Managing feline gastrointestinal lymphoma (Proceedings)

Gastrointestinal (GI) (or alimentary) lymphoma is the most common form of lymphoma in cats1-3. Feline GI lymphoma is histologically classified as low, intermediate or high grade according to the size and anaplasticity of the neoplastic lymphoid cells. Low-grade, small cell, lymphocytic feline GI lymphoma is composed of small relatively well-differentiated neoplastic lymphocytes, while high grade, lymphoblastic feline GI lymphoma is composed of large, poorly differentiated neoplastic lymphocyte. Clinical signs of low grade GI lymphoma are often chronic in nature, reflecting the generally slow onset and progression of the disease and commonly include weight loss, anorexia and lethargy with or without vomiting and diarrhea2-5. In contrast, high grade GI lymphoma is a more acute and severe disease3. Anorexia, weight loss, palpable abdominal mass and an acute presentation due to intestinal obstruction or perforation are common3. The epidemiology, presentation, diagnosis and staging of feline GI lymphoma are reviewed elsewhere2,3.

Important Considerations For Diagnosis Of GI Lymphoma

Definitive diagnosis of gastrointestinal lymphoma requires histological evaluation of gastrointestinal tissue. Although biopsy specimens can be obtained endoscopically or during exploratory laparotomy, recent evidence suggests full thickness gastrointestinal biopsies are superior to endoscopic biopsies in differentiating GI lymphoma from IBD, especially in the small intestine which is the most common site of feline GI lymphoma4. Further, histological evaluation of transmural intestinal biopsies along with extraintestinal tissue (mesenteric lymph nodes and liver) is helpful in differentiating neoplastic from inflammatory disease6.

Surgery

Indications for surgery in cats with GI lymphoma are gastrointestinal obstruction, gastrointestinal perforation or to obtain biopsy samples of gastrointestinal and extraintestinal tissues (Richter). In most cases, chemotherapy is indicated following resection of a focal mass as microscopic diffuse intestinal involvement or systemic spread is likely2.

Chemotherapy For Low Grade GI Lymphoma

Prednisone or prednisolone (5-10 mg PO q24hrs) and chlorambucil (2 mg PO q2-3 days or 15mg/m2 PO q24 hours for 4 consecutive days, repeat every 3 weeks). The tendency for low grade lymphoma to be slowly progressive allows for outpatient treatment with a less intense, oral chemotherapy protocol5. Most cats with low grade GI lymphoma respond favourably to prednisone and chlorambucil therapy and experience extended survival times. Among 26 cats with low grade GI lymphoma treated with prednisone and chlorambucil, 9 demonstrated complete, 16 partial and 1 no response to treatment with a collective median survival time of 745 days5. In a separate study, 76% of cats (13/17) achieved complete remission with a median remission time of 18.9 months1. It has been demonstrated that cats that achieve complete remission achieve longer survival times than cats that do not1,5. However both groups of cats experience relatively long median survival times. Two recent retrospective reviews reported median survival times of 587 and 897 days for cats that achieved complete remission and 125 and 428 days for cats that did not1,5. The effect of chlorambucil regimen (alternate day versus high-dose pulse therapy) on median survival time has yet to be investigated. Adverse effects of chlorambucil therapy are infrequent and include gastrointestinal signs and myelosuppression (neutropenia and/or thrombocytopenia)1. A complete blood count (CBC) should be performed prior to initiation of therapy, one week after the first dose of chlorambucil and every 2-3 weeks (alternate day chlorambucil regimen) or prior to each chlorambucil treatment period (high dose pulse therapy chlorambucil regimen)3. Once complete remission is achieved and/or no leukopenia or trend towards leukopenia is observed on serial CBCs over a few months, the frequency of CBC monitoring can be decreased to once every 4-6 weeks3. Chlorambucil should be discontinued in cats with persistent or displaying a trend towards neutropenia or thrombocytopenia3. Cats with low grade lymphoma that do not respond to or develop progressive disease in the face of prednisone and chlorambucil therapy should be treated as per high grade lymphoma, described below.

Chemotherapy For High Grade GI Lymphoma

Most reports of treatment of feline high grade lymphoma describe a group of cats that vary in terms of anatomical site of disease, anatomic staging and clinical substage (sick versus well)2,7, making comparisons between reports and precise treatment recommendations difficult. Reports describing detailed results in a large group of cats with high grade GI lymphoma treated with a uniform chemotherapy protocol are lacking. Based on the available data some conclusions can be drawn7. First, multidrug protocols are generally more effective than single agent protocols at inducing first remission2,7-9. For example, compared to multidrug protocols, partial and (16-32%) complete remission rates (26-32%) are poor when doxorubicin is used as single agent therapy8,9. Second, the addition of doxorubicin to COP (cyclophosphamide, oncovin/vincristine, prednisone) based protocols appears beneficial, resulting in acceptable response rates and improved median duration of remission and median survival time10-12. Currently, a CHOP chemotherapy protocol is logical for initial treatment of high-grade feline lymphoma. CHOP (a.k.a. University of Madison-Wisconsin protocol) is an alternating, weekly treatment regimen consisting of cyclophosphamide (C), doxorubicin (a.k.a. hydroxydaunorubicin (H)), vincristine (a.k.a. oncovin (O)), and prednisone (P)11. In a recent retrospective study of 38 cats with all anatomical forms of lymphoma (including 16 cats with GI lymphoma) 84% (47% complete response and 42% partial response) responded to treatment13. Although the response to treatment of the 16 cats with GI lymphoma was not specifically discussed, anatomic form was not statistically associated with duration of first remission or survival time13. Duration of first remission (654 days versus 114 days) and median survival time (654 days versus 122 days) were significantly longer for cats with complete remission compared to cats with partial remission13. Neutropenia necessitating a 5-7 day delay in chemotherapy was observed in 34% of cats13. Chemotherapy-related gastrointestinal toxicosis is also possible but is difficult to differentiate from clinical signs of disease in cats with GI lymphoma. COP has also been retrospectively evaluated for treatment of feline lymphoma with acceptable response rates and median survival time14,15 and is a logical treatment choice when doxorubicin therapy is not feasible. A recent retrospective study of 23 cats with all anatomical forms of lymphoma treated with a combination chemotherapy protocol consisting of L-asparaginase, vincristine, cyclophosphamide, doxorubicin, methotrexate, and prednisolone, a complete remission rate of 74% with a median duration of 264 days was described16. However, anatomical location had a significant impact on duration of complete remission. Among the 5 cats with GI lymphoma the median duration of remission was 52 days, compared with 522 and 264 days for cats with mediastinal or extranodal disease, respectively16. Consultation with or referral to a veterinary oncologist is recommended for cats with high grade lymphoma that do not respond to or develop progressive disease in the face of CHOP or COP chemotherapy.

Nutritional Support

Cats with GI lymphoma are at risk of malnutrition. At the time of diagnosis, many cats with GI lymphoma have a chronic history of weight loss and inappetance / anorexia and could already be considered malnourished. Nutritional support should be considered for any cat that has been anorexic or has had inadequate voluntary caloric intake for more than 3 days, cats that have lost ≥ 10% of their body weight and cats with other overt signs of malnutrition such as poor hair coat, muscle wasting, poor wound healing, etc.17. Whenever possible, enteral nutrition is preferred over parenteral nutrition as it is simpler, less expensive, has fewer complications and is more physiologically sound17. Cats with GI lymphoma have a serious underlying disease that can be expected to take weeks to months to fully control. Further, gastrointestinal signs such as anorexia and vomiting may be exacerbated by or develop as an adverse effect of chemotherapy. As such, temporary enteral feeding options such as force feeding or nasoesophageal tube placement should only be employed in the short term (i.e. few days). Placement of a more permanent enteral feeding tube such as an esophagostomy or gastrotomy tube is recommended. Both tubes types can be left in place long-term (i.e. months), are of sufficient diameter to allow feeding of a blenderized diet, can be used for administration of most oral medications and rank highly in terms of owner satisfaction17. To avoid a second anesthesia, tube placement should be considered when the cat is anesthetized for collection of GI biopsies. Careful consideration must be given to the choice of feeding tube. For example, esophagostomy tubes are contraindicated in cats with persistent vomiting, while gastrotomy tube placement may not be safe in cats with gastric neoplasia. Indications, contraindications and techniques for tube placement as well as specific instructions on institution of enteral feeding are reviewed elsewhere17. Nutrient malabsorption and gastrointestinal protein loss due to infiltration by neoplastic cells are best addressed by treating the underlying disease. However, if malabsorptive disease is severe parenteral nutrition may be required until chemotherapy takes effect17. Parenteral nutrition is also indicated in cats that do not tolerate enteral feeding or as a supplement to enteral nutrition as the volume of tube feedings is gradually increased to meet the cat's resting energy requirement.

Cobalamin Supplementation

Cobalamin (B12) is a dietary, water-soluble, B vitamin. Bound to intrinsic factor, dietary cobalamin absorption occurs in the ileum. Cobalamin deficiency due to poor dietary absorption is common in cats with small intestinal disease, including GI lymphoma5. Among cats with low grade lymphoma, 78% of those tested had low serum cobalamin concentrations5. Measurement of serum cobalamin and folate levels is recommended in all cats with GI lymphoma, especially in those cases where weight loss, anorexia, diarrhea and vomiting do not fully respond to appropriate chemotherapy. Many cats with hypocobalaminemia may require supplementation of cobalamin before they will respond appropriately to therapy3. Measurement of cobalamin and folate levels can be combined with assessment of feline pancreatic lipase immunoreactivity (fPLI) to evaluate for pancreatitis and determine if cobalamin supplementation is necessary3. Dosing regimens for cobalamin supplementation in the cat have not been critically evaluated. One suggested regimen for cobalamin supplementation is: cyanocobalamin 150-250 µg per cat SQ q7 days for 6 weeks, then q14 days for 6 weeks, then q30 days for 1 injection followed by re-evaluation of serum cobalamin levels 1 month later18. Following this regimen, serum cobalamin concentration should be above the reference range18. If, however, it is within the reference range, supplementation is continued on a monthly basis and if it is below the reference range supplementation is continued on a weekly to biweekly basis and reconsideration of the suspected diagnosis and treatment protocol is recommended18.

Probiotics

Probiotics are microorganisms added to food and are thought to convey health benefits to the animal consuming them. Most probiotic products contain Enterococcus faecium (Purina Fortiflora™), Lactobacillus spp. or Bifidobacterium spp.. Data to support a beneficial health effect of probiotics in companion animals is lacking. Theoretical benefits of probiotic therapy in feline GI lymphoma could include synthesis of B vitamins by Lactobacillus spp., correction of altered gastrointestinal bacterial flora, immunomodulation and maintenance of epithelial barrier function19. Whether probiotics exert any of these effects in feline GI lymphoma, or in veterinary patients in general, is unknown. Before initiating prebiotic therapy, careful consideration must be given to whether persistent diarrhea reflects incomplete disease remission or a secondary infectious cause as these are conditions that can not be expected to ameliorate with prebiotic therapy. Prebiotic therapy can be considered if persistent diarrhea is felt to be an adverse effect of chemotherapy or a complication of enteral tube feeding (especially common if feeding a liquid diet). Probiotic Lactobacillus spp. bacteremia has been occasionally reported in immunocompromised human patients19. While bacteremia secondary to dietary probiotics has yet to be reported in veterinary patients19, it is a potential complication that must be considered in chemotherapy patients given the risk of immunocompromise due to neutropenia.

Antiemetics, Gastroprotectants, and Appetite Stimulants

The impact of nausea on patient quality of life is an important consideration in veterinary oncology. Clinical signs of nausea are not limited to vomiting and may include hypersalivation, bruxism, retching or anorexia. Prior to initiation of antiemetic therapy, the clinician must consider whether nausea is most likely indicative of incomplete control over the underlying disease, an adverse effect of treatment or development of a complicating condition such as pancreatitis. Antiemetic therapy may be indicated prior to treatment with drugs know or suspected to cause vomiting as an adverse effect (e.g. doxorubicin). Antiemetic treatment options for feline patients include: metoclopramide (0.2-0.4 mg/kg PO, SQ, IV q8 hours or 1-2 mg/kg/24 hours CRI), ondansetron (0.1 mg/kg IV or PO q 12-24 hours), chlorpromazine (0.3-0.5 mg/kg SQ q8 hours) and maropitant (off-label use, 1 mg/kg PO or SQ q24 hours for 5 days)20. Indications, contraindications and adverse effects of each drug should be reviewed on a case by case basis. Of note, metoclopramide is contraindicated where intestinal obstruction is suspected, chlorpromazine has been associated with development of extrapyramidal signs in cats and because of the risk of hypotension, chlorpromazine must only be used in well hydrated patients.

In the absence of GI ulceration, gastroprotectants are not specifically indicated in the management of feline GI lymphoma. If GI ulceration is suspected or if indicated for management of other gastrointestinal signs, consider an H2 receptor antagonist (famotidine 0.5-1.0 mg/kg PO, SQ or slow IV q12 hours) or H2 receptor blocker (0.7-1.5 mg/kg PO q24 hours)21.

Pharmacological stimulation of appetite in sick cats is generally unreliable, short-lived and may delay implementation of an enteral feeding plan17. In inappetant or anorexic cats with GI lymphoma, it is the author's opinion that pharmacological stimulation of appetite is only indicated in the short term (i.e. days) for outpatients that are consuming >50% of their required calories voluntarily or in patients whose owners are not prepared to consent to feeding tube placement. Pharmacological stimulation of appetite should not be relied on or used in lieu of feeding tube placement. Appetite stimulants include cyprohepatadine (2-4 mg per cat PO q12-24 hours) or mirtazapine (1.875-3.75 mg per cat PO q72 hours) (Plumb, CA formulary). Side effects of cyproheptadine include behavioural changes (sedation or paradoxical hyperexcitability) and anticholinergic effects17,21. Side effects of mirtazapine include anecdotal reports of behaviour changes and hyperexcitability. Mirtazapine should not be used in combination with selective serotonin reuptake inhibitors (risk of serotonin syndrome) and should be used in caution in cats with hepatic disease17.

Prognostic Indicators

Short survival times are expected in cats that are FeLV positive or show no response to treatment. Duration first remission and median survival time are longer for cats that reach complete remission compared to cats that reach only partial remission13. Immunophenotype (T-cell versus B-cell) has not been shown to be a prognostic indicator in feline lymphoma22.

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