primary frontal sinus squamous cell carcinoma in three dogs treated with piroxicam combined with...

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


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



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


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



pFS-SCC, because no definitive conclusion can be

drawn from the outcome in a single case.

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