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Dose‐escalated simultaneously integrated boost radiation protocol fails to result in a survival advantage for sinonasal tumors in dogs

Abstract The prognosis for canine sinonasal tumors remains rather poor despite definitive‐intent radiotherapy (RT). Theoretical calculations predicted improved outcomes with simultaneously integrated boost (SIB) protocols. With the hypothesis of clinically detectable differences in outcome between groups, our retrospective study evaluated prognostic variables and outcome in dogs treated with regular versus SIB RT. Dogs with sinonasal tumors treated with either a regular (10 × 4.2 Gy) or new SIB protocol (10 × 4.83 Gy to macroscopic tumor) were included. Information regarding signalment, tumor stage, type, clinical signs, radiation toxicity, response, and outcome was collected. Forty‐nine dogs were included: 27 treated regularly and 22 treated with SIB RT. A total of 69.4% showed epistaxis, 6.1% showed epileptic seizures, 46.9% showed stage IV tumors, and 6.1% showed lymph node metastases. Early toxicity was mostly mild. Late grade 1 skin toxicity (alopecia/leucotrichia) was seen in 72.1% of dogs, and a possible grade 3 ocular toxicity (blindness) was seen in one dog. Complete/partial resolution of clinical signs was seen in 95.9% of patients as best clinical response and partial remission was seen as best imaging response in 34.7%. The median progression‐free survival (PFS) was 274 days (95% CI: 117–383) for regular and 300 days (95% CI: 143–451) for SIB RT, which was not significantly different (P = 0.42). Similarly, the median overall survival (OS) was 348 days (95% CI: 121–500) for regular and 381 days (95% CI: 295–634) for the SIB RT (P = 0.18). Stratified by protocol, the hazard ratio of stage IV versus stage I–III tumors was 2.29 (95% CI: 1.156‐4.551, P = 0.02) for OS but not PFS. All dogs showed acceptable toxicity. In contrast to theoretical predictions, however, we could not show a statistically significant better outcome with the new protocol.


INTRODUCTION
While radiation therapy (RT) is the standard of care for sinonasal tumors in dogs, the prognosis remains fair to poor. Prognosis depends in part on tumor stage, histologic type, and differentiation, but radiation dose and fractionation most likely also play a role. [1][2][3][4] Several definitive-intent, moderately to severely hypofractionated RT protocols are used in dogs. 1,[3][4][5][6][7][8] The term hypofractionation is defined as fraction size > 2 Gy in human radiation oncology, while regular irradiation protocols use 2 Gy per fraction. In veterinary radiation oncology, however, most or all fractionation schedules use larger fraction sizes.
Definitive-intent protocols usually use daily fractions of 2.5-3 Gy with total dose > 40 Gy and are sometimes called finely fractionated protocols, whereas palliative protocols often use once-or twice-weekly fractions of 5-8 Gy with total dose < 40 Gy and are termed coarsely fractionated protocols. 9 To date, it is unclear which total dose or fractionation is best to achieve long-term control. The goal of a simultaneously integrated boost (SIB) radiotherapy protocol is to increase the dose to the part of the target volume with the highest tumor cell density (gross tumor volume, GTV) and possibly increased risk of failure, while treating the remaining volume (clinical target volume (CTV, microscopic disease) and planning target volume (PTV, setup uncertainties) with the regular dose during the same treatment session, thereby limiting radiation toxicity. [10][11][12][13] Compared to the newly emerging stereotactic protocols, a SIB protocol combines the benefit of a higher total dose with the advantage of fractionation. Reoxygenation of hypoxic tumor areas and redistribution of tumor cells to more sensitive cell cycle phases between fractions increase the antitumor effect. 14,15 An early fractionated SIB RT study showed severe (fatal) early radiation toxicity in dogs with sinonasal tumors, and such protocols were henceforth not further investigated prior to the advent of highly conformal radiation therapy. 10 Theoretical tumor control probability computations in a previous study foresaw an increase in the 1year tumor-control probability from 29% (found as clinical outcome data by Lawrence et al. 2010) to 74% when using a SIB protocol of 10 × 4.83 Gy to the gross disease instead of the regular 10 × 4.2 Gy protocol and predicted acceptable toxicity with highly conformal RT. 12 A clinical pilot study used the same SIB protocol with intensitymodulated radiation therapy (IMRT) and reported tolerable early toxicity. 11 In this study, we evaluated prognostic variables, progression-free survival (PFS) and overall survival (OS) in dogs with our regular 10 × 4.2 Gy versus a SIB protocol; we hypothesized that dogs treated with the SIB protocol would show significantly longer PFS/OS and a higher progression-free rate at 1 year.

Case selection
Dogs were included under the following criteria: nonhematopoietic, cytologically or histologically confirmed, newly diagnosed sinonasal tumors of all stages, without pulmonary metastasis, and RT with either a definitive-intent daily (Monday-Friday) 10 × 4.2 Gy protocol (group 1) or SIB protocol with 10 × 4.2 Gy +20% to the GTV (group 2). Signalment, lymph node status, tumor type, location, stage, and clinical signs were documented. 3 The minimal pretreatment staging workup included hematology, serum biochemistry, bilateral mandibular lymph node cytology, CT of the head, and thoracic radiographs or CT.
This study was originally planned as a prospective, randomized, con-

Treatment setup, contouring, planning
The CT characteristics and positioning are described in Appendix 1. Contouring of organs at risk (eyes, lenses, lacrimal glands, brain) and target volumes was performed as previously described. 11 This study was originally planned as a prospective, randomized, controlled clinical trial. A power analysis for the computation of the optimal sample size was therefore conducted. It was based on the outcome (percentage of patients free of progression at 1 year) of a previously published study where the same standard protocol and treatment technique (IG-IMRT) was used. 4 Calculation was performed with a power of 80%, significance level (Alpha) set at 5% and dropout rate equal to 5% when applying a two-sided log-rank test using the formula of Schoenfeld. 24 We assumed that a simultaneously integrated boost of 20% would increase the tumor control probability from 29% to 74% at one year, as proposed by a theoretical planning study. 12 Given a drop-out rate of 5%, for a power of 0.80, the sample size needed is

Case selection
Forty-nine dogs were included ( Figure 1). In total, 27 dogs were treated with the regular 10 × 4.2 Gy, and 22 dogs were treated with the SIB protocol.

Dog and tumor characteristics
Details regarding signalment, clinical signs, pretreatment, tumor type, location, and stage are described in Table 1 and Appendix 1. There were no statistically significant differences between groups 1 and 2 (P-values > 0.05). The majority of dogs (57.1%) had carcinomas, and almost one-third (30.6%) had sarcomas. Other tumor types were angiofibroma (n = 1), extensive polyp (n = 1), and esthesioneuroblastoma (n = 1), and nasal biopsies were nondiagnostic, but CT showed clear signs of bony lysis (n = 4). In one of the latter, esthesioneuroblastoma with distant metastasis was diagnosed at necropsy.
Clinical signs are described in Table 1

Treatment setup, contouring, planning
Delineation of GTV and PTV was performed as described in Section 2 in all dogs, delineation of CTV adhered to the rules in 41 dogs and devi-

Follow-up and response
Clinical and imaging responses are described in Appendix 3. More than

Radiation toxicity
Radiation toxicity is shown in Five dogs were euthanized due to epileptic seizures. In all dogs, local progressive disease rather than radiation toxicity was suspected.

Outcome
The partial imaging remission 6 months after the end of RT and was humanely euthanized due to breathing difficulties 500 days after RT.
This was most likely due to the previously known heart disease according to the owner (but no imaging or information from the private veterinarian was available).

DISCUSSION
In contrast to theoretical predictions, neither median progression-free survival nor overall survival at 1 year was significantly longer in dogs treated with the SIB protocol than in those treated with our regular protocol. While radiation toxicity has decreased with more conformal Most studies reported OS after RT in the past, and only a few reported progression-free-interval or -survival. In the current study, we chose PFS as a conservative measure (as the endpoint is either progression or death) but also described the 1-year progression-free rate, which was 40.7% with the regular protocol and 45.5% with the SIB protocol. This is higher than the 29% reported by Forrest et al. 30 Despite theoretical calculations by Gutierrez et al. 12 predicting a marked increase in tumor control probability with an increase in GTV dose to 48.3 Gy, our study could not demonstrate improved outcome with the SIB protocol, in line with prior findings of Bradshaw et al. 31 Multivariate analysis showed no significant difference in PFS or OS between the different protocols. While hazard ratios of <1 suggested a possible protective effect of the SIB protocol, the confidence intervals contain 1; therefore, there was no statistical significance between the two protocols.
Our study included a high percentage of dogs with epistaxis (69.4%), stage IV tumors (46.9%), and stage IV tumors with marked intracranial invasion (14.3%), all of which were found to be negative prognostic factors in previous studies. [2][3][4]8,32,33 This might point toward a population with advanced disease and could explain the rather poor outcome, even though those factors were not found to be of importance in our study.
Predictions based on theoretical calculations depend on assumptions made and can therefore be flawed. In the study by Gutierrez et al., for example, computations were made using human data (due to lack of appropriate dog data). 12 This could be a possible reason why we could not detect a difference between the two protocols. Another possibility would be insufficient dose escalation, as the theoretical tumor control probability at one year was higher (86%) when the dose to the GTV was escalated to 51.3 Gy according to the abovementioned calculations.
We used a fractionated approach to total dose escalation with a subvolume (GTV) receiving a higher dose. Dogs treated with the doseescalated SIB protocol showed similar early and late radiation toxicity compared to the regular protocol (descriptive statistics only, due to small groups), and toxicity was clinically acceptable in all dogs. This is different from SBRT protocols, where severe (grade 3) presumed late toxicity was seen in 12-38% of dogs. 5 As most dogs with nasal tumors show visible remaining tumors after radiation therapy, this is most likely true for the intracranial part as well.
As long as there is a space-occupying lesion in the region of the olfactory bulb/frontal lobe, seizures can occur.
One ( 29 The question of whether GTV/CTV was adequate in our study remains unanswered, as mentioned below.
End of RT imaging response is rarely reported in dogs. 35  In conclusion, dogs treated with dose-escalated SIB RT showed clinically acceptable toxicity. In contrast to theoretical predictions, however, there was no significant difference in outcome compared to the regular protocol. Given the well-tolerated side effects, a higher boost dose/other protocol adjustments should be considered.

ACKNOWLEDGMENTS
Open Access Funding provided by Universitat Zurich.