Clinical outcomes, Kadish-INSICA staging and therapeutic targeting of somatostatin receptor 2 in olfactory neuroblastoma

Abstract

Introduction: Olfactory neuroblastoma (ONB) is a rare cancer of the sinonasal region. We provide a comprehensive analysis of this malignancy with molecular and clinical trial data on a subset of our cohort to report on the potential efficacy of somatostatin receptor 2 (SSTR2)-targeting imaging and therapy.

Methods: We conducted a retrospective analysis of 404 primary, locally recurrent, and metastatic olfactory neuroblastoma (ONB) patients from 12 institutions in the United States of America, United Kingdom and Europe. Clinicopathological characteristics and treatment approach were evaluated. SSTR2 expression, SSTR2-targeted imaging and the efficacy of peptide receptor radionuclide therapy [PRRT](177Lu-DOTATATE) were reported in a subset of our cohort (LUTHREE trial; NCT03454763).

Results: Dural infiltration at presentation was a significant predictor of overall survival (OS) and disease-free survival (DFS) in primary cases (n = 278). Kadish-Morita staging and Dulguerov T-stage both had limitations regarding their prognostic value. Multivariable survival analysis demonstrated improved outcomes with lower stage and receipt of adjuvant radiotherapy. Prophylactic neck irradiation significantly reduces the rate of nodal recurrence. 82.4% of the cohort were positive for SSTR2; treatment of three metastatic cases with SSTR2-targeted peptide-radionuclide receptor therapy (PRRT) in the LUTHREE trial was well-tolerated and resulted in stable disease (SD).

Conclusions: This study presents pertinent clinical data from the largest dataset, to date, on ONB. We identify key prognostic markers and integrate these into an updated staging system, highlight the importance of adjuvant radiotherapy across all disease stages, the utility of prophylactic neck irradiation and the potential efficacy of targeting SSTR2 to manage disease.

Keywords: Adjuvant; Diagnostic imaging; Esthesioneuroblastoma; Human; Olfactory; Prognosis; Radiotherapy; Receptors; SSTR2 protein; Somatostatin.

Conflict of interest statement

Conflict of interest statement NL receives research funding from Merck Inc., not related to this manuscript, and was a consultant for CoolTech Inc. and holds stock in Navigen Pharmaceuticals, both of which are unrelated to this manuscript. SW is on the advisory board of ALK, Genentech, OptiNose, SinopSys and a Consultant to NeurENT, Stryker, all of which are unrelated to this manuscript. All other authors declare no potential relevant conflicts of interest.

Copyright © 2021 Elsevier Ltd. All rights reserved.

Figures

Figure 1:. Clinical characteristics of olfactory neuroblastoma.

A) Anatomical localization and representative images of histology (H&E staining), expression of common markers (S100, chromogranin A, synaptophysin) and SSTR2, which were assessed by immunohistochemistry; B) Heatmap representation of clinical annotations; C) Bar graph representation of common symptoms at presentation; D) Kaplan-Meier overall survival of primary cases.

Figure 2.. Survival outcomes of primary cases by clinicopathological characteristics and treatment approach.

Univariable and multivariable Cox regression survival analysis of clinicopathological characteristics and treatment approach.

Figure 3.. Survival outcomes of primary cases by clinicopathological characteristic.

A) Kaplan-Meier survival of Hyams Grade. B) Kaplan-Meier survival curve of Kadish-Morita stage. C) Kaplan-Meier survival curve of Dulguerov T-stage. D) Kaplan-Meier survival curve of a modification of the Kadish-Morita staging, which stratifies the Kadish C group into those who present with or without dural infiltration.

Figure 4.. Survival outcomes of primary cases by clinicopathological characteristics and treatment approach.

A)-D) Kaplan-Meier survival analyses demonstrating survival differences between patients who receive adjuvant radiotherapy and those who do not; further analyses of early-stage patients also demonstrated. E) Number of recurrences (occurring 10 years post-initial diagnosis of the primary or earlier) at the cervical lymph nodes, considering receipt of adjuvant radiotherapy to the primary tumor only, compared to additional prophylactic neck irradiation. Kaplan-Meier event-free (where event is cervical lymph node recurrence) survival analysis demonstrating the difference in the incidence of cervical lymph node recurrence between patients who receive adjuvant radiotherapy to the primary tumor only, compared to the ones who receive additional prophylactic neck irradiation.

Figure 5:. Confirmation of SSTR2 expression in local recurrences and metastases and clinical trial on Somatostatin receptor (SSTR) 2-positive olfactory neuroblastoma.

A) Representative images of SSTR2 expression, with corresponding H&E, in local recurrence and lymph node metastasis, determined by IHC. B)-D) Immunohistochemical characterization of tumor biopsies (SSTR2 and Chromogranin correlation of SSTR2 IHC with in vivo uptake of 68Ga-DOTATATE in PET MRI imaging of 3 patients who were enrolled in the LUTHREE trial (NCT03454763) and underwent SSTR2-targeted peptide-radionuclide receptor therapy (PRRT). Pre-treatment 68Ga-DOTATATE PET MRI with corresponding MRI and subsequent MRI 1-year post-treatment.

Figure 6:. Kadish-INSICA staging system.

Definitions and proposed management guidelines.