Clinical response and survival time of cats with carcinoma of the nasal cavity treated with palliative coarse fractionated radiotherapy

Abstract

Objectives

Carcinoma is the second most common tumour of the nasal cavity in cats. Few studies assessing the response and survival of cats with carcinoma of the nasal cavity treated with palliative coarse fractionated radiotherapy have been published.

Methods

Twenty-eight cats were diagnosed with histologically confirmed carcinoma of the nasal cavity. All patients treated with a coarse fractionated radiotherapy protocol were retrospectively reviewed.

Results

Improvement of the clinical signs were reported in 24 cases; median survival time (MST) was 342 days; and cats with Adams modified stage IV and facial deformity had a significantly reduced MST of 152 days (P = 0.0013) and 67 days (P = 0.0002), respectively. Severe radiotherapy-related clinical signs were not reported and alopecia and leukotrichia were the most common side effects reported in ten cases.

Conclusions and relevance

Coarse fractionated radiotherapy treatment for carcinoma of the nasal cavity in cats is effective in relieving clinical signs. Long survival times can be achieved, in particular in cases with a less advanced stage of the tumour.

Introduction

Carcinoma is the second most common tumour of the nasal cavity in cats. ¹ As is the case in dogs, cats with nasal tumours often present with dyspnoea, chronic nasal discharge, sneezing and epistaxis. ² Palliative coarse fractionated and definitive fractionated radiotherapy have been used in nasal tumours in dogs and cats.^3–5 The advantages of palliative coarse fractionated radiotherapy over a definitive fractionated protocol are fewer acute side effects, a reduced cost of the treatment and a reduced number of general anaesthesias, less stress for the patients and less commitment for the owner, who often needs to travel long distances to the referral radiotherapy centre. However, coarse fractionated radiotherapy is more likely to cause severe late-term radiotherapy side effects.

The difference in terms of efficacy for nasal carcinoma in cats has not been well established. Numerous studies have, even recently, extensively investigated radiotherapy and chemotherapy treatment for the more common feline nasal lymphoma.^6,7 However, for nasal carcinoma, large studies investigating treatment outcomes and prognostic factors have not been published. Radiotherapy treatment for feline nasal carcinoma has been investigated in a few, now dated, small studies.^3,6 Survival times have been reported to be between 2 and 36 months for fractionated radiotherapy, ³ and between 382 days and 450 days with coarse fractionated radiotherapy protocols.^4,5

Adams staging of nasal carcinoma in dogs has been reported to be of prognostic significance. ⁸ However, large studies investigating the importance of staging in cats are lacking. Even in the more common feline nasal lymphoma, invasion of the cribriform plate as a prognostic factor is still controversial.^6,9 The outcome and adverse effects of palliative coarse fractionated radiotherapy in a population of cats from Japan suffering from nasal tumours of different histology types were recently published. In this study, the Adams staging system was reported to not be prognostically significant. ⁵ The aim of the present study was to retrospectively investigate the outcome of feline nasal carcinoma treated in the UK with coarse fractionated radiotherapy and correlate survival/outcomes with the modified Adams staging system.

Materials and methods

The medical records of cats with histologically confirmed carcinomas of the nasal cavity (all different carcinoma subtypes or any malignant epithelial neoplasia without further specification), treated with palliative coarse fractionated radiation therapy at a single referral centre during a period from 2008 to 2019, were evaluated retrospectively. Tumours of the nasal planum were excluded. Age, breed, sex, weight, acute and late-term side effects, and response to the treatment were evaluated for each patient. Tumour staging was based on advanced MRI or CT scans of the head. Modified Adams staging was applied to the feline patients, as previously published in dogs (Table 1). ⁸ Cats with stage IV nasal carcinoma were compared with all the other stages. Patients with a facial deformity with any Adams stages were also separately allocated for outcome investigation. All cats that we had intended to treat with palliative coarse fractionated radiotherapy were included whether or not they completed their radiotherapy treatment, but the latter were not included in the survival analysis.

Table 1.

Modified Adams stage for nasal tumours in dogs ⁸

Stage	Description
I	Confined to one nasal passage, paranasal and frontal sinus, no bone involvement beyond turbinate
II	Any bone involvement with no evidence of involvement of orbit, subcutaneous/submucosal tissue
III	Any involvement of the orbit and/or nasopharyngeal and/or subcutaneous/submucosal tissue
IV	Involvement of the cribriform plate/invasion of the brain

The radiotherapy treatment consisted of four weekly 8.5 Gy fractions of radiotherapy or a six, twice weekly, 6 Gy fraction protocol. All cats, except two that did not finish their treatment, received the four- or six-fraction scheduled treatment with 6 MV photons (34 Gy in total) delivered by a Varian Clinac 2100 IX DMX. Treatment plans were carried out manually with square field and lead blocks used in a subset of patients to block surrounding critical normal tissues (brain or eyes) if necessary or possible. Treatments were delivered in one single beam, with the aim of achieving around 90–99% of the applied dose to all tumour tissue, with 0.2–0.5 cm margins around the tumour when possible. Source–surface distance was always 100 cm and 1 cm tissue-equivalent bolus material was used in the treatment to achieve an adequate dose at the tumour surface.

All patients were anaesthetised and positioned in sternal recumbency. The head was elevated with cushions and the maxilla with a mouth gag so as to achieve a more even surface between the nose and the frontal sinus, reducing the dose to the tongue. This angle also often allowed an easier inclusion of the soft palate and rhinopharynx in the treatment field when needed, slightly reducing the radiotherapy field length caudally, so as to spare, when possible, as much as of the olfactory lobe of the brain. Tumour extension was assessed at the start of radiotherapy based on clinical examination and CT or MRI scans. Response to radiotherapy, based on clinical improvement as described below, was documented during the course of treatment and, when available, 2 and 6 weeks post-radiotherapy treatment, or by telephone with the referring veterinary surgeon. Assessment of clinical improvement was based on a combination of findings, including reduced frequency of sneezing and nasal discharge, increased nasal airflow and the owner’s perception of increased quality of life. Treatment-related toxicity was assessed by reviewing the patient’s medical records. Subsequent follow-up data were not standardised owing to the retrospective nature of the study.

Statistical analysis was performed with a log-rank (Mantel–Cox) test to analyse the difference in median survival times between groups and Kaplan–Meier survival curves were generated. A P value of <0.05 was considered significant. Cats that were lost to follow-up, were still alive or that had died as a result of other causes unrelated to the nasal tumour, were censored. GraphPad Prism version 8.1.2 was used for the statistical analysis.

Results

Twenty-eight cats (mean age 11.8 years, range 8–15 years) were diagnosed with carcinoma of the nasal cavity: 15 adenocarcinomas, one squamous cell carcinoma, one poorly differentiated carcinoma and 11 unspecified carcinomas. Twenty cats were neutered males and eight were neutered females. There were 22 domestic shorthair cats, one Maine Coon, two British Shorthairs and three domestic longhairs. Three cats did not receive advanced imaging and the modified Adams tumour stage could not be assessed. The remaining 25 cases were staged based on MRI or CT; of these, five were stage II, 12 were stage III and eight were stage IV. Four cats also had facial deformities; of these, three were stage IV, and in one case advanced imaging was not performed.

Twenty-six cats completed the treatment protocol and two patients received only one fraction. The treatment was interrupted due to deterioration of the clinical signs in one case and in the other case owing to asthma-related respiratory deterioration during the long journey to reach the radiotherapy treatment centre. Of the 26 cases that completed the radiotherapy, 23 received four fractions and three received six fractions. Twenty-four cases (92%) were reported to show a significant improvement in clinical signs. In only one case was there no improvement and in one other case there was a deterioration in clinical signs, despite radiotherapy. Three of the four cats with a facial deformity also responded with a significant reduction in the tumour and improvement of the facial deformity.

Twenty-three cases that completed the radiotherapy treatment had follow-up data available (median follow-up 240 days; mean follow-up 325 days). Of the 23 cats with 6-week post-radiotherapy treatment data, 13 were censored (six went on to be lost during follow-up, five were still alive and two died of unrelated causes) and 10 died or were euthanased owing to the recurrence of the disease.

The median survival time for all 23 cases with different stages of disease was 342 days (Figure 1). Survival time for cats with a stage IV tumour was 152 days vs median not reached for all the other stages taken together, and this difference was statistically significant (95% confidence interval [CI] 1.5–38.5; P = 0.0013) (Figure 2). Cats with a facial deformity also had a significantly shorter survival time compared with all the other patients (67 days vs median not reached, 95% CI 3.6–41.7; P = 0.0002); however, most of them were also stage IV, so the significance of this finding is uncertain. Side effects (alopecia and leukotrichia) were reported in 10 cases and did not affect the patients’ quality of life. Conjunctivitis, keratitis and ocular discharge was reported in only one case, and these complications responded to symptomatic treatment. One case developed a fistula in the nose 3 months post-radiotherapy. However, this was most likely the result of tumour progression rather than a side effect of radiotherapy (Table 2).

Figure 1.

Kaplan–Meier survival curve for all patients. Dots indicate censored patients

Figure 2.

Kaplan–Meier survival curve showing stage IV in blue vs all other stages in red. Dots represent censored patients

Table 2.

Summary of the 28 treated cats

Breed	Age (years) and sex	Tumour type	No. of fractions of radiotherapy	Total dose (cGy)	Stage	Side effects	Clinical response	ST (days)	Cause of death/follow-up
DSH	10 MN	Adenocarcinoma	4	3200	NP	NR	Improvement	NA	NA
BSH	11 MN	Ca	4	3200	Stage II	NR	Improvement	NA	NA
DSH	9 MN	Ca	4	3200	Stage IV, FD	NR	No improvement	35	PTS, tumour-related
DSH	10 MN	Adenocarcinoma	4	3400	Stage III	NR	Improvement	241	PTS, tumour-related
DSH	12 FN	Ca, poorly differentiated	4	3400	Stage IV	NR	Improvement	216	PTS, tumour-related
DLH	10 MN	SCC	4	3400	NP, FD	Alopecia, oronasal fistula	Improvement	90	PTS, tumour-related
DSH	14 MN	Adenocarcinoma	1	800	Stage III	NR	Worsening	NA	PTS, deterioration of breathing
DSH	14 MN	Adenocarcinoma	4	3400	Stage IV	NR	Improvement	90	Lost to follow-up
DLH	12 MN	Adenocarcinoma	4	3400	NP	Alopecia, leukotrichia	Worsening	140	Lost to follow-up
DSH	15 MN	Ca	1	850	Stage II	NR	Worsening	NA	NA
DSH	16 MN	Ca	4	3400	Stage III	Alopecia, leukotrichia	Improvement	NA	NA
DSH	8 MN	Ca	4	3400	Stage III	NR	Improvement	823	PTS, tumour-unrelated
DSH	11 FN	Adenocarcinoma	4	3400	Stage III	Leukotrichia, ocular discharge, conjunctivitis, keratitis	Improvement	454	Lost to follow-up
DSH	11 MN	Ca	4	3400	Stage III	NR	Improvement	364	Lost to follow-up
DSH	14 FN	Adenocarcinoma	4	3400	Stage II	Alopecia, leukotrichia	Improvement	998	Alive
DSH	15 MN	Adenocarcinoma	4	3200	Stage III	NR	Improvement	342	PTS, tumour-related
DSH	10 MN	Adenocarcinoma	4	3400	Stage III	Alopecia, leukotrichia	Improvement	106	PTS, tumour-related
DSH	16 FN	Ca	4	3400	Stage IV	Alopecia, leukotrichia	Improvement	280	PTS, tumour-related
Maine Coon	13 MN	Adenocarcinoma	4	3400	Stage II	NR	Improvement	263	Lost to follow-up
DSH	14 FN	Adenocarcinoma	4	3400	Stage III	Leukotrichia, alopecia	Improvement	491	Lost to follow-up
DSH	15 MN	Adenocarcinoma	4	3200	Stage IV, FD	NR	Improvement	45	PTS, tumour-related, neurological signs
DSH	15 FN	Adenocarcinoma	4	3400	Stage III	Leukotrichia	Improvement	750	Alive
DLH	9 FN	Adenocarcinoma	4	3200	Stage III	NR	Improvement	275	Died, tumour-unrelated
DSH	13 MN	Adenocarcinoma	4	3400	Stage IV, FD	NR	Improvement	152	PTS, tumour-related
DSH	10 FN	Ca	6	3600	Stage II	Leukotrichia	Improvement	1092	Alive
DSH	14 MN	Ca	6	3600	Stage IV	NR	Improvement	33	PTS, tumour-related
BSH	12 MN	Ca	6	3550	Stage III	NR	Improvement	90	NA
DSH	9 MN	Ca	4	3200	Stage IV	NR	Improvement	120	Alive

cGy = centigray; ST = survival time; DSH = domestic shorthair; MN = male neutered; BSH = British Shorthair; Ca = unspecified carcinoma; FD = facial deformity; PTS = euthanasia (ie, put to sleep); FN = female neutered; DLH = domestic longhair; SCC = squamous cell carcinoma; NP = not performed; NR = not reported; NA = not available

Discussion

This study investigated the response and outcome of feline nasal carcinomas treated with coarse fractionated radiotherapy. Recent large studies investigating treatment outcomes for feline nasal carcinoma in UK are lacking. The prognostic significance of Adams staging applied to nasal carcinomas in a UK cat population have also not been previously published.

Clinical response to treatment and survival times reported in our study were similar to that previously reported. Théon et al ³ reported a survival range between 2 and 36 months with fractionated radiotherapy. Mellanby et al ⁴ and Fujiware-Igarashi et al ⁵ used coarse fractionated radiotherapy protocols and reported survival times of 382 and 450 days, respectively.

In our study, cats with advanced disease (stage IV) had a significantly reduced survival time compared with stage II and III cats (152 days for stage IV vs median not reached for stages II and III). This is different from the findings of the Fujiware-Igarashi et al ⁵ study, where the stage of disease did not affect survival time. However, the Japanese study included a high percentage of stage IV cats (62% vs 30% in our study), ⁵ which could be responsible for the close, but not statistically significant, difference found in the study by Fujiware-Igarashi et al (the P value of survival difference between stage IV vs all the other stages was 0.059). ⁵ Other possibilities are the different populations of cats present in Japan vs the UK, or different radiotherapy planning between the two institutions, with a more conservative approach and smaller margins applied to the tumour at our institution to reduce the dose to the brain, compared with the study by Fujiware-Igarashi et al. ⁵ The manual planning is not as precise as the computer planning and so this could also have caused a portion of the tumour extending in to the brain to be missed.

In our study, cats with facial deformities also had a very short survival time of only 67 days. However, most of the cats with facial deformities were also stage IV, making the correlation with survival uncertain. This finding will need to be confirmed in a larger cohort of patients.

Studies assessing survival time for untreated cats with nasal carcinoma have not been published. However, the prognosis for untreated dogs with nasal tumours is considered to be poor (around 3 months), ¹⁰ and this is likely to be the case in cats as well. In our study, the median survival of cats with stage II and III disease was not reached with a mean survival of 483 days (range 90–1092 days), similar to what has previously been reported. ³ However, in our study, owing to the high percentage of cats that were censored, this result needs to be considered with caution. This is the first study to prove that Adams stage IV cats with nasal carcinoma and possibly cats with facial deformities have a poorer prognosis than cats with a lesser Adams stage when treated with coarse fractionated radiotherapy; however, a larger study is needed to confirm this finding.

Radiotherapy side effects were mild and often not clinically significant; they did not have an impact on the quality of life of the cats, which is similar to what has been previously reported.^4,5 Late-term side effects are a well-known major concern in patients treated with a coarse fractionated radiotherapy protocol, with radionecrosis of the bone and brain, oronasal fistula, eye cataract keratoconjunctivitis sicca and corneal ulceration, and secondary malignancy being the most likely to cause significant morbidity.^4,11 However, the incidence of these side effects for cats treated with coarse fractionated radiotherapy is largely unknown.

In the largest recent series of cats treated with coarse fractionated radiotherapy for nasal tumours of various histology, treated in Japan, the late-term side effects were reported to be rare, with only 2/67 cases developing severe late-term side effects and 20% developing cataracts. ⁵ In our study, severe late-term side effects were not reported; however, this could be underestimated due to the retrospective nature of the study. It is also possible that severe late-term effects did not have enough time to develop, especially in cases that had a short survival time, underestimating the real incidence. Compared with the Japanese study, ⁵ cataracts were not reported in any of the patients; however, this could be due to under-reporting owing to a lack of scheduled ophthalmology examinations, so that a mild cataract could have been missed on routine clinical examination. It is also possible that, compared with the Japanese study, ⁵ a more conservative approach was used, shielding the eye more often when in the radiotherapy treatment field.

Although unlikely, cats with stage IV disease may have had a reduced survival time caused by radiotherapy side effects to the brain; however, neurological signs were reported only in one case. Even in this case, the neurological signs (depression and circling) were most likely due to tumour progression rather than the radiotherapy, considering the short time frame of manifestation (45 days post-treatment). However, local extension to the brain could not be confirmed due to the lack of post-mortem examination.

Other limitations of the study were that the histopathological diagnosis of carcinoma was not reviewed, post-mortem examinations were not performed for any of the patients and assessment of the tumour by repeating the CT/MRI scan were rarely performed. For this reason, tumour response was assessed by clinical signs, especially nasal airflow, and tumour time to progression could not be estimated accurately. Additional limitations of the study were the lack of accurate software planning and imaging guided radiotherapy. The present study lacked stage standardisation, as patients were staged based on CT or MRI scans. Although not previously investigated in cats, it is possible, as in dogs, that MRI could have caused a stage migration compared with the cats that were staged based on CT scans, particularly as meninges enhancement is more visible on MRI.^12,13 This could also have been the reason for the slightly high incidence of stage IV tumours. However, in another study on nasal tumours in dogs, CT was found to be of a similar value as MRI. ¹⁴

Conclusions

Coarse fractionated radiotherapy treatment for nasal carcinoma in cats is effective in relieving clinical signs. Long survival times can be achieved, in particular in cases with a less advanced tumour stage. However, large-scale prospective studies with regimented follow-up are needed to better define the role of radiotherapy in the palliation of feline nasal carcinoma. The owner should be informed of the possibility that coarse fractionated radiotherapy could cause severe late-term side effects, even if they are rare.