Photodynamic therapy of feline cutaneous squamous cell carcinoma using a newly developed liposomal photosensitizer: preliminary results concerning drug safety and efficacy

BACKGROUND: Squamous cell carcinomas are common skin tumors in cats. We investigated photodynamic therapy (PDT) using a new liposomal photosensitizer as a minimally invasive, effective treatment that can be easily performed while achieving good cosmetic results. AIM: The goal of this study was to assess and describe possible toxicities using a liposomal formulation of the photosensitizer meta-(Tetrahydroxyphenyl)Chlorin (m-THPC) and investigate if favorable pharmacokinetics translate into favorable tumor response and control. ANIMALS: Eighteen client-owned cats with 20 spontaneous cutaneous squamous cell carcinomas were included in the study. METHODS: PDT was performed using a new, liposomal formulation of the photosensitizer. Toxicity, tumor response, and tumor control were evaluated retrospectively. RESULTS: No general adverse effects were observed in cats treated with the new liposomal formulation. Mild local toxicity such as erythema and edema were seen in 15% of the patients. All cats responded to therapy, with a complete response rate of 100%. The overall 1-year control rate was 75%. The tumor recurrence rate was 20% with a median time to recurrence of 172.25 +/-87.1) days. CONCLUSIONS AND CLINICAL IMPORTANCE: A new liposomal photosensitizer was successfully used for squamous cell carcinoma in cats and was well tolerated. There were no systemic adverse effects observed with the liposomal formulation. The favorable pharmacokinetics of the liposomal drug resulted in a favorable tumor response.     

Photodynamic therapy of superficial nasal planum squamous cell carcinomas in cats: 55 cases

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 recurrence 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.     

Photodynamic therapy as a treatment for esophageal squamous cell carcinoma in a dog

Intrathoracic esophageal squamous cell carcinoma was diagnosed by endoscopy in an 11-year-old, castrated male Labrador retriever with signs of regurgitation and weight loss. Photodynamic therapy with photofrin was administered three times under endoscopic guidance over a two-month period. A partial response to photodynamic therapy was supported by a reduction in tumor size (noted on serial endoscopic examinations) and by a return to oral alimentation. The dog was euthanized due to recurrent regurgitation and aspiration pneumonia nine months after the onset of therapy. Necropsy revealed marked local invasiveness and regional lymph node metastasis of the esophageal squamous cell carcinoma in addition to pneumonia. The application of photodynamic therapy in the treatment of canine esophageal squamous cell carcinoma is discussed and compared with the human literature.     

Treatment of corneal squamous cell carcinoma using topical 1% 5‐fluorouracil as monotherapy

The purpose of this report is to discuss the use of topical 1% 5‐fluorouracil as a sole therapy for canine corneal squamous cell carcinoma (SCC). A 12‐year‐old castrated male pug was evaluated for a well‐demarcated, central, 3 mm in diameter, pale pink, raised, right corneal mass. An incisional biopsy was obtained using a #64 beaver blade after topical anesthesia and without sedation. A definitive diagnosis of corneal SCC was obtained after histopathologic evaluation of the biopsy. Topical 1% 5‐fluorouracil ointment was applied to the right eye four times daily for 2 weeks followed by no treatment for 2 weeks, then treatment again twice daily for 2 weeks. The cornea remained free of recurrence 10 months after cessation of treatment. In dogs affected with corneal SCC, topical 1% 5‐fluorouracil monotherapy may be a viable and cost‐effective treatment option with minimal side effects. This chemotherapy agent may also have an effect on corneal pigmentation. Chronic cyclosporine therapy did not contribute to the pathogenesis of corneal SCC in the case described.     

Fatty acid synthase as a potential therapeutic target in feline oral squamous cell carcinoma

Oral squamous cell carcinoma (OSCC) is an aggressive and treatment‐resistant malignancy in both feline and human patients. Recent work has demonstrated aberrant expression of fatty acid synthase (FASN) and an increased capacity for lipogenesis in human OSCC and other cancers. In human OSCC, inhibition of FASN decreased cell viability and growth in vitro, and diminished tumour growth and metastasis in murine preclinical models. This study aimed to characterize FASN as a therapeutic target in feline OSCC. Immunohistochemistry revealed high FASN expression in primary feline OSCC tumours, and FASN expression was detected in OSCC cell lines (3 feline and 3 human) by immunoblotting and quantitative real‐time‐polymerase chain reaction (qRT‐PCR). Orlistat, a FASN inhibitor, substantially reduced cell viability in both feline and human OSCC lines, although feline cell lines consistently displayed higher sensitivity to the drug. FASN mRNA expression among cell lines mirrored sensitivity to orlistat, with feline cell lines expressing higher levels of FASN. Consistent with this observation, diminished sensitivity to orlistat treatment and decreased FASN mRNA expression were observed in feline OSCC cells following incubation under hypoxic conditions. Treatment with orlistat did not potentiate sensitivity to carboplatin in the cell lines investigated; instead, combinations of the 2 drugs resulted in additive to antagonistic effects. Our results suggest that FASN inhibition is a viable therapeutic target for feline OSCC. Furthermore, cats may serve as a spontaneous large animal model for human oral cancer, although differences in the regulation of lipogenesis between these 2 species require further investigation.     

Photodynamic therapy response in cats with cutaneous squamous cell carcinoma as a function of fluence

The response of advanced stage cutaneous squamous cell carcinomas (SCC) following treatment with photodynamic therapy (PDT) has been poor. It was the aim of this pilot study to determine whether an increase in the delivered fluence (i.e. energy density) would improve the duration of tumour remission in cats with advanced-stage SCC. Tumours were treated with aluminium phthalocyanine tetrasulphonate (AlPcS₄) PDT at a fluence of either 100 J cm⁻² or 200 J cm⁻² and tumour response was evaluated at regular intervals. Those feline tumours treated with a fluence of 100 J cm⁻² ( n = 8) had a significantly shorter median remission duration (69 days; range 0–619 days) than those feline tumours treated with 200 J cm⁻² ( n = 6; 522 days; range 151–1057 days). It is our conclusion that a fluence of 200 J cm⁻² is well tolerated and more effective when treating cats with advanced stage cutaneous SCC.     

Photodynamic therapy for the treatment of periocular squamous cell carcinoma in horses: a pilot study

Objective  Local photodynamic therapy (PDT) is a novel cancer therapy in veterinary ophthalmology. A prospective pilot study seeking to demonstrate proof of principle and safety for the treatment of equine periocular squamous cell carcinoma (PSCC) was therefore conducted. We hypothesized that surgical excision with adjunctive local PDT is an effective and safe treatment for equine PSCC.
Procedures  Nine horses (10 eyes) with PSCC were treated with surgical resection, local infiltration of resulting wound beds with 2-[1-hexyloxyethyl]-2-devinylpyropheophorbide-a (HPPH) and irradiation with 665-nm wavelength diode laser. Regular follow-up ophthalmic examinations were performed.
Results  Surgical resection and PDT yielded disease-free intervals of 25–68 months in our study horses as of January, 2008. These results were obtained following a single treatment in seven horses and two treatments in one horse. In one horse, carcinoma in situ developed 2.5 months after partial surgical excision and PDT, requiring local excision under standing sedation.
Conclusions  Preliminary results suggest that surgical resection and adjunctive local PDT is a safe and effective novel treatment for PSCC in horses. More research is needed before PDT for the treatment of equine PSCC can be adequately compared with other current modalities. Important to future investigations regarding PDT, tumor recurrence rate, length of hospitalization, number of treatment episodes required to effect tumor remission, and total treatment costs should be examined in a controlled manner. Our present results and experiences suggest that this treatment may be useful in the treatment of equine PSCC.     

Assessment of predictive molecular variables in feline oral squamous cell carcinoma treated with stereotactic radiation therapy

This study evaluated molecular characteristics that are potentially prognostic in cats with oral squamous cell carcinoma (SCC) that underwent stereotactic radiation therapy (SRT). Survival time (ST) and progression‐free interval (PFI) were correlated with mitotic index, histopathological grades, Ki67 and epidermal growth factor receptor expressions, tumour microvascular density (MVD), and tumour oxygen tension (pO₂). Median ST and PFI were 106 and 87 days, respectively (n = 20). Overall response rate was 38.5% with rapid improvement of clinical symptoms in many cases. Patients with higher MVD or more keratinized SCC had significantly shorter ST or PFI than patients with lower MVD or less keratinized SCC (P = 0.041 and 0.049, respectively). Females had significantly longer PFI and ST than males (P ≤ 0.016). Acute toxicities were minimal. However, treatment‐related complications such as fractured mandible impacted quality of life. In conclusion, SRT alone should be considered as a palliative treatment. MVD and degree of keratinization may be useful prognostic markers.     

Apparent clinical resolution of pinnal actinic keratoses and squamous cell carcinoma in a cat using topical imiquimod 5% cream

Imiquimod is a topical immune response modifier and stimulator used in humans to treat a number of cutaneous neoplasms. This case report describes a cat with actinic keratoses and squamous cell carcinoma of the pinnae. The pinnal lesions were treated with topical 5% imiquimod three times per week. Treatment was discontinued after 82 days of therapy. Twelve weeks of topical imiquimod application resulted in clinical resolution of the pinnal lesions. Although no post-treatment biopsies were performed, there was no relapse of the pinnal lesions in 5 months of clinical follow-up. Expected side effects were limited to erythema, crusting, alopecia, and mild discomfort at the sites of application during the first 3 weeks of application. These results suggest that topical imiquimod, although unproven, might be a therapeutic option or adjunct to therapy for cats with actinic keratoses and squamous cell carcinoma, especially those cats for whom surgery and radiation therapy are not an option.     

Gemcitabine as a radiosensitizer for nonresectable feline oral squamous cell carcinoma

Eight cats with locally advanced, oral squamous cell carcinoma (SCC) were treated with a combination of gemcitabine and palliative radiotherapy. Low-dose gemcitabine was administered twice weekly (25 mg/m2) in conjunction with megavoltage radiation in 6 Gray (Gy) fractions for a total dose of 36 Gy. Responses included two complete and four partial responses, and two cats had no response to therapy. Median duration of remission was 42.5 days (range, 11 to 85 days). Median survival time was 111.5 days (range, 11 to 234 days). This data suggests that a combination of low-dose gemcitabine and palliative radiation therapy may be tolerable for cats with oral SCC and may cause a therapeutic benefit.     

Detection of papillomaviral DNA sequences in a feline oral squamous cell carcinoma

Oral squamous cell carcinomas (OSCCs) are common and often fatal feline neoplasms. Factors that predispose to neoplasm development in cats are poorly defined. Around 25% of human OSCCs are caused by papillomaviruses (PVs). To determine if PVs are associated with OSCCs in cats, three sets of consensus primers were used to evaluate 20 feline OSCCs and 20 non-neoplastic feline oral lesions for the presence of PV DNA. Papillomaviral sequences were detected within one OSCC, but no non-neoplastic lesion. Sequencing of the amplified DNA revealed a previously unreported PV that was most similar to human PV type 76. This is the first time PV DNA has been amplified from the oral cavity of a cat. However, while these results suggest that feline gingival epithelial cells can be infected by PVs, they do not support a causal association between viral infection and the development of feline OSCCs.     

Superficial keratectomy and topical mitomycin C as therapy for a corneal squamous cell carcinoma in a dog

A 10-year-old female West Highland white terrier was presented with refractory hyperplastic keratitis of the left cornea of one month's duration. At this time, a vascularised and rough lesion 5 mm in diameter was observed on the left cornea. No other abnormality was recognised on the affected eye. The corneal neoplasm was surgically removed and histologically diagnosed as a squamous cell carcinoma. For two months after the surgery, 0.04 percent mitomycin C (MMC) eye drops were applied as adjuvant chemotherapy. Primary corneal squamous cell carcinoma with no history of keratoconjunctivitis sicca is rare in dogs. In the present report, surgical removal of the neoplasm was combined with the topical administration of the anticancer drug mitomycin C and a good prognosis was obtained. The result indicates that the combination treatment used in this case may be an appropriate therapeutic choice for corneal squamous cell carcinoma in dogs.     

Photodynamic detection of a canine glioblastoma using 5-aminolevulinic acid

Photodynamic detection using 5-aminolevulinic acid has been used to identify the surgical margins during resection of human primary brain tumours. Although there are some reports on its use in malignant tumours in veterinary medicine, it has never been used for primary brain tumours. Here we describe a canine glioblastoma that was detected at autopsy with protoporphyrin IX fluorescence induced by orally administered 5-aminolevulinic acid. The fluorescence was strongest towards the centre of the lesion and was absent in normal brain tissue. Moreover, the fluorescence findings were consistent with MRI and histopathological findings. Our findings suggest that photodynamic detection using 5-aminolevulinic acid might be useful for intraoperative fluorescence-guided resection of malignant gliomas in dogs.     

Detection of human papillomavirus DNA in feline premalignant and invasive squamous cell carcinoma

Squamous cell carcinoma (SCC) is the most common malignant cutaneous and oral neoplasm of cats. Papillomavirus (PV) DNA has been identified in a proportion of feline Bowenoid in situ carcinomas (BISCs), cutaneous SCCs and a single oral SCC, but its exact role in the pathogenesis remains unknown. In humans, it has been suggested that ultraviolet (UV) light and human PV (HPV) may act as cofactors in cutaneous SCC carcinogenesis. Little is known about the influence of UV light on PV prevalence in feline cutaneous lesions, including actinic keratosis (AK). Additionally, PV prevalence in noncutaneous feline lesions, including oral SCC, is largely not known. This study aimed to determine the presence of PV in 84 cats with premalignant and invasive SCC from cutaneous and noncutaneous sites using polymerase chain reaction and to investigate an association with UV light. Papillomaviral DNA was amplified from two of 12 cases of AK, seven of 22 BISCs, nine of 39 cutaneous SCCs and two of 35 non‐cutaneous SCCs. Of the PV DNA sequenced, 50% was most similar to HPV of the genus Betapapillomavirus, while the other 50% was most similar to Felis domesticus PV type 2. Exposure to UV was not associated with an increase in PV for cutaneous SCC. The results of this study suggest that in the cat, HPV DNA may be detectible within a higher percentage of squamous lesions than previously demonstrated, UV exposure may not be a confounder for PV presence, and noncutaneous lesions may have a low prevalence of PV.