PURPOSE This prospective Brazilian single-arm trial was conducted to determine response to chemotherapy and survival after response-based radiotherapy in children with intracranial germinomas, in the setting of a multi-institutional study in a middle-income country (MIC) with significant disparity of subspecialty care. PATIENTS AND METHODS Since 2013, 58 patients with histologic and/or serum and CSF tumor marker evaluations of primary intracranial germ cell tumors were diagnosed; 43 were germinoma with HCGβ levels ≤200 mIU/mL and five between 100 and 200 mIU/mL. The treatment plan consisted of four cycles of carboplatin and etoposide followed by 18 Gy whole-ventricular field irradiation (WVFI) and primary site(s) boost up to 30 Gy; 24 Gy craniospinal was prescribed for disseminated disease. RESULTS Mean age 13.2 years (range, 4.7-25.5 years); 29 were males. Diagnosis was made by tumor markers (n = 6), surgery (n = 25), or both (n = 10). Two bifocal cases with negative tumor markers were treated as germinoma. Primary tumor location was pineal (n = 18), suprasellar (n = 14), bifocal (n = 10), and basal ganglia/thalamus (n = 1). Fourteen had ventricular/spinal spread documented by imaging studies. Second-look surgery occurred in three patients after chemotherapy. Thirty-five patients achieved complete responses after chemotherapy, and eight showed residual teratoma/scar. Toxicity was mostly grade 3/4 neutropenia/thrombocytopenia during chemotherapy. At a median follow-up of 44.5 months, overall and event-free survivals were 100%. CONCLUSION The treatment is tolerable, and WVFI dose reduction to 18 Gy preserves efficacy; we have demonstrated the feasibility of successfully conducting a prospective multicenter trial in a large MIC despite resource disparity.

Cases Presentations: Case 1: A 1-year-old boy with suprasellar pilocytic astrocytoma with previous history of shunting disfunction, treatment according vinblastine protocol due to anaphylactic reaction with carboplatin presented with ascites and necessity of ventricular-atrial shunt. Due to high protein cerebrospinal fluid (CSF) level (551mg/dl) he was submitted to external ventricular drainage and bevacizumab 10mg/kg was associated to his oncology treatment. After three cycles of bevacizumab, the patients’ CSF protein levels decreased dramatically 178 mg/dL, allowing the shunt procedure without complications and shorter hospital stay. Case 2: A ten-year-old boy with suprasellar pilocytic astrocytoma treated with three lines of chemotherapy showed tumor progression one year after the end of carboplatin-vincristine protocol and shunting disfunction. External ventricular drainage was performed, and the CSF showed 590mg/dl protein level. He was treated with vinblastine 6mg/m2 weekly and bevacizumab 10mg/kg each 14 days. After two cycles of bevacizumab, the protein level was 191mg/dl allowing another V-P shunt procedure. Discussion: Optic pathway gliomas frequently cause elevated cerebrospinal fluid protein concentrations leading to shunts occlusions and failures, necessity of external ventricular drainage and longtime hospitalization, implicating risk of serious infections. Bevacizumab is a monoclonal antibody with immunomodulatory and anti-vascular endothelial growth factor (VEGF) activities that has been used in combination with other chemotherapeutic agents such as irinotecan and vinblastine to treat low-grade gliomas and has been reported to decrease the CSF protein concentration.Final Comments: Bevacizumab treatment in patients with gliomas and high CSF protein levels seems effective in decreasing protein leakage from the vessels to the ventricles, thereby improving the scope for successful shunt placement.

INTRODUCTION: Primary central nervous system germ cell tumors (CNS GCT) are a heterogeneous group of malignancies that can be divided into germinomas and non-germinomatous GCT (NGGCT), accounting for 2-3% of brain tumors in children/adolescents in the Western hemisphere. The study aim is to report the ability to adequately treat Brazilian patients with CNSGCT through a consortium protocol, reporting their treatment, response and survival. Methods: Since 2013, 58 patients with histologic and/or tumor marker (TM) diagnosis of germinoma with/without HCGβ levels ≤200mIU/ml (n=43), five of them between 100-200mIU/ml, received carboplatin/ etoposide (4 cycles) and NGGCT (n=15), received carboplatin/etoposide/cyclophosphamide (6 cycles), all followed by 18Gy ventricular field irradiation and primary site(s) boost. Autologous hematopoietic cell transplant (AuHCT) was undertaken for NGGCT slow responders. Results: Mean age 13.2 years, 42 males. Diagnosis was made by TM (n=19), surgery (n=25) and both (n=12). Two bifocal cases with negative TM and inconclusive biopsy were treated as germinoma. Primary tumor location was pineal (n=30), suprasellar (n=16), bifocal (n=11) and basal ganglia/thalamus (n=1). Eighteen had ventricular/spinal spread. Second-look surgery occurred in seven patients. For the germinoma group, 36 achieved complete responses (CR) after chemotherapy, seven showed residual teratoma/scar. For the NGGCT after 4/6 cycles, six patients showed CR, two failure/progression and seven partial responses (five with negative TM). Two with positive TM underwent AuHCT. Radiotherapy was utilized as described, except in three patients. Four NGGCT patients died (two disease progression, two other causes with no disease). Toxicity was mostly grade 3/4 neutropenia/thrombocytopenia during chemotherapy. At a median follow-up of 40 months, event-free and overall survival was 100% for germinoma and 64.5% NGGCT. Conclusion: The proposed treatment was feasible to be performed in a developing country, with suitable survival even with VFI dose reduction to 18Gy.