Introduction

Radiation therapy is a cancer treatment modality. Its main goal is the death of neoplastic cells sparing the healthy adjacent tissue (Hand et al. 2004). The squamous cell carcinoma (SCC) is the most common skin tumor in cats, and it is related to the ultraviolet light exposure and local climate. (Carpenter et al. 1987, Ruslander 1997, Moore & Ogilvie 2001) The nose, eyelids and ears, especially of white cats, are more commonly affected (Carpenter et al. 1987, Ruslander 1997, Moore & Ogilvie 2001). Several treatment modalities have been used in the treatment of SCC, which include surgery (Withrow & Straw 1990, Lana et al. 1997, Berg 1998, Schmidt et al. 2005), cryotherapy (Clarke 1991, Lucas & Larrsson 2006), systemic (Thompson 2005, Kisseberth et al. 2008) and intralesional chemotherapy (Theon et al. 1996), hyperthermia (Panjehpour et al. 1991), photodynamic therapy (Frimberger et al. 1998, Emilio & Dagli 2006), radiation therapy (Theon et al. 1995, Fidel et al. 2001, Melzer et al. 2006) and plesiotherapy (Goodfellow et al. 2006), with different results. Radiation therapy is applied in multiple treatments, called fractions, which is an important issue for a better tumor control and minimization of side effects (Carpenter et al 1987, Theon et al. 1994, Moore & Ogilvie 2001). Different radiation protocols have been tested for cutaneous SCC´s, including a Monday-Wednesday-Friday schedule (Cox 1991, Theon et al. 1995), hypofractionated (Carlisle & Gold 1982, Kinzel et al. 2003) and accelerated protocols (Fidel et al. 2001, Melzer et al. 2006). A hypofractionated protocol seems interesting due to lower financial costs and fewer anesthesia procedures needed. The aim of this study was to determine the effectiveness of a hypofractioned radiation protocol in cats with cutaneous facial SCC´s.

Materials and Methods

Nine cats with single or multiple facial SCC´s were treated from August 2006 to April 2008, in a total of 14 lesions. All tumors were diagnosed as squamous cell carcinomas by histopathology. Tumor volume was calculated using a simple cuboidal model of length x width x height in superficial lesions. Each cat was evaluated with routine blood analysis (including blood work, BUN and creatinine) and thoracic radiographs. Staging was done according to the WHO TNM classification for feline tumors of epidermal origin (Owen 1980). When regional metastasis was suspected, a fine needle aspiration of mandibular lymph nodes was made. In this study, only lesions staged as T1, T2 or T3 were included. Treatments were done on Saturdays in the Hospital Universitário Clementino Fraga Filho of the Universidade Federal do Rio de Janeiro (UFRJ), at the Radiation Therapy unit. The equipment used was a linear accelerator Clinac 2100 delivering electrons beam with the energy of 4 or 6 MeV. The lesions were divided into two groups. The first group, with five SCC´s lesions, received four radiation fractions of 7.6 gy each, with one week interval, whereas the second group, with nine neoplastic lesions, received four radiation fractions of 10 grays each, also with one week interval. The planned target volume was determined previously to the treatment with a felt pen. In all cats, a bolus (5-10 mm) was used on the tumor to allow radiation dose to be deposited superficially in the skin. The drugs used for anesthesia were acepromazine maleate (0,03 mg/kg IM), meperidine HCl (3 mg/kg IM), ketamine HCl (2-4 mg/kg IV) and diazepam (0.2 mg/kg IV). Response was graded as complete response (CR) when the tumor completely regressed, partial (PR) when there was a 50% or more reduction in the tumor size, and none (NR) when less than 50% reduction in tumor size or tumor progressed. The SCC´s were observed and photographed weekly during the treatment, and 30 and 60 days after its end. After this period, follow up information was gathered through examinations, phone conversations and photos sent by clients. Acute and late effects were classified according to VRTOG (Ladue & Klein 2001). Progression free interval was calculated from the last radiation treatment to the first detection of tumor return. Survival time was calculated from the beginning of therapy to the day of death (euthanasia). The median survival and progression free interval were calculated by the Kaplan-Meier survival function. This clinical research was in accordance with the principles of COBEA (Colégio Brasileiro de Experimentação Animal).

Results

All cats were totally or partially white, and had frequent sun exposure. The most commonly affected site was the pinna (6/14), followed by eyelid (4/14), nasal planum (3/14) and tempora (1/14). Seven lesions were staged as T1, two staged as T2 and five staged as T3. No cat had evidence of regional or distant metastasis at initial presentation. Eight cats were female and only one male, and the mean age was 10,6 years (range 7-16 years). Six lesions (6/14) had been submitted to previous treatment, including surgery (3/6) and fused silver nitrate stick (3/6). Three cats (3/9) were tested for Leukemia Virus Infection and Feline Immunodeficiency Virus Infection (FeLV/FIV). One cat tested positive for FeLV and other two tested positive for FIV. In the total of 14 lesions irradiated, 8 (57%) were considered as CR, 1 (7%) as PR and 5 (35%) as NR. The cats with no response to the radiation treatment were euthanized due to owner's choices. One lesion had local recurrence 36 days after the treatment, and the cat was euthanized. Seven lesions are still in complete remission. Acute reactions occurred in 10 (71%) lesions and were considered mild/moderate, according to VRTOG (Veterinary Radiation Therapy Oncology Group), including alopecia, conjunctivitis, skin erythema and ulceration. Only one acute reaction of conjunctivitis required treatment with topical non-steroidal anti-inflammatory medication and Elizabethan collar. Lesion ulceration occurred only in the cats tested positive for FIV and was evident two weeks after treatment beginning. All acute reactions were reversible. Late reactions were not observed in the surviving cats. The overall mean survival time was 235 days and the median survival time was 205 days. Mean survival time for cats with a complete response was 322 days and 188 days for those with partial and none response. The mean progression free interval was 266 days.

Discussion

Radiation therapy plays an important role in cancer treatment, but its high cost and unavailability of the equipment needed makes it unreachable in many countries. The fractionation of radiation treatment is important for several reasons. The presence of cells in various stages of the cell cycle (M, S, G1, G2, G0) is a major factor in the response to radiation (Larue & Gillette 2007), as cells in S phase are more resistant, and those in phases G1 and G2 are more sensitive to the effects of radiotherapy. During the interval between fractions, cells in S phase enter the cell cycle and progress to the responsive stages, in a process known as redistribution (Moore & Ogilvie 2001, Larue & Gillette 2007). Moreover, fractionation allows the neighboring healthy tissue cells repair the damage caused by radiation (Hand et al. 2004, Larue & Gillette 2007). The radiotherapy protocols that are known to be effective in the treatment of SCC´s require constant, even daily treatments with small doses of radiation. Different protocols, energy and dose depth were used in previous publications. Some authors used protocols that the animals were submitted to radiation treatment three to five times a week, with cure rates estimated at 50 to 60%, using orthovoltage or megavoltage (Cox et al. 1991, Theon et al 1995). Hypofractionation protocols were also used, the first applied 20 gy monthly in 62 cats, and other applied 8 Gy once a week in 34 cats, at a total dose that ranged from 32 to 48 Gy (Carlisle & Gold 1982, Kinzel et al 2003). Fidel (2001) used an accelerated protocol of protons in 15 cats, with great results. More recently, an electron accelerated protocol was used in 17 cats with SCC, with excellent results (Melzer et al. 2006). Our response rate (64%) can be comparable to some other papers. According to the literature, the acute reactions in the skin are erythema, dry or moist desquamation and epilation (Carpenter et al 1987, Moore & Ogilvie 2001, Colleen & Mayer 2006). The maximum tissue damage occurs 7 to 14 days after treatment. The late reactions can occur months or years after radiotherapy, and include depigmentation, irreversible alopecia, fibrosis, necrosis, fistulas formation, chronic conjunctivitis, keratoconjunctivitis sicca and cataracts (Carpenter et al 1987, Moore & Ogilvie 2001, Colleen & Mayer 2006). In this study, the side effects observed were considered mild/moderate according to VRTOG and included erythema, epilation, ulceration and conjunctivitis, which were easily resolved with supportive treatment. There were no late reactions to treatment until this date, but it is still possible that they will occur in the next months or years. Cats with SCC in this study were totally or partially white, with frequent sun exposure and median age of 10,6 years, in accordance with previous publications (Cox et al. 1991, Lana et al. 1997). Main facial sites were the pinnae, followed by eyelids, nasal planum and temples, and differed from other papers, although this information cannot be considered here due to the low number of studied cats.

Conclusion

The hypofractionated radiation protocol presented in this study was well tolerated by the cats, and lead to a complete remission of 57% and partial remission of 7%, in a response rate of 64%. However, further investigation is needed to determine the efficacy of this protocol. Modifications of this protocol are being planned with the objective of improving the cure rates in the future.

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