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- Materials And Methods
Nasal and paranasal tumours account for 1 to 2% of all canine tumours (Turek 2007). Fifty to seventy-five per cent of nasal/paranasal tumours are epithelial in origin, while most remaining tumours are sarcomas (Patnaik 1989, Adams et al. 2005, Turek 2007, Adams et al. 2009). Nasal tumours are locally invasive; systemic metastasis is infrequent, affecting 0 to 12% of dogs at presentation. Local lymph node involvement is reported in up to 24% of cases (Henry 1998, Rassnick et al. 2006, Buchholz 2009, Maruo et al. 2011).
Clinical signs of nasal tumours include nasal discharge, sneezing, stertor, epistaxis, facial pain and behavioural changes (Burk 1992, Tasker et al. 1999, Lefebvre et al. 2005, Rassnick et al. 2006, Turek 2007, Buchholz 2009, Kuehn 2009). Differential diagnoses include inflammatory rhinitis, aspergillosis and intranasal foreign bodies. The diagnosis of intranasal neoplasia is complicated by the difficulty in obtaining a representative biopsy and many neoplasms are initially diagnosed as inflammatory disease.
Computed tomography (CT) is the imaging modality of choice for diagnosing nasal neoplasia (Drees et al. 2009), although radiographs are often adequate (Gibbs et al. 1979, Morris et al. 1996). CT is superior for staging and also has some advantages over magnetic resonance imaging (MRI) (including reduced cost to the client and shorter anaesthesia time for the patient) (Thrall et al. 1989, Saunders 2003, Drees et al. 2009). MRI is more sensitive for identifying intracranial involvement (Moore 1990). CT is required for radiotherapy treatment planning in most centres.
Several CT-based staging systems have been proposed for canine nasal tumours (Adams et al. 1998, Kondo et al. 2008, Adams et al. 2009). Most studies report an association between CT or radiographic stage at presentation with overall survival (Morris et al. 1996, Adams et al. 1998, Kondo et al. 2008, Adams et al. 2009), although this is controversial (LaDue et al. 1999, Mellanby et al. 2002, Lana et al. 2004).
The treatment of choice for canine nasal tumours is definitive radiotherapy, with reported median survival times of around 450 days (range, 428 to 474) (Henry 1998, Lana et al. 2004, Adams et al. 2005, Adams et al. 2009, Hunley et al. 2010). Reported median survival times for late stage tumours are 221 days (Henry 1998) to 315 days (Adams et al. 1998), and dogs with cribriform plate involvement have survival times in the region of 200 days (Kondo et al. 2008, Adams et al. 2009). The presence of local or distant metastasis has been associated with reduced survival times (Henry 1998).
All published work on the CT staging of canine nasal tumours has been from the USA, Japan and Switzerland. The purpose of this study was to assess the presentation of nasal tumours in a UK population using a previously reported CT staging system (Adams et al. 2009), and describe treatment outcomes. Late stage tumours were defined as stage 3 to 4 nasal tumours. It was hypothesized that UK dogs are frequently presented with late stage disease; that this negatively affected choice of treatment and clinical outcome and that time from initial presentation to diagnosis would correlate with tumour stage.
Materials And Methods
- Top of page
- Materials And Methods
The CT database of the Small Animal Teaching Hospital, University of Liverpool was searched for dogs having nasal CT and findings consistent with a nasal tumour (soft tissue opacity within the nasal cavity, turbinate or other bone destruction) between April 2007 and August 2011. Seventy-eight dogs met the criteria. Dogs with no or non-diagnostic biopsies were included if the CT report was consistent with neoplasia.
Medical records were reviewed and the following data was recorded: age, sex, breed, weight, time from initial presentation to the referring veterinary surgeon to referral, staging performed (thoracic CT or radiographs and local lymph node aspiration), presence of metastasis, biopsy result, tumour type, treatment, and time from diagnosis to death (survival time).
Transverse CT images of the head and thorax were acquired from rostral to caudal with the patient in sternal recumbency (Somatom Volume Zoom; Siemens). Postcontrast images were acquired using the same parameters following administration of 740 mgI/kg iopromide, intravenously (370 mgI/mL Ultravist 370; Bayer HealthCare Pharmaceuticals Inc). Images were reconstructed using a soft tissue algorithm (3 mm slice thickness, 3 mm increment) and a bone algorithm (slice thickness (1·25 mm slice thickness, 1·2 mm increment). Images were viewed in transverse and multi-planar format in soft tissue (window level 50, window width 350) and bone (WL 700, WW 4000) windows using proprietary software (OsiriX v.4.1.1; Pixmeo).
One ACVR diplomate and one resident in diagnostic imaging were provided with case numbers and asked to review the CT scans and stage the tumour. Staging was by the modified Adams system (Table 1). In cases where there was disagreement between radiologists (22 cases), they re-reviewed the scan together and made a consensus decision on the tumour stage.
Table 1. Modified Adams CT staging system for canine nasal tumours (Adams et al 2009)
|T1||Tumour confined to one nasal passage with no bone involvement beyond turbinates|
|T2||Any bone involvement beyond turbinates but with no evidence of orbit involvement or subcutaneous/submucosal mass|
|T3 (T3a)||Orbit involved or subcutaneous/submucosal mass (Nasopharyngeal involvement)|
|T4||Tumour causing lysis of the cribiform plate|
Date and cause of death was obtained from patient records or telephone follow-up with referring veterinarians. Where the cause of death or reason for euthanasia was not known, it was assumed to be the nasal tumour. None of the dogs had postmortem examination. Survival time was calculated from the date of CT scan (date of diagnosis) to the date of death to allow comparison between treatment groups.
Treatment groups comprised: (1) No histological/cytological diagnosis-palliative medical care only (NSAIDs± antibiotic±additional analgesia). (2) Definitive diagnosis-palliative medical care (NSAIDS±antibiotic±additional analgesia. (3) Hypofractionated (palliative) radiotherapy and (4) Definitive radiotherapy. A single dog who received epirubicin/carboplatin was excluded from survival analysis. Dogs which received no treatment and/or where owners indicated that they planned to euthanase the dog imminently or elected for euthanasia at the time of diagnosis were grouped separately and excluded from survival analysis.
Median survival times for treated dogs were calculated using Kaplan-Meier survival plots in a commercial package (SPSS 16.0 for Windows; SPSS Inc). Dogs still alive or lost to follow-up were right censored. Kruskall-Wallis test was used to assess significance of time from presentation to referral and log rank tests were used to determine significance of survival times between groups. Fisher's exact test was used to assess significance of tumour stage on treatment group. P<0.05 was used to set significance.
Hypofractionated (palliative) radiotherapy consisted of 4 weekly fractions of 9Gy. Definitive radiotherapy was defined as 12 fractions of 4Gy on a Monday, Wednesday, Friday basis. Patients were treated with a Dual Energy Linear Accelerator (Clinac 2100C; Varian). All treatments were carried out at 6MV, and were 3D planned from CT using Pinnacle (version 8; Phillips Healthcare NV), with the intent to include 95% of the planning treatment volume (planning treatment volume based on clinical target volume plus 0.5 cm, adjusting planned treatment volume margins manually in some cases to spare one eye or brain tissue) in the 95 to 105% isodose (i.e. scheduled dose heterogeneity <15%). Plans utilized three to seven beams, created using a Mark 2 series 80 leaf multi-leaf collimator. Patients were immobilized in a head immobilization device made up of a thermoplastic mask and a customized head support, which were then secured to a plastic base frame with four-point fixation (Kent et al. 2009). Portal imaging was carried out at the time of the first and at the time of the seventh fraction. Dogs having radiotherapy treatment also received non-steroidal anti-inflammatory medications or glucocorticoids and antibiotics as determined by the attending clinician.
This study was carried out under the institution's ethical approval which did not permit contacting the owners of dogs involved in the study.
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- Materials And Methods
These results confirm that dogs with nasal tumours in this UK population are commonly presented late in the disease course. Sixty-six of 76 (87%) dogs were classified as CT stage 3 to 4 (late stage) with 45 (59%) in CT stage 4. Previous studies of dogs receiving definitive radiotherapy or medical palliation reported late stage tumours in 48 to 61% of the population, with stage 4 dogs making up 32 to 38% of the population (Adams et al. 1998, Rassnick et al. 2006, Adams et al. 2009). While the distribution of tumour stage in these previous studies may reflect the fact that dogs with lower stage disease are more likely to receive definitive treatment, two populations of dogs treated palliatively also had fewer late stage tumours than the current population (Rassnick et al. 2006, Gieger et al. 2008). Two studies of dogs receiving hypofractionated radiation protocols showed that 79 to 81% of treated dogs presented with late stage tumours (Buchholz 2009, Maruo et al. 2011); however, these treatment groups do not represent the entire presented population of dogs as hypofractionated protocols are commonly recommended for dogs with late stage tumours. Owner constraints may also influence the decision to pursue hypofractionated versus definitive radiotherapy treatment (Gieger et al. 2008), although this should be equal across groups in this study.
No attempt was made to correlate the time clinical signs were present with the tumour stage at presentation, due to inconsistencies in record-keeping. On review of the records it was found that when recorded, information given to the referring veterinarian often differed from that given to the referral clinician. As owners’ recollections of events could not be retrospectively confirmed, instead, the time from first visit to the referring veterinarian to referral was calculated and the median time for all dogs was 52 days, which is similar to or less than previous studies (Mellanby et al. 2002, Rassnick et al. 2006, Maruo et al. 2011). Late presentation and late referral may both contribute to advanced tumour stage at diagnosis. Future studies are required to try to establish the length of time clinical signs are present before presentation of dogs with nasal tumours, and the significance of this on tumour stage at presentation and outcome with treatment.
Dogs with non-diagnostic biopsies (12) were included in the survival data for medically treated patients, provided they met the CT criteria for consistent with neoplasia, as a study objective was to report CT stage. Patients without biopsy (6) were also included, as these tended to be patients where the client had decided against radiotherapy before the CT scan should the findings be highly suggestive of tumour. Previous studies have shown good correlation between CT findings and histopathology consistent with neoplasia (Burk 1992). Exclusion of these cases would have biased the population, particularly as cases without biopsy were frequently those with advanced CT findings and significant clinical signs. The population with non-diagnostic biopsy had CT staging similar to the overall population (one stage 2, five stage 3a and six stage 4), and survival time was not significantly different between medically managed dogs with a definitive diagnosis versus dogs without diagnosis.
It is widely accepted that nasal biopsies can be non-diagnostic in nasal neoplasia [12 of 72 (17%) in this study] due to local inflammation surrounding the tumour (Meler et al. 2008). Repeat biopsy procedures are often needed to obtain a diagnosis (Withrow et al. 1985). Dogs with non-diagnostic biopsies did not undergo repeat sampling as their owners had elected not to pursue radiotherapy treatment. It is unlikely that dogs with severe inflammatory rhinitis could have inadvertently been included in the analysis given the different CT findings in cases of inflammatory rhinitis from nasal neoplasia (Adams et al. 1998, Henry 1998, LaDue et al. 1999, Mellanby et al. 2002, Yoon et al. 2008, Adams et al. 2009, Hunley et al. 2010, Bommarito et al. 2011, Maruo et al. 2011).
Reported rates of lymph node metastasis at diagnosis range from 6 to 24% (Henry 1998, LaDue et al. 1999, Rassnick et al. 2006). The finding of 13·7% local lymph node metastasis is consistent with previous reports, but only 29 dogs had FNA procedures documented, and the actual rate could be higher. Many dogs in this study did not have local lymph node aspiration performed or this data was not included on the clinical record. In some cases, this was due to owners’ preference; if they elected palliative care only, then this procedure would not have changed the outcome. In other cases, lymph nodes would have been aspirated (as hospital protocol is for all dogs undergoing radiotherapy to have this performed), but a change in the clinical database in 2008 did not consistently archive this information. As metastasis has been shown to negatively affect outcomes and may affect an owner's decision to proceed with radiotherapy treatment, this procedure should be carried out routinely. Pulmonary lesions consistent with distant metastases were present in 7 of 67 (10·4%) dogs which is slightly higher than previous reports (Henry 1998, Rassnick et al. 2006) and may reflect the increased sensitivity for CT over radiography in diagnosis of metastatic disease (Nemanic et al. 2006, Eberle et al. 2011). However, as none of the lesions were cytologically confirmed it is possible that single nodules could represent another disease process.
Median survival times were comparable with those previously reported, despite the late presentation. This is encouraging given that previous patient groups generally had less extensive disease. The previously reported median survival times of around 200 days in stage 4 tumours (Adams et al. 1998, Adams et al. 2009) may influence clients choosing medical palliation over radiotherapy treatment. The study median survival of 427 days for all dogs and 274 days for dogs with cribriform plate involvement treated with radiotherapy is encouraging, and suggests that it is worth pursuing treatment in these patients as good individual outcomes are possible. No attempt was made to attach statistical significance to these figures as the groups were small and further studies with larger numbers of definitively treated patients are required.
Interestingly, three of the six RT dogs alive at the time of analysis had already survived beyond the median. These were all stage 3a dogs, and a sub-set of stage 3a dogs has been reported as having extended survivals in a previous study (Adams et al. 2009). A small number of dogs treated with palliative medical therapy also lived for a long time, which is consistent with a previous study (Rassnick et al. 2006). The longest surviving medically managed dog was also CT stage 3a, suggesting that dogs with this tumour stage may have more tolerable clinical signs than dogs with tumours in other stages. Larger studies on dogs with stage 3a nasal tumours would further quantify this finding.
One dog in this study received chemotherapy as the owners declined radiation therapy due to thoracic metastasis. Whilst it is widely documented that chemotherapy is ineffective in the face of gross disease, there are two small studies on the use of chemotherapy for treatment of canine nasal tumours in which a response was documented in some dogs (Hahn et al. 1992, Langova et al. 2004).
Our median survival times of 114 days with medical palliation and 174 days for hypofractionated radiotherapy protocols were also comparable with previous studies (Mellanby et al. 2002, Buchholz 2009, Maruo et al. 2011). Hypofractionated radiotherapy may be recommended to owners of dogs with late stage tumours due to the perception that outcomes with definitive therapy may be poor and therefore protocols with lesser acute radiation side effects are more appropriate. The decision to pursue this protocol may also be due to financial or logistic considerations.
Our data shows that the group of dogs having definitive radiotherapy was not dissimilar to the group as a whole, but overall dogs with late stage tumours were less likely to have any treatment. This may reflect owners reluctance to pursue treatment if the tumour is extensive or clinicians bias in recommending treatment given previously reported survival times being worse for dogs with late stage tumours.
The reason for the higher number of dogs presenting with stage 4 disease compared to previous studies is not clear and may reflect geographic differences in owners’ attitudes to seeking treatment for clinical signs such as sneezing, snoring, nasal discharge or epistaxis. It may also reflect a failure of veterinary surgeons to diagnose nasal tumours promptly, although a difference between groups in the median time from presentation to referral was not detected, numbers were small and most of the dogs had late stage disease. A small number of dogs in this study (6 of 64) were referred 5 months or more after initial presentation, all of which had late stage tumours at diagnosis.
In conclusion, dogs in this UK referral population were presented with a higher than previously reported prevalence of advanced stage nasal tumours. Despite this, median survival time of this population dogs with cribriform plate involvement was better than previously reported survival times. A few dogs with stage 3a disease had prolonged survival times. Time from first presentation to referral did not correlate with late stage at presentation, but dogs referred late in the course of disease (more than 5 months after first seeing the referring veterinarian) all had late stage tumours. While a significant number of dogs with late stage tumours had definitive radiotherapy, treatment was pursued less often in dogs with late stage tumours than in dogs with early stage disease, and while numbers are small, none of the dogs with stage 2 tumours received palliative radiation therapy.
Veterinary surgeons and owners should be aware of the clinical signs associated with nasal neoplasia and pursue diagnosis early in the course of the disease. Radiotherapy is the treatment of choice and dogs with nasal tumours should be referred to a radiation oncologist to discuss treatment as good outcomes can be achieved, even with late stage tumours.
Conflict of interest
None of the authors of this article has a financial or personal relationship with other people or organizations that could inappropriately influence or bias the content of this paper.