Adverse Childhood Experiences, Resilience, and Cardiovascular Disease in Adult Survivors of Childhood Cancer: A Report from the Childhood Cancer Survivor Study.

BACKGROUND: The impact of Adverse Childhood Experiences (ACEs: e.g., abuse, neglect and/or household dysfunction experienced before age 18) and resilience on risk for cardiovascular disease (CVD) has not previously been investigated in adult survivors of childhood cancer. METHODS: We conducted a nested case-control study among long-term, adult-aged survivors of childhood cancer from the Childhood Cancer Survivor Study (CCSS). Self-report questionnaires ascertained ACEs and resilience, and scores were compared between cases with serious/life-threatening CVD and controls without CVD matched on demographic and cardiotoxic treatment factors. RESULTS: Among 95 cases and 261 controls, the mean ACE score was 1.4 for both groups; 53.4% of survivors endorsed ≥1 ACE. There was no association between ACEs or resilience and CVD in adjusted models. CONCLUSIONS: ACEs and resilience do not appear to contribute to CVD risk for adult survivors of childhood cancer with cardiotoxic treatment exposures. IMPACT: Although not associated with CVD in this population, ACEs are associated with serious health issues in other populations. Therefore, future studies could investigate effects of ACEs on other health outcomes affecting childhood cancer survivors.

Impact of risk-based therapy on late morbidity and mortality in neuroblastoma survivors: a report from the Childhood Cancer Survivor Study.

BACKGROUND: Early efforts at risk-adapted therapy for neuroblastoma are predicted to result in differential late effects; the magnitude of these differences has not been well described. METHODS: Late mortality, subsequent malignant neoplasms (SMNs), and severe/life-threatening chronic health conditions (CHCs), graded according to CTCAE v4.03, were assessed among 5-year Childhood Cancer Survivor Study (CCSS) survivors of neuroblastoma diagnosed 1987-1999. Using age, stage at diagnosis, and treatment, survivors were classified into risk groups (low [n = 425]; intermediate [n = 252]; high [n = 245]). Standardized mortality ratios (SMRs) and standardized incidence ratios (SIRs) of SMNs were compared with matched population controls. Cox regression models estimated hazard ratios (HRs) and 95% confidence intervals for CHC compared with 1029 CCSS siblings. RESULTS: Among survivors (49.8% male; median age = 21 years, range = 7-42; median follow-up = 19.3 years, range = 5-29.9), 80% with low-risk disease were treated with surgery alone, whereas 79.1% with high-risk disease received surgery, radiation, chemotherapy ± autologous stem cell transplant (ASCT). All-cause mortality was elevated across risk groups (SMRhigh = 27.7 [21.4-35.8]; SMRintermediate = 3.3 [1.7-6.5]; SMRlow = 2.8 [1.7-4.8]). SMN risk was increased among high- and intermediate-risk survivors (SIRhigh = 28.0 [18.5-42.3]; SIRintermediate = 3.7 [1.2-11.3]) but did not differ from the US population for survivors of low-risk disease. Compared with siblings, survivors had an increased risk of grade 3-5 CHCs, particularly among those with high-risk disease (HRhigh = 16.1 [11.2-23.2]; HRintermediate = 6.3 [3.8-10.5]; HRlow = 1.8 [1.1-3.1]). CONCLUSION: Survivors of high-risk disease treated in the early days of risk stratification carry a markedly elevated burden of late recurrence, SMN, and organ-related multimorbidity, whereas survivors of low/intermediate-risk disease have a modest risk of late adverse outcomes.

The ENGAGE study: a 3-arm randomized hybrid type 1 effectiveness and implementation study of an in-home, collaborative PCP model of remote telegenetic services to increase uptake of cancer genetic services in childhood cancer survivors.

BACKGROUND: Germline cancer genetic testing has become a standard evidence-based practice, with established risk reduction and screening guidelines for genetic carriers. Access to genetic services is limited in many places, which leaves many genetic carriers unidentified and at risk for late diagnosis of cancers and poor outcomes. This poses a problem for childhood cancer survivors, as this is a population with an increased risk for subsequent malignant neoplasms (SMN) due to cancer therapy or inherited cancer predisposition. The ENGaging and Activating cancer survivors in Genetic services (ENGAGE) study evaluates the effectiveness of an in-home, collaborative PCP model of remote telegenetic services to increase uptake of cancer genetic testing in childhood cancer survivors compared to usual care options for genetic testing. METHODS: The ENGAGE study is a 3-arm randomized hybrid type 1 effectiveness and implementation study within the Childhood Cancer Survivor Study population which tests a clinical intervention while gathering information on its delivery during the effectiveness trial and its potential for future implementation among 360 participants. Participants are randomized into three arms. Those randomized to Arm A receive genetic services via videoconferencing, those in Arm B receive these services by phone, and those randomized to Arm C will receive usual care services. DISCUSSION: With many barriers to accessing genetic services, innovative delivery models are needed to address this gap and increase uptake of genetic services. The ENGAGE study evaluates the effectiveness of an adapted model of remote delivery of genetic services to increase the uptake of recommended genetic testing in childhood cancer survivors. This study assesses the uptake in remote genetic services and identify barriers to uptake to inform future recommendations and a theoretically-informed process evaluation which can inform modifications to enhance dissemination beyond this study population and to realize the benefits of precision medicine. TRIAL REGISTRATION: This protocol was registered at clinicaltrials.gov (NCT04455698) on July 2, 2020.

Accelerating pediatric Hodgkin lymphoma research: the Hodgkin Lymphoma Data Collaboration (NODAL).

Data commons have proven to be an indispensable avenue for advancing pediatric cancer research by serving as unified information technology platforms that, when coupled with data standards, facilitate data sharing. The Pediatric Cancer Data Commons, the flagship project of Data for the Common Good (D4CG), collaborates with disease-based consortia to facilitate development of clinical data standards, harmonization and pooling of clinical data from disparate sources, establishment of governance structure, and sharing of clinical data. In the interest of international collaboration, researchers developed the Hodgkin Lymphoma Data Collaboration and forged a relationship with the Pediatric Cancer Data Commons to establish a data commons for pediatric Hodgkin lymphoma. Herein, we describe the progress made in the formation of Hodgkin Lymphoma Data Collaboration and foundational goals to advance pediatric Hodgkin lymphoma research.

Performance of the FACT-GOG-Ntx to assess chemotherapy-induced peripheral neuropathy (CIPN) in pediatric high risk Hodgkin lymphoma: report from the Children's Oncology Group AHOD 1331 study.

BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) is an under-recognized complication of several chemotherapy agents used as part of curative-intent therapy for Hodgkin Lymphoma (HL). In the absence of validated self- or proxy-report measures for children and adolescents, CIPN reporting has relied on clinician rating, with grading scales often restricted to severe manifestations. In a proof-of-concept study, we assessed the feasibility and psychometric performance of the Functional Assessment of Cancer Therapy-Gynecologic Oncology Group-Neurotoxicity (FACT-GOG-Ntx), a unidimensional CIPN symptom scale widely used adults with CIPN, in pediatric HL at risk for CIPN. METHODS: Youth (11+ years) and parents of all children (5-17.9 years) with newly diagnosed high-risk HL enrolled on Children's Oncology Group AHOD1331 (NCT02166463) were invited to complete the FACT-GOG-Ntx and a health-related quality of life (HRQL) measure at pre-treatment (Time 1), and during cycles 2 (Time 2) and 5 (Time 3) of chemotherapy during the first half of study accrual. Clinical grading of CIPN by providers was also assessed using the Balis Pediatric Neuropathy Scale. We evaluated Cronbach's alpha, construct validity, and agreement between raters. Change in FACT-GOG-Ntx scores over time was assessed using a repeated measures model. RESULTS: 306 patients had at least one completed FACT-GOG-Ntx with time-specific completion rates of > 90% for both raters. Cronbach's alpha was > 0.7 for youth and parent-proxy report at all time points. Correlations between FACT-GOG-Ntx and HRQL scores were moderate (0.41-0.48) for youth and parent-proxy raters across all times. Youth and parent-proxy raters both reported worse FACT-GOG-Ntx scores at Time 3 for those who had clinically-reported CIPN compared to those who did not. Agreement between raters was moderate to high. Compared to baseline scores, those at Time 3 were significantly lower for youth (ß = - 2.83, p < 0.001) and parent-proxy raters (ß = - 1.99, p < 0.001). CONCLUSIONS: High completion rates at all time points indicated feasibility of eliciting youth and parent report. Psychometric performance of the FACT-GOG-Ntx revealed acceptable reliability, evidence of validity, and strong inter-rater agreement, supporting the use of this self- or proxy-reported measure of CIPN in youth with high-risk HL exposed to tubulin inhibitors, as part of a Phase 3 clinical trial. CLINICAL TRIAL INFORMATION: Clinical Trials Registry, NCT02166463. Registered 18 June 2014, https://clinicaltrials.gov/ct2/show/study/NCT02166463.

Subsequent female breast cancer risk associated with anthracycline chemotherapy for childhood cancer.

Anthracycline-based chemotherapy is associated with increased subsequent breast cancer (SBC) risk in female childhood cancer survivors, but the current evidence is insufficient to support early breast cancer screening recommendations for survivors treated with anthracyclines. In this study, we pooled individual patient data of 17,903 survivors from six well-established studies, of whom 782 (4.4%) developed a SBC, and analyzed dose-dependent effects of individual anthracycline agents on developing SBC and interactions with chest radiotherapy. A dose-dependent increased SBC risk was seen for doxorubicin (hazard ratio (HR) per 100 mg m-2: 1.24, 95% confidence interval (CI): 1.18-1.31), with more than twofold increased risk for survivors treated with ≥200 mg m-2 cumulative doxorubicin dose versus no doxorubicin (HR: 2.50 for 200-299 mg m-2, HR: 2.33 for 300-399 mg m-2 and HR: 2.78 for ≥400 mg m-2). For daunorubicin, the associations were not statistically significant. Epirubicin was associated with increased SBC risk (yes/no, HR: 3.25, 95% CI: 1.59-6.63). For patients treated with or without chest irradiation, HRs per 100 mg m-2 of doxorubicin were 1.11 (95% CI: 1.02-1.21) and 1.26 (95% CI: 1.17-1.36), respectively. Our findings support that early initiation of SBC surveillance may be reasonable for survivors who received ≥200 mg m-2 cumulative doxorubicin dose and should be considered in SBC surveillance guidelines for survivors and future treatment protocols.

Neurocognitive outcomes in adult survivors of neuroblastoma: A report from the Childhood Cancer Survivor Study.

BACKGROUND: Despite survival improvements, there is a paucity of data on neurocognitive outcomes in neuroblastoma survivors. This study addresses this literature gap. METHODS: Neurocognitive impairments in survivors were compared to sibling controls from the Childhood Cancer Survivor Study (CCSS) using the CCSS Neurocognitive Questionnaire. Impaired emotional regulation, organization, task efficiency, and memory defined as scores ≥90th percentile of sibling norms. Modified Poisson regression models evaluated associations with treatment exposures, era of diagnosis, and chronic conditions. Analyses were stratified by age at diagnosis (≤1 and >1 year) as proxy for lower versus higher risk disease. RESULTS: Survivors (N = 837; median [range] age, 25 [17-58] years, age diagnosed, 1 [0-21] years) were compared to sibling controls (N = 728; age, 32 [16-43] years). Survivors had higher risk of impaired task efficiency (≤1 year relative risk [RR], 1.48; 95% confidence interval [CI], 1.08-2.03; >1 year RR, 1.58; 95% CI, 1.22-2.06) and emotional regulation (≤1 year RR, 1.51; 95% CI, 1.07-2.12; >1 year RR, 1.44; 95% CI, 1.06-1.95). Impaired task efficiency associated with platinum exposure (≤1 year RR, 1.74; 95% CI, 1.01-2.97), hearing loss (≤1 year RR, 1.95; 95% CI, 1.26-3.00; >1 year RR, 1.56; 95% CI, 1.09-2.24), cardiovascular (≤1 year RR, 1.83; 95% CI, 1.15-2.89; >1 year RR, 1.74; 95% CI, 1.12-2.69), neurologic (≤1 year RR, 2.00; 95% CI, 1.32-3.03; >1 year RR, 2.29; 95% CI, 1.64-3.21), and respiratory (>1 year RR, 2.35; 95% CI, 1.60-3.45) conditions. Survivors ≤1 year; female sex (RR, 1.54; 95% CI, 1.02-2.33), cardiovascular (RR, 1.71; 95% CI, 1.08-2.70) and respiratory (RR, 1.99; 95% CI, 1.14-3.49) conditions associated impaired emotional regulation. Survivors were less likely to be employed full-time (p < .0001), graduate college (p = .035), and live independently (p < .0001). CONCLUSIONS: Neuroblastoma survivors report neurocognitive impairment impacting adult milestones. Identified health conditions and treatment exposures can be targeted to improve outcomes. PLAIN LANGUAGE SUMMARY: Survival rates continue to improve in patients with neuroblastoma. There is a lack of information regarding neurocognitive outcomes in neuroblastoma survivors; most studies examined survivors of leukemia or brain tumors. In this study, 837 adult survivors of childhood neuroblastoma were compared to siblings from the Childhood Cancer Survivorship Study. Survivors had a 50% higher risk of impairment with attention/processing speed (task efficiency) and emotional reactivity/frustration tolerance (emotional regulation). Survivors were less likely to reach adult milestones such as living independently. Survivors with chronic health conditions are at a higher risk of impairment. Early identification and aggressive management of chronic conditions may help mitigate the level of impairment.

The Association of Neighborhood Characteristics and Frailty in Childhood Cancer Survivors: A Report from the St. Jude Lifetime Cohort Study.

BACKGROUND: Childhood cancer survivors experience reduced physiologic reserve, or frailty, earlier and more frequently than peers. In other populations, frailty is impacted by one's neighborhood. This study's purpose was to evaluate associations between neighborhood characteristics and frailty in childhood cancer survivors. METHODS: Participants in the St. Jude Lifetime Cohort Study with geocoded residential addresses were analyzed. Pre-frailty/Frailty was defined as having 1-2/≥3 of sarcopenia, muscle weakness, poor endurance, slow walking speed, and exhaustion from direct assessments. Neighborhood characteristics [e.g., access to exercise opportunities and healthy food, neighborhood socioeconomic status (nSES), and rurality/urbanicity] were determined using publicly available geospatial data. Nested multivariable logistic regression models identified associations between neighborhood characteristics and pre-frailty/frailty, adjusting for chronic health conditions, individual health behaviors and socio-demographics, and high-risk cancer treatment exposures. RESULTS: For our cohort (N = 3,806, 46.79% female, 81.40% white, mean age 33.63±9.91 years), compared with non-frail survivors (n = 2,573; 67.6%), pre-frail (n = 900; 23.6%) and frail survivors (n = 333; 8.7%) were more likely to live in neighborhoods with decreased exercise opportunities (frail OR: 1.62, 1.26-2.09), reduced healthy food access (pre-frail OR: 1.28, 1.08-1.51; frail OR: 1.36, 1.06-1.75), and lower nSES (pre-frail OR: 1.31, 1.12-1.52; frail OR: 1.64, 1.30-2.07). Participants had 8% increased odds (95% confidence interval, 2%-14%) of being pre-frail/frail if they lived in "resource poor" neighborhoods as opposed to "resource rich" neighborhoods after adjusting for other pre-frailty/frailty risk factors. CONCLUSIONS: The neighborhood a childhood cancer survivor resides in as an adult is associated with pre-frailty/frailty. IMPACT: This study provides valuable information for creating interventions using neighborhood-level factors to mitigate frailty and improve health outcomes in survivors. See related commentary by Bhandari and Armenian, p. 997.

Financial Hardship in Adult Survivors of Childhood Cancer in the Era After Implementation of the Affordable Care Act: A Report From the Childhood Cancer Survivor Study.

PURPOSE: To estimate the prevalence of financial hardship among adult survivors of childhood cancer compared with siblings and identify sociodemographic, cancer diagnosis, and treatment correlates of hardship among survivors in the era after implementation of the Affordable Care Act. METHODS: A total of 3,555 long-term (≥ 5 years) survivors of childhood cancer and 956 siblings who completed a survey administered in 2017-2019 were identified from the Childhood Cancer Survivor Study. Financial hardship was measured by 21 survey items derived from US national surveys that had been previously cognitively tested and fielded. Principal component analysis (PCA) identified domains of hardship. Multiple linear regression examined the association of standardized domain scores (ie, scores divided by standard deviation) with cancer and treatment history and sociodemographic characteristics among survivors. RESULTS: Survivors were more likely than siblings to report hardship in ≥ 1 item (63.4% v 53.7%, P < .001). They were more likely to report being sent to debt collection (29.9% v 22.3%), problems paying medical bills (20.7% v 12.8%), foregoing needed medical care (14.1% v 7.8%), and worry/stress about paying their rent/mortgage (33.6% v 23.2%) or having enough money to buy nutritious meals (26.8% v 15.5%); all P < .001. Survivors reported greater hardship than siblings in all three domains identified by principal component analysis: behavioral hardship (mean standardized domain score 0.51 v 0.35), material hardship/financial sacrifices (0.64 v 0.46), and psychological hardship (0.69 v 0.44), all P < .001. Sociodemographic (eg,

Long-Term Morbidity and Mortality Among Survivors of Neuroblastoma Diagnosed During Infancy: A Report From the Childhood Cancer Survivor Study.

PURPOSE: To describe the risk of late mortality, subsequent malignant neoplasms (SMNs), and chronic health conditions (CHCs) in survivors of neuroblastoma diagnosed in infancy by treatment era and exposures. METHODS: Among 5-year survivors of neuroblastoma in the Childhood Cancer Survivor Study diagnosed age < 1 year between 1970 and 1999, we examined the cumulative incidence of late (> 5 years from diagnosis) mortality, SMN, and CHCs (grades 2-5 and 3-5). Multivariable Cox regression models estimated hazard ratios (HRs) and 95% CIs by decade and treatment (surgery-alone v chemotherapy with or without surgery [C ± S] v radiation with or without chemotherapy ± surgery [R ± C ± S]) among survivors and between survivors and 5,051 siblings. RESULTS: Among 1,397 eligible survivors, the 25-year cumulative incidence of late mortality was 2.1% (95% CI, 1.3 to 3.9) with no difference by treatment era. Among 990 participants who completed a baseline survey, fewer survivors received radiation in more recent eras (51.2% 1970s, 20.4% 1980s, and 10.1% 1990s; P < .001). Risk of SMN was elevated only among individuals treated with radiation-containing regimens compared with surgery alone (HR[C ± S], 3.2 [95% CI, 0.9 to 11.6]; HR[R ± C ± S], 5.7 [95% CI, 1.2 to 28.1]). In adjusted models, there was a 50% reduction in risk of grade 3-5 CHCs in the 1990s versus 1970s (HR, 0.5 [95% CI, 0.3 to 0.9]; P = .01); individuals treated with radiation had a 3.6-fold risk for grade 3-5 CHCs (95% CI, 2.1 to 6.2) versus those treated with surgery alone. When compared with siblings, risk of grade 3-5 CHCs for survivors was lowest in the most recent era (HR[1970s], 4.7 [95% CI, 3.4 to 6.5]; HR[1980s], 4.6 [95% CI, 3.3 to 6.4]; HR[1990s], 2.5 [95% CI, 1.7 to 3.9]). CONCLUSION: Neuroblastoma survivors treated during infancy have a relatively low absolute burden of late mortality and SMN. Encouragingly, risk of CHCs has declined in more recent eras with reduced exposure to radiation therapy.

Adverse childhood experiences and resilience in childhood and adolescent and young adult cancer patients.

Childhood and adolescent and young adult (AYA) cancer survivors experience poor health outcomes in adulthood. Adverse childhood experiences (ACEs) also portend poor health outcomes for the general population. Resilience can mitigate effects of ACEs. We examined the feasibility of assessing ACEs and resilience in childhood and AYA cancer patients. We also described occurrences of ACEs, resilience, and poor health outcomes. Of 52 participants, most rated their study experience favorably, with privacy in answering sensitive questions. Half reported ACEs, and those with ACEs had lower resilience; X2 (3, N = 52) = 9.4, p = .02. Further investigations of ACEs and resilience in larger cohorts are warranted to delineate associations with long-term health outcomes.

Health Benefits and Cost-Effectiveness of Children's Oncology Group Breast Cancer Screening Guidelines for Chest-Irradiated Hodgkin Lymphoma Survivors.

PURPOSE: To evaluate the outcomes and cost-effectiveness of the Children's Oncology Group Guideline recommendation for breast cancer (BC) screening using mammography (MAM) and breast magnetic resonance imaging (MRI) in female chest-irradiated childhood Hodgkin lymphoma (HL) survivors. Digital breast tomosynthesis (DBT), increasingly replacing MAM in practice, was also examined. METHODS: Life years (LYs), quality-adjusted LYs (QALYs), BC mortality, health care costs, and false-positive screen frequencies of undergoing annual MAM, DBT, MRI, MAM + MRI, and DBT + MRI from age 25 to 74 years were estimated by microsimulation. BC risks and non-BC mortality were estimated from female 5-year survivors of HL in the Childhood Cancer Survivor Study and the US population. Test performance of MAM and MRI was synthesized from HL studies, and that of DBT from the general population. Costs (2017 US dollars [USD]) and utility weights were obtained from the medical literature. Incremental cost-effectiveness ratios (ICERs) were calculated. RESULTS: With 100% screening adherence, annual BC screening extended LYs by 0.34-0.46 years over no screening. If the willingness-to-pay threshold to gain a quality-adjusted LY was ICER < $100,000 USD, annual MAM at age 25-74 years was the only cost-effective strategy. When nonadherence was taken into consideration, only annual MAM at age 30-74 years (ICER = $56,972 USD) was cost-effective. Supplementing annual MAM with MRI costing $545 USD was not cost-effective under either adherence condition. If MRI costs were reduced to $300 USD, adding MRI to annual MAM at age 30-74 years could become more cost-effective, particularly in the reduced adherence condition (ICER = $133,682 USD). CONCLUSION: Annual BC screening using MAM at age 30-74 years is effective and cost-effective in female chest-irradiated HL survivors. Although annual adjunct MRI is not cost-effective at $545 USD cost, it could become cost-effective as MRI cost is reduced, a plausible scenario with the emergent use of abbreviated MRI.

Persistence of Racial and Ethnic Disparities in Risk and Survival for Patients with Neuroblastoma over Two Decades.

BACKGROUND: Racial/ethnic survival disparities in neuroblastoma were first reported more than a decade ago. We sought to investigate if these disparities have persisted with current era therapy. METHODS: Two patient cohorts were identified in the International Neuroblastoma Risk Group Data Commons (INRGdc) (Cohort 1: diagnosed 2001-2009, n=4359; Cohort 2: diagnosed 2010-2019, n=4891). Chi-squared tests were used to assess the relationship between race/ethnicity and clinical and biologic features. Survival was estimated by the Kaplan-Meier method. Cox proportional hazards regression analyses were performed to investigate the association between racial/ethnic groups and prognostic markers. RESULTS: Significantly higher 5-year event-free survival (EFS) and overall survival (OS) were observed for Cohort 2 compared to Cohort 1 (P<0.001 and P<0.001, respectively). Compared to White patients, Black patients in both cohorts had a higher proportion of high-risk disease (Cohort 1: P<0.001; Cohort 2: P<0.001) and worse EFS (Cohort 1: P<0.001; Cohort 2 P<0.001) and OS (Cohort 1: P<0.001; Cohort 2: P<0.001). In Cohort 1, Native Americans also had a higher proportion of high-risk disease (P=0.03) and inferior EFS/OS. No significant survival disparities were observed for low- or intermediate-risk patients in either cohort or high-risk patients in Cohort 1. Hispanic patients with high-risk disease in Cohort 2 had significantly inferior OS (P=0.047). Significantly worse OS, but not EFS, (P=0.006 and P=0.02, respectively) was also observed among Black and Hispanic patients assigned to receive post-Consolidation dinutuximab on clinical trials (n=885). CONCLUSION: Racial/ethnic survival disparities have persisted over time and were observed among high-risk patients assigned to receive post-Consolidation dinutuximab.

Brentuximab Vedotin with Chemotherapy in Pediatric High-Risk Hodgkin's Lymphoma.

BACKGROUND: In adults with advanced-stage Hodgkin's lymphoma, the CD30-directed antibody-drug conjugate brentuximab vedotin combined with multiagent chemotherapy has been shown to have greater efficacy, but also more toxic effects, than chemotherapy alone. The efficacy of this targeted therapy approach in children and adolescents with Hodgkin's lymphoma is unclear. METHODS: We conducted an open-label, multicenter, randomized, phase 3 trial involving patients 2 to 21 years of age with previously untreated Hodgkin's lymphoma of stage IIB with bulk tumor or stage IIIB, IVA, or IVB. Patients were assigned to receive five 21-day cycles of brentuximab vedotin with doxorubicin, vincristine, etoposide, prednisone, and cyclophosphamide (brentuximab vedotin group) or the standard pediatric regimen of doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide (standard-care group). Slow-responding lesions, defined by a score of 4 or 5 (on a 5-point scale, with scores of 1 to 3 indicating rapid-responding lesions), were identified on centrally reviewed positron-emission tomography-computed tomography after two cycles. Involved-site radiation therapy was administered after the fifth cycle of therapy to slow-responding lesions and to large mediastinal adenopathy that was present at diagnosis. The primary end point was event-free survival, defined as the time until disease progression occurred, relapse occurred, a second malignant neoplasm developed, or the patient died. Safety and overall survival were assessed. RESULTS: Of 600 patients who were enrolled across 153 institutions, 587 were eligible. At a median follow-up of 42.1 months (range, 0.1 to 80.9), the 3-year event-free survival was 92.1% (95% confidence interval [CI], 88.4 to 94.7) in the brentuximab vedotin group, as compared with 82.5% (95% CI, 77.4 to 86.5) in the standard-care group (hazard ratio for event or death, 0.41; 95% CI, 0.25 to 0.67; P<0.001). The percentage of patients who received involved-site radiation therapy did not differ substantially between the brentuximab vedotin group and the standard-care group (53.4% and 56.8%, respectively). Toxic effects were similar in the two groups. Overall survival at 3 years was 99.3% (95% CI, 97.3 to 99.8) in the brentuximab vedotin group and 98.5% (95% CI, 96.0 to 99.4) in the standard-care group. CONCLUSIONS: The addition of brentuximab vedotin to standard chemotherapy resulted in superior efficacy, with a 59% lower risk of an event or death, and no increase in the incidence of toxic effects at 3 years. (Funded by the National Institutes of Health and others; AHOD1331 ClinicalTrials.gov number, NCT02166463.).

Association of Changes in Cancer Therapy Over 3 Decades With Risk of Subsequent Breast Cancer Among Female Childhood Cancer Survivors: A Report From the Childhood Cancer Survivor Study (CCSS).

Importance: Breast cancer is the most common invasive subsequent malignant disease in childhood cancer survivors, though limited data exist on changes in breast cancer rates as primary cancer treatments have evolved. Objective: To quantify the association between temporal changes in cancer treatment over 3 decades and subsequent breast cancer risk. Design, Setting, and Participants: Retrospective cohort study of 5-year cancer survivors diagnosed when younger than 21 years between 1970 and 1999, with follow-up through December 5, 2020. Exposures: Radiation and chemotherapy dose changes over time. Main Outcomes and Measures: Breast cancer cumulative incidence rates and age-specific standardized incidence ratios (SIRs) compared across treatment decades (1970-1999). Piecewise exponential models estimated invasive breast cancer and ductal carcinoma in situ (DCIS) risk and associations with treatment exposures, adjusted for age at childhood cancer diagnosis and attained age. Results: Among 11 550 female survivors (median age, 34.2 years; range 5.6-66.8 years), 489 developed 583 breast cancers: 427 invasive, 156 DCIS. Cumulative incidence was 8.1% (95% CI, 7.3%-9.0%) by age 45 years. An increased breast cancer risk (SIR, 6.6; 95% CI, 6.1-7.2) was observed for survivors compared with the age-sex-calendar-year-matched general population. Changes in therapy by decade included reduced rates of chest (34% in the 1970s, 22% in the 1980s, and 17% in the 1990s) and pelvic radiotherapy (26%, 17%, and 13% respectively) and increased rates of anthracycline chemotherapy exposures (30%, 51%, and 64%, respectively). Adjusting for age and age at diagnosis, the invasive breast cancer rate decreased 18% every 5 years of primary cancer diagnosis era (rate ratio [RR], 0.82; 95% CI, 0.74-0.90). When accounting for chest radiotherapy exposure, the decline attenuated to an 11% decrease every 5 years (RR, 0.89; 95% CI, 0.81-0.99). When additionally adjusted for anthracycline dose and pelvic radiotherapy, the decline every 5 years increased to 14% (RR, 0.86; 95% CI, 0.77-0.96). Although SIRs of DCIS generally increased over time, there were no statistically significant changes in incidence. Conclusions and Relevance: Invasive breast cancer rates in childhood cancer survivors have declined with time, especially in those younger than 40 years. This appears largely associated with the reduced use of chest radiation therapy, but was tempered by concurrent changes in other therapies.

Development and validation of a population-based anatomical colorectal model for radiation dosimetry in late effects studies of survivors of childhood cancer.

PURPOSE: The purposes of this study were to develop and integrate a colorectal model that incorporates anatomical variations of pediatric patients into the age-scalable MD Anderson Late Effects (MDA-LE) computational phantom, and validate the model for pediatric radiation therapy (RT) dose reconstructions. METHODS: Colorectal contours were manually derived from whole-body non-contrast computed tomography (CT) scans of 114 pediatric patients (age range: 2.1-21.6 years, 74 males, 40 females). One contour was used for an anatomical template, 103 for training and 10 for testing. Training contours were used to create a colorectal principal component analysis (PCA)-based statistical shape model (SSM) to extract the population's dominant deformations. The SSM was integrated into the MDA-LE phantom. Geometric accuracy was assessed between patient-specific and SSM contours using several overlap metrics. Two alternative colorectal shapes were generated using the first 17 dominant modes of the PCA-based SSM. Dosimetric accuracy was assessed by comparing colorectal doses from test patients' CT-based RT plans (ground truth) with reconstructed doses for the mean and two alternative models in age-matched MDA-LE phantoms. RESULTS: When using all 103 PCA modes, the mean (min-max) Dice similarity coefficient, distance-to-agreement and Hausdorff distance between the patient-specific and reconstructed contours for the test patients were 0.89 (0.85-0.91), 2.1 mm (1.7-3.0), and 8.6 mm (5.7-14.3), respectively. The average percent difference between reconstructed and ground truth mean and maximum colorectal doses for the mean (alternative 1, 2) model were 6.3% (8.1%, 6.1%) and 4.4% (4.3%, 4.7%), respectively. CONCLUSIONS: We developed, validated and integrated a colorectal PCA-based SSM into the MDA-LE phantom and demonstrated its dosimetric performance for accurate pediatric RT dose reconstruction.

Leveraging Clinical Trial Populations and Data from the Children's Oncology Group for Cancer Survivorship Research.

Children and adolescents diagnosed with cancer can now expect an average 85% 5-year overall survival, with significant improvements in longer-term morbidity and mortality reported over the past several decades. However, the long-term impact of therapeutic agents and modalities introduced in recent years remains unclear and will require dedicated follow-up in the years ahead. The Children's Oncology Group (COG), a part of the NCI's National Clinical Trials Network, with over 200 sites across North America and beyond, enrolls more than 10,000 patients onto research protocols annually, inclusive of first-line clinical trials and nontherapeutic studies. COG provides a platform to conduct survivorship research with several unique strengths: (i) a huge catchment to ascertain relatively rare but important adverse events, (ii) study populations that are otherwise too rare to study in smaller consortia, including access to highly diverse patient populations, (iii) long-term follow-up of clinical trial populations linked to the original trial data, and (iv) a natural platform for intervention research. Enhancements in COG infrastructure facilitate survivorship research, including a COG patient registry (Project:EveryChild), availability of a long-term follow-up tracking resource, and successful deployment of various remote-based study procedures to reduce the burden on participants and participating institutions.

High-Risk and Relapsed Neuroblastoma: Toward More Cures and Better Outcomes.

Approximately half of the patients diagnosed with neuroblastoma are classified as having high-risk disease. This group continues to have inadequate cure rates despite multiagent chemotherapy, surgery, high-dose chemotherapy with autologous stem cell rescue, and immunotherapy directed against GD2. We review current efforts to try to improve outcomes in patients with newly diagnosed disease by integrating novel targeted therapies earlier in the course of the disease. We further examine a growing list of options available for patients with relapsed or refractory high-risk disease, with an eye toward graduating successful strategies from a relapsed/refractory setting to the frontline setting. Last, we review efforts to study and potentially mitigate the array of late effects faced by survivors of high-risk neuroblastoma.