Purpose The study was designed to determine whether response-based therapy improves outcomes in intermediate-risk Hodgkin lymphoma. We examined patterns of first relapse in the study. Methods From 9/02 – 7/10, 1712 patients <22 yrs of age with stage I–IIA with bulk, I–IIAE, I–IIB, and IIIA–IVA with/without bulk were enrolled. Patients were categorized as rapid (RER) or slow early responders (SER) after 2 cycles of doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide (ABVE-PC). SER patients were randomized to 2 additional ABVE-PC cycles or augmented chemotherapy with 21Gy IFRT. RER patients were stipulated to undergo 2 additional ABVEPC cycles and were then randomized to 21Gy IFRT or no further treatment if complete response (CR) was achieved. RER without CR patients were non-randomly assigned to 21Gy IFRT. Relapses were characterized with respect to site (initial, new or both; and initial bulk or initial non-bulk), and IFRT field (in-field, out-of-field, or both). Patients were grouped by treatment assignment (SER; RER/no CR; RER/CR/IFRT; and RER/CR/no IFRT). Summary statistics were reported. Results At 4-year median follow-up, 244 patients had relapsed, 198 of whom were fully evaluable for review. Those who progressed on treatment (n=30) or lacked relapse imaging (n=16) were excluded. Median time to relapse was 12.8 months. Of the 198 patients, 30% were RER/no CR, 26% were SER, 26% were RER/CR/no IFRT, 16% were RER/CR/IFRT, and 2% remained uncategorized. 74% and 75% relapses involve initially bulky and non-bulky sites, respectively. First relapses rarely occurred at exclusively new or out-of-field sites. In contrast, relapses usually occurred at nodal sites of initial bulky and non-bulky disease. Conclusion While response-based therapy has helped define treatment for select RER patients, it has not improved outcome for SER patients or facilitated refinement of IFRT volumes or doses.

Purpose: Associations of radiation therapy (RT) deviations and outcomes in medulloblastoma have not been defined well, particularly in the era of reduced-dose craniospinal irradiation and chemotherapy. The aim of this study is to evaluate the quality of RT on Children’s Cancer Group/Pediatric Oncology Group 9961 and analyze associations of RT deviations with outcome. Materials and Methods: Major volume deviations were assessed based on the distance from specified anatomical region to field edge. We investigated associations of RT deviations with progression-free survival (PFS), overall survival (OS), and explored associations with demographics and clinical variables. Results: Of the 308 patients who were evaluable for volume deviations, 101 patients (33%) did not have any. Of the remaining 207 patients, 50% had only minor deviations, 29% had only major deviations, and 21% had both minor and major deviations. Of the patients with major deviations, 73% had a single major deviation. The most common major deviation was in the cribriform plate region, followed by the posterior fossa (PF); PF deviations resulted from treating less than whole PF. There were no significant differences in PFS or OS between patients with deviations and those without. There was no evidence of associations of deviations with patient age. Conclusions: Approximately one-third of patients had major volume deviations. There was no evidence of a significant association between these and outcome. This lack of correlation likely reflects the current high quality of RT delivered in Children’s Oncology Group institutions, our strict definition of volume deviations, and the relatively few instances of multiple major deviations in individual patients. In is noteworthy that the types of PF volume deviations observed in this study were not adversely associated with outcome. As we move forward, quality assurance will continue to play an important role to ensure that deviations on study do not influence study outcome.

Purpose A phase III trial assessing response-based therapy in intermediate-risk Hodgkin lymphoma, mandated real-time central review of involved field radiotherapy and imaging records by a centralized review center to maximize protocol compliance. We report the impact of centralized radiotherapy review upon protocol compliance. Methods Review of simulation films, port films, and dosimetry records was required pre-treatment and after treatment completion. Records were reviewed by study-affiliated or review center-affiliated radiation oncologists. A 6–10% deviation from protocol-specified dose was scored as “minor”; >10% was “major”. A volume deviation was scored as “minor” if margins were less than specified, or “major” if fields transected disease-bearing areas. Interventional review and final compliance review scores were assigned to each radiotherapy case and compared. Results Of 1712 patients enrolled, 1173 underwent IFRT at 256 institutions in 7 countries. An interventional review was performed in 88% and a final review in 98%. Overall, minor and major deviations were found in 12% and 6%, respectively. Among the cases for which ≥ 1 pre-IFRT modification was requested by QARC and subsequently made by the treating institution, 100% were made compliant on final review. In contrast, among the cases for which ≥ 1 modification was requested but not made by the treating institution, 10% were deemed compliant on final review. Conclusion In a large trial with complex treatment pathways and heterogeneous radiotherapy fields, central review was performed in a large percentage of cases pre-IFRT and identified frequent potential deviations in a timely manner. When suggested modifications were performed by the institutions, deviations were almost eliminated.

The Children's Oncology Group (COG) has a strong quality assurance (QA) program managed by the Imaging and Radiation Oncology Core (IROC). This program consists of credentialing centers and providing real‐time management of each case for protocol compliant target definition and radiation delivery. In the International Society of Pediatric Oncology (SIOP), the lack of an available, reliable online data platform has been a challenge and the European Society for Paediatric Oncology (SIOPE) quality and excellence in radiotherapy and imaging for children and adolescents with cancer across Europe in clinical trials (QUARTET) program currently provides QA review for prospective clinical trials. The COG and SIOP are fully committed to a QA program that ensures uniform execution of protocol treatments and provides validity of the clinical data used for analysis.

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