ADC Histogram Analysis of Pediatric Low-Grade Glioma Treated with Selumetinib: A Report from the Pediatric Brain Tumor Consortium.

Sridhar Vajapeyam ,A Ziaei,Gilbert Vézina ,Benita Tamrazi ,Ira J Dunkel ,Douglas L Brown ,Sofia Haque ,Shengjie Wu ,Maryam Fouladi ,Blaise V Jones ,Kristen W Yeom ,Ashok Panigrahy ,Soonmee Cha ,Zoltán Patay ,Jason Fangusaro ,Jessica Stern ,David S Enterline ,Jeremy Jones ,Arzu Onar‐Thomas ,Tina Young Poussaint

doi:10.3174/ajnr.a7433

Abstract

Selumetinib is a promising MAP (mitogen-activated protein) kinase (MEK) 1/2 inhibitor treatment for pediatric low-grade gliomas. We hypothesized that MR imaging-derived ADC histogram metrics would be associated with survival and response to treatment with selumetinib. Children with recurrent, refractory, or progressive pediatric low-grade gliomas who had World Health Organization grade I pilocytic astrocytoma with KIAA1549-BRAF fusion or the BRAF V600E mutation (stratum 1), neurofibromatosis type 1-associated pediatric low-grade gliomas (stratum 3), or sporadic non-neurofibromatosis type 1 optic pathway and hypothalamic glioma (OPHG) (stratum 4) were treated with selumetinib for up to 2 years. Quantitative ADC histogram metrics were analyzed for total and enhancing tumor volumes at baseline and during treatment. Each stratum comprised 25 patients. Stratum 1 responders showed lower values of SD of baseline ADC_total as well as a larger decrease with time on treatment in ADC_total mean, mode, and median compared with nonresponders. Stratum 3 responders showed a greater longitudinal decrease in ADC_total. In stratum 4, higher baseline ADC_total skewness and kurtosis were associated with shorter progression-free survival. When all 3 strata were combined, responders showed a greater decrease with time in ADC_total mode and median. Compared with sporadic OPHG, neurofibromatosis type 1-associated OPHG had lower values of ADC_total mean, mode, and median as well as ADC_enhancement mean and median and higher values of ADC_total skewness and kurtosis at baseline. The longitudinal decrease in ADC_total median during treatment was significantly greater in sporadic OPHG compared with neurofibromatosis type 1-associated OPHG. ADC histogram metrics are associated with progression-free survival and response to treatment with selumetinib in pediatric low-grade gliomas.

Highlights

BACKGROUND AND PURPOSESelumetinib is a promising MAP kinase (MEK) 1/2 inhibitor treatment for pediatric low-grade gliomas
ADC histogram metrics are associated with progression-free survival and response to treatment with selumetinib in pediatric low-grade gliomas
We hypothesized that ADC histogram metrics would be associated with response in Pediatric low-grade gliomas (pLGGs) treated with selumetinib

Summary

MATERIALS AND METHODS

This was a multicenter, National Cancer Institute–sponsored Phase II study conducted by the PBTC using the MEK 1/2 inhibitor selumetinib in patients with pediatric low-grade gliomas treated at 11 PBTC member hospitals.[8,9] Patients 3–21 years of age with a Lansky/Karnofsky Performance Status score of .60 and the presence of recurrent, refractory, or progressive pediatric low-grade glioma after at least 1 standard therapy, including chemotherapy and radiation therapy, were eligible for inclusion. For each of the imaging metrics, the baseline value and the time-dependent longitudinal change in the metrics during the course of treatment were examined for associations with tumor volume, response, and PFS. There were significant associations of response with longitudinal change across time on treatment in the ADC_total mean (P = .02, q = 0.05), ADC_total mode (P = .02, q = 0.07), and ADC_total median (P = .03, q = 0.1), with responders showing a larger decrease in these parameters across time than nonresponders. Of the 21 enhancing tumors in stratum 1, sixteen were eligible for longitudinal analysis and 8 of these showed a response to selumetinib. None of the histogram metrics of ADC_enhancement were associated with a response in the longitudinal analyses.

RESULTS

CONCLUSIONS