Children's Oncology Group

Bone tumours present significant challenges for affected patients, as multimodal therapy often leads to prolonged physical limitations. This is particularly critical during childhood and adolescence, as it can negatively impact physiological development and psychosocial resilience. Exercise programmes have demonstrated beneficial effects regarding these aspects in both paediatric oncology and orthopaedic rehabilitation. However, evidence on patients with paediatric bone tumours remains scattered. This review summarises the existing literature on exercise interventions for children, adolescents and young adults with bone tumours. A systematic literature search was conducted across four databases until March 2025. References of retrieved articles were screened for additional relevant studies. Methodological quality was assessed through critical appraisals. Seven studies, including 169 patients and survivors aged 4-41 years, met the inclusion criteria; however, the methodological quality was limited. Interventions were conducted at various treatment phases, including prehabilitation, early and late rehabilitation. Exercise modalities varied and were frequently combined, with strength and functional training being the most common. Outcome measures differed, assessing parameters such as physical function and patient-reported outcomes. Individualised, multimodal exercise programmes should be implemented early. They are safe, feasible and can improve physical function and quality of life. High-quality research is needed for more substantial evidence.

Abstract Background Childhood obesity can result in adverse health outcomes. Objectives Objectives were to describe the prevalence of obesity and determine the association between obesity at cancer diagnosis and event-free survival (EFS) and overall survival (OS) in children diagnosed with cancer in Canada. Design/Methods We conducted a retrospective cohort study using the Cancer in Young People in Canada database, a population-based surveillance program collecting data from all paediatric cancer patients. This study included all children with newly diagnosed cancer aged 2 to 18 years across Canada from 2001 to 2020. Obesity was defined as age and sex-adjusted body mass index ≥ 95th percentile. EFS was defined as the time from diagnosis to first event (relapse, progression, secondary malignancies, or death). Univariate and multivariable Cox proportional hazards models compared EFS and OS between patients with and without obesity. Results A total of 11,291 patients were included (37.1% leukemias, 14.5% lymphomas, 21.8% central nervous system (CNS) tumors, 26.6% non-CNS solid tumors). At diagnosis, 10.5% were obese and the prevalence of obesity was significantly higher at 1 year (15.7%, p<0.001) and 2 years (20.1%, p<0.001) after diagnosis. The prevalence of obesity was higher in the leukemia and lymphoma cohort compared to other cancer categories (11.4% vs. 9.5%, p=0.001). In multivariable models controlling for age at diagnosis, sex, ethnicity, neighborhood income quintile, treatment era and cancer categories, obesity at diagnosis remained significantly associated with inferior EFS [adjusted HR (aHR) 1.16, 95% CI 1.02–1.32] and OS [aHR 1.29, 95% CI 1.11–1.49]. In children with acute lymphoblastic leukemia (ALL) (n=3458, 82.5% of all leukemias), after adjusting for high-risk features such as age, white blood cell count and CNS status, obesity at diagnosis remained significantly associated with inferior EFS [aHR 1.55, 95% CI 1.17–2.04] and OS [aHR 1.75, 95% CI 1.23–2.49]. In patients with CNS tumors, obesity at diagnosis was also independently associated with inferior EFS [aHR 1.38, 95% CI 1.09–1.76] and OS [aHR 1.47, 95% CI 1.13–1.91]. Conclusion In this population-based study of children with cancer, the prevalence of obesity was 11% at diagnosis and continued to increase in the following 2 years. Obesity at cancer diagnosis was independently associated with inferior survival across the entire cohort, especially in children with ALL and CNS tumors. Prevention of childhood obesity should be emphasized as it can lead to several adverse health outcomes in children with cancer.

CHIPS (Childhood Hodgkin International Prognostic Score), a predictive score for event-free-survival (EFS), was originally developed using factors presenting at diagnosis in patients with intermediate-risk Hodgkin lymphoma (HL). Prospective validation of CHIPS in patients was a pre-specified aim of AHOD1331, a trial comparing brentuximab-vedotin, doxorubicin, vincristine, etoposide, prednisone, and cyclophosphamide (Bv-AVEPC) to standard ABVE-PC (and response-adapted radiation) in children with high-risk HL. AHOD1331 was a multicenter randomized phase 3 study. Patients were aged 2-21years with untreated stages IIB+bulk, IIIB, IV HL. CHIPS was determined by assigning one point each for: Stage IV disease, large mediastinal adenopathy (greater than one-third thoracic diameter), albumin (<3.5g/dL), and fever (T≥38°C). Associations between CHIPS, baseline patient, and disease characteristics were tested. The validity of CHIPS to predict EFS was evaluated by both overall and within pre-specified subgroups defined by treatment arm, PET2 response, and disease stage. The four CHIPS components were analyzable in 576 of the 587 eligible patients. Distribution of CHIPS did not differ by study treatment arm (p = 0.158). CHIPS was significantly prognostic for EFS in this high-risk cohort (p = 0.008) and was independently predictive of EFS regardless of treatment arm, PET2 response, or stage. In subset analyses, CHIPS remained independently prognostic among patients with PET2 rapid responding lesions (RRL; p = 0.021) or Stage IVB disease (p = 0.047). CHIPS were predictive of EFS in patients with high-risk HL treated on AHOD1331. CHIPS may aid in the allocation of patients to risk-based treatment algorithms, and can serve as an effective, inexpensive, and feasible proxy for more biologically based factors.

10032 Background: Identifying clinical and biological factors associated with outcomes in localized Ewing sarcoma (ES) will enable risk-stratified clinical trials with the goal of improved outcomes for high-risk patients and decreased treatment toxicity for low-risk patients. The specific aims of this analysis in localized ES patients were 1) to classify extraosseous (EO) primary tumors with subdivisions into deep (viscera, glands, body cavities, muscle, nerves) and superficial (cutaneous and subcutaneous) sites, and 2) to understand the relationship between baseline clinical factors (age, sex, primary tumor site, size (maximum dimension and volume)) and event-free survival (EFS). Methods: The analytic cohort included ES patients treated with ICC on AEWS0031 and AEWS1031. Primary tumor sites were defined as pelvic, non-pelvic, and EO (deep vs. superficial). Post-enrollment EFS was the primary endpoint. Univariate analyses used the Kaplan–Meier method (logrank test). Multivariable analyses used Cox proportional hazards models. To assess the impact of tumor volume as a continuous variable, a subgroup analysis was conducted using AEWS1031 only, as tumor volumes were collected prospectively on this study. Visual exploration of effects of continuous variables on EFS event hazard used restricted cubic splines with 3 knots. Tests were performed at the 5% level. Results: AEWS0031 (n = 628) and AEWS1031 Regimen B (n = 283) yielded 911 patients. In univariate analyses, difference in risk of EFS event was observed between tumor sites ( P = 0.03). EO tumors had the highest estimated EFS compared to pelvic and non-pelvic (5 year EFS 84.7% vs. 72.4% and 75.9%). Superficial EO appeared to be a very low-risk group, albeit interpretations are limited by the small group size and singular event (one second malignant neoplasm among 15 patients). In multivariable analysis of the combined cohort, sex, race, and ethnicity were not prognostic. EO tumors may be associated with decreased hazard compared with non-pelvic bone primaries (HR 0.58, P = 0.07), and tumors ≥200 mL with increased hazard (HR 1.56, P &lt; 0.01). In the subgroup analysis, tumor volume and age were prognostic and in visualizations age was non-linearly related to the hazard of EFS event, increasing until approximately 15 years. Tumor volume was non-linearly related to the hazard of EFS event and increased until approximately 400 mL. Conclusions: Patients with ES and primary tumors ≥200 mL continue to be at higher risk of an EFS event when treated with ICC, and EO tumors may be lower risk compared with other sites. Risk of an event appears to remain constant in ES patients ≥15 years or with primary tumors ≥400 mL. These findings should be validated in prospective trials and tumor biology integrated with clinical factors to improve risk stratification for localized ES.

10045 Background: Osteosarcoma is characterized by complex chromosomal alterations and genomic instability. MYC copy number (CN) gains are observed in 10%-60% of cases, and MYC amplification is associated with poor outcomes in single-center cohorts and genomic studies of relapsed or high-risk patients. This study aimed to validate the prognostic role of MYC amplification in a large, multi-center cohort of patients enrolled on Children’s Oncology Group (COG) up-front treatment and biobanking protocols. We also assessed other genes linked to survival. Methods: This retrospective, IRB-approved case-control study used banked FFPE DNA from 137 osteosarcoma samples from the COG biorepository for SNP microarray (Affymetrix OncoScan). Patients were enrolled on INT-0133, P9754, AOST0331 and APEC14B1 from 1993-2024. Amplifications of MYC, CCNE1 , CDK4 , and the 6p21.1 locus, as well as chromosome 6, 8, 12, and 19 ploidy were assessed. Gene amplification was defined as the ratio of gene to chromosome copies (e.g. MYC CN/chr8 CN) &gt; 2.0. The primary outcome was occurrence of event-free survival (EFS) event. Patients were matched on metastatic status and follow-up time. Univariate conditional logistic regression models were fit for each genetic feature to obtain the odds ratio (OR) of EFS event associated with amplification (95% confidence interval (CI)) and to conduct one-sided tests for the null hypothesis OR £ 1 at the 5% level. Results: Sixty-five case-control pairs for MYC, CDK4 , and 6p21.1, and 63 for CCNE1 were analyzed. MYC amplification was estimated to have a 1.87-fold increase in odds of EFS event (95% CI: 0.79, 4.42; p = 0.08). CDK4 amplification was associated with a 5-fold increase in odds of event (95% CI: 1.10, 22.82; p = 0.02). Neither amplification of 6p21.1 or CCNE1 were associated with increased odds of event, with ORs of 1.33 (95% CI 0.56, 3.16; p = 0.26) and 0.73 (95% CI: 0.29, 1.81; p = 0.25), respectively. Conclusions: MYC amplification may be associated with increased odds of EFS event in this cooperative group cohort. Though the result did not reach statistical significance, this finding aligns with prior studies demonstrating increased EFS-event risk for patients with MYC amplification. While our selection of a ratio cut point &gt; 2.0 to define amplification was informed by prior studies, the optimal cut point has not been determined and cut points may be assay dependent. Although CDK4 amplification appears associated with increased odds of event, confidence in this finding is limited by a sparse-data bias, due to a low number of control patients with CDK4 amplification. Future analyses will explore MYC and CDK4 copy number ratio as a continuous variable and assessing the relationship between additional genomic features and EFS events in this population.

10001 Background: Dinutuximab, irinotecan, temozolomide and GM-CSF (DIT) is widely used in first relapsed/ refractory high-risk neuroblastoma (r/r HRNB), however &lt;50% of patients (pts) respond. ODC1 is a key enzyme important for NB cell survival. Difluoromethylornithine (DFMO) irreversibly inhibits ODC1, suppressing polyamine biosynthesis and driving anti-NB activity. DFMO also inhibits arginase and may enhance immunotherapy in r/r NB. COG ANBL1821 was a randomized phase 2 study for pts with r/r NB that evaluated response to DIT with or without DFMO (NCT03794349). Methods: Patients with first episode of r/r NB were randomized 1:1 to DIT (Arm A) or DIT with DFMO (6750 mg/m 2 divided TID; Arm B). They were stratified by measurable/evaluable disease, MYCN status, prior anti-GD2 therapy, and prior DFMO therapy. Cycles were 21 days. On Arm B, DFMO was initially given continuously; discontinuous DFMO dosing (days 1-7 and 15-21) was instituted due to ototoxicity in the initial cohort. Objective Response Rate [(ORR); sum of complete (CR), partial (PR), and minor (MR) responses per the 2017 International Neuroblastoma Response Criteria (INRC)] was determined based on central review of imaging. Toxicities were graded per CTCAE v5.0. Results: 91 eligible and evaluable pts (44 Arm A, 47 Arm B) were randomized May 2019-Jan 2024. 28/44 (63.6%) of Arm A pts and 32/47 (68.1%) of Arm B pts had relapsed or progressive disease (RPD); the remaining pts had refractory disease. The ORR was 61.4% (27/44) for Arm A and 57.4% (27/47) for Arm B (p=0.566). On Arm A, 22/44 (50%) achieved CR or PR compared to 23/27 (48.9%) on Arm B. Response rates for pts with RPD were similar to those with refractory disease in both arms. The 1-year progression-free survival (PFS) for Arm A was 70.0±8.0% and 56.8±8.2% for Arm B. Overall survival was 87.0±5.7% and 81.4±6.3% for Arms A and B, respectively. The most common toxicities reported on both arms were hematologic and gastrointestinal. Fewer pts on Arm B (n=7) had Grade 3+ pain than on Arm A (n=15) (p=0.0326). Hearing loss was a toxicity of interest; with continuous dosing, 55.6% (5/9) of Arm B pts developed hearing loss requiring DFMO dose hold. With discontinuous dosing, hearing loss was 15.8% (6/38) on Arm B compared to 6.3% (2/32) on Arm A (p=0.275). 14/16 (87.5%) NB+ marrows were GD2+ at enrollment; loss of GD2 was not detected on persisting NB cells in on therapy marrows analyzed. Conclusions: The addition of DFMO to DIT did not improve response rates in pts with first r/r HRNB, though the response rates in both arms confirmed DIT activity in this population. The ORR to DIT is higher than previously reported, likely due to use of the 2017 INRC that includes MR in calculation of ORR. Rates of CR+PR in this trial were similar to those previously reported. DFMO was associated with an increased incidence of hearing loss which was partially mitigated by discontinuous dosing. Clinical trial information: NCT03794349 .