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INTRODUCTION Cross-sectional tumor measures are used as endpoints in clinical trials of DIPG, but may not capture meaningful changes in disease burden. Volumetric measures may provide a more accurate assessment of tumor growth. We measured the correlation between cross-sectional and volumetric measures and compared their prognostic impact to better understand response evaluation in DIPG. METHODS Patients from the International DIPG Registry with diagnostic and post-radiation MRIs were included. Utilizing mint LesionTM software, tumors were manually contoured by an experienced pediatric neuro-radiologist to extrapolate cross-sectional product (CP) and volume measures. Correlation between CP and volume was assessed by linear regression. Landmark analyses were performed to determine differences in overall survival (OS) (via log-rank) between patients classified as progressive disease (PD) versus non-PD according to CP and volumetric measurements at one-, three-, and five-months post-radiation. Imaging consistent with pseudoprogression was designated non-PD. Hazard ratios (HR) for survival after these timepoints were calculated by Cox regression. RESULTS A total of 317 MRIs from 46 patients were analyzed. When comparing change from smallest previous tumor size, CP increase of 25% (PD by RAPNO) correlated with volume increase of 28% (R2=0.685). There was no difference in OS between patients classified as PD versus non-PD by CP at one-month, three-months, or five-months post-radiation (p >0.05). However, significant differences in OS were observed between patients classified as PD versus non-PD by volume (28% increase) at one-month (2.7 vs. 12.8 months, p=0.005), three-months (1.9 vs. 10.7 months, p=0.036), and five-months post-radiation (3.7 vs. 9.1 months, p=0.023). PD by volume, but not by CP, was predictive of survival at all timepoints (HR: 5.0, 2.4, 2.4). CONCLUSIONS Volumetric assessments of PD correlated better with survival than CP at all post-radiation timepoints. Tumor volume likely represents a more accurate, prognostically-relevant measure of disease burden that deserves investigation in future DIPG trials.

There is no standard of care for cerebrospinal (CSF) diversion in children with diffuse intrinsic pontine glioma (DIPG), nor understanding of survival impact. We evaluated CSF diversion characteristics in children with DIPG to determine incidence, indications and potential impact on survival. Data was extracted from subjects registered in the International DIPG registry (IDIPGR). IDIPGR team personnel obtained clinical and radiographic data from the registry database and when appropriate, abstracted additional data from individual medical records. Univariable analyses were performed using the Fisher’s exact test or Wilcoxon rank sum test. Survival was estimated using the Kaplan-Meier method. Evaluable patients (n=457) met criteria for DIPG diagnosis by central radiology review. Ninety-two patients (20%) had permanent CSF diversion. Indications for permanent diversion were hydrocephalus (41%), hydrocephalus and clinical symptoms (35%), and clinical symptoms alone (3%). Those with permanent diversion were significantly younger at diagnosis than those without diversion (median 5.3 years vs 6.9 years, p=0.0002), otherwise no significant differences in gender, race, or treatment were found. The progression-free and overall survival of those with permanent CSF diversion compared to those without permanent diversion was 4.5 and 10.9 months vs 6.9 and 11.2 months, respectively (p=0.001, p= 0.4). There was no significant difference in overall survival in patients with or without permanent CSF diversion among a large cohort of DIPG patients. Patients without permanent diversion had significantly prolonged progression free survival compared to those with permanent diversion. The qualitative risks and benefits of permanent CSF diversion need to be further evaluated.

INTRODUCTION Medulloblastoma is one of the most common malignant brain tumors in children. To date, the treatment of average-risk (non-metastatic, completely resected) medulloblastoma includes craniospinal radiation therapy and adjuvant chemotherapy. Modern treatment modalities and now risk stratification of subgroups have extended the survival of these patients, exposing the long-term morbidities associated with radiation therapy. METHODS We performed a single-arm, multi-institution study, seeking to reduce the late effects of treatment in patients with average-risk medulloblastoma prior to advances in molecular subgrouping. To do so, we reduced the dose of craniospinal irradiation by 25% to 18 gray with the goal of maintaining the therapeutic efficacy as described in CCG 9892 with maintenance chemotherapy. RESULTS 28 patients aged 3–30 years were enrolled across three institutions between April 2001 and December 2010. Median age at enrollment was 9 years with a median follow-up time of 11.7 years. The 3-year relapse-free (RFS) and overall survival (OS) were 78.6% (95% CI 58.4% to 89.8%) and 92.9% (95% CI 74.4% to 98.2%), respectively. The 5-year RFS and OS were 71.4% (95% CI 50.1% to 84.6%) and 85.7% (95% CI 66.3% to 94.4%), respectively. Toxicities were similar to those seen in other studies; there were no grade 5 toxicities. CONCLUSIONS Given the known neurocognitive adverse effects associated with cranial radiation therapy, studies to evaluate the feasibility of dose reduction are needed. In this study, we demonstrate that select patients with average-risk medulloblastoma may benefit from reduced craniospinal radiation dose of 18 gray without impacting relapse-free or overall survival.

PURPOSE To review data from DIPG Registry patients recorded to have received a second course of radiation therapy (rRT). METHODS The International DIPG Registry was searched for patients with DIPG who were treated with a known dose of rRT. Doses of rRT, timing from initial diagnosis and primary radiation therapy (pRT), radiographic response to rRT and survival from diagnosis (OS) were evaluated. RESULTS Sixty (11.2%) of 535 Registry patients underwent rRT; dose was provided for 44 patients. Median (range) data from those 44 revealed that rRT was given at 12 (2–65) months from initial diagnosis of DIPG and at 9.6 (1–61) months from completion of pRT at a dose of 26.7 (1.8–74) Gy. After completion of rRT, MRI showed response, progression, stable disease or was not available in 19, 8, 3 and 14 patients, respectively. Median PFS and OS were 11 and 18.1 months, respectively. 475 Registry patients did not undergo rRT; their ages, duration of symptoms, and primary treatment with or without chemotherapy were not significantly different from the rRT cohort. Median PFS and OS for the non-rRT patients were 6.9 and 10 months, respectively. rRT patients were more likely to have had radiographic evidence of tumor necrosis at diagnosis than non-rRT patients. CONCLUSIONS Administration of rRT to patients with DIPG has been inconsistent with respect to timing and dose. Toxicity, response and quality of life data are incomplete, but survival appears to be lengthened with rRT. Prospective clinical trials will elucidate benefits and risks of rRT.

OBJECTIVE To estimate the 6-month Progression Free Survival (PFS6) associated with everolimus for progressive/recurrent pLGGs and to determine if activated PI3K/Akt/mTOR pathway as measured by positive phosphorylated-ribosomal protein S6 (p-RPS6) status was associated with response. METHOD: Patients 3–21 years of age with recurrent or progressive pLGG were enrolled. Everolimus was administered orally at 5 mg/m2 daily. Tissue availability for molecular analysis was mandatory. Immunohistochemistry (IHC) for p-RPS6 was performed centrally. An adaptive Simon two-stage design was employed based on p-RPS6 status. Based on results of the first stage, enrollment in the second stage was either limited to pathway activated patients or open to all subjects. RESULTS From December 2012 to July 2019 a total of 65 subjects enrolled [median age 9 years (range 3–19); 43% female]. As of December 15, 2019 median number of treatment cycle is 8 (range 1–24); 7 patients remain on treatment. Toxicity profile is similar to published reports with rash and elevated lipid profiles as most common adverse events. PFS6 for the entire cohort is 63%; PFS6 is 64% for the activated and 61% for the non-activated patients. Central imaging review (n=52) revealed 1 partial response, 1 complete response, 33 stable disease, and 17 progressive disease at the end of study treatment. Initial molecular analysis identified BRAF alterations in 35/65 patients. CONCLUSION Everolimus is well tolerated and active in a subset of pLGGs. Ongoing analyses will assess predictive biomarkers of response and will be reported at the meeting.

BACKGROUND Vemurafenib is an orally available, selective ATP-competitive inhibitor of BRAF-V600E kinase, approved in adult metastatic melanoma patients with the V600E mutation. This study was designed to determine the recommended phase 2 dose (RP2D) in patients < 18yrs with BRAF-V600E mutant brain tumors.

Children with diffuse intrinsic brainstem glioma (DIPG) have a median survival of less than 1 year despite radiation ± chemotherapy. The International DIPG Registry, a collaborative effort among researchers in North America and Australia has enrolled 395 patients with data for over 900 patients committed from 35 institutions. Among the 395 patients, 32 long-term survivors (LTS) (overall survival [OS] ≥2 years) have been identified. Preliminarily, we report clinical, radiographic, and histologic data for 75 of 395 patients, including the 32 LTS and 43 in the comparison (C) group. On central radiographic review, 5 were deemed not to represent DIPG (3 LTS and 2 C). Median age at diagnosis for LTS and C groups was 5.5 and 6.1 years, respectively. Fifty-seven percent of LTS had >6 weeks between onset of symptoms and diagnosis versus 28% for the comparison group (p < 0.05). Incidence of signs and symptoms at diagnosis (cranial nerve, cerebellar, or pyramidal) was similar in both groups. All patients, except 3 LTS, underwent radiation at diagnosis; all but 6 received adjunct chemotherapy. Median OS was 28.4 and 10.8 months for the LTS and C groups, respectively. Two patients (1 LTS) had an H3.3K27M mutation and 2 (1 LTS) had an H3.1K27M mutation. Biology data from 25 other patients from autopsy (n = 12) or biopsy (n = 13) are under analysis. Presence of enhancement on diagnostic imaging was associated with poorer survival (p = 0.02). There was no significant difference in radiographic evidence of hemorrhage, necrosis, diffusion restriction, or tumor size between LTS and C groups. Preliminary data in children with DIPG suggest that LTS have a longer duration of presenting signs and symptoms and less often display radiographic evidence of enhancement at diagnosis. Complete clinical, radiographic, and biology (where available) data on all 395 patients enrolled are currently being analyzed and will be presented.