Received:May Revised: September Accepted: November
Toceranib phosphate in the management of canine insulinoma: A
retrospective multicentre study of cases (–)
Sabina Sheppard-OlivaresNora M. BelloChad M. Johannes
Samuel E. HockerBarbara BillerBrian HusbandsElizabeth Snyder
Mattison McMillanTalon McKe eRaelene M. Wouda
Department of Clinical Sciences, College of Veterinary Medicine, Kansas State University, Manhattan, Kansas, USA
Department of Statistics, College of Arts and Sciences, Kansas State University, Manhattan, Kansas, USA
Department of Clinical Sciences, College of Veterinary Medicine, Iowa State University, Ames, Iowa, USA
Flint Animal Cancer Center, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, Colorado, USA
Veterinary Clinical Sciences Department, College of Veterinary Medicine, University of Minnesota, St. Paul, Minnesota, USA
Department of Medical Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin, USA
Las Vegas Veterinary Specialty Center, Las Vegas, Nevada, USA
Clinical Studies Department, VCA Inc., Los Angeles, California, USA
Raelene M. Wouda,Department of Clinical Sci-
ences, College of VeterinaryMedicine, Kansas State
University, Denison Avenue, Manhattan,KS
Sabina Sheppard-Olivares, Guadalupe Street,
Samuel E. Hocker,Dep artmentof Clinical Sciences,
College of VeterinaryMedicine, Kansas State
University, Denison Avenue, Manhattan,KS
Barbara Biller, Clydesdale Pkwy,L oveland,CO
Brian Husbands,Department of Veterinary Clinical
Sciences, College of Veterinary Medicine, The Ohio
StateUniversity, Coey Road,Columbus,OH
Elizabeth Snyder, BluePearl Specialty and E mer-
Spring, TX , USA.
Mattison McMillan, Col lege of Ve terinary
Medicine, Washington State University, Pullman,
WA , USA.
This study was self-funded.
Background: Insulinomas are the most common tumour of the endocrine pancreas in
dogs. These malignant tumours have a high metastatic rate and limited chemotherapeu-
tic options. The multi-receptor tyrosine kinase inhibitor sunitinib malate has benet in
the treatment of metastatic insulinoma in people. Toceranib phosphate, an analogous
veterinary agent, may provide benet for dogs.
Methods: A retrospective study describing the extent and duration of clinical outcomes
and adverse events (AEs) in dogs diagnosed with insulinoma and receiving toceranib.
Results: Records for dogs diagnosed with insulinoma and having received toceranib
were identied from a medical record search of ve university and eight referral hospi-
tals. The median progression-free interval and overall survival time were days (%
condence interval (CI): [, days]) and days (% CI: [, days]), respec-
tively. Of the dogs for which the canine Response evaluation criteria for solid tumours
tool could be applied, the majority (.%) showed either a complete response, partial
response or stable disease. Time to clinical progression was associated with prior inter-
vention and type of veterinary practice. Larger dogs were at increased risk for disease
progression and death. No novel AEs were reported.
Conclusions: Most dogs diagnosed with insulinoma and receiving toceranib appeared
to have a clinical benet. Randomised, prospective studies are needed to better elucidate
and objectively quantify the potential eect and survival benet of toceranib therapy for
management of insulinoma in dogs.
Insulinomas are insulin-secreting tumours arising from pan-
creatic beta cells. Insulinomas are the most common tumour
of the endocrine pancreas in dogs.– They are malignant
tumours, with macroscopic metastatic lesions present in
approximately % of dogs at the time of diagnosis.–
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original
work is properly cited.
©TheAuthors.Veterinary Record Open published by John Wiley & Sons Ltd on behalf of British Veterinary Association.
Moreover, it is clinically anticipated that remaining dogs will
develop metastasis and/or locoregional recurrence, with asso-
ciated clinical signs, despite surgery.–,,
The most frequent clinical signs in dogs with insuli-
noma are due to neuroglycopenia, including weakness, ataxia,
collapse, disorientation, behaviour changes and seizures.–
Immediate treatment aims to correct the hypoglycaemia and
Vet R ec Op en. ;:e. wileyonlinelibrary.com/journal/vro of
of V R O
ameliorate these clinical signs. Longer term treatment ideally
addresses the primary tumour and metastasis.–,
Despite debate around the benet of surgery for advanced
stage disease,,– partial pancreatectomy remains the main-
stay of treatment.–,,– Survival times between and
days are reported for dogs undergoing surgical exci-
sion of macroscopic disease.– Nevertheless, surgery alone
is unlikely to be curative as historical outcomes indicate most
dogs have at least micrometastasis at diagnosis,,,,,, and
disease progression is often life-limiting.– Moreover, certain
cases may not be amenable to surgery due to location and/or
extent of disease, inability to localise lesion(s) and/or owner
Medical management options for dogs with insulinoma
include lifestyle and dietary modications, and/or phar-
maceutical management with glucocorticoids, diazoxide,
glucagon, octreotide, propranolol, alloxan or streptozocin,
with only the latter two being cytotoxic.–,,,– Draw-
backs to these include unpredictable responses, side eects
and logistical issues with the route and frequency of admin-
istration, product availability and cost.,,– There remains
a need to identify eective, well-tolerated and practical med-
ical interventions, to manage clinical signs and disease pro-
gression, while maintaining quality of life in dogs with insuli-
Sunitinib malate (Sutent®; Pzer, Inc., New York, NY, USA)
is an oral small molecule inhibitor, initially approved by
the USA Food and Drug Administration for the treatment
of imatinib-resistant gastrointestinal stromal tumour, and
advanced renal cell carcinoma in people;, additional appli-
cations have been identied., Sunitinib was approved for
the treatment of locally advanced, or metastatic, pancre-
atic neuroendocrine tumours (pNETs) in people, a classi-
cation encompassing all tumours arising from the multipo-
tent stem cells of the pancreatic ductal epithelium, including
Toceranib phosphate (Palladia®; Zoetis Animal Heath,
Madison, NJ, USA) is a veterinary oral small molecule
inhibitor, with similar molecular targets to sunitinib.–
ical responses to toceranib have been documented in dogs
with a spectrum of solid tumour types, including several of
neuroendocrine histology.,– A retrospective study of ve
dogs diagnosed with metastatic or recurrent insulinoma and
treated with toceranib suggested improved outcomes when
compared with seven dogs treated palliatively. Acasereport
describing a dog with metastatic insulinoma reported long-
term glycaemic control with toceranib.
The objectives of this retrospective study were to describe
the extent and duration of clinical outcomes and adverse
events (AEs), in dogs diagnosed with insulinoma and treated
MATERIALS AND METHODS
The medical record databases of ve collaborating academic
and eight referral veterinary hospitals in the US and Canada
were searched for cases in which dogs diagnosed with insuli-
March . Inclusion criteria were: () documentation of
fasting hyperinsulinaemia with paired hypoglycaemia and/or
cytological or histological diagnosis of a primary pancre-
atic tumour with neuroendocrine morphology; () reasonable
elimination of other causes of hypoglycaemia, as decided by
the clinicians primarily responsible for each case and doc-
umented in the medical records, typically considering his-
tory, physical examination ndings, laboratory anomalies or
lack thereof and imaging; () documentation of any prior,
concurrent or subsequent treatments; () documentation of
toceranib dosage and schedule; () at least one documented
follow-up assessment during the toceranib treatment period.
Exclusion criteria were: () absence of a clinical diagnosis of
insulinoma and () insucient details documenting toceranib
treatment and follow-up.
Information collated included: signalment, weight, clini-
cal signs at diagnosis and at subsequent visits, glucose and
insulin measurements at diagnosis and subsequently, ndings
of any imaging performed at diagnosis and subsequently, his-
tological and/or cytological diagnoses, details of any clinico-
pathologic analyses performed at baseline or subsequently,
blood pressure measurement at diagnosis, toceranib dose and
administration regimen, response to treatment, AEs, dura-
tion of toceranib therapy, reason for cessation, any anticancer
therapy after toceranib, comorbidities, concomitant medica-
tions, and the date and reason for death or euthanasia. Addi-
tional details were obtained from the referring veterinarian(s)
and/or owner(s) where necessary.
End points were progression-free interval (PFI) and over-
all survival time (OST). The PFI was dened as the interval
in days from the date of toceranib initiation to the date of
documented clinical progression (CP). The CP was dened
as either the return of clinical signs associated with neuro-
glycopenia as reported by the overseeing clinician(s) and/or
owner(s), loss of glycaemic control based upon serial fasting
blood glucose measurements, or the development of novel
metastasis, metastatic progression and/or local progressive
disease (PD) according to the canine Response evaluation
criteria for solid tumours (cRECIST), applied based upon
repeated abdominal ultrasound, CT and/or thoracic radio-
graphs when available. For cases in which CP was not doc-
umented, PFI was considered right-censored and dened as
interval in days to date of last data submission or date of death
or euthanasia. The OST was dened as the interval in days
from the date of diagnosis to the date of death or euthanasia.
was considered right-censored and dened as the interval
from the date of diagnosis to the date of last data submission.
As in previous studies, stage was retrospectively assigned
according to the World Health Organization (WHO) Tumour
Node Metastasis (TNM) system.,, With stage I being dis-
ease conned to the pancreas, stage II indicating lymph node
metastasis and stage III indicating distant metastasis. The
WHO recommendations advise lymph node examination by
laparotomy or laparoscopy, however, the present study recog-
nised non-invasive assessments, such as ultrasound and CT,
The AEs were retrospectively graded according to the
Veterina r y Co-op e r a t i ve Oncology Gro u p – C o m mon Ter-
minology Criteria for Adverse Events (VCOG-CTCAE)
V R O of
following chemotherapy or biological antineoplastic therapy
in dogs and cats.
The Kaplan–Meier estimator was applied to estimate the
survival distribution of the two continuous right-censored
response variables, PFI and OST. Censoring criteria for PFI
and OST were as previously dened. Computations were con-
ducted using the LIFETEST procedure of SAS (Version .,
Cary, NC, USA). Condence intervals (CIs) at given time
points were calculated based on log–log transformations. A
Cox proportional hazards (PH) model was tted to each
response variable, PFI and OST. The linear predictor in the
PH model evaluated several, non-time-dependent, explana-
tory covariates as potential risk factors, specically sex, age
at diagnosis, weight at diagnosis, type of veterinary practice,
tumour stage, therapy prior to toceranib, toceranib dose, dos-
ing regimen and all two-way interactions. Selection of covari-
ates into the model was conducted by stepwise selection at a
% signicance level for entry and % for removal. For each
model, the PH assumption was evaluated. Computations were
conducted using the PHREG procedure of SAS (Version .).
dogs, two Boston terriers, two Chihuahuas, two Labrador
retrievers and one of each of the following breeds: Afghan
hound, Australian shepherd, chow chow, cocker spaniel,
coonhound, dachshund, Doberman pinscher, Irish setter,
Jack Russell terrier, papillon, Pekingese, Pomeranian, Scot-
tish terrier, shar pei, West Highland white terrier and York-
shire terrier. There were neutered male (.%) and
spayed female (.%) dogs. The median age at diagnosis was
years (min—max: – years). The median weight was
. kg (min—max: .–. kg).
Presentation, diagnosis and staging
The majority of dogs (n=/, %) initially presented
with clinical signs attributable to neuroglycopenia, including
seizures (n=), collapse (n=), ataxia (n=), muscle
tremors (n=) and twitching (n=). Two dogs presented
with lethargy and two with vomiting. Four dogs had hypogly-
caemia incidentally identied on blood tests, although were
routine annual examination and the fourth for a subcutaneous
A histopathological or cytological diagnosis was available
for / dogs. Twenty-one dogs underwent partial pan-
guided ne needle aspirate biopsy (FNA) of a pancreatic mass
was performed, with cytology. All dogs were also hypo-
glycaemic; / dogs had an inappropriate fasting insulin
level in the presence of hypoglycaemia. Of the remaining
/ dogs, four were diagnosed based on an inappropriate
fasting insulin level in the presence of hypoglycaemia, com-
bined with an imaging ndings of a pancreatic nodule on CT
(n=) or ultrasound (n=), with no pathological conr-
mation. One dog was diagnosed based on clinical signs con-
sistent with neuroglycopenia, combined with an inappropri-
all cases, alternative causes of hypoglycaemia, including idio-
pathic in toy breed dogs, sepsis, hepatic dysfunction, renal
failure, adrenocortical insuciency, toxin exposure and extra-
pancreatic tumour-associated paraneoplastic hypoglycaemia,
were considered and reasonably eliminated.
All dogs were hypoglycaemic at the time of diagnosis.
Although the normal reference range varied for each labora-
tory evaluating the fasting blood glucose concentrations, all
laboratories asserted values below . mmol/L were abnor-
mal. Twenty-eight dogs had fasting hypoglycaemia in the
presence of a normal or increased insulin level. Although the
normal insulin reference range also varied for each laboratory
evaluating it, all laboratories asserted values between and
pmol/L to be normal and above pmol/L abnormal.
which were diagnosed based upon histopathology and/or con-
sistent cytology. The median fasting blood glucose concentra-
tion at diagnosis was . mmol/L (.–. mmol/L) and
Based on the diagnostic tests performed, eight dogs had
WHO TNM stage I, stage II and nine stage III disease.
Imaging tests performed included abdominal ultrasound
(n=), thoracic radiographs (n=) and/or abdomi-
nal ±thoracic CT (n=). Imaging ndings and their
clinical sequelae are reported in Table .Metastaticloca-
tions conrmed by FNA and cytology, or tissue biopsy and
histopathology, included the locoregional pancreatic lymph
nodes (n=), liver (n=), distant lymph nodes (n=),
hepatic lymph nodes (n=) and spleen (n=). Some of these
dogs had imaging abnormalities as documented in Table .
For eight of the dogs with lymph node metastasis conrmed
by histopathology and two dogs with histopathologically con-
rmed liver metastasis, prior imaging was not suggestive of
metastasis. Moreover, not all imaging anomalies were further
investigated (Table ).
See Supporting Information for details on haematologi-
cal and biochemical analyses, co-morbidities and concurrent
Treat m ent
Twenty-one dogs underwent partial pancreatectomy prior to
toceranib. One of these dogs underwent a second surgery for
PD, years after the initial surgery, then received toceranib.
One dog underwent regional lymph node extirpation at
therapy for these dogs that included regional lymph
node metastasis present at diagnosis (n=), hepatic ±
lymph node metastasis at diagnosis (n=), inability to
successfully excise the pancreatic mass (n=), recurrence
of clinical signs associated with hypoglycaemia (n=) and
a recurrent pancreatic nodule days following partial
of V R O
TAB L E Summary of imaging tests undertaken in dogs diagnosed with insulinoma and commencing toceranib therapy, imaging ndings, any further
investigations then undertaken and results consistent with neuroendocrine disease
Staging test and reported ndings
Number of cas es
undergoing staging tests
Number of these cases
investigation of potential
disease and/or metastasis
Number of these cases with
Thoracic radiographs NA NA
No signicant ndings NA NA
At least one hypoechoic pancreatic nodule
Locoregional pancreatic lymphadenopathy
Non-regional lymphadenopathy aa
Multiple hypoechoic hepatic nodules bb
Multiple hypoechoic splenic nodules cc
Cranial abdominal mass
Thickened intestinal walls
No signicant ndings dd
Computed tomography (abdomen ±thorax)
Pancreatic nodules with arterial phase enhancement
Locoregional pancreatic lymphadenopathy
Hypoattenuating hepatic nodules with venous contrast
At least one hypoattenuating splenic nodule
Subcutaneous mass e
No sig nicant ndings NA NA
aDetermined to be mast cell tumour metastasis via ne needle aspirate (FNA) and cytology.
bOne of the four cases was determined to be metastatic mast cell disease via FNA and cytology.
cDetermined to be metastatic mast cell disease in one case and lymphoid proliferation in the other via FNA and cytology.
dThree of ve cases underwent surgical tissue biopsies conrming the primary pancreatic disease and locoregional lymph node metastasis.
eDiagnosed as a narrowly excised high-grade soft tissue sarcoma via subsequent histopathology.
pancreatectomy (n=). The median duration of time
between the initial surgery and starting toceranib was days
(min–max: – days).
Three of the aforementioned dogs received adjuvant
cytotoxic chemotherapy. One of these dogs commenced
toceranib days after completing an adjuvant course of four
doses of doxorubicin ( mg/mintravenously (IV) every
weeks), one received two adjuvant doses of streptozotocin
( mg/mIV diluted in ml NaCl (.%) every weeks)
with prednisone before treatment was changed to toceranib
and another dog received six adjuvant doses of vinorel-
bine ( mg/mIV every – days) before commencing
Nine dogs did not undergo partial pancreatectomy. Six
of these dogs received prednisone prior to toceranib. One
of these dogs briey received glucagon with prednisone,
although clinical signs persisted and the glucagon was ceased
after only days. All dogs receiving prednisone were started
with toceranib when persistence, or recurrence, of clini-
cal signs associated with hypoglycaemia were observed. The
median duration between diagnosis and toceranib treatment
for these six dogs was days (min–max: – days). Three
of these nine dogs did not receive any treatment prior to
commencing toceranib. The median duration between diag-
nosis and starting toceranib treatment in these dogs was
days (min–max: – days).
The median starting dose of toceranib was . mg/kg
(min–max: .–. mg/kg) by mouth (PO). Twenty-four
dogs initially received toceranib on a Monday, Wednes-
day, Friday (MWF) schedule and six dogs according to
every other day (EOD) schedule. The overall median start-
ing dose intensity was . mg/kg/week (min–max: .–
. mg/kg/week). For the dogs initially receiving toceranib
on a MWF schedule (n=), the median starting dose
intensity was . mg/kg/week (.–. mg/kg/week). For
the dogs initially receiving toceranib according to an EOD
schedule (n=), the median starting dose intensity was
. mg/kg/week (min–max: .—. mg/kg/week).
The AEs likely or potentially associated with toceranib
therapy are detailed in Table .Fourteendogs(.%)were
reported to develop at least one, grade or , self-limiting
haematological AE during toceranib therapy. Biochemical
anomalies were documented in dogs (.%). Seventeen
dogs (.%) were reported with one or more gastrointesti-
nal AEs. The majority of these were grade or , although a
dose reduction was instituted for dogs (.%) due to gas-
Twenty-three dogs were concurrently administered pred-
. mg/kg). Eleven of these dogs were receiving prednisone,
with inadequately controlled disease, at the time of commenc-
ing toceranib. Twelve dogs were commenced on prednisone
V R O of
TAB L E Dogs diagnosed with insulinoma and records of adverse events likely or potentially attributable to toceranib phosphate therapy
Adverse event Grade n(%) Grade n(%) Grade n(%) Grade n(%) Grade n(%)
Anorexia () (.) (.) – –
Vom i tin g ( ) (. ) – – –
Gastric ulceration – – – – a(.)
Fever () – – – –
Weight Loss () – – – –
Lethargy (.) (.) – – –
Anaemia (.) – – – –
Neutropenia (.) (.) – – –
Thrombocytopenia (.) – – – –
Azotaemia (.) – – – –
Increased blood urea nitrogen (.) – – – –
Increased alkaline phosphatase (.) (.) (.) – –
Increased alanine aminotransferase (.) (.) (.) – –
Increased aspartate aminotransferase (.) (.) – – –
Hypoalbuminaemia (.) – – – –
Increased cholesterol (.) – – – –
Hypocalcaemia (.) – – – –
Hypertension (.) (.) – – –
Proteinuria (.) (.) (.) – –
Note: Cases were graded according to the Veterinary Co-operative Oncology Group – Common Terminology Criteria for Adverse Events (VCOG-CTCAE) followingchemotherapy
or biological antineoplastic therapy in dogs and cats v..
aSuspected clinically, but not conrmed with postmortem examination.
around the time of commencing toceranib. Two of these dogs
received both prednisone and diazoxide (– mg/kg PO twice
daily) during treatment with toceranib.
All dogs were treated in the setting of documented PD or
with CP as dened in the section Materials and Methods.
This included three dogs that had undergone successful par-
tial pancreatectomy, with no appreciable residual disease,
who then developed recurrent clinical signs attributed to
Response criteria as dened by cRECIST were able to be
assigned for dogs; baseduponrepeatedimaging,abdom-
inal ultrasound (n=) ±thoracic radiographs (n=) or
CT-scan (n=). Intervals between assessments were not stan-
dardised and intervals were documented between week and
months. Of the dogs with a cRECIST response reported,
.% of dogs showed a clinical benet; six (%) dogs
showed a complete response (CR), one (.%) dog had a par-
tial response (PR), three (%) dogs had stable disease (SD)
and ve (.%) dogs had PD. All dogs that had a CR, PR or
SD were also reported to be normoglycaemic at each response
Twelve dogs were monitored based on clinical signs and
repeated blood glucose measurements. Intervals between
these assessments were not standardised and even the mon-
itoring intervals for each individual dog varied as treatment
time progressed, however, the intervals were documented to
be between week and months. The median duration of
reported normoglycaemia and lack of associated clinical signs
was days (min–max: – days).
measurements; they were re-evaluated based solely on clinical
signs associated with hypoglycaemia. One of these dogs was
reported to have CP after just days of toceranib treatment,
reported to have CP after days. In these cases, the intervals
were dependent upon the owners’ reporting.
The median duration of toceranib treatment for all dogs
was days (min–max: –). For dogs toceranib
was stopped. Nineteen dogs were discontinued because of
CP; including one dog after days due to an unspecied
of V R O
0 200 400 600 800 1000 1200 1400
% Progression Free
FIGURE Estimated Kaplan–Meier survival curve for median overall progression-free interval for dogs with insulinoma treated with toceranib. In
absence of documentation of progressive disease, disease progression was considered not observed for dogs, up until the last veterinary visit and the
progression-free interval was right-censored for these cases
increase in liver enzyme values, another dog because of
nancial concerns, another dog after days, because of
a persistent absence of CP, but then was recommenced on
toceranib when CP was documented another days later.
FNA after days, yet continued to receive toceranib. Eight
dogs remained on toceranib without documentation of CP
until study conclusion (n=) or death (n=) – this dog died
acutely days after commencing toceranib, presumably
as a consequence of gastrointestinal ulceration, although no
postmortem examination was performed.
One dog that developed CP subsequently received
masitinib (∼. mg/kg PO once daily). However, the dog’s
clinical signs acutely worsened, masitinib was stopped and
metronomic cyclophosphamide ( m/monce daily) admin-
istered for days before the dog was euthanased. One dog
that developed CP then received two doses of streptozotocin
( mg/mIV every weeks) before therapy was ceased.
Four dogs were continued on prednisone until euthanasia
The CP was documented in dogs (.%). For the dogs
without documented CP, PFI was right-censored at the time
of ceasing toceranib because of AEs (n=) or the last vet-
erinary visit (n=). The median PFI was days (% CI:
[, days]) (Figure ). The probability of a dog being free
(±standard error), . ±. and . ±., respectively.
details were lacking for ve. One dog died of complica-
tions of presumptive gastrointestinal ulceration, days after
toceranib initiation, although not conrmed by postmortem
examination. In the absence of a death record, OST was right-
censored for nine dogs that were alive and receiving toceranib
CI: [, days]) (Figure ). The probability of survival
to , , and days was estimated at . ±.,
. ±., . ±. and . ±., respectively.
Of the explanatory covariates examined with respect to PFI,
the stepwise model selection approach indicated statistical
evidence for a signicant association between PFI and sev-
eral covariates considered jointly; therapy prior to toceranib
(p=.), type of practice (p=.) and weight at
nary practice and weight, dogs that received prior therapy
showed an estimated hazard ratio (HR) for PD of . (% CI:
[., .]), relative to dogs that did not. After adjusting for
prior therapy and weight, dogs treated at an academic insti-
tution showed an estimated HR for CP of . (% CI: [.,
.]) relative to dogs treated in referral veterinary practice.
After accounting for the aforementioned covariates, every kg
increase in body weight increased the hazard of CP by an esti-
mated multiplier of . (% CI: [., .]). There was
no statistical evidence of any association between PFI and any
of the other proposed covariates at a % level of signicance
Of the covariates examined with respect to OST the only
explanatory variable identied was weight at diagnosis. For
every kg increase in body weight, there was an increased
hazard of death by an estimated multiplier of . (% CI:
[., .]). There was no statistical evidence of any associ-
ation between OST and any of the other proposed covariates
at a % of signicance (p>.).
In this study, improvement in clinical signs attributed to hypo-
glycaemia was observed in all dogs diagnosed with insuli-
noma and treated with toceranib. For all dogs, the median
PFI and OST were days (% CI: [, days]) and
days (% CI: [, days]), respectively. Ten of dogs
(.%), for which cRECIST could be applied, had reported
V R O of
0 500 1000 1500 2000 2500 3000
FIGURE Estimated Kaplan–Meier survival curve for median overall survival time for dogs with insulinoma treated with toceranib. In the absence of
a death record, the overall survival time was right-censored for nine dogs that were alive and still receiving toceranib at the time of last assessment
either a CR, PR or SD. Toceranib was generally well-tolerated,
with a comparable AE prole to previous reports and no novel
Prior studies evaluating risk factors for measures of out-
come in dogs with insulinoma have found stage to be
prognostic,,,, however, stage was not signicantly asso-
ciated with PFI or OST in this study. As with other studies in
which stage was not signicant, the inconsistency is likely a
nation with a limited size of the study population, thereby pre-
cluding powerful statistical comparisons between sub-groups.
Additionally, the retrospective application of the WHO TNM
underestimated some stages.
In this study, dogs that received therapy for insulinoma
prior to toceranib had a greater hazard for PD than dogs
receiving toceranib as rst-line treatment. It is possible that
this nding is just a consequence of the retrospective nature
tion bias and should not be attributed any cause–eect mean-
ing. A formal assessment of cause and eect would require
a follow up experimental study in which dogs are randomly
assigned to treatment schemes to avoid confounding eects.
In this retrospective study, the dogs that had received prior
interventions, with PD being the reason for then commencing
toceranib, may have had intrinsically resistant disease or dis-
ease now selected for resistance mechanisms. Other potential
confounding eects, known or unknown, cannot be refuted
either based on the observational nature of the data. This nd-
ing should be further considered alongside other studies that
have demonstrated medical management alone to be a poor
prognostic factor,, as well as those that have described its
In this study, dogs treated at university hospitals had an
hospitals. The clinical relevance of this observation is specula-
tive and the nding likely impacted by biases related to the ret-
rospective nature of the study. Possible explanations include
academic institutions pursuing more comprehensive follow-
up and/or documentation, or cases with more advanced dis-
ease stages being more commonly referred to academic insti-
tutions. Outcomes for other cancers have been associated
with practice type. However, previous studies describing treat-
ment and outcomes for canine insulinoma have been largely
undertaken through academic sites and it would be irrespon-
sible to draw conclusions based on this retrospective study
alone.,,,,, Prospective, randomised or controlled cohort
studies, would be required to legitimately compare dierent
treatment settings and to better evaluate the clinical implica-
tions for dogs with insulinoma.
There was an increased hazard of both CP and death for
every kg increase in body weight at diagnosis. Insulino-
mas are commonly reported in medium and large breed
dogs, yet body weight has not been previously described as
prognostic factor.,,,,, Apotentialimpactofbodysize
and obesity on treatment and outcomes warrants further
Similar to previous reports,,– gastrointestinal AEs
were the most common AE reported in this study. The
majority of gastrointestinal AEs were grade or , although
dosing modications were necessary in dogs. Moreover,
although dose interval was not associated with outcome, the
dog receiving the highest dose and dose intensity of toceranib
(. mg/kg PO EOD), while showing a CR, did present on an
emergency basis with suspected gastrointestinal perforation.
Although postmortem examination was not performed this
AE. This case highlights that the labelled dose of toceranib
causes more marked AEs in dogs,, andalsoemphasisesthe
importance of the studies demonstrating equivalent biologi-
cal activity and comparable clinical responses with doses of
toceranib lower than the labelled dose.,
Additional AEs included grades –, constitutional, haema-
tological and biochemical AEs (Table ), which were not asso-
ciated with overt clinical signs, nor necessitated dosing mod-
ications. At least some of the biochemical AEs were likely
the result of pre-existing conditions based upon compari-
son with biochemical values obtained prior to commencing
toceranib. Ultimately, the AE prole of toceranib, at an appro-
priate dose, seems more tolerable than that described for alter-
native cytotoxic agents, considered for the management of
In people, there are reports of diabetic and non-diabetic
patients experiencing alterations in blood glucose levels,
of V R O
including hyperglycaemia and hypoglycaemia, with vari-
ous receptor tyrosine kinase inhibitors (RTKIs), including
sunitinib.– The mechanism by which RTKIs aect glu-
cose homeostasis remains unclear.– While the authors
are unaware of documented hypoglycaemia associated with
toceranib administration in dogs, it cannot be excluded that
dogs may benet because of an impact on glucose homeosta-
sis. Furthermore, it is important for clinicians to be aware of
the hypothetical risk of iatrogenic hypoglycaemia or hyper-
glycaemia, when electing toceranib for the management of
insulinoma, because it has the potential to obscure treatment
response, especially if response assessment is based solely on
glycaemic control and clinical signs.
This study has several limitations, largely due to its retro-
spective and multicentre design. The diagnostic, staging and
monitoring tests, and resultant clinical decisions, were not
standardised and were doubtlessly inuenced by the over-
seeing clinicians’ and owners’ preferences and even nances.
While arguably not ideal, this approach recapitulates clin-
ical practice and is consistent with previous insulinoma
studies.,, Re-staging tests and intervals were also not uni-
formly performed. While response assessments and measures
of outcome would ideally be based upon the routine re-
evaluation of clinical signs associated with hypoglycaemia,
repeated blood glucose measurements and imaging enabling
the designation of cRECIST, this was not always the case. Most
importantly, the PFI and OST may have been extended by
the administration of supportive medications. Owner deci-
sions regarding pursuing ongoing treatment and euthanasia
perceived quality of life, which in turn may be impacted by
supportive medications. Finally, several dogs received con-
current prednisone. While a statistical association was not
detected, previous studies have described benet with pred-
nisone administration;–,, an impact cannot be discounted.
The authors genuinely appreciate the assistance of Philip
Bergman, Craig Cliord, Samantha Bajorek, John Chretin,
Catherine McDonald, Danielle O’Brien, Erin Portillo, Andrew
Vaughn and Zachary Wright, in facilitating data collection.
The authors also acknowledge the considerable support and
insights of Mary Lynn Higginbotham.
CONFLICTS OF INTEREST
The authors declare they have no conicts of interest.
DATA AVAILABILITY STATEMENT
All data relevant to the study are included in the article. The
able from the corresponding author upon reasonable request.
Sabina Sheppard-Olivares https://orcid.org/--
Chad M. Johannes https://orcid.org/---
Raelene M. Wouda https://orcid.org/---
. Goutal CM, Burgmann BL, Ryan KA. Insulinoma in dogs: a review. J Am
Anim Hosp Assoc. ;:–.
. Lunn KF, Boston SE. Tumours of the endocrine system. In: Vail DM,
Thamm DH, Liptak JM, editors. Withrow and MacEwen’s small animal
clinical oncology. th ed. St. Louis, MO, USA: Elsevier; . p. –.
. Nelson RW. Beta cell neoplasia: insulinoma. In: Feldman EC, Nelson
RW, Reusch C, Scott-MoncrieJC, B ehrend E, editors.Canine and feline
endocrinology. th ed. St. Louis, MO, USA: Elsevier; . p. –.
. Caywood DD, Klausner JS, O’Leary TP, Withrow SJ, Richardson RC,
Harvey HJ et al. Pancreatic insulin-secreting neoplasms: clinical, diag-
nostic, and prognostic features in dogs. J Am Anim Hosp Assoc.
. Kruth SA, Feldman EC, Kennedy PC. Insulin-secreting islet cell
tumours: establishing a diagnosis and the clinical course for dogs. J
Am Vet Med Assoc. ;:–.
. Leifer CE, Peterson ME, Matus RE. Insulin-secreting tumour: diagnosis
and medical and surgical management in dogs. J Am Vet Med Assoc.
. Madarme H, Kayanuma H, Shida T, Tsuchiya R. Retrospective study of
canine insulinomas: eight cases (-). J Vet Med Sci. ;:–
. Tobin RL, Nelson RW, Lucroy MD, Woodridge JD, Feldman EC. Out-
come of surgical versus medical treatment of dogs with beta cell neopla-
sia: cases (-). J Am Vet Med Assoc. ;:–.
. Trifonidou MA, Kirpensteijn J, Robben JH. A retrospective evaluation
of dogs with insulinoma. Vet Q. ;:S–.
. Polton GA, White RN, Brearley MJ, Eastwood JM. Improved survival
in a retrospective cohort of dogs with insulinoma. J Sm Anim Pract.
. Cleland NT, Morton J, Delisser PJ. Outcome after surgical management
of canine insulinoma in cases. Vet Comp Oncol. ;():–.
. Del Busto I, German AJ, Treggiari E, Romanelli G, O’C onnellEM, B atch-
elor DJ, et al. Incidence of postoperative complications and outcome of
dogs undergoing surgical management of insulinoma. J Vet Intern
Med. ;():–. https://doi.org/./jvim.
. Harris ME, Weatherton L, Bloch CP. Glucagon therapy in canines with
an insulinoma: a retrospective descriptive study of dogs. Can Vet J.
. Meleo K. Management of insulinoma patients with refractory hypo-
glycemia. Probl Vet Med. ;:–.
. Moore AS, Nelson RW, Henry CJ, Rassnick KM, Kristal O, Ogilvie GK,
et al. Streptozocin for treatment of pancreatic islet cell tumors in dogs:
cases (-). J Am Vet Med Assoc. ;():–. https://doi.
. Northrup NC, Rassnick KM, Gieger TL, Kosarek CE, McFadden CW,
Rosenberg MP. Prospective evaluation of biweekly streptozotocin in
dogs with insulinoma. J Vet Intern Med. ;():–. https://doi.
. Robben JH, van den Brom WE, Mol JA, van Haeften TW, Rijnberk
A. Eect of octreotide on plasma concentrations of glucose, insulin,
glucagon, growth hormone, and cortisol in healthy dogs and dogs with
insulinoma. Res Vet Sci. ;:–.
. Simpson KW, Stepien RL, Elwood CM, Boswood A, Vaillant CR. Eval-
uation of the long-acting somatostatin analogue octreotide in the man-
agement of insulinoma in three dogs. J Small Anim Pract. ;:–
. Demetri GD, van Oosterom AT, Garrett CR, Blackstein ME, Shah MH,
Verweij J, et al. Ecacy and safety of sunitinib in patients with advanced
gastrointestinal stromal tumour after failure of imatinib: a randomised
controlled trial. Lancet ;():–. https://doi.org/./
buru JV, et al. Approvalsummar y: sunitinib for the treatment ofimatinib
refractory or intolerant gastrointestinal stromal tumors and advanced
renal cell carcinoma. Clin Cancer Res. ;():–. https://doi.
. Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM,
Rixe O, et al. Sunitinib versus interferon alfa in metastatic renal-cell
carcinoma. N Engl J Med. ;():–. https://doi.org/./
. Carlisle B, Demko N, Freeman G, Hakala A, MacKinnon N, Ramsay
T, et al. Benet, risk, and outcomes in drug development: a system-
atic review of sunitinib. J Natl Cancer Inst. ;():djv. https:
V R O of
. Hao Z, Sadek I. Sunitinib: the antiangiogenic eects and beyond. Onco
Targets Ther. ;:–.
. Kulke MH, Lenz HJ, Meropol NJ, PoseyJ, Ryan DP, Picus J, et al. Activity
of sunitinib in patients with advanced neuroendocrine tumors. J Clin
Oncol. ;():–. https://doi.org/./JCO...
C, et al. Sunitinib malate for the treatment of pancreatic neuroen-
docrine tumors. N Engl J Med. ;():–. https://doi.org/.
. Blumenthal GM, Cortazar P, Zhang JJ, Tang S, Sridhara R, Murgo A,
et al. FDA approval summary: sunitinib for the treatment of progressive
well-dierentiated locally advanced or metastatic pancreatic neuroen-
docrine tumors. Oncologist ;():–. https://doi.org/./
. Faivre S, Delbaldo C, Vera K, Robert C, Lozahic S, Lassau N, et al. Safety,
pharmacokinetic, and antitumor activity of SU, a novel oral mul-
titarget tyrosine kinase inhibitor, in patients with cancer. J Clin Oncol.
. Liao AT, Chien MB, Shenoy N, Mendel DB, McMahon G, et al. Inhi-
bition of constitutively active forms of mutant kit by multitargeted
indolinone tyrosine kinase inhibitors. Blood ;:–.
. London CA, Hannah AL, Zadovoskaya R, Chien MB, Kollias-Baker C,
Rosenberg M, et al. Phase I dose-escalating study of SU, a small
molecule receptor tyrosine kinase inhibitor, in dogs with spontaneous
malignancies. Clin Cancer Res. ;():–.
. Pryer NK, Lee LB, Zadovaskaya R, Xiaoming Y, Sukbuntherng J, et al.
Proof of target for SU: inhibition of KIT phosphorylation in canine
mast cell tumors. Clin Cancer Res. ;:–.
. London CA, Malpas PB, Wood-Follis SL, Boucher JF, Rusk AW, Rosen-
berg MP, et al. Multi-center, placebo-controlled, double-blind, random-
ized study of oral toceranib phosphate (SU), a receptor tyrosine
kinase inhibitor, for the treatment of dogs with recurrent (either local
or distant) mast cell tumor following surgical excision. Clin Cancer Res.
. Berger EP, Johannes CM, Jergens AE, Allenspach K, Powers BE, Du Y,
et al. Retrospective evaluation of toceranib phosphate (Palladia®) use in
the treatment of gastrointestinal stromal tumors of dogs. J Vet Intern
Med. ;():–. https://doi.org/./jvim.
. Elliott JW. Response and outcome following toceranib phosphate treat-
ment for stage four anal sac apocrine gland adenocarcinoma in dogs:
cases (-). J Am Vet Med Assoc. ;:–.
. Gustafson TL, Biller B. Use of toceranib phosphate in the treatment of
canine bladder tumors: cases. J Am Anim Hosp Assoc. ;:–.
. Heaton CM, Fernandes AFA, Jark PC, Pan X. Evaluation of toceranib
for treatment of apocrine gland anal sac adenocarcinoma in dogs. J Vet
Intern Med. ;:–.
. Heishima K, Iwasaki R, Kawabe M, Murakami M, Sakai H, Maruo K,
et al. Short-term administration of single-agent toceranib in six cases of
inoperable massive canine hepatocellular carcinoma. J Am Anim Hosp
Assoc. ::–. https://doi.org/./JAAHA- MS-
. Lew FH, McQuown B, Borrego J, Cunningham S, Burgess KE. Retro-
spective evaluation of canine heart base tumours treated with toceranib
phosphate (Palladia): –. Vet Comp Oncol. ;:–.
. London C, Mathie T, Stingle N, Cliord C, Haney S, Klein MK, et al.
Preliminary evidence for biologic activity of toceranib phosphate (Pal-
. Musser ML, Taikowski KL, Johannes CM, Bergman PJ. Retrospective
evaluation of toceranib phosphate (Palladia®) use in the treatment of
inoperable, metastatic, or recurrent canine phaeochromocytomas:
dogs (-). BMC Vet Res. ;:.
. Rippy SB, Gardner HL, Nguyen SM, Warry EE, Portela RA, Drost WT,
et al. A pilot study of toceranib/vinblastine therapy for canine transi-
tional cell carcinoma. BMC Vet Res. ;:. https://doi.org/./
. Sheppard-Olivares S, Bello NM, Wood E, Szivek A, Biller B, Hocker S,
et al. Toceranib phosphate in the treatment of canine thyroid carcinoma:
cases (-). Vet Comp Oncol. ;():–. https://doi.
ment of postoperative adjuvant treatment using toceranib phosphate
against adenocarcinoma in dogs. J Vet Intern Med. ;():–.
. Alonso-Miguel D, García-San José P, González Sanz S, Clarés Moral I,
Pérez-Alenza MD. Evaluation of palliative therapy, alone or in combi-
nation with toceranib phosphate, in dogs diagnosed with metastatic or
recurrent beta-cell neoplasia. NZ Vet J. ;:–.
. Flesner BK, Fletcher JM, Smithee T, Boudreaux B. Long-term survival
and glycemic control with toceranib phosphate and prednisone for a
metastatic canine insulinoma. J Am Anim Hosp Assoc. ;:e–.
. Nguyen SM, Thamm DH, Vail DM, London CA. Response evaluation
criteria for solid tumours in dogs (v.): a Veterinary C ooperativeOncol-
ogy Group (VCOG) consensus document. Vet Comp Oncol. ;:–
. Owen LN. Alimentary system, pancreas, liver. In: Owen LN, editor.
World health organization (WHO) TNM classication of tumours in
domestic animals. Geneva, Switzerland: World Health Organization;
. p. –.
. Veterinary cooperative oncology group – common terminology crite-
ria for adverse events (VCOG-CTCAE) following chemotherapy or bio-
logical antineoplastic therapy in dogs and cats v.. Vet Comp Oncol.
. Buishand FO, Visser J, Kik M, Gröne A, Keesler RI, Briaire-de Bruijn
IH, et al. Evaluation of prognostic indicators using validated canine
insulinoma tissue microarrays. Vet J. ;():–. https://doi.org/
. Buishand FO, Kik M, Kirpensteijn J. Evaluation of clinico-pathological
criteria and the Ki index as prognostic indicators in canine insuli-
noma. Vet J. ;:–.
. Bernabe LF, Portela R, Nguyen S, Kisseberth WC, Pennell M, Yancey
MF, et al. Evaluat ion of the adverse event prole and pharm acodynamics
of toceranib phosphate administered to dogs with solid tumors at doses
below the maximum tolerated dose. BMC Vet Res. ;:. https://
. Agostino NM, Chinchilli VM, Lynch CJ, Koszyk-Szewczyk A, Gin-
grich R, Sivik J, et al. Eect of the tyrosine kinase inhibitors (sunitinib,
sorafenib, dasatinib, and imatinib) on blood glucose levels in diabetic
and nondiabetic patients in general clinical practice. J Oncol Pharm
Pract. ;():–. https://doi.org/./
. Breccia M, Molica M, Alimena G. How tyrosine kinase inhibitors
impair metabolism and endocrine system function: a systematic updated
review. Leuk Res. ;:–.
. Buer P, Bouillet B, Smati S, Archambeaud F, Cariou B, Verges B. Expert
opinion on the metabolic complications of new anticancer therapies:
tyrosine kinase inhibitors. Ann Endocrinol (Paris). ;():–.
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How to cite this article: Sheppard-Olivares S, Bello
NM, Johannes CM, Hocker SE, Biller B, Husbands B,
et al. Toceranib phosphate in the management of
canine insulinoma: a retrospective multicentre study
of cases (–). Vet Rec Open. ;e.