Safety of bevacizumab in patients younger than 4 years of age

Millan, Natalia; Poveda, María Antonia Martorell; Cruz, Ofelia; Mora, Jaume

doi:10.1007/s12094-015-1389-5

Cited by 13 publications

(14 citation statements)

References 15 publications

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“…24 In anecdotal reports in pediatric patients with relapsed malignancies, significant adverse events appeared to be more frequent especially in children with brain tumors. 25,26 Pharmacokinetic parameters in children were similar to those measured in adults 27 as were objective responses when used as a single agent.…”

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confidence: 72%

Combination of bevacizumab, irinotecan, and temozolomide for refractory or relapsed neuroblastoma: Results of a phase II study

Modak

Kushner

Basu

et al. 2017

Pediatric Blood & Cancer

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Background The rationale for studying the combination of bevacizumab, irinotecan and temozolomide (BIT) in neuroblastoma is based on: (a) vascular endothelial growth factor (VEGF) expression is associated with an aggressive phenotype, (b) anti-VEGF antibody bevacizumab enhances irinotecan-mediated suppression of neuroblastoma xenografts, (c) bevacizumab safety has been established in pediatric phase I studies and, (d) irinotecan+temozolomide (IT) is a standard salvage chemotherapy. Procedure We conducted a phase II study of BIT in patients with measurable/evaluable refractory or relapsed high-risk neuroblastoma (www.clinicaltrials.gov NCT01114555). Each cycle consisted of bevacizumab (15mg/kg intravenously) on days 1 and 15 plus irinotecan (50mg/m2/day intravenously) and temozolomide (150mg/m2/day orally) on days 4–8. Patients could have previously received, but not relapsed on, IT. An early stopping rule mandated continuing therapy only if >5/27 evaluable patients achieved partial (PR) or complete response (CR) after 4 cycles. Results 33 heavily pretreated patients (9 primary refractory; 24 relapsed) received 1–8 cycles of BIT. Toxicities were expected and transient. Grade 4 toxicities were neutropenia (30%) and thrombocytopenia (24%). Grade 3 toxicities included hepatic transaminitis (15%), proteinuria (9%) and diarrhea (3%). Overall responses were: 3 CR, (all in prior IT-treated patients), 18 no response and 12 progressive disease. Only 1/23 patients assessable for the early stopping rule regarding efficacy achieved PR/CR, so patient accrual was discontinued. Median progression-free and overall survival was 7.7±1.7 and 31.5±5.6 months respectively; all patients continued anti-neuroblastoma therapy post-BIT. Conclusions BIT was well tolerated, but addition of bevacizumab did not improve response rates in resistant neuroblastoma compared to historical data for IT.

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confidence: 72%

Combination of bevacizumab, irinotecan, and temozolomide for refractory or relapsed neuroblastoma: Results of a phase II study

Modak

Kushner

Basu

et al. 2017

Pediatric Blood & Cancer

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“…Studies published in the last 10 years evaluating the adverse effects of bisphosphonates, denosumab, and bevacizumab on dental development and the risk of jaw osteonecrosis were selected. The search resulted in 18 articles (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(37)(38)(39)(40)(41)(42)(43).…”

Section: Methodsmentioning

confidence: 99%

Use of new targeted cancer therapies in children: effects on dental development and risk of jaw osteonecrosis: a review

Hernandez

Phulpin

Mansuy³

et al. 2016

J Oral Pathology Medicine

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New targeted cancer therapies such as bisphosphonates, denosumab, and bevacizumab are routinely used in adult for the past decades. Their introduction into pediatric medicine is more recent that means there is a paucity of data on long-term effects on dental development and on the risk of osteonecrosis of jaw. This study aimed to outline adverse effects of new targeted cancer therapies on oral cavity including dental abnormalities observed in pediatric population treated with these molecules and the risk of osteonecrosis of the jaw (ONJ). The impact of bisphosphonates and denosumab on bone remodeling (inhibition of osteoclasts) could interfere with teeth exfoliation and eruption processes, causing a tooth eruption delay. This hypothesis was confirmed, bisphosphonate-treated rats presented tooth eruption delay, and bisphosphonate therapy was associated with a mean delay of 1.67 years in tooth eruption in children with osteogenesis imperfecta. Another study showed that the inhibition of RANK/RANKL by denosumab was associated with a lack of tooth eruption in animals. Several animal studies reported that bisphosphonate could also induce dental abnormalities including defective amelogenesis and dentinogenesis in rats, but there is no evidence of such effects in children; only one case of enamel hypoplasia in a child treated for idiopathic arterial calcification with bisphosphate was reported. To date, there has been no reported case of ONJ in children treated with bisphosphonates, denosumab, or bevacizumab.

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“…Growth, bone development, and epiphyseal maturation are of concern in pediatric patients receiving antiangiogenic agents such as bevacizumab . However, few publications have reported safety data on the use of bevacizumab in children and adolescents . Growth plate abnormalities were evaluated in a combined analysis of six phase I trials in children with different tumors evaluating new antiangiogenic therapies.…”

Section: Discussionmentioning

confidence: 99%

“…19 However, few publications have reported safety data on the use of bevacizumab in children and adolescents. 13,19,20,[28][29][30][31] Growth plate abnormalities were evaluated in a combined analysis of six phase I trials in children with different tumors evaluating new antiangiogenic therapies. Although most patients had no evidence of growth plate toxicity, five patients (9.4%) had epiphyseal abnormalities.…”

Section: Discussionmentioning

confidence: 99%

Integrated analysis of long‐term growth and bone development in pediatric and adolescent patients receiving bevacizumab

Müller

Merks

Geoerger

et al. 2018

Pediatric Blood & Cancer

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Background We conducted an integrated analysis of clinical data to describe long‐term effects of bevacizumab on growth and bone development in pediatric and adolescent patients with solid tumors. Procedure Clinical data were pooled from five phase I/II trials of bevacizumab versus chemotherapy: BERNIE, HERBY, and AVF4117s enrolled newly diagnosed patients, AVF3842s and AVF2771s enrolled patients with relapsed/refractory disease. Height, weight, body mass index (BMI), and bone‐age data were pooled by treatment group. Growth charts were used to track and monitor growth in relation to a reference population of healthy children. Bone age was measured based on X‐ray of the left hand and wrist. Analyses were exploratory/descriptive. Results Overall, 268 patients received bevacizumab ± chemotherapy and 135 received chemotherapy alone. Baseline characteristics were generally balanced. Median duration of long‐term follow‐up was 41.8 months (range, 2.4‐75.1) with bevacizumab and 22.9 months (range, 2.8‐69.2) with chemotherapy alone. Patients had age‐appropriate baseline height and weight. Mean height and weight percentiles decreased over time in both treatment groups, but remained within the normal range (height: mean standard deviation score [SDS] range −2 to +3; weight: mean SDS range −2 to +1). Similar trends were seen in BMI. A tendency for reduced growth velocity relative to the reference population was observed at 6 months and 1 year in both groups, but there was no additional decrease for patients receiving bevacizumab. Conclusion Bevacizumab did not appear to have additional negative effects on growth or development of pediatric and adolescent patients with solid tumors.

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Safety of bevacizumab in patients younger than 4 years of age

Abstract: Our results suggest that the use of bevacizumab is safe for the youngest children.

Cited by 13 publications

References 15 publications

Combination of bevacizumab, irinotecan, and temozolomide for refractory or relapsed neuroblastoma: Results of a phase II study

Combination of bevacizumab, irinotecan, and temozolomide for refractory or relapsed neuroblastoma: Results of a phase II study

Use of new targeted cancer therapies in children: effects on dental development and risk of jaw osteonecrosis: a review

Integrated analysis of long‐term growth and bone development in pediatric and adolescent patients receiving bevacizumab

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