Abstract
Objectives
Squamous cell carcinoma (SCC) is the most common eyelid tumour in cats. The main treatment is extensive surgery and the cosmetic outcome can be worrisome for some owners. Strontium 90 (ST-90) plesiotherapy is a therapeutic modality used for superficial tumours, including SCC. The aim of this study was to describe the use and response of feline eyelid SCC to ST-90 plesiotherapy either as single treatment or as adjuvant therapy following surgery.
Methods
A referral centre clinical database was searched for all cats diagnosed with SCC located on an eyelid. Cats treated with ST-90 plesiotherapy were included. The response to treatment was evaluated visually every 4–6 weeks until complete healing and based on response evaluation criteria in solid tumours (RECIST). Descriptive statistics of the survival were applied to the data collected.
Results
Eight cats treated between 2014 and 2017 met the inclusion criteria. The median age was 10.8 years. In six cases, ST-90 was used as the only treatment modality, while in two cats it was used as an adjuvant to surgery. Four cats received a single protocol and four a hypofractionated protocol. In the six cats in which ST-90 was used as the primary treatment, the response was 100%. Four cats died at a median time of 9 months (3–17 months) after ST-90 due to causes unrelated to SCC. Of the remaining four cats, three had no signs of recurrence at a median time of 34 months and one was lost to follow-up at 17 months with no signs of recurrence.
Conclusions and relevance
This small study showed that ST-90 can be used for treatment of eyelid SCC with good therapeutic and cosmetic outcomes.
Introduction
Squamous cell carcinoma (SCC) is a malignant tumour affecting the epidermis. In cats, it is a common neoplasia, accounting for 15 to 25% of cutaneous tumours in this species. 1 A recent study assessing 680 feline tumours reported that 35.1% were of skin origin, with 28.8% of these being SCCs. 2 According to another recent study, SCC is the most common malignant tumour in cats’ eyelids, accounting for 28% of the cases. 3 SCC is commonly seen in older cats with median age of onset of 10–12 years. 4 Tumour development is associated with exposure to ultraviolet light, especially to ultraviolet B (UVB) radiation. 4 The haircoat seems to function as a physical barrier for ultraviolet (UV) damage, as SCC is most often seen in lightly haired, non-pigmented areas of the head, with white cats or coloured cats with white areas being over-represented. 5 Clinical presentation can be variable, from plaque-like lesions to ulcerated non-healing wounds on the nasal planum, eyelids or pinnae; often the lesions can be seen in different areas simultaneously. 4 The disease is described to metastasise rarely, with metastatic disease reported later in the course of disease mainly to the local draining lymph nodes and lungs. 4 Based on a study describing patients with more advanced disease, lung metastasis was present in 40% of the cats at the time of diagnosis. 6
Feline SCC is staged based on the tumurs, node and distant metastasis (TNM) staging system, as described in Table 1. 7 Complete staging, including sampling of the regional lymph nodes and thoracic imaging, is recommended before starting therapy. The treatment of eyelid SCC is primarily surgical, 4 but a more conservative approach can be considered for cases presented at an early stage (such as carcinoma in situ Tis or T1), or when pet owners are against aggressive surgery. Strontium 90 (ST-90) plesiotherapy is a form of radiotherapy particularly indicated for the treatment of superficial tumours by directly applying the radioactive device to the tumour surface. ST-90 undergoes decay by emitting β-particles, which are characterised by limited penetration ability (2–3 mm) into the irradiated tissue. This allows use of high doses of radiation to the surface without damaging the underlying tissues. 8
World Health Organization staging system 7
The use of ST-90 has been previously described for the treatment of multiple superficial neoplasia in both cats and dogs, including nasal planum SCC in cats.9,10 For feline nasal planum SCC, two main protocols have been reported involving single (single-dose protocol) or multiple treatments (fractionated protocol).9,10 In a more recent study, the two protocols were compared and reported similar results to what had been previously published. 5 A complete response was seen in 74% of the cases with a median disease-free interval of 780 days and a recurrence rate of 17%. The disease-free interval of cats treated with a fractionated protocol was significantly longer; however, response rates and overall survival were not statistically different between the two protocols. 5 The cosmetic outcome was described as excellent.
To our knowledge, there are no data regarding the use of ST-90 for the treatment of eyelid SCC in cats. Therefore, the aim of this retrospective study was to describe the use, response, outcome and side effects, in a series of cats with eyelid SCC treated with ST-90, either with a single-dose regimen or with a multifractionated protocol. We hypothesised that both the previously described ST-90 protocols would be effective in the management of feline eyelid SCC and the treatment would be well tolerated.
Materials and methods
The clinical database of a referral centre was searched for cats with eyelid SCC treated with ST-90 from 2014 to 2018. Cats were included if they had cytological or histological diagnosis of SCC and were treated with ST-90. Patients that had been treated previously or were receiving concurrent systemic treatment or the presence of SCC at other sites (ie, nasal planum or pinnae) were included in the study population. Cats with no follow-up available were excluded.
Data retrieved from the clinical records included signalment, location and size of the lesions, method of diagnosis, staging performed (ie, bloodwork fine-needle aspiration of the regional lymph nodes, thoracic and abdominal imaging), other treatments and/or concurrent medications, ST-90 treatment protocol performed (ie, single-dose or fractionated protocol as previously described9,10), total dose of radiation and side effects following ST-90. The side effects of the treatment were recorded based on the toxicity criteria described by the Veterinary Radiation Therapy Oncology Group (VRTOG). 11 The response to the treatment was defined by the response evaluation criteria in solid tumours (RECIST) method. 12 Follow-up information was obtained from the medical records of the referral institute or from the referring veterinarian by telephone conversation.
All cats received ST-90 under general anaesthesia in a specially designated radiation area. The anesthetic protocol was individually developed for each patient after assessment by an anaesthetist. The treatment was delivered with an ophthalmic applicator with 0.7 cm2 active area that incorporated an ST-90 source by an oncologist or by a resident/intern in oncology under the supervision of a senior oncologist. The two previously described protocols were used.9,10 The single-dose protocol consisted of a single administration of 100–120 Gy in total, while the fractionated protocol consisted of five applications of 40 Gy each (200 Gy in total) on a Monday/Wednesday/Friday basis. The radiation field was planned with an adequate number of applications to cover the entire lesion with 2–3 mm lateral margins. If the single-fraction protocol was used, care was taken not to overlap the radiation fields. A Jaeger lid plate was placed to shield the eye from the radiation during the treatment. The duration of exposure to deliver the intended fraction was calculated at the time of first treatment, taking into account the ST-90 decay over time (half-life of 28.6 years). The choice of the protocol was based on the characteristics of the lesion, identified comorbidities and the owner’s preference.
The response to the treatment was defined according to the RECIST method 12 and divided into complete response (no residual macroscopic disease), partial response (tumour decreased by ⩾30%), stable disease (tumour decreased by <30% or increased by <20%) and progressive disease (tumour increased by ⩾20%). The side effects of the ST-90 therapy were assessed based on the toxicity criteria of the VRTOG. 11 The response was initially assessed 4–6 weeks after completing the treatment protocol and then every 3 months thereafter. If the patient was unable to attend the visit, the owners were asked to provide the clinician with pictures of the progression of the treated areas. In case of complete response, the disease-free interval (DFI) was calculated from the time of resolution of the lesion until local or distant recurrence was documented. Overall survival was measured as the time between the delivery of the first treatment with ST-90 until death due to SCC or another cause.
Ethical approval was gained prior to starting the study as per institution guidelines (approval number 14-2018).
Results
Eight cats met the inclusion criteria. Seven were domestic shorthair cats and one was a domestic longhair cat. Seven were castrated male cats and one was a spayed female cat. The median age was 10 years and 8 months (range from 9 years to 13 years and 1 month). Seven cats had white or white mixed with ginger hair around the eyes; one cat was black and white, but hair colour distribution was not specified in the patient file. Three of the cats had lesions only on the eyelid, while the rest of the cats presented with lesions also on other sites such as the nasal planum and/or pinnae. The SCC was located in the left eyelid in five cats, right eyelid in one cat and in both eyelids in two cats. In all cats but one, the tumour was affecting the lower eyelid.
The diagnosis of SCC was made via fine-needle aspiration/cytology in three cats and tissue biopsy/histology in five cats. The samples were taken from the eyelids in six cats, while two cats had the diagnosis confirmed on samples taken from another site. These cats were included due to the typical presentation and signalment for SCC.
Complete staging, including thoracic radiographs and fine-needle aspiration of the mandibular lymph nodes were performed in five cats; one of these cats also had abdominal ultrasound performed looking for comorbidities. Three cats only had pre-anaesthetic bloods prior to ST-90. In one case, this was due to financial reasons; for the other two, the reason for the lack of staging was not specified. No evidence of metastatic disease was detected in any of the cats undergoing staging. All the cats treated with ST-90 had stage Tis or T1 disease.
In six cats ST-90 was used as primary treatment, while in the remaining two it was used as adjunctive treatment following surgery (ie, to treat microscopic residual disease). Two cats had undergone multiple surgeries for eyelid SCC prior to ST-90 and one of them had also been previously treated with cryotherapy.
Regarding the ST-90, four cats received a single-fraction protocol delivered as one to two non-overlapping fields. The total dose delivered was 100 Gy in one cat and 120 Gy in three cats. The remaining four cats were treated with a multifractionated protocol, receiving five fractions of 40 Gy each (200 Gy in total) on a Monday/Wednesday/Friday basis. Five of six cats treated with ST-90 as primary treatment achieved complete response (CR), four of them received a single fraction and one cat was treated with a fractionated protocol. One achieved partial response (PR) with the multifractionated protocol for an overall response rate of 100%. The two cats treated in adjuvant settings had no signs of recurrence; the first cat died due to unrelated causes in 9 months and the second cat was lost to follow-up at 17 months. The overall survival time for the eight cats in our study was 20.1 months (range 3 months to 51 months), with no cats dying because of the SCC. The five cats achieving CR were still free of disease after a median follow-up time of 26 months (range 9 months to 51 months). Of these, two cats were still alive at 51 months and 20 months, whilst the other three had died owing to unrelated causes at 9 months, 35 months and 17 months after ST-90. The reported causes of death were solitary intrathoracic mass, upper respiratory signs and hyperthyroidism. The single cat achieving a partial response did not present any evidence of tumour progression after 35 months (Figure 1). Of the two cats treated with adjuvant ST-90 (Figure 2), one was still disease-free at 17 months, while the other died in clinical remission 9 months post-treatment due to aortic thromboembolism. Table 2 summarises the study population.
Treatment planning. Three fields were applied to cover the entire lesion and margins. A Jaeger lid plate was used to shield the eye from the radiation during the treatment. (b) Ten days post-treatment: grade I acute side effects (dry desquamation, erythema and epilation) can be seen. (c) Five weeks post-treatment: suspected small residual disease present in the mid aspect of the lower eyelid. (d) Eight weeks post-treatment: grade 1 long-term side effect can be seen as permanent alopecia. Persistent suspected residual disease still visible in the mid aspect of the eyelid. (e) Six months post-treatment: magnified view of the left lower eyelid. Two small superficial crusty lesions visible on the ventrolateral aspect of the lower eyelid considered to be residual disease
Treatment planning for the cat previously treated with multiple surgeries. Four fields were applied to cover the entire lesion with margins. (b) The same cat as in (a), 1 month after completing the protocol: grade II side effects (mild mucositis) can be seen
Characteristics of the study population
VRTOG = Veterinary Radiation Therapy Oncology Group; DFI = disease-free interval; MN = male neutered; FN = female neutered; DSH = domestic shorthair; DLH = domestic longhair; CR = complete response; PR = partial response; NA = not applicable; single = single-dose treatment protocol; multi = multifractionated protocol
None of the cats undergoing the single-dose protocol developed acute or delayed toxicity. Of the cats treated with the multifractionated protocol, three developed acute grade II and one grade III skin toxicity. The patient with grade III toxicity developed chemosis and hyperaemia that was well controlled with symptomatic treatment with systemic meloxicam (0.05 mg/kg PO q24h) and topical dexamethasone and neomycin sulphate (Maxitrol) applied to the treated eye q12h. The described acute side effects resolved within 2–3 weeks post-treatment. Long-term side effects were limited to alopecia, which was described in three cats.
Discussion
Although SCC is the most common tumour of the eyelids in cats, limited data are available in the literature in terms of treatment options and outcome. Based on the literature, aggressive surgical resection is usually the treatment of choice for eyelid SCC in cats. 13 Nonetheless, studies often only include a small number of cases. Cosmetic outcome after surgery is described as satisfactory to excellent; however, possible complications include reduced eyelid function, reduced lacrimal production, exposure keratitis, corneal ulceration and anatomical complications such as superficial flap necrosis.13–15 Median survival times range from 7 months to more than 12 months, with a few cats experiencing long-term survival.3,13–15 Despite aggressive surgery and the achievement of complete margins, local recurrence has been described.3,13 Moreover, in one study describing 43 cats with eyelid tumours, SCC, lymphomas, adenocarcinomas and peripheral nerve sheath tumours were reported to recur after surgical excision. 3 In particular for the 12 SCCs included in the study,3 nine cats had follow-up available reporting suspected recurrence in one out of two cats with reported complete excision.
ST-90 plesiotherapy is a well-described treatment for superficial tumours, including feline SCC of the nasal planum5,9 and mast cell tumours. 16 To our knowledge, no information exists on the use of this treatment for eyelid SCC in cats. Therefore, the aim of the current study was to describe a small number of cats treated with ST-90 plesiotherapy as primary or adjuvant treatment following surgery for eyelid SCC. In our patients, the overall response rate in the gross disease setting was 100%, with all cats achieving complete response and being free of disease for a median follow up of 20.1 months (range 13 months to 51 months). Two cats received ST-90 plesiotherapy as adjuvant therapy following incomplete surgical excision. Both cats were disease free at 9 and 17 months. The treatment appeared to be well tolerated as none of the cats required any long-term management, which is useful if we consider the overall resistance of cats to manipulation and their general stressful nature. No changes in the functionality of the eyelid were reported. Moreover, the cosmetic outcome with ST-90 treatment was considered excellent with only alopecia seen as a long-term side effect. Although in small numbers, the ST-90 treatment was efficient in adjuvant settings, with no side effects, and therefore could be considered even in more advanced tumours in a post-surgical setting, especially in the event of incomplete tumour excision.
The cats in our study had a median age of 10 years and 8 months, which is similar to what has been reported previously in the literature. Moreover, seven cats included in the study were reported to have light periocular hair. Most of the tumours were located on the lower eyelid (7/8; 87.5%), with only one cat having the tumour located on the upper eyelid. The predilection for SCC to develop more often on the lower eyelid is due to the fur present on the upper palpebra functioning as a physical barrier against the UVB light, exposure to which is associated with the tumour development. 4
The treatment appeared to be well tolerated in this population. However, for 50% of the patients there was no record of side effects on the follow-up examinations. It is assumed that, had side effects occurred, these would have been reported. The rest of the patients experienced short-term acute side effects, with 37.5% of the patients experiencing grade 2 and 12.5% of the patients grade 3. The patients with grade 2 side effects did not receive any additional treatment and the clinical signs were self-resolving within 2–3 weeks. Only one cat with grade 3 side effects (chemosis and hyperemia) was treated symptomatically with ocular suspension of dexamethasone, polymyxin B sulfate and neomycin sulfate (Maxitrol) and sodium hyaluronate (Hyabax). Overall, this shows the good tolerance to the treatment with no effect on the quality of life of the patients. Information on long-term side effects was available for four cats and revealed only permanent alopecia. This is an expected side effect with radiation, and it is considered acceptable as it has no effect on the cat’s quality of life. The cosmetic outcome was considered very good. These results are similar to those reported in previous studies on nasal planum SCC in cats treated with ST-90. Moreover, there was no difference seen in use of the fractionated or single dose protocol; nevertheless, this study population may be too small to reveal the significance, although the response and side effects are described as similar if applied on the nasal planum.
Limitations
There are numerous limitations in our study. First, even though SCC is the most common feline eyelid neoplasm, only eight cats were included in this study. A larger cohort would facilitate better assessment of response, outcome and associated side effects. A definitive diagnosis was not obtained in all patients; however, these cats presented with multiple lesions and the clinical signs together with signalment were considered tumour specific. Additionally, the method of diagnosis was not standardised and both cytology and histology were used. Only five cats underwent complete staging, which included thoracic radiographs and fine-needle aspiration of the lymph nodes; the remaining three cats only had pre-anaesthetic bloodwork performed. The incomplete staging may have underestimated the presence of metastatic disease; however, due to the early stage of disease of the patients treated, metastatic disease was considered unlikely. Additionally, all cats had a complete physical examination prior to any procedure and the regional lymph nodes were considered of normal size. Furthermore, none of the cats in this population died because of the progression of the disease. Therefore, lack of staging was not considered to have affected the outcome of this cohort. Lastly, there were multiple treatment protocols included in the study and not all cats attended re-evaluation.
Conclusions
This small retrospective study shows that ST-90 could be used for the treatment of early stages of SCC of the eyelids, with excellent response rates and long-term control. Moreover, this treatment modality could be considered in the adjuvant setting in cases of incomplete resection to treat microscopic disease. No major side effects were associated with the treatment and should be considered a valid alternative to more aggressive surgical resection.
Footnotes
Acknowledgements
This work was presented as an oral abstract at the BSAVA 2019 Congress.
Conflict of interest
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.
Ethical approval
The work described in this manuscript involved the use of non-experimental (owned or unowned) animals. Established internationally recognised high standards (‘best practice’) of veterinary clinical care for the individual patient were always followed and/or this work involved the use of cadavers. Ethical approval from a committee was therefore not specifically required for publication in JFMS. Although not required, where ethical approval was still obtained it is stated in the manuscript.
Informed consent
Informed consent (verbal or written) was obtained from the owner or legal custodian of all animal(s) described in this work (experimental or non-experimental animals, including cadavers) for all procedures undertaken (prospective or retrospective studies). No animals or people are identifiable within this publication, and therefore additional informed consent for publication was not required.
