The role of irinotecan-bevacizumab as rescue regimen in children with low-grade gliomas: a retrospective nationwide study in 72 patients

Abstract

At least half of children with low-grade glioma (LGG) treated with rst line chemotherapy experience a relapse/progression and may therefore need a second-line chemotherapy. Irinotecan-bevacizumab has been recommended in this setting in France after encouraging results of pilot studies. We performed a retrospective analysis to de ne the e cacy, toxicity and predictors for response to the combination on a larger cohort. Methods.We reviewed the les from children < 19 years of age with progressive or refractory LGG treated between 2009 and 2016 in 7 French centers with this combination. Results.72 patients (median age 7.8 years [range, 1-19]) received a median of 16 courses (range, 3-30). The median duration of treatment was 9 months (range, 1.4-16.2). 96% of patients experienced at least disease stabilization. The 6-month and 2-year progression-free survivals (PFS) were 91.7% [IC 95% 85.5-98.3] and 38.2% [IC 95% 28.2-51.8] respectively. No progression occurred after treatment in 18 patients with a median follow-up of 35.6 months (range, 7.6-75.9 months). Younger patients had a worse PFS (p=0.005). Prior chemoresistance, NF1 status, duration of treatment, histopathology or radiologic response did not predict response. The most frequent toxicities related to bevacizumab included grades 1-2 proteinuria in 21, epistaxis in 10, fatigue in 12 and hypertension in 8 while gastro-intestinal toxicity was the most frequent side effect related to irinotecan. Conclusion.Bevacizumab-irinotecan is highly effective for children with recurrent LGG who have failed standard chemotherapy regimens whatever their clinical characteristics, only younger children had a worse PFS.

Safety of Anti-Angiogenic Drugs in Pediatric Patients with Solid Tumors: A Systematic Review and Meta-Analysis

“…After screening, six additional clinical studies with results on clinicaltrials.gov were included in the analysis. In total, 70 records (64 published articles and 6 clinical trials with published results retrieved from clinicaltrials.gov) reporting AEs of anti-angiogenic drugs in pediatric patients with solid tumors were included in the systematic review [ 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 ,…”

“…Most of the studies evaluated AEs of anti-angiogenic drugs in patients with central nervous system tumors (sixteen various glioma [ 24 , 25 , 29 , 32 , 43 , 44 , 45 , 46 , 65 , 75 , 76 , 80 , 81 , 82 , 83 , 84 ], eight various brain tumors [ 28 , 33 , 54 , 59 , 61 , 64 , 72 , 88 ], three ependymoma [ 30 , 70 , 79 ], two medulloblastoma [ 23 , 51 ], one astrocytoma [ 47 ], and two neuroblastoma [ 56 , 78 ]). Twenty-three studies referred to a cohort of patients with various solid tumors [ 27 , 31 , 34 , 37 , 38 , 39 , 40 , 41 , 50 , 53 , 55 , 58 , 60 , 63 , 66 , 68 , 71 , 73 , 74 ,…”

“…Twenty studies reported the number of AEs of anti-angiogenic drugs used as monotherapy (three for bevacizumab [ 40 , 43 , 72 ], four for sorafenib [ 47 , 71 , 90 , 91 ], three for sunitinib [ 31 , 67 , 70 ], two for pazopanib [ 41 , 73 ], two for vandetanib [ 42 , 49 ], one for aflibercept [ 39 ], one for axitinib [ 37 ], one for cabozatinib [ 27 ], one for trebananib [ 50 ], one for lenvatinib [ 35 ], one for regorafenib [ 38 ], and one for ramucirumab [ 74 ]), thirty-six reported anti-angiogenic drugs used in combination with standard chemotherapy (twenty-nine for bevacizumab [ 23 , 26 , 28 , 29 , 33 , 44 , 45 , 46 , 51 , 52 , 54 , 55 , 56 , 57 , 58 , 64 , 66 , 68 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 ], four for sorafenib [ …”

“…Two studies reported that TKIs induce hypothyroidism through tissue ischemia (inhibition of thyroid blood flow) or apoptosis of the thyroid follicular cells [ 103 , 104 ]. Unfortunately, this systematic review retrieved only seven observational studies (six for bevacizumab, one for pazopanib) that meet the inclusion criteria for meta-analysis [ 23 , 28 , 29 , 46 , 55 , 61 , 62 ], and given the different regimens analyzed, indications and doses these studies were not pooled together and no conclusive evidence on the long-term safety of anti-angiogenic drugs in pediatric patients could possibly be drawn. This aspect is important in light of preclinical and clinical evidence on adults patients: in particular, pazopanib is reported to increase risk for bone shortening and fragility, and tooth remodeling (the effects are reported in young rats at ≥10 mg/kg/day) as well as evidence coming from some TKIs, which are associated with cardiovascular events [ 105 , 106 ].…”

Impact of Bevacizumab on Visual Function, Tumor Size, and Toxicity in Pediatric Progressive Optic Pathway Glioma: A Retrospective Nationwide Multicentre Study

“…Treatment of LGG with BVZ tends to stabilize tumor volume, but progression frequently occurs after discontinuation of BVZ (14–93%) within a median of 5–12 months after cessation of BVZ [ 7 , 8 , 9 , 11 , 12 , 14 ]. Studies on the toxicity profile are reported and show an acceptable profile of grade 3 toxicity according to CTCAE criteria (Common Terminology Criteria for Adverse Events) [ 8 , 10 , 11 , 12 ], which is reversible after cessation [ 8 , 11 ].…”