Evaluation of long-term outcome and prognostic factors of feline squamous cell carcinomas treated with photodynamic therapy using liposomal phosphorylated meta-tetra(hydroxylphenyl)chlorine

Abstract

Objectives

The aim of this study was to evaluate the efficacy, long-term outcome and prognostic factors of feline squamous cell carcinoma (SCC) treated with photodynamic therapy (PDT).

Methods

Cats with histologically verified SCC of the head and neck received an intravenous injection of liposomal phosphorylated meta-tetra(hydroxylphenyl)chlorine (mTHPC) and 4 h later 652 nm light was delivered by a diode laser. One group received ⩽10 J/cm², the other 20 J/cm². Tumour response and duration were analysed with stage, tumour diameter, location and treatment intensity as prognostic factors.

Results

In total, 63 lesions in 38 cats underwent treatment with ⩽10 J/cm2 (n = 22) and 20 J/cm² (n = 41). Overall response rate was 84% (complete remission 61%, partial remission 22%) with a mean progression-free interval of 35 months (median not reached) and a median overall survival time of 40 months (95% confidence interval 33–47). With regard to tumour stage, invasiveness yielded a highly significant worse outcome (P <0.017). All patients with invasive tumours showed progression at less than 6 months. Larger lesions were associated with inferior control and treatment intensity, and tumour location did not influence response and duration.

Conclusions and relevance

PDT using a systemic photosensitiser leads to excellent long-term tumour control in the majority of cats. However, invasive and large tumours had a clearly inferior outcome, even if treated with the higher-dose intensity. This suggests that advanced lesions are not indications for PDT.

Introduction

Squamous cell carcinomas (SCCs) are frequently occurring skin tumours in cats. As in humans, there is a predisposition for non-pigmented skin areas, and an aetiological correlation between tumour development and exposure to ultraviolet light is known. SCCs are locally invasive but rarely metastasise. ¹ The spectrum of lesions ranges clinically and histologically from actinic keratosis (pre-cancerous, mild dysplasia due to chronic sun exposure) to carcinoma in situ (cancer cells within their site of origin) to invasive SCC (penetration of basement membrane) (Figure 1). The most common locations for cats are the sparsely haired areas of the nasal planum, eyelids and pinnae ² – locations where surgical interventions lead to non-optimal cosmetic appearance and function.

Figure 1

(a) Photograph demonstrating a pre-cancerous, mild dysplasia due to chronic solar exposure (actinic keratosis) involving the nasal planum. (b) Cat with carcinoma in situ and (c) cat with a T2b lesion affecting the nasal planum (>1.5 cm in diameter) and penetrating the deeper skin

Radiation therapy has been reported to achieve appealing response rates and control durations but is associated with multiple treatment sessions for the patient and should be reserved for larger, more invasive stages of the tumour.^3–6 Electrochemotherapy, cryotherapy and strontium-90 plesiotherapy also achieve satisfying lesion control but are not widely available.^7–9 Photodynamic therapy (PDT) is a non-invasive treatment modality, which involves the use of a photosensitiser, light and endogenous molecular oxygen to kill cancer cells. Previous studies have shown the efficacy of PDT in treating feline SCC, as well as other superficial tumours, yielding a superb cosmetic outcome and satisfying tumour control for superficial tumours.^9–11 PDT using Foslip (Biolitec) or phosphorylated meta-tetra(hydroxylphenyl)-chlorine (mTHPC), a second-generation photosensitiser is one of the most common systemic sensitisers for cats studied to date and a good tolerability has been described.^10,11

The purpose of this retrospective study was to evaluate the efficacy and long-term outcome of systemic PDT using liposomal mTHPC on treatment-naive and recurrent cutaneous carcinomas in a large cohort of cats and to evaluate tumour and treatment variables associated with local control and survival. It was hypothesised that tumour size/invasiveness would be one of the strongest prognostic factors regarding disease-free interval (DFI) and overall survival.

Materials and methods

Animals

Cats with histologically verified carcinoma in situ or infiltrative SCC were entered in the study. Previous surgical interventions or photodynamic treatments were allowed, as were cats with multiple lesions. Tumours were staged according to a modification of the World Health Organization system and categorised into four groups. The first group (T1a) included non-invasive lesions measuring <1.5 cm in diameter. The second group (T1b) included cats with invasive tumours <1.5 cm in diameter. The third group (T2a) had non-invasive neoplasms >1.5 cm in diameter and the fourth group comprised invasive tumours >1.5 cm in diameter. ¹² Staging included tumour cytology or histology, complete blood count, serum biochemistry, regional lymph node aspiration and thoracic radiographs. All cats were treated at the Division of Radiation Oncology at the Vetsuisse Faculty at the University of Zurich, Switzerland, between April 2011 and July 2016.

Photodynamic therapy

Liposomal m-THPC (Foslip; Biolitec) was administered intravenously over 5 mins at a dose of 0.15 mg/kg body weight. Six hours after injection, a 652 nm diode laser was used as a light source. The light was delivered by an optical quartz fibre to non-contact surface illumination of the visible tumour with an additional security margin of 5 mm. The laser was adjusted to 0.5 W/cm² non-thermal power density. One group of patients received ⩽10 J/cm² over a treatment time of 100 s, the other group 20 J/cm² within 200 s. Cats were otherwise protected from light as much as possible. After discharge, owners were instructed to keep the cat indoors away from strong light sources and direct sun light exposure for approximately 2 weeks.

Anaesthesia and pain management

Cats were anaesthetised with propofol (Propofol 1% Fresenius; Fresenius Kabi) administered in combination with midazolam (Dormicum; Roche Pharma) or ketamine (Narketan 10; Vetoquinol) to effect and were maintained on isoflurane/oxygen (IsoFlo Abbott). For pain management, fentanyl 7 μg/kg (Fentanyl Sintetica; Mendrisio) was injected at induction, 10 μg/kg buprenorphine (Temgesic; ESSEX Chemie) was administered intravenously q8h overnight; at home, meloxicam 0.1 mg/kg daily orally (Metacam for Cats; Boehringer Ingelheim) for 10–14 days was prescribed.

Tumour response and control

Complete response (CR) was defined as complete resolution of all lesions. Cats were considered to have had a partial response (PR) when there was at least a 50% decrease in the size of the measureable tumour and as no response when tumour size reduction was <50% or if tumour progression was present. Tumour size was measured with callipers.

Cats were examined 4–8 weeks after PDT and follow-up data were collected thereafter approximately every 3 months by direct examination, telephone communication, per mail and photos either with the owner or the referring veterinarian. A minimum follow-up period of 6 months was requested.

Statistical analysis

All data reported are given as mean ± SD unless otherwise specified. Progression-free interval (PFI) was calculated from the date of the first PDT treatment until documentation of recurrence. Cases that were lost to follow-up or that remained free of recurrence were censored at the date of the last follow-up evaluation or death of the cat. Median time to recurrence was reported with the 95% confidence interval (CI). A Kaplan–Meier survival analysis was performed using SPSS 24 (IBM) to calculate PFI and overall survival time (OST). Tumour response and duration were analysed with stage, tumour diameter, tumour location and treatment intensity with the log rank statistic after ensuring even distribution of cases per group. Results were considered significant at values of P <0.05.

Results

Animals

The study population consisted of 38 cats, with the majority being domestic shorthair cats (n = 36); there was one Siamese and one Maine Coon. Sixteen of the cats were female spayed and 22 were male neutered. The median age at time of treatment was 12.9 ± 3.8 years and median weight was 4.8 ± 1.2 kg. Nineteen of the cats had one lesion, 13 had two and six cats had three lesions, resulting in a total of 63 lesions. Histologically, the majority (n = 50) were classified as infiltrative SCCs and 13 as carcinoma in situ (of which seven had Bowen’s disease). All tumours were located on the head and neck, with 20 located on the eyelid, 19 on the nasal planum, nine in the temporal or ear base region, and 15 in the facial skin or on the neck. All tumours were diagnosed histologically. Most tumours were non-invasive with 41 categorised as T1a (<1.5 cm in diameter) and three as T2a (<1.5 cm in diameter). Ten cats had T1b tumours (invasive, <1.5 cm) and nine had T2b tumours (invasive, >1.5 cm). Lymph node aspiration was performed in 11 cats and thoracic radiographs were available for all cats. All staged free of metastatic disease (N0M0).

PDT

Intravenous liposomal mTHPC was well tolerated by all patients and no systemic adverse events were noted. Mild acute local adverse effects, including erythema and oedema (grade 0–1), were seen in 42% of cats shortly after PDT and resolved within 2–7 days after therapy. In most cats, tumour necrosis and scab formation at the PDT site were observed within 2 weeks of treatment (Figure 2). Maximum response to therapy was documented after 8 weeks.

Figure 2

Photograph demonstrating a small carcinoma (T1a) in situ affecting the left and right nasal planum. Same cat (a) before, and (b) 2 weeks and (c) 6 weeks after photodynamic therapy

Post-treatment nasal obstruction and dyspnoea occurred in one cat with a large T2b nasal planum lesion. This cat was euthanased after 1 month when there was no improvement on supportive therapy and no tumour response noted.

Tumour response and control

In total, 63 lesions in 38 cats underwent treatment with ⩽10 J/cm² (n = 22) and 20 J/cm² (n = 41). Overall response rate was 84% (CR 61%, PR 22%) with a mean PFI of 35 months (median not reached) (Figure 3) and a median OST of 40 months (95% CI 33–47). Tumour stage, maximum tumour diameter, tumour location and treatment intensity were evaluated as possible prognostic factors. With regard to tumour stage, invasiveness (T1b and T2b tumours) yielded a significantly worse outcome (P <0.017). All patients with invasive tumours showed progression at less than 6 months. Also, larger lesions were associated with inferior control – increasing tumour diameter resulted in decreased PFI. Treatment intensity (⩽10 J/cm² or 20 J/cm²) and tumour location did not influence response and duration (P >0.05).

Figure 3

Progression-free survival of all cats

Discussion

The results of the present study support previously reported data on the role of PDT with a systemically applied photosensitiser in the treatment of feline SCC.^10–12 We have shown that PDT using liposomal mTPHC results in good control of cutaneous SCCs in cats obtaining an overall response rate of 84% with a mean PFI of 35 months.

From all prognostic factors analysed, tumour invasiveness and maximum tumour diameter were the only ones shown to be of significance for treatment response. Larger and more advanced lesions (T1b and T2b) responded less often and complete and relapsed sooner . Clearly, one key element in eradicating tumour cells by PDT is adequate light delivery to all areas of the tumour. Penetration depth of the photo-activating light is not sufficient in such large, invasive tumours. In the present study, local control rates for more advanced, invasive tumours were clinically unsatisfactory and PDT should not be recommended as the treatment choice.

Among other factors, the success of PDT is further dependent on the total light dose delivered into the target tissue, and treatment intensity was evaluated for its influence on outcome. ¹³ No difference in outcome was observed whether tumours were treated with ⩽10 J/cm² or 20 J/cm², indicating a saturation of photosensitiser–light combination at the lower intensity. Also tumour location (pinnae/ear base, nasal planum, eyelid/peri-orbital, or other cutaneous sites) did not affect response to PDT (P >0.05).

Magne et al ¹² revealed that PDT based on a chlorophyll A derivative photosensitiser, HPPH-23 (pyropheophorbide-alpha-hexyl-ether), was effective in early tumour stage (small, non-invasive), whereas the local control rate of large, invasive tumours was unacceptable. In our cohort all cats failed locally, the latest within 6 months of PDT, if an invasive lesion had affected them. However, cats with non-invasive tumours remained free of disease for at least 5 years once they had achieved complete remission.

In the same study of Magne et al ¹² the morbidity associated with the application of HPPH-23 was reported to be high, with all cats treated for T1b and T2b lesions showing post-treatment nasal obstruction and dyspnoea. Further, anorexia affected approximately half of the treated cats, and although easily controlled with antibiotics, secondary bacterial infection was another common complication reported. In the present study, PDT with intravenous liposomal mTHPC was well tolerated by the majority of treated cats. Local reactions following treatment with intravenous mTHPC have to be expected and mainly consist of scab formation and hypersensitivity to light for 2 weeks. In the population treated herein, these reactions were minimal and were easily managed symptomatically and with owner communication. Only one cat with a large T2b tumour lesion developed stertor and dyspnoea due to nasal obstruction and had to be euthanased because of that complication. No other unacceptable side effects were observed in the current study or in the one by Buchholz et al, which used a similar treatment protocol. ¹¹

The study performed by Buchholz et al ¹¹ described an overall response rate of 100% after systemic liposomal mTHPC. Four out of 20 (20%) treated cats had a recurrence within a median of 5.6 months, but no impact of tumour stage was detected. However, the number of treated cats was smaller than in our study, which might have limited the power of some analyses.

Although initial response rates were encouraging in the present study, systemic PDT did not lead to durable remission or cure in any of the invasive and large tumours. We propose to treat these advanced tumour stages with external beam radiotherapy, which was shown to be a valuable treatment option resulting in long tumour control. The most recent study from our group evaluated an accelerated radiation protocol of 10 × 4.8 Gy delivered twice daily at least 6 h apart on five consecutive days for tumour and treatment associated variables. ⁶ Of the 44 treated cats, all showed complete response to radiotherapy with a median DFI of 916 days and a 1 year DFI of 71%. Again, with all tested variables, including external-beam radiation therapy, tumour size showed a tendency to influence DFI, with larger tumours having a greater risk of recurrence than smaller ones. Acute and late toxicities were mild to moderate.

Limitations of the current study are certainly the retrospective nature, the total number of cats treated and the number of cats per stage. Follow-up information was inconsistently gained via direct examination, telephone or mail communication with the owner or the referring veterinarian, which might have resulted in incomplete data. Further, there was a pre-selection of cases as some owners had refused multiple treatment sessions under anaesthesia as required for radiotherapy, or had refused irradiation because of financial or logistical reasons.

PDT should be considered for treatment of SCC when there are multiple lesions, in areas where surgeries would result in morbidity (eg, the eyelid) or diminished cosmetic function and when lesions are known to be non-invasive. The appealing advantages of PDT as opposed to other treatment modalities are a low toxicity profile, no cumulative toxicity after multiple sessions, that it is performed in a single treatment session and that the cosmetic outcome is very rewarding. The main limitation is the inability to treat large, invasive tumours effectively.

Conclusions

PDT using liposomal mTHPC leads to excellent long-term tumour control in the majority of cats. However, invasive and large tumours had a clearly inferior outcome, even if treated with the higher dose intensity. This suggests that advanced lesions are not indications for PDT.