Treatment of Canine Lymphomas

Since canine malignant lymphoma is virtually a systemic disease, the role of therapeutic surgery is limited. Perhaps surgery can be considered in stage I or II, but there have been no reports on the efficacy of such treatment. Splenectomy has been advocated in systemic lymphoma as a means of rapid tumour cytoreduction or to relieve signs of massive splenomegaly including splenic rupture. Treatment with a corticosteroid as a single agent has often been used because it is inexpensive and relatively non-toxic. Complete remission rates of 17–43% and mean remission times of only 1–2 months have been achieved.

Chemotherapy is the most frequently used method of treatment for canine malignant lymphoma. Chemotherapy of lymphoma may restore the animal to a good quality of life, while achieving alleviation from symptoms for extended periods of time. Therapy should only be considered after a thorough diagnostic work-up, providing not only the cytologic/histologic and immunologic diagnosis but also information on clinical performance, extension of the disease and function of important organs. Severe dysfunction of the kidney, liver or heart limits therapeutic possibilities. Also, poor clinical performance (grade 4–5) in itself has an adverse effect upon prognosis. Induction of remission is the first phase in chemotherapy and is more intense than maintenance therapy. If there is no improvement during the first phase, changing to another protocol may be worthwhile in some cases but discontinuation of therapy should be seriously considered.

A wide variety of protocols have been designed using several drugs, either alone or in combination. In general, the results of combination chemotherapy are better than those of single-agent chemotherapy. The highest response rates (88–96%), the longest disease-free periods (215–330 days), and the longest median survival times (325–357 days) have been obtained with combination protocols of sequential L-asparaginase, vincristine, cyclophosphamide, and doxorubicin or methotrexate, in conjunction with decreasing doses of prednisone. Approximately 10–20% of the dogs treated according to this combination protocol were classified as long-term survivals or even as being cured.

Although initially all histological and immunological multicentric lymphomas were treated with the same protocols, newer insights have suggested that low-grade T-cell lymphomas have a much better prognosis than B-cell lymphomas and high-grade T-cell lymphomas, and can perhaps be treated less aggressively with prednisolone and chlorambucil only. Investigations are underway to see if high-grade T-cell lymphomas should be treated differently than B-cell lymphomas.

In most dogs in which chemotherapy is used, a relapse will eventually occur. Depending on the induction protocol and the maintenance protocol that has been used, re-induction with the same protocol may be effective. However, in most cases remission rates and duration of remissions will be less after the second treatment than after the first. When the first treatment did not include doxorubicin or L-asparaginase, use of these agents in the second treatment should be considered. However, a multidrug resistance (MDR) induced by the initial treatment should be expected. The overexpression of a plasma membrane protein, P-glycoprotein (member of the ABC transporter family), which acts as a drug efflux pump, has been found to be partly responsible for this phenomenon. Therefore the use of drugs not influenced by MDR might be considered (e.g., CCNU, temozolomide).

Pretreatment with prednisolone in dogs with lymphoma has a negative influence on chemotherapy outcome, presumably because of P-glycoprotein induction. However, glucocorticoids are included in all protocols. Therefore we investigated the additional role of prednisolone in a multidrug protocol in a randomized clinical trial. We could not find any benefit of the prednisolone in treatment outcomes, but also not a negative effect. Glucocorticoids also did not have an effect on ABC transporter mRNA expression, although the occurrence of treatment resistance was associated with increased ABCB5 and ABCC5 expression. At this moment an experimental anti-CD20 monoclonal immunotherapy is available in the US. This therapy can be used in addition to chemotherapy. Most likely, its highest efficacy will be for those animals with a B-cell lymphoma that are in complete remission. Large clinical studies still have to come out.

The treatment of cutaneous lymphoma depends on the presentation of the disease. When the cutaneous involvement is part of a systemic disease, the protocols for treatment of multicentric malignant lymphoma can be used. In primary, solitary cutaneous lymphoma, surgical excision or radiotherapy is the treatment of choice. In widespread cutaneous lymphoma, chemotherapy protocols including doxorubicin can be used. The initial response may be good but survival times are usually shorter than in dogs with multicentric lymphoma. In epitheliotropic cutaneous lymphoma the prognosis is usually poor. Treatment is difficult. Lomustine/CCNU, at a starting dose of 70 mg/m² has been reported in the treatment of canine epitheliotropic lymphoma. Objective response was measured in 78% of the 36 dogs, with a median duration of 106 days. Toxicoses after CCNU chemotherapy included myelosuppression, gastrointestinal signs, and increased liver enzymes. The use of retinoids such as isotretinoin and etretinate has been reported to achieve remission in 6 out of 14 dogs with cutaneous lymphoma. However, larger studies confirming the efficacy of this treatment are lacking. Incidental successes with photodynamic therapy have been reported. Usually responses are short lasting. Recently, in a study in 10 dogs with epitheliotropic lymphoma, the potential role of masitinib, a tyrosine kinase inhibitor, was investigated. Complete remission occurred in 2 of 10 dogs and lasted for median 85 days. Five dogs went into partial remission for median 60.5 days. As in none of these tumours KIT expression was demonstrated, masitinib's effects are most likely not generated through the KIT receptor.

Treatment and Prognosis in Feline Malignant Lymphoma

Due to the systemic character of most malignant lymphomas, regional therapy alone, either surgery or radiotherapy, will usually not be effective enough and therefore chemotherapy is the preferred treatment modality. In contrast to the extensive literature on the treatment of canine malignant lymphoma, there are fewer reports of clinical trials in cats.

For the treatment of cats with malignant lymphoma several chemotherapy protocols have been published, including a monotherapy with doxorubicin and combination protocols, like the COP protocol and the Madison-Wisconsin-like protocols (CHOP-based protocols). The COP protocol was already published in the eighties; however, recently we published new results. Based on these studies, a complete remission rate of 75–79% can be achieved, although the different subtypes give different results. The highest percentage CRs are achieved in the mediastinal form (92%), the peripheral form (80–85%) and the nasal form (75%). Although the remission rates were comparable with protocols including doxorubicin, to our surprise the longest survival times were reported with this simple COP protocol. For the total group 50–54% survived 1 year and 40–48% 2 years. Almost all that survived one year could be considered as cured as they did not need additional treatment. Perhaps the very low percentage of FeLV-negative cats (only 7%) was responsible for these very good results. Interestingly, independent from other characteristics, Siamese cats had a much better prognosis in this study than the other breeds. The COP protocol is well tolerated by the cats. Haemorrhagic cystitis is seldom seen in the cat. Also alopecia is not a problem, although loss of the whiskers is a frequent side effect. Other investigators have demonstrated also that in cats a COP protocol is not inferior to doxorubicin-consisting multidrug protocols.

In our second report on the COP protocols in cats we have administered both cyclophosphamide and vincristine intraperitoneal (IP) in all cats instead of IV. Till this moment we have performed more than 600 administrations IP and did not encounter any significant toxicity. No signs of peritonitis or pain have been seen. The results were comparable to the IV administrations. In addition, we performed a bioavailability study and demonstrated comparable bioavailability for IV and IP administration.

There have been no reports on the use of rescue therapy in cats with relapse of lymphoma, but doxorubicin or idarubicin may also be used in cats that have been treated with protocols not including anthracyclines. For gastrointestinal lymphomas hypofractionated radiation protocols have been effective in inducing second remissions, which were relatively long lasting.

References

1.  Teske E, Van Straten G, Van Noort R, Rutteman GR. Chemotherapy in cats with malignant lymphoma: new results with an old protocol. J Vet Intern Med. 2002;16:179–186.

2.  Zandvliet M, Rutteman GR, Teske E. Prednisolone inclusion in a first-line multidrug cytostatic protocol for the treatment of canine lymphoma does not affect therapy results. Vet J. 2013;197:656–661.

3.  Teske E, van Lankveld AJ, Rutteman GR. Intraperitoneal antineoplastic drug delivery: experience with a cyclophosphamide, vincristine and prednisolone protocol in cats with malignant lymphoma. Vet Comp Oncol. 2014, 12:37-46.

4.  Voorhorst MJ, van Maarseveen EM, van Lankveld AJ, Teske E. Bioavailability of cyclophosphamide and vincristine after intraperitoneal administration in cats. Anticancer Drugs. 2014;25:1211–1214.

5.  Zandvliet M, Teske E, Schrickx JA, Mol JA. A longitudinal study of ABC transporter expression in canine multicentric lymphoma. Vet J. 2015;205:263–271.

6.  Zandvliet M, Teske E. Mechanisms of drug resistance in veterinary oncology - A review with an emphasis on canine lymphoma. Vet Sci. 2015;2:150–184.

7.  Holtermann N, Kiupel M, Kessler M, Teske E, Betz D, Hirschberger J. Masitinib monotherapy in canine epitheliotropic lymphoma. Vet Comp Oncol. 2015 Sep 14. [Epub ahead of print]