Canine and Feline Lymphoma:
Review of Prognostic Factors and Treatment Options

Rodney Page United States

Canine Lymphoma

Prognostic Factors

1. Phenotype (lymphocyte lineage): The most important prognostic factor identified to date is whether the neoplasm arises from a B-cell lineage or a T-cell lineage. Several large retrospective reviews have concluded that T-cell lymphomas are more likely to fail than are B-cell tumors. At least half of the T-cell derived tumors are helper T cells (CD4+), secrete parathyroid-like hormone and are thus, hypercalcemic. Overall, only 20% of all dogs with lymphoma are of T-cell origin, the remaining 80% of B-cell tumors represent a large number of dogs. Within this group, the response to chemotherapy is also very diverse. Means of further delineating �responding� from �non-responding� B-cell lymphoma is necessary.

2. Cranial Mediastinal Lymphadenopathy: The presence of any lymphadenopathy within the cranial mediastinum was identified as another negative predictor of outcome in a large retrospective study. This association was observed with even mild (small) mediastinal involvement and was also found to be unassociated with phenotype (i.e., the effect was equally strong within the B and T cell categories).

3. WHO Stage and Substaging: Dogs with stage I�III were found to have better response to treatment than were dogs with stage IV/V. Dogs with systemic manifestations of their tumor (fever, depression, coagulopathies, GI symptoms) were more likely to fail than dogs without signs of illness (substage A vs. B).

4. Gender: Intact male dogs have been found by several investigators to be at higher risk of death than other genders. The role of testosterone on chemosensitivity is not well characterized.

5. Cell proliferation status: The number cells actively cycling and the rate of cell proliferation (doubling time) has been examined in several different studies for relevance to outcome. Data has been mixed in these studies.

TABLE 1: Multivariate analysis of factors identified as significant for remission (Rem) and (Surv)

TABLE 2: Complete response (CR) rate, progression free survival (PFS�days) and overall survival (Surv�days) for dogs treated with combination chemotherapy in various immunophenotypic categories of lymphoma

Immuno Phenotype (n)	CR rate (%)	All Dogs PFS� Surv		Dog�s achieving CR PFS� Surv
Any T (27)	67%	52a	153 a	60 a	168 a
Any B (119)	81	160	330	188	385
��� B5 Low (57)	79	125b	202 b	155 b	245 b
��� B5 Norm (23)	83	203 b	385 b	232 b	420 b

^a Log Rank and Wilcoxon statistic < 0.0001 between T-cell lymphoma and any of the B�cell lymphoma categories. ^b Log Rank and Wilcoxon statistic < 0.05 for comparison between B5(low) and B5(Normal) categories of B-cell lymphomas.

Feline Lymphoma

Prognostic Factors

1. Stage: Feline lymphoma is classically staged according to a similar scheme as that in dogs. In addition, the extent of disease (bulky tumor involvement of liver/spleen or massive abdominal involvement) is considered an additional aid in assessing potential response to conventional therapy. Cats with bulky stage III or IV disease may fail to achieve a complete remission more often (50%) than cats without extensive tumor burdens (90%). Presentation of cats with systemic illness is also a negative prognostic factor as in dogs.

2. FeLV antigenemia: In addition to negative effect of FeLV infection, other manifestations of the FeLV infection may limit the use aggressive therapy and may require substantial supportive therapy (blood component administration and nutritional assistance).

6. Morphologic grade in intestinal, infiltrative disease.

7. Response to initial therapy is perhaps the most reliable prognostic factor. Although this requires commitment from the owner to initiate treatment and maintain the treatment for a sufficient period to determine response, this time frame is often not more than four to eight weeks. Cats that achieve a complete remission initially may continue to have durable remissions, extending for more than 12-18 months. Encouraging the owner of cat with lymphoma to attempt treatment and setting a decision point four to eight weeks following the treatment will give the benefit to the cats and does not risk substantial toxicity or expense.

Staging Criteria	Prognostic Factor Med Surv	(mo.s)
Stage I      Single lymph node, tumor (thymic or extranodal)
Stage II     Regional lymph nodes, one side of diaphragm.	Response to Therapy
Single, resectable GI nodule	CR	7
Stage III    Generalized lymphadenopathy�	PR	2.5
Unresectable/multiple GI Nodule	Stage
Stage IV�    Liver and/or spleen involvement�	I, II	7.6
Epidural involvement	III, IV, V	3.0
+/- Stage III�	FeLV Status
�	Neg	9
Stage V     Blood and/or bone marrow involvement.�	Pos	4.2
Multiple or infiltrative extranodal involvement.�	FeLV Neg/ Stage I,II	17.5
(pulmonary, CNS)�	GI�well differentiated	>18
+/- Stage III or IV.
Additional considerations: Substage a vs. b Extensive tumor burden (organomegaly)

General Recommendations for Therapy

 Inducing a complete remission is the most important aspect of treatment. Several induction protocols exist and owners should be encouraged to include this component in the treatment regimen even if less aggressive maintenance therapy is elected.

 Combination chemotherapy is more effective than single agent chemotherapy. However, the activity of each single must be known before incorporation into multi-agent protocol. The use of prednisone alone is considered palliative therapy, and in fact, may reduce the ability to subsequent effectiveness of combination protocols. Therefore, initiate combination therapy within a short time following diagnosis rather than start prednisone for several weeks with the intention of instituting the rest of the drugs later.

 The incorporation of doxorubicin into combination protocols has provided a significant benefit to many dogs with lymphoma. This compound requires more extensive monitoring and knowledge regarding management of potential side effects. However, it is currently recommended as a component of the treatment regimen, unless contraindications to its use exist.

 Numerous protocols exist and several can be found in general textbooks. The general response and survival for many of the common protocols are listed below. Remember that each of the numbers here is a median without consideration of any single prognostic category. The specific data for groups of dogs with prognostically distinct characteristics treated with combination protocols is located in the tables above.

Comparison of Treatment Protocols for Canine Lymphoma.
Treatment�	Remission Times	Survival Times
Untreated�	-	~ 30 days
Prednisone	20-40 days	30-120 days
COP	150 days	200 days
L-AspPCOM	132 days	219 days
Adriamycin-based	� ~ 240 days�	�~ 365 days
COAP�	180 days	220 days
C = Cyclophosphamide, O = Oncovin� (vincristrine), P = prednisone,� M = Methotrexate, A = Cytosine Arabinoside, L-Asp = L-asparaginase

 Additional chemotherapeutic agents known to be effective for canine lymphoma:

CCNU (CeeNU or Lomustine),�� Mechlorethamine (Mustargen).
Procarbazine (Matulane), Chlorambucil (Leukeran).

 Cats with low-grade, infiltrative, intestinal lymphoma:

Prednisone (5 mg q12 PO or q24h) plus Chlorambucil (2 mg PO EOD).

 Other Considerations:

Half-Body Radiotherapy following chemotherapy.
Single GI nodule with or without mesenteric lymphadenopathy or infiltrate�consider surgery followed by chemotherapy.
Solitary, extranodal lymphoma (cutaneous, CNS, ocular, etc)

FelV (+) � local control with surgery or radiation plus systemic chemotherapy.
FelV (-) � local control only (surgery or radiation).