Criteria for Selection of Cases

The electronic medical record system of the Veterinary Medical Teaching Hospital at the University of California, Davis, was searched for cats for which a diagnosis of SCC of the nasal planum had been made between January 1990 and March 2006. The medical records were then reviewed. Cats were included in the study if SCC or SCC in situ (wherein the tumor did or did not penetrate the epidermal basement membrane, respectively) had been histologically confirmed, initial treatment consisted of 1 fraction of 90Sr radiotherapy, and adequate follow-up information was available. Cats that had received previous treatment for SCC, other than prednisone or antimicrobials, were excluded.

Procedures

Information collected included signalment, pigmentation or color of affected skin area, lesion location, results of histologic examination of biopsy specimens, presence of lesions in other locations, environment (ie, primarily outdoor vs indoor cat), FeLV and FIV infection status, radiotherapy details (number of probe applications and calculated surface dose), concurrent treatment, radiotherapy-related response and complications, interval from treatment to SCC recurrence at the treated site, interval from treatment to development of new lesions, interval from treatment to death of the cat, and cause of death. Information regarding treatment of recurrent lesions was also collected when possible. When follow-up information was not available in the medical record, owners or referring veterinarians were contacted by telephone.

Pretreatment evaluation was performed according to clinician preference but generally consisted of a CBC, serum biochemical analyses, and thoracic radiography. All cats were anesthetized in a designated and sign-posted room. Anesthetic protocols varied, but anesthesia was induced in most cats by use of thiopental or propofol; cats were then intubated, and anesthesia was maintained by use of isoflurane. All treatments were administered or supervised by a radiation oncologist. Treatment consisted of a single high-dose fraction of 1 or multiple overlapping site applications of a ⁹⁰Sr ophthalmic applicator that had a 0.87-cm² active area. Sufficient applications were given to treat the entire lesion. Doses were prescribed at the discretion of the attending clinician (range, 97 to 195 Gy). The dose rate was 83 to 57 cGy/s, depending on the year in which the cats were treated. Each cat was positioned with foam wedges and sandbags. The 90Sr probe was placed in a holding device, applied to the surface of the lesion, and left in place for the time required to deliver the dose. For lesions requiring > 1 probe application, the probe circumference was marked and adjacent fields overlapped by 2 mm. In keeping with the concepts that maximizing distance from the radioactive source, providing adequate shielding between the radiation source and attendant staff, and minimizing overall exposure time to the radioactive source help to minimize exposure of personnel to radiation, cats were monitored during treatment through a window or via a closed-circuit camera from outside the room.

The Kaplan-Meier product-limit method was used to estimate progression-free survival and overall survival times. Overall survival was calculated from the date of ⁹⁰Sr treatment to the date of death or last follow-up. For calculation of overall survival, cats were censored if they were alive or if they had died of disease unrelated to SCC. Progression-free survival was calculated from the date of ⁹⁰Sr treatment until the recorded date of SCC recurrence. The development of any lesion within the treatment field was considered a recurrence event. For the calculation of progression-free survival, cats were censored if free of SCC at the time of death. Cats were considered to have had recurrence of SCC and were not censored for statistical analysis if lost to follow-up. Time to the development of new lesions was calculated from the date of initial ⁹⁰Sr treatment until the recorded date of new lesions. A complete response was defined as no visible lesions 8 weeks following treatment. Cats that had improvement, but not complete resolution of their lesions were considered to have had a partial response. Variables assessed for effects on progression-free and overall survival times included FeLV and FIV infection status, a diagnosis of SCC vs SCC in situ, number of probe applications, complications following treatment, treatment against clinician advice, response (complete vs partial), and dose of ⁹⁰Sr. The log-rank test was used to evaluate prognostic factors for relationships between categorical variables and progression-free and overall survival times. Cox regression analysis was used to evaluate the effect of dose on progression-free survival and overall survival times. All statistical analyses were performed by use of a commercially available statistics program.^a Results of statistical tests were considered significant at a value of P < 0.05.

Results

One hundred eleven cats that received treatment of a suspected SCC of the nasal planum with ⁹⁰Sr were identified from medical records. Thirty cats were excluded because they had received other treatment prior to 90Sr radiotherapy. Twenty-nine were excluded because of a lack of a histologic diagnosis of SCC. Follow-up information for 3 cats was considered inadequate because they were not reexamined after the 2-week posttreatment evaluation.

For the 49 cats that met the inclusion criteria, the histologic diagnosis was SCC (ie, evidence that the tumor penetrated the epidermal basement membrane) in 35 cats and SCC in situ (ie, evidence that the tumor did not penetrate the epidermal basement membrane) in 14 cats. Thirteen were spayed females, 35 were neutered males, and 1 was a sexually intact male. Breeds included domestic shorthair (n = 27), domestic medium hair (6), domestic longhair (9), Siamese (2), Maine Coon (1), American Shorthair (1), Persian (1), Angora (1), and Norwegian Forest Cat (1). Mean and median age at the time of diagnosis were each 12 years (range, 4 to 16 years). Information regarding pigmentation was available for 37 cats. In 36 of these cats, the lesion occurred in a white or lightly pigmented area. Two cats were identified as cats that remained primarily indoors; all others spent most of their time outdoors.

No cats were seropositive for FeLV, and 2 cats had FIV infections. Twenty-four of the cats had concurrent medical problems at the time of plesiotherapy, including renal disease (n = 7 cats), cardiac disease (8), renal and cardiac disease (1), chronic upper respiratory tract infection (4), uncontrolled hyperthyroidism (2), diaphragmatic hernia (1), and inflammatory bowel disease (1). Twelve cats were receiving concurrent treatments of prednisone (n = 4 cats), antimicrobials (3), prednisone and antimicrobials (3), cyclosporine (1), and amlodipine (1). Eight cats had SCC lesions in addition to the lesions of the nasal planum; affected sites included the pinna (n = 4 cats), medial canthus (2), lip (1), and face (1). These lesions were treated with ⁹⁰Sr at the same time.

Information regarding the number of probe applications used was available for 47 cats. The calculated dose delivered to the surface of each site was 97 to 195 Gy (median dose, 128 Gy). The radiation dose was determined on the basis of the calculated activity of the probe during the month of treatment and the duration of application. Cats each received 1 to 6 applications: 10 cats received a single application, 17 cats received 2 applications, 10 cats received 3 applications, 6 cats received 4 applications, 2 cats received 5 applications, and 2 cats received 6 applications.

Forty-eight of the 49 (98%) cats had a response to treatment. Forty-three cats had a complete response, 5 cats had a partial response, and 1 cat with SCC had no response to 90Sr treatment. All cats with SCC in situ had a complete response. The cats that had a partial response were treated with doses of 118, 122, 130, 137 and 138 Gy; whereas the cat that had no response received a dose of 181 Gy. The owners of the 5 cats that had a partial response reported an improvement in their cats' quality of life even though lesions did not resolve completely. Owners reported that the cats had a decrease in frequency and severity of bleeding and irritation in the SCC-affected area and that, in general, they perceived the cats to be more comfortable than they were prior to treatment. Two of the 5 cats were eventually euthanized because of progression of their SCC at 242 and 581 days following initial treatment. This occurred even though additional treatment, including application of additional fractions of ⁹⁰Sr at a later time and surgery, was pursued for these cats. The remaining 3 cats died of causes unrelated to their neoplastic disease without additional treatment.

Ten of the 35 cats with SCC and none of the 14 cats with SCC in situ had recurrence of the neoplasm. The overall recurrence rate was 20%. Of the 10 cats that had recurrence, 3 had 1 probe application, 1 had 2 probe applications, 2 had 3 probe applications, 3 had 4 probe applications, and 1 had 6 probe applications. These cats received doses of 105, 188, 126, 130, 134, 137, 138, 181, 188, and 195 Gy, respectively. Median time to recurrence of the SCC was 308 days (range, 0 to 1,515 days). Additional treatment following recurrence was variable and included no treatment (n = 3 cats), definitive course of orthovoltage radiotherapy (2), surgery (2), photodynamic therapy (1), administration of piroxicam (1), and retreatment with ⁹⁰Sr (1).

After the initial treatment, 16 of the 49 (33%) cats developed new lesions at sites other than the original treatment site. Locations affected included nares or other sites on the nasal planum (n = 6 cats), pinnae (5), face (3), lips (2), and eyelids (1). Median time to the development of a new lesion was 310 days (range, 56 to 2,190 days). Six of the 10 cats that had SCC recurrence at the treated site also developed new lesions at a distant location.

At the end of the study period, 11 cats were alive. Five had been euthanized for progression of their nasal lesions, 2 cats were euthanized as a result of SCC in other locations, and 26 had died as a result of causes unrelated to SCC. The status of 5 cats was unknown. Four of the cats that had recurrence of their nasal lesions died as a result of causes unrelated to their SCC. The median follow-up time period was 1,018 days (range, 166 to 4,168 days).

Records indicated that complications following ⁹⁰Sr treatment had developed in 4 cats; those complications included a moderate to marked amount of inflammation or signs of discomfort at the site (n = 2 cats), delayed healing (3), and infection (1). Two of these cats had FIV infections. Treatments for complications included administration of prednisone (n = 2 cats) and antimicrobials (1). Complications were mild and all resolved completely. Of the cats that developed complications, 3 had ≤ 3 probe applications. Those cats received doses (105, 108, 120, and 138 Gy) that were similar to or less than the median dose of 128 Gy.

At the time of initial evaluation, 5 cats included in the study had lesions that were subjectively assessed as being excessively invasive for ⁹⁰Sr plesiotherapy to be effective. Although proceeding with treatment against advice did not significantly (P = 0.07) impact progression-free survival time, 2 of those 5 cats had SCC recurrence and 1 had only a partial response to 90Sr treatment. Because of the small number of cats treated, there may not have been sufficient statistical power to detect an influence of treatment against advice on progression-free survival time.

The median progression-free survival time was 1,710 days (95% confidence interval, 1,044 to 2,376; Figure 1). The 1-, 2-, and 5-year progression-free survival rates were 88%, 80%, and 49%, respectively (95% confidence intervals, 75% to 95%, 63% to 89%, and 22% to 72%, respectively). Median overall survival time was 3,076 days (95% confidence interval, 1,635 to 4,517; Figure 2). The 1-, 2-, and 5-year overall survival rates were 98%, 92%, and 55%, respectively (95% confidence intervals, 85% to 99%, 77% to 97%, and 27% to 77%, respectively). A diagnosis of SCC versus SCC in situ did not significantly affect progression-free survival time or overall survival time. Cats that had a complete response had a significantly longer (P < 0.001) overall survival time than cats that had a partial response (3,076 vs 581 days; Figure 3). Progression-free or overall survival time was not affected by FIV infection status, number of probe applications, or delivered dose of ⁹⁰Sr.

View Full Size

Kaplan-Meier curve of progression-free survival in 49 cats with SCC of the nasal planum that were treated with a single application of ⁹⁰Sr. Tick marks represent censored cats.

Citation: Journal of the American Veterinary Medical Association 231, 5; 10.2460/javma.231.5.736

• Download Figure
• Download figure as PowerPoint slide

View Full Size

Kaplan-Meier curve of overall survival in 49 cats with SCC of the nasal planum that were treated with a single application of ⁹⁰Sr. Tick marks represent censored cats.

Citation: Journal of the American Veterinary Medical Association 231, 5; 10.2460/javma.231.5.736

• Download Figure
• Download figure as PowerPoint slide

View Full Size

Overall survival rate of 49 cats with SCC of the nasal planum that were treated with a single application of ⁹⁰Sr and had a complete response to treatment (n = 43; dashed line) or had a partial response (5; solid line). One cat had no response to treatment. Tick marks represent censored cats.

Citation: Journal of the American Veterinary Medical Association 231, 5; 10.2460/javma.231.5.736

• Download Figure
• Download figure as PowerPoint slide

Discussion

The signalment of the cats in the present study was similar to cats with SCC of the nasal planum described in other reports.^4,18,19 Although not reported for all cats, the affected area was white or lightly pigmented in at least 97% (n = 36/37) of the cats in the present study.

It has been suggested that cats infected with FIV are at an increased risk for the development of SCC, compared with uninfected cats.²⁰ Cats infected with FIV have also been reported to be prone to more severe radiation reactions.^7,19 Two cats in the present study were infected with FIV. Both of those cats had moderate to marked radiation reactions in the form of inflammation and discomfort at the treatment site and delayed healing of the lesion. Although the reactions were considered worse than those that develop in most other cats, the lesion sites did eventually completely heal in both cats. Neither of those cats had recurrence of SCC or died from SCC-related causes. Among the cats of the present study, FIV infection status and complications following ⁹⁰Sr treatment did not appear to affect progression-free survival and overall survival times; however, with so few cats with FIV infection or that developed treatment-related complications, the statistical analyses may have lacked the power to detect any association. Only 2 cats in the present study were considered to be primarily indoor cats; thus, the effect of an indoor habitat on progression-free survival and overall survival times could not be assessed.

At initial evaluation, 8 of the 49 (16%) cats in the present study had SCCs in other body areas in addition to the lesions of the nasal planum. Treatment of multiple SCC-affected areas with ⁹⁰Sr was performed in these cats during the same anesthetic episode. Although outcome of SCC at these sites was not analyzed, it can be expected that it may have been similar to that achieved in the nasal planum region after treatment. Sixteen of the 49 (33%) cats developed new SCC lesions during the study period. This was not unexpected as it is likely that the entire face of each cat had received considerable exposure to solar radiation by the time the initial lesions developed.⁴

Squamous cell carcinoma in cats is often staged according to the World Health Organization classification of tumors of epidermal origin.^7,8,12,21 This system classifies tumors on the basis of the degree of invasiveness and the size of the lesion.²² In the present study, the size of the lesion was not determined or not reported for all cats; however, it could be estimated by the number of probe applications necessary to treat the entire tumor volume. The number of probe applications was not significantly associated with progression-free survival and overall survival times, but 4 of the 10 cats that had tumors requiring 4 or more probe applications had recurrence of the SCC. Of the 4 cats that had complications as a result of ⁹⁰Sr radiotherapy, 3 had ≤ 3 probe applications. These cats received doses that were similar to or less than median dose.

Tumors were described as SCC in situ if neoplastic cells were confined to the epidermis or as SCC if invasion of neoplastic cells through the basement membrane and into the dermis was evident. Although diagnosis of SCC versus SCC in situ did not have a significant impact on progression-free or overall survival times, 10 of 35 (29%) cats with a diagnosis of SCC had tumor recurrence, whereas no recurrence developed in cats with a diagnosis of SCC in situ. It is possible that the small sample size did not allow the detection of a significant difference between these 2 groups.

Results of the present study have indicated that treatment of SCC of the nasal planum of cats with ⁹⁰Sr plesiotherapy can be effective. Median progression-free survival time of these cats was 4.7 years (1,710 days), and a median overall survival time of > 8 years (3,076 days) was determined. These results compare favorably with those reported for other treatments.^5-7,9-12,18

Cats that had a complete response to treatment lived significantly longer than cats that had a partial response (3,076 vs 581 days), which suggests that more aggressive treatments should be pursued in cats that fail to respond completely to initial ⁹⁰Sr treatment of SCC.

Treatment was tolerated well by most cats in the present study. Complications following ⁹⁰Sr radiotherapy were recorded for 4 cats and included a moderate to marked amount of inflammation or discomfort at the site, delayed healing, and infection. Complications were mild and resolved completely in all affected animals. None of these 4 cats had recurrence of their SCC lesions. Administration of analgesics was not necessary in these cats. The median age at the time of initial evaluation was 12 years, and many of the cats had concurrent illness such as renal and cardiac disease. There were no complications as a result of anesthesia. One advantage of the treatment protocol used in the cats of the present study was that it involved application of a single fraction of ⁹⁰Sr; therefore, cats underwent a single anesthetic episode. This decreased the risk associated with multiple anesthetic episodes.

Compared with external beam radiotherapy, 90Sr treatment offers several other advantages for the treatment of small, minimally invasive, SCC of the nasal planum in cats. In addition to requiring only 1 anesthetic episode, treatment times are generally short (3 to 5 min/application). Lesions in multiple areas can be treated during a single anesthetic episode. Equipment and treatment costs associated with ⁹⁰Sr presently are significantly lower than those of surgery or external beam therapy. Because the use of ⁹⁰Sr requires trained personnel and strict adherence to radiation safety and shielding regulations, the availability of ⁹⁰Sr treatment is generally limited to large specialty practices and educational institutions.

There are several limitations to the present study in addition to its retrospective nature. Numerous cases were excluded from analysis because of the lack of histologic confirmation of SCC. The dose of radiation delivered to tumors was variable. Although calculations to account for probe decay were made on a regular basis, the number of probe applications necessary to treat an entire lesion was based on the size of the lesion. As there are currently no established dosing protocols for ⁹⁰Sr in cats, doses were extrapolated from doses recommended for humans and were determined by the attending clinician at the time of treatment. Doses reported for the treatment of conjunctival SCC in people range from single-fraction treatment of 30 to 180 Gy to fractionated therapy of 60 to 140 Gy delivered via 7 fractions.^16,23 Among the cats of the present study, dose did not significantly affect outcome. To date, the minimum effective dose of ⁹⁰Sr for treatment of SCC in cats remains unknown. Because the size of lesions at the time of treatment was not available for all cats, application of the World Health Organization tumor staging criteria could not be performed. It is unknown whether tumor staging would have been helpful in predicting outcome in the cats of the present study.

In the medical records, some descriptions of recurrent lesions were inadequate for determining whether lesions were truly recurrences of the SCC or the development of new lesions close to the treatment field. In those cases, it was assumed that the lesions represented tumor recurrence. This assumption could have falsely increased the recurrence rate and underestimated the progression-free survival time. Because there was a prolonged interval between the time of initial treatment and the time of presumed tumor recurrence in several cats, it is also possible that these lesions actually represented late radiation reactions and not SCC recurrence. Development of skin atrophy is a reported late consequence of irradiation in experiments involving pig skin, and it has been shown to develop after irradiation with 30 to 120 Gy.^24–27 Histologically, we have observed that these late radiation reactions may have segmental hyperkeratosis, acanthosis, and spongiosis of the stratum spinosum with epithelial dysplasia as well as vascular changes and collagen hyalinization. In the nasal planum, vascular and dermal hyalinosis and elastosis have also been seen to be induced by solar radiation.³ It is not always possible to determine whether these changes represent further actinic damage to the nasal planum, late effects of radiotherapy, or preneoplastic changes.²⁸ Collection of biopsy specimens to confirm recurrent SCC was not often performed for the cats in the present study. The observation that several of the cats that had tumor recurrence survived for a long period of time following the development of these lesions also suggests that the lesions may not have been SCC. In assuming that these lesions represented tumor recurrence, the rate of late developing complications could have been underestimated.

The results of the present study have indicated that a single fraction of ⁹⁰Sr is an effective and well-tolerated treatment of superficial SCC of the nasal planum in cats. This method of treatment may be advantageous over other therapies, especially in older cats for which multiple anesthetic episodes are undesirable or in cats that have lesions in multiple locations. A prospective analysis would be useful to confirm these findings and further evaluate possible prognostic indicators.