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.

Next Steps: Survivor Healthcare Passport - A Novel Form of Survivorship Care Plan in the Pediatric Population.

PURPOSE: Survivorship care plans (SCPs) have been instrumental in aiding transition from cancer treatment to survivorship care, which contains the diagnosis, treatment, potential late effects, and recommended follow-up. There has been paucity of research on its efficacy and lack of guidelines on development and delivery of SCPs. The Next Steps Survivorship Clinic at Children's Wisconsin uses a Survivorship Healthcare Passport (SHP), a SCP pocket-sized card. This study aims to improve understanding of patient and parent use of the SHP at a single institution. MATERIALS AND METHODS: An electronic survey was distributed to cancer survivors (14 to 28 y old) and parents/guardians who received the SCP. Data was analyzed with descriptive and correlation statistics. RESULTS: Older survivors were reliable in carrying their SHP, and endorsed greater confidence in understanding its contents leading to a notion of improved ability to coordinate care. Younger survivors tend to rely on their parents. A preference for a smartphone application as another platform was noted. CONCLUSIONS: This form of SCP has shown to benefit older survivors which directly impacts the notion of efficacy in care coordination. IMPLICATION FOR CANCER SURVIVORS: Providing easy-to-access information may encourage survivors to advocate for their health and to facilitate transition of care.

Dexrazoxane and Long-Term Heart Function in Survivors of Childhood Cancer.

PURPOSE: For survivors of childhood cancer treated with doxorubicin, dexrazoxane is cardioprotective for at least 5 years. However, longer-term data are lacking. METHODS: Within the Children's Oncology Group and the Dana Farber Cancer Institute's Childhood Acute Lymphoblastic Leukemia Consortium, we evaluated four randomized trials of children with acute lymphoblastic leukemia or Hodgkin lymphoma, who received doxorubicin with or without dexrazoxane, and a nonrandomized trial of patients with osteosarcoma who all received doxorubicin with dexrazoxane. Cumulative doxorubicin doses ranged from 100 to 600 mg/m2 across these five trials, and dexrazoxane was administered uniformly (10:1 mg/m2 ratio) as an intravenous bolus before doxorubicin. Cardiac function was prospectively assessed in survivors from these trials, plus a matched group of survivors of osteosarcoma treated with doxorubicin without dexrazoxane. Two-dimensional echocardiograms and blood biomarkers were analyzed centrally in blinded fashion. Multivariate analyses adjusted for demographic characteristics, cumulative doxorubicin dose, and chest radiotherapy determined the differences and associations by dexrazoxane status. RESULTS: From 49 participating institutions, 195 participants were assessed at 18.1 ± 2.7 years since cancer diagnosis (51% dexrazoxane-exposed; cumulative doxorubicin dose 297 ± 91 mg/m2). Dexrazoxane administration was associated with superior left ventricular fractional shortening (absolute difference, +1.4% [95% CI, 0.3 to 2.5]) and ejection fraction (absolute difference, +1.6% [95% CI, 0.0 to 3.2]), and lower myocardial stress per B-type natriuretic peptide (-6.7 pg/mL [95% CI, -10.6 to -2.8]). Dexrazoxane was associated with a reduced risk of having lower left ventricular function (fractional shortening < 30% or ejection fraction < 50%; odds ratio, 0.24 [95% CI, 0.07 to 0.81]). This protective association was primarily seen in those treated with cumulative doxorubicin doses ≥ 250 mg/m2. CONCLUSION: Among young adult-aged survivors of childhood cancer, dexrazoxane was associated with a cardioprotective effect nearly 20 years after initial anthracycline exposure.

Post-Traumatic Stress Symptoms in Adolescent Hodgkin Lymphoma Survivors: A Report from Children's Oncology Group AHOD0031.

Purpose: The intrusive thoughts of cancer diagnosis, treatments, re-experiencing, and avoidance associated with post-traumatic stress symptoms (PTSS) can negatively affect Hodgkin lymphoma (HL) survivors. This study investigates the associations between experiences and beliefs and PTSS among adolescent survivors of intermediate-risk HL treated on the Children's Oncology Group (COG) AHOD0031 study. Methods: COG AHOD0031 participants completed self-report surveys at end of therapy concerning post-treatment medical conditions, activity limitations, fatigue, future concerns, exercise, and PTSS. Results: One thousand one hundred ten of 1721 participants in AHOD0031 completed the first survey at a median of 6.7 months post-diagnosis (interquartile range: 5.3-11.5 months), and of these, 736 (66.3%) completed a second survey at a median of 12.4 (10.1-17.6) months following the first. The mean PTSS score (ranging from 0 to 20) was 5.5 (standard deviation [SD] = 5.1) on survey 1 and 4.4 (SD = 4.8) on survey 2. Increased fatigue (odds ratio [OR] = 1.14, p < 0.01), concerns for the future (OR = 1.13, p < 0.01), activity limitations (OR = 1.05, p < 0.01), and relapse history (OR = 2.18, p < 0.05) were associated with higher PTSS scores in the initial survey. Increased fatigue (OR = 1.16, p < 0.01), concerns for the future (OR = 1.14, p < 0.01), activity limitations (OR = 1.05, p < 0.05), and higher PTSS scores on the first survey (OR = 1.19, p < 0.01) were associated with higher PTSS scores in the subsequent survey. Longer time since diagnosis (OR = 0.85, p < 0.05; OR = 0.84, p < 0.05) was associated with lower PTSS scores on both surveys. Conclusions: Based on our findings, future research should examine the onset and trajectory of PTSS among HL survivors, focusing on early recognition and intervention to improve quality of life.

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.

A gene expression-based model predicts outcome in children with intermediate-risk classical Hodgkin lymphoma.

Classical Hodgkin lymphoma (cHL) is a common malignancy in children and adolescents. Although cHL is highly curable, treatment with chemotherapy and radiation often come at the cost of long-term toxicity and morbidity. Effective risk-stratification tools are needed to tailor therapy. Here, we used gene expression profiling (GEP) to investigate tumor microenvironment (TME) biology, to determine molecular correlates of treatment failure, and to develop an outcome model prognostic for pediatric cHL. A total of 246 formalin-fixed, paraffin-embedded tissue biopsies from patients enrolled in the Children's Oncology Group trial AHOD0031 were used for GEP and compared with adult cHL data. Eosinophil, B-cell, and mast cell signatures were enriched in children, whereas macrophage and stromal signatures were more prominent in adults. Concordantly, a previously published model for overall survival prediction in adult cHL did not validate in pediatric cHL. Therefore, we developed a 9-cellular component model reflecting TME composition to predict event-free survival (EFS). In an independent validation cohort, we observed a significant difference in weighted 5-year EFS between high-risk and low-risk groups (75.2% vs 90.3%; log-rank P = .0138) independent of interim response, stage, fever, and albumin. We demonstrate unique disease biology in children and adolescents that can be harnessed for risk-stratification at diagnosis. This trial was registered at www.clinicaltrials.gov as #NCT00025259.

Late health outcomes after dexrazoxane treatment: A report from the Children's Oncology Group.

BACKGROUND: The objective of this study was to examine long-term outcomes among children newly diagnosed with cancer who were treated in dexrazoxane-containing clinical trials. METHODS: P9404 (acute lymphoblastic leukemia/lymphoma [ALL]), P9425 and P9426 (Hodgkin lymphoma), P9754 (osteosarcoma), and Dana-Farber Cancer Institute 95-01 (ALL) enrolled 1308 patients between 1996 and 2001: 1066 were randomized (1:1) to doxorubicin with or without dexrazoxane, and 242 (from P9754) were nonrandomly assigned to receive dexrazoxane. Trial data were linked with the National Death Index, the Organ Procurement and Transplantation Network, the Pediatric Health Information System (PHIS), and Medicaid. Osteosarcoma survivors from the Childhood Cancer Survivor Study (CCSS; n = 495; no dexrazoxane) served as comparators in subanalyses. Follow-up events were assessed with cumulative incidence, Cox regression, and Fine-Gray methods. RESULTS: In randomized trials (cumulative prescribed doxorubicin dose, 100-360 mg/m2 ; median follow-up, 18.6 years), dexrazoxane was not associated with relapse (hazard ratio [HR], 0.84; 95% confidence interval [CI], 0.63-1.13), second cancers (HR, 1.19; 95% CI, 0.62-2.30), all-cause mortality (HR, 1.07; 95% CI, 0.78-1.47), or cardiovascular mortality (HR, 1.45; 95% CI, 0.41-5.16). Among P9754 patients (all exposed to dexrazoxane; cumulative doxorubicin, 450-600 mg/m2 ; median follow-up, 16.6-18.4 years), no cardiovascular deaths or heart transplantation occurred. The 20-year heart transplantation rate among CCSS osteosarcoma survivors (mean doxorubicin, 377 ± 145 mg/m2 ) was 1.6% (vs 0% in P9754; P = .13). Among randomized patients, serious cardiovascular outcomes (cardiomyopathy, ischemic heart disease, and stroke) ascertained by PHIS/Medicaid occurred less commonly with dexrazoxane (5.6%) than without it (17.6%; P = .02), although cardiomyopathy rates alone did not differ (4.4% vs 8.1%; P = .35). CONCLUSIONS: Dexrazoxane did not appear to adversely affect long-term mortality, event-free survival, or second cancer risk.

Cardiometabolic Risk in Childhood Cancer Survivors: A Report from the Children's Oncology Group.

BACKGROUND: Childhood cancer survivors are at risk for cardiovascular disease. We assessed the burden of potentially modifiable cardiometabolic risk factors (CRF) among survivors compared with population-matched controls. METHODS: Survivors previously enrolled on Pediatric Oncology Group protocols 9404, 9425, 9426, 9754, and Dana-Farber Cancer Institute 95-01 from 1996 to 2001 with acute lymphoblastic leukemia/lymphoma, Hodgkin lymphoma, or osteosarcoma were prospectively assessed for the prevalence of CRFs and compared with an age, sex, and race/ethnicity-matched 2013 National Health and Nutrition Examination Survey (NHANES) population. We estimated future predicted cardiovascular risk based on general population (e.g., Framingham) and Childhood Cancer Survivor Study (CCSS) models. RESULTS: Compared with NHANES (n = 584), survivors [n = 164; 44.5% female, median age 28 years (range, 16-38 years); median 17.4 years (range, 13-22 years) since cancer diagnosis; median doxorubicin dose 300 mg/m2; 30.5% chest radiation] had similar rates of obesity, diabetes, and dyslipidemia, but more prehypertension/hypertension (38.4% vs. 30.1%, P = 0.044). Survivors had fewer metabolic syndrome features compared with NHANES (≥2 features: 26.7% vs. 55.9%; P < 0.001). Survivors were more physically active and smoked tobacco less (both P < 0.0001). Therefore, general population cardiovascular risk scores were lower for survivors versus NHANES. However, with CCSS models, 30.5% of survivors were at moderate risk of ischemic heart disease, and >95% at moderate/high risk for heart failure, with a 9% to 12% predicted incidence of these conditions by age 50 years. CONCLUSIONS: Childhood cancer survivors exhibited similar or better cardiometabolic and lifestyle profiles compared with NHANES, but nonetheless are at risk for future clinically significant cardiovascular disease. IMPACT: Further strategies supporting optimal CRF control are warranted in survivors. See related commentary by Mulrooney, p. 515.

Survival by age in paediatric and adolescent patients with Hodgkin lymphoma: a retrospective pooled analysis of children's oncology group trials.

BACKGROUND: Adolescents with Hodgkin lymphoma have worse disease outcomes than children. Whether these differences persist within clinical trials is unknown. We examined survival, by age, in patients receiving response-adapted therapy for Hodgkin lymphoma on Children's Oncology Group (COG) trials. METHODS: Patients (aged 1-21 years) diagnosed with classical Hodgkin lymphoma and enrolled between Sept 23, 2002, and Jan 19, 2012, on one of three phase 3 COG trials in the USA and Canada were eligible for inclusion. The three COG trials were defined by risk group according to Ann Arbor stage, B-symptoms, and bulk (AHOD0431 [low risk; NCT00302003], AHOD0031 [intermediate risk; NCT00025259], or AHOD0831 [high risk; NCT01026220]). The outcomes of this study were event-free survival (death, relapse, or subsequent neoplasm) and overall survival. Cox proportional hazards models estimated survival, adjusting for disease and treatment factors both overall and in patients with mixed cellularity or non-mixed cellularity (nodular sclerosing and not-otherwise-specified) disease. FINDINGS: Of 2155 patients enrolled on the three trials, 1907 (88·4%; 968 [50·8%] male and 939 [49·2%] female; 1227 [64·3%] non-Hispanic White) were included in this analysis. After a median follow-up of 7·4 years (IQR 4·3-10·2), older patients (aged ≥15 years) had worse unadjusted 5-year event-free survival (80% [95% CI 78-83]) than did younger patients (aged <15 years; 86% [83-88]; HR 1·38 [1·11-1·71]; p=0·0038). Older patients also had worse unadjusted 5-year overall survival than did younger patients (96% [95% CI 95-97] vs 99% [98-99]; HR 2·50 [1·41-4·45]; p=0·0012). In patients with non-mixed cellularity histology, older patients had a significantly increased risk of having an event than did younger patients with the same histology (HR 1·32 [1·03-1·68]; p=0·027). Older patients with mixed cellularity had significantly worse 5-year event-free survival than did younger patients in unadjusted (77% [95% CI 65-86] for older patients vs 94% [88-97] for younger patients; HR 2·93 [1·37-6·29]; p=0·0039) and multivariable models (HR 3·72 [1·56-8·91]; p=0·0032). Overall, older patients were more likely to die than younger patients (HR 3·08 [1·49-6·39]; p=0·0025). INTERPRETATION: Adolescents (≥15 years) treated on COG Hodgkin lymphoma trials had worse event-free survival and increased risk of death compared with children (<15 years). Our findings highlight the need for prospective studies to examine tumour and host biology, and to test novel therapies across the age spectrum. FUNDING: National Institutes of Health, St Baldrick's Foundation, and Lymphoma Research Foundation.

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.

Pediatric classical Hodgkin lymphoma.

Over the past century, classical Hodgkin lymphoma (HL) has been transformed from a uniformly fatal disease to one of the most curable cancers. Given the high cure rate, a major focus of classical HL management is reducing the use of radiation therapy (RT) and chemotherapy agents such as procarbazine and doxorubicin to minimize long-term toxicities. In both North America and Europe, an important philosophy in the management of classical HL is to guide the intensity of treatment according to the risk category of the disease. The main factors used for risk classification are tumor stage, bulk of disease, and the presence of B symptoms. Response to chemotherapy is an important factor guiding the utilization of RT in ongoing Children's Oncology Group (COG) and European Network Pediatric Hodgkin Lymphoma (EuroNet-PHL) trials. Both trial groups have transitioned to reduced RT volumes that target the highest risk sites using highly conformal techniques, along with standard or intensified chemotherapy regimens to improve outcomes in higher risk patients. However, given the potential acute toxicities of intensified chemotherapy, immunoregulatory drugs are being investigated in upcoming trials. The purpose of this review is to summarize current approaches to treating pediatric classical HL according to the COG and EuroNet-PHL.

Subsequent malignant neoplasms among children with Hodgkin lymphoma: a report from the Children's Oncology Group.

Survivors of Hodgkin lymphoma (HL) have an increased risk of subsequent malignant neoplasms (SMNs). Response-adapted treatment may decrease this risk by reducing exposure to therapy associated with SMN risk. The Children's Oncology Group study AHOD0031 evaluated response-adapted therapy for children and adolescents with intermediate-risk HL. We report the SMNs among 1711 patients enrolled in AHOD0031. Patients were treated with 4 cycles of doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide with or without involved-field radiation therapy (RT). Patients with a slow early response to initial chemotherapy were randomized to 2 additional cycles of dexamethasone, etoposide, cisplatin and cytarabine or no additional chemotherapy, and all received RT. At a median follow-up of 7.3 years, an analysis of SMNs was performed. The 10-year cumulative incidence of SMN was 1.3% (95% confidence interval [CI], 0.6-2.0). SMNs included 3 patients with acute myeloid leukemia (AML), 11 with solid tumors, and 3 with non-Hodgkin lymphoma. Sixteen of 17 patients with an SMN had received combined modality therapy. The standardized incidence ratio for SMN was 9.5 (95% CI, 4.5-15.2) with an excess absolute risk of 1.2 per 1000 person-years. The cumulative incidence of SMNs was higher among patients who received RT (P = .037). In multivariate analysis, RT, B symptoms, and race were associated with SMN risk. Given the latency from exposure, we have likely captured all cases of secondary leukemia and myelodysplastic syndrome (MDS). Longer follow-up is needed to determine the risk of solid tumors. Avoidance of RT without sacrificing disease control should remain a goal for future therapeutic approaches. This trial was registered at www.clinicaltrials.gov as #NCT00025259.

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.

Survival by Race and Ethnicity in Pediatric and Adolescent Patients With Hodgkin Lymphoma: A Children's Oncology Group Study.

PURPOSE: Population-based studies of children and adolescents with Hodgkin lymphoma (HL) report a survival disadvantage in nonwhite-non-Hispanic black (NHB) and Hispanic-patients. Whether disparities persist after adjustment for clinical and treatment-related variables is unknown. We examined survival by race/ethnicity in children receiving risk-based, response-adapted, combined-modality therapy for HL in contemporary Children's Oncology Group trials. PATIENTS AND METHODS: This pooled analysis used individual-level data from 1,605 patients (younger than age 1 to 21 years) enrolled in phase III trials for low-risk (AHOD0431), intermediate-risk (AHOD0031), and high-risk (AHOD0831) HL from 2002 to 2012. Event-free survival (EFS) and overall survival (OS) were compared between non-Hispanic white (NHW) and nonwhite patients. Cox proportional hazards for survival were estimated for both de novo and relapsed HL, adjusting for demographics, disease characteristics, and therapy. RESULTS: At median follow up of 6.9 years, cumulative incidence of relapse was 17%. Unadjusted 5-year EFS and OS were 83% (SE, 1.2%) and 97% (SE, < 1%), respectively. Neither differed by race/ethnicity. In multivariable analyses for OS, nonwhite patients had a 1.88× higher hazard of death (95% CI, 1.1 to 3.3). Five-year postrelapse survival probabilities by race were as follows: NHW, 90%; NHB, 66%; and Hispanic, 80% (P < .01). Compared with NHW, Hispanic and NHB children had 2.7-fold (95% CI, 1.2 to 6.2) and 3.5-fold (95% CI, 1.5 to 8.2) higher hazard of postrelapse mortality, respectively. CONCLUSION: In patients who were treated for de novo HL in contemporary Children's Oncology Group trials, EFS did not differ by race/ethnicity; however, adjusted OS was significantly worse in nonwhite patients, a finding driven by increased postrelapse mortality in this population. Additional studies examining treatment and survival disparities after relapse are warranted.

Survival and prognosis with osteosarcoma: outcomes in more than 2000 patients in the EURAMOS-1 (European and American Osteosarcoma Study) cohort.

BACKGROUND: High-grade osteosarcoma is a primary malignant bone tumour mainly affecting children and young adults. The European and American Osteosarcoma Study (EURAMOS)-1 is a collaboration of four study groups aiming to improve outcomes of this rare disease by facilitating randomised controlled trials. METHODS: Patients eligible for EURAMOS-1 were aged ≤40 years with M0 or M1 skeletal high-grade osteosarcoma in which case complete surgical resection at all sites was deemed to be possible. A three-drug combination with methotrexate, doxorubicin and cisplatin was defined as standard chemotherapy, and between April 2005 and June 2011, 2260 patients were registered. We report survival outcomes and prognostic factors in the full cohort of registered patients. RESULTS: For all registered patients at a median follow-up of 54 months (interquartile range: 38-73) from biopsy, 3-year and 5-year event-free survival were 59% (95% confidence interval [CI]: 57-61%) and 54% (95% CI: 52-56%), respectively. Multivariate analyses showed that the most adverse factors at diagnosis were pulmonary metastases (hazard ratio [HR] = 2.34, 95% CI: 1.95-2.81), non-pulmonary metastases (HR = 1.94, 95% CI: 1.38-2.73) or an axial skeleton tumour site (HR = 1.53, 95% CI: 1.10-2.13). The histological subtypes telangiectatic (HR = 0.52, 95% CI: 0.33-0.80) and unspecified conventional (HR = 0.67, 95% CI: 0.52-0.88) were associated with a favourable prognosis compared with chondroblastic subtype. The 3-year and 5-year overall survival from biopsy were 79% (95% CI: 77-81%) and 71% (95% CI: 68-73%), respectively. For patients with localised disease at presentation and in complete remission after surgery, having a poor histological response was associated with worse outcome after surgery (HR = 2.13, 95% CI: 1.76-2.58). In radically operated patients, there was no good evidence that axial tumour site was associated with worse outcome. CONCLUSIONS: In conclusion, data from >2000 patients registered to EURAMOS-1 demonstrated survival rates in concordance with institution- or group-level osteosarcoma trials. Further efforts are required to drive improvements for patients who can be identified to be at higher risk of adverse outcome. This trial reaffirms known prognostic factors, and owing to the large numbers of patients registered, it sheds light on some additional factors to consider.

Factors influencing survival after recurrence in osteosarcoma: A report from the Children's Oncology Group.

BACKGROUND: Despite drastic improvement in overall survival for pediatric patients with cancer, those with osteosarcoma have stable rates of survival since the 1980s. This project evaluates the effect of several variables on survival after first recurrence in patients with osteosarcoma. METHODS: Data from three prospective North American cooperative group trials for newly diagnosed osteosarcoma are included: INT-0133, POG-9754, and AOST0121. The analytic population for this study is all enrolled patients with first event-free survival (EFS) event of relapse. The primary outcome measure for this retrospective analysis was survival after recurrence (SAR). RESULTS: The analytic population consisted of N = 431 patients. SAR was statistically significantly associated with age at enrollment (<10 years, P = 0.027), presence of metastatic disease at diagnosis (localized, P < 0.0001), site of relapse (combination lung + bone, unfavorable, P = 0.005), and time to first relapse (2+ years, favorable, P < 0.0001) in multivariate analysis. Ethnicity, primary site of tumor, race, and sex were not significantly related to SAR. CONCLUSIONS: Prolonged SAR in patients with relapsed osteosarcoma is associated with age, extent of disease at diagnosis, site of and time to relapse. Adolescent and young adult patients with osteosarcoma have shorter SAR than younger patients, consistent with studies showing decreased overall survival in this group. Although patients with primary metastatic disease have shorter SAR, there is a subset of patients who relapse greater than 2 years from initial diagnosis that will become survivors. Histological response was significantly associated with time to relapse, but was not predictive of SAR.

Effects of dexrazoxane on doxorubicin-related cardiotoxicity and second malignant neoplasms in children with osteosarcoma: a report from the Children's Oncology Group.

BACKGROUND: Dexrazoxane protects from lower-cumulative-dose doxorubicin cardiotoxicity, but the effect of dexrazoxane in children with sarcoma treated with higher-cumulative-dose doxorubicin is unknown. METHODS: We evaluated children with osteosarcoma (OS) on two Children's Oncology Group trials with higher dose doxorubicin (375-600 mg/m2) preceded by dexrazoxane (10:1 dexrazoxane:doxorubicin dosing). They were evaluated after the minimum expected treatment time (METT), defined as 28 weeks. Cardiotoxicity was identified by echocardiography and serum N-terminal pro-brain natriuretic peptide (NT-proBNP). Second malignant neoplasm (SMN) data was collected. RESULTS: All children had normal left ventricular (LV) systolic function as measured by LV fractional shortening and no heart failure. The end-diastolic septal thickness Z-scores (P < 0.01) and LV mass Z-scores (P < 0.01) were significantly smaller than normal for body-surface area in both sexes. The average LV mass Z-scores were significantly smaller for girls (P < 0.01) and marginally smaller for boys (P = 0.06). Girls had significantly smaller LV end-diastolic dimension Z-scores normalized to BSA (P < 0.01) compared to healthy controls and had significant increases in NT-proBNP. Four children developed SMNs as first events, a rate similar to historical controls. CONCLUSIONS: Dexrazoxane prevented LV dysfunction and heart failure in children with OS receiving higher dose doxorubicin. However, LV structural changes were not fully prevented, especially in girls. As a result, hearts become abnormally small for body size, resulting in higher LV stress. Dexrazoxane did not increase the risk of SMN. Dexrazoxane should be used in this population, particularly for girls, to mitigate anthracycline-induced cardiotoxicity. TRIAL REGISTRATIONS: ClinicalTrials.gov: NCT00003937 (P9754) registered 1 Nov 1999, and NCT00023998 (AOST0121) registered 13 Sept 2001.

Outcomes in intermediate-risk pediatric lymphocyte-predominant Hodgkin lymphoma: A report from the Children's Oncology Group.

PURPOSE: Optimal management of patients with intermediate-risk lymphocyte-predominant Hodgkin lymphoma (LPHL) is unclear due to their small numbers in most clinical trials. Children's Oncology Group AHOD0031, a randomized phase III trial of pediatric patients with intermediate-risk Hodgkin lymphoma (HL), included patients with LPHL. We report the outcomes of these patients and present directions for future therapeutic strategies. PROCEDURE: Patients received two cycles of doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide (ABVE-PC) followed by response evaluation. Slow early responders were randomized to two additional ABVE-PC cycles ± two dexamethasone, etoposide, cisplatin, and cytarabine cycles and all received involved field radiotherapy (IFRT). Rapid early responders (RERs) received two additional ABVE-PC cycles. RERs with complete response (CR) were randomized to IFRT or no further therapy. RERs without CR received IFRT. RESULTS: Ninety-six (5.6%) of 1711 patients on AHOD0031 had LPHL. Patients with LPHL were more likely to achieve RER (93.6% vs. 81.0%; P = 0.002) and CR (74.2% vs. 49.3%; P = 0.000005) following chemotherapy compared with patients with classical HL. Five-year event-free survival (EFS) was superior in patients with LPHL (92.2%) versus classical HL (83.5%) (P = 0.04), without difference in overall survival (OS). Among RERs with CR following chemotherapy (n = 33), there was no difference in EFS or OS between those randomized to receive or not receive IFRT. CONCLUSION: Children and adolescents with intermediate-risk LPHL represent ideal candidates for response-adapted therapy based on their favorable outcomes. The majority of patients treated with the ABVE-PC backbone achieve RER with CR status and can be treated successfully without IFRT.