Update on canine lymphoma: Where are we going? (Proceedings)

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, staging, prognosis – dogs

The typical dog with LSA will present with generalized (or less commonly regional) lymphadenopathy. 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. The WHO has developed a clinical staging system for dogs with multicentric LSA (See Table 1). Most dogs that present are WHO Stage IIIa or IVa.

Table 1: WHO Staging Criteria for Canine Lymphoma

Factors that have historically carried the most prognostic significance for remission duration and survival include clinical signs at presentation (substage b), hypercalcemia, mediastinal lymphadenopathy, significant bone marrow infiltration, and T cell immunophenotype. 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.

Diagnosis, staging, prognosis – cats

Generalized lymphadenopathy is an uncommon presentation for cats with LSA. Clinical signs are dependent on the body system affected. Due to the changes in FeLV testing and vaccination, there has been a shift in the anatomic distribution of feline LSA over the past 15 years. Whereas the mediastinal form, occurring in young FeLV+ cats previously predominated, we are now seeing a great deal more of the alimentary form in older, FeLV- cats. Given the anatomic distribution in cats, diagnosis is more often achieved through histopathology after exploratory laparotomy or endoscopy. Needle aspiration cytology of enlarged peripheral lymph nodes in cats can be difficult to interpret, as cats are subject to a variety of lymphoid hyperplastic conditions that can mimic LSA cytologically.

Clinical staging in cats with LSA is very similar to that in the dog. However, addition of FeLV and FIV serology is reasonable, due to its impact n prognosis and husbandry. A pre-treatment abdominal ultrasound is also important to establish a pre-treatment baseline in cats with alimentary LSA.

What's new – diagnosis, staging, prognosis

Most veterinary pathology laboratories are now capable of immunophenotyping lymphomas with the use of immunohistochemistry. However, this does require a biopsy. The University of California at Davis, Colorado State University and North Carolina State University can perform immunophenoptying on fresh fine-needle aspirates using flow cytometry. A third method for establishing immunophenotype is through PCR for antigen receptor rearrangement (PARR). This molecular diagnostic test evaluates the presence or absence of a clonally expanded population of B cells or T cells, and is approximately 85% sensitive and 95% specific for canine lymphoid neoplasia. An advantage of this technique is that it can be performed on almost any type of sample, including air-dried or previously stained cytology slides, effusions, aspirates, cerebrospinal fluid, and peripheral blood. Formalin-fixed tissues cannot be used for this technique.

A recent publication suggests that immunostaining for the cellular survival protein survivin may be a useful prognostic factor in dogs with stage IIIa and IVa B cell lymphoma, a population for which there are no reliable prognostic factors currently. These interesting preliminary findings need to be confirmed in additional studies.

Treatment and outcome - dogs

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. In addition, dogs that are systemically ill will often show improvements in appetite, activity and attitude. Finally, steroids may reduce the magnitude of hypercalcemia, 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 palliative option for some owners if chemotherapy is declined. However, it is important that owners understand 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 simple, low-toxic and inexpensive chemotherapy protocol with intermediate efficacy is the COP protocol (CTX/Vincristine/Prednisone) protocol. Prednisone is administered orally as above, CTX is administered orally every 3 weeks, and vincristine (VCR) 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. 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. 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 injectable protocols that include doxorubicin. A protocol of this type (one of many published protocols) is employed at the Colorado State University. (It has been referred to in publications as the UW-Madison protocol or L-ASP-VCAM.) This treatment utilizes sequential injections of VCR, CTX, and DOX, combined with daily oral prednisone for the first 4 weeks (See Table 2). 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. The likelihood of a patient experiencing some type of adverse side effect is approximately 20%. However, the vast majority of side effects observed are mild and self-limiting, and do not require hospitalization. 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.

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

Treatment and outcome – cats

The basic tenets of treatment for feline LSA are very similar to canine. One important difference, however, is that single-agent doxorubicin appears to have less activity in feline LSA. Even with injectable multiagent chemotherapy, response and survival rates are lower in cats than in dogs, with approximately 70% of cats achieving a complete response, and median survival times in the 6-8 month range, even with aggressive therapy. However, approximately 30% of cats may do well for a very long time, with survival times exceeding 2 years.

What's new – treatment and outcome

Asparaginase vs. no asparaginase

Older publications routinely include a single injection of asparaginase at the beginning of multi-agent treatment. Recently, 2 studies have demonstrated no improvement in any measure of outcome in dogs receiving asparaginase. For this reason, the author chooses to omit asparaginase from initial treatment and save it for use as a potential therapy at relapse.

Maintenance vs. no maintenance

One of the debates among veterinary oncologists centers around the utility of "extended maintenance" chemotherapy for pets with LSA. In human medicine, treatment is rarely continued for longer than 6 to 10 months, and randomized trials have not demonstrated significant survival advantage for patients receiving extended maintenance chemotherapy. We previously investigated the effect of discontinuing treatment after 25 weeks of standard-dose chemotherapy. Analysis of a cohort of 50 dogs treated with this protocol showed no statistical difference in survival time or disease-free interval when compared with dogs receiving a similar protocol including extended maintenance chemotherapy. There are no studies in the literature investigating the necessity for maintenance chemotherapy in feline LSA.

Radiation therapy

Since LSA is considered a systemic disease in most circumstances, radiation therapy (RT) is not used commonly. One exception is in cases of feline nasal LSA, which is often solitary at presentation. In this disease, RT can be very efficacious. LSA can be very sensitive to RT, and thus is can be useful as a palliative treatment in animals with clinical signs related to lymphoma at a specific site (e.g. pleural effusion from mediastinal disease). Several studies have been published recently evaluating the outcome of dogs treated with chemotherapy combined with half-body radiation therapy, in which one half of the body is irradiated, then several weeks later the other half is irradiated: definitive evidence of improvement in outcome is lacking.

Other new findings

A recent report suggests that cats with low-grade gastrointestinal LSA may respond favorably and enjoy comparably long survival times when a protocol employing oral chlorambucil (15 mg/m2 PO daily for four days, repeated every 3 weeks) and prednisone is employed. It is not known if this treatment is appropriate for cats with low-grade LSA of other sites or for dogs with low-grade LSA.

Recently, a retrospective study demonstrated that the incidence of sterile hemorrhagic cystitis, a known adverse effect following injectable cyclophosphamide chemotherapy, can be reduced by more than half (from about 7% to less than 2%) if a single dose of injectable furosemide is given concurrently (1 mg/kg).

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 is shown in Table 3.

Table 3: Response to Chemotherapy in Dogs with Relapsed Lymphoma

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. The Author's current favorite second-line protocol is a combination of prednisone, asparaginase and lomustine; 85% of dogs will respond, and the median response duration is approximately 2 months.

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

1. Vail DM, Young KM. Canine lymphoma and lymphoid leukemia. In: Withrow SJ and Vail DM, eds. Small Animal Clinical Oncology (4th Ed). Philadelphia: Saunders, 2007. pp. 699-733.

2. Vail DM. Feline lymphoma and leukemia. In: Withrow SJ and Vail DM, eds. Small Animal Clinical Oncology (4th Ed). Philadelphia: Saunders, 2007. pp. 733-756.

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

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

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

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

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

8. Saba CF, Thamm DH, Vail DM. Combination chemotherapy with L-asparaginase, lomustine, and prednisone for relapsed canine lymphoma. J Vet Intern Med 21: 127-132, 2007.

9. MacDonald VS, Thamm DH, Kurzman ID, Turek MM, Vail DM. Does L-asparaginase influence efficacy or toxicity when added to a standard CHOP protocol for dogs with lymphoma? J Vet Intern Med 19(5): 732-736, 2005.