A phase I study of irinotecan and temozolomide with bevacizumab in children with recurrent/refractory central nervous system tumors

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 [ …”

“…For non-serious AEs, a high heterogeneity was found for combination of bevacizumab + irinotecan + temozolomide (three studies: I 2 86%) and for bevacizumab + temozolomide (two studies: I 2 91%). As for the first combination, in the study of Modak et al [ 56 ] (which reported the higher proportion of serious AEs), bevacizumab was administered at 15 mg/kg, while in the other two studies (Levy et al; Metts et al [ 51 , 54 ]), bevacizumab was administered at 10 mg/kg. Moreover, the in the study of Metts et al [ 54 ], the irinotecan was administered only at day 1 and 15 of a 28-day cycle, while in the other two studies [ 51 , 56 ], it was administered for the first five days of each cycle.…”

“…As for the first combination, in the study of Modak et al [ 56 ] (which reported the higher proportion of serious AEs), bevacizumab was administered at 15 mg/kg, while in the other two studies (Levy et al; Metts et al [ 51 , 54 ]), bevacizumab was administered at 10 mg/kg. Moreover, the in the study of Metts et al [ 54 ], the irinotecan was administered only at day 1 and 15 of a 28-day cycle, while in the other two studies [ 51 , 56 ], it was administered for the first five days of each cycle. Finally, as for the combination bevacizumab + temozolomide, temozolomide was given as 150–200 mg/m 2 /dose.…”