Bexfield et al 2008 Journal of Veterinary Internal Medicine

Prévia do material em texto

Photodynamic Therapy of Superficial Nasal Planum Squamous
Cel l Carcinomas in Cats: 55 Cases
N.H. Bexfield, A.J. Stell, R.N. Gear, and J.M. Dobson
Background: Squamous cell carcinomas (SCCs) are common skin tumors in cats. We investigated photodynamic therapy
(PDT) using the photosensitizing agent 5-aminolaevulinic acid (5-ALA) topically and a high-intensity red light source.
Hypothesis: PDT is a safe and effective treatment for feline SCCs.
Animals: Fifty-five client-owned cats with superficial nasal planum SCCs.
Methods: Prospective, uncontrolled clinical trial. PDT was performed using topical 5-ALA and light of peak wavelength
635 nm. Adverse effects, response, and tumor control were evaluated.
Results: 53/55 (96%) cats responded to therapy, and there was a complete response in 47/55 (85%). Six cats (11%) had a
partial response. Of the 47 cats with complete response to a single treatment, 24 recurred (51%), with a median time to recur-
rence of 157 days (95% confidence interval, 109–205 days). Repeat PDT was performed in 22 cats, and at a median follow-up of
1,146 days, 23 (45%) cats were alive and disease free, 17 (33%) had to be euthanized due to tumor recurrence, and 11 (22%)
were euthanized for other reasons.Only transient mild local adverse effects were observed after treatment.
Conclusions and Clinical Importance: PDT using 5-ALA and a red light source was safe, well tolerated, and effective in the
treatment of superficial nasal planum SCCs of cats and offers an alternative to conventional therapy. Although initial response
rates were high, this treatment did not lead to a durable remission or cure in all cases.
Key words: 5-aminolaevulinic acid; PDT; Photosensitizer; Skin tumor; Treatment.
Squamous cell carcinoma (SCC) is one of the mostcommon skin tumors of the cat and tends to occur in
sites which are nonpigmented and have relatively little
hair covering, such as the nasal planum, eyelids, and pin-
nae.1 SCCs are classified according to the World Health
Organization staging system for feline tumors of epider-
mal origin.2 Cutaneous tumors, classified as Tis, T1, or
T2 can be treated by surgery,
3 radiotherapy,4,5 hyper-
thermia,6 chemotherapy,7 and plesiotherapy.8
Photodynamic therapy (PDT) using a variety of pho-
tosensitizers and light sources has also been used for the
treatment of feline cutaneous SCCs.9–14 PDT is a method
of cancer therapy that uses visible light to activate sys-
temically or topically administered photosensitizer
agents that localize in target tissue.15 The photosensitizer
agent is preferentially taken up by tumor cells and
retained at higher concentrations than in the surround-
ing normal tissue, leading to selective toxicity. There are
differences in this selective toxicity depending on the
photosensitizer used. Subsequent exposure of this photo-
sensitizer agent to light of a certain wavelength results in
activation of the agent and selective destruction of tumor
cells.
The photosensitizing agent 5-aminolaevulinic acid (5-
ALA) is widely used in the treatment of human skin tu-
mors including SCC and Bowen’s disease (carcinoma in
situ). 5-ALA can be administered topically and is prefer-
entially absorbed through damaged keratin overlying the
tumor, but has little penetration through normal intact
keratin.16 Once it has diffused into the cell, 5-ALA is
converted to protoporphyrin IX, a light-sensitive chem-
ical, by the heme cycle. Activation of this chemical by
light then results in cell death and vascular damage by
the production of reactive oxygen species, and immune
activation against tumor cells.17
We are aware of only 1 study that describes the treat-
ment of feline tumors with PDT using 5-ALA, and this
evaluated a small number of cats with superficial SCCs in
varying sites.13 The aim of this prospective study was to
report the long-term outcome in a larger cohort of cats
with superficial nasal planum SCC treated by PDT.
Materials and Methods
Animals
Fifty-five cats with SCC lesions of the nasal planum referred to
the Queen’s Veterinary School Hospital (QVSH) at the University
of Cambridge were entered into this prospective study. Tumors were
staged according to the World Health Organization system for clas-
sification of feline tumors of epidermal origin, where Tis is defined as
a preinvasive carcinoma (carcinoma in situ), and T1 as a tumor
o2 cm in maximum diameter, which is superficial or exophytic.
Forty-five tumors were confirmed by biopsy and histologic examin-
ation as T1 and 4 as Tis. For 6 cats, the diagnosis was based on
cytology from either scrapings or an impression smear of the lesion.
Forty-seven cats were domestic shorthaired and 8 were domestic
longhaired. The median age of cats was 11 years (range 6–18 years).
All cats were healthy based on results of clinical examination and
routine CBC and biochemical evaluations, with the exception of 4
cases, which had clinicopathologic evidence of hyperthyroidism.
These cases received medical treatment before PDT. Thoracic ra-
diographs or other imaging was not performed due to the low
From the Department of Veterinary Medicine, University of Cam-
bridge, Cambridge, UK (Bexfield, Gear, Dobson); and the Royal
Veterinary College, University of London, London, UK (Stell). Pre-
viously presented in part at the 48th Annual Congress of the British
Small Animal Veterinary Association, Birmingham, UK, April 7–10,
2005. This work was done at The Department of VeterinaryMedicine,
University of Cambridge, Cambridge, UK.
Corresponding author: Nicholas H. Bexfield, BVetMed, DSAM,
DipECVIM-CA,MRCVS, Department of VeterinaryMedicine, Uni-
versity of Cambridge, Cambridge CB3 0ES, UK; e-mail: nb289@
cam.ac.uk.
Submitted February 8, 2008; Revised May 18, 2008; Accepted
July 16, 2008.
Copyright r 2008 by the American College of Veterinary Internal
Medicine
10.1111/j.1939-1676.2008.0186.x
J Vet Intern Med 2008;22:1385–1389
metastatic rate of these tumors.18 The owners were offered conven-
tional treatments for their cats (surgery or radiotherapy), but opted
for PDT. The exact location and size of the tumor were recorded in
the clinical records.
Photosensitizer
Twenty percent 5-ALA creama was applied to the lesion, includ-
ing a 5mm surrounding margin of apparently normal tissue,
approximately every 30 minutes for 6–8 hours. Cream was applied
using either a gloved finger or cotton wool bud. All cats were lightly
sedated with acepromazineb and buprenorphinec during this period,
and an Elizabethan collar was applied in all cases. Areas of scab
were removed as early as possible during application of the cream.
Uptake of the 5-ALA and conversion to protoporphyrin IX were
demonstrated by exposure of the treatment area to a Wood’s ultra-
violet lamp. Regions exhibiting protoporphyrin IX synthesis
fluoresced red.
Illumination Procedure
The light source consisted of 172 high-intensity (6Cd) light-emit-
ting diodes with a peak wavelength of 635 nm. The intensity of the
light source had been previously measured at 6.9mW/cm2 at a dis-
tance of 1 cm using a scanning spectral radiometer with a calibration
traceable to the National Physics Laboratory. A dose of 12 J/cm2
was delivered and the treatment time (1,800 seconds) was controlled
by a countdown timer.
Illumination was performed with cats positioned in sternal re-
cumbency and under general anesthesia. Anesthesia was induced
with propofol,d tracheal intubation performed and maintained with
a gaseous combination of isofluranee and oxygen. The light source
was positioned perpendicular to the tumor site at a distance of ap-
proximately 1 cm. Other areas of the head, including the eyes, were
shielded from the light source using swabs and plastic eye protector
discs. Sixteen cats received carprofen,f and 12 received meloxicamgperioperatively. Forty-two cats received an infra-orbital nerve block
with bupivacance.h Of those cats receiving an infra-orbital nerve
block, 9 also received carprofen and 6 received meloxicam. All cats
received either carprofen, meloxicam, or an infra-orbital nerve
block. Cats were hospitalized for 24 hours after treatment to mon-
itor for adverse effects and to provide further analgesia if required.
Examination of Intoxication
Evidence of local intoxication of skin and subcutaneous tissue
was clinically assessed during application of 5-ALA cream, during
the illumination procedure and for 24 hours after treatment. Cats
were also observed for signs of generalized intoxication, although
blood samples were not taken to monitor an effect of treatment on
organ function.
Tumor Response and Tumor Control
Cats were reassessed at the QVSH 1 month after PDT. Subse-
quent reassessments were performed either at the QVSH or with the
original referring veterinarian.
A complete response was defined as a complete disappearance of
the lesion with re-epithelialization to healthy skin. Response was
defined as partial when there was a reduction in tumor size of
450%, and as no response when tumor size reduction was o50%
or if tumor progression was present. Tumor response at reassess-
ment was judged by visual assessment only and not by repeat
biopsy, and tumor size was measured by a ruler or calipers. Several
cats received further PDT treatment due to recurrence of disease or
lack of a complete response. Repeat PDT was offered to all such
cases, but some owners declined further treatment. Repeat PDTwas
performed as described previously.
Additional information on long-term outcome was obtained
from the clinical records or through telephone contact with the re-
ferring veterinarian or owners. Follow-up times were based on a
censor date of September 25, 2007.
The endpoint used was disease-free interval (DFI), defined as
the interval between the PDT and the recurrence of visible tumor at
the original site. Cats were censored from DFI evaluation if they
were lost to follow-up, alive without tumor recurrence, or died of a
disease that was not associated with the tumor or treatment.
Statistical Analysis
DFI plots were generated according to the Kaplan-Meier
method.19 Median time to recurrence was reported with 95% con-
fidence interval (CI). Statistical analysis was performed by a
statistical software package.i
Results
Fifty-three of 55 cats (96%) responded to therapy, and
a complete response occurred in 47 cats (85%). Six cats
(11%) demonstrated a partial response and each of the
partial responders had a small crusting lesion remaining
4–8 weeks after treatment with subsequent progression.
Two cats had no response to therapy.
When DFI was analyzed, 24 of the 47 (51%) tumors
showing complete response recurred with a median time
to recurrence of 157 days (95% CI, 109–205 days; Fig 1).
Eighteen cats received a repeat PDT treatment, with 15
showing complete remission again and 3 showing partial
remission. Tumors returned in 10 cats with a median time
to recurrence of 68 days (range 28–224 days).
Of the 6 cats showing a partial response, 4 received re-
peat PDT, with 3 cats showing a complete response and 1
cat showing no response. Of those that demonstrated a
complete response, tumors retuned in 2 cats with a me-
dian time to recurrence of 92 days.
300025002000150010005000
Time after treatment (days)
1.0
0.8
0.6
0.4
0.2
0.0
Pr
op
or
tio
n 
di
se
as
e 
fre
e
Fig 1. Kaplan-Meier plot for disease-free interval for all tumors
(n 5 47) showing an initial complete response to photodynamic
therapy.1, censored cats; DFI, disease-free interval.
1386 Bexfield et al
The long-term outcome was known in 51 out of 55
cases, and 4 cases were lost to follow-up. Median follow-
up time was 38.2 months (range 8.4–92.2 months).
Twenty-three cats (45%) were alive and disease free, 17
(33%) had to be euthanized due to tumor recurrence and
11 (22%) were euthanized for other reasons.
Following treatment lesions became erythematous and
slightly edematous in all cats. In a few cats the lesions
appeared to cause some discomfort manifested by occa-
sional rubbing of the nasal planum. These changes were
seen immediately, or up to 3 days after therapy. No cats
exhibited any other adverse effects of treatment.
Discussion
The results of this study suggest that 96% of superficial
nasal planum SCCs treated with PDT using topical
5-ALA respond to therapy, with a complete response rate
of 85%. This compares favorably with previous studies
using a variety of systemically administered photodynam-
ic agents and laser illumination,9–12 although response
rates were higher in a recent study.14 Similar results are
achieved in the treatment of human SCCs.20–23 Combined
results of several human studies using 5-ALA demon-
strated average complete response rates of 81% for a total
of 41 tumors, although follow-up times were short.24
Although initial response rates found in the present
study were encouraging, PDT did not lead to a durable
remission or cure in all cases, with a recurrence rate of
51% at a median of 157 days. Previous studies reported
tumor-free intervals of 3–18 months for 10 tumors show-
ing a complete response to a single PDT treatment using
aluminum phthalocyanine tetrasulfhonate,10 and 1-year
overall control rate of 62% using an alternative photo-
sensitizer, pyropheophorbide-a-hexyl-ether (HPPH-23),
to treat 61 cats with facial SCCs.11 In a recent study,14 an
overall recurrence rate of 20% was observed after a me-
dian of 172 days.
Although the treatment protocol used in this study
does appear to produce a complete remission for pro-
longed periods in some cases, average remission times for
feline nasal planum SCC treated with PDT are not as
long as for other treatments. In cats with invasive SCCs,
surgery with partial amputation of the nose provides
long-term control, with a median DFI of 524 days.18
Megavoltage radiation using 60cobalt results in a median
DFI of 361 days.18 Using fractionated orthovoltage ra-
diation, the 5-year progression-free survival rate for
superficial (T1) SCCs was 56%, whereas that for T2 was
10.6% only.5 90Strontium plesiotherapy resulted in an
85% complete response rate and no recurrence of disease
during a median follow-up period of 652 days.8 PDT
therapy using 5-ALA does have the advantage of pro-
ducing good cosmetic results with minimal scarring,
possibly because cells such as fibroblasts are relatively
resistant to the effects of PDT.25 90Strontium plesiother-
apy also results in good cosmetic results although
multiple treatments are required. PDT has the additional
advantage that it is also completed on a single occasion,
avoiding the need for multiple anesthetics and does not
require access to specialist radiation facilities.
SCCs in this study were assessed to be either stage Tis
or T1. Because of limited numbers of cats with Tis (n5 4)
stage tumors it was not possible to compare the response
rate of these 2 groups, however. Previous studies have
demonstrated that complete response rate, as well as lo-
cal control of feline facial SCCs, is significantly related to
tumor stage.11 For instance, complete response was
achieved for 100% of T1a (o1.5 cm, noninvasive) tu-
mors, but only 18% of T2b (41.5 cm, invasive) tumors.
11
Human invasive skin lesions treated by PDT also have a
worse initial response rate and higher rate of recur-
rence.24 It is possible that some tumors in the present
study were misclassified as Tis, when they were in fact T1
tumors. Furthermore, as it is difficult to fully appreciate
tumor invasiveness, it is possible that some tumors
should have been classified as higher stage tumors. More
accurate methods toclassify feline SCCs may better de-
fine response rates. Despite the low metastatic rate of
these tumours,18 metastases do occur and it is possible
that some animals in this study may have developed met-
astatic disease. Optimal staging should include ab-
dominal and thoracic imaging, but was not performed
in the present study.
Eighteen cats that achieved complete remission re-
ceived a second PDT following tumor recurrence, and a
further complete remission was achieved in 15 cases. Re-
peat treatments of human superficial skin tumors using
5-ALA are more effective than a single treatment.26 Ex-
perimental evidence suggests that light-dark intervals
may increase the efficacy, possibly due to tumor re-
oxygenation.27 During PDT, the concentration of
oxygen in tissue is reduced by either damage to the vas-
cular system and/or consumption in the oxidative
process. As this and previous studies have demonstrated
that repeat treatments can be administered safely to cats,
future studies should assess the effects of light-dark in-
tervals or repeated PDT in cats with SCCs with the aim
of reducing tumor recurrence rates.
Although topical PDT is commonly used to treat hu-
man skin tumors, its use is infrequently reported in the
veterinary literature. Advantages include a potential re-
duction in systemic adverse effects and direct application
of the PDT agent in the tissue to be treated. The main
limitation of PDT in general and for topical PDT in par-
ticular is the inability to treat large invasive tumors. With
topical administration of ALA, the penetration and up-
take of ALA is the limiting factor particularly in nodular
or thickened lesions, but this may be improved by the use
of skin penetration enhancers such as oleic acid.28 Skin
penetration enhancers were not used as this study was
designed to assess the response to a commercial formu-
lation of topical 5-ALA. Skin penetration enhancers may
have also potentially resulted in adverse effects, which
would have been difficult to differentiate from those due
to 5-ALA. The addition of penetration enhancers may
have partial curettage may also enhance 5-ALA penetra-
tion, and for this reason surface scabs were removed as
early as possible during application of the cream.
Many light sources are available, although no signifi-
cant difference in efficacy has been demonstrated.26 The
light source used in the present study was constructed for
1387PDT of Nasal Planum Tumors
use in a previous study,13 and consists of an array of light
emitting diodes. It has the advantage of being cheaper
and safer than a laser, readily portable, and allows the
treatment of a large area. The use of laser light sources in
combination with an IV photosensitizer has been re-
ported in the treatment of cats with cutaneous SCCs.14
Penetration of light into tissues is not uniform for all
wavelengths, and the depth of photon penetration corre-
lates positively with increased wavelength.17 Light of
wavelength 635 nm was used as this has been shown to
provide optimal tissue penetration.29 Although the light
source produced a relatively low applied light dose, no
significant difference in efficacy is noted when low and
high doses of red light are used in the treatment of human
neoplastic skin lesions.30 A lower light dose, or fluence,
has been reported to result in higher local tumor control
rates and more efficient tumor killing, likely due to re-
duced oxygen consumption.31 The light source used in
the present study was shown to be effective in activating
the photodynamic process, as uptake of the 5-ALA and
conversion to protoporphyrin IX was demonstrated by
exposure of the treatment area to a Wood’s ultraviolet
lamp. It is possible that changing the light dose may have
resulted in an improved tumor response in the patients in
this study. In view of the apparent lack of adverse effects,
tolerability, and excellent results in some cats, it was de-
cided to continue with this light dose until completion of
the study. It was also considered that lack of penetration
of the photosensitizer was a more likely limiting factor to
the effectiveness of therapy than the applied light dose.
The recurrence rate in this study was relatively high,
and there are several possible explanations. It could rep-
resent genuine recurrence due to inadequate therapy and
residual neoplastic tissue, as recurrence generally oc-
curred at the original site rather than in surrounding
tissue. As previously discussed, this may be due to in-
sufficient penetration of 5-ALA. Alternatively, dysplastic
cells in grossly normal appearing skin not included in the
initial treatment could have undergone neoplastic trans-
formation. It is also possible that, although all SCCs
were staged as superficial, some were more deeply inva-
sive and hence less responsive to PDT. Multiple deep
biopsies may allow more accurate assessment of these
SCCs, although in view of the small size of some lesions,
this is difficult to justify.
Application of 5-ALA was difficult in some cats, al-
though sedation improved compliance. In other studies
5-ALA has been given systemically (IV or PO),11,14,15
and may result in improved response rates. For instance
administration of a lipsosomal formulation of the pho-
tosensitizer m-THPC resulted in a complete response
rate of 100%, with an overall 1-year control rate of
75%.14 Magne et al11 performed PDT with a photosen-
sitizer (pyropheophorbide-a-hexyl-ether) administered
IV and a complete response rate was achieved in 49% of
tumors, with an overall 1-year tumor control of 61.7%.
Systemic administration of 5-ALA might allow a more
even distribution of ALA-derived porphyrins. However,
adverse effects including thrombocytopenia, anorexia,
hyperbilirubinemia, and high serum liver enzyme activ-
ity, are reported following systemic administration of
5-ALA to feline patients,15 and similar effects are noted
in humans as well.24 Bioadhesive patch formulations for
the cutaneous delivery of 5-ALA have recently been de-
veloped for use in humans and may show application to
feline patients.32
Adverse effects observed in the present study were mi-
nor and included local erythema and mild swelling.
Similar adverse effects are seen in human patients.16
Overt discomfort was not apparent in cats in this study,
although opioid analgesia was administered peri-opera-
tively. Some animals were also given additional analgesia
using nonsteroidal anti-inflammatory drugs. These drugs
are known to inhibit the action of cyclooxygenase en-
zymes.33 Many tumors over express cyclooxygenase, and
this can be associated with tumor resistance.34 The use of
nonsteroidal anti-inflammatory drugs during PDT has
been shown to result in enhanced antitumor activity
when studied in vitro and in vivo.35,36 The use of these
drugs during PDT in cats warrants further studies, par-
ticularly as feline oral SCCs have been shown to over
express cyclooxygenase-2.37
In conclusion, results of this study have demonstrated
that PDT using topical 5-ALA and a noncoherent red
light source is effective for the treatment of superficial
nasal planum SCCs in cats. It has the benefit of being
safe, well tolerated, produces cosmetically acceptable re-
sults and hence offers an alternative to other therapies.
Although initial response rates are high, this treatment
does not lead to a durable remission or cure in all cases.
Further work is required to establish an optimum treat-
ment protocol using topical 5-ALA.
Acknowledgments
NHB gratefully acknowledges the Alice Noakes Trust
for sponsoring his residency. The authors are also grate-
ful to the owners and patients for their participation in
this study, and to referring veterinarians for providing
follow-up information.
Grant: This work was not supported by any grant.
Footnotes
aAladerm, Crawford Pharmaceuticals, Goostrey, Cheshire, UK
bACP, NovartisAnimal Health, Litlington, Herts, UK
cVetergesic, Alstoe Animal Health, York, North Yorkshire, UK
dRapinovet, Schering-Plough Animal Health, Middlesex, UK
e IsoFlo, Abbott Animal Health, Kent, UK
fRimadyl, Pfizer Animal Health, Tadworth, Surrey, UK
gMetacam, Boehringer Ingelheim, Bracknell, Berkshire, UK
hMarcaine, AstraZeneca, kings Langley, Hertfordshire, UK
i SPSS 13.0 for Windows, SPSS Inc, Surrey, UK
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