Feline exocrine pancreatic carcinoma:a retrospective study of 34 cases by Francisco Alvarez

Original Article

DOI: 10.1111/j.1476-5829.2012.00320.x

Feline exocrine pancreatic carcinoma: a retrospective study of 34 cases M. J. Linderman1 , E. M. Brodsky1 , L.-P. de Lorimier2 , C. A. Clifford3 and G. S. Post1 1 The

Veterinary Oncology and Hematology Center, Norwalk, CT, USA Hopital Veterinaire Rive Sud, Brossard, QC, Canada 3 Redbank Veterinary Hospital, Tinton Falls, NJ, USA 2

Abstract

Keywords adenocarcinoma, carcinoma, cat, feline, gemcitabine, pancreas, pancreatic

Thirty-four cases were reviewed in this retrospective study for information on clinical presentation, prognostic indicators, survival time and response to various therapies. The most common presenting clinical signs were weight loss, decreased appetite, vomiting, palpable abdominal mass and diarrhoea. Metastatic disease was confirmed in 11 cats. The overall median survival was 97 days. The median survival times for patients who received chemotherapy or had their masses surgically removed was 165 days. Those patients who had an abdominal effusion present at the time of diagnosis survived a median of 30 days. Cats that received non-steroidal anti-inflammatory drug therapy had a median survival of 26 days. This study confirms that exocrine pancreatic carcinoma in cats is an aggressive tumour with a high metastatic rate and poor prognosis, although three patients survived over 1 year. Fifteen percent of the patients were diabetic, which raises the question as to what the link between diabetes and pancreatic cancer in people and cats may be.

Introduction

Correspondence address: M. J Linderman The Veterinary Oncology and Hematology Center Norwalk, CT USA e-mail: mlinderman@oncovet.com

Exocrine pancreatic carcinoma is an aggressive disease in people, cats and dogs. It is a relatively rare tumour in cats with an incidence of less than 0.5%.1 – 3 It is unknown whether these tumours arise from the ductular cells or acini as there is current evidence that supports both theories.4 – 6 The differential diagnoses for mass lesions of the pancreas includes pancreatitis, asymptomatic nodular hyperplasia, benign pseudocysts, adenomas, exocrine pancreatic tumours, metastatic tumours, rare endocrine tumours such as beta cell tumours, gastrinomas or multiple endocrine neoplasias. For poorly differentiated tumours, immunohistochemical staining with chromogranin A, neuron-specific enolase or antibodies to insulin, glucagon or somatostatin may be required to determine the pancreatic cell of origin.4 Primary non-epithelial tumours such as spindle cell sarcoma or lymphoma have been infrequently reported and there is question as to

whether they were truly primary neoplastic lesions or metastatic from another organ.4,7 Secondary neoplasias may metastasize to the pancreas or invade the pancreas from other organs.2 – 4 There are currently few reports in the literature on the subject of feline pancreatic exocrine carcinomas and information on response to therapy is scarce. The purpose of this retrospective study was to gather information on the clinical course of pancreatic exocrine carcinomas, evaluate for prognostic indicators and evaluate outcomes with current therapy. Earlier reports indicate that this is typically a disease of older cats with no breed or sex predisposition.2,4,8,9 Common clinical signs are often non-specific and include abdominal pain, lethargy, weight loss, jaundice and vomiting.2,9 The survival times are usually short because of the rapid progression and early metastasis of the disease.4,8 In Seamans case study including eight cats, all died or were euthanized within 7 days of diagnosis.2 According to previous reports, the most

2 M. J. Linderman et al.

common sites for metastatic disease are the liver, peritoneum and local lymph nodes.2,4,8,9 Although, metastasis to the lungs, spleen, ovary, kidneys, pleura, heart, diaphragm and gastrointestinal tract have been reported as well.2,4,8 Pancreatic and biliary carcinomas have been associated with a dermatologic paraneoplastic syndrome that may occur symmetrically on the ventrum, face and limbs.8,10,11 It is described as a non-pruritic (unless complicated by secondary infections) glistening alopecia associated with excessive grooming, easily epilated hair and there are reports of resolution of the syndrome with removal of the pancreatic tumour.10 – 12 Cutaneous and visceral panniculitis and steatitis have also been associated with pancreatic tumours in cats and is possibly the result of systemic release of lipolytic enzymes.13 Pancreatic cancer has been documented more commonly in people who smoke, have chronic pancreatitis or have diabetes mellitus; however, it is unknown whether these are predisposing factors in our veterinary patients.

computer software SAS V 9.1 (Cary, NC, USA). Kaplan–Meier survival curves were constructed to calculate median and mean survival times for all cats (Fig. 1). Kaplan–Meier survival curves were compared between categorical factors using log-rank tests (Fig. 2). Cox proportional hazards regression was used to test for relationships of continuous factors with survival time and progression-free survival time. All hypothesis tests were two-sided with α = 0.05. Kaplan–Meier curves and log-rank tests were performed in PROC LIFETEST in SAS V 9.1. Cox proportional hazards regression was performed in PROC PHREG in SAS V 9.1. Categorical factors that were statistically evaluated included signalment, presenting clinical signs, duration of clinical signs, clinicopathologic data, presence of effusion, lymphadenopathy, diagnosis of diabetes, presence of confirmed metastasis, tumour size, degree of tumour differentiation, treatment with surgery, treatment with chemotherapy, treatment with tyrosine kinase inhibitors (TKI) and treatment with non-steroidal anti-inflammatory drugs (NSAIDs) (Fig. 3).

Materials and methods The medical records of The Veterinary Oncology and Hematology Center, Veterinary Referral Emergency Center of Westbury (formerly The Center for Specialized Veterinary Care), The Hopital Veterinaire Rive Sud, The New England Veterinary Oncology Group, RedBank Veterinary Hospital, Southeast Veterinary Oncology, Cheshire Veterinary Hospital, and Southpaws Veterinary Specialists and Emergency Center, were searched for a diagnosis of pancreatic exocrine carcinoma. Cats were included in the study if a cytological or histopathological diagnosis of pancreatic carcinoma was confirmed. Six cases of abdominal metastatic carcinoma where the organ of origin could not be determined were excluded. Data on signalment, presentation, diagnostic results, treatments and survival from 34 cats diagnosed between 2004 and 2010 were included in this study. Survival time was defined as the time interval between diagnosis and death. The progression-free interval was defined as the interval of time between diagnosis and evidence of progressive disease noted in the record. All analyses were performed using

Results Thirty-four cats with exocrine pancreatic carcinoma were included in the study. Twenty-one were domestic short hair, four were Maine coon, four were domestic long hair and there was one each of Himalayan, Persian, Bengal, domestic medium hair and Norwegian forest cat. Twenty were male castrate and 14 female spayed. The average age was 11.6 years with a range of 4–19 years. The average weight was 4.8 kg with a range of 2.7–7.1 kg. None of the cats in this study had a necropsy performed. The most common presenting clinical signs upon presentation were weight loss (68%), anorexia/decreased appetite (53%), vomiting (41%), palpable abdominal mass (41%) and diarrhoea (15%). Less common (<6%) clinical signs included haematochezia, constipation, dehydration, decreased grooming, vocalization, lethargy, icterus, polyuria/polydipsia, inappropriate urination, fever and dyspnea. The average duration of clinical signs reported by the owners was 41 days with a range of 2–180 days. Sixteen cats had no reported prior medical problems. There

Feline exocrine pancreatic carcinoma: 34 cases 3

Survival distribution function

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Figure 1. Survival curve: abdominal effusion versus none.

Survival distribution function

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Figure 2. Survival curve: surgery versus none.

were seven cats with murmurs or heart disease, six hyperthyroid cats and five had diabetes mellitus. Other reported prior medical problems included urinary tract infections, urinary calculi, chronic renal disease, inflammatory bowel disease, chronic constipation and idiopathic hypercalcaemia. One cat was diagnosed with a gastrointestinal small-cell lymphoma via histology at the time of excision and diagnosis of the pancreatic tumour. None of the cats in this study had developed paraneoplastic alopecia.

Complete blood count (CBC) results were available for all cats. Twenty cats presented with a normal CBC. Five were anaemic, 12 had a mature neutrophilia, 2 had thrombocytosis, 1 had eosinophilia and 1 had an elevated haematocrit (dehydration). Of the five anemic cats, two were grade I, two were grade II and one was grade III. Reticulocytes were run on three samples and all revealed non-regenerative anaemias. All neutrophilias were under 30 000 cells/ÎźL and mature.

ÂŠ 2012 Blackwell Publishing Ltd, Veterinary and Comparative Oncology, doi: 10.1111/j.1476-5829.2012.00320.x

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Survival distribution function

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Figure 3. Survival curve: chemotherapy versus none.

Serum biochemical analysis results were available for all but one cat. Three cats had an elevated lipase, two had an elevated amylase and none had elevations in both. Four values were mild and one lipase value was severely elevated. Eleven cats had mild elevations of their renal values (eight BUN, five creatinine), five cats had liver enzyme elevation (four ALP, five ALT, one AST, one GGT, two billirubin) and nine were hyperglycaemic. Five of the hyperglycaemic cats were diabetic while the other four were presumed to have a hyperglycaemia because of stress. None of the haematologic abnormalities were consistent among patients with pancreatic tumours and none of the values had statistically significant effects on survival or progression-free interval. This was consistent with previous case studies.2,9 A feline trypsin-like immunoreactivity (fTLI) was run on two patients and was elevated in both cats [150 and 165 (range 12–82 μg/L)]. A feline pancreatic lipase immunoreactivity (fPLI) test was run on the abdominal fluid of one cat and was also elevated (43.2 reference range for serum 2–6.8 μg/L). To the authors’ knowledge, no studies have been performed documenting the usefulness of fPLI on abdominal fluid. Twenty-three cats had chest radiographs as part of their staging at the time of diagnosis. Fourteen (61%) were within normal limits, five (22%) revealed cardiomegaly, three (13%) revealed pulmonary masses, two (9%) revealed sternal

lymphadenopathy and two (9%) revealed pleural effusions (some cats had more than one abnormality). Only three of the five cats with cardiomegaly had murmurs; two of these three had an echocardiogram and were started on cardiac medications. One cat died at 195 days from congestive heart failure. Of the three cats with pulmonary masses, two of them had diffuse nodules and one had a solitary nodule although none of them were sampled. Abdominal radiographs were taken on 16 cats. Four (25%) were within normal limits, six (38%) revealed loss of detail, six (38%) revealed a cranial abdominal mass effect and two (13%) revealed haepatomegaly (some cats had more than one abnormality). All cats with loss of detail on abdominal films had effusion confirmed on abdominal ultrasound. Thirty-three cats had abdominal ultrasonography performed and nodular pancreatic changes were observed in all of them. Ultrasonographers either did not report or could not determine which part of the pancreas was affected in 17 cases. There were seven masses reported in the left limb, four in the body, two in the head and three in the right limb. Abdominal effusion was present in 16 cats, there were liver abnormalities in 12 cats, splenic nodules in 2, abdominal lymphadenopathy identified in 11, nodular appearance to adipose tissue in 3 cases and 2 each with bile duct and pancreatic duct dilation. The size of the pancreatic nodules ranged from 1.5 to 6 cm with a median of 3.95 cm. Four of the

Feline exocrine pancreatic carcinoma: 34 cases 5

cats had multiple nodules. There was no statistical significance with respect to survival and the size or number of pancreatic nodules. The median survival of the 16 cats with abdominal effusion at diagnosis was 30 days compared with 165 days for cats with no effusion. This was statistically significant with a P-value of 0.0379. There were only four cats that had cytology performed on their effusions. Of the two cats with carcinomatosis, one died and one was euthanized at 22 and 25 days, respectively, despite starting chemotherapy. The cat with a neutrophilic inflammation on effusion cytology was also hyperbilirubinaemic with a dilated bile duct and was euthanized 6 days after diagnosis because of disease severity. The cat with chylous abdominal effusion died from progressive disease 36 days later despite chemotherapy. Cytology of pleural effusion of one cat revealed a chronic modified transudate with atypical immature lymphoid cells suspicious for lymphosarcoma. No further tests were run on the effusion to investigate this further. Only two of the cats with effusion underwent a surgical procedure and they had median survival times of 48 and 330 days. Six of the cats with effusion received NSAIDs as part of their therapy. The median survival time for cats with an effusion that received NSAID therapy was 26 days, compared with a median survival time of 75 days for cats with effusion that did not receive NSAID therapy. Liver abnormalities described on ultrasound ranged from solitary (2) to multiple (6) or diffuse nodules (3). There were target lesions, cysts, hyperechoic and hypoechoic masses. Of the 12 cats with liver abnormalities, 3 were aspirated with results including metastatic carcinoma, lymphoplasmacytic hepatitis with lipidosis and extramedullary haematopoesis with lipidosis. Four livers were biopsied with results including hydropic degeneration with lipofuscin pigment accumulation, hepatic lipidosis, cholangiohepatitis and metastatic carcinoma. The two metastatic liver lesions that were sampled were described as a target lesion and as haepatomegaly with diffuse nodules on ultrasound. Cytology of a splenic nodule resulted in a diagnosis of metastatic carcinoma. Twenty-three of the pancreatic masses were evaluated via fine needle aspiration cytology. Five (22%) of these aspirations resulted in

non-diagnostic samples or inconclusive results and those patients went on to have biopsies of their tumours. Pathologists occasionally reported evidence of necrosis or suppurative, histiocytic or lymphocytic inflammation within the samples. Sixteen pancreatic masses were evaluated via histopathology obtained by either percutaneous ultrasound guided Tru-Cut biopsy, surgical incisional biopsy or excisional biopsy. The tumour cells often formed acinar structures in a fibrous connective stroma but were sometimes described as forming sheets, nests or cords. Intracytoplasmic zymogen granules were occasionally noted in the description and the degree of nuclear pleomorphism was very variable. A few samples had evidence of tumour necrosis or inflammation, and in one biopsy a lymphoid infiltrate was described. Six tumours were described as well differentiated, two of the tumours were described as poorly differentiated and eight were reported without a grade of differentiation. Mitotic divisions ranged from rare to 2â&#x20AC;&#x201C;3 per HPF. No complications were reported in the records for aspiration or biopsy of any of the lesions. Neither mitotic rate nor degree of differentiation was statistically significant with respect to survival or disease progression. Twelve of the 34 cats had a surgical procedure to biopsy or remove their pancreatic tumour. In three of these cats, the surgeon performed an incisional wedge biopsy as the tumours were not resectable because of extensive local invasion. At least one cat required a duodenal resection and anastamosis to resect the mass. The median survival for cats undergoing surgery was 165 days compared with 30 days for cats that did not. This was considered statistically significantly with a P-value of 0.0145. Excluding the cats that had incisional biopsies, the median survival remained at 165 days. The median survival for the 10 cats that received post-operative chemotherapy was also 165 days. The two cats that did not have post-operative chemotherapy survived 135 and 330 days and both had well-differentiated tumours. Twenty-three of 34 cats received chemotherapy as part of their treatment. Fifteen cats were treated with single agent gemcitabine as the first line of chemotherapy, five cats received a gemcitabine/ carboplatin doublet therapy as a first line, two cats received carboplatin (one intravenous and one

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intracavitary due to abdominal effusion), and one cat was started on mitoxantrone. Rescue therapies included mitoxantrone, gemcitabine, carboplatin, doxorubicin, cyclophosphamide, chlorambucil, CCNU or methotrexate. There were two cats that were treated with low dose oral chemotherapy with cyclophosphamide or chlorambucil after stopping an injectable chemotherapy protocol. Ten cats underwent surgery prior to starting chemotherapy. Overall median survival time increased from 7 to 165 days with the use of chemotherapy. This was considered statistically significant with a P-value of 0.0001. The median survival time for the nine patients receiving neither surgery nor chemotherapy was only 6 days. In 14 of the 17 cats (82%) for which clinical responses were reported in the record, the clinicians documented clinical improvement in their patients. Chemotherapy was well tolerated in most cases, although eight cats were reported to have side effects including neutropenia (one grade III, one grade IV), vomiting (two grade I, one grade II), lethargy (one grade I), anorexia (one grade I, two grade II, one grade III and one unknown severity) and diarrhoea (one grade I, one grade II and one unknown severity). An oesophageal feeding tube was placed in one cat because of anorexia either caused by the disease process or intravenous chemotherapy. No complications from the feeding tube were reported and it was removed once the patient began to eat regularly. One cat each received therapy with TKI imatinib, masitinib and toceranib. TKIs were initiated in patients after they were stabilized with chemotherapy, or as a last line of therapy but not at the same time as cytotoxic agents. Masitinib was discontinued in one patient after 2 weeks because of vomiting. One patient had stable disease for 3 months on toceranib before contact was lost. One patient was taken off imatinib after a month and switched to another therapy because of progressive disease. Eight patients in this study received NSAID therapy. Six cats were given meloxicam while two were given piroxicam. Median survival time for patients receiving concurrent NSAIDs was 26 days compared with 165 days for cats not receiving NSAIDs. This difference was statistically significant with a P-value of 0.0256. Two of these cats underwent surgery and had survival times of 414

and 48 days, respectively. Five cats had concurrent chemotherapy and had a median survival of 27 days. Six of the eight cats had an abdominal effusion, which was also calculated statistically to be a negative prognostic indicator in this study, and had a median survival time of 26 days. The overall median survival time for cats in this study was 97.5 days [95% confidence interval (CI) 27–165] while the mean survival time for all cats was 180.9 days (range 1–570+). The median progression-free interval was 37 days (95% CI 13–54) with a mean of 64 (range 1–391+). Twenty-three of the cats were believed to have died or were euthanized because of progressive pancreatic carcinoma. Five cats died of unknown causes, five were lost to follow-up and one died from congestive heart failure. None of the cats in the study had a postmortem examination. Three (8.8%) of the 34 cats in this study survived longer than 1 year. Of these three cats, one had a poorly differentiated tumour with lymph node metastasis, but survived 414 days before dying of progressive disease. This cat was diagnosed via abdominal explore with removal of the tumour and biopsy of the node. The cat still had no measurable disease after 12 doses of gemcitabine and concurrent meloxicam, but the tumour began to grow while on metronomic cyclophosphamide. Over the next 7 months, the clinician switched from carboplatin to mitoxantrone to CCNU and then metronomic chlorambucil as the tumour progressed. Another cat survived 510 days with a diagnosis of epithelial neoplasia on fine needle aspiration of a pancreatic mass. This cat received gemcitabine initially, then carboplatin, and then cyclophosphamide as the tumour progressed. The third cat had been transiently diabetic for 2 years before being diagnosed with an exocrine pancreatic adenocarcinoma via complete surgical resection. He received five doses of gemcitabine and survived 1 year before progressive disease was palpated on physical exam. The owner opted not to treat further and contact was lost after that visit.

Discussion Feline pancreatic exocrine carcinomas are uncommon tumours associated with a high metastatic rate and a poor prognosis.2,8,9 The author is aware of

Feline exocrine pancreatic carcinoma: 34 cases 7

only one cat prior to this study that had been documented to live longer than 1 year from time of diagnosis of this disease.14 The median progressionfree interval was 37 days in this case study and none of the categorical data compared was statistically significant. It is conceivable that data on disease progression was inaccurate because of the multiinstitution retrospective nature of the study. The overall median survival time in this case series was 97.5 days. The diagnosis of exocrine pancreatic carcinoma was made by histopathology in 16 cases and cytology in 18 cases. It is feasible, that because of potential error of cytological results that some cats did not have pancreatic carcinoma, although care was taken to exclude those cases where the organ of origin was unknown or where cytology was ambiguous. In one study evaluating cytology of 62 pancreatic lesions suspicious for malignancy, there were no false positive results.15 Of the three cases surviving longer than 1 year, two were confirmed by histopathology and one was diagnosed via pancreas aspiration. The case diagnosed by cytology was described as an epithelial neoplasia. Although it is possible that this was a metastatic lesion, the 3 Ă&#x2014; 4 cm mass in the pancreas was the only mass lesion seen on staging. It is notable that only a small number of patients had elevations of pancreatic enzymes; however, there were elevations in both of the fTLIs that were run. The only fPLI, which was run on abdominal fluid, was also elevated. While these tests have become clinically useful for diagnosing exocrine pancreatic insufficiency or pancreatitis, respectively, further investigation is needed to see if pancreatic neoplastic disease can be detected with these tests. It is also notable that 5/34 (14%) of the cats in this study were diabetic compared to an estimate of 2.45/1000 cat-years-of-risk in databases at 17 academic institutions.16 This raises the questions of whether diabetes is a predisposing factor to pancreatic cancer as it is in people and what that specific link may be.17 Abdominal radiography revealed loss of detail or an abdominal mass effect in 11 of the 16 cats (69%) where films were available. In this case series, ultrasound has proven to be a more sensitive diagnostic tool for the diagnosis of pancreatic diseases as nodular changes were seen in all 33 cats

that were imaged. The size of the tumours was not prognostic for survival or disease-free interval. One study of 19 cats revealed that neoplastic lesions of the pancreas often image as larger (<2 cm) single lesions while nodular hyperplasia often manifests as multiple smaller lesions.3 In humans, contrast-enhanced ultrasonography using carbon dioxide microbubbles has been shown to help differentiate between benign versus malignant and even endocrine versus exocrine tumours based on vascular patterns.18 This modality has also been used to differentiate between normal and pathologic pancreas of feline patients and has potential to help make ultrasound more sensitive for determining malignant pathology.18 Over the last decade, the purine analogue gemcitabine has been the most commonly used chemotherapeutic agent for this disease in people, as it was slightly more effective than fluorouracil in controlled studies.17 For this reason, gemcitabine has also been used for treatment in our veterinary patients, although there are few studies evaluating the use of chemotherapy for this disease.14 The majority of clinicians (20/23) in this study initiated chemotherapy treatments with gemcitabine or gemcitabine/carboplatin doublet therapy. Studies documenting the outcome of human patients with pancreatic carcinomas receiving gemcitabine revealed that the majority of patients receiving the treatment had relief from clinical signs.17 Although a direct comparison cannot be made, analysis of the data available revealed that 82% of the feline patients in this study experienced a decrease in clinical signs associated with their disease. Our ability to determine the quality of life benefit of chemotherapy in a retrospective veterinary study however, is questionable. Ideally this would be performed with a controlled study using standard performance scores (such as with the Karnofsky scale, Lansky scale or the recently published veterinary quality of life questionnaire19 ) to evaluate and compare patient response. In this study, the assessment was made by gathering data written by clinicians regarding appetite, energy, vomiting, diarrhoea and other quality of life concerns before and after chemotherapy administration. Although the median survival time increased from 7 to 165 days with the use of

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chemotherapy, results may be biased, with respect to the cats that were able to receive therapy. Six of the cats within the study were euthanized or died within the first week of diagnosis and may have been too unstable to consider therapy. Despite this possibility, administration of chemotherapy appears beneficial to pancreatic carcinoma patients and results in acceptable levels of toxicity. Phase III trials combining gemcitabine with other cytotoxic drugs failed to produce better results than gemcitabine alone in people.17 Furthermore, most of the targeted therapies that were tested in combination with gemcitabine did not add any benefit in phase III studies except for a modest improvement in survival combining gemcitabine with the TKI erlotinib.17,20 The safety and efficacy of erlotinib in veterinary patients is unknown. It would be fascinating to determine whether those patients that benefited from TKIs in the human study had mutations or upregulation of expression of tyrosine kinase receptors (TKRs) or their ligands (such as TGFR, EGFR, PDGFR, FAK, Src and Lyn) in their tumours. In this study, there were three cats that received three different TKIs. At this time, more information is needed before drawing conclusions as to whether TKIs will have a beneficial effect on patients with pancreatic carcinomas, whether there is a subset of pancreatic tumours where TKIs will be more effective, and whether it is more effective in combination with other agents. Studies to reveal mutations or over expression of TKRs may help to predict response to TKI therapy for cats in the future.21 Upregulation of COX-II has been documented in human pancreatic adenocarcinoma,22,23 and there is some evidence that the use of aspirin may reduce the incidence of these tumours.24 While the effectiveness of non-aspirin NSAIDs are indisputable with colorectal tumours, they have not shown the same benefit in pancreatic cancer and there is a meta-analysis that disproves the conclusion that aspirin use has an effect on the incidence of pancreatic cancer.24,25 A study looking at COX-II expression in feline pancreatic carcinomas showed that only 25% were positive on immunohistochemical staining.22 From this data, it was postulated that NSAIDs may have limited use in the treatment of this malignancy.22 Interestingly,

cats that received NSAID therapy in this study had statistically significant decreased survival times. Six of eight cats receiving NSAIDs had an abdominal effusion, which was also a category shown to have statistically lower survival times in this study. It is feasible that clinicians chose to use NSAIDs in patients with more severe disease or evidence of pain/discomfort. Owing to the many variables and clinician bias for choosing therapy in this retrospective study, caution should be taken before linking NSAID use and survival. No toxicity from NSAID use was documented in this study. Complete resection of pancreatic carcinomas have resulted in the best chance for long-term survival in people, with 15â&#x20AC;&#x201C;20% surviving over 3 years.20,26 It appears that surgical resection has the potential to extend survival time in our feline patients as well.20 Clinician bias to recommend surgery only in patients they deemed strong enough to undergo an invasive procedure with a favourable outcome may have affected the statistical significance in this study. In addition, owners that decline surgery or other therapy may have also been more inclined to euthanize at an earlier time. The survival times for those cats that had only an incisional biopsy performed during abdominal explore because of extensive local disease were 48, 135 and 570 days and exclusion of these cats from the surgery category did not change the median survival time. There was no statistical significance with respect to disease progression or survival relative to histopathological differentiation or mitotic rate. In fact, one of the cats with a poorly differentiated tumour lived over 1 year from the time of surgical removal. Evidence of metastatic disease is also usually considered a poor prognostic indicator, although confirmed metastatic disease was not determined to be statistically significant in this study either. The median survival time for those cats with confirmed metastatic disease trended lower (33 days) although two of these cats lived over 10 months. The low power, inconsistent staging and retrospective nature of this study may account for the lack of statistical significance. Investigation into genetic mutations or immunohistochemical stains may provide us with more prognostic information in the future.

ÂŠ 2012 Blackwell Publishing Ltd, Veterinary and Comparative Oncology, doi: 10.1111/j.1476-5829.2012.00320.x

Feline exocrine pancreatic carcinoma: 34 cases 9

Biopsies and aspirates obtained through ultrasound guidance and exploratory surgery determined that many of the animals in this study may not have had metastatic disease despite nodular changes in various organs. For example, inflammation or necrosis of mesenteric or omental fat may create firm nodules that should not be assumed to be metastatic disease.4 Despite the poor overall prognosis, caution should be taken before assuming there is gross metastatic disease or discouraging a surgical procedure. The percentage of inaccurate cytology results obtained via imaging guided needle biopsy of internal organs has ranged from 2 to 40% in various veterinary studies.27 – 30 For this reason, and because of the low number of samples reported in this study, additional information is required to draw accurate conclusions about the metastatic rate.

Conclusion Currently, surgery and traditional chemotherapeutic agents such as gemcitabine appear to be reasonable therapy for this aggressive tumour in feline patients, although survival times are not impressive. Quality of life is an important goal of therapy and chemotherapy may help to decrease clinical signs associated with malignancy. It is unclear if abdominal effusion or NSAID administration is a poor prognostic indicator or if clinician bias affected the decision to perform surgery or administer anti-inflammatory therapy. It is also unclear what the relationship between diabetes and pancreatic tumours is, but as in people, diabetes appears to be a predisposing factor. To obtain longer survival times, the future treatment of this disease likely lies in the genetic, proteomic and immunologic discoveries being made.

Comparative oncology Pancreatic carcinomas are the fourth leading cause of human cancer mortality and the 5-year survival rate has remained less than 5% because of the high frequency of metastasis at the time of diagnosis.17,26 Earlier this year, a study was published describing better survival times than gemcitabine using oxaliplatin, irinotecan, fluorouracil and leucorvin combination therapy.31 Other exciting new frontiers in pancreatic cancer therapy include immunotherapy with injectable vaccines. An allogeneic granulocyte-macrophage colony stimulating factor modified whole cell pancreatic tumour vaccine has been in clinical trials resulting in a subset of human patients surviving over 10 years.26 An autologous heat-shock protein vaccine has shown promising results and there have been no dose limiting toxicities associated with the injections.32 There is also a dendritic cell-based vaccine that has proven to be safe and effective in early clinical trials.33 So far, the number of genetic mutations discovered in human pancreatic cancers is numerous but the vast majorities involve dysregulation of 12 cellular signalling pathways which are potential targets for therapy.34 Targeted therapies in tumours where many pathways are altered via mutations may consist of a combination of small molecule targeting medications designed to target the physiological effects of the altered pathways.

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