Background: Metronomic chemotherapy (MC) is defined as the frequent administration of chemotherapy at doses below the maximal tolerated dose and with no prolonged drug-free break. MC has shown its efficacy in adult tumor types such as breast and ovarian cancer and has to some extent been studied in pediatrics.Objective: To assess the anti-tumor activity and toxicity of a four-drug metronomic regimen in relapsing/refractory pediatric brain tumors (BT) with progression-free survival (PFS) after two cycles as primary endpoint.Methods: Patients ≥4 to 25 years of age were included with progressing BT. Treatment consisted of an 8-week cycle of celecoxib, vinblastine, and cyclophosphamide alternating with methotrexate. Kepner and Chang two-steps model was used with 10 patients in the first stage. If stabilization was observed in ≥2 patients, 8 additional patients were recruited. Assessment was according WHO criteria with central radiology review.Results: Twenty-nine patients (27 evaluable) were included in two groups: ependymoma (group 1, N = 8), and miscellaneous BT (group 2): 3 medulloblastoma (MB), 5 high grade glioma (HGG), 11 low grade glioma (LGG), 2 other BT. After first stage, recruitment for ependymoma was closed [one patient had stable disease (SD) for 4 months]. Cohort 2 was opened for second stage since 1 HGG and 3 LGG patients had SD after two cycles. Recruitment was limited to LGG for the second stage and 2 partial responses (PR), 6 SD and 2 progressive disease (PD) were observed after two cycles. Of these patients with LGG, median age was 10 years, nine patients received vinblastine previously. Median number of cycles was 6.8 (range: 1–12). Treatment was interrupted in five patients for grade 3/4 toxicity.Conclusion: This regimen is active in patients with LGG, even if patients had previously received vinblastine. Toxicity is acceptable.Trial Registration: This study was registered under clinicaltrials.gov – NCT01285817; EUDRACT nr: 2010-021792-81.

Objective To investigate the antitumor activity of a four‐drug metronomic chemotherapy (MC) regimen in relapsed/progressing pediatric extracranial solid tumors (EST). The primary objective was clinical benefit (complete response /partial response/stable disease [SD]) after two cycles of therapy (four months). Methods Patients aged ≥4 to 25 years with progressing EST and adequate organ function were eligible. Treatment consisted of an eight‐week cycle of oral celecoxib b.i.d., weekly vinblastine, and oral cyclophosphamide for three weeks alternating with oral methotrexate for three weeks, with a two‐week rest. The Kepner–Chang two‐stage model was used with 10 patients in the first stage. If primary objective was reached in two or more patients, eight additional patients were included according to four groups: neuroblastoma (NBL), soft‐tissue sarcoma (STS), bone sarcoma (BS), and miscellaneous (Misc.). Results Forty‐four patients were evaluable. The NBL cohort could be expanded to 18 patients: 4 of 18 patients stabilized with MC treatment for 6 (n = 1) and 12 (n = 3) months. In STS, two of seven patients (metastatic hemangioendothelioma and angiosarcoma) had SD for > 2 cycles. One of nine Misc. (metastatic myoepithelial carcinoma) had SD for one year. All patients with BS had progressive disease. One‐year progression‐free survival of the whole cohort was 6.8% and one‐year overall survival was 55.3%. Grade 3 toxicity occurred in 18 patients and grade 4 in 15 patients. The most frequent toxicity was hematologic, predominantly neutropenia. Conclusions This MC has no activity in BS and limited though interesting activity in NBL with some patients being stable for > 1 year. It is not possible to conclude activity in STS and Misc.

Background Pediatric low‐grade gliomas (PLGG) are the most common brain tumors diagnosed during childhood and represent a heterogeneous group associating variable molecular abnormalities. To go further and develop specific statistical patterns between tumor molecular background, imaging features, and patient outcome, a retrospective study was performed in a group of non‐neurofibromatosis type 1 (non‐NF1) grade 1 PLGGs. Patients and methods Seventy‐eight children, followed from 2004 to 2017, were retrospectively reported. In this population, we analyzed radiological and molecular parameters. Their therapeutic management comprised surgery or surgery plus chemotherapies. Results Considering all 78 patients, 59 had only a surgical removal and 19 patients were treated with postoperative chemotherapy. Twelve progressions were reported in the partially resected and chemotherapeutic groups, whereas four deaths occurred only in the highly treated patients. As expected, in the global cohort, PLGG with BRAF p.V600E and/or CDKN2A loss exhibited poor outcomes and we evidenced significant associations between those molecular characteristics and their imaging presentation. In the chemo‐treated patients, when associating initial and 6‐month magnetic resonance imaging (MRI) parameters to the molecular features, the good risk situations were significantly linked to the presence of a large tumor cyst at diagnosis and the appearance during treatment of a higher cystic proportion that we called cystic conversion. Conclusion So, additionally to the presence of BRAF p.V600E or CDKN2A deletion in grade 1 PLGGs, the absence on diagnostic MRI of cystic parts and/or cystic conversion at 6‐month chemotherapy were significantly linked to a worst prognosis and response to treatment. These imaging features should be considered as prognostic markers in future PLGG studies.