Late Cardiac Toxic Effects Associated With Treatment Protocols for Hodgkin Lymphoma in Children.

Importance: Contemporary North American trials for children with Hodgkin lymphoma (HL) have decreased radiation therapy (RT) use and increased pharmacologic cardioprotection but also increased the cumulative doxorubicin dose, making overall treatment consequences for late cardiac toxic effects uncertain. Objective: To estimate the risk of cardiac toxic effects associated with treatments used in modern pediatric HL clinical trials. Design, Setting, and Participants: For this cohort study, Fine and Gray models were fitted using survivors in the Childhood Cancer Survivor Study who were diagnosed with HL between January 1, 1970, and December 31, 1999, and were followed for a median of 23.5 (range, 5.0-46.3) years. These models were applied to the exposures in the study population to estimate the 30-year cumulative incidence of cardiac disease. The study population comprised patients with intermediate-risk or high-risk HL treated in 4 consecutive Children's Oncology Group clinical trials from September 2002 to October 2022: AHOD0031, AHOD0831, AHOD1331, and S1826. Data analysis was performed from April 2020 to February 2023. Exposures: All patients received chemotherapy including doxorubicin, and some patients received mediastinal RT, dexrazoxane, or mediastinal RT and dexrazoxane. Main Outcomes and Measures: Estimated 30-year cumulative incidence of grade 3 to 5 cardiac disease. Results: The study cohort comprised 2563 patients, with a median age at diagnosis of 15 (range, 1-22) years. More than half of the patients were male (1357 [52.9%]). All 2563 patients received doxorubicin, 1362 patients (53.1%) received mediastinal RT, and 307 patients (12.0%) received dexrazoxane. Radiation therapy use and the median mean heart dose among patients receiving RT decreased, whereas the planned cumulative dose of doxorubicin and use of dexrazoxane cardioprotection increased. For patients treated at age 15 years, the estimated 30-year cumulative incidence of severe or fatal cardiac disease was 9.6% (95% CI, 4.2%-16.4%) in the AHOD0031 standard treatment group (enrolled 2002-2009), 8.6% (95% CI, 3.8%-14.9%) in the AHOD0831 trial (enrolled 2009-2012), 8.2% (95% CI, 3.6%-14.3%) in the AHOD1331 trial (enrolled 2015-2019), and 6.2% (95% CI, 2.7%-10.9%) in the S1826 trial (enrolled 2019-2022), whereas the expected rate in an untreated population was 5.0% (95% CI, 2.1%-9.3%). Despite the estimated reduction in late cardiac morbidity, the frequency of recommended echocardiographic screening among survivors will increase based on current guidelines. Conclusions and Relevance: In this cohort study of sequential HL trials, reductions in the proportion of children receiving mediastinal RT and increases in dexrazoxane use were estimated to offset the increased doxorubicin dose and produce a net reduction in late cardiac disease. Further studies on dexrazoxane are warranted to confirm whether its role in reducing cardiac toxic effects is maintained long term. These findings suggest that survivorship follow-up guidelines should be refined to align with the risks associated with treatment.

Outcomes After Preoperative Chemoradiation With or Without Pazopanib in Non-Rhabdomyosarcoma Soft Tissue Sarcoma: A Report From Children's Oncology Group and NRG Oncology.

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 co-primary 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.ARST1321 was a phase II study designed to compare the near complete pathologic response rate after preoperative chemoradiation with/without pazopanib in children and adults with intermediate-/high-risk chemotherapy-sensitive body wall/extremity non-Rhabdomyosarcoma Soft Tissue Sarcoma (ClinicalTrials.gov identifier: NCT02180867). Enrollment was stopped early following a predetermined interim analysis that found the rate of near complete pathologic response to be significantly greater with the addition of pazopanib. As a planned secondary aim of the study, the outcome data for this cohort were analyzed. Eight-five eligible patients were randomly assigned to receive (regimen A) or not receive (regimen B) pazopanib in combination with ifosfamide and doxorubicin + preoperative radiotherapy followed by primary resection at week 13 and then further chemotherapy at week 25. As of December 31, 2021, at a median survivor follow-up of 3.3 years (range, 0.1-5.8 years), the 3-year event-free survival for all patients in the intent-to-treat analysis was 52.5% (95% CI, 34.8 to 70.2) for regimen A and 50.6% (95% CI, 32 to 69.2) for regimen B (P = .8677, log-rank test); the 3-year overall survival was 75.7% (95% CI, 59.7 to 91.7) for regimen A and 65.4% (95% CI, 48.1 to 82.7) for regimen B (P = .1919, log-rank test). Although the rate of near complete pathologic response was significantly greater with the addition of pazopanib, outcomes were not statistically significantly different between the two regimens.

Prognostic value of chest x-ray- and CT-defined large mediastinal adenopathy in high-risk pediatric Hodgkin lymphoma: A report from the Children's Oncology Group Study AHOD0831.

PURPOSE/OBJECTIVE: We compared the prognostic value of chest radiograph (CXR)- and computed tomography (CT)-derived definition of large mediastinal adenopathy (LMA) in pediatric Hodgkin lymphoma (HL). MATERIALS/METHODS: Total 143 patients treated for stage IIIB/IVB HL on COG AHOD0831 were included in this study. Six definitions of LMA were investigated: (i) mediastinal mass ratio on CXR (MRCXR ) > 1/3; (ii) mediastinal mass ratio on CT (MRCT ) > 1/3; (iii) mediastinal mass volume on CT (MVCT ) > 200 mL; (iv) normalized mediastinal mass volume (MVCT /thoracic diameter [TD]) > 1 mL/mm; (v) mediastinal mass diameter on CT (MDCT ) > 10 cm; and (vi) normalized mediastinal mass diameter (MDCT /TD) > 1/3. RESULTS: Median age at diagnosis was 15.8 years (range: 5.2-21.3 years). In patients with a slow early response (SER) to chemotherapy, MVCT  > 200 mL, MDCT  > 10 cm, and MDCT /TD > 1/3 were associated with worse relapse-free survival (RFS) on MVA, while MRCXR  > 1/3, MRCT  > 1/3, and MVCT /TD > 1 mL/mm trended toward worse RFS; MDCT /TD was the most strongly prognostic for inferior RFS, with a hazard ratio of 6.41 for MDCT /TD > 1/3 versus ≤1/3 on MVA (p = .02). CONCLUSION: LMA according to MVCT  > 200 mL, MDCT  > 10 cm, and MDCT /TD > 1/3 is associated with poor prognosis in advanced-stage HL patients with SER. The normalized mediastinal diameter, MDCT /TD > 1/3 appears to be the strongest predictor of inferior RFS.

Phase II Randomized Trial of Lenalidomide in Children With Pilocytic Astrocytomas and Optic Pathway Gliomas: A Report From the Children's Oncology Group.

PURPOSE: Children with low-grade glioma often require long-term therapy and suffer from treatment morbidity. Although targeted agents are promising, tumor targets often encompass normal developmental pathways and long-term effects of inhibition are unknown. Lenalidomide is an immunomodulatory agent with wide-ranging properties. Phase I studies indicated greater tolerability of lenalidomide in children compared with adults and a potential dose-response effect. PATIENTS AND METHODS: We performed a phase II trial of lenalidomide in children with pilocytic astrocytomas and optic pathway gliomas who failed initial therapy. Primary objectives included determination of objective response rate of children randomly assigned to regimen A, low-dose (20 mg/m2/dose), or regimen B, high-dose (115 mg/m2/dose) lenalidomide, and assessment for early progression. Secondary objectives included estimation of event-free survival, overall survival, incidence of toxic events, and assessment of plasma lenalidomide concentrations. Lenalidomide was administered once daily × 21 days of each 28-day cycle for each regimen. RESULTS: Seventy-four eligible patients were enrolled (n = 37, each arm). The predefined activity level of interest was achieved for both arms. Four objective responses were observed in each arm, and the number of early progressors was low. Eighteen patients completed 26 cycles of therapy (regimen A, n = 12; regimen B, n = 6). The median number of cycles was 14 (range, 2-26) for regimen A and 11 for regimen B (range, 1-26). Of 74 eligible patients who received study drug, 30 required dose reduction for toxicity (regimen A, n = 6; regimen B, n = 24) and 16 discontinued because of toxicity (regimen A, n = 2; regimen B, n = 14). CONCLUSION: Lenalidomide demonstrates a sufficient level of activity in children with low-grade glioma to warrant further exploration. Low-dose (20 mg/m2/dose administered once daily × 21 days of each 28-day cycle) lenalidomide appears to have better tolerability with comparable activity.

Importance of Central Imaging Review in a Pediatric Hodgkin Lymphoma Trial Using Positron Emission Tomography Response Adapted Radiation Therapy.

PURPOSE: We investigated the effects of central review of the interim fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) scan response (iPET) assessment on treatment allocation in the risk-based, response-adapted, Children's Oncology Group study AHOD1331 (ClinicalTrials.gov identifier: NCT02166463) for pediatric patients with high-risk Hodgkin lymphoma. METHODS AND MATERIALS: Per protocol, after 2 cycles of systemic therapy, patients underwent iPET, with visual response assessment by 5-point Deauville score (DS) at their treating institution and a real-time central review, with the latter considered the reference standard. An area of disease with a DS of 1 to 3 was considered a rapid-responding lesion, whereas a DS of 4 to 5 was considered a slow-responding lesion (SRL). Patients with 1 or more SRLs were considered iPET positive, whereas patients with only rapid-responding lesions were considered iPET negative. We conducted a predefined exploratory evaluation of concordance in iPET response assessment between institutional and central reviews of 573 patients. The concordance rate was evaluated using the Cohen κ statistic (κ > 0.80 was considered very good agreement and κ > 0.60-0.80, good agreement). RESULTS: The concordance rate (514 of 573 [89.7%]) had a κ of 0.685 (95% CI, 0.610-0.759), consistent with good agreement. In terms of the direction of discordance, among the 126 patients who were considered iPET positive by institutional review, 38 (30.2%) were categorized as iPET negative by central review, preventing overtreatment with radiation therapy. Conversely, among the 447 patients who were considered iPET negative by institutional review, 21 patients (4.7%) were categorized as iPET positive by the central review and would have been undertreated without radiation therapy. CONCLUSIONS: Central review is integral to PET response-adapted clinical trials for children with Hodgkin lymphoma. Continued support of central imaging review and education about DS are needed.

Baseline metabolic tumour burden improves risk stratification in Hodgkin lymphoma: A Children's Oncology Group study.

The Children's Oncology Group AHOD0831 study used a positron emission tomography (PET) response-adapted approach in high-risk Hodgkin lymphoma, whereby slow early responders (SERs) received more intensive therapy than rapid early responders (RERs). We explored if baseline PET-based characteristics would improve risk stratification. Of 166 patients enrolled in the COG AHOD0831 study, 94 (57%) had baseline PET scans evaluable for quantitative analysis. For these patients, total body metabolic tumour volume (MTV), total lesion glycolysis (TLG), maximum standardized uptake value (SUVmax ) and peak SUV (SUVpeak ) were obtained. MTV/TLG thresholds were an SUV of 2.5 (MTV2.5 /TLG2.5 ) and 40% of the tumour SUVmax (MTV40% /TLG40% ). TLG2.5 was associated with event-free survival (EFS) in the complete cohort (p = 0.04) and in RERs (p = 0.01), but not in SERs (p = 0.8). The Youden index cut-off for TLG2.5 was 1841. Four-year EFS was 92% for RER/TLG2.5  up to 1841, 60% for RER/TLG2.5  greater than 1841, 74% for SER/TLG2.5  up to 1841 and 79% for SER/TLG2.5  greater than 1841. Second EFS for RER/TLG2.5  up to 1841 was 100%. Thus, RERs with a low baseline TLG2.5 experienced excellent EFS with less intensive therapy, whereas RERs with a high baseline TLG2.5 experienced poor EFS. These findings suggest that patients with a high upfront tumour burden may benefit from intensified therapy, even if they achieve a RER.

An Analysis of Major Target Deviations in Craniospinal Irradiation Treatment Plans for Patients With Intermediate-Risk Medulloblastoma Within a Phase 3 Clinical Trial (Children's Oncology Group Study ACNS0331).

Purpose: Craniospinal irradiation remains an essential and yet difficult part of the treatment of patients with medulloblastoma. Whereas technological advances offer promise of increased conformity, realiance on advanced technology is not without risk, and it remains critical to carefully delineate targets. We describe examples of target deviations (TDs) in craniospinal irradiation treatment plans for postoperative patients with medulloblastoma in a phase 3 clinical trial (ACNS 0331). Methods and Materials: The principal investigator independently performed a review of the treatment plans and portal films of enrolled patients and evaluated the plans for TDs. TDs of dose, dose uniformity, and volume were defined as major or minor deviations. Major TDs scored as protocol violations. The effect of major TDs on event-free survival (EFS) and overall survival (OS) was evaluated using the stratified Cox proportional hazards model. Results: Of the 549 patients enrolled, 461 were available for this analysis. Thirty-two (7%) plans did not have data sufficient for TD evaluation. Major TDs were found in 32 of the 461 plans (7%). Of those, 21 were deviations of target volume alone, 7 were deviations of target dose alone, and 4 were deviations of both target volume and dose. The 25 patients with TDs of volume involved 29 sites. The most common major TDs of volume involved the brain (9 of 29) and the posterior fossa (9 of 29). On Cox proportional hazards modeling, the presence of a major TD did not statistically significantly affect EFS (hazard ratio, 0.98; 95% confidence interval, 0.45-2.11; P = .9541) or OS (hazard ratio, 1.10; 95% confidence interval, 0.51-2.38; P = .8113). Conclusions: Although intensity modulated radiation therapy and proton therapy are promising in improving conformity and sparing organs at risk, technology does not substitute for careful anatomic definition of target volumes. The study was not powered to evaluate the effect of TDs on EFS and OS; therefore, the statistical analysis presented in this study must be interpreted with caution.

Targeted radiotherapy for early-stage, low-risk pediatric Hodgkin lymphoma slow early responders: a COG AHOD0431 analysis.

Children's Oncology Group (COG) trial AHOD0431 reduced systemic therapy and used response-adapted involved-field radiotherapy (IFRT) in early-stage pediatric classic Hodgkin lymphoma. We investigated the impact of positron emission tomographic response after 1 cycle (PET1) and on IFRT outcomes and pattern of relapse. Patients in AHOD0431 underwent PET1 response assessment after AVPC (doxorubicin, vincristine, prednisone, and cyclophosphamide). "Rapid early responders" (RERs) had a negative PET1 (PET1-); "slow early responders" (SERs) had a positive PET1 (PET1+). Patients with a partial response by computed tomographic and functional imaging after 3 chemotherapy cycles received 21-Gy IFRT, whereas complete responders had no IFRT. Progression-free survival (PFS) was evaluated for RERs and SERs treated with or without IFRT. Recurrence sites were initial, new, or both. Relapses involving initial sites were characterized as "within the PET1+ site" or "initially involved but outside the PET1+ site." Median follow-up was 118 months. The 10-year PFS rate among RERs was 96.6% with IFRT and 84.1% without IFRT (P = .10), whereas SERs were 80.9% with IFRT and 64.0% without IFRT (P = .03). Among 90 RERs who did not receive IFRT, all 14 relapses included an initial site. Among 45 SERs receiving no IFRT, 14 of 16 relapses were in the initial site (9 PET1+ site only). Among 58 patients receiving IFRT, 5 of 10 relapses were in the PET1+ site. After 3 cycles of AVPC alone, RERs showed favorable results. Conversely, SERs had unfavorable outcomes with AVPC alone, although they improved with 21-Gy IFRT. RT remains an important component of treatment for SERs. This trial was registered at www.clinicaltrials.gov as #NCT00302003.

Prognostic value of baseline metabolic tumor volume in children and adolescents with intermediate-risk Hodgkin lymphoma treated with chemo-radiation therapy: FDG-PET parameter analysis in a subgroup from COG AHOD0031.

BACKGROUND: Positron emission tomography (PET)-based measures of baseline total-body tumor burden may improve risk stratification in intermediate-risk Hodgkin lymphoma (HL). MATERIALS AND METHODS: Evaluable patients were identified from a cohort treated homogeneously with the same combined modality regimen on the Children's Oncology Group AHOD0031 study. Eligible patients had high-quality baseline PET scans. Metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were each measured based on 15 thresholds for every patient. Univariate and multivariable Cox regression and Kaplan-Meier survival analyses assessed for an association of MTV and TLG with event-free survival (EFS). RESULTS: From the AHOD0031 cohort (n = 1712), 86 patients were identified who (i) were treated with four cycles of doxorubicin, bleomycin, vincristine, etoposide, prednisone, cyclophosphamide (ABVE-PC) chemotherapy followed by involved field radiotherapy, and (ii) had a baseline PET scan that was amenable to quantitative analysis. Based on univariate Cox regression analysis, six PET-derived parameters were significantly associated with EFS. For each of these, Kaplan-Meier analyses and the log-rank test were used to compare patients with highest tumor burden (i.e., highest 15%) to the remainder of the cohort. EFS was significantly associated with all six PET parameters (all p < .029). In a multivariable model controlling for important covariates including disease bulk and response to chemotherapy, MTV2BP was significantly associated with EFS (p = .012). CONCLUSION: Multiple baseline PET-derived volumetric parameters were associated with EFS. MTV2BP was highly associated with EFS when controlling for disease bulk and response to chemotherapy. Incorporation of baseline MTV into risk-based treatment algorithms may improve outcomes in intermediate-risk HL.

Automated quantification of baseline imaging PET metrics on FDG PET/CT images of pediatric Hodgkin lymphoma patients.

PURPOSE: For pediatric lymphoma, quantitative FDG PET/CT imaging features such as metabolic tumor volume (MTV) are important for prognosis and risk stratification strategies. However, feature extraction is difficult and time-consuming in cases of high disease burden. The purpose of this study was to fully automate the measurement of PET imaging features in PET/CT images of pediatric lymphoma. METHODS: 18F-FDG PET/CT baseline images of 100 pediatric Hodgkin lymphoma patients were retrospectively analyzed. Two nuclear medicine physicians identified and segmented FDG avid disease using PET thresholding methods. Both PET and CT images were used as inputs to a three-dimensional patch-based, multi-resolution pathway convolutional neural network architecture, DeepMedic. The model was trained to replicate physician segmentations using an ensemble of three networks trained with 5-fold cross-validation. The maximum SUV (SUVmax), MTV, total lesion glycolysis (TLG), surface-area-to-volume ratio (SA/MTV), and a measure of disease spread (Dmaxpatient) were extracted from the model output. Pearson's correlation coefficient and relative percent differences were calculated between automated and physician-extracted features. RESULTS: Median Dice similarity coefficient of patient contours between automated and physician contours was 0.86 (IQR 0.78-0.91). Automated SUVmax values matched exactly the physician determined values in 81/100 cases, with Pearson's correlation coefficient (R) of 0.95. Automated MTV was strongly correlated with physician MTV (R = 0.88), though it was slightly underestimated with a median (IQR) relative difference of - 4.3% (- 10.0-5.7%). Agreement of TLG was excellent (R = 0.94), with median (IQR) relative difference of - 0.4% (- 5.2-7.0%). Median relative percent differences were 6.8% (R = 0.91; IQR 1.6-4.3%) for SA/MTV, and 4.5% (R = 0.51; IQR - 7.5-40.9%) for Dmaxpatient, which was the most difficult feature to quantify automatically. CONCLUSIONS: An automated method using an ensemble of multi-resolution pathway 3D CNNs was able to quantify PET imaging features of lymphoma on baseline FDG PET/CT images with excellent agreement to reference physician PET segmentation. Automated methods with faster throughput for PET quantitation, such as MTV and TLG, show promise in more accessible clinical and research applications.

Pathological response in children and adults with large unresected intermediate-grade or high-grade soft tissue sarcoma receiving preoperative chemoradiotherapy with or without pazopanib (ARST1321): a multicentre, randomised, open-label, phase 2 trial.

BACKGROUND: Outcomes for children and adults with advanced soft tissue sarcoma are poor with traditional therapy. We investigated whether the addition of pazopanib to preoperative chemoradiotherapy would improve pathological near complete response rate compared with chemoradiotherapy alone. METHODS: In this joint Children's Oncology Group and NRG Oncology multicentre, randomised, open-label, phase 2 trial, we enrolled eligible adults (aged ≥18 years) and children (aged between 2 and <18 years) from 57 hospitals in the USA and Canada with unresected, newly diagnosed trunk or extremity chemotherapy-sensitive soft tissue sarcoma, which were larger than 5 cm in diameter and of intermediate or high grade. Eligible patients had Lansky (if aged ≤16 years) or Karnofsky (if aged >16 years) performance status score of at least 70. Patients received ifosfamide (2·5 g/m2 per dose intravenously on days 1-3 with mesna) and doxorubicin (37·5 mg/m2 per dose intravenously on days 1-2) with 45 Gy preoperative radiotherapy, followed by surgical resection at week 13. Patients were randomly assigned (1:1) using a web-based system, in an unmasked manner, to receive oral pazopanib (if patients <18 years 350 mg/m2 once daily; if patients ≥18 years 600 mg once daily) or not (control group), with pazopanib not given immediately before or after surgery at week 13. The study projected 100 randomly assigned patients were needed to show an improvement in the number of participants with a 90% or higher pathological response at week 13 from 40% to 60%. Analysis was done per protocol. This study has completed accrual and is registered with ClinicalTrials.gov, NCT02180867. FINDINGS: Between July 7, 2014, and Oct 1, 2018, 81 eligible patients were enrolled and randomly assigned to the pazopanib group (n=42) or the control group (n=39). At the planned second interim analysis with 42 evaluable patients and a median follow-up of 0·8 years (IQR 0·3-1·6) in the pazopanib group and 1 year (0·3-1·6) in the control group, the number of patients with a 90% pathological response or higher was 14 (58%) of 24 patients in the pazopanib group and four (22%) of 18 patients in the control group, with a between-group difference in the number of 90% or higher pathological response of 36·1% (83·8% CI 16·5-55·8). On the basis of an interim analysis significance level of 0·081 (overall one-sided significance level of 0·20, power of 0·80, and O'Brien-Fleming-type cumulative error spending function), the 83·8% CI for response difference was between 16·5% and 55·8% and thus excluded 0. The improvement in pathological response rate with the addition of pazopanib crossed the predetermined boundary and enrolment was stopped. The most common grade 3-4 adverse events were leukopenia (16 [43%] of 37 patients), neutropenia (15 [41%]), and febrile neutropenia (15 [41%]) in the pazopanib group, and neutropenia (three [9%] of 35 patients) and febrile neutropenia (three [9%]) in the control group. 22 (59%) of 37 patients in the pazopanib group had a pazopanib-related serious adverse event. Paediatric and adult patients had a similar number of grade 3 and 4 toxicity. There were seven deaths (three in the pazopanib group and four in the control group), none of which were treatment related. INTERPRETATION: In this presumed first prospective trial of soft tissue sarcoma spanning nearly the entire age spectrum, adding pazopanib to neoadjuvant chemoradiotherapy improved the rate of pathological near complete response, suggesting that this is a highly active and feasible combination in children and adults with advanced soft tissue sarcoma. The comparison of survival outcomes requires longer follow-up. FUNDING: National Institutes of Health, St Baldrick's Foundation, Seattle Children's Foundation.

Higher Reported Lung Dose Received During Total Body Irradiation for Allogeneic Hematopoietic Stem Cell Transplantation in Children With Acute Lymphoblastic Leukemia Is Associated With Inferior Survival: A Report from the Children's Oncology Group.

PURPOSE: To examine the relationship between lung radiation dose and survival outcomes in children undergoing total body irradiation (TBI)-based hematopoietic stem cell transplantation (HSCT) for acute lymphoblastic leukemia on the Children's Oncology Group trial. METHODS AND MATERIALS: TBI (1200 or 1320 cGy given twice daily in 6 or 8 fractions) was used as part of 3 HSCT preparative regimens, allowing institutional flexibility regarding TBI techniques, including lung shielding. Lung doses as reported by each participating institution were calculated for different patient setups, with and without shielding, with a variety of dose calculation techniques. The association between lung dose and transplant-related mortality, relapse-free survival, and overall survival (OS) was examined using the Cox proportional hazards regression model controlling for the following variables: TBI dose rate, TBI fields, patient position during TBI, donor type, and pre-HSCT minimal residual disease level. RESULTS: Of a total of 143 eligible patients, 127 had lung doses available for this analysis. The TBI techniques were heterogeneous. The mean lung dose was reported as 904.5 cGy (standard deviation, ±232.3). Patients treated with lateral fields were more likely to receive lung doses ≥800 cGy (P < .001). The influence of lung dose ≥800 cGy on transplant-related mortality was not significant (hazard ratio [HR], 1.78; P = .21). On univariate analysis, lung dose ≥800 cGy was associated with inferior relapse-free survival (HR, 1.76; P = .04) and OS (HR, 1.85; P = .03). In the multivariate analysis, OS maintained statistical significance (HR, 1.85; P = .04). CONCLUSIONS: The variability in TBI techniques resulted in uncertainty with reported lung doses. Lateral fields were associated with higher lung dose, and thus they should be avoided. Patients treated with lung dose <800 cGy in this study had better outcomes. This approach is currently being investigated in the Children's Oncology Group AALL1331 study. Additionally, the Imaging and Radiation Oncology Core Group is evaluating effects of TBI techniques on lung doses using a phantom.

Conformal Radiation Therapy for Pediatric Patients with Low-Grade Glioma: Results from the Children's Oncology Group Phase 2 Study ACNS0221.

PURPOSE: To determine the rate of marginal relapse, progression-free survival (PFS), and overall survival (OS) in patients with pediatric low-grade glioma (PLGG) treated with conformal radiation therapy (CRT) with a clinical target volume (CTV) margin of 5 mm in the Children's Oncology Group trial ACNS0221. METHODS AND MATERIALS: Patients aged 3 to 21 years with unresectable progressive, recurrent, or residual PLGG were eligible for this study. Patients younger than 10 years were required to have received at least 1 chemotherapy course. Patients with neurofibromatosis type I were not eligible. All patients underwent magnetic resonance imaging-based planning and received 54 Gy CRT in 30 fractions with a 5-mm CTV margin. RESULTS: Of 85 eligible patients (median age, 13.6 years) treated between March 2006 and December 2010, 14 were younger than 10 years and 36 received prior chemotherapy. Sixty-six had pilocytic astrocytoma, 15 had other histologic subtypes, and 4 had unbiopsied chiasmatic lesions. Events included 23 relapses (19 central, 4 distant, and no marginal) and 7 deaths. At a median follow-up of 5.15 years, 5-year PFS was 71% ± 6% and OS was 93% ± 4%. Male sex (P = .068) and large tumor size (P = .050) trended toward significance for association with decreased PFS. Age, histology, tumor location, time between diagnosis and study entry, and MIB-1 status were not associated with PFS. OS was negatively associated with male sex (P = .064), non-pilocytic astrocytoma histology (P = .010), and large tumor size (P = .0089). CONCLUSIONS: For patients with PLGG, CRT with a CTV margin of 5 mm yields an acceptable PFS and does not lead to a high rate of marginal relapse.

Preoperative Intensity Modulated Radiation Therapy Compared to Three-Dimensional Conformal Radiation Therapy for High-Grade Extremity Sarcomas in Children: Analysis of the Children's Oncology Group Study ARST0332.

PURPOSE: For pediatric patients with large, high-grade, extremity nonrhabdomyosarcoma soft-tissue sarcomas, preoperative radiation therapy (RT) provides the opportunity for smaller radiation fields and tumor shrinkage resulting in less extensive surgery. The potential disadvantage is an increased risk of wound complications after surgery compared with rates after postoperative chemoradiation. We assessed the impact of preoperative RT technique on target coverage in relationship to dose to skin and adjacent joints to determine whether acute wound complications and late musculoskeletal injury might be influenced by treatment technique. METHODS AND MATERIALS: Of 550 eligible patients <30 years of age, 200 were enrolled in arm D of ARST0332 and received neoadjuvant ifosfamide/doxorubicin, then chemoradiotherapy (45 Gy and ifosfamide) and surgery followed by postoperative RT if gross or microscopic positive surgical margins. One-hundred thirteen patients had extremity nonrhabdomyosarcoma soft-tissue sarcomas, of which 56 patients had preoperative RT plans for digital review. The doses to the target volume, skin (surface to 5 mm depth), adjacent joint, and extremity diameter were analyzed with respect to RT technique. RESULTS: Thirty-eight patients (65%) received 3-dimensional conformal RT (3D-CRT) and 18 (32%) received intensity modulated RT (IMRT). There was no difference in clinical target volume (CTV) size between groups (P = .920); however, IMRT plans had improved CTV coverage to 100% of the prescription dose compared with 3D-CRT plans (median CTV coverage, 92.7% vs 98.6%; P = .011). In patients without target overlap with the skin, IMRT use was associated with reduced percent volume of skin receiving 45 Gy or more (V45Gy) compared with 3D-CRT (median, 1.6% vs 6.3%, respectively; P = .005). IMRT was also associated with reduced V45Gy to the adjacent joint compared with 3D-CRT (median, 1.1% vs 13.2%; P = .018). CONCLUSIONS: Preoperative IMRT may improve CTV coverage and reduce the volume of skin and adjacent joint treated to high doses. Future studies should assess whether these dosimetric findings produce differences in clinical and toxicity outcomes.

Cardiac-Sparing Whole Lung IMRT in Patients With Pediatric Tumors and Lung Metastasis: Final Report of a Prospective Multicenter Clinical Trial.

PURPOSE: A prospective clinical trial was conducted for patients undergoing cardiac sparing (CS) whole lung irradiation (WLI) using intensity modulated radiation therapy (IMRT). The 3 trial aims were (1) to demonstrate the feasibility of CS IMRT with real-time central quality control; (2) to determine the dosimetric advantages of WLI using IMRT compared with standard anteroposterior (AP) techniques; and (3) to determine acute tolerance and short-term efficacy after a protocol-mandated minimum 2-year follow-up for all patients. METHODS AND MATERIALS: All patients underwent a 3-dimensional chest computed tomography scan and a contrast-enhanced 4-dimensional (4D) gated chest computed tomography scan using a standard gating device. The clinical target volume was the entire bilateral 3-dimensional lung volume, and the internal target volume was the 4D minimum intensity projection of both lungs. The internal target volume was expanded by 1 cm to get the planning target volume. All target volumes, cardiac contours, and treatment plans were centrally reviewed before treatment. The different cardiac volumes receiving percentages of prescribed radiation therapy (RT) doses on AP and IMRT WLI plans were estimated and compared. RESULTS: The target 20 patients were accrued in 2 years. Median RT dose was 15 Gy. Real-time central quality assurance review and plan preapproval were obtained for all patients. WLI using IMRT was feasible in all patients. Compared with standard AP WLI, CS IMRT resulted in a statistically significant reduction in radiation doses to the whole heart, atria, ventricles, and coronaries. One child developed cardiac dysfunction and pulmonary restrictive disease 5.5 years after CS IMRT (15 Gy) and doxorubicin (375 mg/m2). The 2- and 3-year lung metastasis progression-free survival was 65% and 52%, respectively. CONCLUSIONS: We have demonstrated the feasibility of WLI using CS IMRT and confirmed the previously reported advantages of IMRT, including superior cardiac protection and superior dose coverage of 4D lung volumes. Further studies are required to establish the efficacy and safety of this irradiation technique.

Patterns of Involved-Field Radiation Therapy Protocol Deviations in Pediatric Versus Adolescent and Young Adults With Hodgkin Lymphoma: A Report From the Children's Oncology Group AHOD0031.

PURPOSE: The presented protocol for pediatric intermediate-risk Hodgkin lymphoma evaluated the use of a dose-intensive chemotherapy regimen (ABVE-PC [doxorubicin, bleomycin, vincristine, etoposide, cyclophosphamide, prednisone]) with response-based therapy augmentation (addition of DECA [dexamethasone, etoposide, cisplatin, cytarabine]) or therapy reduction (elimination of radiation). METHODS AND MATERIALS: A central review of the radiation therapy data for quality assurance was performed, and the association between radiation protocol deviation (RPD) and relapse was assessed in the pediatric group (age <15 years) and adolescent and young adult (AYA) group (age ≥15-21 years). Involved-field radiation therapy (IFRT) planning was reviewed before the start of treatment and at treatment completion. The records were reviewed through the Quality Assurance Review Center's central review to identify RPD, classified according to dose deviation (DD), volume deviation (VD), undertreatment (UT), and overtreatment (OT). DDs and VDs were further classified as major or minor. RESULTS: Of the 1712 patients enrolled, 1155 received IFRT, of whom, 216 (18.7%) had RPDs. The DD and VD patterns were similar between the pediatric and AYA groups. Minor VDs were most common. UT RPDs accounted for 69% in the pediatric group and 75% in the AYA group. Of the 35 patients with relapse and a RPD, 29 had an undertreatment RPD. Among the patients who received IFRT, a significant difference was found in the cumulative incidence rates of relapse between the pediatric and AYA groups (P = .03); however, no significant difference was found between patients with and without RPD (P = .2). CONCLUSIONS: Most RPDs were minor and consisted of UT in the AYA and pediatric populations both. No difference was observed in RPDs between the pediatric and AYA patients. Thus, in a well-defined and standardized protocol, the RPD distributions for AYA patients will be similar to those for pediatric population. However, the increased cumulative incidence of relapse in the AYA patients who had received IFRT compared with the pediatric population requires further exploration, given the potential differences in clinical outcomes in the AYA population.

Radiotherapy quality assurance report from children's oncology group AHOD0031.

PURPOSE: A phase 3 trial assessing response-based therapy in intermediate-risk Hodgkin lymphoma mandated real-time central review of involved field radiation therapy (IFRT) and imaging records by a centralized review center to maximize protocol compliance. We report the impact of centralized radiation therapy review on protocol compliance. METHODS AND MATERIALS: Review of simulation films, port films, and dosimetry records was required before and after treatment. Records were reviewed by study-affiliated or review center-affiliated radiation oncologists. A deviation of 6% to 10% from protocol-specified dose was scored as "minor"; a deviation of >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 radiation therapy case and compared. RESULTS: Of 1712 patients enrolled, 1173 underwent IFRT at 256 institutions in 7 countries. An interventional review was performed in 88% of patients and a final review in 98%. Overall, minor and major deviations were found in 12% and 6% of patients, respectively. Among the cases for which ≥1 pre-IFRT modification was requested by the Quality Assurance Review Center and subsequently made by the treating institution, 100% were made compliant on final review. By contrast, among the cases for which ≥1 modification was requested but not made by the treating institution, 10% were deemed compliant on final review. CONCLUSIONS: In a large trial with complex treatment pathways and heterogeneous radiation therapy fields, central review was performed in a large percentage of cases before IFRT and identified frequent potential deviations in a timely manner. When suggested modifications were performed by the institutions, deviations were almost eliminated.

Patterns of relapse from a phase 3 Study of response-based therapy for intermediate-risk Hodgkin lymphoma (AHOD0031): a report from the Children's Oncology Group.

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. PATIENTS AND METHODS: From September 2002 to July 2010, 1712 patients <22 years old with stage I-IIA with bulk, I-IIAE, I-IIB, and IIIA-IVA with or without doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide 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). The SER patients were randomized to 2 additional ABVE-PC cycles or augmented chemotherapy with 21 Gy involved field radiation therapy (IFRT). RER patients were stipulated to undergo 2 additional ABVE-PC cycles and were then randomized to 21 Gy IFRT or no further treatment if complete response (CR) was achieved. RER without CR patients were non-randomly assigned to 21 Gy IFRT. Relapses were characterized without respect to site (initial, new, or both; and initial bulk or initial nonbulk), and involved field radiation therapy 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 experienced relapse, 198 of whom were fully evaluable for review. Those who progressed during treatment (n=30) or lacked relapse imaging (n=16) were excluded. The median time to relapse was 12.8 months. Of the 198 evaluable patients, 30% were RER/no CR, 26% were SER, 26% were RER/CR/no IFRT, 16% were RER/CR/IFRT, and 2% remained uncategorized. The 74% and 75% relapses involved initially bulky and nonbulky sites, respectively. First relapses rarely occurred at exclusively new or out-of-field sites. By contrast, relapses usually occurred at nodal sites of initial bulky and nonbulky disease. CONCLUSION: Although response-based therapy has helped define treatment for selected RER patients, it has not improved outcome for SER patients or facilitated refinement of IFRT volumes or doses.