Concurrent Chemoradiotherapy as an Adjuvant Treatment of Primary Central Nervous System Neuroblastoma

We report a case of a primary CNS neuroblastoma in a 20-year-old woman without past medical history who presented with increased intracranial pressure symptoms and progressive headaches, vomiting, and vision disturbances. Neurological examination revealed no other anomalies such as cerebral motor dysfunction or balance or speech disorder.

Magnetic resonance imaging (MRI) of the brain before and after gadolinium injection showed a right frontal tumor measuring 71 × 78 × 60 mm with a polylobed cystic component and diffuse contrast enhancement. Invasion of the corpus callosum and the contralateral cerebral hemisphere were noted with substantial perilesional edema and cerebral herniation. Perfusion was clearly increased. Spectroscopy documented a clear increase of choline with collapse of the N-acetyl aspartate peak without any other metabolite detected elsewhere. The morphological aspect, contrast enhancement, and spectroscopy were in favor of a high-grade neuroglial tumor.

A craniotomy was performed with incomplete tumor removal. Histological diagnosis was CNS neuroblastoma Foxr2- and OLIG2-positive. Metastatic workup included a supine MRI, lumbar puncture, and thoracic-abdominal-pelvic computed tomography, which showed no distant metastases. The cerebrospinal fluid showed no evidence of viable tumor cells. The postoperative course was uneventful; the patient did not show any neurological deficit. The postoperative MRI showed a subtotal tumor resection (Figure 1). The patient was finally diagnosed with primary cerebral neuroblastoma.

Based on multidisciplinary decision the patient was planned for concomitant chemoradiotherapy. The patient underwent adjuvant 3D conformal radiotherapy. A planning computed tomography (CT) scan was performed in the supine position with 3 points-head immobilization mask. CT images were not contrast-enhanced and were acquired with a 1- to 1.5-mm slice thickness. Treatment planning was carried out with Monaco treatment planning system (version 5.1) using a collapsed cone algorithm. Contrast-enhanced MRI scans were fused with planning CT to aid target delineation. Two clinical target volumes (CTV) were defined: for the primary tumor (CTVp) and brain. The CTVp was the tumor volume prior to surgical resection as defined by MRI with a 1-cm expansion. CTV brain corresponded to the whole brain. Planning target volume was defined by a 5 mm CTVp and CTV brain expansion (Figure 2).

The prescription dose was 30.6 Gy to the whole brain and 23.4 Gy boost to the initial tumor bed, delivered in 1.8-Gy single daily fractions, with 5 fractions per week. Radiotherapy was delivered with 6- and 18-mV photon beams. The treatment plan was optimized using beam modifiers such as wedges, angles, collimator angles, multiple leafs collimators, and field-in-field technique in order to respect the dosimetric constraints of the organs at risk (brainstem, bilateral optic nerves, chiasma, eyes, and brain) (Figure 3). Concomitantly, the patient received chemotherapy with a combination of cisplatin (100 mg/m²/d) and etoposide (120 mg/m²/d), for 3 days every 4 weeks. Chemotherapy was interrupted due to grade 3 neutropenia after the second and third course. Radiotherapy was poorly tolerated too, with symptoms of increased intracranial pressure such as headaches and a right hemiparesis; the patient was put on corticosteroids with a good response. A timeline of the case appears in Table 1.

The patient was followed up regularly for 14 months, with physical examination and brain MRI every 3 months. MRI at 3 months post-radiation showed a 32% regression of the tissue component of the frontal lesion. The patient remained stable and free of distant metastases for 14 months after the end of radiation treatment (Figure 1). Radiotherapy was well tolerated in the long term. No cognitive impairment, sensory motor deficits, or alopecia were reported. The patient has returned to normal life and resumed full-time engagement with her occupations.

Primary CNS neuroblastoma mostly occur in the first decade, with 26% of cases in children under 2 years old; it is rarely reported in adults. It is located in the cerebral hemisphere, most often in the parietal and frontal lobes.^5,6 The World Health Organization 2016 classification of CNS tumors defined primary CNS neuroblastoma as an embryonal tumor characterized by poorly differentiated neuroepithelial cells, groups of neurocytic cells, and variable neuropil-rich stroma.¹ Based on their histological features and clinical behavior, these tumors are considered highly malignant tumors.⁷ However, in the literature disease-related mortality is 12.5%, lower than generally reported for other embryonal tumors.⁴ In line with its preferential supratentorial location, the clinical presentation of CNS neuroblastoma varies from signs and symptoms related to focal mass effects (neurological deficits), seizures, and neurocognitive impairment, to signs of increased intracranial pressure due to impairment of cerebrospinal fluid pathways such as headache, vomiting, and abnormal head circumference growth^{8 9,10}

The diagnosis of a primary CNS neuroblastoma is most commonly performed on the removed tumor tissue at the time of the histological examination. The basic appearance of magnetic resonance sequences is not unique to the disease. In most cases, the tumor appears heterogeneous due to the common coexistence of solid and cystic components and is apparently separated from the normal CNS tissue.¹¹ However, solid tumors have been described. The solid part is usually isointense and may also not partially enhance after the administration of gadolinium. Surrounding edema is inconsistent, whereas vascular structures crossing the tumor are not uncommon. Spectroscopy shows an increase in the choline peak and inversion of the choline/N-acetyl aspartate rate, indicating an aggressive brain tumor, but again this is not a unique feature of primary CNS neuroblastoma. Perfusion sequences show elevated values of relative cerebral blood volume with a tendency to recover the slope.¹²

Due to the rarity of these malignancies, data regarding their optimal therapeutic management are inconclusive. However, most authors recommend surgery as the first line of treatment for primary CNS neuroblastoma with the aim of complete tumor resection whenever possible.¹³ Adjuvant management of primary CNS neuroblastoma remains controversial. Lu et al used the SEER (Surveillance, Epidemiology, and End Results) database to identify patients diagnosed with primary CNS neuroblastoma from 1973 to 2013, including 300 patients;² however, data regarding adjuvant treatment were insufficient and therefore not included in the analysis. Earlier reports showed high rates of local failure with surgery alone, suggesting the potential benefit of adjuvant radiotherapy in local control improvement.^13-15 In our case, the treatment protocol we adopted was detailed.

Radiotherapy as an adjuvant method for the primary site is a standard procedure for high-risk extracranial neuroblastomas, which could effectively reduce recurrence of the primary site,¹⁵ but its effects in patients with primary CNS neuroblastoma have not been evaluated. In addition, data regarding target volumes and optimal doses are lacking, and reported radiotherapy modalities are inconsistent. Our patient had 30.6 Gy to the whole brain with a 23.4 Gy boost to the initial tumor bed. In the absence of any evidence of the tumor’s spread in the supine MRI and spinal tap, we decided to omit spinal axis radiotherapy and avoid the increased chance of radiation toxicity. Bennett et al suggested that prophylactic whole-brain and spinal irradiation was probably justified because of the propensity of primary site recurrence and cerebrospinal metastases.¹⁶

The side effects of radiotherapy on the CNS remain an important problem, especially for younger patients with underdeveloped CNS. Problems such as parenchymal radionecrosis could disable late cognitive function and result in other side effects, such as to the lung, heart, or kidneys.^17,18 Berger et al showed that receiving radiation therapy as an adjuvant treatment improved overall survival in their 11-case series.¹⁹ Chemotherapy has been performed most frequently as adjuvant treatment. Due to their histological aggressiveness and brain location, CNS neuroblastoma are treated according the supratentorial primitive neuroectodermal tumor protocols.²⁰ Chemotherapy combined with radiotherapy has occasionally been used in early series, and favorable clinical responses were obtained.²¹ Berger et al recommended chemotherapy for patients whose tumors were subtotally resected.¹⁹ For nonmetastatic tumors, therapy with multiple chemotherapeutic agents is considered. The most common ones are vincristine, lomustine, cisplatin, and etoposide. In our case, the protocol used associated VP1-6 and carboplatin. This protocol was poorly tolerated by our patient, who developed grade 3-4 neutropenia; the interruption of chemotherapy was necessary. Other less-toxic protocols need to be evaluated.

In the other hand, radiotherapy was completed at 54 Gy with good outcomes and late tolerance, including tumor stability after 14 months and the absence of cognitive impairment. When compared with the efficacy of radiation in managing high-risk neuroblastoma, adjuvant radiotherapy should be considered for primary CNS neuroblastoma, especially in patients with high-grade tumors and subtotal resection.