Risk factors associated with delayed methotrexate clearance and increased toxicity in pediatric patients with osteosarcoma

Abstract

High‐dose methotrexate (HD‐MTX; 12 g/m2) is part of standard therapy for pediatric osteosarcoma (OS). Risk factors associated with MTX toxicity in children with OS are not well defined. We investigated the association between peak MTX levels (four‐hour) and delayed MTX clearance or treatment toxicity. Information was retrieved from electronic medical records of 33 OS patients treated with HD‐MTX at Texas Children's Hospital from 2008 to 2015. We found that the four‐hour MTX level did not contribute to toxicity or delayed MTX clearance. We demonstrated that certain demographic characteristics are associated with delayed clearance and increased toxicity.

ABCC2(rs717620), and ABCC3 (rs4793665) affect high dose Methotrexate toxicity, and outcome in children with osteosarcoma

“…The young children have high body water content leading to more MTX elimination than elder children. These results match those observed in earlier studies of (Csordas, Hegyi et al 2013, Luetke, Meyers et al 2014, Wippel, Gundle et al 2019, Young, Cheng et al 2020). The study of (Csordas, Hegyi et al 2013) reported the significant association between high levels in children age older than 14 years because the metabolism resembles those of adult patients.…”

“…The variability might relate to the difference in gender sensitivity to chemotherapy. The study of (Young, Cheng et al 2020) confirmed our findings that severe neutropenia had associated with younger children with low body surface area. The current results offered some essential insights into the absence of a significant other hematological toxicity with studied gene SNPs in agreement with (Yang, Wang et al 2013, Suthandiram, Gan et al 2014, Membrive, Ramírez et al 2020.…”

“…Regarding hematological toxicity risk, the present study showed severe neutropenia, which was a statistically significant association with young children as consistent with (Ferrari, Palmerini et al 2009, Young, Cheng et al 2020. Male gender was less likely to associate with severe anemia as compared to females due to normal physiology as consistent with (Ferrari, Palmerini et al 2009).…”

“…These factors may be due to higher MTX levels after multiple HDMTX cycles or other factors. The previous studies offered contradictory findings about several factors participate in this association such as; (Hoekstra, Van Ede et al 2003, Li, Sui et al 2019, Mandal, Samaddar et al 2020, Young, Cheng et al 2020. MTX level wouldn't predict appearance specific type of toxicity except nephrotoxicity after multiple HDMTX cycles, described by (Tsurusawa, Gosho et al 2015).…”

MTHFR Polymorphism Is Associated With Severe Methotrexate-Induced Toxicity in Osteosarcoma Treatment

“…( 10 ). The presence of toxicity is influenced by multiple factors such as age, gender, ethnicity, and genetic background ( 9 , 12 ). In this setting, patients may benefit from individualized chemotherapy that is tailored according to their disease characteristics and background.…”