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NANT2011-11 evaluatedThe cohort included 99 patients who had at least one biomarker available for analysis. Significant modulation in most biomarkers between baseline, 72 hours, and 96 hours followingPeripheral blood biomarkers relevant to radiation exposure demonstrate significant modulation after 131I-MIBG and concomitant radiation sensitizers impact extent of modulation. Biomarkers related to hematopoietic damage and apoptosis were associated with hematologic toxicity.

Purpose The use of stereotactic body radiation therapy (SBRT) in pediatric patients has been underreported. We reviewed practice patterns, outcomes, and toxicity of SBRT in this population. Methods and Materials In this multi-institutional study, 55 patients with 107 non-central nervous system lesions treated with SBRT between 2010 and 2016 were reviewed. Treatment response was evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and modified RECIST v1.1 criteria for soft-tissue and bone lesions, respectively. Patterns of local failure (LF) were assessed dosimetrically. The cumulative incidence of LF and toxicity were estimated accounting for the competing risk event of death. Predictors of LF were identified through joint frailty models for clustered competing risks. Results The median (range) dose/fraction was 7 (4.5-25) Gy, the total (range) dose/site was 35 (12-45), and the median (range) number of fractions was 5 (1-9). The radiographic response rates of bone and soft-tissue lesions were 90.6% and 76.7%, respectively. Symptom improvement was observed for 62% of symptomatic sites. A total of 27 LFs were documented, with 14 in-field, 9 marginal, and 4 out-of-field LFs. The 1-year estimated cumulative LF rate, progression-free survival, and overall survival were 25.2% (95% confidence interval [CI], 17.2%-36.1%), 17.5% (95% CI, 9.0%-34.1%), and 61% (95% CI, 48.9%-76.1%), respectively. Lesion type (soft tissue vs bone) was the only significant predictor of LF on multivariable analysis (P = .04), with increased hazard for soft-tissue lesions. No acute or late toxicity of grade 4 or higher was observed; the estimated 1-year cumulative incidence of late toxicity of any grade was 7.5% (95% CI, 3.6%-12.1%). Conclusions The SBRT was well tolerated and resulted in radiographic response and symptom palliation in most pediatric patients with advanced disease. The 1-year cumulative LF rate of 25% will serve as a benchmark for further modifications to radiation therapy indications, parameters, and combination therapy.

To identify potential clinical prognostic factors associated with a higher risk of local recurrence in localized pelvic Ewing sarcoma (ES) patients treated with radiation therapy.Data for 101 patients treated with definitive radiotherapy (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, so surgery alone patients were not included. Cumulative incidence rates for local failure at 5-years from time of local control were calculated accounting for competing risks.The most common pelvic subsite was sacrum (44.6%). RT was utilized 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=0.046). 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=0.02, vs. sacrum and iliac/buttock tumors), particularly those treated with RT (50.0%, p=0.06). A higher incidence of local failure was seen with each additional 100 mL of tumor at diagnosis (p=0.04). Multivariable analysis demonstrated RT alone (HR 5.1, p=0.04), tumor subsite (particularly ischiopubic-acetabulum tumors, HR 4.6, p=0.02), and increasing volume per 100 mL (HR 1.2, p=0.01) were associated with a higher incidence of local recurrence.Combination surgery and RT is associated with improved local control in patients with pelvic ES compared to 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.

Purpose Few tools exist to predict clinical outcomes after radiopharmaceutical therapy. Our goal was to identify associations between blood-based biomarkers of radiation effect and clinical outcomes after 131 I-metaiodobenzylguanidine ( 131 I-MIBG) therapy in patients with neuroblastoma. Methods and Materials We conducted a prospective, single-center cohort study in children with advanced neuroblastoma treated with 131 I-MIBG as monotherapy or in combination with systemic putative radiation sensitizers. We collected serial peripheral blood samples after 131 I-MIBG infusions and quantified a panel of protein and messenger RNA markers. We plotted relative change from baseline to assess degree of modulation over time and then evaluated association of marker modulation with toxicity and response endpoints. Results The cohort included 40 patients (30 male/10 female; median age 7 years). We observed significant modulation of the majority of markers between baseline and hour 72 after 131 I-MIBG. Greater fold increase of plasma FLT3 ligand was associated with subsequent grade 4 neutropenia ( P =.039). Modulation of peripheral blood BCLXL and DDB2 was associated with grade 3+ nonhematologic toxicity ( P =.043 and .048, respectively). No markers were associated with tumor response. Greater plasma FLT3 ligand, BCLXL , and BCL2 modulation was observed in patients receiving 131 I-MIBG in combination with radiation sensitizers. Among 9 patients who received 2 courses, the degree of modulation in serum amylase was significantly lower after the second course ( P =.012). Conclusions Peripheral blood biomarkers relevant to radiation exposure are significantly modulated during the acute period after 131 I-MIBG. The degree of modulation of a subset of these markers is associated with toxicity and receipt of concomitant radiation sensitizers.

Purpose External beam radiation therapy to initial sites of disease may influence relapse patterns in high-risk neuroblastoma. However, the effect of systemic irradiation by use of total body irradiation (TBI) on anatomic patterns of relapse has not previously been investigated. Methods and Materials We retrospectively analyzed patients receiving definitive treatment of high-risk neuroblastoma with subsequent relapse in bony metastatic sites, with a date of relapse between January 1, 1997, and December 31, 2012. Anatomic sites of disease, defined by metaiodobenzylguanidine (MIBG) avidity, were compared at diagnosis and at first relapse. The Fisher exact test was performed to compare relapse in initially involved sites between patients treated with and without TBI. Results Seventy-four patients with a median age at diagnosis of 3.5 years (range, 0.3-15.3 years) had relapse in 227 sites of MIBG-avid metastatic disease, with a median time to relapse of 1.8 years. Of the 227 sites of first relapse, 154 sites (68%) were involved at diagnosis. When we compared relapse patterns in patients treated with and without TBI, 12 of 23 patients (52%) treated with TBI had relapse in ≥1 previously MIBG-avid site of disease whereas 40 of 51 patients (78%) treated without TBI had relapse in ≥1 previously MIBG-avid site of disease ( P =.03). Conclusions Patients treated with systemic irradiation in the form of TBI were significantly less likely to have relapse in prior sites of disease. These findings support further investigation into the role of radiopharmaceutical therapies in curative multimodality therapy.

To identify clinical and treatment variables associated with a higher risk of local failure in Ewing sarcoma patients treated on recent Children's Oncology Group protocols.Data for 956 patients treated with ifosfamide and etoposide-based chemotherapy on INT-0091, INT-0154, and AEWS0031 were analyzed. Local treatment modalities were defined as surgery, definitive radiation therapy (RT), or surgery plus radiation (S+RT). Five-year cumulative incidence of local failure was determined.The local failure rate for the entire cohort was 7.3%, with a 3.9% rate for surgery, 15.3% for RT (P.01), and 6.6% for S+RT (P=.12). The local failure incidence was 5.4% for extremity tumors, 13.2% for pelvis tumors (P.01), 5.3% for axial non-spine tumors (P=.90), 9.1% for extraskeletal tumors (P=.08), and 3.6% for spine tumors (P=.49). The incidence of local failure was 14.8% for extremity tumors and 22.4% for pelvis tumors treated with RT, compared with 3.7% for extremity tumors and 3.9% for pelvis tumors treated with surgery (P≤.01). There was no difference in local failure incidence by local treatment modality for axial non-spine, spine, and extraskeletal tumors. The local failure incidence was 11.9% in patients aged ≥18 years versus 6.7% in patients aged18 years (P=.02). Age ≥18 years (hazard ratio 1.9, P=.04) and treatment with RT (hazard ratio 2.40, P.01) remained independent prognostic factors for higher local failure incidence on multivariate analysis. Tumor size (/≥ 8 cm) was available in 40% of patients and did not correlate with local failure incidence.Local tumor control is excellent and similar between surgery and RT for axial non-spine, spine, and extraskeletal tumors. Age ≥18 years and use of RT, primarily for pelvis and extremity tumors, are associated with the highest risk of local failure. Further efforts should focus on improving outcomes for these patients.

Few tools exist to predict clinical outcomes after radiopharmaceutical therapy. Our goal was to identify associations between blood-based biomarkers of radiation effect and clinical outcomes afterWe conducted a prospective, single-center cohort study in children with advanced neuroblastoma treated withThe cohort included 40 patients (30 male/10 female; median age 7 years). We observed significant modulation of the majority of markers between baseline and hour 72 afterPeripheral blood biomarkers relevant to radiation exposure are significantly modulated during the acute period after

Purpose/Objectives Despite recent improvements in outcomes, 40% of children with high-risk neuroblastoma will experience relapse, facing a guarded prognosis for long-term cure. Whether recurrences are at new sites or sites of original disease may guide decision making during initial therapy. Methods and Materials Eligible patients were retrospectively identified from institutional databases at first metastatic relapse of high-risk neuroblastoma. Included patients had disease involving metaiodobenzylguanidine (MIBG)-avid metastatic sites at diagnosis and first relapse, achieved a complete or partial response with no more than one residual MIBG-avid site before first relapse, and received no total body irradiation or therapy with 131 I-MIBG before first relapse. Anatomically defined metastatic sites were tracked from diagnosis through first relapse to determine tendency of disease to recur at previously involved versus uninvolved sites and to assess whether this pattern was influenced by site irradiation. Results Of 159 MIBG-avid metastatic sites identified among 43 patients at first relapse, 131 (82.4%) overlapped anatomically with the set of 525 sites present at diagnosis. This distribution was similar for bone sites, but patterns of relapse were more varied for the smaller subset of soft tissue metastases. Among all metastatic sites at diagnosis in our subsequently relapsed patient cohort, only 3 of 19 irradiated sites (15.8%) recurred as compared with 128 of 506 (25.3%) unirradiated sites. Conclusions Metastatic bone relapse in neuroblastoma usually occurs at anatomic sites of previous disease. Metastatic sites identified at diagnosis that did not receive radiation during frontline therapy appeared to have a higher risk of involvement at first relapse relative to previously irradiated metastatic sites. These observations support the current paradigm of irradiating metastases that persist after induction chemotherapy in high-risk patients. Furthermore, they raise the hypothesis that metastatic sites appearing to clear with induction chemotherapy may also benefit from radiotherapeutic treatment modalities (external beam radiation or 131 I-MIBG).

Purpose To evaluate the role of radiation therapy (RT) as a component of multimodality therapy for pediatric desmoids. Methods and Materials Twenty-one children diagnosed between 1987 and 2005 were identified. Median age at start of treatment was 13 years (range, 2–21). Primary therapy consisted of resection alone (10), resection + external beam radiation therapy (EBRT) (5), resection + chemotherapy (CT; 3), EBRT alone (1), and CT alone (2). Results The median follow-up from start of treatment is 75.7 months (range, 16–162). Examining patients with gross total resections (GTRs) (-) margins and those who had GTRs (+) margins followed by EBRT, only 2 of 7 failed primary treatment. Conversely, 13 of 14 patients with other primary treatments failed locally. Of the 15 patients who recurred, only 1 patient had a GTR (-) margins. Seven of these patients had salvage therapy that did not include RT, and of these only 2 have no evidence of disease (NED) at last follow-up. In contrast, the remaining 8 patients received RT as a component of their final salvage therapy and 7 of these are NED at last follow-up. At last follow-up, no patient has died, although toxicities of therapy have occurred. Conclusions Local control is difficult to achieve in pediatric patients with desmoids. In the setting in which negative surgical margins cannot be achieved, RT plays a key role in achieving NED status. Even after multiple recurrences, successful salvage is achievable, particularly when high-dose focal therapy is incorporated.

followed by distal limb edema (5%), joint stiffness (3.3%), and bone growth abnormality (1.6%). There was no neuropathy, non-healing ulcer or second malignancy. Conclusions: Interstitial BRT with or without EBRT result in excellent outcome in children with STS. Radical BRT alone, when used judiciously in select groups of children, results in excellent local control and functional outcome with reduced treatment-related morbidity. Author Disclosure: S. Laskar: None. N. Khanna: None. A. Puri: None. S. Qureshi: None. A. Gulia: None. T. Vora: None. B. Rekhi: None. S. Medhi: None. S. Desai: None. G. Chinnaswamy: None. S. Juvekar: None. S. Desai: None. M. Ramadwar: None. N. Jambhekar: None. M. Muckaden: None.