Our report confirms that ENB is very rare in pediatric age and that its behavior is aggressive, since most children presented with locally disseminated disease. As localized ENB (Kadish stage A) seems to be rare in children, and our series only contained tumors in Kadish stages B and C, our discussion focuses on locally advanced ENB.
Tumor resection is generally the first therapeutic measure in adults with ENB (though this often requires a craniofacial approach), followed by radiotherapy [9
]. Chemotherapy is mainly reserved for patients with advanced, recurrent or metastatic disease. Preoperative radiotherapy in doses in the range of 55 to 65 Gy has been preferred by some authors for stage C ENB [10
]. These procedures are highly aggressive, however, and skull base surgery is particularly difficult in children because of the small size of the area, and because of the bone and neurovascular structures located in the craniofacial region. Up to one in three patients therefore risk postoperative morbidities, including complications involving the local wounds, the central nervous system (e.g. cerebrospinal fluid leakage and meningitis) and the ocular orbit. Postoperative mortality has also been reported in up to 5% of patients [11
]. Radiotherapy may also cause significant late effects in children, including craniofacial growth impairment and damage to the permanent teeth, endocrine dysfunctions, and loss of the sense of smell [12
]. In our series, multiple-agent chemotherapy was adopted systematically and judged preferable to invasive surgery as an initial approach. This had numerous advantages for the patients, since no major surgical complications were reported and tumor shrinkage after chemotherapy meant that delayed surgery could be less aggressive. Unfortunately, complete tumor resection was still very difficult to achieve, but our experience suggests that chemotherapy and radiotherapy may be enough to control postoperative residuals, and some patients were cured without any major surgery.
In our experience radiotherapy is the mainstay of treatment for ENB, as it is for other parameningeal pediatric tumors for which surgery cannot be considered oncologically complete. Two young children in our series were not irradiated and both relapsed locally, but one of them was cured thanks to further treatment, including radiotherapy. Experiences and other data in the literature indicate that irradiation should not be withheld, but future studies should address whether a major response to initial chemotherapy might be enough to reduce the burden of irradiation and its likely long-term sequelae. New techniques, such as proton therapy, may also be helpful to limit the side effects of treatment [13
Our findings show that ENB in children can be considered a chemosensitive tumor. This is in agreement with recent reports of tumor size reductions when chemotherapy was given preoperatively [12
]. The agents most often used in children are doxorubicin, cyclophosphamide/ifosfamide, vincristine, and etoposide, whereas platinum-based regimens are adopted in adults [16
The above drugs were used in our studies too, and gave rise to a satisfactory response rate. The limited number of children in our series made it impossible to analyze the different regimens separately or make any more precise recommendations on the type and duration of chemotherapy. This could be done by considering other experiences too, comparing and discussing our experience with those of other national groups interested in rare pediatric tumors. This is one of the main future goals of the TREP Project. In our opinion, the overall strategy for unresectable tumors may be similar to the one adopted for other parameningeal tumors, namely RMS, for which intensive chemotherapy and early radiotherapy are recommended.
The survival results reported here are higher than those described in previously-published series. This may be due to the systematic use of a multidisciplinary approach in all the patients concerned. It may also be that ENB is more aggressive in children than in adults and/or more sensitive to current treatments. This seems to be the case for other rare tumors that behave differently in different age groups. Unfortunately, the need for an aggressive treatment approach can also mean severe side effects and this issue should be addressed when planning future treatments.