Metastatic Esthesioneuroblastoma: A Systematic Review and Meta-analysis

Background Patients with esthesioneuroblastoma (ENB) frequently develop metastatic disease, and this feature significantly increases mortality.^{1, 2} However, limited data currently exist regarding the specific implications of distant metastatic disease beyond the cervical lymph nodes. Several factors are contributory. First, these patients are often categorized along with patients exhibiting neck metastases alone due to staging convenience (i.e., Kadish)³ and overall disease rarity; next, previous investigation of this topic is largely confined to case reports and case series from tertiary referral centers.⁴ As a result of these limitations, little is known about the clinical relevance or best management practices for patients with disseminated ENB.

Objective To determine the clinical implications and review the management strategies for ENB with distant metastases.

Methods A systematic review and meta-analysis was performed from 1995 to June, 2017 for English language studies with data regarding incidence, survival, or treatment of ENB with distant metastases (full study selection outlined in [Fig. 1]). Distant metastatic disease was defined as systemic disease beyond the head and cervical lymph nodes. In addition, we conducted a retrospective analysis of all patients who developed disseminated ENB at our institution (synthesis of these data also outlined in [Fig. 1]).

Results Two hundred and fifty-six unique articles were identified, 48 of which met inclusion criteria for analysis of incidence, survival, and/or treatment. The overall incidence of distant metastases was 12% (83 out of 678). The median time-to-distant metastases was 12 months (range = 0.75–276). The distant metastases-free survival significantly differed depending on primary treatment (p = 0.041; [Fig. 2A]). Overall survival was not significantly influenced by the location of distant metastases (p = 0.30; [Fig. 2B]) or platinum versus nonplatinum chemotherapy regimens (p = 0.88; [Fig. 2C]). Multimodality treatment consisting of chemotherapy in combination with surgery and/or radiation exhibited the best overall survival when compared with monotherapy and no treatment (p < 0.001; [Fig. 2D]). However, most patients received either no therapy or monotherapy (66%) despite insignificant differences in the number and location of metastases among the three treatment groups (p = 0.85). Older age was also associated with worse survival (p = 0.007). Both treatment modality (p < 0.001) and age (p = 0.002) were significantly associated with overall survival on multivariable analysis (Table 1). A total of 21 different chemotherapy regimens were used across all studies.

Conclusion Distant metastases with ENB are uncommon but portend a poor prognosis. Management strategies for patients varied considerably. Combination therapy was associated with improved overall survival. These results establish a standard of care for patients with metastatic ENB until more definitive evidence is obtained. Further research into systemic therapeutic regimens for these patients is critical. The degree of patient care variation underscores the importance of multi-institutional participation in prospective single arm or randomized investigation into the best medical management for these patients.

Fig. 1 Overview of study selection and data synthesis of our case series.

Fig. 2 Survival rates for (A) distant metastases-free survival following date of primary ENB diagnosis, (B) overall survival (OS) by location of distant metastatic disease, (C) platinum versus nonplatinum chemotherapy regimens, and (D) by treatment approach for metastatic disease, from the date of diagnosis of metastatic disease.

Table 1 Overview of all analyses performed examining factors influencing overall survival following onset of distant metastases and metastases-free survival following primary diagnosis of ENB.