National Cancer Institute Workshop on Proton Therapy for Children: Considerations Regarding Brainstem Injury.

PURPOSE: Proton therapy can allow for superior avoidance of normal tissues. A widespread consensus has been reached that proton therapy should be used for patients with curable pediatric brain tumor to avoid critical central nervous system structures. Brainstem necrosis is a potentially devastating, but rare, complication of radiation. Recent reports of brainstem necrosis after proton therapy have raised concerns over the potential biological differences among radiation modalities. We have summarized findings from the National Cancer Institute Workshop on Proton Therapy for Children convened in May 2016 to examine brainstem injury. METHODS AND MATERIALS: Twenty-seven physicians, physicists, and researchers from 17 institutions with expertise met to discuss this issue. The definition of brainstem injury, imaging of this entity, clinical experience with photons and photons, and potential biological differences among these radiation modalities were thoroughly discussed and reviewed. The 3 largest US pediatric proton therapy centers collectively summarized the incidence of symptomatic brainstem injury and physics details (planning, dosimetry, delivery) for 671 children with focal posterior fossa tumors treated with protons from 2006 to 2016. RESULTS: The average rate of symptomatic brainstem toxicity from the 3 largest US pediatric proton centers was 2.38%. The actuarial rate of grade ≥2 brainstem toxicity was successfully reduced from 12.7% to 0% at 1 center after adopting modified radiation guidelines. Guidelines for treatment planning and current consensus brainstem constraints for proton therapy are presented. The current knowledge regarding linear energy transfer (LET) and its relationship to relative biological effectiveness (RBE) are defined. We review the current state of LET-based planning. CONCLUSIONS: Brainstem injury is a rare complication of radiation therapy for both photons and protons. Substantial dosimetric data have been collected for brainstem injury after proton therapy, and established guidelines to allow for safe delivery of proton radiation have been defined. Increased capability exists to incorporate LET optimization; however, further research is needed to fully explore the capabilities of LET- and RBE-based planning.

A pediatric brain tumor consortium phase II trial of capecitabine rapidly disintegrating tablets with concomitant radiation therapy in children with newly diagnosed diffuse intrinsic pontine gliomas.

BACKGROUND: We conducted a phase II study of oral capecitabine rapidly disintegrating tablets given concurrently with radiation therapy (RT) to assess progression-free survival (PFS) in children with newly diagnosed diffuse intrinsic pontine gliomas (DIPG). PATIENTS AND METHODS: Children 3-17 years with newly diagnosed DIPG were eligible. Capecitabine, 650 mg/m2 /dose BID (maximum tolerated dose [MTD] in children with concurrent radiation), was administered for 9 weeks starting the first day of RT. Following a 2-week break, three courses of capecitabine, 1,250 mg/m2 /dose BID for 14 days followed by a 7-day rest, were administered. As prospectively designed, 10 evaluable patients treated at the MTD on the phase I trial were included in the phase II analyses. The design was based on comparison of the PFS distribution to a contemporary historical control (n = 140) with 90% power to detect a 15% absolute improvement in the 1-year PFS with a type-1 error rate, α = 0.10. RESULTS: Forty-four patients were evaluable for the phase II objectives. Capecitabine and RT was well tolerated with low-grade palmar plantar erythrodyesthesia, increased alanine aminotransferase, cytopenias, and vomiting the most commonly reported toxicities. Findings were significant for earlier progression with 1-year PFS of 7.21% (SE = 3.47%) in the capecitabine-treated cohort versus 15.59% (SE = 3.05%) in the historical control (P = 0.007), but there was no difference for overall survival (OS) distributions (P = 0.30). Tumor enhancement at diagnosis was associated with shorter PFS and OS. Capecitabine was rapidly absorbed and converted to its metabolites. CONCLUSION: Capecitabine did not improve the outcome for children with newly diagnosed DIPG.

Effect of cranial irradiation on sperm concentration of adult survivors of childhood acute lymphoblastic leukemia: a report from the St. Jude Lifetime Cohort Study†.

STUDY QUESTION: Does lower dose (<26 Gy) cranial radiation therapy (CRT) used for central nervous system prophylaxis in acute lymphoblastic leukemia (ALL) adversely affect sperm concentration or morphology? SUMMARY ANSWER: CRT doses <26 Gy had no demonstrable adverse effect on sperm concentration or morphology. WHAT IS KNOWN ALREADY: Treatment with alkylating agents produces oligospermia and azoospermia in some patients. No prior study has been large enough to evaluate the independent effects of alkylating agents and lower dose (<26 Gy) CRT on sperm concentration or morphology. STUDY DESIGN, SIZE, DURATION: This cross-sectional study included male adult survivors of pediatric ALL who had received alkylating agent chemotherapy with or without CRT and who enrolled in the St. Jude Lifetime Cohort Study (SJLIFE) from September 2007 to October 2013. PARTICIPANTS/MATERIALS, SETTING, METHODS: The inclusion criteria were males, ≥18 years of age, ≥10 years after diagnosis, treated at St. Jude Children's Research Hospital for ALL, and received alkylating agent chemotherapy. Semen analyses were performed on 173 of the 241 (78.1%) adult survivors of pediatric ALL who had received alkylating agent chemotherapy with or without CRT. Cumulative alkylating agent treatment was quantified using the cyclophosphamide equivalent dose (CED). Log-binomial multivariable models were used to calculate relative risks (RRs) and 95% CI. MAIN RESULTS AND THE ROLE OF CHANCE: Compared to those without CRT, risk of oligospermia or azoospermia was not increased for CRT <20 Gy (P = 0.95) or 20-26 Gy (P = 0.58). Participants 5-9 years of age at diagnosis compared to those 0-4 years of age (RR = 1.30, 95% CI, 1.05-.61) or those treated with 8-12 g/m2 CED (RR = 2.06, 95% CI, 1.08-3.94) or ≥12 g/m2 CED (RR = 2.12, 95% CI, 1.09-4.12) compared to those treated with >0 to <4 g/m2 CED had an increased risk for oligospermia or azoospermia. LIMITATIONS, REASONS FOR CAUTION: Our study relied on the results of one semen analysis. ALL survivors who did not participate in SJLIFE or who declined to submit a semen analysis may also have biased our results regarding the proportion with azoospermia or oligospermia, since those who provided a semen specimen were less likely to have previously fathered children compared to those who did not. The lower rate of previous parenthood among participants may have resulted in a higher observed frequency of azoospermia and oligospermia. WIDER IMPLICATIONS OF THE FINDINGS: Treatment with <26 Gy CRT did not increase the risk of oligospermia or azoospermia, although a CED exceeding 8 g/m2 and an age at diagnosis of 5-9 years did increase risk of oligospermia and azoospermia. These findings can be used to counsel adult survivors of pediatric ALL. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the National Institutes of Health (grant numbers CA 21765, CA 195547, CA00874) and the American Lebanese Syrian Associated Charities (ALSAC). The authors have no competing interests to declare.

A phase I trial of the MEK inhibitor selumetinib (AZD6244) in pediatric patients with recurrent or refractory low-grade glioma: a Pediatric Brain Tumor Consortium (PBTC) study.

BACKGROUND: Activation of the mitogen-activated protein kinase pathway is important for growth of pediatric low-grade gliomas (LGGs). The aim of this study was to determine the recommended phase II dose (RP2D) and the dose-limiting toxicities (DLTs) of the MEK inhibitor selumetinib in children with progressive LGG. METHODS: Selumetinib was administered orally starting at 33 mg/m2/dose b.i.d., using the modified continual reassessment method. Pharmacokinetic analysis was performed during the first course. BRAF aberrations in tumor tissue were determined by real-time polymerase chain reaction and fluorescence in situ hybridization. RESULTS: Thirty-eight eligible subjects were enrolled. Dose levels 1 and 2 (33 and 43 mg/m2/dose b.i.d.) were excessively toxic. DLTs included grade 3 elevated amylase/lipase (n = 1), headache (n = 1), mucositis (n = 2), and grades 2-3 rash (n = 6). At dose level 0 (25 mg/m2/dose b.i.d, the RP2D), only 3 of 24 subjects experienced DLTs (elevated amylase/lipase, rash, and mucositis). At the R2PD, the median (range) area under the curve (AUC0-∞) and apparent oral clearance of selumetinib were 3855 ng*h/mL (1780 to 7250 ng × h/mL) and 6.5 L × h-1 × m-2 (3.4 to 14.0 L × h-1 × m-2), respectively. Thirteen of 19 tumors had BRAF abnormalities. Among the 5 (20%) of 25 subjects with sustained partial responses, all at the RP2D, 4 had BRAF aberrations, 1 had insufficient tissue. Subjects received a median of 13 cycles (range: 1-26). Fourteen (37%) completed all protocol treatment (26 cycles [n = 13], 13 cycles [n = 1]) with at least stable disease; 2-year progression-free survival at the RP2D was 69 ± SE 9.8%. CONCLUSION: Selumetinib has promising antitumor activity in children with LGG. Rash and mucositis were the most common DLTs.

Late outcomes of adult survivors of childhood non-Hodgkin lymphoma: A report from the St. Jude Lifetime Cohort Study.

BACKGROUND: Survivors of childhood non-Hodgkin lymphoma (NHL) are at increased risk for chronic health conditions. The objective of this study was to characterize health conditions, neurocognitive function, and physical performance among a clinically evaluated cohort of 200 childhood NHL survivors. METHOD: Chronic health and neurocognitive conditions were graded as per a modified version of the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) and impaired physical function defined as performance < 10th percentile of normative data. Multivariable regression was used to investigate associations between sociodemographic characteristics, therapeutic exposures, and outcomes. RESULTS: Survivors were a median age of 10 years (range 1-19) at diagnosis and 34 years (range 20-58) at evaluation. Eighty-eight (44%) received radiation, 46 (23%) cranial radiation, and 69 (35%) high-dose methotrexate. Most prevalent CTCAE Grades 3-4 (severe life-threatening) conditions were obesity (35%), hypertension (9%), and impairment of executive function (13%), attention (9%), and memory (4%). Many had impaired strength (48%), flexibility (39%), muscular endurance (36%), and mobility (36%). Demographic and treatment-related factors were associated with the development of individual chronic diseases and functional deficits. CONCLUSIONS: Clinical evaluation identified a high prevalence of chronic health conditions, neurocognitive deficits, and performance limitations in childhood NHL survivors.

Apparent diffusion coefficient histogram metrics correlate with survival in diffuse intrinsic pontine glioma: a report from the Pediatric Brain Tumor Consortium.

BACKGROUND: Diffuse intrinsic pontine glioma (DIPG) is associated with poor survival regardless of therapy. We used volumetric apparent diffusion coefficient (ADC) histogram metrics to determine associations with progression-free survival (PFS) and overall survival (OS) at baseline and after radiation therapy (RT). METHODS: Baseline and post-RT quantitative ADC histograms were generated from fluid-attenuated inversion recovery (FLAIR) images and enhancement regions of interest. Metrics assessed included number of peaks (ie, unimodal or bimodal), mean and median ADC, standard deviation, mode, skewness, and kurtosis. RESULTS: Based on FLAIR images, the majority of tumors had unimodal peaks with significantly shorter average survival. Pre-RT FLAIR mean, mode, and median values were significantly associated with decreased risk of progression; higher pre-RT ADC values had longer PFS on average. Pre-RT FLAIR skewness and standard deviation were significantly associated with increased risk of progression; higher pre-RT FLAIR skewness and standard deviation had shorter PFS. Nonenhancing tumors at baseline showed higher ADC FLAIR mean values, lower kurtosis, and higher PFS. For enhancing tumors at baseline, bimodal enhancement histograms had much worse PFS and OS than unimodal cases and significantly lower mean peak values. Enhancement in tumors only after RT led to significantly shorter PFS and OS than in patients with baseline or no baseline enhancement. CONCLUSIONS: ADC histogram metrics in DIPG demonstrate significant correlations between diffusion metrics and survival, with lower diffusion values (increased cellularity), increased skewness, and enhancement associated with shorter survival, requiring future investigations in large DIPG clinical trials.

Central precocious puberty following the diagnosis and treatment of paediatric cancer and central nervous system tumours: presentation and long-term outcomes.

OBJECTIVES: To estimate the prevalence of central precocious puberty (CPP) after treatment for tumours and malignancies involving the central nervous system (CNS) and examine repercussions on growth and pubertal outcomes. DESIGN: Retrospective study of patients with tumours near and/or exposed to radiotherapy to the hypothalamus/pituitary axis (HPA). PATIENTS AND MEASUREMENTS: Patients with CPP were evaluated at puberty onset, completion of GnRH agonist treatment (GnRHa) and last follow-up. Multivariable analysis was used to test associations between tumour location, sex, age at CPP, GnRHa duration and a diagnosis of CPP with final height <-2SD score (SDS), gonadotropin deficiency (LH/FSHD) and obesity, respectively. RESULTS: Eighty patients (47 females) had CPP and were followed for 11·4 ± 5·0 years (mean ± SD). The prevalence of CPP was 15·2% overall, 29·2% following HPA tumours and 6·6% after radiotherapy for non-HPA tumours. Height <-2SDS was more common at the last follow-up than at the puberty onset (21·4% vs 2·4%, P = 0·005). Obesity was more prevalent at the last follow-up than at the completion of GnRHa or the puberty onset (37·7%, 22·6% and 20·8%, respectively, P = 0·03). Longer duration of GnRHa was associated with increased odds of final height <-2SDS (OR = 2·1, 95% CI 1·0-4·3) and longer follow-up with obesity (OR = 1·3, 95% CI 1·1-1·6). LH/FSHD was diagnosed in 32·6%. There was no independent association between CPP and final height <-2SDS, and LH/FSHD and obesity in the subset of patients with HPA low-grade gliomas. CONCLUSIONS: Patients with organic CPP experience an incomplete recovery of growth and a high prevalence of LH/FSHD and obesity. Early diagnosis and treatment of CPP may limit further deterioration of final height prospects.

A phase I trial and PK study of cediranib (AZD2171), an orally bioavailable pan-VEGFR inhibitor, in children with recurrent or refractory primary CNS tumors.

BACKGROUND: Cediranib (AZD2171), an oral pan-vascular endothelial growth factor (VEGF) inhibitor, was evaluated in this phase I study to determine its toxicity profile, dose-limiting toxicities (DLTs), maximum-tolerated dose (MTD), pharmacokinetics, and pharmacodynamics in children and adolescents with recurrent or refractory primary central nervous system (CNS) tumors. METHODS: Children and adolescents <22 years were enrolled into one of two strata: stratum I­those not receiving enzyme-inducing anticonvulsant drugs (EIACD) and stratum II­those receiving EIACDs. Dose-level selection was based on the continual reassessment method (CRM). RESULTS: Thirty-six eligible patients with median age of 12.7 years (range, 5.4-21.7 years) in stratum I (24 males) and 12 patients (7 males) in stratum II with median age of 13.4 years (range, 8.9-19.5 years) were initially assessed over a 4-week DLT evaluation period, modified to 6 weeks during the study. An MTD of 32 mg/m(2)/day was declared; however, excessive toxicities (transaminitis, proteinuria, diarrhea, hemorrhage, palmer-planter syndrome, reversible posterior leukoencephalopathy) in the expansion cohort treated at this dose suggested that it might not be tolerated over a longer time period. An expansion cohort at 20 mg/m(2)/day also demonstrated poor longer-term tolerability. Diffusion and perfusion MRI and PET imaging variables as well as biomarker analysis were performed and correlated with outcome. At 20 mg/m(2)/day, the median plasma area under the concentration-time curve at steady state was lower than that observed in adults at similar dosages. CONCLUSIONS: While the MTD of once daily oral cediranib in children with recurrent or progressive CNS tumors was initially defined as 32 mg/m(2)/day, this dose and 20 mg/m(2)/day were not considered tolerable over a protracted time period.

Phase I trial of weekly MK-0752 in children with refractory central nervous system malignancies: a pediatric brain tumor consortium study.

PURPOSE: Amplification and high levels of NOTCH ligand expression have been identified in several types of pediatric brain tumors. A phase I trial of weekly MK-0752, an oral inhibitor of gamma-secretase, was conducted in children with recurrent central nervous system (CNS) malignancies to estimate the maximum tolerated dose, dose-limiting toxicities (DLT), pharmacokinetics (PK), and pharmacodynamics of weekly MK-0752. METHODS: MK-0752 was administered once weekly at 1000 and 1400 mg/m(2) using a rolling-6 design. PK analysis was performed during the first course. NOTCH and HES expression was assessed by immunohistochemistry and Western blot. RESULTS: Ten eligible patients were enrolled (median age 8.8 years; range 3.1-19.2) with diagnoses of brain stem glioma (n = 3), ependymoma (n = 2), anaplastic astrocytoma (n = 1), choroid plexus carcinoma (n = 2), medulloblastoma (n = 1), and primitive neuroectodermal tumor (n = 1). Nine were evaluable for toxicity. One DLT of fatigue occurred in the six evaluable patients enrolled at 1000 mg/m(2)/dose. No DLTs were experienced by three patients treated at 1400 mg/m(2)/dose. Non-dose-limiting grade 3 toxicities included lymphopenia, neutropenia, and anemia. Median number of treatment courses was 2 (range 1-10). Two patients continued on therapy for at least 6 months. The median (range) C(max) of MK-0752 was 88.2 µg/mL (40.6 to 109 µg/mL) and 60.3 µg/mL (59.2 to 91.9 µg/mL) in patients receiving 1000 and 1400 mg/m(2)/week, respectively. NOTCH expression was decreased in six of seven patients for whom tissue was available at 24 h post-MK-0752. CONCLUSION: MK-0752 is well tolerated and exhibits target inhibition at 1000 and 1400 mg/m(2)/week in children with recurrent CNS malignancies.

Anterior hypopituitarism in adult survivors of childhood cancers treated with cranial radiotherapy: a report from the St Jude Lifetime Cohort study.

PURPOSE: To estimate the prevalence of and risk factors for growth hormone deficiency (GHD), luteinizing hormone/follicle-stimulating hormone deficiencies (LH/FSHD), thyroid-stimulatin hormone deficiency (TSHD), and adrenocorticotropic hormone deficiency (ACTHD) after cranial radiotherapy (CRT) in childhood cancer survivors (CCS) and assess the impact of untreated deficiencies. PATIENTS AND METHODS: Retrospective study in an established cohort of CCS with 748 participants treated with CRT (394 men; mean age, 34.2 years [range, 19.4 to 59.6 years] observed for a mean of 27.3 years [range, 10.8 to 47.7 years]). Multivariable logistic regression was used to study associations between demographic and treatment-related risk factors and pituitary deficiencies, as well as associations between untreated deficiencies and cardiovascular health, bone mineral density (BMD), and physical fitness. RESULTS: The estimated point prevalence was 46.5% for GHD, 10.8% for LH/FSHD, 7.5% for TSHD, and 4% for ACTHD, and the cumulative incidence increased with follow-up. GHD and LH/FSHD were not treated in 99.7% and 78.5% of affected individuals, respectively. Male sex and obesity were significantly associated with LH/FSHD; white race was significant associated with LH/FSHD and TSHD. Compared with CRT doses less than 22 Gy, doses of 22 to 29.9 Gy were significantly associated with GHD; doses ≥ 22 Gy were associated with LH/FSHD; and doses ≥ 30 Gy were associated with TSHD and ACTHD. Untreated GHD was significantly associated with decreased muscle mass and exercise tolerance; untreated LH/FSHD was associated with hypertension, dyslipidemia, low BMD, and slow walking; and both deficits, independently, were associated with with abdominal obesity, low energy expenditure, and muscle weakness. CONCLUSION: Anterior pituitary deficits are common after CRT. Continued development over time is noted for GHD and LH/FSHD with possible associations between nontreatment of these conditions and poor health outcomes.

Phase I and pharmacokinetic trial of PTC299 in pediatric patients with refractory or recurrent central nervous system tumors: a PBTC study.

PTC299 is a novel, orally-bioavailable small molecule that selectively inhibits vascular endothelial growth factor receptor protein synthesis at the post-transcriptional level. Based on promising preclinical results, we conducted a pediatric phase I study to estimate the maximum tolerated dose, describe dose-limiting toxicities (DLT) and characterize the pharmacokinetic profile of PTC299 in children with recurrent CNS tumors. PTC299 was administered orally twice or three times daily, depending on the regimen. Four regimens were evaluated using the rolling 6 design, starting with 1.2 mg/kg/dose twice daily and escalating to 2 mg/kg/dose three times daily. Pharmacokinetic studies were performed during the first two courses. Twenty-seven children (14 male, median age 11.2, range 5.5-21 years) with recurrent brain tumors were treated; 21 were fully evaluable for toxicity assessment. Therapy was well-tolerated, and the only DLT was grade 3 hyponatremia. Grade three and grade four toxicities were uncommon in subsequent cycles. Median AUC0-Tlast values at the 2 mg/kg were similar to those observed in adults. The study was terminated while patients were being treated at the highest planned dose, due to hepatotoxicity encountered in the ongoing adult phase I studies. No complete or partial responses were observed. Two patients with low-grade gliomas were noted to have minor responses, and at the time of the study's closure, 5 children with low-grade gliomas had been on therapy for 8 or more courses (range 8-16). PTC299 was well-tolerated at the highest dose level tested (2 mg/kg/dose TID) in children with recurrent brain tumors and prolonged disease stabilization was seen in children with low-grade gliomas.

Subsequent neoplasms in survivors of childhood central nervous system tumors: risk after modern multimodal therapy.

BACKGROUND: Multimodal therapy has improved survival for some childhood CNS tumors. However, whether risk for subsequent neoplasms (SNs) also increases is unknown. We report the cumulative incidence of, and risk factors for, SNs after a childhood primary CNS tumor and determine whether treatment that combines radiation therapy (RT) with chemotherapy increases risk for SNs. METHODS: Analyses included 2779 patients with a primary CNS tumor treated at St Jude Children's Research Hospital between 1985 and 2012. Cumulative incidence and standardized incidence ratios (SIRs) were estimated for SNs confirmed by pathology report. Cumulative incidence among the 237 five-year medulloblastoma survivors treated with multimodal therapy (RT + chemotherapy) was compared with a historical cohort of 139 five-year survivors treated with RT but no chemotherapy in the Childhood Cancer Survivor Study. RESULTS: Eighty-one survivors had 97 SNs. The cumulative incidence of first SN was 3.0% (95% CI: 2.3%-3.9%) at 10 years, and 6.0% (95% CI: 4.6%-7.7%) at 20 years from diagnosis. Risks were highest for subsequent glioma, all grades (SIR = 57.2; 95% CI: 36.2-85.8) and acute myeloid leukemia (SIR = 31.8; 95% CI: 10.2-74.1). Compared with RT alone, RT + chemotherapy did not increase risk for SNs (hazard ratio: 0.64; 95% CI: 0.38-1.06). Among five-year survivors of medulloblastoma treated with multimodal therapy, cumulative incidence of SN was 12.0% (95% CI: 6.4%-19.5%) at 20 years, no different than survivors treated with RT alone (11.3%, P = .44). CONCLUSION: The cumulative incidence of SNs continues to increase with time from treatment with no obvious plateau, but the risk does not appear to be higher after exposure to multimodal therapy compared with RT alone. Continued follow-up of survivors as they age is essential.

Pubertal development and primary ovarian insufficiency in female survivors of embryonal brain tumors following risk-adapted craniospinal irradiation and adjuvant chemotherapy.

BACKGROUND: Female survivors of central nervous system (CNS) tumors are at an increased risk for gonadal damage and variations in the timing of puberty following radiotherapy and alkylating agent-based chemotherapy. PROCEDURE: Clinical and laboratory data were obtained from 30 evaluable female patients with newly diagnosed embryonal CNS tumors treated on a prospective protocol (SJMB 96) at St. Jude Children's Research Hospital (SJCRH). Pubertal development was evaluated by Tanner staging. Primary ovarian insufficiency (POI) was determined by Tanner staging and FSH level. Females with Tanner stage I-II and FSH > 15 mIU/ml, or Tanner stage III-V, FSH > 25 mIU/ml and FSH greater than LH were defined to have ovarian insufficiency. Recovery of ovarian function was defined as normalization of FSH without therapeutic intervention. RESULTS: Median length of follow-up post completion of therapy was 7.2 years (4.0-10.8 years). The cumulative incidence of pubertal onset was 75.6% by the age of 13. Precocious puberty was observed in 11.1% and delayed puberty in 11.8%. The cumulative incidence of POI was 82.8%, though recovery was observed in 38.5%. CONCLUSIONS: Treatment for primary CNS embryonal tumors may cause variations in the timing of pubertal development, impacting physical and psychosocial development. Female survivors are at risk for POI, a subset of whom will recover function over time. Further refinement of therapies is needed in order to reduce late ovarian insufficiency. Pediatr Blood Cancer 2015;62:329-334. © 2014 Wiley Periodicals, Inc.

A phase 1 and pharmacokinetic study of enzastaurin in pediatric patients with refractory primary central nervous system tumors: a pediatric brain tumor consortium study.

BACKGROUND: We sought to estimate the maximum tolerated or recommended phase 2 dose and describe the pharmacokinetics and toxicities of enzastaurin, an oral inhibitor of protein kinase Cß, in children with recurrent central nervous system malignancies. METHODS: Enzastaurin was administered continuously once daily at 3 dose levels (260, 340, and 440 mg/m(2)) and twice daily at 440 mg/m(2)/day. Plasma pharmacokinetics were evaluated following a single dose and at steady state. Inhibition of protein kinase C and Akt cell signaling in peripheral blood mononuclear cells was evaluated. Akt pathway activity was measured in pretreatment tumor samples. RESULTS: Thirty-three patients enrolled; 1 was ineligible, and 3 were nonevaluable secondary to early progressive disease. There were no dose-limiting toxicities during the dose-finding phase. Two participants receiving 440 mg/m(2) given twice daily experienced dose-limiting toxicities of grade 3 thrombocytopenia resulting in delayed start of course 2 and grade 3 alanine transaminase elevation that did not recover within 5 days. There were no grade 4 toxicities during treatment. The concentration of enzastaurin increased with increasing dose and with continuous dosing; however, there was not a significant difference at the 440 mg/m(2) dosing level when enzastaurin was administered once daily versus twice daily. There were no objective responses; however, 11 participants had stable disease >3 cycles, 7 with glioma, 2 with ependymoma, and 2 with brainstem glioma. CONCLUSION: Enzastaurin was well tolerated in children with recurrent CNS malignancies, with chromaturia, fatigue, anemia, thrombocytopenia, and nausea being the most common toxicities. The recommended phase 2 dose is 440 mg/m(2)/day administered once daily.

18F-FDG PET and MR imaging associations across a spectrum of pediatric brain tumors: a report from the pediatric brain tumor consortium.

UNLABELLED: The purpose of this study was to describe (18)F-FDG uptake across a spectrum of pediatric brain tumors and correlate (18)F-FDG PET with MR imaging variables, progression-free survival (PFS), and overall survival (OS). METHODS: A retrospective analysis was conducted of children enrolled in phase I/II clinical trials through the Pediatric Brain Tumor Consortium from August 2000 to June 2010. PET variables were summarized within diagnostic categories using descriptive statistics. Associations of PET with MR imaging variables and PFS and OS by tumor types were evaluated. RESULTS: Baseline (18)F-FDG PET was available in 203 children; 66 had newly diagnosed brain tumors, and 137 had recurrent/refractory brain tumors before enrolling in a Pediatric Brain Tumor Consortium trial. MR imaging was performed within 2 wk of PET and before therapy in all cases. The (18)F-FDG uptake pattern and MR imaging contrast enhancement (CE) varied by tumor type. On average, glioblastoma multiforme and medulloblastoma had uniform, intense uptake throughout the tumor, whereas brain stem gliomas (BSGs) had low uptake in less than 50% of the tumor and ependymoma had low uptake throughout the tumor. For newly diagnosed BSG, correlation of (18)F-FDG uptake with CE portended reduced OS (P = 0.032); in refractory/recurrent BSG, lack of correlation between (18)F-FDG uptake and CE suggested decreased PFS (P = 0.023). In newly diagnosed BSG for which more than 50% of the tumor had (18)F-FDG uptake, there was a suggestion of lower apparent diffusion coefficient (P = 0.061) and decreased PFS (P = 0.065). CONCLUSION: (18)F-FDG PET and MR imaging showed a spectrum of patterns depending on tumor type. In newly diagnosed BSG, the correlation of (18)F-FDG uptake and CE suggested decreased OS, likely related to more aggressive disease. When more than 50% of the tumor had (18)F-FDG uptake, the apparent diffusion coefficient was lower, consistent with increased cellularity. In refractory/recurrent BSG, poor correlation between (18)F-FDG uptake and CE was associated with decreased PFS, which may reflect concurrent tissue breakdown at sites of treated disease and development of new sites of (18)F-FDG-avid malignancy.

A phase I trial of veliparib (ABT-888) and temozolomide in children with recurrent CNS tumors: a pediatric brain tumor consortium report.

BACKGROUND: A phase I trial of veliparib (ABT-888), an oral poly(ADP-ribose) polymerase (PARP) inhibitor, and temozolomide (TMZ) was conducted in children with recurrent brain tumors to (i) estimate the maximum tolerated doses (MTDs) or recommended phase II doses (RP2Ds) of veliparib and TMZ; (ii) describe the toxicities of this regimen; and (iii) evaluate the plasma pharmacokinetic parameters and extent of PARP inhibition in peripheral blood mononuclear cells (PBMCs) following veliparib. METHODS: TMZ was given once daily and veliparib twice daily for 5 days every 28 days. Veliparib concentrations and poly(ADP-ribose) (PAR) levels in PBMCs were measured on days 1 and 4. Analysis of pharmacokinetic and PBMC PAR levels were performed twice during study conduct to rationally guide dose modifications and to determine biologically optimal MTD/RP2D. RESULTS: Twenty-nine evaluable patients were enrolled. Myelosuppression (grade 4 neutropenia and thrombocytopenia) were dose limiting. The RP2Ds are veliparib 25 mg/m(2) b.i.d. and TMZ 135 mg/m(2)/d. Only 2 out of 12 patients treated at RP2Ds experienced dose-limiting toxicities. Although no objective response was observed, 4 patients had stable disease >6 months in duration, including 1 with glioblastoma multiforme and 1 with ependymoma. At the RP2D of veliparib, pediatric pharmacokinetic parameters were similar to those in adults. CONCLUSIONS: Veliparib and TMZ at the RP2D were well tolerated in children with recurrent brain tumors. A phase I/II trial to evaluate the tolerability and efficacy of veliparib, TMZ, and radiation in children with newly diagnosed brainstem gliomas is in progress.

Phase II Trial of Erlotinib during and after Radiotherapy in Children with Newly Diagnosed High-Grade Gliomas.

BACKGROUND: Epidermal growth factor receptor is overexpressed in most pediatric high-grade gliomas (HGG). Since erlotinib had shown activity in adults with HGG, we conducted a phase II trial of erlotinib and local radiotherapy (RT) in children with newly diagnosed HGG. METHODS: Following maximum surgical resection, patients between 3 and 21 years with non-metastatic HGG received local RT at 59.4 Gy (54 Gy for spinal tumors and those with ≥70% brain involvement). Erlotinib started on day 1 of RT (120 mg/m(2) per day) and continued for 2 years unless there was tumor progression or intolerable toxicities. The 2-year progression-free survival (PFS) was estimated for patients with intracranial anaplastic astrocytoma (AA) and glioblastoma (GBM). RESULTS: Median age at diagnosis for 41 patients with intracranial tumors (21 with GBM and 20 with AA) was 10.9 years (range, 3.3-19 years). The 2-year PFS for patients with AA and GBM was 15 ± 7 and 19 ± 8%, respectively. Only five patients remained alive without tumor progression. Twenty-six patients had at least one grade 3 or 4 toxicity irrespective of association with erlotinib; only four required dose modifications. The main toxicities were gastrointestinal (n = 11), dermatologic (n = 5), and metabolic (n = 4). One patient with gliomatosis cerebri who required prolonged corticosteroids died of septic shock associated with pancreatitis. CONCLUSION: Although therapy with erlotinib was mostly well-tolerated, it did not change the poor outcome of our patients. Our results showed that erlotinib is not a promising medication in the treatment of children with intracranial AA and GBM.

"Occult" post-contrast signal enhancement in pediatric diffuse intrinsic pontine glioma is the MRI marker of angiogenesis?

INTRODUCTION: In diffuse intrinsic pontine gliomas (DIPG), subtracting pre-contrast from post-contrast T1-weighted images (T1WI) occasionally reveals subtle, "occult" enhancement. We hypothesized that this represents intravascular enhancement related to angiogenesis and hence that these tumors should have greater blood volume fractions than do non-enhancing tumors. METHODS: We retrospectively screened MR images of 66 patients initially diagnosed with DIPG and analyzed pretreatment conventional and dynamic susceptibility contrast (DSC) perfusion MRI studies of 61 patients. To determine the incidence of occult enhancement, cerebral blood volume (CBV) values were compared in areas of occult enhancement (OcE), no enhancement (NE), and normal-appearing deep cerebellar white matter (DCWM). RESULTS: Tumors of 10 patients (16.4 %) had occult enhancement; those of 6 patients (9.8 %) had no enhancement at all. The average CBV in areas of occult enhancement was significantly higher than that in non-enhancing areas of the same tumor (P = .03), within DCWM in the same patient (P = .03), and when compared to anatomically paired/similar regions of interest (ROI) in patients with non-enhancing tumors (P = .005). CONCLUSION: Areas of OcE correspond to areas of higher CBV in DIPG, which may be an MRI marker for angiogenesis, but larger scale studies may be needed to determine its potential relevance to grading by imaging, treatment stratification, biopsy guidance, and evaluation of response to targeted therapy.

Incidental detection of late subsequent intracranial neoplasms with magnetic resonance imaging among adult survivors of childhood cancer.

PURPOSE: Survivors of childhood cancer are at an increased risk of developing subsequent neoplasms. In long-term survivors of childhood malignancies treated with and without cranial radiation therapy (CRT), undergoing unenhanced magnetic resonance imaging (MRI) of the brain, we estimated detection of intracranial neoplasms. METHODS: To investigate neurocognitive outcomes, 219 survivors of childhood cancer underwent unenhanced screening MRI of the brain. Of the survivors, 164 had been treated for acute lymphoblastic leukemia (ALL) (125 received CRT) and 55 for Hodgkin lymphoma (HL) (none received CRT). MRI examinations were reviewed and systematically coded by a single neuroradiologist. Demographic and treatment characteristics were compared for survivors with and without subsequent neoplasms. RESULTS: Nineteen of the 219 survivors (8.7 %) had a total of 31 subsequent intracranial neoplasms identified by neuroimaging at a median time of 25 years (range 12-46 years) from diagnosis. All neoplasms occurred after CRT, except for a single vestibular schwannoma within the cervical radiation field in a HL survivor. The prevalence of subsequent neoplasms after CRT exposure was 14.4 % (18 of 125). By noncontrast MRI, intracranial neoplasms were most suggestive of meningiomas. Most patients presented with no specific, localizing neurological complaints. In addition to the schwannoma, six tumors were resected based on results of MRI screening, all of which were meningiomas on histologic review. CONCLUSION: Unenhanced brain MRI of long-term survivors of childhood cancer detected a substantial number of intracranial neoplasms. Screening for early detection of intracranial neoplasms among aging survivors of childhood cancer who received CRT should be evaluated. IMPLICATIONS FOR CANCER SURVIVORS: The high prevalence of incidentally detected subsequent intracranial neoplasms after CRT in long-term survivors of childhood cancer and the minimal symptoms reported by those with intracranial tumors in our study indicate that brain MRI screening of long-term survivors who received CRT may be warranted. Prospective studies of such screening are needed.

Efficacy of bevacizumab plus irinotecan in children with recurrent low-grade gliomas--a Pediatric Brain Tumor Consortium study.

BACKGROUND: A phase II study of bevacizumab (BVZ) plus irinotecan (CPT-11) was conducted in children with recurrent low-grade glioma to measure sustained response and/or stable disease lasting ≥6 months and progression-free survival. METHODS: Thirty-five evaluable patients received 2 doses (10 mg/kg each) of single-agent BVZ intravenously 2 weeks apart and then BVZ + CPT-11 every 2 weeks until progressive disease, unacceptable toxicity, or a maximum of 2 years of therapy. Correlative studies included neuroimaging and expression of tumor angiogenic markers (vascular endothelial growth factor [VEGF], VEGF receptor 2, hypoxia-inducible factor 2α, and carbonic anhydrase 9). RESULTS: Thirty-five evaluable patients (median age 8.4 y [range, 0.6-17.6]) received a median of 12 courses of BVZ + CPT-11 (range, 2-26). Twenty-nine of 35 patients (83%) received treatment for at least 6 months. Eight patients progressed on treatment at a median time of 5.4 months (range, 1-17.8). Six patients (17.7%) still in follow-up have had stable disease without receiving additional treatment for a median of 40.1 months (range, 30.6-49.3) from initiating therapy. The 6-month and 2-year progression-free survivals were 85.4% (SE ± 5.96%) and 47.8% (SE ± 9.27%), respectively. The commonest toxicities related to BVZ included grades 1-2 hypertension in 24, grades 1-2 fatigue in 23, grades 1-2 epistaxis in 18, and grades 1-4 proteinuria in 15. The median volume of enhancement decreased significantly between baseline and day 15 (P < .0001) and over the duration of treatment (P < .037). CONCLUSION: The combination of BVZ + CPT-11 appears to produce sustained disease control in some children with recurrent low-grade gliomas.