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.     

Feline large granular lymphocyte lymphoma: An Italian Society of Veterinary Oncology (SIONCOV) retrospective study

Feline large granular lymphocyte (LGL) lymphoma is an uncommon subtype of lymphoma characterized by a grave prognosis and scarce response to chemotherapy. There are limited reports on clinico‐pathological and prognostic factors. One‐hundred and 9 cats with newly diagnosed LGL lymphoma that underwent initial staging (including hematology, serum biochemistry, thoracic radiographs and abdominal ultrasound), and followed‐up were retrospectively evaluated. LGL lymphoma was localized within the gastrointestinal tract with or without extra‐intestinal involvement in 91.7% of the cases, and at extra‐gastrointestinal sites in 8.3%. Symptoms were frequent. Anemia (31.2%) and neutrophilia (26.6%) were commonly observed, and 14 (12.8%) cats had neoplastic circulating cells. Frequent biochemistry abnormalities included elevated ALT (39.4%) and hypoalbuminemia (28.4%). Twenty (54.1%) of 37 cats had elevated serum LDH. Treatment varied among cats, and included surgery (11%), chemotherapy (23%), corticosteroids (38.5%) and no treatment (27.5%). Median time to progression (MTTP) was 5 days, and median survival time (MST) 21 days. MST was significantly shorter in the case of substage b, circulating neoplastic cells, lack of chemotherapy administration, and lack of treatment response. A small subset of cats (7.3%) survived more than 6 months, suggesting that a more favorable clinical course can be found among LGL lymphoma patients.     

A retrospective evaluation of lomustine (CeeNU) in 32 treatment naïve cats with intermediate to large cell gastrointestinal lymphoma (2006–2013)

Multi‐drug chemotherapy protocols for feline lymphoma have demonstrated variable efficacy and tolerability. In phase I trials, lomustine has demonstrated efficacy for cats with lymphoma though its use for treatment naïve feline intermediate/large cell gastrointestinal (GI) lymphoma remains unknown. This study evaluated the efficacy and tolerability of lomustine for the treatment of feline GI lymphoma. Thirty‐two cats with histologically or cytologically confirmed intermediate/large cell GI lymphoma were evaluated retrospectively. Factors assessed included clinical signs, hematologic/biochemical parameters and use of l ‐asparaginase at induction. A response rate of 50% (16/32), with median duration of response of 302 days (range 64–1450 days), was found. Median progression‐free interval was 132 days (range 31–1450 days), with overall median survival time of 108 days (range 4–1488 days). History of hyporexia, presence of anaemia and dose of lomustine were significantly associated with progression‐free survival. Overall, lomustine is a well‐tolerated and effective treatment for feline GI lymphoma.     

Chemotherapy with cyclophosphamide, vincristine, and prednisolone (COP) in cats with malignant lymphoma: new results with an old protocol

This retrospective study in 61 cats with malignant lymphomas examined the efficacy of a well-established chemotherapy protocol (cyclophosphamide, vincristine, and prednisolone [COP]) in the Netherlands, a country with a low prevalence of feline leukemia virus (FeLV). Twenty-two cats (36.1%) had mediastinal lymphoma, 11 (18.0%) had alimentary lymphoma, 7 (11.5%) had peripheral lymphoma, 8 (13.1%) had nasal lymphoma, and 13 (21.3%) had miscellaneous lymphoma (including renal lymphoma in 2 [3.3%]). Of the 54 cats that were tested, only 4 (7.4%) were FeLV positive. Complete remission (CR) was achieved in 46 of the 61 cats (75.4%). The estimated 1- and 2-year disease-free periods (DFPs) in the 46 cats with CR were 51.4 and 37.8%, respectively, whereas the median duration of remission was 251 days. The overall estimated 1-year survival rate in all cats was 48.7%, and the 2-year survival rate was 39.9%, with a median survival of 266 days. The median survival time and the 1-year survival rate for mediastinal lymphoma were 262 days and 49.4%. respectively. Siamese cats had a more favorable prognosis for survival and remission than other breeds. Response to therapy in this study was shown to be a significant prognostic indicator. CR is necessary for long-term survival. Cats that did not achieve CR had little chance of survival for longer than I year. Young Siamese cats in this study had a greater tendency to develop mediastinal malignant lymphoma at a young age, and all were FeLV negative. In comparison with results reported in other studies with different combination chemotherapy protocols, these are among the highest percentages of remission and the longest survival rates for cats with malignant lymphoma.     

Evaluation of P-glycoprotein expression in feline lymphoma and correlation with clinical outcome

P-glycoprotein (Pgp) is a transmembrane protein pump involved in drug resistance in canine and human lymphoma. There are no published clinical studies evaluating Pgp expression in feline lymphoma. The purpose of this study is to evaluate the level of Pgp expression in feline lymphoma and correlate it with clinical outcome. Two human Pgp monoclonal antibodies, C219 and C494, were used to detect Pgp expression in tissue samples from 63 cats with lymphoma. Demographic results appear comparable to recently published feline lymphoma studies. The Kaplan–Meier median remission and survival times were 164 and 571 days, respectively. Fourteen cats had positive expression of Pgp using MAb C219, and 40 were positive with C494. Variables statistically associated with survival included bone marrow involvement, stage, substage, and use of radiation therapy as a part of treatment. Pgp expression as assessed by MAb C219 and C494 is not predictive of remission or survival time in cats with lymphoma.     

Feline Lymphoma (145 Cases): Proliferation Indices, Cluster of Differentiation 3 Immunoreactivity, and Their Association with Prognosis in 90 Cats

Paraffin-embedded, formalin-fixed tissue samples from 145 cats with lymphoma were analyzed for cluster of differentiation 3 (CD3, a surface antigen) immunoreactivity, argyrophilic nucleolar organizer region (AgNOR) frequency, and proliferating cell nuclear antigen labeling index (PCNA-LI). This information along with signalment, anatomic site, and feline leukemia virus (FeLV) antigen status was used to determine the potential of these indicators to predict response to therapy, remission, and survival times, and to characterize cats with lymphoma in the era of general availability of FeLV testing and vaccination. Alimentary lymphoma, primarily occurring in older, FeLV-negative cats, was the most common site of involvement. Although the majority of tumors from FeLV-positive cats were CD3-immunoreactive, only one half of CD3-immunoreactive tumors occurred in FeLV-positive cats. Median remission duration and survival times were 126 days and 143 days, respectively, for all cats. Measures of tumor cell proliferation (AgNOR frequency and PCNA-LI) and CD3-immunoreactivity were not predictive of outcome. When all prognostic factors were accounted for by multivariate analysis, response to therapy, FeLV status, and clinical substage were predictive of outcome. FeLV-negative cats that achieved a complete response following induction therapy were likely to have durable (ie, > 6-month) responses, particularly when doxorubicin was included in the chemotherapy protocol. However, FeLV-positive cats had significantly shorter remission and survival times with available chemotherapeutic protocols.     

Feline extranodal lymphoma: response to chemotherapy and survival in 110 cats

O bjective : To determine response to treatment, survival and prognostic factors for feline extranodal lymphoma in the UK.
M ethods : Records of cats diagnosed with lymphoma of extranodal sites at seven referral centres were reviewed and information on signalment, tumour location, prior treatment and chemotherapy protocol recorded. Factors influencing response to treatment and survival were assessed.
R esults : One hundred and forty-nine cases met inclusion criteria. Sixty-nine cats had nasal lymphoma, 35 renal, 15 central nervous system, 11 laryngeal and 19 miscellaneous locations. Sixty-six cats received cyclophosphamide, vincristine, prednisolone, 25 Wisconsin-Madison doxorubicin-containing multi-agent protocol, 10 prednisolone alone and nine other combinations. The response rate for the 110 treated cats was 85·5 per cent. Of cyclophosphamide, vincristine, prednisolone treated cats 72·7 per cent achieved complete remission, median survival 239 days. Sixty-four per cent of Wisconsin-Madison treated cats achieved complete remission, median survival 563 days. Cats with nasal lymphoma achieving complete remission had the longest survival (749 days) and cats with central nervous system lymphoma the shortest (70 days). If complete remission was achieved, prior treatment with corticosteroids significantly reduced survival time.
C linical S ignificance : Cats with extranodal lymphoma respond to chemotherapy and achieve survival times comparable to other locations. Corticosteroid pretreatment reduced survival time in cats achieving complete remission.     

Treatment and prognostic factors in lymphoma in cats: 103 cases (1977-1981)

The records of 103 cats with lymphoma that underwent chemotherapy were reviewed. Diagnosis was confirmed by cytologic or histopathologic examination of appropriate tissue specimens. Sixty-four cats (62%) had a complete response to chemotherapy (median survival time, 7 months); 21 cats (20%) had a partial response (median survival time, 2.5 months); and 18 cats had a minimal response (median survival time, 1.5 months). Seventy-seven cats (75%) died of recurrent or progressive lymphoma, 9 cats died of feline leukemia-related anemia, 13 cats died of unrelated causes, and 4 cats were alive. Stage of disease was significantly (P = 0.009) related to response to treatment, and stage of disease and FeLV status were both significantly (P = 0.002 and P less than 0.001, respectively) related to survival.     

Incidence of persistent viraemia and latent feline leukaemia virus infection in cats with lymphoma

In the past, feline leukaemia virus (FeLV) infection, and also latent FeLV infection, were commonly associated with lymphoma and leukaemia. In this study, the prevalence of FeLV provirus in tumour tissue and bone marrow in FeLV antigen-negative cats with these tumours was assessed. Seventy-seven diseased cats were surveyed (61 antigen-negative, 16 antigen-positive). Blood, bone marrow, and tumour samples were investigated by two polymerase chain reaction (PCR) assays detecting deoxyribonucleic acid (DNA) sequences of the long terminal repeats (LTR) and the envelope (env) region of the FeLV genome. Immunohistochemistry (IHC) was performed in bone marrow and tumour tissue. None of the antigen-negative cats with lymphoma was detectably infected with latent FeLV. The prevalence of FeLV viraemia in cats with lymphoma was 20.8%. This suggests that causes other than FeLV play a role in tumorigenesis, and that latent FeLV infection is unlikely to be responsible for most feline lymphomas and leukaemias.     

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.     

Vaccine site-associated sarcoma and malignant lymphoma in cats: a report of six cases (1997-2002)

Six cats developed malignant lymphoma 3 to 45 months after treatment for vaccine site-associated sarcoma. During the same time period, 184 cats were evaluated in the teaching hospital for vaccine site-associated sarcomas. Feline vaccine site-associated sarcoma is not believed to be associated with feline leukemia virus (FeLV) infection. Five of six cats were negative by enzyme-linked immunosorbent assay for FeLV antigens at the times of diagnosis of both sarcoma and lymphoma, and no cats were infected with feline immunodeficiency virus.     

Feline gastrointestinal lymphoma.

Gastrointestinal lymphoma is a common cause of anorexia and weight loss in older cats, with or without vomiting or diarrhea. Most cats are feline leukemia virus-negative and feline immunodeficiency virus-negative. Low-grade gastrointestinal lymphoma may be more common than previously thought, and these cats respond better to chemotherapy agents than cats with high-grade lymphoma. The most significant prognostic indicator is initial response to chemotherapy, with cats that survive the initial induction period generally achieving long-term remission. Thus far, investigations into molecular markers and immunophenotyping have failed to identify useful prognostic indicators.     

Combination chemotherapy in feline lymphoma: treatment outcome, tolerability, and duration in 23 cats

BACKGROUND: Different chemotherapy regimes have been described for feline lymphoma with varying outcomes. HYPOTHESIS: In cats with lymphoma, a long-term, multiagent chemotherapy protocol will be effective and carry acceptable toxicity. ANIMALS: Twenty-three cats with histologically or cytologically confirmed diagnosis of lymphoma. METHODS: Prospective, single-arm clinical trial in which cats were treated with a chemotherapy protocol consisting of a cyclic combination of l-asparaginase, vincristine, cyclophosphamide, doxorubicin, methotrexate, and prednisolone with a planned total treatment time of 122 weeks. RESULTS: Complete remission (CR) rate was 74% (n = 17). Fourteen percent of cats attained partial remission (PR). Median duration of first CR was 264 days (range, 45-2,485 days). Six-month, 1-, and 2-5-year remission rates were 75, 50, and 34%, respectively. Duration of PR ranged between 23 and 63 days. Median survival in cats with CR was 296 days (range, 50-2,520 days). Six-month, 1-, 2-, and 3-5-year survival rates in cats with CR were 82, 47, 34, and 27%, respectively. Survival of cats achieving PR ranged between 38 and 120 days. Of the analyzed variables, only anatomical location had a significant influence on remission duration (P=.022). Actual median treatment time in cats with CR was 128 days (18 weeks). Hematologic and gastrointestinal toxicosis was infrequent and mostly low grade. CONCLUSIONS AND CLINICAL IMPORTANCE: In this population of cats with lymphoma, chemotherapy was effective. With infrequent and mostly low-grade toxicosis, tolerability of the protocol may be considered good.     

Rescue therapy with doxorubicin-based chemotherapy for relapsing or refractory feline lymphoma: a retrospective study of 23 cases

This study examined the efficacy of doxorubicin-based chemotherapy used for rescue therapy in refractory feline lymphoma. Records of 23 cats with lymphoma treated with chemotherapy who received doxorubicin for the first time in a rescue setting were reviewed. Seventeen (74%) of the 23 cats had only one treatment of doxorubicin. Five (22%) of the 23 cats had a positive response to doxorubicin and were given additional doses. The response to therapy in 4/5 of these responders could be assessed objectively, of which, two cats (9%) achieved partial remission (PR) and two cats (9%) achieved complete remission (CR). The two cats that achieved CR had differing response durations (6 weeks and greater than 47 months). Three of these five (60%) responders had also received concurrent other chemotherapy in addition to doxorubicin. Cell type and the use of concurrent chemotherapy were significant predictors of response. Cats with small-medium cell lymphomas (P=0.001) and cats that received concurrent chemotherapy with doxorubicin rescue (P=0.007) were more likely to respond favorably. This study suggests that doxorubicin-based chemotherapy is not an effective rescue protocol for feline lymphoma.     

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.     

Prognostic significance of weight changes during treatment of feline lymphoma

The study purpose was to determine the prognostic significance of weight changes during feline lymphoma treatment. A secondary purpose was to compare weight changes according to baseline body weight, cell type and location. Records of 209 cats treated for lymphoma with chemotherapy from 1995 to 2007 were evaluated. Signalment, cell type, lymphoma location, baseline body weight, weight during treatment, and outcome information were collected. Lymphoma specific survival (LSS) was compared according to baseline weight and weight changes during treatment. Weight change over time was compared according to cell type (small versus large), location (gastrointestinal versus non-gastrointestinal) and baseline weight. Cats with large cell lymphoma that lost ≥ 5% body weight at 1 month had significantly shorter LSS than those that gained or had stable weight (P = 0.004). Percentage weight change over time differed significantly according to baseline weight group. These findings demonstrate the prognostic importance of weight loss in feline large cell lymphoma.     

Surgical cytoreduction for the treatment of non-lymphoid vertebral and spinal cord neoplasms in cats: retrospective evaluation of 26 cases (1990–2005)

Medical records of 26 cats with non‐lymphoid vertebral and spinal cord neoplasms treated surgically were reviewed to determine outcome and prognostic factors for survival. Of the factors examined, only tumour phenotype was significantly associated with survival. Osteosarcoma (3/26 cats) and meningioma (16/26 cats) were the most common malignant and benign tumours, respectively. The median survival time for cats with malignant neoplasms was 110.5 days, compared with 518 days for cats with benign tumours. Cytoreductive surgery resulted in clinical improvement in 25/26 cats, but local treatment failure occurred in 10/26 cats. Overall, 19/26 cats died of confirmed (12/19) or suspected (7/19) tumour‐related causes, including all eight cats with malignant neoplasms. Results suggest that contemporary neurosurgical techniques commonly result in incomplete excision of feline non‐lymphoid vertebral and spinal cord tumours but are efficacious at palliation of clinical signs of spinal cord dysfunction.     

RESPONSE OF NINETEEN CATS WITH NASAL LYMPHOMA TO RADIATION THERAPY AND CHEMOTHERAPY

The records of 19 cats treated for stage I nasal lymphoma with radiation therapy and chemotherapy were reviewed to determine response to therapy, treatment outcome and possible prognostic indicators. All cats were treated with megavoltage radiation therapy to a total dose ranging from 22 to 48 Gy (median dose = 42 Gy). All cats were prescribed at least 6 months of multiagent chemotherapy. The median progression-free interval for all cats was 945 days (31 months). Two cats did not achieve clinical remission. Of 17 cats evaluable for relapse, 10 (58.8%) were progression free during the entire follow-up period. Four cats (23.5%) suffered local recurrence, while three (17.6%) experienced distant relapse. The median survival time was 955 days (31.4 months). The only variable found to have a significant negative impact on survival was destruction of the cribriform plate before therapy (P= 0.002). The long progression free and survival times reported here indicate that cats with stage I nasal lymphoma treated with aggressive local and systemic therapy can have a favorable outcome when compared with other anatomic forms of lymphoma. Despite strong clinical responses to the multimodality therapy used, the fact that three (17.6%) cats relapsed distantly supports the recommendation that treatment with radiation therapy alone is insufficient until further prospective studies can be performed.     

Response rates and survival times for cats with lymphoma treated with the University of Wisconsin-Madison chemotherapy protocol: 38 cases (1996-2003)

OBJECTIVE: To determine response rates and survival times for cats with lymphoma treated with the University of Wisconsin-Madison chemotherapy protocol. DESIGN: Retrospective study. ANIMALS: 38 cats with lymphoma. PROCEDURE: Medical records were reviewed, and information on age, sex, breed, FeLV and FIV infection status, anatomic form, clinical stage, and survival time was obtained. Immunophenotyping was not performed. RESULTS: Mean +/- SD age of the cats was 10.9 +/- 4.4 years. Overall median survival time was 210 days (interquartile range, 90 to 657 days), and overall duration of first remission was 156 days (interquartile range, 87 to 316 days). Age, sex, anatomic form, and clinical stage were not significantly associated with duration of first remission or survival time. Eighteen of the 38 (47%) cats had complete remission, 14 (37%) had partial remission, and 6 (16%) had no response. Duration of first remission was significantly longer for cats with complete remission (654 days) than for cats with partial remission (114 days). Median survival time for cats with complete remission (654 days) was significantly longer than median survival time for cats with partial remission (122 days) and for cats with no response (11 days). CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that a high percentage of cats with lymphoma will respond to treatment with the University of Wisconsin-Madison chemotherapy protocol. Age, sex, anatomic form, and clinical stage were not significantly associated with duration of first response or survival time, but initial response to treatment was.     

Clinical aspects of feline immunodeficiency and feline leukemia virus infection

Feline leukemia virus (FeLV) and feline immunodeficiency virus (FIV) are retroviruses with a global impact on the health of domestic cats. The two viruses differ in their potential to cause disease. FIV can cause an acquired immunodeficiency syndrome that increases the risk of developing opportunistic infections, neurological diseases, and tumors. In most naturally infected cats, however, FIV itself does not cause severe clinical signs, and FIV-infected cats may live many years without any health problems. FeLV is more pathogenic, and was long considered to be responsible for more clinical syndromes than any other agent in cats. FeLV can cause tumors (mainly lymphoma), bone marrow suppression syndromes (mainly anemia) and lead to secondary infectious diseases caused by suppressive effects of the virus on bone marrow and the immune system. Today, FeLV is less important as a deadly infectious agent as in the last 20 years prevalence has been decreasing in most countries.