BRAF fusions in pediatric histiocytic neoplasms define distinct therapeutic responsiveness to RAF paradox breakers.

Pediatric histiocytic neoplasms are hematopoietic disorders frequently driven by the BRAF-V600E mutation. Here, we identified two BRAF gene fusions (novel MTAP-BRAF and MS4A6A-BRAF) in two aggressive histiocytic neoplasms. In contrast to previously described BRAF fusions, MTAP-BRAF and MS4A6A-BRAF do not respond to the paradox breaker RAF inhibitor (RAFi) PLX8394 due to stable fusion dimerization mediated by the N-terminal fusion partners. This highlights a significant and clinically relevant shift from the current dogma that BRAF-fusions respond similarly to BRAF-inhibitors. As an alternative, we show suppression of fusion-driven oncogenic growth with the pan-RAFi LY3009120 and MEK inhibition.

Role of Metastatic Site Irradiation in Pediatric Patients With Metastatic Ewing Sarcoma.

BACKGROUND: The use of radiation therapy to treat metastases in patients with metastatic Ewing sarcoma (MES) has been controversial and variable. The authors report outcomes and patterns of failure after metastatic site irradiation (MSI). PROCEDURE: A total of 27 pediatric patients with MES were treated with chemotherapy and received radiation therapy to their primary site. Ten patients additionally received MSI, which consisted of whole-lung irradiation (WLI) in patients with lung metastases. Metastatic sites were followed from diagnosis to the first relapse. RESULTS: Median follow-up was 29 months. Seventy-eight percent of patients relapsed. Two-year progression-free survival (PFS) and overall survival with and without MSI were 30 versus 29% (log rank P=0.38) and 60 versus 70% (log rank P=0.11), respectively. The median time to relapse among patients who relapsed was 19.5 versus 12.3 months for those receiving MSI versus those who did not (P=0.04).Seven of 20 (35%) patients with lung metastases received WLI±other MSI. Two-year PFS with and without MSI was 43% versus 23% (log rank P=0.02). Among patients with a complete response to computed tomography, 5 of 14 (36%) patients received MSI. Two-year PFS with and without MSI was 60% versus 33% (log rank P=0.04).In the cohort of patients who relapsed, among all metastatic sites at diagnosis, the disease recurred at 15% of irradiated sites and 31% of unirradiated sites. On logistic regression, no factors were statistically associated with increased risk of recurrence at initial sites of metastases. CONCLUSIONS: Relapses frequently occur at sites of prior unirradiated disease in patients with MES. WLI may improve 2-year PFS, regardless of chemotherapy response. Further investigation of the role of MSI is warranted.

Fundamental problems with pediatric adaptive dosing of carboplatin using nuclear-medicine-based estimates of renal function.

BACKGROUND: Carboplatin is often adaptively dosed based on glomerular filtration rate (GFR), usually estimated by nuclear medicine tests. At least five pediatric adaptive dosing formulas have been developed. In an effort to standardize dosing in Children's Oncology Group protocols, we explored methodologic variation in GFR estimation and adaptive-dosing formula performance. PROCEDURE: Nuclear medicine GFR data from published series of ≥100 children with cancer were compared. Data from patients for whom body surface area, weight, GFR, and tracer half-life were available were used to compare formulas. RESULTS: Differences in methods used to estimate GFR in children with cancer resulted in highly variable population results, with median GFRs ranging from 96 to 150 mL/min/1.73m2 . The choice of adaptive formula had a major impact on calculated dose. When targeting an area under the curve of 7.9 mg/mL • min, the median difference between the formula yielding the lowest and highest carboplatin dose for individual subjects was 289 (range 96-1 737) mg/m2 . CONCLUSIONS: Wide variation in GFR obtained with nuclear-medicine-based tests in children with cancer primarily results from systematic methodologic errors. Formulas for calculating carboplatin dose produce additional and substantial variation that may place children with cancer at unnecessary risk for excessive toxicity or underdosing. These findings indicate a need for the development of a uniform, validated method for GFR determination in children that should be utilized in all centers. Currently, adaptive dosing of carboplatin based on GFR has serious limitations and in most clinical settings should arguably not be used in place of body-surface-area-based dosing.

A phase II study of eribulin in recurrent or refractory osteosarcoma: A report from the Children's Oncology Group.

BACKGROUND: Patients with recurrent or refractory osteosarcoma have a poor prognosis with less than 30% surviving two years. Eribulin is a synthetic analog of halichondrin B, has a novel mechanism of action when compared with other microtubule inhibitors, and may have antitumor activity in osteosarcoma. METHODS: A prospective study was designed to assess the disease control success at four months and objective response rates in patients with recurrent or refractory osteosarcoma treated with eribulin. Eligible patients were between 12 and 50 years of age, had measurable tumor, and met standard organ function requirements. Patients were given eribulin 1.4 mg/m2 /dose on days 1 and 8 of each 3-week cycle for up to 24 months if there was no progressive disease. Response to therapy was assessed using RECIST 1.1 criteria after cycles 2 and 5 and every fourth cycle thereafter. RESULTS: Nineteen patients enrolled on the AOST1322 study. The median age of enrollment was 16 years (range, 12-25 years). Twelve patients were male and seven female. Eribulin was well tolerated, with neutropenia identified as the most common toxicity. The median progression-free survival was 38 days and no patients reached the four-month time point without progression. No objective responses were seen in any patient. CONCLUSION: This study rapidly assessed the clinical activity of a novel agent in this patient population. Eribulin was well tolerated, but there were no patients who demonstrated objective response, and all patients had progression prior to four months.

Pantoprazole, an Inhibitor of the Organic Cation Transporter 2, Does Not Ameliorate Cisplatin-Related Ototoxicity or Nephrotoxicity in Children and Adolescents with Newly Diagnosed Osteosarcoma Treated with Methotrexate, Doxorubicin, and Cisplatin.

LESSONS LEARNED: Using a randomized crossover design and continuous variables such as change in hearing threshold and biomarkers of acute renal injury as short-term endpoints, it was determined that pantoprazole, an organic cation transporter 2 inhibitor, did not ameliorate cisplatin-associated nephrotoxicity or ototoxicity.Cystatin C is a robust method to estimate glomerular filtration rate in patients with cancer. Using a patient-reported outcome survey, all patients identified tinnitus and subjective hearing loss occurring "at least rarely" after cycle 1, prior to objective high-frequency hearing loss measured by audiograms.New therapies that improve outcome with less acute and long-term toxicity are needed. BACKGROUND: Organic cation transporter 2 (OCT2), which is a cisplatin uptake transporter expressed on renal tubules and cochlear hair cells but not on osteosarcoma cells, mediates cisplatin uptake. Pantoprazole inhibits OCT2 and could ameliorate cisplatin ototoxicity and nephrotoxicity. Using a randomized crossover design, we evaluated audiograms, urinary acute kidney injury (AKI) biomarkers, and glomerular filtration rate (GFR) estimated from cystatin C (GFRcysC) in patients receiving cisplatin with and without pantoprazole. MATERIALS AND METHODS: Cisplatin (60 mg/m2 × 2 days per cycle) was administered concurrently with pantoprazole (intravenous [IV], 1.6 mg/kg over 4 hours) on cycles 1 and 2 or cycles 3 and 4 in 12 patients with osteosarcoma (OS) with a median (range) age of 12.8 (5.6-19) years. Audiograms, urinary AKI biomarkers, and serum cystatin C were monitored during each cycle. RESULTS: Pantoprazole had no impact on decrements in hearing threshold at 4-8 kHz, post-treatment elevation of urinary AKI biomarkers, or GFRcysC (Fig. 1, Table 1). Histological response (percent necrosis) after two cycles was similar with or without pantoprazole. All eight patients with localized OS at diagnosis are alive and in remission; three of four patients with metastases at diagnosis have died. CONCLUSION: Pantoprazole did not ameliorate cisplatin ototoxicity or nephrotoxicity. The decrease in GFRcysC and increase in N-acetyl-ß-glucosaminidase (NAG) and creatinine demonstrate that these biomarkers can quantify cisplatin glomerular and proximal tubular toxicity. OCT2 inhibition by pantoprazole did not appear to alter antitumor response or survival.

Proton therapy for pediatric head and neck malignancies.

PURPOSE: Pediatric head and neck malignancies are managed with intensive multimodality therapy. Proton beam therapy (PBT) may reduce toxicity by limiting exposure of normal tissue to radiation. In this study, we report acute toxicities and early outcomes following PBT for pediatric head and neck malignancies. MATERIALS AND METHODS: Between 2010 and 2016, pediatric patients with nonhematologic malignancies of the head and neck were treated with PBT. Clinical and dosimetric data were abstracted from the medical record and treatment planning system with institutional review board approval. RESULTS: Sixty-nine consecutive pediatric patients were treated with proton-based radiotherapy for head and neck malignancies. Thirty-five were treated for rhabdomyosarcoma to a median dose of 50.4 Gy relative biological effectiveness [RBE]. Ten patients were treated for Ewing sarcoma to a median dose of 55.8 Gy[RBE]. Twenty-four patients were treated for other histologies to a median dose of 63.0 Gy[RBE]. Grade 3 oral mucositis, anorexia, and dysphagia were reported to be 4, 22, and 7%, respectively. Actuarial 1-year freedom from local recurrence was 92% (95% CI 80-97). Actuarial 1-year overall survival was 93% (95% CI 79-98) in the entire cohort. Oral cavity mucositis was significantly correlated with oral cavity dose (D80 and D50 [P < 0.05], where D80 and D50 are dose to 50% of the volume and dose to 80% of the volume, respectively). CONCLUSIONS: In this study, we report low rates of acute toxicity in a cohort of pediatric patients with head and neck malignancies. PBT appears safe for this patient population, with local control rates similar to historical reports. Longer follow-up will be required to evaluate late toxicity and long-term disease control.

Management of Refractory Pediatric Kaposiform Hemangioendothelioma With Sirolimus and Aspirin.

Kaposiform hemangioendothelioma (KHE) is a rare vascular tumor characterized by aggressive local invasion and a syndrome of platelet trapping known as Kasabach-Merritt phenomenon that, through deposition of platelet derived growth factors, may perpetuate the growth of the tumor. Although many cases of KHE are successfully treated with local control or low-intensity chemotherapy, some cases are often refractory even to aggressive treatment. Herein, we describe a patient with a refractory, recurrent KHE despite multiple attempts at local control and intensive chemotherapy, that ultimately was successfully treated with rationally designed and low-intensity combination therapy of sirolimus and aspirin.

Dosing anticancer drugs in infants: Current approach and recommendations from the Children's Oncology Group's Chemotherapy Standardization Task Force.

An analysis of dose modifications for infants in 29 Children's Oncology Group protocols across 10 cancer types revealed 11 sets of criteria defining the infant population using age, weight, body surface area (BSA), or a combination of these parameters and eight dose modification methods. A new method of dosing anticancer drugs in infants was developed based on the rationale that prior modifications were implemented to reduce toxicity, which is not cancer-specific. The new method uses BSA dose banding in dosing tables for infants and children with a BSA <0.6 m2 and gradually transitions from body weight based to BSA-based dosing.

Surgical treatment of pelvic sarcoma in children: outcomes for twenty six patients.

PURPOSE: Pelvic sarcoma is uncommon in children and challenging to treat. This study examined different surgical approaches to treat pelvic sarcoma with the aim of assessing the oncologic, and functional outcomes. METHODS: We retrospectively examined the medical records of patients younger than 21 years of age who underwent surgery for pelvic sarcoma at our institution from 1992 to 2010. The functional status of the patients was examined after a minimum follow-up of two years. RESULTS: Twenty-six patients were included in the analysis. Nineteen (73%) patients were male and seven (27%) were female. Mean age at presentation was 12.0 ± 3.9 years. Nineteen patients had Ewing sarcoma (73%), five had osteosarcoma (19%), one had chondrosarcoma (4%) and one had rhabdomyosarcoma (4%). Iliac wing resection with no reconstruction was done in three patients. Reconstruction with free fibular graft A-frame was performed in four patients, saddle endoproshtesis in five patients, iliac autoclave in one patient, and internal hemipelvectomy in nine patients. Hindquarter amputation was performed in five patients. Median follow-up was 4.6 years (range, 2.6-16 years). Nineteen patients were alive (73%); of those, 13 were known to be without disease, three were with disease and three did not have known tumor status. Six patients were reported deceased, three had osteosarcoma and three had Ewing sarcoma. Function was assessed in 17 patients; 64% were asymptomatic and ambulatory and 36% were symptomatic and ambulatory. CONCLUSIONS: Salvage reconstruction for pelvic sarcoma can be performed through various procedures on the extent of necessary bony resection. Survival rate and functional outcomes were promising in the performed study.

Local Control Modality and Outcome for Ewing Sarcoma of the Femur: A Report From the Children's Oncology Group.

BACKGROUND: The choice of a local control (LC) modality for Ewing sarcoma (EWS) of the femur is controversial. This study aimed to determine the effect of LC modality on tumor LC and patient outcomes. METHODS: The study reviewed the treatment and outcomes for 115 patients who had EWS of the femur treated with similar chemotherapy in three cooperative group trials. Patient outcomes were analyzed according to the LC modality using the log-rank test and the cumulative incidence of local or distant failure using competing risks regression. RESULTS: The median age of the patients was 13 years. The most common tumor location was the proximal femur followed by the mid femur. For 55 patients with available data, the tumor was larger than 8 cm in 29 patients and 8 cm or smaller in 26 patients. For 84 patients (73 %), surgery only was performed, whereas 17 patients (15 %) had surgery plus radiation, and 14 patients (12 %) had radiation only. The 5-year event-free survival (EFS) rate was 65 % (95 % confidence interval [CI], 55-73 %), and the 5-year overall survival (OS) rate was 70 % (95 % CI, 61-78 %). Patient outcomes did not differ significantly according to tumor location within the femur (proximal, mid or distal) or tumor size (<8 vs ≥8 cm). The findings showed no statistically significant differences in EFS, OS, cumulative incidence of local failure, or cumulative incidence of distant failure according to LC modality (surgery, surgery plus radiation, or radiation). CONCLUSIONS: The LC modality did not significantly affect disease outcome for EWS of the femur. Further study of treatment complications and functional outcome may help to define the optimal LC modality.

Pilot Study of Adding Vincristine, Topotecan, and Cyclophosphamide to Interval-Compressed Chemotherapy in Newly Diagnosed Patients With Localized Ewing Sarcoma: A Report From the Children's Oncology Group.

BACKGROUND: The combination of topotecan and cyclophosphamide is active in relapsed Ewing sarcoma family of tumors (ESFT). The feasibility of adding these agents combined with vincristine (vincristine-topotecan-cyclophosphamide [VTc]) to standard five-drug chemotherapy with vincristine-doxorubicin-cyclophosphamide (VDC) and ifosfamide-etoposide (IE) administered in an interval-compressed (2-week instead of 3-week intervals) schedule was investigated. PROCEDURE: Newly diagnosed patients with localized ESFT < 31 years, with good performance status and adequate organ function were eligible. Seventeen alternating cycles of chemotherapy with VTc, VDC, and IE were administered at 2-week intervals. Local control (LC) of the primary tumor occurred following six cycles. Primary endpoints were the ability to deliver chemotherapy in an interval-compressed schedule, and the rate of grade 3 or greater nonhematologic toxicity and grade 4 hematologic toxicity, which delayed chemotherapy by ≥2 weeks. Secondary endpoints were event-free survival (EFS) and overall survival (OS). RESULTS: Thirty-five patients with a median age of 11 years were enrolled. The mean time to last dose of chemotherapy prior to LC was 12.6 ± 1.4 weeks and 45.5% of patients received intended chemotherapy without any delay prior to LC. There were no toxic deaths or unexpected toxicities. Five-year EFS was 79.6% (95% confidence interval [CI]: 61.8-89.7%) and 5-year OS was 88% (95% CI: 71.4-95.3%). CONCLUSIONS: The addition of VTc to standard therapy was tolerable with sufficient interval compression compared to historical standard 3-week cycles.

Identification of Discrete Prognostic Groups in Ewing Sarcoma.

BACKGROUND: Although multiple prognostic variables have been proposed for Ewing sarcoma (EWS), little work has been done to further categorize these variables into prognostic groups for risk classification. PROCEDURE: We derived initial prognostic groups from 2,124 patients with EWS in the SEER database. We constructed a multivariable recursive partitioning model of overall survival using the following covariates: age; stage; race/ethnicity; sex; axial primary; pelvic primary; and bone or soft tissue primary. Based on this model, we identified risk groups and estimated 5-year overall survival for each group using Kaplan-Meier methods. We then applied these groups to 1,680 patients enrolled on COG clinical trials. RESULTS: A multivariable model identified five prognostic groups with significantly different overall survival: (i) localized, age <18 years, non-pelvic primary; (ii) localized, age <18, pelvic primary or localized, age ≥18, white, non-Hispanic; (iii) localized, age ≥18, all races/ethnicities other than white, non-Hispanic; (iv) metastatic, age <18; and (v) metastatic, age ≥18. These five groups were applied to the COG dataset and showed significantly different overall and event-free survival based upon this classification system (P < 0.0001). A sub-analysis of COG patients treated with ifosfamide and etoposide as a component of therapy evaluated these findings in patients receiving contemporary therapy. CONCLUSIONS: Recursive partitioning analysis yields discrete prognostic groups in EWS that provide valuable information for patients and clinicians in determining an individual patient's risk of death. These groups may enable future clinical trials to adjust EWS treatment according to individualized risk.

Comparison of clinical features and outcomes in patients with extraskeletal versus skeletal localized Ewing sarcoma: A report from the Children's Oncology Group.

BACKGROUND: The prognostic significance of having extraskeletal (EES) versus skeletal Ewing sarcoma (ES) in the setting of modern chemotherapy protocols is unknown. The purpose of this study was to compare the clinical characteristics, biologic features, and outcomes for patients with EES and skeletal ES. METHODS: Patients had localized ES and were treated on two consecutive protocols using five-drug chemotherapy (INT-0154 and AEWS0031). Patients were analyzed based on having an extraskeletal (n = 213) or skeletal (n = 826) site of tumor origin. Event-free survival (EFS) was estimated using the Kaplan-Meier method, compared using the log-rank test, and modeled using Cox multivariate regression. RESULTS: Patients with extraskeletal ES (EES) were more likely to have axial tumors (72% vs. 55%; P < 0.001), less likely to have tumors >8 cm (9% vs. 17%; P < 0.01), and less likely to be white (81% vs. 87%; P < 0.001) compared to patients with skeletal ES. There was no difference in key genomic features (type of EWSR1 translocation, TP53 mutation, CDKN2A mutation/loss) between groups. After controlling for age, race, and primary site, EES was associated with superior EFS (hazard ratio = 0.69; 95% confidence interval: 0.50-0.95; P = 0.02). Among patients with EES, age ≥18, nonwhite race, and elevated baseline erythrocyte sedimentation rate were independently associated with inferior EFS. CONCLUSION: Clinical characteristics, but not key tumor genomic features, differ between EES and skeletal ES. Extraskeletal origin is a favorable prognostic factor, independent of age, race, and primary site.

Comparative evaluation of local control strategies in localized Ewing sarcoma of bone: a report from the Children's Oncology Group.

BACKGROUND: Patients with Ewing sarcoma require local primary tumor control with surgery, radiation, or both. The optimal choice of local control for overall and local disease control remains unclear. METHODS: Patients with localized Ewing sarcoma of bone who were treated on 3 consecutive protocols with standard-dose, 5-drug chemotherapy every 3 weeks were included (n=465). Propensity scores were used to control for differences between local control groups by constructing multivariate models to assess the impact of local control type on clinical endpoints (event-free survival [EFS], overall survival, local failure, and distant failure) independent of differences in their propensity to receive each local control type. RESULTS: Patients who underwent surgery were younger (P=.02) and had more appendicular tumors (P<.001). Compared with surgery, radiation had higher unadjusted risks of any event (hazard ratio [HR], 1.70; 95% confidence interval [CI], 1.18-2.44), death (HR, 1.84; 95% CI, 1.18-2.85), and local failure (HR, 2.57; 95% CI, 1.37-4.83). On multivariate analysis, compared with surgery, radiation had a higher risk of local failure (HR, 2.41; 95% CI, 1.24-4.68), although there were no significant differences in EFS (HR, 1.42; 95% CI, 0.94-2.14), overall survival (HR, 1.37; 95% CI, 0.83-2.26), or distant failure (HR, 1.13; 95% CI, 0.70-1.84) between local control groups. CONCLUSIONS: In this large group of similarly treated patients, choice of the mode of local control was not related significantly to EFS, overall survival, or distant failure, although the risk of local failure was greater for radiation compared with surgery. These data support surgical resection when appropriate, whereas radiotherapy remains a reasonable alternative in selected patients.

Tumoral TP53 and/or CDKN2A alterations are not reliable prognostic biomarkers in patients with localized Ewing sarcoma: a report from the Children's Oncology Group.

BACKGROUND: A growing collection of retrospective studies have suggested that TP53 mutations and/or CDKN2A deletions have prognostic significance in Ewing sarcoma. We sought to evaluate these variables in patients with localized disease treated prospectively on a single Children's Oncology Group protocol. PROCEDURE: Of the 568 patients enrolled on Children's Oncology Group protocol AEWS0031 (NCT00006734), 112 had tumor specimens of sufficient quality and quantity to allow for analysis of TP53 mutations status by DNA sequencing, and CDKN2A deletion by dual color fluorescent in situ hybridization. RESULTS: Eight of 93 cases (8.6%) were found to have TP53 point mutations and 12 of 107 cases (11.2%) demonstrated homozygous CDKN2A deletion. Two cases were found to have an alteration in both genes. There was no significant difference in event-free survival of patients with TP53 mutations and/or CDKN2A deletions compared to patients with normal TP53/CDKN2A gene status, as demonstrated by log rank test (p = 0.58). CONCLUSIONS: Although previous retrospective studies suggest their significance, TP53 mutation and/or CDKN2A deletion are not reliable prognostic biomarkers in localized Ewing sarcoma.

Proactive enteral tube feeding in pediatric patients undergoing chemotherapy.

BACKGROUND: To determine feasibility and safety of proactive enteral tube feeding (ETF) in pediatric oncology patients. METHODS: Pediatric patients with newly diagnosed brain tumors, myeloid leukemia or high-risk solid tumors were eligible. Subjects agreeing to start ETF before cycle 2 chemotherapy were considered proactive participants (PPs). Those who declined could enroll as chart collection receiving nutritional standard of care. Nutritional status was assessed using standard anthropometric measurements. Episodes of infection and toxicity related to ETF were documented from diagnosis to end of therapy. A descriptive comparison between PPs and controls was conducted. RESULTS: One hundred four eligible patients were identified; 69 enrolled (20 PPs and 49 controls). At diagnosis, 17% of all subjects were underweight and 26% overweight. Barriers to enrollment included physician, subject and/or family refusal, and inability to initiate ETF prior to cycle 2 of chemotherapy. Toxicity of ETF was minimal, but higher percentage of subjects in the proactive group had episodes of infection than controls. Thirty-nine percent of controls eventually started ETF and were twice as likely to receive parenteral nutrition. PPs experienced less weight loss at ETF initiation than controls receiving ETF and were the only group to demonstrate improved nutritional status at end of study. CONCLUSIONS: Proactive ETF is feasible in children with cancer and results in improved nutritional status at end of therapy. Episodes of infection in this study are concerning; therefore, a larger randomized trial is required to further delineate infectious risks and toxicities that may be mitigated by improved nutritional status.

Proton versus photon radiation therapy for patients with high-risk neuroblastoma: the need for a customized approach.

BACKGROUND: Proton therapy for treatment for high-risk neuroblastoma may offer sparing of organs at risk (OAR) when compared to intensity-modulated X-ray therapy (IMXT). PROCEDURE: Double-scattered proton plans and IMXT plans delivering 2,160 cGy to the primary tumor site and other residual disease were developed for 13 consecutive HR-NBL patients. Radiation doses to target volumes and OAR were calculated to determine the optimal modality for each. RESULTS: All patients received radiation (5/13 ≥ 2 sites). No patient has experienced local recurrence or clinical organ toxicity. Coverage was excellent using both protons and IMXT: median % dose delivered to 95% clinical target volume was 99% and 100%, respectively. For nine patients with lateralized disease, proton therapy offered sparing of the contralateral kidney both with regard to median dose and dose to 20% (median <1 cGy vs. 362 cGy, P = 0.01; median 100 cGy vs. 634 cGy, P = 0.02, respectively). Proton therapy did not reduce ipsilateral kidney dose, and for 2 select patients with lateralized disease IMXT improved overall bilateral renal sparing. Proton therapy improved median bowel (median 33 cGy vs. 590 cGy, P = 0.01), total body (median <1 cGy vs. 30 cGy, P = 0.15), and liver dose (median <1 cGy vs. 529, P < 0.001). When chest RT was required, proton therapy decreased median heart dose and mean lung dose. CONCLUSIONS: For most patients (11/13), proton therapy offered the optimal combination of target coverage and organ sparing, and is a feasible treatment for HR-NBL. We recommend a customized approach with careful evaluation of renal dosimetry; IMXT may be preferred for select patients.

Long-Term Outcomes in Patients With Localized Ewing Sarcoma Treated With Interval-Compressed Chemotherapy on Children's Oncology Group Study AEWS0031.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned coprimary or secondary analyses are not yet available. Clinical trial updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.Long-term outcomes from Children's Oncology Group study AEWS0031 were assessed to determine whether the survival advantage of interval-compressed chemotherapy (ICC) was maintained over 10 years in patients with localized Ewing sarcoma (ES). AEWS0031 enrolled 568 eligible patients. Patients were randomly assigned to receive vincristine-doxorubicin-cyclophosphamide and ifosfamide-etoposide alternating once every 3 weeks (standard timing chemotherapy [STC]) versus once every 2 weeks (ICC). For this updated report, one patient was excluded because of uncertainty of original diagnosis. The 10-year event-free survival (EFS) was 70% with ICC compared with 61% with STC (P = .03), and 10-year overall survival (OS) was 76% with ICC compared with 69% with STC (P = .04). There was no difference in the 10-year cumulative incidence of second malignant neoplasms (SMNs; PC [see Data Supplement, online only] = .5). A test for interaction demonstrated that ICC provided greater risk reduction for patients with tumor volume ≥200 mL than for patients with tumors <200 mL, but no evidence for a significant interaction in other subgroups defined by age, primary site, and histologic response. With longer-term follow-up, ICC for localized ES is associated with superior EFS and OS without an increased risk for SMN compared with STC. ICC is associated with improved outcomes even in adverse-risk patient groups.

Analysis of Local Control Outcomes and Clinical Prognostic Factors in Localized Pelvic Ewing Sarcoma Patients Treated With Radiation Therapy: A Report From the Children's Oncology Group.

PURPOSE: To identify potential clinical prognostic factors associated with a higher risk of local recurrence in patients with localized pelvic Ewing sarcoma treated with radiation therapy. METHODS AND MATERIALS: Data for 101 patients treated with definitive radiation therapy (RT) or both surgery and radiation (S + RT) to primary pelvic tumors on INT-0091, INT-0154, and AEWS0031 were analyzed. Imaging data for patients who did not receive radiation were not available for central review; therefore, patients with surgery alone were not included. Cumulative incidence rates for local failure at 5 years from time of local control were calculated accounting for competing risks. RESULTS: The most common pelvic subsite was sacrum (44.6%). RT was used in 68% of patients and S + RT in 32%. The local failure rate was 25.0% for RT and 6.3% for S + RT (P = .046). There was no statistically significant difference in local control modality by tumor characteristics. Tumors originating in the ischiopubic-acetabulum region were associated with the highest local failure incidence, 37.5% (P = .02, vs sacrum and iliac/buttock tumors), particularly those treated with RT (50.0%, P = .06). A higher incidence of local failure was seen with each additional 100 mL of tumor at diagnosis (P = .04). Multivariable analysis demonstrated RT alone (hazard ratio [HR], 5.1; P = .04), tumor subsite (particularly ischiopubic-acetabulum tumors; HR 4.6; P = .02), and increasing volume per 100 mL (HR, 1.2; P = .01) were associated with a higher incidence of local recurrence. CONCLUSIONS: Combination surgery and RT is associated with improved local control in patients with pelvic Ewing sarcoma compared with definitive RT. Tumors involving the ischiopubic-acetabulum region and increasing tumor volume at diagnosis are associated with inferior local control. Tumor characteristics did not correlate with choice of local therapy modality suggesting an opportunity to develop best local therapy practices guidelines for future studies based on tumor features.

Randomized Phase III Trial of Ganitumab With Interval-Compressed Chemotherapy for Patients With Newly Diagnosed Metastatic Ewing Sarcoma: A Report From the Children's Oncology Group.

PURPOSE: Monoclonal antibodies directed against insulin-like growth factor-1 receptor (IGF-1R) have shown activity in patients with relapsed Ewing sarcoma. The primary objective of Children's Oncology Group trial AEWS1221 was to determine if the addition of the IGF-1R monoclonal antibody ganitumab to interval-compressed chemotherapy improves event-free survival (EFS) in patients with newly diagnosed metastatic Ewing sarcoma. METHODS: Patients were randomly assigned 1:1 at enrollment to standard arm (interval-compressed vincristine/doxorubicin/cyclophosphamide alternating once every 2 weeks with ifosfamide/etoposide = VDC/IE) or to experimental arm (VDC/IE with ganitumab at cycle starts and as monotherapy once every 3 weeks for 6 months after conventional therapy). A planned sample size of 300 patients was projected to provide 81% power to detect an EFS hazard ratio of 0.67 or smaller for the experimental arm compared with the standard arm with a one-sided α of .025. RESULTS: Two hundred ninety-eight eligible patients enrolled (148 in standard arm; 150 in experimental arm). The 3-year EFS estimates were 37.4% (95% CI, 29.3 to 45.5) for the standard arm and 39.1% (95% CI, 31.3 to 46.7) for the experimental arm (stratified EFS-event hazard ratio for experimental arm 1.00; 95% CI, 0.76 to 1.33; 1-sided, P = .50). The 3-year overall survival estimates were 59.5% (95% CI, 50.8 to 67.3) for the standard arm and 56.7% (95% CI, 48.3 to 64.2) for the experimental arm. More cases of pneumonitis after radiation involving thoracic fields and nominally higher rates of febrile neutropenia and ALT elevation were reported on the experimental arm. CONCLUSION: Ganitumab added to interval-compressed chemotherapy did not significantly reduce the risk of EFS event in patients with newly diagnosed metastatic Ewing sarcoma, with outcomes similar to prior trials without IGF-1R inhibition or interval compression. The addition of ganitumab may be associated with increased toxicity.