Use of a cyclical hypofractionated radiotherapy regime (‘QUAD shot’) for the treatment of feline sinonasal carcinomas

Abstract

Objectives

Radiation therapy is the treatment of choice for cats with sinonasal carcinomas. Different protocols have been described in the literature, though a clear consensus regarding the optimal protocol is lacking. The aim of the study was to describe the tolerability, efficacy and outcome of cats treated with a cyclical hypofractionated protocol.

Methods

Cats with histologically diagnosed sinonasal carcinomas in a single institution were retrospectively included. All patients were treated with a cyclical hypofractionated protocol (‘QUAD shot’ regime). Cats were treated with 4 Gray (Gy) delivered in four fractions within 48 h, with a minimum of 6 h between two treatments, and repeated every 3–4 weeks for a total dose of 48 Gy in three cycles.

Results

Seven cats met the inclusion criteria. Nasal discharge and sneezing were the most common presenting complaints. All cats presented with advanced stage of disease with CT examination (three with modified Adams stage 3 and four with stage 4). Clinical improvement was seen in six cats. Five cats had a follow-up CT; one had a complete response, two had partial responses, one had stable disease and one had progressive disease. Two cats were still alive at the time of writing while four were euthanased owing to tumour-related causes. The median overall survival time was 460 days. The 1-year survival time was 80% and the 2-year survival time was 0%. Severe acute or late toxicity was not reported.

Conclusions and relevance

This is the first report of a cyclical hypofractionated protocol in the veterinary literature that can provide prolonged survival in cats with advanced stage sinonasal carcinoma. Its use should be considered in patients when prolonged hospitalisation can be detrimental to quality of life, while still delivering a therapeutic total dose of radiation therapy.

Introduction

Nasal tumours represent one of the most common diagnoses in cats presenting with signs of nasal disease.^1,2 Sinonasal carcinomas and lymphomas are the most common nasal neoplasia in this population, with carcinomas accounting for 43% of diagnosed tumours. ³ Radiation therapy is considered the treatment of choice in feline patients with this histological diagnosis and different treatment protocols have been previously reported in the literature.^4–8 Until recently, a consensus over the use of finely fractionated vs hypofractionated protocols regarding the overall survival could not be reached,^4–8 though a recent study showed an improvement in the overall survival in cats treated with definitive-intent protocols (including stereotactic and traditional three-dimensional external beam radiation therapy given in finely fractionated protocols). ⁸ The median survival time in these populations of cats ranged between 342 and 591 days.^4–8 Common hypofractionated protocols in sinonasal carcinomas in cats include doses of 16–36 Gray (Gy),^4,5,7,8 while finely fractionated protocols aim for a dose of at least 40 Gy given in ⩾10 fractions.^6,8

Palliative-intent radiation treatment remains an important tool in human medicine and is used for disease control; symptoms, disease extent and comorbidity are considered, while accepting that a cure is not possible. ⁹ A similar approach is taken with veterinary patients undergoing radiation therapy for intranasal tumours. ¹⁰ A hypofractionated protocol consisting of short cyclical courses of treatment has been used in people with inoperable pelvic, head and neck cancer.^11,12 The concept of this protocol has previously been described in the human literature. ¹² In summary, the aim is to deliver a biologically equivalent dose, just below the threshold that would produce mucositis, in short cyclical courses. The number of dose fractions in each cycle is set at four as a compromise that would allow for tumour reoxygenation without protracting the duration of each cycle of treatment, while the treatment cycles are separated by an interval sufficient for depleted mucosal stem cells to repopulate before the next cycle. ¹² Similar repopulation could be anticipated to occur in the tumour, though the longer lag time for onset of tumour cell repopulation would favour the normal epithelium. Treatment is given twice daily for two consecutive days, with an interval of at least 6 h between treatments. This is repeated every 3–4 weeks for three cycles in total. ¹² This regime is considered appropriate for patients in poor physical or mental condition, in cases of severe comorbidities, in patients with very advanced disease or in those with non-compliance to numerous daily treatments.^12,13 Similar protocols could be implemented in veterinary patients, especially cats, in which prolonged hospitalisation can be a stressful period leading to inappetence and reduced calorie intake. ¹⁴ While the cyclical protocol is considered a palliative-intent option in human medicine, a high total dose of radiation therapy is given, which is similar to other finely fractionated protocols used in veterinary medicine.^6,8

To the best of the authors’ knowledge, the use of such a cyclical hypofractionated protocol has not been reported in the veterinary literature. The aim of our study was to determine the tolerability, efficacy and outcome for cats with sinonasal carcinoma treated with this protocol.

Materials and methods

This was a retrospective single centre study. The database of the hospital was manually searched for cats with histologically confirmed sinonasal carcinomas, treated with a cyclical hypofractionated protocol as a sole treatment option. Radiation therapy was delivered in four fractions within 48 h (4 Gy per fraction, 16 Gy within 48 h). The delivery of the treatment was given in two different ways to facilitate logistics of the hospital: (1) delivery of two treatments per day for two consecutive days (day 1: one treatment in the morning and one in the afternoon, day 2: one treatment in the morning and one in the afternoon); or (2) delivery of four treatments within 3 days (day 1: one treatment in the afternoon, day 2: one treatment in the morning and one treatment in the afternoon, day 3: one treatment in the morning). There was a minimum of 6 h between each treatment. The four treatments were delivered within 48 h with both approaches. This cycle was repeated two more times every 3–4 weeks for three cycles in total (final dose of 48 Gy in 12 fractions). The use of non-steroidal anti-inflammatory drugs (NSAIDs) and steroids was allowed prior to the start of the treatment. Tumours of the nasal planum were excluded. Cats were excluded if they were prescribed a different radiation protocol, if they did not complete the radiation therapy protocol, if they had received previous anti-neoplastic treatment or if they had a histopathological diagnosis other than carcinoma. Cats that were lost to follow-up within 3 months of the completion of the treatment were also excluded.

Medical record review

Medical records were retrospectively evaluated from January 2011 to December 2020. Signalment, including age, weight, sex and breed were recorded. Clinical data information was collected from the medical records of each patient, including: clinical signs; diagnostic results (haematology, biochemistry, histological type); staging tests (head CT or MRI, cervical and thoracic imaging, lymph node cytology) at diagnosis and after radiation therapy; tumour stage according to the canine modified Adams staging system (Table 1); ¹⁵ tumour response on radiation therapy based on clinical signs and CT imaging; date of repeated imaging; date of tumour progression; therapy at the time of progression; date and cause of death. The diagnostic imaging studies performed for tumour staging and radiation therapy planning were initially reported by a European College of Veterinary Diagnostic Imaging or American College of Veterinary Radiology board-certified veterinary radiologist. One of the authors (PSF) reviewed the results of those studies regarding the staging. Referring veterinarians were contacted for cause and date of death when information was not included in the medical record. Fine needle aspiration from the locoregional lymph nodes was performed according to the decision of the attending clinician and the results were reviewed from the pathology reports. The tumour response was assessed by repeated imaging of the nasal cavity and head. When repeated imaging was not available, the clinical response was assessed during follow-up appointments by physical examination and the owner’s perception of the clinical signs.Radiation therapy

Table 1

Modified Adams staging system

Stage	Description
1	Confined to one nasal passage, paranasal sinus or frontal sinus, with no bone involvement beyond turbinates
2	Any bony involvement (beyond turbinates), but with no evidence of orbit/subcutaneous/submucosal mass
3	Orbit involved, or nasopharyngeal, subcutaneous or submucosal mass
4	Tumour causing lysis of the cribriform plate

All cats received the scheduled 12 fractions of treatment, to a total dose of 48 Gy in each case. All cats were treated with three-dimensional external beam radiation therapy. Radiation was delivered with a 6 MV photon linear accelerator (Varian Clinac 600x iX DMX; Varian). For radiation treatment planning, pre- and post-contrast standard CT scans of the head were performed under general anaesthesia. For treatment planning, the Eclipse External Beam Planning system (version 15.1; Varian Oncology Systems), CadPlan (version 2.5; Varian Oncology Systems) and Oncentra (version 4.3; Elekta) were used. Owing to the retrospective nature of the study, details about contouring gross target volumes and organs at risk were not collected. Patient positioning and the treatment planning process were standardised and all treatments were performed with the patients under general anaesthesia and in sternal recumbency. Positioning was based on CT. Port films were taken prior to the first treatment of each cycle. Immobilisation of the head was achieved by using either a maxillary dental mold bite block or a tile for elevation of the head and a mouth gag was placed in the maxilla to try to reduce the dose in the tongue.

Follow-up

Re-examination was recommended 2–3 weeks after the end of the radiation therapy for assessment of acute toxicity. Physical examination was then recommended every 3 months. A CT scan of the nose and head was recommended 3–6 months after the end of the protocol to evaluate clinical response.

Objective tumour response assessed by CT was reported according to response evaluation criteria in solid tumours (RECIST), ¹⁶ and the best objective response documented for each case was used to describe tumour response. In cases where a CT scan was not performed, the clinical improvement was based on the owner’s perception of the disease and the clinical examination findings. Complete response (CR) was defined as complete resolution of the nasal lesions during CT examination. Partial response (PR) was defined as improvement of the clinical signs (if a CT scan was not available) or at least 30% reduction in the sum of diameters of the nasal mass. Cats were considered to have stable disease (SD) if there was less than 30% reduction or 20% increase in the sum of diameters of the nasal mass or the nasal signs remained stable if advanced imaging was not available. Local progressive disease (PD) was defined as either tumour progression on CT imaging (>20% increase in the sum of diameters) or recurrence of clinical nasal signs if advanced imaging was not performed. Radiation toxicity was recorded retrospectively as described in the medical record according to the Veterinary Radiation Therapy Oncology Group (VRTOG) toxicity criteria. ¹⁷ Acute toxicity was defined as occurring within 3 months after radiation therapy, while late toxicity occurred more than 3 months after radiation therapy. The cut-off period of 3 months has been previously chosen in studies of cats^6,18 and dogs ¹⁹ as the time point for late effects owing to late ocular complications, including cataracts, retinal haemorrhages and vasculopathies that can develop in the 3–6 month period after radiation therapy in the dog.^18,20

Statistical analysis

Data were coded in Microsoft Excel and analysed with a commercial statistical software package (IBM SPSS Statistics, Version 28; IBM Corporation). Kaplan–Meier survival curves were generated. Cats were censored if they were lost to follow-up, were still alive or had died as a result of causes unrelated to the nasal tumour. If the cause of death was unknown, it was assumed to be due to tumour-related causes.

Time to progression (TTP) was defined as the interval between the first day of radiation therapy until suspected or confirmed progression of disease (clinically suspected or radiologically confirmed). Cats that were free of progression and that were still alive at the time of data collection were censored for TTP analysis. Overall survival (OS) time was defined as between the first treatment day and death, or date of last contact. Patients were censored from TTP analysis if they were alive without PD, or died of causes unrelated to the nasal tumour, without evidence of PD. Patients were censored from OS analysis if alive at last contact, died of causes unrelated to the nasal tumour without evidence of PD or were lost to follow-up. TTP and OS were analysed with the Kaplan–Meier product-limit estimator. Median TTP and median OS are reported with the corresponding 95% confidence intervals (CI).

Results

Seven cats with nasal carcinomas treated with the cyclical protocol described above were identified in the database. All cats completed the protocol and had adequate follow-up to meet the criteria for inclusion in the study (Table 2). There were four neutered females and three neutered males. The median age at diagnosis was 12 years (range 7–13 years) and the median body weight on presentation was 4.3 kg (range 2.37–5.34 kg). There were three domestic shorthair (DSH) cats, two Siamese, one Burmese and one Maine Coon. The most common clinical signs on presentation were nasal discharge (n = 5), sneezing (n = 3), epistaxis (n = 2), epiphora (n = 2) and inappetence (n = 1). The histopathological diagnosis was adenocarcinoma in three cats, unspecified carcinoma in two, acinar cell carcinoma in one and transitional cell carcinoma in one. According to the modified Adams staging system, three cases were classified as stage 3 and four as stage 4. There were no cases classified as stage 1 or 2. Four cats had a CT scan of the thorax performed for staging purposes, while one cat had thoracic radiographs. Two cats had no thoracic staging. Metastatic disease was not identified in any case. In one cat, fine needle aspirates were collected from the locoregional lymph nodes and there was no cytological evidence of metastatic disease. The duration of the protocol was 6 weeks in four cases and 8 weeks in three cases. More specifically, the cycles were repeated every 3 weeks in four cases and every 4 weeks in the remaining three cases.

Table 2

Summary of the seven treated cats

Breed	Age (years)	Sex	Histological diagnosis	Modified Adams stage	Duration of protocol (weeks)	Acute toxicity	Late toxicity	Best radiographic response	Best clinical response	TTP (days)	OS (days)	Cause of death
DSH	13	FN	Adenocarcinoma	4	8	Alopecia	Leukotrichia	PR	Resolution	472	526	PD
Maine Coon	12	MN	Acinar cell carcinoma	4	8	None	Epistaxis	CR	Improvement	345	394	PD
Siamese	12	MN	Undifferentiated carcinoma	3	8	None	Alopecia	No CT follow-up	Improvement	662	662	PD
Siamese	13	FN	Undifferentiated carcinoma	3	6	Ocular discharge	None	PD	Worsening	103	184	PD
DSH	13	FN	Adenocarcinoma	4	6	None	None	SD	Improvement	LTFU	LTFU	LTFU
DSH	11	MN	Adenocarcinoma	4	6	None	None	No CT follow-up	Improvement	NA	Alive	Alive (368 days)
Burmese	7	FN	TCC	3	6	None	Leukotrichia	PR	Improvement	NA	Alive	Alive (146 days)

TTP = time to progression; OS = overall survival; DSH = domestic shorthair; FN = female neutered; PR = partial response; PD = progressive disease; MN = male neutered; CR = complete response; SD = stable disease; LTFU = lost to follow-up; NA = not applicable; TCC = transitional cell carcinoma

Follow-up was not standardised. Five cats had repeated CT examination of the head at a median of 147 days (range 94–232 days) after the beginning of the protocol. CR was identified in one cat, PR in two, SD in one and PD in one case. A clinical benefit, as assessed by radiographic response or improvement in the clinical signs, was seen in six cats. The one cat with no clinical benefit had PD in the repeat CT (Table 2). The one cat with SD had improvement of the clinical signs.

The median time to progression was 408.5 days (95% CI: 278; 665), while the median OS time for all cats was 460 days (95% CI: 242; 809) (Figure 1). The 1-year survival rate for cats with known outcome was 80% while the 2-year survival rate was 0%. More specifically, two cats were still alive at the time of writing of the manuscript (Table 2). One cat with SD during a follow-up CT scan was lost to follow-up 113 days after the start of the treatment, while four cats were euthanased owing to PD based on clinical signs. Post-mortem examination was not performed in any of the cases. No cats received additional chemotherapy or a second radiation therapy treatment once recurrence was noticed.

Figure 1

Kaplan–Meier overall survival curve for all patients treated with cyclical hypofractionated protocol

Toxicities were retrospectively recorded based on the clinical records. Two cats developed alopecia (one early VRTOG grade 1 and one late VRTOG grade 2), while two cats developed leukotrichia (late VRTOG grade 1). These changes did not affect the patients’ quality of life. One cat that was initially presented due to epistaxis developed intermittent episodes of epistaxis 4 months after the end of the radiation therapy, despite confirmed CR during CT examination. This was considered to be due to chronic rhinitis, although further investigation was declined by the owner. One cat developed left-sided ocular discharge within the first 3 months of the radiation therapy protocol. A more accurate time of the onset of the signs could not be retrieved from the records. A distinction between VRTOG grade 1 or grade 2 ocular toxicity could not be made. It is not clear whether this change was due to radiation therapy toxicity or PD, as in this patient PD was documented with CT 2 months later. One cat developed mucopurulent nasal discharge and anorexia 7 days after the end of the second cycle of the protocol, attributed to a secondary bacterial infection. The clinical signs resolved after the administration of amoxicillin/clavulanate. Two cats received NSAIDs and one cat received prednisolone during the treatment. Six cats received NSAIDs at some point in the post-treatment period. Five cats received meloxicam only. One cat was treated initially with meloxicam, though the cat was transitioned to robenacoxib after experiencing gastrointestinal toxicity with meloxicam. The same patient also received prednisolone to control intermittent signs of rhinitis. The medication was prescribed after the discontinuation of robenacoxib, as this failed to control the signs.

Discussion

To the best of the authors’ knowledge, this is the first published study in the veterinary literature investigating the use of a cyclical hypofractionated protocol. This type of protocol has been well described in the human literature and poses certain advantages for its use that could be adapted in a veterinary population of patients.

Survival times and clinical response associated with the use of the described protocol was similar to those reported in previous studies in cats with sinonasal carcinomas.^4–8 Different radiation therapy protocols have been previously described, though the efficacy of one over another has not been thoroughly investigated. Yoshikawa et al were the first to compare different treatment protocols in a population of cats with sinonasal carcinomas and it was reported that cats receiving definitive-intent fractionated radiation therapy or definitive-intent stereotactic radiation therapy (SRT) had a longer survival time compared with cats receiving palliative-intent protocols. ⁸ In this study, many of the patients in the palliative group received only a small total dose (most cats had 32 Gy or less) or had advanced clinical stage disease. ⁸ More specifically, the survival time of cats receiving palliative-intent (hypofractionated) protocols was 284 days, compared with 721 days in the definitive-intent (fractionated/SRT) group. ⁸ Furthermore, in other studies of cats receiving hypofractionated protocols, the survival times range from 342 to 450 days, which is similar to the survival in the present study.^4,5,7 Overall, the survival of cats presented here is similar, though direct comparison with previous studies cannot be made due to the different population of cats. Stage 4 disease has been shown to be a negative prognostic indicator in dogs with nasal tumours. ¹⁵ However, this finding has only been confirmed in a single retrospective study of cats with sinonasal cancer treated with a hypofractionated protocol. ⁷ All the cats in the present study had advanced disease (either modified Adams stage 3 or 4). This is in agreement with previous studies in dogs ²¹ and cats ⁷ in the UK. It is unknown whether the modified Adams staging scheme is prognostically valid for cats and further work is needed to establish this.

A quality-of-life assessment was not performed owing to the retrospective nature of the study. A few recent studies have assessed owners’ perceptions of the quality of life of patients undergoing radiation therapy.^22–24 In two of those studies only dogs were included, while in the third only two cats were included. Therefore, none of the questionnaires used are validated for feline patients. A prospective study that would include comparison of different radiation therapy protocols for nasal tumours, the owner’s perspective on the quality of life and accurate measurement of food consumption and body weight changes during protocols would provide insights about the different treatment options. Data collection of body weight changes, as a more objective measure of the tolerance of the protocol, was not attempted as retrospective assessment of weight loss is challenging. It would be difficult to assess whether any body weight changes were related to the protocol, other comorbidities, limited exercise or reduced appetite secondary to the tumour (considering that all cats in this protocol were of advanced stage).

The use of a cyclical hypofractionated protocol in human medicine was first used for the treatment of pelvic cancer,^11,25,26 though over the last 15 years this protocol has been used for the treatment of head and neck carcinoma^12,27–30 and skin cancer. ¹³ This type of protocol offers flexibility in patients non-compliant to daily treatments, those with advanced disease or other comorbidities.^12,13 Flexibility is important for veterinary patients, as the treatment decision depends largely on owners’ preferences. ³¹ In addition, it is likely that cats staying in the hospital environment for a prolonged period of time may show signs of stress and hyporexia, leading to treatment discontinuation, while alternative treatment protocols can be sought as there are no ‘gold standard’ protocols in many disease states in veterinary cancer patients.^10,32 In addition, 28% and 57% of the patients had acute and late radiation toxicity, respectively. The toxicity levels with the cyclical protocol, though, were low and did not affect patients’ quality of life. There is always a potential for increased late toxicity with hypofractionated protocols, ³² though as most cats with sinonasal tumours do not survive long enough the actual percentage of affected patients may be underestimated.

The limitations of the present study mainly lie in its retrospective nature. There was a small number of patients and therefore a statistical comparison between clinical signs, stage of the disease and duration of protocol was not performed. In addition, most of the cases did not have a standardised follow-up, although a follow-up CT scan was performed in the majority of cases. None of the cases had a second CT following treatment to better assess response. It was also difficult to assess for late toxicity of the current protocol, as many cats did not survive long enough or the toxicity was underestimated owing to the retrospective collection of data. Toxicity may also have been under-reported as some of the follow-up examinations were performed at primary care clinics and not the hospital where the treatment was delivered, overall, though the late toxicity was reported to be low or of cosmetic importance (such as alopecia and leukotrichia) in previous studies.^7,8 VRTOG criteria were only partially applied, owing to the difficulty in retrospectively categorising the toxicity, as it was not always clearly recorded in the medical records. Post-mortem examination was not performed in any of the cases, therefore it is likely that some cats with progressive nasal signs had rhinitis due to late toxicity, rather than tumour progression. Finally, staging was inconsistent, and the histological diagnosis was based on the reports at the time of presentation, while immunohistochemistry was not performed in any case.

Conclusions

The present study has found comparable survival outcomes to previous studies in a population of patients with advanced disease stage using a novel radiation protocol. The principle of a cyclical hypofractionated protocol in cats with nasal carcinoma is safe, provides improvement of the clinical signs and tumour responses, a high total radiation dose, flexibility to the owners and a less stressful experience for cats that may not tolerate prolonged or continuous hospital stays.