Inhibition of the BTK-IDO-mTOR axis promotes differentiation of monocyte-lineage dendritic cells and enhances anti-tumor T cell immunity.

Monocytic-lineage inflammatory Ly6c+CD103+ dendritic cells (DCs) promote antitumor immunity, but these DCs are infrequent in tumors, even upon chemotherapy. Here, we examined how targeting pathways that inhibit the differentiation of inflammatory myeloid cells affect antitumor immunity. Pharmacologic inhibition of Bruton's tyrosine kinase (BTK) and the tryptophan-degrading enzyme indoleamine 2,3-dioxygenase (IDO) or deletion of Btk or Ido1 allowed robust differentiation of inflammatory Ly6c+CD103+ DCs during chemotherapy, promoting antitumor T cell responses and inhibiting tumor growth. Immature Ly6c+c-kit+ precursor cells had epigenetic profiles similar to conventional DC precursors; deletion of Btk or Ido1 promoted differentiation of these cells. Mechanistically, a BTK-IDO axis inhibited a tryptophan-sensitive differentiation pathway driven by GATOR2 and mTORC1, and disruption of the GATOR2 in monocyte-lineage precursors prevented differentiation into inflammatory DCs in vivo. IDO-expressing DCs and monocytic cells were present across a range of human tumors. Thus, a BTK-IDO axis represses differentiation of inflammatory DCs during chemotherapy, with implications for targeted therapies.

Children's Oncology Group's 2023 blueprint for research: Young investigators.

The Children's Oncology Group (COG) Young Investigators (YI) Committee is an administrative committee in which liaisons represent 30 COG committees, and was created to facilitate the integration of YIs into the organization, and prepare them for future COG leadership roles. The mentorship program has mentored over 400 YIs since 2005 and currently has 175 active participants. The COG YI Master Roster is a database YIs can join, which allows them to post their interests and accomplishments to COG leadership, and 321 YIs have already joined this list. The YI Committee has held virtual symposia designed to describe how COG operates and provide guidance on how YIs can reach their goals; over 300 YIs have attended these since 2021 and have consistently rated them as helpful. Through these and other elements of the program, the YI Committee remains committed to developing a future pipeline of new investigators.

A phase 1 study of simvastatin in combination with topotecan and cyclophosphamide in pediatric patients with relapsed and/or refractory solid and CNS tumors.

BACKGROUND: 3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) can inhibit tumor proliferation, angiogenesis, and restore apoptosis in preclinical pediatric solid tumor models. We conducted a phase 1 trial to determine the maximum tolerated dose (MTD) of simvastatin with topotecan and cyclophosphamide in children with relapsed/refractory solid and central nervous system (CNS) tumors. METHODS: Simvastatin was administered orally twice daily on days 1-21, with topotecan and cyclophosphamide intravenously on days 1-5 of a 21-day cycle. Four simvastatin dose levels (DLs) were planned, 140 (DL1), 180 (DL2), 225 (DL3), 290 (DL4) mg/m2 /dose, with a de-escalation DL of 100 mg/m2 /dose (DL0) if needed. Pharmacokinetic and pharmacodynamic analyses were performed during cycle 1. RESULTS: The median age of 14 eligible patients was 11.5 years (range: 1-23). The most common diagnoses were neuroblastoma (N = 4) and Ewing sarcoma (N = 3). Eleven dose-limiting toxicity (DLT)-evaluable patients received a median of four cycles (range: 1-6). There were three cycle 1 DLTs: one each grade 3 diarrhea and grade 4 creatine phosphokinase (CPK) elevations at DL1, and one grade 4 CPK elevation at DL0. All patients experienced at least one grade 3/4 hematologic toxicity. Best overall response was partial response in one patient with Ewing sarcoma (DL0) and stable disease for four or more cycles in four patients. Simvastatin exposure increased with higher doses and may have correlated with toxicity. Plasma interleukin 6 (IL-6) concentrations (N = 6) showed sustained IL-6 reductions with decrease to normal values by day 21 in all patients, indicating potential on-target effects. CONCLUSIONS: The MTD of simvastatin with topotecan and cyclophosphamide was determined to be 100 mg/m2 /dose.

Infectious events in pediatric patients with acute lymphoblastic leukemia/lymphoma undergoing evaluation for fever without severe neutropenia.

BACKGROUND: Infections cause significant treatment-related morbidity during pediatric acute lymphoblastic leukemia/lymphoma (ALL/LLy) therapy. Fevers during periods without severe neutropenia are common, but etiologies are not well-described. This study sought to describe the bloodstream infection (BSI) and non-BSI risk in children undergoing therapy for ALL/LLy. METHODS: Demographic and clinical data were abstracted for febrile episodes without severe neutropenia at two children's hospitals. Treatment courses were stratified by intensity. Multivariate logistic regression evaluated characteristics associated with infection. RESULTS: There were 1591 febrile episodes experienced by 524 patients. Of these, 536 (34%) episodes had ≥1 infection; BSI occurred in 30 (1.9%) episodes. No BSIs occurred in episodes with a recent procedural sedation or cytarabine exposure. Presence of hypotension, chills/rigors, higher temperature, and infant phenotype were independently associated with BSI (p < .05). Of the 572 non-BSIs, the most common was upper respiratory infection (URI) (n = 381, 67%). Compared to episodes without infection, URI symptoms, higher temperature, absolute neutrophil count 500-999/µl, and evaluation during a low-intensity treatment course were more likely to be associated with a non-BSI (p < .05) and inpatient status was less likely to be associated with a non-BSI (p < .05). CONCLUSIONS: The BSI rate in pediatric patients with ALL/LLy and fever without severe neutropenia is low, but one-third of the time, patients have a non-BSI. Future research should test if the need for empiric antibiotics can be tailored based on the associations identified in this study.

A phase 1 study of prexasertib (LY2606368), a CHK1/2 inhibitor, in pediatric patients with recurrent or refractory solid tumors, including CNS tumors: A report from the Children's Oncology Group Pediatric Early Phase Clinical Trials Network (ADVL1515).

BACKGROUND: Prexasertib (LY2606368) is a novel, second-generation, selective dual inhibitor of checkpoint kinase proteins 1 (CHK1) and 2 (CHK2). We conducted a phase 1 trial of prexasertib to estimate the maximum-tolerated dose (MTD) and/or recommended phase 2 dose (RP2D), to define and describe the toxicities, and to characterize the pharmacokinetics (PK) of prexasertib in pediatric patients with recurrent or refractory solid and central nervous system (CNS) tumors. METHODS: Prexasertib was administered intravenously (i.v.) on days 1 and 15 of a 28-day cycle. Four dose levels, 80, 100, 125, and 150 mg/m2 , were evaluated using a rolling-six design. PK analysis was performed during cycle 1. Tumor tissue was examined for biomarkers (CHK1 and TP53) of prexasertib activity. RESULTS: Thirty patients were enrolled; 25 were evaluable. The median age was 9.5 years (range: 2-20) and 21 (70%) were male. Twelve patients (40%) had solid tumors and 18 patients (60%) had CNS tumors. There were no cycle 1 or later dose-limiting toxicities. Common cycle 1, drug-related grade 3/4 toxicities (> 10% of patients) included neutropenia (100%), leukopenia (68%), thrombocytopenia (24%), lymphopenia (24%), and anemia (12%). There were no objective responses; best overall response was stable disease in three patients for five cycles (hepatocellular carcinoma), three cycles (ependymoma), and five cycles (undifferentiated sarcoma). The PK appeared dose proportional across the 80-150 mg/m2 dose range. CONCLUSIONS: Although the MTD of prexasertib was not defined by this study, 150 mg/m2 administered i.v. on days 1 and 15 of a 28-day cycle was determined to be the RP2D.

A phase I study of sirolimus in combination with metronomic therapy (CHOAnome) in children with recurrent or refractory solid and brain tumors.

BACKGROUND/PURPOSE: To determine the maximum tolerated dose, toxicities, and response of sirolimus combined with oral metronomic therapy in pediatric patients with recurrent and refractory solid and brain tumors. PROCEDURE: Patients younger than 30 years of age with recurrent, refractory, or high-risk solid and brain tumors were eligible. Patients received six-week cycles of sirolimus with twice daily celecoxib, and alternating etoposide and cyclophosphamide every three weeks, with Bayesian dose escalation over four dose levels (NCT01331135). RESULTS: Eighteen patients were enrolled: four on dose level (DL) 1, four on DL2, eight on DL3, and two on DL4. Diagnoses included solid tumors (Ewing sarcoma, osteosarcoma, malignant peripheral nerve sheath tumor, rhabdoid tumor, retinoblastoma) and brain tumors (glioblastoma multiforme [GBM], diffuse intrinsic pontine glioma, high-grade glioma [HGG], medulloblastoma, ependymoma, anaplastic astrocytoma, low-grade infiltrative astrocytoma, primitive neuroectodermal tumor, nongerminomatous germ cell tumor]. One dose-limiting toxicity (DLT; grade 4 neutropenia) was observed on DL2, two DLTs (grade 3 abdominal pain and grade 3 mucositis) on DL3, and two DLTs (grade 3 dehydration and grade 3 mucositis) on DL4. The recommended phase II dose of sirolimus was 2 mg/m2 (DL3). Best response was stable disease (SD) in eight patients, and partial response (PR) in one patient with GBM. A patient with HGG was removed from the study with SD and developed PR without further therapy. Western blot analysis showed inhibition of phospho-S6 kinase in all patients during the first cycle of therapy. CONCLUSION: The combination of sirolimus with metronomic chemotherapy is well tolerated in children. A phase II trial of this combination is ongoing.

Provocative questions in osteosarcoma basic and translational biology: A report from the Children's Oncology Group.

Patients who are diagnosed with osteosarcoma (OS) today receive the same therapy that patients have received over the last 4 decades. Extensive efforts to identify more effective or less toxic regimens have proved disappointing. As we enter a postgenomic era in which we now recognize OS not as a cancer of mutations but as one defined by p53 loss, chromosomal complexity, copy number alteration, and profound heterogeneity, emerging threads of discovery leave many hopeful that an improving understanding of biology will drive discoveries that improve clinical care. Under the organization of the Bone Tumor Biology Committee of the Children's Oncology Group, a team of clinicians and scientists sought to define the state of the science and to identify questions that, if answered, have the greatest potential to drive fundamental clinical advances. Having discussed these questions in a series of meetings, each led by invited experts, we distilled these conversations into a series of seven Provocative Questions. These include questions about the molecular events that trigger oncogenesis, the genomic and epigenomic drivers of disease, the biology of lung metastasis, research models that best predict clinical outcomes, and processes for translating findings into clinical trials. Here, we briefly present each Provocative Question, review the current scientific evidence, note the immediate opportunities, and speculate on the impact that answered questions might have on the field. We do so with an intent to provide a framework around which investigators can build programs and collaborations to tackle the hardest problems and to establish research priorities for those developing policies and providing funding.

Gemcitabine/nab-paclitaxel for pediatric relapsed/refractory sarcomas.

BACKGROUND: Pediatric patients with relapsed/refractory sarcomas have poor outcomes and need novel therapies that provide disease control while maintaining an acceptable quality of life. The activity and toxicity of gemcitabine and nab-paclitaxel in combination has not been reported in pediatrics. PROCEDURE: We reviewed the records of fifteen relapsed/refractory patients and one treatment-naïve patient who received gemcitabine/nab-paclitaxel at our institution. RESULTS: Sixteen patients (median age 13.5 years, range 3-19 years) received 53 cycles of gemcitabine/nab-paclitaxel. Twenty-nine cycles (55%) resulted in ≥Grade 3 toxicity, with nonhematologic Grade ≥3 toxicities occurring in only eight of 53 cycles (15%). Patients received red blood cell and platelet transfusions in 23% and 4% of cycles, respectively. Grade ≥3 infectious toxicities occurred in 4% of cycles. Of 14 patients with measurable disease, there were no complete responses (CR), one partial response (PR; 7%), and six patients (43%) with stable disease (SD; median SD: 4.5 months, range: 2-19 months). In total, 31% of the patients derived clinical benefit (CR + PR + SD ≥ 4 months). Median time to progression was 72 days with a 4-month progression-free survival of 31% ± 12% and 1-year overall survival of 19% ± 10%. With a median follow-up for all 16 patients of 21 months from the first treatment with gemcitabine/nab-paclitaxel, one (6%) remains alive with disease. CONCLUSIONS: Gemcitabine/nab-paclitaxel is a relatively safe regimen with mainly hematologic toxicities. It offers a well-tolerated, palliative option providing clinical benefit in a subset of patients. A phase I trial of this combination is underway.

Successful Use of Extracorporeal Life Support in a Hematopoietic Stem Cell Transplant Patient with Neuroblastoma.

Respiratory failure associated with hematopoietic stem cell transplantation (HSCT) has been considered a contraindication for use of extracorporeal membrane oxygenation (ECMO) at many centers. We describe a child with neuroblastoma and hypoxemic respiratory failure following HSCT who was successfully managed with veno-venous (VV) ECMO. The patient was an 18-month-old female with high-risk neuroblastoma status post tumor resection, chemotherapy, autologous HSCT, and primary site radiation. On day 113 posttransplant while receiving maintenance immunotherapy, she had an acute respiratory decompensation because of rhinovirus, aspiration pneumonia, and capillary leak syndrome. The patient was intubated and transitioned to a high frequency oscillatory ventilation and inhaled nitric oxide. Because of refractory hypoxemia, she was cannulated for VV ECMO. She was weaned and decannulated after 7.5 days on ECMO, then subsequently transferred for inpatient rehabilitation. The most recent Extracorporeal Life Support Organization registry analysis showed low survival (3/29) in patients requiring ECMO after HSCT, and 2 of 3 survivors had nononcological diagnoses. However, our patient's outcome suggests that HSCT status should not be an absolute contraindication. The presence of a reversible single organ failure and the absence of significant bleeding risk in an engrafted, neurologically intact, and non-neutropenic HSCT patient with a favorable prognosis can support the potential benefit of ECMO.

Prolonged Isotretinoin in Ultra High-Risk Neuroblastoma.

Patients with high-risk neuroblastoma remain a therapeutic challenge with significant numbers of patients failing to respond sufficiently to initial therapy. These patients with poor response to induction are considered as ultra high-risk and are in need of novel treatment strategies. Isotretinoin is part of the standard of care treatment for patients with high-risk disease who undergo high-dose chemotherapy with autologous stem cell rescue although some have questioned the optimal administration schedule. Prolonged use of isotretinoin was well tolerated and may have contributed to long-term survival in a group of patients with ultra high-risk neuroblastoma.

Pulmonary Relapse of Osteosarcoma Following Presentation With a Pneumomediastinum and Localized Disease at Diagnosis.

Pneumothorax is a well-described complication of osteosarcoma. Conversely, the presence of a pneumomediastinum to our knowledge has been reported just once in a patient with osteosarcoma, and never without detectable lung metastasis. We report the case of an 18-year-old male with a localized, distal femur osteosarcoma who was found to have an asymptomatic pneumomediastinum and pneumatocele at diagnosis, and then 16 months later experienced a pulmonary relapse. Our case suggests that these findings may represent the presence of occult metastatic disease and cautions providers to treat appropriately and provide surveillance with a high index of suspicion for pulmonary recurrence.

Respiratory Difficulties in Children With Underlying Asthma During Immunotherapy for High-risk Neuroblastoma.

Treatment of high-risk neuroblastoma now includes antibody based antitumor immunotherapy as part of standard care. Although this therapy has resulted in dramatic improvements in survival, it is associated with significant side effects. Children with underlying respiratory issues, and in particular asthma, may be more susceptible to immunotherapy associated respiratory compromise and pulmonary complications. Early routine involvement of pulmonology care is warranted for these patients in an effort to allow maximal delivery of immunotherapy and minimize acute and long-term complications.

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.

Comparison of survival at adult versus pediatric treatment centers for rare pediatric tumors in an adolescent and young adult (AYA) population in the State of Georgia.

BACKGROUND: The type of treatment center where 15-21-year-old adolescent and young adult (AYA) patients with rare pediatric tumors achieve their best clinical outcome is unknown. PROCEDURE: We performed a retrospective analysis using the Georgia Cancer Registry (GCR) of 15-21-year old patients with a malignant, rare pediatric tumor diagnosed during the period from 2000-2009. Patients were identified as being treated at one of five Georgia pediatric cancer centers or at an adult center. Data were analyzed for 10 year overall survival, patient characteristics associated with death, and patient characteristics present at diagnosis associated with choice of treatment center. RESULTS: There was a total of 479 patients in our final study population, of which 379 (79.1%) were treated at an adult center and 100 (20.9%) were treated at a pediatric center. Patients treated at an adult center had a 10 year overall survival of 86% compared to 85% for patients treated at a pediatric center (P = 0.31). Race and poverty were not significantly associated with death. Patients with nasopharyngeal carcinoma (OR = 7.38; 95% CI = 2.30-23.75) and 'other carcinomas' (OR = 2.64; 95% CI = 1.25-5.60) were more likely to be treated at a pediatric center. Patients with higher-stage disease (OR = 4.24; 95% CI = 1.71-10.52) and higher poverty (OR = 2.32; 95% CI = 1.23-4.37) were also more likely to be treated at a pediatric center. CONCLUSION: Our data suggest that there is no difference in survival for 15-21-year old patients with rare pediatric tumors when treated at an adult or pediatric center.

Clinical features and outcomes of infants with Ewing sarcoma under 12 months of age.

BACKGROUND: Ewing sarcoma peaks in incidence in adolescence. Infants <12 months old have rarely been reported. We aimed to compare clinical features, treatment, and survival of infants <12 months to those of older pediatric patients with Ewing sarcoma. PROCEDURE: We utilized the SEER database to identify patients <12 months of age diagnosed with Ewing sarcoma between 1973 and 2011. We used Fisher exact tests to compare clinical features and treatment modalities between these patients and patients aged 1-19 years. We used Kaplan-Meier methods to describe overall survival in these two groups. RESULTS: Of 1,957 patients in the cohort, 39 (2.0%) were diagnosed at <12 months of age. Infants had a different distribution of primary tumor sites, with lower extremity tumors under represented. Compared to older patients, infants were more likely to have soft tissue tumors (81.6% vs. 27.1%; P < 0.001); have primitive neuroectodermal tumor/Askin tumor (61.5% vs. 19.9%; P < 0.001); and have tumors <8 cm (81.0% vs. 53.2%; P < 0.014). Infants were less likely to receive radiation therapy (13.2% vs. 53.3%; P < 0.001). Infants were at increased risk for early death (P < 0.013 by Wilcoxon), though long-term overall survival was not different between age groups (P < 0.25 by log rank). CONCLUSIONS: Ewing sarcoma is rare in infants, with different clinical presentations and treatment approaches. These patients appear to be at higher risk for early death, but long-term survival is similar to older pediatric patients.

Outcomes After Radiation Therapy to Metastatic Sites in Patients With Stage 4 Neuroblastoma.

In patients with high-risk metastatic neuroblastoma, the benefit of radiation therapy (RT) to metastatic sites as part of primary treatment has not been fully investigated. The purpose of this single-institution study was to evaluate local control of irradiated metastatic sites, and characterize metastatic disease burden and anatomic distribution in patients with high-risk metastatic neuroblastoma. The records of all patients diagnosed with stage 4 neuroblastoma between August 2000 and January 2010 were reviewed. Exclusion criteria included: bone-marrow only metastatic site, total body irradiation, or no imaging follow-up. A total of 37 patients met eligibility criteria. Median follow-up period for patients without relapse was 61 months. Five-year overall survival for all patients was 67%. Thirteen patients (35%) received RT to a metastatic site as part of their primary treatment. Among these patients, in-field recurrence occurred in three patients (23%), including two of three treated calvarial sites. In patients treated with or without RT to a metastatic site, respectively, there was no significant difference in 5-year overall survival (73% vs. 63%, P=0.84) or relapse-free survival (46% and 55%, P=0.48). Current metastatic site RT dose may be suboptimal, and certain locations may predict for a poor response. Further studies are necessary to elucidate the optimal role of RT to metastatic sites.

Standardized process used in the emergency department for pediatric oncology patients with fever and neutropenia improves time to the first dose of antibiotics.

OBJECTIVES: This study aimed to evaluate the effect of a standardized process on time to the first dose of antibiotics in pediatric oncology patients presenting to the emergency department (ED) with fever and neutropenia (F-N). METHODS: A standardized process and order set were created to be used on all pediatric febrile neutropenic patients who presented to the ED of a large academic children's hospital. The order set was used for patients with a known oncologic diagnosis, a fever greater than 38.3°C, and who were presumed or known to be neutropenic. A retrospective chart review was then performed for the 18 months before and the 6 months after implementation of the new process to evaluate if the time to the first dose of antibiotics was significantly reduced. RESULTS: A total of 130 occurrences of F-N were analyzed. This included 100 episodes before the implementation of the new process and 30 episodes afterward. The time to antibiotics being ordered was reduced by over half, with a median time of 72 minutes preprocess and 27 minutes postprocess implementation (P = 0.04). Median time from the arrival in the ED to the administration of the first dose of antibiotics was reduced by almost an hour, taking 154 minutes before the new process compared with 95 minutes after its implementation (P = 0.0001). CONCLUSIONS: The use of a standardized process that uses a standardized order set can reduce the time to the first dose of antibiotics in pediatric oncology patients with F-N.

Long-term results and explant analysis of the ReMotion total wrist arthroplasty.

The ReMotion wrist replacement has good short- to medium-term survival with an acceptable complication profile as we previously reported in a cohort of patients with rheumatoid arthritis. We now report the long-term results of the same cohort and details of explant analysis of revisions undertaken for aseptic loosening. A total of 16 wrists were reviewed. Seven prostheses remain in situ with no obvious signs of wear or radiological loosening at a mean follow-up of 15.5 years. Three wrists had been revised: one for infection and two for aseptic loosening. Five patients (six wrists) died 2-9 years after operation from unrelated causes. Explant analysis demonstrated relatively minor wear compared with the published results of the Universal-2 prosthesis. We hypothesize that this may be explained by differences in polyethylene sterilization and prosthetic design. The ReMotion wrist replacement has favourable long-term results in patients with rheumatoid arthritis with a 16-year survival rate of 78%-86%.Level of evidence: IV.

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.