Long-term clinical control of feline pancreatic carcinoma with toceranib phosphate

Abstract

An 11-year-old, spayed female, domestic shorthair cat was presented with a non-resectable abdominal mass diagnosed as carcinomatosis of pancreatic origin. Treatment with toceranib phosphate was started. Abdominal ultrasound approximately 1 year after diagnosis revealed progressive disease. The cat was humanely euthanized approximately 792 days after initial presentation due to progressive clinical signs.

Case description

An 11-year-old, spayed female, domestic shorthair cat was presented to her primary veterinarian because of a 3-day history of anorexia and lethargy. Abdominal radiographs revealed a space-occupying mass within the abdomen. Gross findings by the primary veterinarian on laparotomy included a cystic mass extending from the pancreas to the omentum surrounding the jejunum. Due to advanced stage of disease, surgical biopsies of the abnormal omentum were collected for diagnosis without further debulking of the tumor. Histopathology was consistent with carcinoma with spread throughout the omentum. The mitotic index of the mass was 3/10 high power field (hpf ). The cat recovered well after surgery, but still had a decreased appetite. She was then referred to the Oncology Service at the Louisiana State University (LSU) Veterinary Teaching Hospital.

The cat was presented to LSU 10 d after exploratory laparotomy. Upon presentation, the cat was noted to be obese (body condition score 8/9). A mass was palpated in the mid-abdomen on physical examination. Recent skin wounds were noted on the right flank. Complete blood (cell) count (CBC) revealed a mild leukocytosis [white blood cells 13.2 × 10⁹/L, reference range (RR): 6.0 to 10.0 × 10⁹ cells/L]. Serum chemistry revealed hyperglycemia (10.2 mmol/L, RR: 4.7 to 6.3 mmol/L), likely due to stress, and a mild hypercholesterolemia (5.4 mmol/L, RR: 2.5 to 4.6 mmol/L). Urinalysis was unremarkable. Three-view thoracic radiographs did not reveal any evidence of pulmonary metastasis. Abdominal ultrasound revealed a 5.5 cm, complex, cystic mass arising from the right limb of the pancreas with extension into the omentum.

Serial sections from the original biopsy performed by the primary veterinarian were available for second-opinion histologic evaluation. One section consisted entirely of fibrinosuppurative exudate. The other 2 sections showed a band of connective and adipose tissue, interpreted as omentum, thickened up to 2 mm by granulation tissue, acute hemorrhage, and superficial fibrinosuppurative exudate. Cuboidal to columnar epithelial cells proliferated multifocally along the surface and formed occasional deeply located glandular-like structures. The cells had moderate to abundant eosinophilic cytoplasm and basally oriented, crowded, round, vesicular nuclei with prominent single nucleoli (Figure 1). Cell atypia was mild; mitoses were rare, (< 1/10 hpf ). Multiple cells had strong cytoplasmic immunoreactivity to cytokeratin 7 and cytokeratin 20 (Figure 2).

Figure 1.

Biopsy of the cranial abdominal mass. The section consists of mature adipose tissue, interpreted as omentum, which is partially replaced by congested granulation tissue and an invasive adenocarcinoma. The neoplasm is characterized by single-layered cuboidal to columnar epithelial cells that line part of the surface of the specimen (arrows) and form several intralesional glandular-like structures (asterisks). Neoplastic cells have a moderate to abundant amount of eosinophilic cytoplasm, basally oriented round vesicular nuclei, and single prominent nucleoli, resembling cells of the exocrine pancreas (inset). Hematoxylin and eosin stain. Bars = 200 μm and 50 μm (inset).

Figure 2.

Biopsy of the cranial abdominal mass. Neoplastic cells, seen proliferating along the surface of the omental granulation tissue, have strong cytoplasmic immunoreactivity to Cytokeratin 7 (A) and Cytokeratin 20 (B). Bar = 50 μm.

The biopsy specimens in this case were sampled from the omentum. Histologic findings were therefore interpreted as omental carcinomatosis. While a pancreatic mass was identified via both abdominal exploratory surgery and follow-up abdominal imaging, routine histopathology alone could not completely rule out intestinal origin of the tumor. Nonetheless, the dual cytokeratin 7 and 20 positive immunophenotype further supported the diagnosis of exocrine pancreatic carcinoma, particularly in light of the repeated clinical diagnostic imaging findings (1).

Cefovecin (Convenia; Zoetis, Parsippany, New Jersey, USA), 8 mg/kg body weight (BW), SC, once, and buprenorphine (Par Pharma; Chestnut Ridge, New Jersey, USA), 0.01 mg/kg BW, PO, q8h, were prescribed for the skin wounds and tender abdomen, respectively, due to the cat’s fractious nature while in the veterinary hospital. A recheck was conducted 2 wk later. Reported anorexia had resolved so toceranib phosphate (Palladia; Zoetis), 15 mg [2.5 mg/kg body weight (BW), PO, Monday, Wednesday, Friday] was prescribed.

The pancreatic mass was noted to be stable in size via ultrasound examination 6 wk after commencement of drug therapy. Repeat staging was delayed for several months due to the cat’s temperament and lack of clinical signs.

Throughout treatment with toceranib, CBC, blood chemistry, and urinalysis were determined approximately every 4 to 6 wk. An intermittent Veterinary Cooperative Oncology Group (VCOG) grade I (2) thrombocytopenia of 113 to 188 × 10⁹/L (RR: 190 to 368 × 10⁹/L) was observed on several occasions. Platelet clumping was noted on blood smear at some, but not all time points. No other clinicopathologic abnormalities were documented.

Repeat staging was done ~11 mo after initial presentation to LSU. No evidence of pulmonary metastasis was noted on 3-view thoracic radiography. Abdominal ultrasound revealed a progressive, complex, cystic pancreatic mass, along with colic lymphadenopathy and regional peritonitis consistent with the previous diagnosis of pancreatic carcinoma. Chemotherapy with toceranib was continued despite progressive disease as the patient no longer had the initial presenting clinical signs of anorexia and lethargy. Her weight remained stable throughout the treatment period. She developed diabetes mellitus 18 mo post-diagnosis but was well-regulated with insulin glargine (Lantus; Sanofi, Laval, Quebec) in addition to a high protein, low carbohydrate canned diet (Purina Pro Plan Veterinary Diets DM, Dietetic Management Feline Formula; Nestle Purina, St. Louis, Missouri, USA). The cat was presented 792 d after initial presentation for progressive clinical signs (e.g., anorexia); she was humanely euthanized at that time. A postmortem examination was declined by the owner.

To our knowledge, this is the first report of long-term control of clinical signs such as anorexia and lethargy, in addition to prolonged survival for a cat with pancreatic carcinoma treated with toceranib phosphate.

Discussion

Exocrine pancreatic carcinoma is a rare tumor of pancreatic acinar or ductular epithelial cells in the cat (3,4). The exact cell of origin of this neoplasm remains controversial. The biologic behavior can best be described as locally aggressive and highly metastatic. Sites of spread include regional lymph nodes, liver, spleen, peritoneal lining, gastrointestinal tract, kidney, mesentery, diaphragm, pleura, lung, and heart (5–8). Most affected cats are older at the time of diagnosis, with a mean age of 11.0 to 11.6 y (7,8). No sex or breed predispositions have been noted. Clinical signs are non-specific, overlapping with other gastrointestinal diseases, and most commonly include anorexia, weight loss, vomiting, and diarrhea. An increased prevalence of exocrine pancreatic carcinoma has been noted in diabetic cats (7–9). A palpable abdominal mass is a common physical examination finding (7,8).

The prognosis for cats with pancreatic carcinomas is grave due to the high degree of local invasion and early metastasis, with reported survival times of only days to weeks (7,8). The presence of abdominal effusion at presentation is a negative prognostic indicator for survival. Surgery and chemotherapy have been shown to prolong survival. Even with these treatments, however, less than 10% of affected cats live longer than 1 y. These long-term responders (n = 3) received either traditional maximum tolerated dose (MTD) chemotherapy alone (n = 1) or in combination with surgery (n = 2) (8).

No specific chemotherapy protocols have been established for pancreatic carcinomas due to the rarity and generally poor prognosis of this tumor. The use of a combination of gemcitabine and carboplatin resulted in prolonged survival in 1 of 3 cats with pancreatic carcinoma (10). The other 2 cats experienced progressive disease on this chemotherapy regimen. Unfortunately, 14.3% of cats experienced grade 3 or 4 neutropenia and 50% of cats experienced gastrointestinal toxicity. This led to 42.8% of the study population experiencing treatment delays. The side effect profile of this protocol has limited its use.

Molecular therapies targeting tumor angiogenesis have been intensely studied in human pancreatic cancer. Although the influence of pro-angiogenic factors remains in question, evidence suggests that blockage of vascular endothelial growth factor receptors (VEGFR) with drugs such as the tyrosine kinase inhibitor sunitinib may be beneficial. Sunitinib has a similar profile to toceranib phosphate and has shown success in prolonging survival in human patients with pancreatic adenocarcinoma when used as a maintenance therapy (11).

Toceranib phosphate is a tyrosine kinase inhibitor with known activity against KIT, platelet-derived growth factor α and β, VEGFR 1 and 2, Fms-like tyrosine kinase 3 (FLT 3), and colony-stimulating factor 1 receptor (CSR1R) (12). It is approved for use in dogs with Patnaik grades II and III, recurrent, cutaneous mast cell tumors with or without regional lymph node involvement. Toceranib has been reported to provide clinical benefit to dogs with various neoplasms, including multiple types of carcinomas (13). Although there has not been any research regarding the efficacy of tyrosine kinase inhibitors in treatment of feline exocrine pancreatic carcinomas, in a retrospective study of cats with this type of tumor, 3 were placed on different tyrosine kinase inhibitors (imatinib, masitinib, toceranib). Only the one which received toceranib had stable disease for at least 3 mo. This cat was then unfortunately lost to follow-up (8). The median survival time of cats not receiving surgery or chemotherapy was only 6 d (7).

With the advent of new targeted cancer therapies have come new challenges in determining response to treatment. For many traditional cytotoxic chemotherapy agents, response to treatment is defined as an objective decrease in size [i.e., Response Evaluation Criteria In Solid Tumors (RECIST)]. However, a therapy such as toceranib likely exhibits its effects in some cancers by inhibiting angiogenesis (14–16). Drugs that work by targeting tumor blood vessel formation help stabilize or slow disease progression. Thus, while not valued under the traditional tumor response paradigm, patients still receive clinical benefit from either stable disease or slowing of the disease progression, which can be difficult to quantitate.

Although not approved for use in cats, toceranib and other tyrosine kinase inhibitors have been used off-label in this species and appear to be well-tolerated (17–23). The main side effects reported in cats include myelosuppression, azotemia, increased alanine aminotransferase activity, and gastrointestinal signs (19–23). The mild thrombocytopenia that occurred in our cat was most likely due to an artificial decrease in platelet number as platelet clumping was noted on most complete blood cell counts. Alternatively, drug-induced myelosuppression cannot be ruled out. Regardless of the cause, the cat did not experience any clinical signs as a result of this abnormality.

Toceranib phosphate appeared to provide clinical benefit to this cat. Clinically significant side effects were not encountered during the approximately 25-month course of treatment. Use of tyrosine kinase inhibitors, specifically toceranib phosphate, may lead to improved outcomes in exocrine pancreatic carcinoma. The oral administration of this medication allows for less frequent veterinary visits that can help maintain the quality of life of the affected cat. Further study of this medication and its role in treatment of exocrine pancreatic carcinoma in cats is needed.

The histopathologic specimen obtained for diagnosis in this cat was a metastatic lesion from the omentum, making determination of organ of origin difficult. Feline ductal adenocarcinoma has been shown to have dual expression of cytokeratin 7 and 20 such as found in our samples whereas feline intestinal adenocarcinoma is generally only cytokeratin 20 positive (1). Immunohistochemistry findings, combined with surgical visualization by the primary veterinarian and findings at multiple ultrasound examinations of a cystic pancreatic mass, make intestinal adenocarcinoma unlikely.

In conclusion, while exocrine pancreatic carcinoma typically carries a poor long-term prognosis, with the use of toceranib the cat in this report experienced long-term survival of 792 d after initial presentation. Previous literature suggests that less than 10% of affected cats treated with both complete surgical removal of the pancreatic mass and chemotherapy or chemotherapy alone will survive longer than 1 y (8). Median survival time reported for cats with exocrine pancreatic carcinoma without treatment is 6 d (8). The longest reported survival of a cat with exocrine pancreatic carcinoma noted in the literature was 532 d (10). The cat in that study was treated with MTD chemotherapy only. The cat described in this case report had macroscopic pancreatic disease that was treated only with toceranib. While she was euthanized 792 d after initial presentation due to clinical signs consistent with disease progression, significant side effects from chemotherapy were not encountered. Based upon historical data documenting the typical biologic behavior of this tumor, toceranib phosphate appears to have provided significant clinical benefit, although the presence of a more indolent form of disease cannot be excluded. CVJ