Introduction

Lymphoma (LSA) is a relatively common disease entity in veterinary medicine.  Most small animal practitioners will encounter LSA in their practice, and will be asked to provide information and treatment recommendations for pets with this condition.

Diagnosis and Staging – Dogs

The typical dog with LSA will present with generalized (or less commonly regional) lymphadenopathy.  Differential diagnoses for generalized lymphadenopathy can include Ehrlichiosis or other immune-mediated diseases, systemic mycosis, severe pyoderma or other skin disease, and reactive hyperplasia.  The most simple way do discern the cause for lymphadenopathy is via needle aspiration cytology of an affected lymph node.  If possible, the submandibular lymph nodes should be avoided due to the likelihood of some component of reactive hyperplasia being present due to drainage from the mouth and ears.  Although many clinical pathologists are able to confirm a diagnosis of canine LSA cytologically, excisional biopsy of an affected lymph node provides the most information.  It is critical that empiric prednisone therapy not be employed prior to diagnosis if lymphoma is a differential, as this may mask the signs of illness and has the potential to induce resistance to other forms of chemotherapy (See below).

Complete clinical staging helps to ascertain the extent of disease, ensures that other types of medical problems are not present, and can provide prognostic information for the client.  Complete staging should include complete blood count, serum chemistry panel, urinalysis, thoracic radiographs, and a bone marrow aspirate.  Imaging of the abdominal cavity is of limited use, unless abdominal palpation is extremely difficult, or if abnormalities other than cranial organomegaly are palpated or clinical signs consistent with primary gastrointestinal disease are present.  The World Health Organization has developed a clinical staging system for dogs with multicentric LSA, which takes into account the number and location of involved lymph nodes, presence or absence of hepatosplenomegaly, and the presence or absence of disease in the bone marrow, central nervous system, or other extranodal sites.  In addition, a substage is assigned, (a) representing a patient without clinical signs of illness, and (b) representing a patient with clinical signs (anorexia, lethargy/weakness/ depression, significant weight loss, vomiting, diarrhea, etc.) (See Table 1).  Most dogs that present are WHO Stage IIIa or IVa.

Table 1:      WHO Staging Criteria for Canine Lymphoma.

Stage I:           Disease confined to a single lymph node.

Stage II:          Regional lymphadenopathy (confined to one side of diaphragm).

Stage III:         Generalized lymphadenopathy.

Stage IV:         Hepatosplenomegaly (with or without lymphadenopathy)

Stage V:          Bone marrow, CNS, or other extranodal site involvement

Substage a:       No clinical signs

Substage b:       Clinical signs of illness

Complete staging allows a thorough assessment of factors that may help to predict the outcome with treatment for an individual patient.  Factors that have historically carried the most prognostic significance for remission duration and survival include presence of clinical signs at presentation (substage b), presence of hypercalcemia, mediastinal lymphadenopathy, and significant bone marrow infiltration.  It is probable that both hypercalcemia and mediastinal lymphadenopathy are actually surrogate markers for LSA with a T cell immunophenotype, a very powerful predictor of outcome. Most veterinary pathology laboratories are capable of immunophenotyping lymphomas with the use of CD3 immunohistochemistry.  Additionally, the University of California at Davis, Colorado State University and North Carolina State University can perform this evaluation on fine-needle aspirates using flow cytometry or PCR for antigen receptor rearrangement (PARR). These prognostic factors do not typically alter the likelihood that a patient will achieve a complete response (CR); they do however, affect the likely duration of that response.

Treatment and Prognosis

Chemotherapy is the mainstay of treatment for LSA.  A large number of single-agent and multi-agent chemotherapy protocols have been investigated over the last 20 years.  However, one optimal chemotherapy protocol has not been identified which can integrate positive outcome, toxicity and cost.  In general, combination chemotherapy is considered more efficacious than single-agent chemotherapy.

Corticosteroids alone have been shown to induce at least partial remission in many dogs with LSA by their direct cytotoxic effect on the tumor cells.  In addition, dogs that are systemically ill will often show improvements in appetite, activity and attitude while receiving steroids.  Finally, steroids may reduce the magnitude of hypercalcaemia, if present.  Oral corticosteroids (most commonly prednisone at 2 mg/kg/day initially, then tapered over time to 0.5-1 mg/kg/day) are an excellent treatment option for some owners if chemotherapy is declined.  However, it is important that owners understand the ramifications of utilizing prednisone as a single agent before initiating treatment.  I will commonly inform owners that “Prednisone is a one-way street”. While most dogs will experience significant short-term improvement, the duration of that improvement is typically on the order of only 1-2 months, and prednisone appears to be a powerful inducer of chemotherapy resistance.  In other words, multi-agent chemotherapy is much less likely to be efficacious if a patient has come out of remission after treatment with prednisone alone.

A relatively simple, non-toxic and inexpensive chemotherapy protocol with intermediate efficacy is the COP (CTX/Vincristine/Prednisone) protocol.  Prednisone is administered orally as above, cyclophosphamide is administered either orally or injectably at 200 mg/m2 every 3 weeks, and vincristine is injected weekly for 4 weeks, then every 3 weeks thereafter.  Response rates of approximately 75% can be achieved, and the median survival times are in the range of 6-8 months in most reports.  Another protocol with similar efficacy is single-agent doxorubicin (DOX).  This has become more affordable for many clients since DOX has become available in a generic form, and has the advantage of requiring only one injection every three weeks.  In addition, if a side effect is encountered the drug responsible is easy to identify.  Two unique effects of DOX are its potential for cumulative cardiac toxicity in dogs and cumulative nephrotoxicity in cats, and its potential to cause severe skin necrosis if extravasated.

Generally, the most successful chemotherapy protocols have been multiagent protocols that include doxorubicin.   A protocol of this type (one of many published protocols), referred to here as LA-CHOP, is employed at many institutions.  (It has also been referred to in publications as the UW-Madison protocol, UW-25, or L-ASP-VCAM.)  This treatment utilizes sequential injections of vincristine, CTX, and DOX, combined with daily oral prednisone for the first 4 weeks (See Table 2).

Table 2: LA-CHOP (UW-Madison) Protocol for Canine Lymphoma

Week 1: Vincristine 0.7 mg/m2 IV Prednisone 2 mg/kg PO QD

Week 2: *Cyclophosphamide 250 mg/m2 IV Prednisone 1.5 mg/kg PO QD

Week 3: Vincristine 0.7 mg/m2 IV Prednisone 1 mg/kg PO QD

Week 4: Doxorubicin 30 mg/m2 IV Prednisone 0.5 mg/kg PO QD

Week 6: Vincristine 0.7 mg/m2 IV Prednisone: Discontinue

Week 7: Cyclophosphamide 250 mg/m2 IV

Week 8: Vincristine 0.7 mg/m2 IV

Week 9:Doxorubicin 30 mg/m2 IV

Week 11: Vincristine 0.7 mg/m2 IV

Week 13: Cyclophosphamide 250 mg/m2 IV

Week 15: Vincristine 0.7 mg/m2 IV

Week 17: Doxorubicin 30 mg/m2 IV

Week 19: Vincristine 0.7 mg/m2 IV

Week 21: Cyclophosphamide 250 mg/m2 IV

Week 23: Vincristine 0.7 mg/m2 IV

Week 25: Doxorubicin 30 mg/m2 IV

* 1 mg/kg furosemide is given concurrently with each cyclophosphamide injection to

diminish the occurrence of sterile hemorrhagic cystitis

Complete response rates are 85-90% with these protocols, and median survival times are approximately 12 months, with 20-25% of dogs living longer than 2 years. Despite the improvements made in recent years in extending disease-free interval and survival time in dogs with LSA, all but 5% of patients will eventually relapse.

Rescue

When remission is lost (either after an interval with no chemotherapy or after treatment at 2 or 3 week intervals), a large number of patients may experience a second remission simply by returning to the “top of the protocol”, i.e. switching back to weekly treatments and re-initiating prednisone therapy.  However, a rule of thumb is that the second remission is likely to be about half as long as the first.  After a period of time, the tumor cells will acquire resistance to the initial drugs utilized, and “rescue” or “salvage” chemotherapy drugs or protocols can be considered.  A summary of rescue agents/protocols that have been systematically evaluated in dogs is shown in Table 3.

Table 3:         Response to Chemotherapy in Dogs with Relapsed Lymphoma.

Drug(s)                     Resp. Rate        Resp. Duration              Comments

Actinomycin D               0-83%                 0-42 days             Variable between studies

Mitoxantrone                21-47%              42-126 days          Variable between studies

VP-16 (Etoposide)            16%              8 and 90 days        Severe pruritus in 85%

CCNU (Lomustine)          26%                    86 days              Cum. thrombocytopenia

Asparaginase/CCNU        87%                    63 days              111 days if CR attained

Taxol   (paclitaxel)           33%                       NR                 Hypersensitivity reactions

Doxorubicin                     42%                   145 days             No prior exposure to DOX

DOX/DTIC                       74%                 30-106 days

Cisplatin/Cytosar             30%                 30-108 days

MOPP                             65%                  47-63 days           Severe myelosuppression

D-MAC                            80%                  28-86 days           12 weeks if CR attained

DTIC: Also called dacarbazine.  MOPP: Mechlorethamine (nitrogen mustard), vincris-

tine, procarbazine, prednisone.   D-MAC: Dexamethasone, melphalan, actinomycin D,

cytosine  arabinoside.  NR: Not reported.  Response rates refer to a combination of

complete and partial responses.

The take-home message is that while there are many different drugs that can be utilized in this setting, no one agent or protocol is uniformly superior over the others in terms of response rate and duration.   Sometimes, attaining a second or third remission can be a matter of trial and error, until an efficacious drug is found.

In summary, although LSA is a disease that can rarely be cured, it can be managed effectively in the majority of cases.  Therapy is typically very well tolerated, and patients experience an excellent quality of life.  Significant improvements have been made in recent years with regard to the treatment of this common disease, and we are hopeful that the coming years will bring equally great improvements.

References

Cotter SM (1983). Treatment of lymphoma and leukemia with cyclophosphamide, vincristine and prednisone: 1. Treatment of dogs. J Am An Hosp Assoc Vol. 19: 159-165.

Garrett LD, Thamm DH, Chun R, Dudley R, Vail DM (2002). Evaluation of a six-month chemotherapy protocol with no maintenance therapy for dogs with lymphoma. J Vet Intern Med Vol. 16: 704-709.

Kristal O, Lana SE, Ogilvie GK, Rand WM, Cotter SM, Moore AS (2001). Single-agent chemotherapy with doxorubicin for feline lymphoma: a retrospective study of 19 cases (1994-1997). J Vet Intern Med Vol. 15: 125-130.

Lingard AE, Briscoe K, Beatty JA, Moore AS, Crowley AM, Krockenberger M, Churcher RK, Canfield PJ, Barrs VR (2009). Low-grade alimentary lymphoma: clinicopathological findings and response to treatment in 17 cases. J Feline Med Surg Vol. 11: 692-700.

Postorino NC, Susaneck SJ, Withrow SJ, Macy DW(1989). Single agent therapy with adriamycin for canine lymphosarcoma. J Am An Hosp Assoc Vol. 25: 221-225.

Teske E, van Straten G, van Noort R, Rutteman GR (2002). Chemotherapy with cyclophosphamide, vincristine, and prednisolone (COP) in cats with malignant lymphoma: new results with an old protocol. J Vet Intern Med Vol. 16: 179-186.

Vail DM, Moore AS, Ogilvie GK, Volk LM (1998). Feline lymphoma (145 cases): proliferation indices, CD3 immunoreactivity, and their association with prognosis in 90 cats. J Vet Intern Med Vol. 12: 349-354.

Vail DM, Thamm DH.  Hematopoietic tumors.  In: Ettinger S, Feldman E (eds), Textbook of Veterinary Internal Medicine, 6th Ed.  Philadelphia: Saunders, 2005. pp. 732-746.