included tumor grade and presence of metastasis at diagnosis. Dogs with Grade I and II tumors survived longer than dogs with Grade III tumors. Variables, including sex, age, gross versus microscopic disease, and treatment type were not found to affect survival. Local control rate was 75% at 1 year and 50% at 3 years. Tumor grade was the only variable found to affect local control. Dogs with Grade I tumors had longer disease-free intervals than those with Grade II tumors, and dogs with Grade II tumors had longer disease-free intervals than dogs with Grade III tumors. Eight of 9 dogs dying of MCT had local or regional disease progression. Muzzle MCT a rebiologically aggressive tumors with higher regional metastatic rates than previously reported for MCT in other sites.     

Canine hemangiosarcoma treated with standard chemotherapy and minocycline

Standard treatments for canine hemangiosarcoma include surgery and chemotherapy with doxorubicin, but in spite of treatment most dogs with this disease die within 6 months of diagnosis. Tumor growth and metastasis are angiogenesis dependent. Antiangiogenic drugs such as minocycline may provide therapeutic benefits in cancer patients. The purpose of this prospective study was to evaluate the efficacy of chemotherapy with doxorubicin and minocycline, an antiangiogenic agent, in dogs with hemangiosarcoma. Eighteen dogs with histologically confirmed hemangiosarcoma of any stage were treated with doxorubicin, cyclophosphamide, and minocycline. Complete staging was performed before and during the treatment period to assess remission status and response to therapy. No statistically significant difference was found in survival between the dogs treated with chemotherapy and minocycline, and historical controls consisting of dogs that received chemotherapy alone. Postmortem examination revealed widespread metastasis, suggesting that minocycline is ineffective as a single antiangiogenic agent in canine hemangiosarcoma.     

Evaluation of some prognostic factors for advanced multicentric lymphosarcoma in the dog: 147 cases (1978-1981)

A total of 147 dogs treated with a combination of chemotherapy procedure (vincristine, L-asparaginase, cyclophosphamide, and methotrexate) were evaluated for response to therapy and the influence of age, sex, clinical stage, and body weight to duration of response. Complete response was achieved in 113 dogs (77%), partial response in 26 dogs (17.7%), and no response in 8 dogs (5.4%). The median survival time for the dogs with complete and partial responses was 265 days. An analysis of factors associated with prognosis revealed that age, clinical stage, and body weight were not associated with response to therapy, whereas sex was. Females had a significantly prolonged remission and survival time (P = 0.0001).     

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.     

Serum thymidine kinase 1 activity as a prognostic biomarker in dogs with chemotherapy-treated diffuse large B-cell lymphoma

Diffuse large B-cell lymphoma (DLBCL) is frequently treated with chemotherapy incorporating cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP), which induces remission in 80% to 95% of cases. However, not all dogs derive meaningful benefit from CHOP, and prognostic factors for dogs with DLBCL are poorly defined. Serum thymidine kinase 1 (TK1) activity, a marker of tumour cell proliferation, has shown promising initial results as a prognostic biomarker in dogs with multicentric lymphomas. The purpose of this study was to determine if baseline serum TK1 activity is associated with clinical outcome in dogs with CHOP-treated DLBCL. Baseline serum TK1 activity was measured in banked sera from 98 dogs with CHOP-treated DLBCL using a commercially available ELISA kit. Data on other potential prognostic factors were abstracted retrospectively from electronic medical records. Multivariable statistical methods were used to identify associations between TK1 and other potential prognostic factors with progression-free survival (PFS) and attainment of complete remission. TK1 activity at baseline was not associated with PFS (p = .299) or attainment of complete remission (p = .910) following CHOP chemotherapy. Of the other prognostic factors analysed, only purebred (vs. mixed breed) status (HR 8.81, 95% CI 1.68–46.30, p = .010), attainment of complete (vs. partial) remission (HR 0.09, 95% CI 0.02–0.49, p = .006), and baseline serum C-reactive protein concentration (HR 1.19, 95% CI 1.07–1.32, p = .001) were independently associated with PFS. Based on these findings, baseline serum TK1 activity does not appear to be a useful prognostic biomarker in dogs with CHOP-treated DLBCL.     

Prognostic Value of Argyrophilic Nucleolar Organizer Region (AgNOR) Staining in Feline Intestinal Lymphoma

Limited information is available on prognostic factors for cats with lymphoma. The quantity of argyrophilic nucleolar organizer region (AgNOR) proteins can be used as a measurement of cellular proliferative activity. To determine if AgNORs were of prognostic value for feline intestinal lymphoma, the silver staining technique was performed on paraffin-embedded sections of 31 cases. Mean number of AgNORs per nucleus ranged from 1.02 to 4.32. Twenty-four (78%) cats had small AgNORs and 7 (22%) had large AgNORs. All cats were treated identically with a combination chemotherapy protocol. Response to chemotherapy was 87%. Median remission duration and survival times were 120 days and 201 days, respectively. No significant correlation was found between mean number of AgNORs per nucleus or AgNOR size and remission rate, remission duration, or survival time. This study indicates that AgNOR staining is not a useful prognostic factor for cats with intestinal lymphoma.     

Retrospective analysis of factors affecting clinical outcome following CHOP‐based chemotherapy in dogs with primary nodal diffuse large B‐cell lymphoma

Numerous factors are known to affect the prognosis of dogs with chemotherapy‐treated lymphomas. However, prognostic factors for dogs with specific subtypes of lymphoma are less clearly defined. The objective of this study was to identify prognostic factors for dogs receiving CHOP‐based chemotherapy for primary nodal diffuse large B‐cell lymphoma (DLBCL). Medical records of dogs treated for DLBCL at the Purdue Veterinary Teaching Hospital (PUVTH) from 2006 to 2016 were reviewed. Factors potentially related to prognosis were analysed using multivariable statistical methods. Ninety‐eight dogs were included in the study. Best overall response to chemotherapy was complete remission in 80 dogs (81.6%) and partial remission in 18 dogs (18.4%). Median progression‐free survival (PFS) for the entire population was 252 days (range 19‐1068). Factors significantly associated with achieving partial (rather than complete) remission following CHOP included presence of thrombocytopenia at diagnosis (OR 6.88; 95% CI 1.98‐23.93; P = .002), baseline serum globulin concentration (OR 2.63; 95% CI 1.03‐6.75; P = .044), and age at diagnosis (OR 1.36; 95% CI 1.08‐1.71; P = .009). Factors significantly associated with PFS in the lowest quartile (≤93 days) included presence of thrombocytopenia at diagnosis (OR 8.72; 95% CI 1.54‐49.33; P = .014), age at diagnosis (OR 1.47; 95% CI 1.12‐1.94; P = .005), and baseline neutrophil count (OR 1.18; 95% CI 1.02‐1.37; P = .025). Presence of thrombocytopenia, greater age, higher neutrophil count, and higher serum globulin concentration all may be associated with a particularly poor outcome in dogs receiving CHOP‐based chemotherapy for DLBCL.     

A retrospective study of the incidence and prognostic factors of multicentric lymphoma in dogs (1998-2000)

Sixty-three dogs with multicentric lymphoma were evaluated for risk of diseases. The greatest risk of disease concerned rottweilers as compared to other breeds (odds ratio 6.01 to 0.32-2.75, respectively). A group of 43 dogs under chemotherapy was evaluated for defining factors influencing first remission time duration and survival time. The most important factors for results of chemotherapy were response to therapy, stage and sub-stage of disease according the World Health Organization staging system at the time of diagnosis.