Therapeutic Choices for the Medical Management of Feline Lymphoma

Leslie E. Fox, DVM, MS, Diplomate ACVIM (Internal Medicine)

College of Veterinary Medicine, Iowa State University
Ames, IA, USA

INTRODUCTION
Changes in disease frequency and presentation of feline lymphoma necessitate a somewhat different approach to
protocol selection and supportive care. The incidence, signalment, and etiology of this disease has changed
during the 80’s and 90’s. Overall, it appears that feline leukemia virus infection has declined along with the
frequency of some anatomic forms. Previously, lymphoma was most commonly a disease of younger, FeLV
antigen positive cats often with mediastinal or multicentric involvement. Today, the younger cat with lymphoma
is likely to be FeLV antigen positive, however, most affected cats are older (10–12 years old), FeLV antigen
negative with the alimentary anatomic form predominating. Lymphoma involving the peripheral nodes and
extranodal lymphomas are diagnosed more frequently as well. Compared with earlier studies, FIV is more
common. An association between FIV- induced immunosuppression and lymphoma has been demonstrated in
infected cats. Additionally, there are geographic differences in the causation and frequency of anatomic types of
lymphoma as well as, differences in response to the same protocols based on geography.
Recent changes in the presentation of feline lymphoma make selecting and delivering potentially efficacious
treatment that meets the needs of the individual patient challenging. In almost all cases, feline lymphoma is a
systemic disease that needs to be treated systemically. With the exception of a subset of GI lymphomas, a
multidrug protocol that includes at least doxorubicin and l-asparaginase, is the most efficacious, well-tolerated,
treatment protocol currently available. Solitary lymphoma can be treated with surgery or radiation therapy
followed by multidrug chemotherapy. Many cats (more than 85% in one study) are sick either from their
lymphoma or because of unrelated geriatric diseases. Nutritional support is essential during the first 3–6 weeks of
therapy for all patients, but particularly for those patients with gastrointestinal (GI) involvement. Geriatric
patients often have age-associated diseases such as renal insufficiency, hyperthyroidism, and diabetes mellitus
which complicate therapy and need be addressed before chemotherapy is initiated.
It is possible to predict the long-term outcome for many patients in the first 4–6 weeks of a multidrug
chemotherapy protocol that includes doxorubicin and l-asparaginase, such as the AMC and UW-Madison-
Wisconsin protocols (See Table 1). After 4–6 weeks of therapy, the patient will have received five of the most
commonly used drugs with antitumor activity against lymphoma. At the end of 6 weeks, it is possible to make a
good assessment of protocol efficacy and potential drug toxicity. The cat’s initial response to therapy tells you,
perhaps more reliably than any other factor, how the treatment is going to progress. While cats with a partial
response to therapy (greater than 50% reduction in tumor size) often enjoy improved quality of life, cats with an
initial complete response to therapy live longer (12–18 months vs 6–8 months). Generally, cats that have not
responded favorably to the first 4–6 weeks of therapy continue to have a poor response to therapy despite the
addition of other drugs. Likewise, cats that experience frequent adverse drug events requiring treatment delays
and dose reductions often continue to have difficulty tolerating other anticancer drugs. Repeated dose reductions
resulting in subtherapeutic treatment dosages will shorten disease free interval and decrease lifespan.

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Table 1. Selected Protocols for the Treatment of Feline Lymphoma
ƒ Cotter-COP
o Day 1, 8, 15, 22: Vincristine 0.75 mg/m2 IV
o Day 1, 22: Cyclophosphamide 300 mg/m2 PO
o Every day: Prednisone 2 mg/kg PO
o After day 22, vincristine and cyclophosphamide were given on the same day every 3 weeks
until relapse or for one year if remission maintained. Also, Mahoney, Moore, Vail.
ƒ Moore-COP plus Doxorubicin: COP as above
o If complete remission is achieved, then begin doxorubicin, 25 mg/m2, IV every 3 wks for 6
additional months
ƒ Jeglum-VCM
o Week 1 and 3: Vincristine 0.025 mg/kg IV
o Week 2: Cyclophosphamide 10 mg/kg IV
o Week 4: Methotrexate 0.8 mg/kg IV
o Every day: 5 mg prednisone PO
o Continue for 2 years. Mediastinal form–add l-asparaginase, 400 U/kg, IM on week 1.
ƒ Mooney-VCM plus l-asparaginase with high dose prednisone
o Week 1: l-asparaginase, 400 U/kg, IM
o Week 1 and 3: Vincristine 0.025 mg/kg IV
o Week 2: Cyclophosphamide 10 mg/kg IV
o Week 4: Methotrexate 0.8 mg/kg IV
o Every day: 2 mg/kg prednisone PO
o Continue for 2 years
o For renal lymphoma after complete remission substitute cytosine arabinoside 600 mg/m2
SQ for cyclophosphamide.
ƒ Rassnick, Mauldin, Zwahlen-AMC Protocol (ACOPA-M)
o Week 1: l-asparaginase 400 IU/kg IM
o Week 1, 4, 8 and 12: Vincristine 0.025 mg/kg IV
o Week 2, 5, 10: Cyclophosphamide 10 mg/kg IV
o Week 3, 6: Doxorubicin 20 mg/m2 IV
o Week 14: Methotrexate 0.8 mg/kg IV
o Every day: prednisone 5 mg/cat PO BID
o If in complete remission, biweekly maintenance therapy consisting of week 8, 10, 12 and 14
therapy is given for 12 months. If still in complete remission, then the same protocol is
given triweekly for 6 months and then increased to 4-week intervals between treatments for
6 months. Therapy is given for a total of 2 years.
ƒ MacEwen-University of WI-Madison
o Week 1, 3, 8, 11, 12, 15, 19, 23: Vincristine 0.7 mg/m2 IV
o Week 1: l-asparaginase 400 IU/kg IM
o Week 2, 7, 13, 21: Cyclophosphamide 250 mg/m2 IV
o Week 4, 9, 25: Doxorubicin 20 mg/m2 IV
o Week 17: Methotrexate 0.8 mg/kg IV
o Every day for the first 2 weeks: Prednisone 2 mg/kg PO, then 1 mg/kg PO daily

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 Continue protocol biweekly for weeks 11–25, then tri-weekly for 6 months, then monthly
o
for 6 months. Therapy is given for 2 years total. Also, Vail.
ƒ Malik-modified AMC—See ref # 7
ƒ Mauldin-MOPP
o Days 1 and 8: Mechlorethamine at 3.0 mg/m2 IV and vincristine at 0.025 mg/kg IV
o Days 1 through 14: Procarbazine at 10 mg PO once daily
o Every day: 5 mg/cat PO BID
ƒ Rassnick-MOPP-AC
o Days 1 and 8: Mechlorethamine at 3.0 mg/m2 IV and vincristine 0.5 mg/m2 IV
o Days 1 through 14: Procarbazine 10 mg/cat PO once daily
o Every day: Prednisone 40 mg/m2 PO daily
o Days 22, 57, 99, 141, 183: Doxorubicin 25 mg/m2 IV
o Days 36, 78, 120, 162, 204: Cyclophosphamide, 200 mg/m2 IV + vincristine 0.5 mg/m2 IV
o If in complete remission at week 30, protocol is discontinued.

REVIEW OF RESPONSE TO PROTOCOLS

Single agent chemotherapy has been tried with disappointing results. While mitoxantrone was not helpful in
10/11 cats, doxorubicin was associated with somewhat better responses, but was not very effective at inducing
and maintaining remission. In one study, 5/19 (25%) had a complete remission; however, the median response
duration was 3 months. Lomustine (CCNU) has been evaluated in a small number of cats where partial
remissions were achieved. Idarubicin has been used with reasonable success for inducing and maintaining
remission; however, currently it is available only in Europe.
The multidrug COP protocol consisting of cyclophosphamide, prednisone, and vincristine has been one of
the standard protocols for feline lymphoma treatment; however, the reported response and survival rates vary
with time and geography. In a 1996 study of 38 northeastern American cats, 18/38 (47%) had a complete
remission lasting less than 3 months. The responders were 6/11 (54%) cats with multicentric lymphoma, 5/12
(41%) cats with alimentary lymphoma, and only 2/9 (22%) cats with renal lymphoma. In comparison, a 1983
study of 38 cats with features less typical than we see today (i.e., more cats were FeLV antigen positive and had
mediastinal lymphoma), the complete remission rate was high (30/38 79% cats) and the median response
duration was 5 months. Geographic differences may be responsible for the good response to COP therapy
reported in 2002 study of cats living in the Netherlands. Most cats were FeLV antigen negative and mediastinal
lymphoma was the most common form. Complete remission was achieved in 46/61 (75%) cats with an overall
median remission duration of 8.3 months and median survival time of 8.8 months.
The addition of doxorubicin and/or l-asparaginase has improved remission and survival times in most
studies. Moore, et al. used doxorubicin as maintenance therapy after complete remission was achieved with COP.
Median remission duration for the 7 cats that received doxorubicin after COP was 9.3 months versus 2.6 months
for cats treated with COP alone. Two cats were still in remission one and 1.5 years after starting
COP/doxorubicin.
Jeglum, et al., used COP plus l-asparaginase and methotrexate to treat 75 cats with a 52% complete response
with a median response duration of 5 months. Cats with multicentric lymphoma had the best response with a
median survival time of 18 months. 9/32 (29%) in the study lived longer than 2 years. Mooney et al. treated 103
cats with a similar protocol (AMC) where 64/103 (62%) had a complete remission with a 7-month median
survival time and 19/64 (29%) lived beyond 1 year. Using the same protocol, Mooney, et al. showed 17/28 (61%)
cats with renal lymphoma achieved a complete response to combination therapy, but median survival times were

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short (5.7 months). Mauldin et al. treated 132 cats with primarily GI lymphoma (72%) with most cats FeLV antigen
negative and clinical substage b or sick with the AMC protocol. In that study, 67% achieved complete remission
with a first remission duration for all 132 cats of 4.9 months (range, 1 day–5.4 years) and median survival time of
6.9 months (range, 0.5 month–5.6 years). More recently, Zwahlen, et al., treated twenty-one FeLV antigen negative
cats with GI lymphomas with the AMC protocol and 8/21 (38%) had a complete response. Median first remission
was 9.8 months and median survival time was 10.2 months.
Using a procarbazine, vincristine, prednisone, and mechlorethamine combination (MOPP) plus
doxorubicin/cyclophosphamide of Rassnick and coworkers, 52% of cats had a CR with a median survival time of
6.5 months. Forty-two percent (15/35) of cats had multicentric and 12/35 (34%) cats had extranodal lymphomas.
Some cats were long-lived (5 cats were still alive at 1.5–2 years after the initiation of therapy).
Second remissions are difficult to achieve and short-lived in cats. Information about effective protocols is
scarce. If COP was used successfully to induce a first remission, then the addition of doxorubicin and/or l-
asparaginase may help reinduce remission. If a doxorubicin/l-asparaginase protocol was used initially and
complete remission was achieved, then the first 4 weeks of that effective protocol can be given again. The MOPP
protocol can be used for rescue for cats with refractory lymphoma. In a Mauldin, et al. study, 17/27 (74%) had GI
lymphoma and most were FeLV antigen and FIV antibody negative. The overall response rate was 13/23 (56%)
with additional median remission duration of 3 weeks and median survival about 2 months after initiation of
MOPP protocol. Although well tolerated, mechlorethamine is not currently available to veterinary patients.
Ifosfamide (900 mg/m2 every 3 weeks, IV) in conjunction with diuresis and mesna for patients without renal
insufficiency may be helpful in the future.
Maintenance therapy for cats is needed until otherwise demonstrated. Cats treated with COP without any
maintenance therapy by Cotter stayed in remission for a median time of 45 days. In contrast, dogs treated with a
high dose, multidrug, doxorubicin-containing protocols given without maintenance therapy live as long as dogs
treated with added maintenance therapy. Current investigations are underway to determine whether feline
lymphoma behaves similarly.
Extranodal or solitary lymphoma can be treated with combined therapy consisting of surgery or radiation
therapy and chemotherapy or with chemotherapy alone. If the tumor is easily resectable, then surgical excision is
appropriate; however, resection of solitary GI masses has not improved survival. Lymphocytes are exquisitely
sensitive to even low doses of radiation, so only a few treatments may be necessary to relieve thoracic or spinal
compression with a response often observed only a few hours after a single dose. In a study of cats (Elmslie, et al.)
with subcutaneous, nasal, oral, mediastinal, and retrobulbar lymphoma treated with 8–40 Gy, most cats achieved
a complete remission which lasted 6 months to 5 years, but most cats received chemotherapy as well. Spinal
lymphoma is may be best treated with combinations of surgical debulking, radiation therapy, and systemic
chemotherapy; however, there are few reports of long-term survival.
Since it is impossible to identify the very few cats that might be cured with local therapy alone, cats with
focal lymphoma are presumed to have systemic disease and should be treated with multidrug chemotherapy.
Small number of cats with nasal lymphoma have been evaluated, but it appears that they enjoy the longest
remission and survival times. It is unclear whether chemotherapy alone, focal radiation therapy, or combination
therapy constitutes the best therapy. Confirmation of focal nasal lymphoma with careful clinical staging
(including bone marrow aspiration cytology) may identify a subpopulation that responds favorably (>1.5 years
MST) to radiation therapy alone; however, there is insufficient numbers of treated cats to recommend not treating
for systemic disease at this time.

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Table 2. Remission Rates, Times, and Survival Times for Cats Treated for Lymphoma
Author– Tumor Location Cases Complete Median Median Reference
Protocol Remission Remission Survival
Rate (%) (Mos) (Mos)

Cotter-COP Thymic 12 92 6.0 NR 1

Mahony-COP Alimentary 7 86 4.5 NR 6
Moore-COP Peripheral nodes 5 80 2.8 NR 12
Multicentric 4 100 5.0 NR
Overall NR. 79 5.0 NR
Alimentary 28 33 7.0 1.5
All Anatomic 38 47 3.0 NR
Types
Moore-COP + All Anatomic 7 47 9.2 NR 12
Doxorubicin Types
Teske-COP Mediastinal 22 82 8.3 8.7 15
Miscellaneous 11 73 5.7 4.6
Alimentary 11 63 8.1 6.3
Nasal 8 75 11.9 *
Peripheral 7 85 12.6 20.8
Overall 61 75 8.3 8.8
Jeglum-VCM + Thymic 31 45 2.0 2.6 4
1-asp Alimentary 9 50 6.0 9.6
Renal 6 16 NR 5.0
Multicentric 16 68 NR 18.0
Overall NR 52 NR 2.0
Mooney-AMC Renal 28 61 5.0 5.7 11
Mooney-AMC All types 103 62 7.0 7.0 10
Rassnick-AMC Alimentary 31 71 (PR+CR) 4 6.7 overall If 6
CR, then 8.6
Malik– All types 61 80 If in CR, 3.8 If in CR, 7
modified AMC then 3.7 then 6.2
Mauldin-AMC All Anatomic 132 67 4.9 6.9 9
Types
Zwahlen-AMC Alimentary 21 38 10 10.3 18
MacEwen-UW- All types 22 68 9.1 7.5 17
Madison
Rassnick - All Anatomic 34 52 NR 6.5 13
MOPP-AC Types
NR = Not reported

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 * Median not reached
CR = complete remission
PR = partial remission

PROGNOSTIC VARIABLES AFFECTING RESPONSE TO THERAPY

Few prognostic factors are consistently associated with remission and survival. Although the cat’s initial response
to therapy is the most consistent variable influencing remission and survival times, histomorphology of GI
lymphomas, tumor location, tumor burden (clinical stage) and the presence of systemic illness have been found to
influence treatment outcome.
Histomorphology of gastrointestinal (GI) lymphoma may be used to guide treatment selection. GI
lymphoma can be histologically graded into lymphocytic, intermediate, and lymphoblastic subtypes. Fondacaro,
et al., treated 29 cats with lymphocytic lymphoma with a minimal protocol consisting of chlorambucil (15 mg/m2
per day for 4 days, every 2 weeks) and prednisone (10 mg/cat/day). Twenty of twenty-six cats (76%) achieved a
complete remission. Median remission duration for cats in complete remission was 20.5 months (5.8–49 months)
with a median survival time of almost 2 years (10–50 months). Cats that came out of remission were treated with
cyclophosphamide (225 mg/m2 every 3 weeks, PO) with a 6-month increase in median survival time for
responders. Eight cats with lymphoblastic lymphoma were treated with the AMC protocol and only 2/8 (21%)
cats achieved a complete remission lasting 12 and 17 months.
Cats with nasal, peripheral nodal, in some reports, mediastinal lymphoma may live longest, while cats
with renal, CNS, spinal lymphoma and nonacute lymphoblastic leukemias have shorter survival. In Klein and
coworkers, 19 cats with nasal lymphoma were treated with chemotherapy alone, 6 with radiation therapy alone,
and 8 with both chemotherapy and radiation therapy where median survival times were 5, 19.7, 5.9 months.
Using COP alone, Teske, et al., treated 8 cats with nasal lymphoma where 6/8 cats (75%) achieved a complete
remission lasting a median of 1 year. With COP, Cotter treated 5 cats with peripheral node involvement, 4/5
(80%) achieved complete remission with a median remission time of 28 months. There are no reports of median
survival times greater than about 5 months for cats with renal lymphoma. The nervous system is either involved
at the time of diagnosis or becomes affected soon after.
Cats that are FeLV antigen and FIV antibody negative and have Clinical Stage I or II live longest. Cats with
advanced clinical stage (Clinical Stage III, IV, and V) do not live as long as cats with less extensive disease
(Clinical Stage I and II) (about 2 months median survival time vs 7.5 months). Cats with a large tumor burden,
thus advanced clinical stage are less likely to go into remission. Cats with massive abdominal tumor volume or
severe hepato/splenomegaly are not as likely to achieve a complete remission when compared with cats with less
tumor burden (50% vs 90%). It appears that in every protocol evaluation, a subset of cats enjoys long-term
survival of 1.5 to 3 + years regardless of anatomic type or clinical stage. It is not known what distinguishes these
cats from other shorter-lived patients.
The sick cat with lymphoma is perhaps the biggest challenge to achieving a good response to therapy. Cats
that are sick at the time of diagnosis are more likely to experience adverse events associated with anticancer drugs
and do not survive as long as cats who are otherwise “healthy.” Using a modified AMC protocol, 20 Australian
cats that survived at least 16 weeks after the start of therapy had a median survival time of 2.3+ years. The FeLV
antigen or FIV antibody positive cat can be treated with the same multidrug protocols administered at the same
dosages/frequency as unaffected cats. In all but one study, FeLV infected cats were as likely to have a complete
response to therapy as noninfected cats, but as might be expected, they do not live as long because of
complications from cytopenias and infectious disease.

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IMPROVING YOUR RESULTS AND CLIENT SATISFACTION
Human patients who receive adequate nutrition live longer and experience fewer adverse drug effects than
malnourished patients. With appropriate supportive care, most cats enjoy a good quality of life during therapy.
Loss of appetite is the most common adverse effect. Megestrol acetate (2.5–5 mg/cat PO once a day) or
cyproheptadine (1–4 mg/cat PO once a day) may stimulate appetite. Supplemental feeding is imperative for cats
with GI lymphoma. Since appetite stimulants are not practical for long-term maintenance of feline patients,
nasogastric, pharyngostomy, or gastrostomy tube feeding is strongly recommended for inappetant and/or
underweight cats. Extensive upper GI disease may necessitate jejunal feeding. Most cats need between 200 and
300 Kcal/day that require 6 to 9 oz of a complete and balanced, canned cat food (1–1.5 kcal/ml). If the cat
responds to chemotherapy, then tube feeding is usually needed for 3–6 weeks.
Vomiting is reported with varying frequency among protocols, but little is said about the frequency of
antiemetic therapy for these patients. Metoclopramide (0.2–0.4 mg/kg PO q 8 hours) is an effective antiemetic for
most patients with chemotherapy-induced vomiting. We give metoclopramide before giving cyclophosphamide,
doxorubicin, vincristine, mechlorethamine and methotrexate routinely and send 2 days of medication for
administration by owners. Withholding food the morning of therapy is advisable. Additional, affordable
antiemetics include chlorpromazine (0.2–0.4 mg/kg SQ q 8h) and prochlorperazine (0.1–0.5 mg/kg IM or SQ q 8
hr).
Anxiety is a problem for some cats receiving weekly chemotherapy. We first try giving valium at home or
soon after arrival at the clinic. If that doesn’t decrease anxiety, then hydromorphone (0.05–0.1 mg/kg IM)
combined with butorphanol (0.05–0.1 mg/kg IM) is given. Acepromazine (0.01–0.05 mg/kg IM) may be added if
needed. Placement of a vascular access port at the start of therapy makes drug administration almost effortless.
(Access Technologies, Norfolk Veterinary Products, Skokie, Il, 60076) Blood samples are easily obtained and
drugs may be given via the same port. When not in use, catheter patency is maintained with a heparinized saline
flush every 4–5 weeks.
Renal insufficiency is the most common cause of adverse drug effects in elderly human patients with
cancer. With adequate hydration, supportive care (erythropoietin, transfusions) and judicious drug dosing, cats
with chronic renal failure can be successfully treated and have a fair prognosis. Doxorubicin and
cyclophosphamide should be used with caution. Procarbazine, piroxicam, and methotrexate should be avoided in
cats with renal insufficiency. Drugs with little renal excretion such as vincristine, vinblastine, l-asparaginase,
chlorambucil, lomustine, and prednisone may be used with reasonable safety. Cats requiring frequent IV fluid
support as well as IV chemotherapy, benefit greatly from permanent vascular access port placement.

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publication or parts thereof without written permission from Waltham USA, Inc. is prohibited. The opinions expressed in these proceedings
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