Proton re-irradiation of Sinonasal Esthesioneuroblastoma: a Case Report

1. Introduction

Esthesioneuroblastoma (ENB) was first described in 1924 by Berger et al. [1]. ENB is a rare tumor originating from the olfactory neuroepithelium of a sinonasal cavity, accounting for 3% of all intranasal cancers [2]. ENBs have various biological behaviors, from benign to highly aggressive. Even if benign, most cases are diagnosed with locally advanced tumors, infiltrating skull base, orbits, intracranial foramens, etc. These features usually make impossible the radical surgery. Thus, radiotherapy (RT) is recommended as adjuvant or primary treatment in advanced tumors. The dose usually ranges from 50 to 66 Gy, while higher levels can damage the organs at risk (OAR), located in a skull base [3]. Locoregional recurrence after prior therapy continues to be the most frequent pattern of failure in EBNs. Stereotactic RT-techniques can be used in case of small recurrence [4]. With its known dosimetric and radiobiological advantages, proton therapy can be effectively used to irradiate large tumor volumes.

2. Case report

In January 2016, a 49-year-old woman with a relapse of EBN, raised from the right side of the nasal cavity and extended to the skull base, was presented to the institutional tumor board. She had her first treatment for EBN (Hyams grade 2, Kadish-Morita stage D) in 2001, with partial resection, followed by radiotherapy 60Gy in 30 fractions (Fx), provided via 60Co-unit. The patient had stable disease until 2016, when tumor relapsed and started to grow, so the patient was transferred from a regional hospital to A.Tsyb MRRC Proton Center. As biopsy from the recurrent tumor (rT4bN0M0) was not available due to localization, so we accepted radiographic signs as sufficient to confirm the relapse.

The recurrent tumor (Fig. 1A) involved optical nerves and chiasm, even though the patient had no vision problems. The surgery was not feasible, and without biopsy, the chemotherapy could not be properly selected. The case was discussed within the tumor board, and since there were no MRIsigns of brain necrosis, re-irradiation with protons was recommended.

The 2nd RT-course was delivered in January-February 2016 via a fixed horizontal spot-scanning synchrotron-based proton beam in a seated position (5). The thermoplastic mask and daily image guidance were used to reduce positioning errors. A dose of 50 Gy in 25 Fx was chosen as our compromise between effective tumor control rate and a vision loss risk, even we considered the dose from prior course as not very relevant after 15 years interim.

Fig. 1. Diagnostic MR-imaging before PT in 2016 (A), VGTV=110.8 cm3, and after 5 years, in 2021 (B), VGTV=93.9 cm3.

Table 1. Approximate cumulative BED to the OARs (α/β = 3)

General tumor volume (GTV) was delineated based on MRI and CT coregistration, and a 3 mm margin was added to make PTV (planning tumor volume). The GTV volume was 110.8 cm3, and the final PTV was 214.3 cm3. Prior 2D RT-plan from 60Co-machine was reconstructed and roughly estimated. The biological effective doses (BED) to the critical structures were calculated to approximate the cumulative limits (Table 1), taking in account also the long interval from the first RT-course.

The PT-dose distribution is shown in Figure 2. The V95 (volume receiving 95% of the prescribed dose) was 92.4%. The maximum dose (Dmax) to the brain stem was 47.9 GyRBE (relative biological efficacy, equal to 1.1). The right visual nerve received 43.6 GyRBE (Dmax), and the left nerve had 46.9 GyRBE. The dose to the chiasma was 40.7 GyRBE. Mean doses to the right and left cochleas were 21.8 GyRBE and 17.0 GyRBE, respectively. Mean dose to the right temporal lobe was 4.5 GyRBE, to the left – 0.7 GyRBE.

Fig. 2 Dose distribution of the proton therapy plan (Intensity-modulation PT, JSC Protomtm TPS).

The patient tolerated PT very well. The acute toxicity was presented by local nasal mucositis (grade 1-2). At 6 months after reirradiation, the follow-up MRI described an 18% decrease in volume (stable disease). The last check-up was performed in February 2021 showing that the recurrent tumor is still controlled (Fig. 1B). No late toxicity has occurred during follow-up (e.g., vision problems or neurocognitive dysfunction), so patient’s quality of life was preserved.

3. Discussion

Local recurrence is the main problem in the management of ENB, reported in 1 /3 of the patients [3]. The choice of treatment depends upon the type of relapse and prior treatment received. Interest in re-irradiation is growing along with the development of new and precise RT techniques, e.g., intensity-modulated RT or proton therapy. Even though re-irradiation is still challenging: professionals have to find a frail balance between RT-dosing and OAR sparing. For small tumor volumes, far enough from the critical structures, stereotactic RT can usually be an effective and safe option [4,6]. Takiar et al. assumed the irradiation volume > 50 cm3 as an indication of poor outcomes, associated with severe toxicity. The PT was shown as an effective treatment with reasonable toxicity in limited series, even for large tumor extension [7]. In 2016, Phan et al. published the results of proton re-irradiation in H&N cancers in 60 patients, demonstrating 1year overall survival (OS) 83.8% and grade 3 late toxicity rate of 16.7% [8]. The study by McDonald et al. included 61 patients, retreated with PT for H&N recurrence or second primary tumor, and 2-year OS was 32.7%. Grade ≥3 toxicities were recorded in 14.7% [9]. Romesser et al. described a 25.1% risk of failure in 12 months and a favorable toxicity profile after PT re-treating of 91 patients [10].

Regarding our case, PT re-irradiation helped achieve 5-year tumor local control without remarkable brain toxicity or vision loss, obviously with cumulative doses to the OARs potentially maxed out.

4. Conclusion

In selected patients, re-RT can be an effective treatment, with acceptable risks of adverse events. From our point of view, PT is the optimal choice for re-irradiation of large tumor volumes, as illustrated in this case.

Abbreviations

CT – computer tomography

ENB – esthesioneuroblastoma

Fx – fraction

GTV – gross tumor volume

Gy – Gray

H&N – head and neck

MRI – magnetic resonance imaging

OAR – organ at risk

PT – proton therapy

PTV – planning tumor volume

RBE – relative biological efficacy

RT – radiotherapy

Statements

Authors’ contributions: KG, IG conceived and planned the case report. KG, AS, OG, DG,

OL, KM, SK, SD carried out the treatment and planning. KG, IG contributed to the interpretation

of the results. KG, IG took the lead in writing the manuscript. SI, AK made the final approval. All

authors provided critical feedback and helped shape the research, analysis and manuscript.

Consent for publication: As corresponding author, I confirm that the manuscript has been

read and approved for submission by all named authors.

Conflict of interests: The authors have no conflicts of interest to declare.

Written informed Consent for Publication of case. The informed consent was obtained

from the patient for publication of this case report and any accompanying images.

Funding Sources: none.

Ethical Approval: The treatment strategy in this case was approved by a local tumor board.

Statement of Ethics: The accompanying manuscript does not contain any studies carried

out by the authors on humans or animals.

Availability of data: The data used to support the findings of this study is restricted by the

Ethical Committee of A. Tsyb MRRC in order to protect patients privacy. Data is available upon

request from the corresponding author for researchers, who meet the criteria for access to

confidential data

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