Canine and Feline Lymphoma: Review of Prognostic Factors and Treatment Options
Rodney L. Page MS, DVM: Diplomate ACVIM
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 lymphomas 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.
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.
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, oOther manifestations of the FeLV infection may limit the use aggressive therapy and may require substantial supportive therapy (blood component administration and nutritional assistance).
3. Morphologic grade in intestinal, infiltrative disease.
4. 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 time period to determine response, this time frame is often not more than 4-8 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 4-8 weeks following the treatment will give the benefit to the cats and does not risk substantial toxicity or expense.
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. Prolonged treatment with Prednisone alone may reduce the future success of combination chemotherapy protocols.
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 period of 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.
C = Cyclophosphamide, O = Oncovin(tm) (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), Mitoxantrone and Cytosine arabinoside.
Cats with low-grade, infiltrative, intestinal lymphoma
Prednisone (5 mg po BID or Q24) plus Chlorambucil (2 mg po EOD).
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.