Original Article DOI: 10.1111/j.1476-5829.2011.00292.x
Primary frontal sinus squamous cellcarcinoma in three dogs treated withpiroxicam combined with carboplatinor toceranib
J. de Vos1, S. Ramos Vega1,2, E. Noorman3 and P. de Vos1
1Veterinary Oncology Referral Centre ‘‘De Ottenhorst’’, Terneuzen, The Netherlands2Facultad de Veterinaria ULPGC, Las Palmas, Gran Canaria, Spain3Clinic for Companion Animal Medicine ‘‘Den Heuvel’’, Best, The Netherlands
AbstractIn human medicine, primary frontal sinus squamous cell carcinoma (pFS-SCC) is not frequently
reported. In veterinary medicine, frontal sinus SCC is exclusively described as an extension of nasal
cavity SCC. To our knowledge, this is the first publication concerning canine pFS-SCC, diagnosed
using histology or cytology and medical imaging, in three dogs. The tumours extended into the orbit
or brain cavity, without nasal involvement. Treatment was initiated with piroxicam–carboplatin.
Prolongation of carboplatin delivery with a low dose intensity was performed on dogs with a
favourable initial response. Dog 1 achieved a complete remission (CR), but was euthanized 344 days
after start of therapy. Dog 2, still alive 3 years after start of therapy and in CR, received 14 carboplatin
deliveries. In dog 3, after changing the treatment protocol into piroxicam–toceranib, a significant
tumour reduction occurred, but the dog was euthanized after 195 days because of a relapse.
Keywordscarboplatin, dog, frontalsinus, piroxicam, squamouscell carcinoma, toceranib
Introduction
Squamous cell carcinoma (SCC), primarily origi-
nating from the mucosal lining of the frontal sinus,
is a rare disease entity both in human beings and in
animals.
Primary frontal sinus squamous cell carcinoma
(pFS-SCC) in human beings was first described in
1907 by Prawssud,1 and accounts for 0.01–0.03%
of all head and neck cancers.2 – 4 In human beings,
nasal and paranasal cancers tend to present most
commonly between 50 and 70 years of age.5 Men are
affected significantly more than women.6,7 Human
literature on pFS-SCC is limited to the description
of case reports, and first line therapy is surgery,
or surgery combined with radiation.4,8 – 12 Incor-
poration of chemotherapy in the treatment plan,
in particular platinum derivatives, had not been a
standard treatment until recent studies showed the
benefits of chemotherapy combined with radiation
therapy.8,9,13 – 15 Medical therapy alone for the treat-
ment of pFS-SCC in human beings is still used
exceptionally.9 In head and neck squamous cell
carcinoma (HNSCC) in human beings, the use of
tyrosine kinase inhibitors directed to the epidermal
growth factor receptor (EGFR), and monoclonal
antibodies towards vascular endothelial growth fac-
tor (VEGF) or EGFR as a single therapy or combined
with non-steroidal anti-inflammatory drugs, plat-
inum derivatives, surgery and radiation therapy is
evolving.9,16,17
In veterinary medicine, pFS-SCC has not been
described yet as a unique entity. Frontal sinus SCC
is only described in dogs as an extension of nasal
SCC.18,19 The recommended treatment of nasal
SCC in dogs is radiation therapy and surgery.20
Only one study has been published in which
a combination of carboplatin, doxorubicin and
piroxicam successfully was used for the treatment
Correspondence address:Dr J. de VosVeterinary OncologyReferral Centre ‘‘DeOttenhorst’’van Diemenstraat 83Terneuzen,The Netherlandse-mail:[email protected]
© 2011 Blackwell Publishing Ltd 1
2 J. de Vos et al.
of canine nasal tumours.21 A favourable outcome
has also been described using the combination of
carboplatin and piroxicam for the treatment of
canine oral SCC.22
The objective of this article is to describe the
clinical outcome in three dogs with pFS-SCC,
treated with a combination of piroxicam and
carboplatin. In one dog, the treatment was changed
into piroxicam and toceranib. To our knowledge,
this is the first publication of the clinical signs and
single medical therapy of pFS-SCC in dogs.
Material and methods
Three dogs with facial deformity, limited to the
frontal sinus region, were diagnosed with SCC using
cytology or histology.
In each dog treatment was started with piroxicam
(Pharmachemie BV, Haarlem, The Netherlands)
(0.3 mg kg−1 s.i.d. p.o), and carboplatin (Carbosin,
Pharmachemie BV, Haarlem, The Netherlands)
(300 mg m−2 i.v., once every 3 weeks). Total infu-
sion time for carboplatin was 20 min, and each dog
was scheduled to receive between 6 and 12 carbo-
platin infusions. After each carboplatin delivery, the
dogs received maropitant (Cerenia, Pfizer Animal
Health, Sandwich, UK) 2 mg kg−1 s.i.d. orally for
4 days. Piroxicam was envisaged to be continued
for the remainder of each dog’s life. Immediately
before the carboplatin infusion, a complete blood
count was performed. Because of the potential for
increased risk of renal toxicity, resulting from the
combination of piroxicam and carboplatin, blood
urea nitrogen and serum creatinine concentrations
were determined immediately before every other
treatment.
The first dog was an 8-year-old, male Farmer
Fox terrier with a 3-cm bulging mass originating
from the left frontal sinus area, without involve-
ment of the overlying skin. Opening the mouth
was painful. There were no clinical signs related to
the nasal cavity during the initial examination, and
metastases could not be detected in the regional
lymph nodes or on thoracic radiographs. Mag-
netic resonance imaging (MRI) showed a soft tissue
mass in the left frontal sinus, extending into the
surrounding anatomical structures with osteolysis
of the frontal bone, and infiltration of the bone
covering the frontal lobes of the brain and olfactory
bulb, but no nasal cavity involvement (Figs 1A,B, 2
and 3A,B). The histopathology of an incisional
biopsy resulted in the diagnosis of SCC. After
six carboplatin deliveries with 3-weekly intervals,
this dog had an additional carboplatin treatment
after 37 days. Then the owner chose to have one
more carboplatin delivery given after 3 months and
to discontinue chemotherapy thereafter, that is,
8 months after the start of therapy.
The second dog was a 4-year old, castrated-male
Border Collie, with a firm, protruding mass in the
A B
Figure 1. Dog 1: transverse (A) and dorsal (B) T1-weighted MRI images of the skull depict extensive tumour growth in theleft frontal sinus with destruction of the frontal bone and extension into the temporalis muscle.
© 2011 Blackwell Publishing Ltd, Veterinary and Comparative Oncology, doi: 10.1111/j.1476-5829.2011.00292.x
Canine primary frontal sinus SCC 3
Figure 2. Dog 1: transverse T1-weighted MRI imageindicates tumour destruction of the bony septum betweenthe left and right frontal sinus.
region of both frontal sinuses. The dog showed
signs of diminished consciousness, was hiding in
quiet places in the house and touching of the head
was painful. Computed tomographic (CT) images
showed bilateral frontal sinus involvement, with
invasion of the tumour into the cranial part of the
brain cavity (Fig. 4A,B), but without nasal extension
and with no enlarged regional lymph nodes. Cytol-
ogy of a CT-guided biopsy revealed a SCC with very
few cells which had undergone keratinization, sug-
gesting a more undifferentiated SCC. No metastases
could be detected in this patient either. The first
six carboplatin deliveries in this dog were given at
4-weekly intervals, because of Grade-1 neutropenia
(according to the VCOG-CTCAE criteria) 3 weeks
after the infusion. In total, this dog received 14 car-
boplatin deliveries of which the final 8 had delivery
intervals of 42, 49, 58, 42, 71, 75, 97 and 99 days.
The third dog was a 5-year-old male, crossed-
Rottweiler with a bulging mass over both frontal
sinuses and exophthalmus of the right eye
(Fig. 5A,B). There were no nasal signs and no
enlarged regional lymph nodes. The owner could
not financially afford a CT or an MRI scan to
determine the extension of the mass, but on
X-rays there was clearly frontal sinus involvement
with retrobulbar extension in the right orbit. A
fine needle aspiration biopsy was performed and
the mass was confirmed to be an SCC, again
with anisocytosis, anisokaryosis and with very few
A
B
Figure 3. Dog 1: massive tumour infiltration into thetemporalis muscle on transverse (A) and sagittal(B) T2-weighted MRI images.
cells showing keratinization, characterizing a more
undifferentiated SCC. After two carboplatin deliv-
eries, there was progressive disease and the tumour
extended into the oral cavity caudal to the last right
upper molar tooth. The treatment was changed into
toceranib (Palladia, Pfizer Animal Health, Sand-
wich, UK) (initial dose 2.75 mg kg−1 e.o.d. p.o.)
with continuation of piroxicam. Two weeks after
the start of toceranib, the dose was increased to
3.25 mg kg−1, and 3 months later to 3.35 mg kg−1.
Results
Dog 1 achieved a complete remission (CR) 3
weeks after the first carboplatin delivery. During
the course of the treatment, no side effects were
© 2011 Blackwell Publishing Ltd, Veterinary and Comparative Oncology, doi: 10.1111/j.1476-5829.2011.00292.x
4 J. de Vos et al.
A
B
Figure 4. Dog 2: both frontal sinuses are completelyinvolved in the process on these CT images. Extensivedestruction of the rostral part of the frontal bone, withinfiltration of the tumour into the cranial parts of the braincavity, is clearly visible.
observed. Two months after the final carboplatin
treatment, with the dog still on piroxicam, there
was a rapid-growing, MRI-confirmed, recurrence
of pFS-SCC and the dog was euthanized at owner’s
request (Fig. 6A,B). Overall survival time (OST) of
this dog was 344 days.
In dog 2, all clinical symptoms disappeared after
the second carboplatin treatment, except for minor
facial deformity in the frontal sinus region. In total,
14 doses of carboplatin were delivered with the last
dose 22 months after start of therapy. Except for
the neutropenia 3 weeks after the carboplatin infu-
sion, there were no side effects during the entire
treatment period. This dog was still alive 441 days
after the last carboplatin treatment, on piroxicam,
A
B
Figure 5. Dog 3: before start of treatment with a bulgingmass over both frontal sinuses and swelling under the righteye.
and in CR with an OST of 1117 days from start
of therapy. A CT scan on day 1068 confirmed
the CR. The persistent facial deformity could be
explained by thickening of the part of the frontal
bone positioned over the frontal sinuses (Fig. 7).
Dog 3 significantly improved after changing
the treatment protocol to toceranib–piroxicam.
Increasing the dose of toceranib did not cause any
side effect. The ulcerated mass in the oral cavity and
the retrobulbar extension of the tumour on the right
side entirely disappeared. The swelling over the right
frontal sinus also almost completely disappeared,
leading to the release of a substantial amount of
necrotic discharge through a fistula under the right
eye (Fig. 8A,B). However, the swelling over the left
frontal sinus went into a partial remission, with a
considerable reduction in solidity. The dog devel-
oped pain on opening the mouth, 160 days after
start of toceranib, preventing chewing with the left
part of the jaws. At that time, there was also a
© 2011 Blackwell Publishing Ltd, Veterinary and Comparative Oncology, doi: 10.1111/j.1476-5829.2011.00292.x
Canine primary frontal sinus SCC 5
A B
Figure 6. MRI images of dog 1, after 2 months of the final carboplatin treatment; there is a relapse of the pFS-SCC withretrobulbar extension (A) and infiltration of the bone between the left frontal sinus and left frontal lobe of the brain (B).
Figure 7. CT image of dog 2 at day 1068: only thickening ofthe frontal bone over the frontal sinus with a normal bonyarchitecture is present; there are no longer visible signs ofpFS-SCC; the bone over the frontal lobe of the brain iscompletely restored.
haemopurulent discharge from the left nasal open-
ing. The dog was euthanized 195 days after start of
toceranib, because of severe diminished conscious-
ness and the inability to walk. No additional imaging
was performed, but most likely these signs were due
to tumour progression from the left frontal sinus
into the brain cavity, with possible invasion of the
frontal lobe of the brain and/or increased intracra-
nial pressure. The OST was 237 days after the start
of therapy.
A
B
Figure 8. Dog 3 (60 days after start of toceranib): a markedreduction in size of the swelling of the right frontal sinus isvisible (A), as well as a fistula just cranial to the medialcanthus of the right eye (B).
Discussion
In human beings with paranasal tumours, there is
a significant correlation between tumour extension
© 2011 Blackwell Publishing Ltd, Veterinary and Comparative Oncology, doi: 10.1111/j.1476-5829.2011.00292.x
6 J. de Vos et al.
and treatment outcome. Spread outside the sinuses
is almost the rule on presentation. In more than 90%
of cases the tumour will have spread through at least
one wall of the involved sinus when discovered.2,5 In
the three dogs described in this article, the primary
tumour was also no longer restricted to the frontal
sinus. As in human patients, CT and MRI imaging
play a critical role not only in diagnosing and locore-
gional staging of canine pFS-SCC but also in treat-
ment planning.23 – 26 Other known prognostic fac-
tors in human beings are histology and surgical mar-
gins. Anaplastic and undifferentiated SCCs have a
significantly worse prognosis compared to the more
differentiated ones.6,25 Curiously, dog 2 had a more
undifferentiated SCC, but in this specific case there
was no association with a poor treatment outcome.
Radiotherapeutic treatment of canine pFS-SCC,
based on the location of this tumour with both
eyes and the brain in close proximity, necessitates
precise focussing on the radiation field to spare
these vital tissues. In the three patients described in
this article, there was already an extension of the
tumour into the orbit and/or the brain cavity, so
radiotherapy was not the preferred treatment. Also,
curative intent or cytoreductive surgery with the
intention of reducing the tumour to a microscopic
level to create a more feasible situation for adjuvant
therapy, seemed not to be a realistic option, at least
in the three dogs described in this article. So it is
our opinion that in veterinary patients it is justi-
fied to consider chemotherapy of pFS-SCC as the
preferred primary treatment.
Several studies have reported the use of carbo-
platin as a single therapeutic agent, or combined
with piroxicam, to be an effective treatment for
canine SCC in general.21,22 Historically, both in
human and veterinary oncology, single agent pro-
tocols consist of four to six doses. However, in
human oncology there is a tendency to increase
the number of doses in single agent protocols.
The hypothesis behind the promising results of
prolonged neoadjuvant treatment is two potential
biological phenomena. First, the conservation of
the tumour and its draining lymph nodes may
prove to be an essential part of this approach, with
particular emphasis on the activation of tumour-
specific cytotoxic T cells through the release of
tumour antigens after chemotherapy-induced cell
lysis. Second, circulating angiogenesis inhibitors
originating from the primary tumour may enhance
the effect of chemotherapy on micrometastases.27,28
In human beings, 80–100% of the HNSCCs has
an overexpression of EGFR.29 This overexpression
of EGFR is not limited to the tumour cells, but is also
present in the normal mucosa of HNSCC patients.29
According to evidence-based medicine, targeting
EGFR in human HNSCC is a logical therapeutic
approach.9,16,17,29 Among the newer compounds,
the most promising for HNSCC are the monoclonal
antibody cetuximab, directed to the extracellular
ligand-binding domain of EGFR, and two EGFR
tyrosine kinase inhibitors, gefitinib and erlotinib.30
Also, the use of bevacizumab, neutralizing VEGF, in
combination protocols is promising.31 Currently,
there are no specific EGFR inhibitors available in
veterinary medicine, only multikinase inhibitors
such as toceranib and masitinib. Sunitinib, used
in human oncology and closely related to
toceranib, is an orally administered multi-targeted
tyrosine kinase inhibitor of the rearranged during
transfection receptor (RET), VEGFR, platelet-
derived growth factor receptor (PDGFR) and
c-KIT. Clinical trials have so far shown a low
activity of sunitinib in human HNSCC patients,
not warranting further investigation.32 However,
motesanib, also a potent inhibitor of VEGFR1, 2
and 3, PDGFR and c-KIT has shown a favourable
interaction when combined with radiation therapy
in HNSCC models.33 Toceranib showed at least in
dog 3 a dramatic but temporary response.
The limitation of this study is of course the small
number of patients. Despite this small number,
the treatment outcomes in these three dogs sug-
gest that additional investigation of a combined
piroxicam–carboplatin therapy in a larger group of
pFS-SCC patients is warranted. In tumour-bearing
dogs, where chemotherapy with carboplatin has
resulted in a CR, extension of the standard pro-
tocol of four to six 3-weekly carboplatin doses to
nine or even a higher number of doses, or a low
dose-intensity prolongation with carboplatin, with
the intention to achieve a significant clinical ben-
efit, could be an interesting concept for further
investigation.
Further studies need to be performed also to
investigate the role of toceranib in patients with
© 2011 Blackwell Publishing Ltd, Veterinary and Comparative Oncology, doi: 10.1111/j.1476-5829.2011.00292.x
Canine primary frontal sinus SCC 7
pFS-SCC, because no definitive conclusion can be
drawn from the outcome in a single case.
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