Treating lymphoma in dogs and cats

Because single-agent lomustine has demonstrated therapeutic activity for the treatment of refractory canine lymphoma, intuitively, it would be expected that lomustine should possess efficacy when used against drug-naïve, high-grade, multicentric canine lymphoma. Given lomustine's oral formulation, relative low cost, therapeutic effectiveness against refractory lymphomas, and reported low incidence of hepatotoxicity, lomustine appears to be an excellent anticancer drug, but keep in mind that conventional, multiagent systemic chemotherapy is still considered the gold standard for treating canine lymphoma. Carefully consider using single-agent lomustine as a first-line treatment option, and make sure you understand and recognize the potential hazards of using lomustine.

FIGURE 6. A laparoscopic view of the gross morphologic appearance of the liver in a standard poodle with hepatotoxicity attributed to chronic lomustine therapy. Morphologic changes are not specific for lomustine-induced hepatotoxicity.

As already demonstrated in dogs treated for refractory lymphoma, the long-term administration of lomustine may result in cumulative thrombocytopenia. When lomustine is used in a rescue setting, lomustine-induced cumulative thrombocytopenia may be of marginal consequence because few effective treatment options remain for heavily treated, relapsing patients. However, in dogs with relapsing lymphoma treated with first-line lomustine, cumulative thrombocytopenia may limit the safe institution of additional myelosuppressive agents, including doxorubicin and cyclophosphamide. In addition to cumulative thrombocytopenia, lomustine's hepatotoxic potential should be carefully considered before its liberal use in cancer-bearing dogs (Figure 6). Although the reported rate of hepatotoxicity is quite low, a recent abstract suggests that the incidence of hepatotoxicity, defined as greater than fourfold elevations in serum alanine transaminase activities, is much higher in dogs treated with a combination of lomustine and oral prednisone. In this study, 23 of 45 dogs treated with lomustine and prednisone had moderately to severely elevated serum alanine transaminase activities.¹⁹ Additionally, most dogs (74%) developed pathologic serum alanine transaminase activity elevations with three or fewer lomustine treatments. These findings suggest that combining lomustine with prednisone may markedly increase the likelihood for acute liver injury, and veterinary practitioners should vigilantly monitor patients with serial serum chemistry profiles before each subsequent dose of lomustine, whether alone or in combination with prednisone. Lomustine should be considered a viable treatment option for dogs with lymphoma, especially in a rescue setting. However, the recommended use of lomustine as a first-line, single-agent should be reserved primarily for pet owners who actively choose to forgo conventional multiagent chemotherapy for their ailing pets. Currently, no published reports define the efficacy of first-line, single-agent lomustine for the treatment of canine lymphoma. Until that information becomes available, it remains difficult to enthusiastically recommend single-agent lomustine therapy rather than the use of a known effective monotherapy such as doxorubicin.

Adjuvant radiation Radiation therapy induces programmed cell death in both normal and malignant lymphocytes. Given the sensitivity of malignant lymphocytes to radiation-induced injury, the efficacy of external beam, megavoltage radiation therapy has been evaluated for the adjuvant treatment of high-grade, multicentric lymphoma in dogs. In one study, 52 dogs were treated with a short course of induction chemotherapy (11 weeks), immediately followed by staged, half-body irradiation.²⁰ Radiation therapy was administered to cranial and caudal body halves for a total dose of 8 Gy, given in two fractions of 4 Gy on consecutive days with cobalt-60 photons and a three-week interval between halves. The side effects associated with half-body irradiation were generally mild and included reversible myelosuppression and gastrointestinal upset. In addition to the safety of combined chemotherapy and adjuvant radiation, the investigated protocol was therapeutically effective, with treated patients achieving a first median remission time of 311 days.²⁰ The findings of this study emphasize that long-lasting remissions can be achieved in dogs with lymphoma by using short treatment protocols that combine chemotherapy and radiation.
Nodal irradiation for chemoresistant lymphoma
Malignant lymphocytes expressing multidrug-resistant phenotypes are afforded a survival advantage when exposed to cytotoxic agents. Attempting to treat resistant lymphocyte clones, even with novel chemotherapeutic agents, still may result in disease progression. Because of the limitations of chemical cytotoxic agents, in conjunction with the inherent radiosensitivity of malignant lymphocytes, the use of total lymphoid irradiation (TLI) for confirmed chemoresistant lymphoma has been investigated. In one study, 11 dogs with confirmed multidrug-resistant lymphoma were treated with total nodal irradiation. A dose of 2 Gy given in six fractions over two weeks was administered to all affected peripheral lymph nodes. By the fourth radiation fraction, all treated lymph nodes had returned to normal size, and dogs treated with nodal irradiation survived for a median of 143 days.²¹ The results of this pilot study demonstrate that dogs with chemoresistant lymphoma may still appreciably benefit from alternative treatment options such as nodal irradiation.
TREATING FELINE LYMPHOMA
Systemic chemotherapy

TABLE 3. Summary of Selected Feline Lymphoma Protocols

Unlike canine lymphoma in which several innovative treatment options have been investigated, the treatment of cats with high-grade lymphoma has not markedly changed during the past decade. Several systemic chemotherapeutic protocols have been evaluated for treating feline lymphoma (Table 3). In general, with the institution of multiagent systemic chemotherapy, most (about 60% to 70%) cats will achieve complete remission, with median survival times approximating six to nine months.¹ Although the treatment of cats with lymphoma has not changed greatly over the past several years, it has been suggested that cats diagnosed with lymphoma are afforded with better quality-of-life scores and survival times, as compared with a decade ago. In part, this suggestion is based on the dramatic decrease in the number of cats infected with FeLV, a reported negative prognostic factor in cats with lymphoma.²²

Because single-agent lomustine has demonstrated therapeutic activity for the treatment of refractory canine lymphoma, intuitively, it would be expected that lomustine should possess efficacy when used against drug-naïve, high-grade, multicentric canine lymphoma. Given lomustine's oral formulation, relative low cost, therapeutic effectiveness against refractory lymphomas, and reported low incidence of hepatotoxicity, lomustine appears to be an excellent anticancer drug, but keep in mind that conventional, multiagent systemic chemotherapy is still considered the gold standard for treating canine lymphoma. Carefully consider using single-agent lomustine as a first-line treatment option, and make sure you understand and recognize the potential hazards of using lomustine.

FIGURE 6. A laparoscopic view of the gross morphologic appearance of the liver in a standard poodle with hepatotoxicity attributed to chronic lomustine therapy. Morphologic changes are not specific for lomustine-induced hepatotoxicity.

As already demonstrated in dogs treated for refractory lymphoma, the long-term administration of lomustine may result in cumulative thrombocytopenia. When lomustine is used in a rescue setting, lomustine-induced cumulative thrombocytopenia may be of marginal consequence because few effective treatment options remain for heavily treated, relapsing patients. However, in dogs with relapsing lymphoma treated with first-line lomustine, cumulative thrombocytopenia may limit the safe institution of additional myelosuppressive agents, including doxorubicin and cyclophosphamide. In addition to cumulative thrombocytopenia, lomustine's hepatotoxic potential should be carefully considered before its liberal use in cancer-bearing dogs (Figure 6). Although the reported rate of hepatotoxicity is quite low, a recent abstract suggests that the incidence of hepatotoxicity, defined as greater than fourfold elevations in serum alanine transaminase activities, is much higher in dogs treated with a combination of lomustine and oral prednisone. In this study, 23 of 45 dogs treated with lomustine and prednisone had moderately to severely elevated serum alanine transaminase activities.¹⁹ Additionally, most dogs (74%) developed pathologic serum alanine transaminase activity elevations with three or fewer lomustine treatments. These findings suggest that combining lomustine with prednisone may markedly increase the likelihood for acute liver injury, and veterinary practitioners should vigilantly monitor patients with serial serum chemistry profiles before each subsequent dose of lomustine, whether alone or in combination with prednisone. Lomustine should be considered a viable treatment option for dogs with lymphoma, especially in a rescue setting. However, the recommended use of lomustine as a first-line, single-agent should be reserved primarily for pet owners who actively choose to forgo conventional multiagent chemotherapy for their ailing pets. Currently, no published reports define the efficacy of first-line, single-agent lomustine for the treatment of canine lymphoma. Until that information becomes available, it remains difficult to enthusiastically recommend single-agent lomustine therapy rather than the use of a known effective monotherapy such as doxorubicin.

Adjuvant radiation Radiation therapy induces programmed cell death in both normal and malignant lymphocytes. Given the sensitivity of malignant lymphocytes to radiation-induced injury, the efficacy of external beam, megavoltage radiation therapy has been evaluated for the adjuvant treatment of high-grade, multicentric lymphoma in dogs. In one study, 52 dogs were treated with a short course of induction chemotherapy (11 weeks), immediately followed by staged, half-body irradiation.²⁰ Radiation therapy was administered to cranial and caudal body halves for a total dose of 8 Gy, given in two fractions of 4 Gy on consecutive days with cobalt-60 photons and a three-week interval between halves. The side effects associated with half-body irradiation were generally mild and included reversible myelosuppression and gastrointestinal upset. In addition to the safety of combined chemotherapy and adjuvant radiation, the investigated protocol was therapeutically effective, with treated patients achieving a first median remission time of 311 days.²⁰ The findings of this study emphasize that long-lasting remissions can be achieved in dogs with lymphoma by using short treatment protocols that combine chemotherapy and radiation.
Nodal irradiation for chemoresistant lymphoma
Malignant lymphocytes expressing multidrug-resistant phenotypes are afforded a survival advantage when exposed to cytotoxic agents. Attempting to treat resistant lymphocyte clones, even with novel chemotherapeutic agents, still may result in disease progression. Because of the limitations of chemical cytotoxic agents, in conjunction with the inherent radiosensitivity of malignant lymphocytes, the use of total lymphoid irradiation (TLI) for confirmed chemoresistant lymphoma has been investigated. In one study, 11 dogs with confirmed multidrug-resistant lymphoma were treated with total nodal irradiation. A dose of 2 Gy given in six fractions over two weeks was administered to all affected peripheral lymph nodes. By the fourth radiation fraction, all treated lymph nodes had returned to normal size, and dogs treated with nodal irradiation survived for a median of 143 days.²¹ The results of this pilot study demonstrate that dogs with chemoresistant lymphoma may still appreciably benefit from alternative treatment options such as nodal irradiation.
TREATING FELINE LYMPHOMA
Systemic chemotherapy

TABLE 3. Summary of Selected Feline Lymphoma Protocols

Unlike canine lymphoma in which several innovative treatment options have been investigated, the treatment of cats with high-grade lymphoma has not markedly changed during the past decade. Several systemic chemotherapeutic protocols have been evaluated for treating feline lymphoma (Table 3). In general, with the institution of multiagent systemic chemotherapy, most (about 60% to 70%) cats will achieve complete remission, with median survival times approximating six to nine months.¹ Although the treatment of cats with lymphoma has not changed greatly over the past several years, it has been suggested that cats diagnosed with lymphoma are afforded with better quality-of-life scores and survival times, as compared with a decade ago. In part, this suggestion is based on the dramatic decrease in the number of cats infected with FeLV, a reported negative prognostic factor in cats with lymphoma.²²

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