Toxicity and outcome in cats with oral squamous cell carcinoma after accelerated hypofractionated radiotherapy and concurrent systemic treatment

Recently, a multimodal approach to oral squamous cell carcinoma (SCC) in cats, combining medical treatment and accelerated radiation therapy, showed a substantial outcome improvement in a small pilot study. Herein we retrospectively review 51 cats with unresectable, histologically confirmed oral SCC and a complete initial staging work‐up: cats in group A (n = 24) received medical anti‐angiogenic treatment consisting of bleomycin, piroxicam and thalidomide, cats in group B (n = 27) received the anti‐angiogenic treatment and concurrent accelerated hypofractionated radiation therapy with 48Gy delivered in 10 fractions. Overall median progression‐free interval (PFI) was poor with 70 days (95% CI: 48;93). In the irradiated cats (group B), however, PFI was significantly longer with 179 days (95% CI: 58;301) days, vs 30 days (95% CI: 23;38) in medically only treated cats (P < .001). Overall median overall survival (OS) was 89 days (95% CI: 55;124), again significantly longer in the irradiated cats (group B) with 136 (95% CI: 40;233) vs 38 days (95% CI: 23;54) (P < .001). In 8 of the 27 (29.6%) cats in group B, however, severe toxicity (grade 3) occurred. Neither onset nor severity of toxicity could be associated with any of the tested variables, including anatomic site, tumour size, clinical stage and duration of neoadjuvant medical treatment. Given the potential severe acute effects and the impact on quality of life after chemo‐radiotherapy, owners must be clearly informed about the risks of treatment. With the overall poor outcome and high occurrence of acute toxicity, we cannot recommend the use of this accelerated radiation protocol combined with anti‐angiogenic therapy for oral SCC in cats.     

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.     

Phase I clinical evaluation of carboplatin in tumor-bearing cats: a Veterinary Cooperative Oncology Group study

BACKGROUND: The dosage of carboplatin in cats has been reported anecdotally and experimentally in non-tumor-bearing cats, but the dosage for carboplatin treatment in tumor-bearing cats has yet to be defined in a prospective clinical trial. PURPOSE: To determine the maximally tolerated dose (MTD) and dose-limiting toxicosis (DLT) of carboplatin in tumor-bearing cats. CATS: Fifty-nine cats with measurable solid tumors. METHODS: The starting dose of carboplatin was 160 mg/m(2) of body surface area IV. Doses were increased by 20 mg/m(2) in cohorts of 3-14 cats until the MTD was reached. RESULTS: The 59 cats entered into this multi-institutional phase I study received 1 or more doses of carboplatin at various dosages and were evaluated for toxicity, response to treatment, or both. The MTD was 240 mg/m(2) and neutropenia was the DLT. For the 1st cycle of treatment in 44 cats evaluated for neutropenia, 6 episodes of grade 3 or greater neutropenia occurred on days 7 (n=1), 14 (n=4), and 21 (n=1). There was no evidence of drug-induced nephrotoxicosis or pulmonary edema. Preliminary evidence of antitumor activity was observed in 7 of 59 (11.9%; 95% CI, 5.6-22.8%) cats evaluated for response to treatment. There was 1 complete response (cutaneous hemangiosarcoma) and 6 partial responses (4 injection site sarcomas, 1 oral squamous cell carcinoma, 1 lymphoma). Responses were of short duration (median, 42 days; range, 7-168 days). CONCLUSIONS AND CLINICAL IMPORTANCE: The dose of carboplatin recommended to treat tumor-bearing cats is 240 mg/m(2) IV every 3-4 weeks.     

Hypofractionated radiation therapy for the treatment of malignant melanoma and squamous cell carcinoma in dogs and cats

This study describes the experience with hypofractionated radiation therapy of squamous cell carcinoma and melanoma in dogs and cats. A total dose of 32-48 Gray (Gy) was delivered once a week in 8 Gy fractions. 34 animals in which a complete surgical excision was impossible were treated. There was no tumor detectable macroscopically in 14 patients at the beginning of radiation therapy. In 20 animals the median volume of the tumor was 9.9 cm3. The median survival times and the local tumor control of squamous cell carcinoma of the oral and nasal cavities and of the body are comparable to results which were reached with a Monday-Wednesday-Friday scheme. For the treatment of Melanoma the hypofractionated radiation therapy is first choice. There are no significant side effects. Late side effects did not occur. 88% of the owners are satisfied with this kind of treatment and would choose it again.     

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.     

Survival of 54 cats with oral squamous cell carcinoma in United Kingdom general practice

OBJECTIVES: To determine the survival of 54 cats with histologically confirmed feline oral squamous cell carcinoma (FOSCC) treated in UK general practice and to determine factors predictive for survival. METHODS: Cases were identified from consecutive samples submitted for histological diagnosis. Observational and survival data were collated retrospectively from submitting practices. Immunohistochemical analysis of cyclooxygenase (COX) expression variables was available using previously published data. Kaplan-Meier product limit estimation for overall survival and Cox proportional hazards regression for potential explanatory variables were performed. RESULTS: The overall median survival time was 44 days [95 per cent confidence interval (CI): 31-79] and 1 year survival was 9.5 per cent. Variables associated with survival were whether the cat was pedigree [hazard ratio (HR)=8.17, 95 per cent CI: 1.96-34.12], whether the cat received non-steroidal anti-inflammatory drug (NSAID) therapy after diagnosis (HR=0.46, 95 per cent CI: 0.21-0.98) and whether the COX-1 staining distribution was patchy rather than diffuse (HR=0.25, 95 per cent CI: 0.08-0.014). CLINICAL SIGNIFICANCE: This study suggests that although the prognosis for inoperable FOSCC remains poor, palliative treatments may offer a survival advantage that compares favourably with more aggressive treatment methods. Further work is needed to evaluate NSAID therapy in this disease, in particular to determine whether the potential survival advantage is because of an analgesic or anticancer effect or both. COX-1 distribution patterns may have a role as a prognostic indicator in this disease.     

Evaluation of plasma folate and homocysteine concentrations in cats with and without oral squamous cell carcinoma

Feline oral squamous cell carcinoma (SCC) is a devastating disease with an extremely poor long‐term prognosis even with aggressive therapy. Folate and homocysteine derangements are identified in people diagnosed with head and neck SCC. The purpose of this study was to measure plasma folate and homocysteine concentrations in cats diagnosed with oral SCC (n = 13) and to compare these concentrations with those found in cats diagnosed with other tumour types (n = 25), cats with oral, non‐neoplastic disease (n = 6) and healthy cats (n = 24). The median plasma folate concentration in cats diagnosed with oral SCC was 14.7 ng mL^?1, while the median plasma homocysteine concentration was 2.61 μg mL^?1. These concentrations did not differ significantly from those of cats in the other groups. This suggests that different factors may contribute to the pathogenesis of this tumour in cats when compared with people, although evaluation of larger numbers of cats may still identify a difference between groups.     

Environmental and lifestyle risk factors for oral squamous cell carcinoma in domestic cats

Oral squamous cell carcinoma (SCC) is a common malignancy in cats, but little currently is known about its etiology. We examined the relationship between risk of oral SCC and factors such as environmental tobacco smoke, flea control products, and diet in 36 domestic cats with histologically confirmed oral SCC and 112 renal disease control cats presented to a large veterinary referral hospital between 1994 and 2000. Questionnaires were mailed to owners of all study and control cats to assess demographic characteristics, lifestyle factors, and level of chemical exposures 2 years before diagnosis. Multivariate relative risks (RR) were used to estimate the relationships between the various factors and the risk of oral SCC. Flea control product use and diet were significantly associated with risk of oral SCC. Cats that wore a flea collar had 5 times the risk of oral SCC as nonusers, after adjustment for other factors (RR = 5.3; P = .002). In contrast, use of flea shampoo substantially reduced risk. Compared to cats eating mostly dry food, those with high canned food intake had a 3-fold increase in risk (RR = 3.6; P = .014); canned tuna fish intake was independently associated with risk (RR = 4.7; P = .004). Exposure to household environmental tobacco smoke was associated with a nonsignificant 2-fold increase in risk (P = .11). Results of this study suggest that flea control products, diet, and perhaps environmental tobacco smoke might be associated with risk of oral SCC and indicate that further investigation into these relationships is warranted.     

Environmental risk factors for the development of oral squamous cell carcinoma in cats

BackgroundRisk factors for oral squamous cell carcinoma (OSCC) in cats are derived from a single study dated almost 20 years ago. The relationship between inflammation of oral tissues and OSCC is still unclear.ObjectivesTo investigate previously proposed and novel potential risk factors for OSCC development, including oral inflammatory diseases.AnimalsHundred cats with OSCC, 70 cats with chronic gingivostomatitis (CGS), 63 cats with periodontal disease (PD), and 500 controls.MethodsProspective, observational case‐control study. Cats with OSCC were compared with an age‐matched control sample of client‐owned cats and cats with CGS or PD. Owners of cats completed an anonymous questionnaire including demographic, environmental and lifestyle information.ResultsOn multivariable logistic regression, covariates significantly associated with an increased risk of OSCC were rural environment (OR: 1.77; 95% CI: 1.03‐3.04; P = .04), outdoor access (OR: 1.68; 95% CI: 1.07‐2.63; P = .02), environmental tobacco smoke (OR: 1.77; 95% CI: 1.05‐3; P = .03), and petfood containing chemical additives (OR: 1.98; 95% CI: 1.04‐3.76; P = .04). Risk factors shared with CGS and PD were outdoor access and petfood containing chemical additives, respectively. A history of oral inflammation was reported in 35% of cats with OSCC but did not emerge as a risk factor.Conclusions and Clinical ImportanceThe study proposes novel potential risk factors for OSCC in cats. Although a history of inflammatory oral disease was not significantly more frequent compared with random age‐matched controls, OSCC shared several risk factors with CGS and PD.     

Liposome-encapsulated doxorubicin (Doxil) and doxorubicin in the treatment of vaccine-associated sarcoma in cats

The purpose of this randomized, multicenter study was to evaluate the toxicity and efficacy of liposome-encapsulated doxorubicin (LED) and doxorubicin (DOX) in the treatment of feline vaccine-associated sarcoma (VAS). Cats were divided according to their disease status into a microscopic arm (no evidence of gross disease) and a macroscopic arm (evidence of gross disease). Each arm was randomized to receive either LED (1-1.5 mg/kg i.v. q3 weeks) or DOX (1 mg/kg i.v. q3 weeks). Thirty-three cats were entered in the macroscopic arm of the study with an overall response rate of 39% (5 complete response and 8 partial response) and a median time to progression of 84 days. Response rates were not different between LED and DOX. Seventy-five cats were entered into the microscopic arm. When compared to a similar historical control population treated with surgery alone, the cats receiving chemotherapy had a prolonged median disease-free interval (388 days versus 93 days). No difference in efficacy was detected between LED and DOX. LED at 1.5 mg/kg induced delayed nephrotoxicosis in 23%, necessitating a decrease in the recommended dosage to 1 mg/kg, and cutaneous toxicosis in 21.7% of treated cats. This study showed that both DOX and LED are efficacious in the treatment of VAS and should be considered in the treatment of this tumor.     

Treatment of canine oral papillary squamous cell carcinoma using definitive‐intent radiation as a monotherapy—a case series

Canine oral papillary squamous cell carcinoma (COPSCC) is a rare neoplasm and although locally invasive it carries a favourable prognosis following wide surgical excision. Radiotherapy has been reported to be effective as an adjunct treatment to surgery. However, limited information is available on the role of radiotherapy as single treatment. This single‐institution retrospective study describes a series of 10 dogs diagnosed with macroscopic COPSCC that were treated with definitive‐intent radiotherapy (DRT) as a monotherapy. These dogs had a median age of 4 years (range: 0.4‐9.6 years). The tumour was located in the rostral oral cavity in all cases with a median tumour size of 2.5 cm (range: 0.8‐6.8 cm). No local or distant metastases were identified. All dogs were treated with electron beam DRT (>32Gy, 10‐16 daily fractions of 3.2Gy). The median follow‐up time was 961 days (range: 333‐3.498 days) with nine dogs achieving a complete response and one dog a partial response. The dog with the partial response developed disease progression at 228 days after initiation of radiotherapy. Two dogs died from non‐tumour‐related causes. The remaining seven dogs were still alive and in complete remission at the time of last follow‐up. Median progression‐free survival time and median survival time were not reached. DRT was generally well tolerated, but all dogs experienced self‐limiting acute radiation mucositis (grade 2‐3) and/or dermatitis (grade 1). No late radiation toxicity was observed. Macroscopic COPSCC appears to be a radiosensitive tumour that can be successfully treated with DRT eliminating the need for aggressive surgery in advanced cases.     

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.     

Bone-invasive oral squamous cell carcinoma in cats: pathology and expression of parathyroid hormone-related protein

Feline oral squamous cell carcinoma (OSCC) is the most common oral tumor in cats. There is no effective treatment, and the average duration of survival after diagnosis is only 2 months. Feline OSCC is frequently associated with osteolysis; however, the mechanisms responsible are unknown. The objective of this study was to characterize the epidemiology and pathology of bone-invasive OSCC in cats and to determine the expression of select bone resorption agonists. In sum, 451 cases of feline OSCC were evaluated. There was no sex or breed predisposition, although there were more intact cats in the OSCC group compared to the control group. Gingiva was the most common site, followed by the sublingual region and tongue. Cats with lingual OSCC were younger (mean, 11.9 years) compared to cats with gingival OSCC (mean, 13.6 years). In addition to osteolysis, there was periosteal new bone formation, osseous metaplasia of tumor stroma, and direct apposition of OSCC to fragments of bone, suggestive of bone-binding behavior. Eighty-two cases were selected for immunohistochemical detection of parathyroid hormone-related protein (PTHrP). Specimens with osteolysis had increased PTHrP expression and nuclear localization, compared to OSCC without osteolysis. Thirty-eight biopsies of OSCC with osteolysis were evaluated for tumor necrosis factor α expression, and only 4 biopsies had such expression in a small proportion of tumor cells. Increased tumor expression of PTHrP and increased localization of PTHrP to the nucleus were associated with osteolysis and may play an important role in bone resorption and tumor invasion in cats with OSCC.     

Treatment of cats with feline infectious peritonitis

Feline infectious peritonitis (FIP) infection resulting in clinical signs is invariably fatal despite clinical intervention. As FIP is an immune-mediated disease, treatment is mainly aimed at controlling the immune response triggered by the infection with the feline coronavirus (FCoV). Immune suppressive drugs such as prednisone or cyclophosphamide may slow disease progression but do not produce a cure. In nearly every published case report of attempted therapy for clinical FIP, glucocorticoids have been used; there are, however, no controlled studies that evaluate the effect of glucocorticoids as a therapy for FIP. Some veterinarians prescribe immune modulators to treat cats with FIP with no documented controlled evidence of efficacy. It has been suggested that these agents may benefit infected animals by restoring compromised immune function, thereby allowing the patient to control viral burden and recover from clinical signs. However, a non-specific stimulation of the immune system may be contraindicated as clinical signs develop and progress as a result of an immune-mediated response to the mutated FCoV.     

In vivo and in vitro efficacy of zoledronate for treating oral squamous cell carcinoma in cats

BACKGROUND: Feline oral squamous cell carcinoma (OSCC) may cause painful bone destruction. Given the local invasiveness and rapid clinical progression of OSCC, conventional therapies are often palliative. In human cancer patients, zoledronate exerts anticancer effects by inhibiting tumor-induced angiogenesis and malignant osteolysis. HYPOTHESIS: Zoledronate will exert in vitro and in vivo anti-angiogenic and antiresorptive effects in feline OSCC. ANIMALS: Eight cats with OSCC were prospectively treated with zoledronate and conventional treatment modalities. METHODS: In vitro, zoledronate's effects in modulating soluble vascular endothelial growth factor (VEGF) secretion and receptor activator of nuclear factor kappaB (NF-kappaB) ligand (RANKL) expression were investigated in a feline OSCC cell line (SCCF1). In vivo, basal serum C-telopeptide (CTx) concentrations were compared among normal and OSCC-bearing cats, and the biologic effects of zoledronate administration in cats with naturally occurring OSCC were quantified by serially assessing circulating serum VEGF and CTx concentrations. RESULTS: In vitro, zoledronate concentrations greater than 3 microM reduce soluble VEGF secretion in the SCCF1 cell line. The expression of RANKL in the SCCF1 cell line was also modulated by zoledronate, with low concentrations (3 microM) decreasing but higher concentrations (30 microM) increasing RANKL expression in comparison with untreated cells. In vivo, cats with bone-invasive OSCC had greater serum CTx concentrations in comparison with geriatric, healthy controls. Treatment with zoledronate rapidly decreased circulating serum VEGF and CTx concentrations in cats with spontaneously occurring OSCC. CONCLUSIONS AND CLINICAL IMPORTANCE: Zoledronate exerts in vitro and in vivo effects that may favor the slowing of tumor growth and pathologic bone turnover associated with OSCC.     

Hypofractionated radiation therapy of oral melanoma in five cats

Five cats with melanoma involving the oral cavity were treated with hypofractionated radiation therapy (RT). Cobalt photons were used to administer three fractions of 8.0 Gray (Gy) for a total dose of 24 Gy. Four cats received radiation on days 0, 7, and 21 and one cat received radiation on days 0, 7, and 13. One of the cats received additional irradiation following the initial treatment course. Two cats received chemotherapy. Their age ranged from 11 to 15 years with a median age of 12 years. Three cats had a response to radiation, including one complete response and two partial responses. All five cats were euthanized due to progression of disease, with one cat having evidence of metastatic disease at the time of euthanasia. The median survival time for the five cats was 146 days (range 66-224 days) from the start of RT. The results of this study suggest that oral melanoma in cats may be responsive to hypofractionated RT, but response does not seem to be durable.     

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.