Recurrent Neuroblastoma in the Central Nervous System

Central nervous system (CNS) involvement, although rare at initial presentation, may occur in 3% to 10% of patients with recurrent neuroblastoma. CNS relapses represented 6% of all metastatic relapses in a series of 1,161 first relapses in 1,977 patients with stage 4 disease treated in a trial of patients with high-risk neuroblastoma.[56] Because up-front treatment for newly diagnosed patients does not adequately treat the CNS, the CNS has emerged as a sanctuary site leading to relapse.[56-58]

Significant risk factors for CNS relapse identified in the International Society of Paediatric Oncology Europe Neuroblastoma (SIOPEN) trial were patient and disease features at diagnosis. These features included female sex (HR, 2.0; P = .016), MYCN amplification (HR, 2.4; P = .0008), hepatic disease (HR, 2.5; P = .01), or more than one metastatic system/compartment involvement (HR, 7.1; P = .047). Neither high-dose chemotherapy nor immunotherapy was associated with higher risk of recurrence. Investigators noted stable incidence of CNS relapse reported over time.[56]

CNS relapses are almost always fatal, with a median time to death of 6 months. The 1-year and 3-year postrelapse OS rates were 25% and 7%, respectively, in the SIOPEN trial.[56] Patients with isolated CNS relapses may be able to achieve long-term survival.[56]

Treatment options for recurrent neuroblastoma in the CNS include the following:

Current treatment approaches generally include eradicating bulky and microscopic residual disease in the CNS and minimal residual systemic disease that may herald further relapses. Neurosurgical interventions serve to decrease edema, control hemorrhage, and remove bulky tumor before starting therapy.

A single institution had some success while testing intraventricular compartmental radioimmunotherapy using intrathecal radioiodinated anti-B7H3 monoclonal antibodies, combined with 18 Gy or 21 Gy of craniospinal irradiation with boosts to gross CNS disease, in patients with recurrent metastatic CNS neuroblastoma.[13] The posttreatment 5-year CNS DFS rate was about 69%, and the 5-year OS rate was about 45%.[59][Level of evidence C2]

For patients who experience prolonged survival after an initial CNS relapse, some may develop a second relapse after cranial spinal irradiation (CSI). Published data for patients who experience a second CNS relapse are limited. A second CNS relapse indicates a poor prognosis.[57]

In a single-institution study that included 128 patients treated with CSI for first CNS relapse, 40 developed a second CNS relapse at a median of 6.3 months from the initial CSI treatment. Patient outcomes after second CNS relapse are poor, although treatment with radiation therapy at the time of second CNS relapse may be associated with longer OS.[60][Level of evidence C1]