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.     

Hematoporphyrin-based photodynamic therapy for cutaneous squamous cell carcinoma in cats

Photodynamic therapy (PDT) using a haematoporphyrin derivative (Photogem®, General Physics Institute and clustes Ltda) as photosensitizer and light emitting diodes (LEDs) as the light source was evaluated in 12 cats with cutaneous squamous cell carcinoma. Lesions were illuminated with LEDs, (300 J/cm for 30 min) 24 h after the administration of the photosensitizer. Clinical responses were classified as complete disappearance of the tumour with total re-epithelialization; partial response (a reduction greater than 50%); and no response (less than 50% reduction). Tumours localized to the pinna treated with one ( n  = 3) or two ( n  = 4) applications of PDT yielded no response. Highly invasive tumours of the nose and nasal planum also showed no response, after two treatments ( n  = 2). A combination of PDT and surgery was performed in three cases. Two cats showed partial response and one complete response with one application of therapy 30 days after nasal surgery. Small and noninfiltrative lesions ( n  = 3) of the nasal planum showed a PR with one application ( n  = 2) and a CR with two applications ( n  = 1). This study shows that PDT using Photogem® and LEDs can provide local control of low-grade feline squamous cell carcinoma. The addition of PDT to surgery in more invasive cases may help prevent recurrence.     

Ki67 reactivity in nasal and periocular squamous cell carcinomas in cats treated with electron beam radiation therapy

Squamous cell carcinomas of sparsely haired skin are relatively common tumors in cats, and these tumors likely exhibit a rapid growth rate. Thus, we evaluated response and duration of response in relation to the Ki67 proliferative reactivity in such tumors. Seventeen cats with confirmed squamous cell carcinomas and treated with an accelerated, hypofractionated electron beam radiation protocol were included in the study. For all of them histologic grading, Ki67 reactivity, response, and disease-free interval (DFI) were evaluated. Response to therapy was excellent (94% complete response rate) with a median DFI of 414 days. Only moderate acute and few long-term adverse effects were seen. Cats with tumors with a low Ki67 reactivity had markedly shorter DFIs than cats with tumors with high Ki67 reactivity. We concluded that an accelerated, hypofractionated electron beam radiation therapy protocol is well suited for feline squamous cell carcinomas. The protocol appears especially efficacious in tumors with a high Ki67 reactivity.     

Evaluation of strontium Sr 90 for the treatment of superficial squamous cell carcinoma of the nasal planum in cats: 49 cases (1990-2006)

OBJECTIVE: To determine progression-free and overall survival times of cats with squamous cell carcinoma (SCC) of the nasal planum following treatment with a single fraction of strontium Sr 90 ((90)Sr). DESIGN: Retrospective case series. ANIMALS: 49 cats with SCC of the nasal planum. PROCEDURES: Information including FIV infection status, diagnosis of SCC vs SCC in situ (ie, evidence that the tumor did or did not penetrate the epidermal basement membrane, respectively), (90)Sr dose and number of probe applications, treatment-related response and complications, and recurrence of SCC and new lesion development was obtained from medical records. The relationships of these variables with calculated progression-free and overall survival times were assessed. RESULTS: Of 49 cats that underwent (90)Sr plesiotherapy (median dose, 128 Gy), 48 (98%) had a response to treatment and 43 (88%) had a complete response. Median progression-free and overall survival times were 1,710 and 3,076 days, respectively. Treatment complications were infrequent (4 [8%] cats) and mild. Following treatment, the SCC recurrence rate was 20% (10/49 cats); 16 (33%) cats developed new lesions in other locations. Overall survival time was significantly longer for cats with a complete response to treatment than for those with a partial response. None of the other variables evaluated had a significant effect on progression-free or overall survival time. CONCLUSIONS AND CLINICAL RELEVANCE: Treatment of cats with SCC of the nasal planum with a single fraction of (90)Sr appeared to be effective and well tolerated. Initial response to treatment was predictive of overall survival time.     

Cutaneous neoplasia in 340 cats.

A total of 340 cases of cutaneous neoplasia were diagnosed in 340 of 3,564 cats that were examined by biopsy or necropsy during a 41-month period from January 1, 1986 through May 31, 1989. Eighteen types of tumor occurred, but four types comprised 77% of the cases. These were basal cell tumor, 89 cases (26%, mean age 10.3); mast cell tumor, 72 cases (21%, mean age 8.6); squamous cell carcinoma, 52 cases (15%, mean age 11.6); and fibrosarcoma, 50 cases (15%, mean age 10.2). For each of these four types of tumors, peak number of cases occurred in cats older than 10 years. Mast cell tumor was the only tumor diagnosed in cats younger than 1 year. The head was the most common site for basal cell tumors, mast cell tumors, and squamous cell carcinomas. The legs were the most common location of fibrosarcomas. Siamese cats had approximately three times as many mast cell tumors as statistically expected, but only one-fourth as many squamous cell carcinomas. Breed predilection for other skin tumors was not apparent. Sex predilection was not detected for any skin tumor.     

PROTON IRRADIATION OF FELINE NASAL PLANUM SQUAMOUS CELL CARCINOMAS USING AN ACCELERATED PROTOCOL

Fifteen cats were treated for squamous cell carcinoma of the nasal planum using proton beam radiation. The protocol used was accelerated with eight equal fractions given on four consecutive days, with a minimum of six hours between fractions. Total dose of radiation delivered was escalated with nine cats receiving 40.4 CGE (60Co Gy equivalent), and three cats each receiving 42.4 and 44.8 CGE. Complete response to the protocol was 60% (9/15), partial response was 33% (5 of 15), and no response was seen in 6.6% (1 of 15). Tumor control rate at one year was 64% and no cat had tumor recurrence after one year. Median survival was 946 days (+/- 516 days). Side effects were minimal with no severe reactions noted in the early or late period. This protocol offers an effective treatment for squamous cell carcinoma of the feline nasal planum with minimal side effects and may be adaptable to conventional radiation sources particularly when the field size is very small.     

Hypercalcemia in two cats with squamous cell carcinomas

Hypercalcemia was identified in 2 cats with squamous cell carcinomas. One cat was referred because of multiple cutaneous tumors; the second cat had metastatic disease from an oral squamous cell carcinoma. In both cats, serum immunoreactive midmolecule parathyroid hormone concentration was within the range determined for clinically normal cats. The high serum calcium concentration in these cats may have resulted from the neoplastic disease, as evidenced by the reduction in serum calcium concentration after decrease in tumor size in response to treatment, and by failure to identify other known causes of hypercalcemia.     

Immunohistochemical analysis of cyclin A, cyclin D1 and P53 in mammary tumors, squamous cell carcinomas and basal cell tumors of dogs and cats

The involvement of cyclin A, cyclin D1 and p53 proteins in canine and feline tumorigenesis was analyzed immunohistochemically. In the present study, a total of 176 cases were examined, among which there were 108 canine cases (75 mammary lesions, 16 squamous cell carcinomas and 17 basal cell tumors) and 68 feline cases (43 mammary lesions, 20 squamous cell carcinomas and 5 basal cell tumors). Speckled nuclear staining for cyclin A was observed in 19/38 (50%) canine malignant mammary tumors and 18/37 (48.6%) feline mammary carcinomas, while this was not seen in benign mammary tumors of either dogs or cats. Marked intense nuclear cyclin A staining was seen in 7/16 (43.8%) canine squamous cell carcinomas and 18/20 (90.0%) feline squamous cell carcinomas. Only 3/17 (17.6%) canine basal cell tumors showed slight and scattered staining for cyclin A. Expression of cyclin D1 was very rare in both canine and feline tumors. Nuclear staining of p53 was found in 7/37 (18.9%) feline mammary carcinomas. Intense immunoreactivity for p53 was found in 6/16 (37.5%) canine squamous cell carcinomas and 8/20 (40%) feline squamous cell carcinomas. These results suggest that cyclin A may have a role in the proliferation of canine malignant mammary tumors, feline mammary carcinomas and squamous cell carcinomas of dogs and cats, and p53 may associate with the tumorigenesis of feline mammary carcinomas and squamous cell carcinomas of dogs and cats.     

CONCOMITANT LIPOSOMAL DOXORUBICIN AND DAILY PALLIATIVE RADIOTHERAPY IN ADVANCED FELINE SOFT TISSUE SARCOMAS

Local recurrence of feline soft tissue sarcomas is common despite aggressive treatment. Liposomal doxorubicin might serve as a depot radiosensitizer if administered concomitantly with daily radiotherapy and thus improve tumor control. In this pilot study, the feasibility of concomitant liposomal radiochemotherapy was evaluated in a palliative setting in 10 cats with advanced soft tissue sarcomas. Cats were treated with median number of 5 (range 5–7) daily fractions of radiotherapy and a median total dose of 20 Gy (range 20–31.5 Gy). One dose of liposomal doxorubicin was administered at the beginning of radiotherapy. Seven cats received further free or liposomal doxorubicin after completion of the liposomal doxorubicin/radiation protocol. Seven of the treated 10 cats (70%) achieved a partial (n=5) or complete (n=2) response with a median response duration of 237 days. The median progression free interval in all 10 cats was 117 days and the median overall survival time was 324 days. Concomitant liposomal radiochemotherapy was tolerated well in nine cats, one cat experienced temporary anorexia. Although the number of patients is too small to make definitive conclusions, results appear promising enough to investigate the role of liposomal doxorubicin as a radiosensitizer further.     

Preclinical study in cats of the pro-photosensitizer 5-aminolevulinic acid

OBJECTIVE: To determine whether feline cells were able to convert 5-aminolevulinic acid (ALA) to protoporphyrin IX (PpIX) in vivo and in vitro, whether i.v. administration of ALA to healthy cats resulted in adverse effects, and whether PpIX accumulated in a squamous cell carcinoma (SCC) of a cat. ANIMALS: 4 healthy adult cats and 1 adult cat with a cutaneous SCC. PROCEDURE: In vitro production of PpIX was determined by incubating Crandell feline kidney cells with ALA. Effects of ALA administration and in vivo production of PpIX were determined by administering ALA (100, 200, or 400 mg/kg of body weight) to healthy cats and collecting skin biopsy specimens for up to 24 hours after drug administration. Blood samples were collected for CBC and serum biochemical analyses, and necropsies were performed. Accumulation of PpIX in a SCC was determined by treating a cat with a facial SCC with ALA and collecting specimens of the tumor and adjacent grossly normal skin. RESULTS: Incubation of ALA with feline cells resulted in time- and dose-dependent cytoplasmic accumulation of PpIX in vitro. After i.v. ALA administration, PpIX was detected in all tissues examined, with the highest fluorescence intensity in epithelia and in squamous cell carcinoma. The tumor-to-skin fluorescence intensity ratio was 5. All cats developed hepatotoxicoses. CONCLUSIONS AND CLINICAL RELEVANCE: Results from this limited number of cats suggest that ALA may be a useful photosensitizer in cats, but that doses > 100 mg/kg, i.v., may not be safe.     

RADIOGRAPHIC APPEARANCE OF PRIMARY LUNG TUMORS IN CATS

The radiographic findings in 41 feline primary lung tumors are reported. Case material includes 29 adenocarcinomas, six bronchiolog-alveolar carcinomas, and six squamous cell carcinomas. Adenocarcinomas tended to occur as focal, solitary, well-circumscribed masses (eight cats), as localized consolidations (six cats), or as multiple, poorly circumscribed masses (five cats). Bronchiolo-alveolar cell carcinomas and squamous cell carcinomas were radiographically pleomorphic. Calcification was recognized in only five cats, four with adenocarcinomas and one with bronchiolo-alveolar carcinoma. Cavitation was identified in seven adenocarcinomas, one squamous cell carcinoma, and one bronchiolo-alveolar carcinoma. Nearly 50% (20 cats) of the patients had radiographic evidence of pleural involvement. Fifteen cats had evidence of regional lymph node involvement.     

Photodynamic therapy of feline superficial squamous cell carcinoma using topical 5-aminolaevulinic acid

A study was undertaken to investigate the treatment of superficial squamous cell carcinoma of the nasal planum, pinna and eyelid in cats by photodynamic therapy, using topical 5-aminolaevulinic acid cream, with subsequent exposure to red light of wavelength 635 nm, supplied by a light-emitting diode source. A total of 13 squamous cell carcinomas were treated, including 10 nasal planum lesions, two pinnal lesions and one eyelid lesion. After a single treatment, complete responses were seen in nine out of 10 nasal planum lesions, one out of two pinnal lesions and the eyelid lesion. The overall complete response rate for lesions managed with a single photodynamic therapy treatment was 85 per cent. Seven of the 11 lesions (63.6 per cent) showing a complete response subsequently recurred; the time to recurrence ranged from 19 to 56 weeks (median 21 weeks, mean 26.7 weeks).     

Primary and metastatic carcinomas in the digits of cats

In the period 1993-1998, digital carcinomas in 64 cats were examined. In all animals primary complaints were painful digit(s). Eight cats had a primary squamous cell carcinoma which involved one digit or two adjacent digits of one leg. Fifty-six cats had metastases of a pulmonary carcinoma in the digits, and in general multiple digits of different legs were involved. In many of these cats metastases also occurred in other organs, including the skin and muscles. No primary sweat gland carcinomas of the digits were seen. Primary squamous cell carcinomas of the digits were characterized by cornification and the absence of PAS-positive cells, PAS-positive secretory material. Immunohistochemically, these neoplasms stained negative with the monoclonal antibody CAM 5.2 directed against Keratin 8 (K 8). The metastases of pulmonary carcinomas to the digits showed one or more of the following histological features: goblet cells, ciliated epithelial cells, PAS-positive cells or lakes, and/or a PAS-positive lining of luminal membranes and no cornification. Immunohistochemically, they showed positive staining for CAM 5.2 (K8). Thoracic radiographs from three cats with a primary squamous cell carcinoma showed no abnormalities, whereas all cases of metastases from a pulmonary carcinoma to the digits available for follow-up showed evidence of a primary pulmonary carcinoma on radiography and/or postmortem examination (25 out of 56). The conclusion of this study was that most carcinomas in the digits of cats were metastases of a primary pulmonary carcinoma (87.5%). Primary squamous cell carcinomas occurred infrequently. The prognosis of metastases of a pulmonary carcinoma in the digits is poor with an average survival time of 4.9 weeks, in contrast to 29.5 weeks in cats with a squamous cell carcinoma. These data stress the importance of taking thoracic radiographs of cats with digital tumours before surgical intervention.     

Photodynamic therapy for the treatment of intranasal tumors in 3 dogs and 1 cat

Three dogs and 1 cat with intranasal tumors were treated with pyropheophorbide-a-hexyl ether-based photodynamic therapy (PDT). PDT was well tolerated by all the animals, and no adverse effects from photosensitizer injection, such as cutaneous photosensitization, were observed. Facial swelling was observed in all animals after each PDT treatment but resolved spontaneously within 72 hours after treatment. All animals had a decrease in severity of epistaxis, frequency of sneezing, and amount of nasal discharge after PDT. Clinical signs were controlled for variable time, although long-term responses were comparable with radiation therapy in 2 animals. This small case series demonstrates another application for PDT in veterinary medicine. On the basis of these findings. further studies are warranted to define the role of PDT in the management of intranasal tumors in dogs and cats.     

Reirradiation of tumors in cats and dogs

Fifty-one cats and dogs with tumor recurrence after irradiation were treated with a second course of radiotherapy, using either teletherapy or brachytherapy. Eighty-six percent of the tumors had partial or complete response at 2 months after reirradiation. Tumor response was significantly (P = 0.041) affected when the interval between the 2 courses of irradiation was greater than 5 months. The estimated local tumor control rate was 38% at 1 year after reirradiation. Of all the factors examined, complete response at 2 months, reirradiation field size less than or equal to 10 cm2, and reirradiation dose greater than 40 gray emerged as predictors of local tumor control. The estimated overall survival rate was 47% at 2 years. Tumor location had a significant (P = 0.001) influence on overall survival; animals with cutaneous tumors had the longest survival times, and those with oral tumors had the shortest survival times. The other significant (P = 0.001) factor affecting overall survival time was the field size of the reirradiated site. Estimated survival time after reirradiation was 41% at 1 year. Favorable prognostic indicators were complete response at 2 months and location of tumor; animals with skin tumors had a favorable prognosis. The acute effects of reirradiation on normal tissues were acceptable, but 12% of the animals had severe delayed complications. Significant risk of complications after reirradiation was associated with squamous cell carcinoma (P = 0.015) and reirradiated field size greater than 30 cm2 (P = 0.056). When the interval between irradiations was greater than 5 months, the risk of complications was significantly (P = 0.022) lower.(ABSTRACT TRUNCATED AT 250 WORDS)     

Fluorescence detection of a new photosensitizer, PAD-S31, in tumour tissues and its use as a photodynamic treatment for skin tumours in dogs and a cat: a preliminary report

We describe here the detection by fluorescence of a new photosensitizer, PAD-S31, in tumours in dogs and cats and the effect of photodynamic therapy (PDT) by using PAD-S31 for skin tumours in two dogs and one cat. PAD-S31 is a hydrophilic photosensitizer that has two peaks at absorption wavelengths 406 and 665 nm in distilled water. In a preliminary experiment in mice transplanted with SCCVII and colon 26, PAD-S31 was retained in tumour tissues rather than in other organs. The tumours resected from dogs and cats after intravenous administration of PAD-S31 at a dose of 15 mg/kg emitted strong red fluorescence under light illumination of 402 nm wavelength. Animals given PAD-S31 showed no cutaneous photosensitivity under room light illumination. Irradiation at laser light 670 nm wavelength (fluence rate 150 mW/cm2 and total light dosage 150 J/cm2) on cutaneous mast cell tumours in dogs ( n=2 ) and a cutaneous basal cell tumour in a cat induced complete remission. These results suggest PAD-S31 could be a promising photosensitizer for use in a small animal veterinary practice.     

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.     

A Candidate Second‐Generation Photosensitizer for Photodynamic Therapy in Veterinary Medicine

Introduction:  Photodynamic therapy (PDT) involves the light activation of a drug within a tumor causing selective tumor cell death. Unfortunately, some photosensitizing drugs have been associated with adverse reactions in veterinary patients. Zinc phthalocyanine tetrasulfonate (ZnPcS4) is a promising second‐generation photosensitizer for use in veterinary medicine, however, it cannot be applied clinically until safety and efficacy data are available.
Methods:  Increasing intraperitoneal doses of ZnPcS4 were given to Swiss Webster mice to assess acute toxicity. Based on mouse toxicity data, a phase I clinical trial of ZnPcS4‐based PDT in tumor‐bearing dogs was designed, using an accelerated titration scheme starting at 0.5% of the minimum toxic dose in mice. 24‐hours after ZnPcS4 administration tumors were irradiated with 675 nm light and dogs were evaluated by routine hematology and serum biochemistry at regular intervals after PDT.
Results:  Doses >125 mg/kg were associated with acute toxicity and mortality in Swiss Webster mice, suggesting the minimum toxic dose is 120–125 mg/kg. One dog, a Golden retriever with a massive malignant fibrous histiocytoma, has been entered into the phase I clinical trial. No deleterious effects were noted after ZnPcS4 administration. Within 48 hours of PDT, the tumor was dark and necrotic, with no grossly visible changes to the surrounding normal tissues. Histological examination of the PDT‐treated tumor confirmed widespread necrosis and thrombosis consistent with PDT‐mediated damage. The owner reported no adverse effects after treatment.
Conclusions:  Although preliminary data are encouraging, additional evaluation of ZnPcS4‐based PDT is required to determine its role in veterinary medicine.     

Tolerability of Gemcitabine and Carboplatin Doublet Therapy in Cats with Carcinomas

Background: This study was performed to determine the toxicity of gemcitabine-carboplatin doublet therapy in cats with carcinomas.
Hypothesis: Gemcitabine and carboplatin are safe in tumor-bearing cats.
Animals: Twenty cats with spontaneously occurring carcinomas.
Methods: A cohort of 6 cats received gemcitabine (2 mg/kg IV) on days 1, 8, and 15 and carboplatin (10 mg/kg IV) immediately after gemcitabine on day 1 of a 21-day cycle. A 2nd cohort of 14 cats received carboplatin 4 hours after gemcitabine on day 1 and gemcitabine on day 8 but not day 15. The cycles were repeated every 21 days.
Results: Cats in the 1st cohort received a median of 3.75 cycles per animal (range, 1–6). Two cats (33.3%) developed grade 3 or 4 neutropenia, 1 (16.7%) grade 4 thrombocytopenia, and 1 (16.7%) grade 3 gastrointestinal toxicity. Gemcitabine dose reductions and treatment delays occurred in 1 and 4 cats, respectively. Cats in the 2nd cohort received a median of 2 cycles per animal (range, 0.5–10). Two cats (14.3%) had grade 3 or 4 neutropenia and 1 (7.1%) had grade 3 and 4 gastrointestinal toxicity. One cat required gemcitabine dose reduction and 6 had treatment delays. In the 2nd cohort, of 11 cats with measurable tumors, there was 1 complete response (pancreatic carcinoma) and 1 partial response (squamous cell carcinoma, receiving concurrent nonsteroidal anti-inflammatory drugs).
Conclusions and Clinical Importance: Gemcitabine-carboplatin combination appears moderately well tolerated in tumor-bearing cats. Minimal patient benefit suggests that alternative schedules or combinations of gemcitabine with other agents should be explored.     

RESPONSE OF FELINE ORAL SQUAMOUS CELL CARCINOMA TO PALLIATIVE RADIATION THERAPY

Seven cats with advanced oral squamous cell carcinoma were treated with palliative radiotherapy. Megavoltage radiation in 8 Gray (Gy) fractions was delivered on days 0, 7, and 21 for a total dose of 24 Gy. Treatment field included the mandible, oropharynx, retropharyngeal lymph nodes, and tonsils. Adjuvant treatment with chemotherapy was variable. Age ranged from 13 to 18 years old with a median age of 15 years. Three of the seven cats (43%) did not complete treatment. Six cats were euthanized due to tumor growth and/or radiation side effects with a median survival time of 60 days (range = 42 to 97 days, mean = 63 +/- 8.4 days). Radiotherapy complications or progression of disease occurred in 6 of 7 (85.7 %) cats and included adverse clinical signs, such as mucositis, serosanguinous oral discharge, pain, and dysphagia. These data suggest that coarse fractionation radiotherapy did not result in palliation in cats with inoperable oral squamous cell carcinoma.