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PURPOSE: We sought to investigate clinical outcomes of relapsed medulloblastoma and to compare molecular features between patient-matched diagnostic and relapsed tumors. METHODS: Children and infants enrolled on either SJMB03 (NCT00085202) or SJYC07 (NCT00602667) trials who experienced medulloblastoma relapse were analyzed for clinical outcomes, including anatomic and temporal patterns of relapse and postrelapse survival. A largely independent, paired molecular cohort was analyzed by DNA methylation array and next-generation sequencing. RESULTS: A total of 72 of 329 (22%) SJMB03 and 52 of 79 (66%) SJYC07 patients experienced relapse with significant representation of Group 3 and wingless tumors. Although most patients exhibited some distal disease (79%), 38% of patients with sonic hedgehog tumors experienced isolated local relapse. Time to relapse and postrelapse survival varied by molecular subgroup with longer latencies for patients with Group 4 tumors. Postrelapse radiation therapy among previously nonirradiated SJYC07 patients was associated with long-term survival. Reirradiation was only temporizing for SJMB03 patients. Among 127 patients with patient-matched tumor pairs, 9 (7%) experienced subsequent nonmedulloblastoma CNS malignancies. Subgroup (96%) and subtype (80%) stabilities were largely maintained among the remainder. Rare subgroup divergence was observed from Group 4 to Group 3 tumors, which is coincident with genetic alterations involving MYC, MYCN, and FBXW7. Subgroup-specific patterns of alteration were identified for driver genes and chromosome arms. CONCLUSION: Clinical behavior of relapsed medulloblastoma must be contextualized in terms of up-front therapies and molecular classifications. Group 4 tumors exhibit slower biological progression. Utility of radiation at relapse is dependent on patient age and prior treatments. Degree and patterns of molecular conservation at relapse vary by subgroup. Relapse tissue enables verification of molecular targets and identification of occult secondary malignancies.

Simple Summary: We discuss the role of risk-stratification and personalized treatment for various pediatric cancer patients, with the goal being to improve tumor control and decrease late effects of radiation in long-term survivors. We discuss settings in which radiation can be safely omitted or de-escalated, such as Hodgkin lymphoma, Wilms tumor with lung metastases and WNT pathway Medulloblastoma, and settings that warrant treatment escalation such as larger tumors with rhabdomyosarcoma or Ewing sarcoma, poor responders to chemotherapy and oligometastatic disease settings. We also summarize currently enrolling COG and other cooperative group trials. While the cure rate of cancer in children has markedly improved in the last few decades, late effects continue to be a problem in survivors. Radiotherapy, which is a major component of treatment in many cancers, is one of the major agents responsible for late toxicity. In the past decade, radiotherapy has been omitted in patients achieving excellent response to chemotherapy, such as in Hodgkin lymphoma and some Wilms tumors with lung metastases. Likewise, response to chemotherapy has been used to determine whether lower doses of radiation can be delivered in intracranial germinoma and pediatric nasopharyngeal carcinoma. Molecular subtyping in medulloblastoma is currently being employed, and in WNT-pathway M0 tumors, the reduction in radiotherapy dose to the craniospinal axis and tumor bed is currently being investigated. Finally, dose escalation was recently evaluated in patients with rhabdomyosarcoma > 5 cm who do not achieve a complete response to initial 9 weeks of chemotherapy as well as for unresectable Ewing sarcoma patients to improve local control. [ABSTRACT FROM AUTHOR]

Purpose The National Wilms Tumor Study (NWTS) treatment of favorable histology Wilms tumor with lung metastases was vincristine/dactinomycin/doxorubicin (DD4A) and lung radiation therapy (RT). The AREN0533 study applied a new risk stratification and treatment strategy to improve event-free survival (EFS) while reducing exposure to lung RT. Methods Patients with favorable histology Wilms tumor and isolated lung metastases showing complete lung nodule response (CR) after 6 weeks of DD4A continued receiving chemotherapy without lung RT. Patients with incomplete response (IR) or loss of heterozygosity at chromosomes 1p/16q received lung RT and four cycles of cyclophosphamide/etoposide in addition to DD4A drugs (Regimen M). AREN0533 was designed to preserve a 4-year EFS of 85% for lung nodule CR and improve 4-year EFS from 75% to 85% for lung nodule IR. Results Among 292 assessable patients, 133 had CR and 159 had IR. For patients with CR, 4-year EFS and overall survival (OS) estimates were 79.5% (95% CI, 71.2% to 87.8%) and 96.1% (95% CI, 92.1% to 100%), respectively. Expected versus observed event rates were 15% and 20.2% ( P = .052), respectively. For patients with IR, 4-year EFS and OS estimates were 88.5% (95% CI, 81.8% to 95.3%) and 95.4% (95% CI, 90.9% to 99.8%), respectively. Expected versus observed event rates were 25% and 12.2% ( P < .001), respectively. Overall, 4-year EFS and OS were 85.4% (95% CI, 80.5% to 90.2%) and 95.6% (95% CI, 92.8% to 98.4%) compared with 72.5% (95% CI, 66.9% to 78.1%; P < .001) and 84.0% (95% CI, 79.4% to 88.6%; P < .001), respectively, in the predecessor NWTS-5 study. Conclusion Excellent OS was achieved after omission of primary lung RT in patients with lung nodule CR, although there were more events than expected. EFS was significantly improved, with excellent OS, in patients with lung nodule IR using four cycles of cyclophosphamide/etoposide in addition to DD4A drugs. The overall AREN0533 treatment strategy yielded EFS and OS estimates that were superior to previous studies.

Background: On the fifth National Wilms Tumor Study, treatment for clear cell sarcoma of the kidney (CCSK) included combined vincristine, doxorubicin, cyclophosphamide, and etoposide (regimen I) plus radiation therapy (RT), yielding 5‐year event‐free survival (EFS) rates of 100%, 88%, 73%, and 29% for patients who had with stage I, II, III, and IV disease, respectively. In the Children's Oncology Group study AREN0321 of risk‐adapted therapy, RT was omitted for stage I disease if lymph nodes were sampled, and carboplatin was added for stage IV disease (regimen UH‐1). Patients who had stage II/III disease received regimen I with RT. Methods: Four‐year EFS was analyzed for patients enrolled on AREN0321 and on those enrolled on AREN03B2 who received AREN0321 stage‐appropriate chemotherapy. Results: Eighty‐two patients with CCSK enrolled on AREN0321, 50 enrolled on AREN03B2 only. The 4‐year EFS rate was 82.7% (95% confidence interval [CI], 74.8%–91.4%) for AREN0321 and 89.6% (95% CI, 81.3%–98.7%) for AREN03B2 only (p =.28). When combining studies, the 4‐year EFS rates for patients who had stage I (n = 10), II (n = 47), III (n = 65), and IV (n = 10) disease were 90% (95% CI, 73.2%–100.0%), 93.4% (95% CI, 86.4%–100.0%), 82.8% (95% CI, 74.1%–92.6%), and 58.3% (95% CI, 34%–100.0%), respectively. There were no local recurrences among seven patients with stage I disease who were treated without RT. One stage I recurrence occurred in the brain, which was the most common site of relapse overall. Among patients with local stage III tumors, neither initial procedure type, margin status, nor lymph node involvement were prognostic. Conclusions: Patients with stage I CCSK had excellent outcomes without local recurrences when treated without RT. Patients with stage IV disease appeared to benefit from a carboplatin‐containing regimen, although their outcomes remained unsatisfactory. Further research is needed to improve outcomes for patients with advanced‐stage disease (ClinicalTrials.gov identifiers NCT00335556 and NCT00898365). The results of this study indicate that treatment of clear cell sarcoma of the kidney can be risk‐adapted based on disease stage, radiotherapy should be omitted for patients with stage I disease if lymph nodes are sampled, and patients with stage IV disease appear to benefit from a carboplatin‐containing regimen. With treatment according to the Children's Oncology Group AREN0321 study, most relapses occurred within 3 years, and the most common sites of recurrence were in the central nervous system. [ABSTRACT FROM AUTHOR]

Background Glioblastoma (GBM) poses therapeutic challenges due to its aggressive nature, particularly for patients with poor functional status and/or advanced disease. Hypofractionated radiotherapy (RT) regimens have demonstrated comparable disease outcomes for this population while allowing treatment to be completed more quickly. Here, we report our institutional outcomes of patients treated with 2 hypofractionated RT regimens: 40 Gy/15fx (3w-RT) and 50 Gy/20fx (4w-RT). Methods A single-institution retrospective analysis was conducted of 127 GBM patients who underwent 3w-RT or 4w-RT. Patient characteristics, treatment regimens, and outcomes were analyzed. Univariate and multivariable Cox regression models were used to estimate progression-free survival (PFS) and overall survival (OS). The impact of chemotherapy and RT schedule was explored through subgroup analyses. Results Median OS for the entire cohort was 7.7 months. There were no significant differences in PFS or OS between 3w-RT and 4w-RT groups overall. Receipt and timing of temozolomide (TMZ) emerged as the variable most strongly associated with survival, with patients receiving adjuvant-only or concurrent and adjuvant TMZ having significantly improved PFS and OS (P <.001). In a subgroup analysis of patients that did not receive TMZ, patients in the 4w-RT group demonstrated a trend toward improved OS as compared to the 3w-RT group (P =.12). Conclusions This study demonstrates comparable survival outcomes between 3w-RT and 4w-RT regimens in GBM patients. Receipt and timing of TMZ were strongly associated with survival outcomes. The potential benefit of dose-escalated hypofractionation for patients not receiving chemotherapy warrants further investigation and emphasizes the importance of personalized treatment approaches. [ABSTRACT FROM AUTHOR]

Introduction: The prognostic impact of positive lymph nodes (LN+) and/or singular loss of heterozygosity (LOH) of 1p or 16q were assessed in children with stage III favorable histology Wilms tumor (FHWT) enrolled on AREN0532 or AREN03B2 alone. Patients and Methods: A total of 635 stage III FHWT vincristine/dactinomycin/doxorubicin (DD4A)–treated patients met inclusion criteria. Event‐free survival (EFS) and overall survival are reported overall and by LN sampling, LN status, LOH 1p, LOH 16q, and a combination of LN status and singular LOH. Patients with unknown or positive combined LOH of 1p and 16q status and AREN03B2‐only patients with unknown outcomes or treatment other than DD4A were excluded. Results: EFS did not differ by study, supporting pooling. Lack of LN sampling (hazard ratio [HR], 2.12; p =.0037), LN positivity (HR, 2.78; p =.0002), LOH 1p (HR, 2.18; p =.0067), and LOH 16q (HR, 1.72; p =.042) were associated with worse EFS. Compared with patients with both LN– and LOH–, those with negative nodes but positive LOH 1p or 16q and those with LN+ but LOH– for 1p or 16q had significantly worse EFS (HR, 3.05 and 3.57, respectively). Patients positive for both LN and LOH had the worst EFS (HR, 6.33; overall group factor, p <.0001). Conclusion: Findings confirm LN+ status as an adverse prognostic factor amplified by presence of singular LOH 1p or 16q, supporting study of intensified therapy for patients with LN+ in combination with singular LOH in a prospective clinical trial. Stage III patients with favorable histology Wilms tumor and a combination of loss of heterozygosity of 1p or 16q and lymph node involvement were examined in an expanded Children's Oncology Group cohort. The combination of loss of heterozygosity status with lymph node status correlated with inferior outcome. [ABSTRACT FROM AUTHOR]