Whilst men with testicular cancer have a twofold increase in second malignant neoplasms (SMNs), the risk in children with germ cell tumors (GCTs) is not fully quantified. SMNs in children treated for GCTs was assessed in the Malignant Germ Cell Tumor International Consortium data commons (n = 917). Thirteen SMNs were identified with median follow-up of only 5.9 years. Assigning cause is nuanced because GCT-related SMNs can either be treatment related, second primary malignancies from a common primordial germ cell progenitor, or somatic malignant transformation of the original GCT. Longer follow-up of children with GCT is needed to ascertain risk and understand causation.

PURPOSE:Mouse models demonstrate a role for RANK and its ligand, RANKL, in osteosarcoma. The primary objective of this single-arm, open-label phase 2 trial was to determine whether denosumab, a RANKL mAb, improved disease control in recurrent osteosarcoma relative to benchmarks derived from historic Children's Oncology Group clinical trial data. PATIENTS AND METHODS:Skeletally mature patients ages 11 to 49 years old with measurable disease were eligible for cohort 1, and those with complete surgical resection of all sites of disease were eligible for cohort 2. Patients received denosumab 120 mg subcutaneously every 4 weeks with calcium and vitamin D supplementation. The primary endpoints were RECIST response and remaining event-free for 4 months for cohort 1 and remaining event-free for 12 months for cohort 2. Toxicity, pharmacokinetics, and pharmacodynamic effects were additional endpoints. RESULTS:Fifteen patients in cohort 1 and 38 in cohort 2 were eligible and evaluable for the primary endpoint. One of 15 cohort 1 patients remained event-free at 4 months. There were no objective responses. Ten of 38 cohort 2 patients were event-free at 12 months. The predefined efficacy criteria were not met in either cohort. The most common ≥ grade 3 adverse events were hypocalcemia and hypophosphatemia (8% and 11%, respectively). At steady state, mean serum denosumab trough concentrations were 23.7 to 31 μg/mL in cycles 2 to 7. Serum c-telopeptide and urine n-telopeptide decreased on treatment. CONCLUSIONS:Denosumab was well-tolerated with anticipated side effects and pharmacokinetic and pharmacodynamic parameters but had insufficient activity for further development in osteosarcoma.

BACKGROUND:Germ cell tumors (GCTs) are heterogeneous neoplasms arising from primordial germ cells. While genome-wide association studies (GWAS) have identified numerous susceptibility loci for adult testicular GCTs (TGCTs), the heritable basis of pediatric TGCT and GCTs that arise outside the testes remain poorly understood. METHODS:We conducted a multi-ancestry GWAS of pediatric GCTs, including 1,927 cases from the Germ Cell Tumor Epidemiology Study (GaMETES) and 10,601 controls. Cases were diagnosed with testicular (n = 678), ovarian (n = 441), intracranial (n = 435), and extragonadal (n = 373) GCT between the ages of 0 to 19 years. RESULTS:We identified four loci reaching genome-wide significance, including variants near BAK1 (chr 6: rs3831846), SPRY4 (chr 5: rs12515244), DMRT1 (chr 9: rs10815910), and DEPTOR (chr 8: rs13277786). Additional genome-wide significant associations were identified in subgroup analyses, including six loci for intracranial GCTs (rs2758612 [PMF1/BGLAP], rs9854760 [PLCL2], rs6851498 [KIT], rs11816992 on chromosome 10, rs3830273 [TFAM], and rs13054014 [LZTR1]), one locus for testicular GCT (rs1907702 [KITLG]), and one locus for males (rs4610628 [MAD1L1]). After Bonferroni correction, 18 of 78 previously reported TGCT loci were significantly associated with GCT overall or in at least one subgroup with a particularly strong correlation between TGCT and iGCT effect estimates (rho = 0.63, P = 5.5x10-10). Expression quantitative trait locus (eQTL) analyses identified candidate genes in the regions identified on chromosome 6 (BAK1, LINC003366, and ITPR3) and chromosome 8 (DEPTOR and RP11-760H22.2). CONCLUSIONS:Our data support a role for germline genetic variation in the development of GCT in locations outside the testes and highlight shared genetic architecture across age group and tumor location.

OBJECTIVE:To evaluate the impact of surgical guidelines on the management of children with hepatoblastoma. BACKGROUND:The Children's Oncology Group study AHEP0731 was the first pediatric cooperative group trial to propose guidelines for the surgical management of children with hepatoblastoma. METHODS:AHEP0731 enrolled children with hepatoblastoma between 2009 and 2018. Surgical guidelines were based upon radiographic extent of disease (PRETEXT, POST-TEXT). Planned non-real-time central review of imaging was completed at diagnosis and after two, four, and six cycles of chemotherapy to determine guideline adherence. Resection rate, event-free survival (EFS), overall survival (OS), and complications were compared between guideline adherent and nonadherent groups. RESULTS:Of 226 enrolled patients, 221 were evaluable of whom 205 (93%) underwent definitive surgical resection. Guideline adherence for protocol recommended timing of resection was 65% (133/205). The nonadherent group included 44/205 (21%) patients who underwent early resection and 28/205 (14%) patients who underwent late resection or late transplantation. Eighty-five patients met criteria for early referral to a liver transplant center, of whom 55 (65%) were referred within the recommended timeframe. Twelve patients received liver transplants outside of surgical guidelines. There were no significant differences in EFS, OS, or complication rates between adherent and nonadherent groups. CONCLUSIONS:Implementation of surgical guidelines, in combination with effective chemotherapy and radiologic staging, produced a higher rate of definitive tumor resection compared to historical trials. Nonadherence with surgical guidelines resulted in liver transplantation in some patients for whom partial hepatectomy might have been an option.

Background:Children's Oncology Group ACNS0333 treated atypical teratoid/rhabdoid tumor (ATRT) with surgery, chemotherapy (induction and consolidation) and radiation therapy (RT). M0 had focal RT and M+ had physician-selected focal RT or craniospinal (CSI). Methods:Forty patients (29 M0, 11 M+) received RT. Pre-RT chemotherapy response was complete, partial, or stable disease. RT timing (age/stage-based) was pre-consolidation (RT-first) or post-consolidation (consolidation-first). Event-free survival (RT-EFS), overall survival (RT-OS), and cumulative incidence of local relapse (CILR) or distant relapse (RT-CIDR) were calculated. Analyses included log-rank tests and relative hazard rates with 95% confidence intervals to estimate proportional hazards regression. Results:Four-year RT-EFS was 56.8% and 4-year RT-OS was 58.8% focal RT: 34 patients, CSI: 6 patients). A trend for superior RT-EFS for M+ compared to M0 (P = .0625, RHR 0.26; 95% CI 0.06-1.18) was shown. RT-EFS was improved for consolidation-first compared to RT-first timing (P = .037, RHR 0.43; 95% CI 0.13-1.37). Pre-RT chemotherapy response was associated with improved RT-EFS (P = .031) and RT-OS (P = .0069). Four-year RT-CILR was 7.84%; no differences in RT-CILR were shown for higher primary RT dose (≥5400 cGy, P = .38) or gross total resection (P = .80). 4-year RT-CIDR was 27.8% for M0 and 9.1% for M+ patients (P = .22). M+ had CSI (n = 6) or focal RT (n = 5). Fatal necrosis potentially-attributable to RT occurred in 3 RT-first patients (occuring either 1.6, 4.6, or 16.2 months post-treatment). Conclusions:RT with intensive systemic therapy showed promising survival outcomes and effective primary disease control in ATRT. Sequencing RT prior to myeloblative chemotherapy, rather than post-consolidation, may be associated with increased risk of fatal radionecrosis.

Understanding the patient experience of treatment toxicities and their impact on health-related quality of life from cancer treatments requires asking patients using patient-reported outcomes. Over the past 20 years, the National Institutes of Health has sponsored several tools—namely, Patient-Reported Outcomes Measurement Information System measures and the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events—for precisely this purpose: to ensure valid, reliable tools to collect and detect patient-reported toxicities or adverse events and their impact on health-related quality of life. These patient-reported outcomes measures have been widely incorporated in clinical trials for adults with cancer. Yet, despite considerable work developing and validating developmentally appropriate versions of these measures for pediatric and adolescent self-report, patient-reported outcomes inclusion in pediatric and adolescent and young adult clinical trials has lagged. Here, we discuss optimal strategies to integrate validated patient-reported outcomes tools and sound analytic methodologies in clinical trials for children and adolescent and young adults with cancer, highlighting lessons learned from recent successes and ongoing experiences developing and opening cross-network trials for children and adolescent and young adults through the Children’s Oncology Group for patients with classic Hodgkin lymphoma, osteosarcoma, and acute lymphoblastic leukemia.

BACKGROUND:In many pediatric malignant germ cell tumor (MGCT) protocols, patients who do not achieve a complete response (CR; normal tumor markers, no radiological/histological residual) after three cisplatin-etoposide-bleomycin (PEb) cycles receive two to three "consolidation" cycles of the same regimen. Evidence for this practice is limited, and historical outcomes for non‑CR patients remain poor. METHODS:We retrospectively reviewed patients diagnosed with intermediate-risk MGCT, enrolled in AGCT0132, between 2003 and 2011. All patients received three cycles of PEb and underwent response assessment at the end of induction. Patients not in CR were prescribed three additional cycles of PEb as consolidation. We compared event-free survival (EFS) and overall survival (OS) for patients who did and did not receive consolidation. RESULTS:Among 210 patients enrolled, two patients were excluded from analyses: one without complete information, and one had rapid progressive disease (PD) and did not complete induction therapy. Out of 208 patients, 193 had a CR after three cycles of induction chemotherapy, and their post-induction 4-year EFS and OS were 93% and 99%. Fifteen patients were not in CR at the end of the first three cycles. Twelve received consolidated chemotherapy as mandated per protocol, and their 4-year EFS and OS were 61% and 65%, respectively. Three patients were deemed to have progressive disease at the end of induction and received second-line therapy. CONCLUSION:Children with MGCTs who did not achieve CR after the first three cycles of chemotherapy had an inferior outcome compared to those with a CR, despite receiving additional cycles of PEb chemotherapy. We conclude that consolidation is of unclear benefit. We suggest that pediatric MGCT patients who fail to achieve a CR after standard induction chemotherapy may receive a salvage regimen with different agents rather than consolidation with more of the same chemotherapy.

Patients with resectable Ewing sarcoma (ES) in select sites, such as the pelvis or chest wall, have a higher risk of positive microscopic margins following surgery. AEWS1031 was the first North American/Australasia ES cooperative group trial allowing standardized preoperative radiotherapy, intended to minimize the morbidity of combined modality local tumor control as well as improve the likelihood of clear surgical margins. In this study, we found that the use of low-dose preoperative radiation to a smaller target volume resulted in a high rate of R0 resection. The robust pathologic response rate strengthens existing evidence illustrating the radiosensitivity of Ewing sarcoma.

PURPOSE:Local therapy (LT) is a critical component of curative treatment for Ewing sarcoma (ES). This analysis evaluated clinical and treatment variables associated with local failure (LF) risk for nonmetastatic patients with ES. METHODS AND MATERIALS:AEWS1031 was a phase 3 randomized trial comparing 2 interval-compressed chemotherapy regimens. Patients who completed induction chemotherapy and started LT of the primary tumor site were analyzed. LT was surgery alone (S), definitive radiation therapy (RT), or surgery and RT (S+RT), and was determined by the treating investigator. The primary endpoint was the cumulative incidence of LF estimated from the time LT was started. Elastic net penalization was used to identify predictors associated with the cause-specific hazard rates of LF. RESULTS:Five hundred eighty-eight patients started LT. Tumor sites were extremity (40%), axial (27%), pelvis (18%), and extraosseous (15%). LT was S (54%), RT (27%), and S+RT (18%). With a median follow-up of 67.6 months, the 5-year cumulative incidence of LF for all patients was 6%. LF incidence was 5% for S, 8.4% for RT, and 5.6% for S+RT (P = .47). LF incidence was 3.5% for extremity, 8.7% for pelvis, 7.7% for axial, and 6.3% for extraosseous (P = .09). LF incidence was higher for tumors ≥200 mL (11.3%) compared with tumors <200 mL (3.9%; P < .01). On multivariable modeling, increasing age at enrollment (cause-specific relative hazard ratio [csRHR] 1.04/y) and increasing maximum tumor dimension (csRHR 1.08/cm) were suggestive of a higher incidence of LF. By tumor subsite, axial tumors were associated with the highest risk of LF (csRHR 1.17) and extremity tumors with the lowest risk (csRHR 0.50). CONCLUSIONS:We report the lowest LF incidence to date for prospective ES trials. Large tumors, older age, and axial tumor subsite were associated with higher LF incidence, indicating further efforts are needed to identify the highest-risk subset most likely to benefit from improved LT strategies.

Introduction The Children’s Hepatic Tumors International Collaboration (CHIC) previously developed the CHIC hepatoblastoma risk stratification (CHIC-HS) model by analyzing the original CHIC dataset (development set). A validation of the results was planned with data from contemporary trials that were ongoing at the time of the initial analysis. Material and Methods Subsequent analysis was performed on the contemporary trials (validation set) SIOPEL 4, SIOPEL 6, COG AHEP0731, and JPLT 2 (2011-2013 cohort) utilizing the same methodology as in the CHIC-HS development. Results 403 patients were available for analysis for validation of the CHIC-HS model. Clinical characteristics were comparable between the validation and development sets. Event free survival (EFS) was similar in the very low and low-risk CHIC-HS strata in both the development and validation sets. EFS was higher in the intermediate and high-risk strata in the validation set as compared with the development set consistent with improved survival of intermediate-risk patients on AHEP0731 and high-risk patients on SIOPEL 4. Conclusions The four risk groups in the CHIC-HS retain their relevance for risk stratification in this analysis, notwithstanding improved outcomes in patients with higher risk hepatoblastoma; therefore, the CHIC-HS remains a valid model which differentiates patients into statistically distinct risk strata. The model will be further evaluated with data from the current pediatric international hepatic tumors trial (PHITT).

To evaluate the impact of surgical guidelines on the management of children with hepatoblastoma. The Children’s Oncology Group study AHEP0731 was the first pediatric cooperative group trial to propose guidelines for the surgical management of children with hepatoblastoma. AHEP0731 enrolled children with hepatoblastoma between 2009 and 2018. Surgical guidelines were based upon radiographic extent of disease (PRETEXT, POST-TEXT). Planned non-real-time central review of imaging was completed at diagnosis and after two, four, and six cycles of chemotherapy to determine guideline adherence. Resection rate, event-free survival (EFS), overall survival (OS), and complications were compared between guideline adherent and nonadherent groups. Of 226 enrolled patients, 221 were evaluable of whom 205 (93%) underwent definitive surgical resection. Guideline adherence for protocol recommended timing of resection was 65% (133/205). The nonadherent group included 44/205 (21%) patients who underwent early resection and 28/205 (14%) patients who underwent late resection or late transplantation. Eighty-five patients met criteria for early referral to a liver transplant center, of whom 55 (65%) were referred within the recommended timeframe. Twelve patients received liver transplants outside of surgical guidelines. There were no significant differences in EFS, OS, or complication rates between adherent and nonadherent groups. Implementation of surgical guidelines, in combination with effective chemotherapy and radiologic staging, produced a higher rate of definitive tumor resection compared to historical trials. Nonadherence with surgical guidelines resulted in liver transplantation in some patients for whom partial hepatectomy might have been an option.

Trends in diagnostic biopsy sample collection approaches for primary bone sarcomas have shifted in the past 2 decades. Although open/incisional biopsies used to be the predominant approach to obtain diagnostic material for Ewing sarcoma and osteosarcoma, image-guided core needle biopsies have increased in frequency and are safe for patients. These procedures are less invasive and reduce recovery times but have potential limitations. The quantity and quality of tissue obtained through these procedures vary between institutions. Acquired viable tissue volumes can be low, limiting the conduct of downstream expanded clinical workup, molecular analyses, and research. Patients with advanced Ewing sarcoma and osteosarcoma continue to have overall poor outcomes despite dose-intensive cytotoxic chemotherapy. The biology of treatment resistance is not currently well understood, partly due to limited availability of relevant tissue to study. There is a need for access to quality tumor specimens for molecular and other analyses to identify high-risk tumor subsets and drive discovery to improve patient outcomes. Given broad variability in bone tumor tissue procurement and processing across member institutions, the Children’s Oncology Group Bone Tumor Committee convened a multidisciplinary group of experts to outline the current and near-future tissue needs for optimal clinical care and access to research platforms. The goal of this working group was to provide high-level guidance on biopsy practices that safely meet these evolving needs. Harmonizing tissue collection practices is paramount to improving the care of children, adolescents, and young adults diagnosed with Ewing sarcoma and osteosarcoma.

Introduction Ewing sarcoma (ES), is a rare cancer affecting children, adolescents and adults. After VIDE (vincristine-ifosfamide-doxorobucin-etoposide) induction chemotherapy, Busulfan-Melphalan (BuMel) high-dose chemotherapy followed by autologous hematopoietic stem cells transplantation improved outcomes in unfavourable localized ES, but with more toxicities than conventional chemotherapy (VAI: Vincristine-dactinomycin-Ifosfamide). We evaluated whether the risk of acute toxicity associated with BuMel compared to VAI varied according to age in patients recruited in the R2Loc and R2Pulm randomised trials of the Euro-E.W.I.N.G.99 and Ewing-2008 trials. Methods We included patients with a localized high-risk disease, or pulmonary or pleural metastasis. We analysed the risk of severe toxicity according to randomised treatment group (VAI versus BuMel) and age group (<12 years, 12-17 years, 18-24 years, ≥25 years). We evaluated the heterogeneity of treatment effects by age group using interaction terms in logistic multivariable models. Results The analysis included 243 patients treated with VAI and 205 with BuMel. Overall, BuMel was associated with a higher risk of severe acute toxicity than VAI particularly haematological, gastrointestinal, liver, sinusoidal occlusive syndrome, and infections. Severe haematological toxicity and lower general condition were significantly more frequent in younger patients, whatever treatment. We did not observe any significant heterogeneity in terms of the excess risk of severe toxicities associated with BuMel compared to VAI according to age group. Conclusion The excess of acute toxicity associated with BuMel compared to VAI does not vary significantly with age, suggesting the feasibility of BuMel across all age groups.

Background In the treatment of resectable hepatoblastoma (HB), it has not been established whether upfront surgery (UF) at diagnosis or neoadjuvant chemotherapy and delayed surgery (DL) is preferred. We compared patients with localized HB who underwent either UF, or DL after neoadjuvant chemotherapy in the Children's Hepatic tumors International Collaboration (CHIC) database of 1605 cases enrolled in eight multicenter hepatoblastoma trials between 1988 and 2010. Methods Among the 512 resectable HB patients who had PRETEXT (PRETreament EXTent of disease) I or II unruptured tumors at diagnosis without extrahepatic invasion, distant metastases, or massive vascular invasion, 172 underwent UF and 340 underwent DL. The primary outcomes were event-free and overall survivals after start of treatment in these two groups. Survival analysis was performed using the Kaplan-Maier analysis with long-rank tests and multivariable Cox regression models. Findings Complete resection rates were comparable (93.6% in UF and 89.7% in DL). The total cycles of chemotherapy of DL (median:6) were significantly more than those of UF (median:4) (P < 0.01). The 5-year event-free survival (EFS) was 90.6% and 86.6% (P = 0.89) in the UF and DL cohorts, respectively. The surgical complications, recurrence rates, and late complications were not significantly different between the cohorts but the EFS rates of DL patients with a low alpha-fetoprotein (AFP) level (100-999 ng/mL) or older age at diagnosis (>= 3 years old) were significantly worse than others. Interpretation The outcomes, surgical resectability, and complications were not significantly different between the UF and DL groups. Eligible patients with a low AFP level (<1000 ng/mL) or older age (>= 3 years old) showed better outcomes in the UF group and might be considered for initial resection.

BACKGROUND:Children living in poverty and those of marginalized race or ethnicity experience inferior disease outcomes across many cancers. Whether survival disparities exist in osteosarcoma is poorly defined. We investigated the association between race, ethnicity, and proxied poverty exposures and event-free and overall survival for children with nonmetastatic osteosarcoma receiving care on a cooperative group trial. METHODS:We conducted a retrospective cohort study of US patients with nonmetastatic, osteosarcoma aged 5-21 years enrolled on the Children's Oncology Group trial AOST0331. Race and ethnicity were categorized to reflect historically marginalized populations, as Hispanic, non-Hispanic Black, non-Hispanic Other, and non-Hispanic White. Poverty was proxied at the household and neighborhood levels. Overall survival and event-free survival functions of time from trial enrollment were estimated using the Kaplan-Meier method. Hypotheses of associations between risks for event-free survival, death, and postrelapse death with race and ethnicity were assessed using log-rank tests. RESULTS:Among 758 patients, 25.6% were household-poverty and 28.5% neighborhood-poverty exposed. Of the patients, 21% of children identified as Hispanic, 15.4% non-Hispanic Black, 5.3% non-Hispanic Other, and 54.0% non-Hispanic White. Neither household or neighborhood poverty nor race and ethnicity were statistically significantly associated with risks for event-free survival or death. Postrelapse risk for death differed statistically significantly across race and ethnicity with non-Hispanic Black patients at greatest risk (4-year postrelapse survival 35.7% Hispanic vs 13.0% non-Hispanic Black vs 43.8% non-Hispanic Other vs 38.9% non-Hispanic White; P = .0046). CONCLUSIONS:Neither proxied poverty exposures or race and ethnicity were associated with event-free survival or overall survival, suggesting equitable outcomes following frontline osteosarcoma trial-delivered therapy. Non-Hispanic Black children experienced statistically significant inferior postrelapse survival. Investigation of mechanisms underlying postrelapse disparities are paramount.

Background Outcomes for children with high-grade gliomas (HGG) remain poor. This multicenter phase II trial evaluated whether concurrent use of vorinostat or bevacizumab with focal radiotherapy (RT) improved 1-year event-free survival (EFS) compared to temozolomide in children with newly diagnosed HGG who received maintenance temozolomide and bevacizumab. Methods Patients ≥ 3 and < 22 years with localized, non-brainstem HGG were randomized to receive RT (dose 54–59.4Gy) with vorinostat, temozolomide, or bevacizumab followed by 12 cycles of bevacizumab and temozolomide maintenance therapy. Results Among 90 patients randomized, the 1-year EFS for concurrent bevacizumab, vorinostat, or temozolomide with RT was 43.8% (±8.8%), 41.4% (±9.2%), and 59.3% (±9.5%), respectively, with no significant difference among treatment arms. Three- and five-year EFS for the entire cohort was 14.8% and 13.4%, respectively, with no significant EFS difference among the chemoradiotherapy arms. IDH mutations were associated with more favorable EFS (P = .03), whereas H3.3 K27M mutations (P = .0045) and alterations in PIK3CA or PTEN (P = .025) were associated with worse outcomes. Patients with telomerase- and alternative lengthening of telomeres (ALT)-negative tumors (n = 4) had an EFS of 100%, significantly greater than those with ALT or telomerase, or both (P = .002). While there was no difference in outcomes based on TERT expression, high TERC expression was associated with inferior survival independent of the telomere maintenance mechanism (P = .0012). Conclusions Chemoradiotherapy with vorinostat or bevacizumab is not superior to temozolomide in children with newly diagnosed HGG. Patients with telomerase- and ALT-negative tumors had higher EFS suggesting that, if reproduced, mechanism of telomere maintenance should be considered in molecular-risk stratification in future studies.