Multimodal therapeutic approach and interdisciplinary challenge for the treatment of unresectable head and neck squamous cell carcinoma in six cats: a pilot study

Original Article DOI: 10.1111/j.1476-5829.2011.00304.x

Multimodal therapeutic approachand interdisciplinary challenge forthe treatment of unresectable head andneck squamous cell carcinoma in six cats:a pilot study

L. Marconato1∗, J. Buchholz2∗, M. Keller3, G. Bettini4, P. Valenti2

and B. Kaser-Hotz2

1Centro Oncologico Veterinario, Sasso Marconi (BO), Italy2Animal Oncology and Imaging Center, Hunenberg, Switzerland3Tierarztliche Spezialistenklinik, Hunenberg, Switzerland4Department of Veterinary Medical Science, University of Bologna, Ozzano Emilia, Italy

AbstractFeline head and neck squamous cell carcinoma (SCC) is a loco-regional disease harbouring a poor

prognosis. The complex anatomic location precludes aggressive surgical resection and tumours recur

within weeks to few months. Response to chemotherapy and local control after radiation therapy has

been disappointing. In this study, a multimodal approach including medical treatment (thalidomide,

piroxicam and bleomycin), radiation therapy (accelerated, hypofractionated protocol) and surgery

was attempted in six cats. Treatment was well tolerated. Three cats with sublingual SCC were alive

and in complete remission at data analysis closure after 759, 458 and 362 days. One cat with laryngeal

SCC died of renal lymphoma after 51 days and the other with maxillary SCC died of a primary lung

tumour 82 days after diagnosis. In both cats, the SCC was in complete remission. Only one cat

developed metastases after 144 days. These encouraging preliminary results merit further evaluation

in future trials.

Keywordsacceleratedhypofractionated radiationtherapy, anti-angiogenesis,feline, head and neck, SCC

Introduction

In cats, squamous cell carcinoma (SCC) is the most

frequent tumour of the oral cavity.1

As a result of similar shared characteristics, the

cat may represent a valuable animal model for

human head and neck cancer which, by definition,

refers to a group of tumours arising from the upper

aerodigestive tract, including nasal cavity, paranasal

sinuses, lips, oral cavity, salivary glands, pharynx

and larynx.2

∗These authors contributed equally to the work.

Early disease is rarely detectable, and diagnostic

delay may partly contribute to the poor prognosis

typically correlated with feline SCC. In fact, most

of the oral SCCs are detected when already

locally advanced, thereby precluding wide surgical

excision.2 At presentation, it is uncommon to detect

regional and/or distant metastasis. It is also unusual

for metastasis to become clinically apparent during

the disease course, as cats usually do not live

long enough to develop overt metastatic disease,

ultimately dying of local failure.2–4

Head and neck SCC in cats is a therapeutic

challenge. Unfortunately, substantial improvement

Correspondence address:Dr L. MarconatoCentro OncologicoVeterinariovia San Lorenzo 1-440037 SassoMarconi (BO), Italye-mail:[email protected]

© 2011 Blackwell Publishing Ltd 1

2 L. Marconato et al.

in outcome has not been made: recurrence rates

after local therapies and deaths caused by local

disease progression continue to be unacceptably

high.5–7 Surgery alone or in combination with

radiation therapy are the mainstay of loco-

regional treatment, but treatment outcome remains

disappointing, with median survival times of

3 months for SCC invading sites other than the

mandible.2,5,8,9

Radiation therapy on its own is not able

to control feline oral SCC, being most likely

attributable to radiation resistance, which might

partly be caused by hypoxia.10 In one study,

11 cats received radiation therapy and etanidazole,

a hypoxic cell sensitizer. All cats achieved a

partial response (PR) with a median volume

regression of 70%. Eventually, all cats died of

local tumour progression with a median survival of

116 days.10 According to one study in which coarse

fractionation radiotherapy was delivered to cats

with SCC, neither improvement of clinical signs

nor local tumour control was observed, thereby

not supporting its use in a palliative setting.9

Six of the seven treated cats were euthanized

because of tumour progression or radiation-

induced side effects with a median survival time

of 60 days.9

One encouraging finding comes from a more

recent study, describing an accelerated radiation

therapy protocol.11 Three of nine cats obtained

complete remission, with a median survival time

of 298 days, whereas the remaining six cats had

partial remission, with a median survival time of

60 days.11 Overall, treatment was well tolerated by

all cats. Using accelerated protocols for SCC does

counteract the rapid proliferation of these tumours

because proliferation of surviving tumour cells

between radiation fractions may lead to decreased

tumour control.

Chemotherapy, either as single treatment modal-

ity or combined with radiation therapy, has shown

minimal effect in cats with oral SCC.10–17 At

the present time, the role of chemotherapy in

the management of oral cancer still remains

investigational.

It is worth noting that, until recently, these

treatment combinations did not have a real impact

on local outcome or survival, with a probability of

less than 10% to live 1 year after diagnosis.2,5,8,9

However, all the efforts made throughout the

past decade undoubtedly are justified and warrant

continued attempts in the future to optimize

treatment strategies to reduce local, regional and

distant failure. Indeed, the disappointing results

may be due to the fact that most tumours are

currently treated in the macroscopic setting. A

combination treatment that would allow resection

of the residual tumour after having reduced its size

may improve outcome.

The goal of the current clinical trial was

to specifically attack the patterns of treatment

failure by using a multimodal therapeutic strategy,

including medical treatment, radiation therapy

and surgery. It was hypothesized that combining

treatment regimens to a multimodal approach,

aiming at obtaining additive and hopefully even

synergistic effects, a therapeutic gain would be

achieved while maintaining quality of life.

Materials and methods

Inclusion criteria

Cats referred to the Animal Oncology and

Imaging Center with histologically confirmed,

unresectable SCC of the oral cavity or neck

region with exclusion of the mandible, and

adequate renal function were enrolled in an

intent-to-treat trial. Although not standardized

between different surgical teams, criteria for tumour

unresectability included tumour immobility and

adherence, invasion of the skull base or deep

musculature of the tongue, encasement of the

vasculature and impossibility of removing the entire

tumour while preserving functionality.

All cats underwent complete staging work-

up, including physical examination, complete

blood cell (CBC) count with differential, serum

biochemistry, cytological evaluation of the regional

lymph nodes, two-view thoracic radiographs,

abdominal ultrasound, CT of the skull if considered

necessary for surgery and radiation therapy

planning. To be enrolled in this study, tumours

needed to be staged M0, regardless of T and N

status.18 Cats were excluded from this study if

they had pre-existing renal disease and/or a second

cancer.

© 2011 Blackwell Publishing Ltd, Veterinary and Comparative Oncology, doi: 10.1111/j.1476-5829.2011.00304.x

Multimodal treatment for feline head and neck squamous carcinoma 3

Treatment protocol

All cats were scheduled to receive induction (neoad-

juvant) medical therapy of at least 2 weeks duration,

consisting of subcutaneous bleomycin (Bleomycin-

Teva, Teva Pharma AG, Aesch/BL, Switzerland)

administered at the dose of 10 UI m−2 on a weekly

basis, oral piroxicam (Piroxicam-Mepha, Mepha

Pharma AG, Aesch/BL, Switzerland) at the dose of

0.3 mg kg−1 every other day and oral thalidomide

(Thalidomid, Bichsel AG, Interlaken, Switzerland)

at the dose of 2 mg kg−1 once daily. Piroxicam was

formulated into 1 and 2 mg capsules. The dose of

thalidomide was arbitrarily chosen based on some

of the authors’ experience (unpublished data); this

drug was delivered to the nearest 10 mg.

Induction medical treatment was administered

until the tumour was considered to have become

surgically removable or had remained of the same

dimension for at least 1 week, and then was

discontinued while the cancer was treated with local

therapy. If cancer was downstaged to resectable

disease, cats underwent marginal surgical excision

of the tumour, aiming at ablating cancer while

minimizing morbidity and preserving or restoring

function. The type of surgery was planned on the

basis of the primary site and the loco-regional

occurrence of metastases. If necessary to ensure

adequate feeding, an esophageal tube was placed

after surgery or after one of the radiation fractions.

To evaluate the completeness of surgical excision,

the surgical samples were appropriately processed

for histology. Margins were classified as clean, if

there was at least 2 mm of non-neoplastic tissue

between the tumour and the edge of resection;

close, if cancer cells extended within 2 mm of the

surgical margins; and infiltrated, if tumour cells

extended to the edge of resection in at least one

section.

One week after surgery, cats underwent radi-

ation therapy. The accelerated, hypofractionated

radiation therapy protocol consisted in the admin-

istration of two radiation fractions per day (6 h

apart) over five consecutive days. The dose per frac-

tion was 4.8 Gray (Gy) to a total dose of 48 Gy.

Depending on location of the tumour, cats were

immobilized with individually prepared bite blocks

or other appropriate positioning devices. Radiation

treatment planning after surgery was carried out

manually using electrons of 6–15 MeV admin-

istered with a linear accelerator (Clinac DMX,

Varian). Different electron energies and field sizes

were used depending on the individual situation.

The radiation field included the whole scar plus

lateral margins of about 1 cm. The deep margin

was chosen depending on tumour location. Bolus

material was used to achieve 95–100% of the pre-

scribed dose to the planning target volume and to

guarantee administration of as low of a dose as

possible to underlying and nearby located normal

tissues.

If SCC was not deemed surgically resectable after

neoadjuvant medical treatment, radiation therapy

was scheduled first, followed by surgery. In this

case, the radiation field included the macroscopic

tumour plus lateral margins of about 1 cm. Again

the deep margin was chosen depending on tumour

location.

Medical treatment consisting of thalidomide and

piroxicam was resumed after local treatment in an

adjuvant setting for six additional months, until

development of progressive disease (PD) or onset of

unacceptable toxicity. Bleomycin was administered

once weekly up to a total of 10 administrations.

Toxicity evaluation and assessment of qualityof life

Toxicity (mainly haematologic, gastrointestinal and

renal) due to medical treatment was assessed

according to Veterinary Cooperative Oncology

Group toxicity scale on a weekly basis before local

treatment and on a monthly basis following local

treatment by means of haematology and serum

biochemical testing.19 Unacceptable toxicity was

defined as grade 4 haematological, gastrointestinal

and/or renal toxicosis.

Radiation-related toxicity was graded according

to the Veterinary Radiation Therapy Oncology

Group (VRTOG) scheme daily during the 5 days

of radiation and weekly during the first month

after the radiation protocol, thereafter monthly

rechecks were scheduled.20 If deemed necessary,

radiation toxicity was treated symptomatically with

systemically administered antibiotics and anti-

inflammatory drugs. More precisely, cats were kept

© 2011 Blackwell Publishing Ltd, Veterinary and Comparative Oncology, doi: 10.1111/j.1476-5829.2011.00304.x

4 L. Marconato et al.

on piroxicam if local acute side effects did not

exceed grade 1 toxicity. If toxicity was > grade 1,

cats received prednisolone at 1 mg kg−1 SID instead

of piroxicam.

Local treatment included flushing the mouth

with cold black tea. Quality of life assessment,

implying evaluation of symptoms and functional

aspects gathered by means of physical examina-

tion and patient history, were assessed at diagnosis,

during and after treatment. Owners were asked

to report on their cat’s general functional sta-

tus (overall happiness, family interaction, appetite,

bowel and bladder habits, anxiety/mental status,

self-care and sleep/fatigue patterns), general cancer

symptoms and signs (depression, pain, nutrition,

sleep and nausea/vomiting), specific oral cancer

symptoms and signs (pain, swallowing, smell, eat-

ing, chewing and oral opening limitation) and

treatment’s secondary symptoms and effects (nau-

sea/vomiting, loss of appetite, weight loss, depres-

sion, diarrhoea, constipation, mucositis/stomatitis

and analgesic use).

Response criteria

Treatment effects were estimated based on clinical

or imaging changes in tumour size in accordance

with the criteria provided by World Health

Organization (WHO) as follows: complete response

(CR) was defined as the disappearance of all

detectable tumours, PR as a reduction of ≥50%

in tumour volume, stable disease (SD) as <50%

reduction or <25% increase in total volume and

PD as ≥25% increase in total volume, or the

appearance of metastasis. All antitumour responses

were required to last at least 21 days. Remissions of

shorter duration were classified as SD.

Follow-up

After having completed the loco-regional

treatment, and during post-operative medical

therapy, cats received regular follow-up exami-

nations, including monthly physical examination

and bloodwork (CBC and biochemical screen)

and bimonthly thoracic radiography. The main

aims of tumour follow-up were evaluation of

therapeutic efficacy, management of impairments

and detection of tumour recurrence and/or

metastases.

Survival time was measured from the onset of

neoadjuvant therapy.

Results

Patient and tumour characteristics, treatment and

outcome are summarized in Table 1.

Patient and tumour characteristics

Between 2009 and 2010, six client-owned cats with

unresectable head and neck SCC were enrolled.

There were three domestic shorthair, two Persians

and one maine coon; four were spayed females

and two were castrated males. Median age was

10 years (range 6–14 years) and median weight

was 4.5 kg (range 2.5–6.3 kg). The primary lesion

sites were the ventral aspect of the tongue in the

region of the frenulum (n = 3), larynx (n = 2)

Table 1. Multimodal treatment schedule and outcome in six cats with oral SCC

CatsTumour site

(stage)

Number ofneoadjuvant-

bleomycinSchedule of local

treatment

Number ofadjuvant-bleomycin

Response totreatment

Outcome and status atdata analysis closure

1 Tongue (II) 3 SX followed by RT 7 CR Alive (759 days), CR

2 Tongue (II) 3 RT followed by SX 7 CR Alive (458 days), CR

3 Tongue (II) 6 RT followed by SX 4 CR Alive (362 days), CR

4 Larynx (III) 2 SX followed by RT None CR Dead due to renal

lymphoma (51 days), CR

5 Larynx (III) 2 SX followed by RT 8 CR Dead due to metastases

(144 days), PD

6 Maxilla (II) 4 RT None PR Dead due to lung

carcinoma (82 days), PR

CR, complete response; RT: radiation therapy; SX, surgery.

© 2011 Blackwell Publishing Ltd, Veterinary and Comparative Oncology, doi: 10.1111/j.1476-5829.2011.00304.x

Multimodal treatment for feline head and neck squamous carcinoma 5

and maxilla (n = 1). At presentation, four cats

had stage II disease (with only one having bone

involvement), whereas the remaining two had stage

III disease. Regional and distant metastases were not

observed in any case, nor did the cats have a second

cancer elsewhere. All cats were treatment naïve at

presentation and were considered as non-surgical

candidates based on local tumour extension.

Treatment

For the whole group of cats, the median overall

treatment time (measured from the onset of

neoadjuvant therapy to the end of treatment) was

218 days (range 51–365 days), with one cat still on

medical treatment at data analysis closure.

All cats underwent neoadjuvant medical treat-

ment. The median interval from neoadjuvant

treatment to local therapy was 25 days (range

11–43 days). Concerning bleomycin treatment,

two cats received two doses, two cats received three

doses, one cat received four doses and one cat

received six doses before local treatment. Neoadju-

vant treatment was administered until the tumour

was considered to have become surgically remov-

able [n = 3: one sublingual SCC (Fig. 1) and two

laryngeal SCCs (Fig. 2)] or has remained of the

same dimension for at least 1 week (n = 3: two

sublingual SCCs and one maxillary SCC). In these

latter three cats, the tumour reduced in size in terms

of 20% and was considered to be stable according

to WHO. The three cases having become surgically

removable experienced a tumour shrinkage of 30,

40 and 80% according to WHO: the sublingual

SCC was assessed based on clinical examination,

whereas the two laryngeal SCCs were evaluated by

means of laryngoscopy and ultrasound, performed

2 weeks after having started the neoadjuvant treat-

ment. Surgery was undertaken before radiation

therapy in three cats downstaged to resectable dis-

ease (one sublingual SCC and one laryngeal SCC).

The aim of surgery was to excise the tumour if pos-

sible, with margins, even though preserving nearby

vital structures was considered paramount. More

precisely, in cat 1 (sublingual SCC), the aim of

surgery was to remove the mass with curative intent

without compromising neither vascularization nor

innervation. In cases 4 and 5, laryngectomy was

not performed because of complications associated

with that procedure, and therefore the tumours

were debulked only.

Histopathologically, margins were considered

clean in the sublingual SCC and infiltrated in both

laryngeal SCCs. As a result of the locally aggressive

A B

Figure 1. (A) Sublingual SCC at presentation in a Persian cat. (B) Twenty-one days after neoadjuvant medical treatment:the tumour has become surgically removable.

© 2011 Blackwell Publishing Ltd, Veterinary and Comparative Oncology, doi: 10.1111/j.1476-5829.2011.00304.x

6 L. Marconato et al.

A B

Figure 2. Laryngoscopic examination in a Maine coon cat. (A) At presentation: the larynx is almost completely obstructedby the tumour. (B) After neoadjuvant medical treatment: the tumour has become surgically removable.

A B

Figure 3. (A) Sublingual SCC at presentation in a Persian cat. (B) After neoadjuvant medical treatment and radiationtherapy: the tumour has become surgically removable.

nature of oral SCC and in view of a multimodal

treatment approach, the decision was made to

use radiation therapy despite the histopathological

description of clean margins in the sublingual SCC

case.

Radiation therapy was initiated in a post-

operative setting after 6, 10 and 11 days, respectively.

All cats received the planned total dose of 48 Gy.

Two cats with sublingual SCC still considered

not to be surgical candidates after neoadjuvant

medical treatment were irradiated first and

underwent surgery thereafter. Both cats completed

the radiation protocol as planned and in both the

tumour was considered surgically removable 13

and 21 days after having completed the radiation

protocol, respectively (Figs 3 and 4). Although

surgery performed after radiation therapy consisted

of a marginal excision, surgical margins were

considered free of neoplastic cells in all cases.

The cat with maxillary SCC was also irradiated

first. However, this cat developed a primary lung

carcinoma with pleural effusion 45 days after

radiation therapy. Radiographically, a solitary lung

mass in the right caudal pulmonary lobe was

observed and on cytology cells showed acinar

formation, suggesting glandular origin. The cat was

euthanized without undergoing any surgery for the

oral SCC, which was considered in PR at death

(Fig. 5).

After local therapy, four of the six cats received

oral piroxicam, oral thalidomide and subcutaneous

bleomycin, the latter administered for 4, 7, 7 and

© 2011 Blackwell Publishing Ltd, Veterinary and Comparative Oncology, doi: 10.1111/j.1476-5829.2011.00304.x

Multimodal treatment for feline head and neck squamous carcinoma 7

A B

Figure 4. (A) Sublingual SCC at presentation in a DSH cat. (B) After neoadjuvant medical treatment and radiation therapy:the tumour has become surgically removable.

8 cycles, respectively, so that the treated cats received

the planned total 10 bleomycin doses. Two cats

developed a second cancer after local therapy and

did not receive any adjuvant treatment.

Response

No cats were lost to follow-up. Median follow-

up time measured from start of neoadjuvant

medical treatment to last visit was 253 days (range

51–759 days). No local failure occurred among cats

completing the scheduled multimodal protocol.

Three cats with sublingual SCC were still alive and

in CR at the end of this study, after 759, 458 and

362 days. One of them was still under medical

treatment at the end of this study; two were taken

off oral therapy 1 year after diagnosis.

One cat with laryngeal SCC experienced regional

(contralateral) treatment failure 121 days after

diagnosis and 100 days after completion of

radiation therapy, with the primary site hav-

ing no evidence of disease. The cat was euth-

anized 144 days after initial presentation at

the owner’s request. Necropsy confirmed metas-

tases to the contralateral submandibular lymph

node.

The other cat with laryngeal SCC developed

renal lymphoma 51 days after diagnosis; this

cat underwent neoadjuvant medical treatment,

radiation therapy and surgery. This cat was

euthanized at the owner’s request with the SCC

being in CR at the primary site. Necropsy confirmed

the renal lymphoma with no evidence of SCC in the

laryngeal area.

© 2011 Blackwell Publishing Ltd, Veterinary and Comparative Oncology, doi: 10.1111/j.1476-5829.2011.00304.x

8 L. Marconato et al.

A B

Figure 5. (A) Maxillary SCC in a DSH cat at presentation. (B) After neoadjuvant medical treatment and radiation therapy.

One cat with maxillary SCC developed a

pulmonary carcinoma with pleural effusion 82 days

after diagnosis and 45 days after having completed

the radiation protocol. When he developed a second

cancer, his maxillary SCC was considered to be in

PR. At that time, the owner elected euthanasia and

did not permit necropsy.

Toxicity

Overall, neoadjuvant and adjuvant medical treat-

ment was well tolerated with no occurrence of any

haematological or non-haematological side effects.

The two cats with sublingual SCC that were

irradiated for macroscopic tumour before surgery

developed grades 1–2 VRTOG local side effects

(mucositis) and underwent placement of an

esophageal tubes at the fifth radiation fraction. One

of these patients developed grade 1 toxicity at the

fifth radiation fraction, which deteriorated to grade

2 at the last fraction. The second cat showed grade

1 toxicity at the last fraction, which deteriorated to

grade 2 from days 2–6 after radiation. Both cats

received prednisolone, the administration of which

did not exceed 2 weeks. Weeks (2–3) after radiation

all acute side effects were healed. The cat with the

sublingual SCC that was irradiated post-operatively

got an esophageal tube placed at the fifth radiation

fraction and did not develop any acute side effects.

The two cats with laryngeal SCC did not experience

perceivable acute side effects, and in only one of

them an esophageal tube was placed during surgery.

The cat with the maxillary SCC developed grade 1

toxicity (mucositis and conjunctivitis) and did not

need an esophageal tube.

Owners’ assessment of their cat’s quality of life

indicated that the general functional status as well

as general and specific oral cancer signs improved

during the treatment protocol. Overall, owners’

satisfaction was high, with no cat being withdrawn

from the protocol because of treatment-related

toxicity.

Discussion

Head and neck cancer is the sixth most common

cancer in human beings and is responsible for

almost 200 000 deaths around the world each

year, with SCC being most common and being

associated with the highest mortality rate.21,22

Advanced (stages III and IV) or recurrent head

and neck SCC is treated by a multidisciplinary

therapeutic approach, which coordinates surgery,

radiation therapy, chemotherapy and molecular-

targeted therapy to improve the final treatment

outcome.23 Nevertheless, these treatments usually

have major impacts on the patient’s ability to

speak, swallow, masticate and, depending on the

© 2011 Blackwell Publishing Ltd, Veterinary and Comparative Oncology, doi: 10.1111/j.1476-5829.2011.00304.x

Multimodal treatment for feline head and neck squamous carcinoma 9

surgical extension, may also cause disfigurement.24

Disappointingly, although progress has been made

in understanding cancer biology, the 5-year survival

rate of patients with head and neck SCC has not

been improved in more than 30 years.23

Over the last decade, comparative oncology has

gained attention, providing a unique opportunity to

conduct animal studies on cancer biology, molec-

ular pathways and response to new treatments,

possibly being relevant for human cancer also.25

Indeed, many tumours spontaneously occurring in

dogs and cats are biologically similar to those affect-

ing people, therefore pets have been proposed as

natural models of cancer.26–28 Concerning SCC,

there are many shared features between the feline

and human species, including pathology, biological

and clinical aggressiveness, outcome and resistance

to treatment, rendering the cat a unique sponta-

neous tumour model for the human disease.1,29

Feline head and neck SCC is usually diagnosed at

advanced clinical stage. As of to date, surgery and

radiotherapy are the treatment of choice; however,

the complex anatomic location prevents from

aggressive and wide surgical resection and tumours

usually recur within weeks to a few months. The

addition of conventional chemotherapeutics has

not shown to be beneficial and the probability for

cats with oral SCC (other than mandibular) to live

1 year after diagnosis is less than 10%.5–9

In this study, we attempted a multimodal

approach, including medical treatment, radiation

therapy and surgery, aiming at improving the

outcome of cats with unresectable head and neck

SCC.

Induction (or neoadjuvant) medical treatment

refers to the use of drugs as the primary treatment

before definitive surgery or radiation therapy,

and it is generally reserved to patients with

localized cancer for whom a completely effective

treatment does not exist. The combination of a

cytotoxic drug (bleomycin) and anti-angiogenetic

drugs (thalidomide and piroxicam) resulted in a

reduction of tumour burden in all treated cats: three

of six cases were downstaged to resectable disease,

whereas three cases experienced a reduction of their

tumours in terms of 20%.

The antineoplastic efficacy of bleomycin30

and piroxicam has already been reported in

cats.31,32 Bleomycin is a phase-specific, antitumour

glycopeptides antibiotic inducing DNA strand

breaks after binding to guanosine–cytosine-rich

portions of DNA.33 Piroxicam is a non-selective

non-steroidal anti-inflammatory drug, binding and

chelating both isoforms of cyclooxygenase (COX-

1 and COX-2). About 20% of feline oral SCCs

overexpress COX-2, thereby being a potential

antineoplastic target for therapeutic strategies.31,34

Thalidomide, an immunomodulatory and anti-

angiogenetic drug,35 has never been used before

in the treatment of feline oral SCC, whereas in

human head and neck SCC, it seems to play a role

if used in combination with cytotoxic drugs.36–38

Furthermore, there are no safety studies performed

in the feline species. In this study, we arbitrarily

decided to administer the dose of 2 mg kg−1

based on the results of an ongoing phase 1 clinical

trial (L. Marconato, personal communication).

Overall, induction medical treatment was well

tolerated, with no occurrence of any side effects,

as demonstrated by owners’ report, physical

examination and blood test. To the authors’

knowledge, this is the first study exploring the safety

of thalidomide administered to feline patients.

However, it must be stressed that these results do

not validate the routine clinical use of thalidomide

in this or any other setting at this time. Downstaging

of the cancer rendered a less extensive surgery

possible, which is important in cats with head

and neck SCC where loss of functional use

can have devastating effects. Surgery followed by

radiation therapy was undertaken in three cats after

induction medical treatment, whereas these two

local treatment modalities were given with reverse

schedule to two cats, as they were considered to still

have unresectable disease after medical treatment,

with the hope of further downstaging the tumour.

Indeed, SCC was reduced to resectable disease

2–3 weeks after having completed the radiation

protocol in both of them. The sixth cat enrolled

in this study died of a primary lung carcinoma

after having finished the radiation protocol, and

therefore never making it to surgery; the oral

tumour was in PR at the time of death.

The optimal regimes of local therapies (i.e.

pre- versus post-operative radiation therapy) are

yet to be determined as contentious issues need

© 2011 Blackwell Publishing Ltd, Veterinary and Comparative Oncology, doi: 10.1111/j.1476-5829.2011.00304.x

10 L. Marconato et al.

to be addressed when designing best treatment.

Our approach to surgery before radiation may

be taken into consideration only if unnecessary

surgical mortality, morbidity and loss of function

can be avoided. Post-operative radiation therapy

aims at sterilizing surgical margins. In our

study, if the surgical procedure was thought to

be associated with complications, then surgery

followed radiation therapy. Both schedules were

well tolerated. Radiation was delivered with an

accelerated (shortened overall treatment time),

hypofractionated (large dose per fraction) protocol,

consisting in the administration of two radiation

fractions per day over five consecutive days. The

rationale was to lower the risk of repopulation

by decreasing breaks during daily and overall

treatment time, leading to an increased tumour

control. Indeed, feline cutaneous SCC has been

reported to have a potential tumour doubling

time of only 5 days.39 Acute side effects (mainly

mucositis including grades 1–2 VRTOG) occurred

in 50% of the patients and were manageable

with symptomatic treatment and placement of

an esophageal tube during the time of radiation.

Quality of life during the whole treatment and

healing phase of acute side effects was evaluated

clinically and was deemed good. The esophageal

tubes were removed after acute side effects were

completely healed, or after a maximum time period

of 6 weeks after tube placement. This demonstrates

the feasibility of administering a relatively high

total dose within a short period of time (high dose

intensity) with acceptable acute side effects in feline

patients for bulky oral tumours. Late side effects

were not observed; however, an extended follow-

up (more than 6 months) was available for three

cats only. It may therefore be possible that late

side effects (such as fibrosis, bone necrosis, nervous

tissue damage) did not have time to develop and

because of the hypofractionation the potential risk

for late effects has to be considered increased.40

Adjuvant medical treatment was administered

to four cats. Although metastasis is infrequent,

the rich lymphatic supply characterizing the oral

cavity and the relatively high metastatic potential of

carcinomas in general prompted us to use medical

treatment in the adjuvant setting as well. Indeed,

we believed that if the tumour is locally controlled,

metastatic disease may have time to occur. In this

series, only one cat with laryngeal SCC developed

regional failure 4 months after diagnosis. In the

remaining three cats, adjuvant therapy may have

eradicated regional and distant micrometastases:

they all had no evidence of disease at the end of

therapy. Anyhow, the most exciting results were

provided by three cats with sublingual SCC, which

were alive and in CR at data analysis closure after

759, 458 and 362 days. They all had a bulky

tumour at diagnosis, compromising their quality

of life, and were free of clinical symptoms at

the end of this study. All owners felt that the

quality of life of their cats was good during the

entire treatment protocol, thereby not regretting

having opted for this multimodal approach. The

high degree of satisfaction despite the complexity

of our therapeutic strategy may be due to the fact

that conventional therapies are either not available

or not effective for cats with SCC.

To conclude, in this pilot study we described a

promising multimodal approach for the treatment

of feline head and neck SCC originating in sites

other than the mandible. The preliminary results

are encouraging and the possible benefit of this

combined strategy merits further evaluation in

future clinical trials. In addition, as no similar

multimodal strategy has been carried out in human

patients with head and neck SCC, we hope that by

using the cat as a natural tumour model important

clinical results may be obtained for human patients

as well.

Acknowledgement

This work was partly supported by a grant from

Margret and Francis Fleitmann Stiftung, Luzern,

Switzerland.

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