Tratamento de carcinoma de células escamosas em gatos

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Original Article DOI: 10.1111/j.1476-5829.2011.00304.x
Multimodal therapeutic approach
and interdisciplinary challenge for
the treatment of unresectable head and
neck squamous cell carcinoma in six cats:
a pilot study
L. Marconato1∗, J. Buchholz1∗, M. Keller2, G. Bettini3, P. Valenti1
and B. Kaser-Hotz1
1Animal Oncology and Imaging Center, Hu¨nenberg, Switzerland
2Tiera¨rztliche Spezialistenklinik, Hu¨nenberg, Switzerland
3Department of Veterinary Medical Science, University of Bologna, Ozzano Emilia, Italy
Abstract
Feline 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 fewmonths. 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.
Keywords
accelerated
hypofractionated radiation
therapy, 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. Marconato
Centro Oncologico
Veterinario
via San Lorenzo 1-4
40037 Sasso
Marconi (BO), Italy
e-mail:
lauramarconato@yahoo.it
© 2012 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 andmethods
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.
© 2012 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 10UI 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 quality
of 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
© 2012 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
Cats
Tumour site
(stage)
Number of
neoadjuvant-
bleomycin
Schedule of local
treatment
Number of
adjuvant-
bleomycin
Response to
treatment
Outcome and status at
data 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), PRCR, complete response; RT: radiation therapy; SX, surgery.
© 2012 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.
© 2012 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 obstructed
by 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 radiation
therapy: 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
© 2012 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.
© 2012 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
© 2012 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
© 2012 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 havea 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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