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To compare antimüllerian hormone (AMH) patterns by cancer status and treatment exposures across 6 years after incident breast cancer using administrative data.In a cross-sectional design, AMH levels in patients who developed incident breast cancer between ages 15-39 years during 2005-2019 were matched 1:10 to levels in females without cancer in the OptumLabs Data Warehouse. Modeled AMH patterns were compared among cyclophosphamide-based chemotherapy, non-cyclophosphamide-based chemotherapy, no chemotherapy, and no breast cancer groups.Commercially insured females in the United States.Females with and without breast cancer.Breast cancer, cyclophosphamide- and non-cyclophosphamide-based chemotherapy.AMH levels.A total of 233 patients with breast cancer (mean age, 34 years; standard deviation, 3.7 years) contributed 278 AMH levels over a median of 2 years (range, 0-6.7 years) after diagnosis; 52% received cyclophosphamide-based chemotherapy, 17% received non-cyclophosphamide-based chemotherapy (80% platinum-based), and 31% received no chemotherapy. A total of 2,777 matched females without cancer contributed 2,780 AMH levels. The pattern of AMH levels differed among the 4 groups. Among females without cancer and breast cancer survivors who did not undergo chemotherapy, AMH declined linearly over time. In contrast, among those who received cyclophosphamide-based and noncyclophosphamide-based chemotherapy, a nonlinear pattern of AMH level of initial fall during chemotherapy, followed by an increase over 2-4 years, and then by a plateau over 1-2 years before a decline was observed.In breast cancer survivors, AMH levels from administrative data supported ovarian toxicity of non-cyclophosphamide-based chemotherapy in breast cancer and efficiently depicted the timing and duration of changes in ovarian reserve to reflect the residual reproductive lifespan.

PDF file - 56K, Diagnosis and treatment-related characteristics of the cancer survivor population (participants) and non-participants.

Background: Women with a history of chest radiotherapy have an increased risk of breast cancer; however, many do not undergo annual recommended screening mammography. We sought to characterize the relationship between mammography and potentially modifiable factors, with the goal of identifying targets for intervention to improve utilization.Methods: Of 625 female participants sampled from the Childhood Cancer Survivor Study, who were treated with chest radiotherapy, 551 responded to a survey about breast cancer screening practices. We used multivariate Poisson regression to assess several lifestyle and emotional factors, health care practices, and perceived breast cancer risk, in relation to reporting a screening mammogram within the last two years.Results: Women who had a Papanicolaou test [prevalence ratio (PR): 1.77; 95% confidence interval (CI) 1.26–2.49], and who perceived their breast cancer risk as higher than the average woman were more likely to have had a mammogram (PR, 1.26; 95% CI, 1.09–1.46). We detected an attenuated effect of echocardiogram screening [PR, 0.70; 95% CI (0.52–0.95)] on having a mammogram among older women compared with younger women. Smoking, obesity, physical activity, coping, and symptoms of depression and somatization were not associated with mammographic screening.Conclusion: Our findings suggest that compliance with routine and risk-based screening can be an important indicator of mammography in childhood cancer survivors. In addition, there is a need to ensure women understand their increased breast cancer risk, as a means to encouraging them to follow breast surveillance guidelines.Impact: Screening encounters could be used to promote mammography compliance in this population. Cancer Epidemiol Biomarkers Prev; 24(11); 1699–706. ©2015 AACR.

Supplementary Table 1a. Analysis of factors associated with having a screening mammogram within the prior two years in women age

Background The likelihood of pregnancy and risk of obstetrical or perinatal complications is inadequately documented in female survivors of pediatric cancer. Methods We assembled a population-based cohort of female survivors of cancer diagnosed at age 21 years and younger in Ontario, Canada, between 1985 and 2012. Survivors were matched 1:5 to women without prior cancer. Multivariable Cox proportional hazards and modified Poisson models assessed the likelihood of a recognized pregnancy and perinatal and maternal complications. Results A total of 4062 survivors were matched to 20 308 comparisons. Median (interquartile range) age was 11 (4-15) years at cancer diagnosis and 25 (19-31) years at follow-up. By age 30 years, the cumulative incidence of achieving a recognized pregnancy was 22.3% (95% confidence interval [CI] = 20.7% to 23.9%) among survivors vs 26.6% (95% CI = 25.6% to 27.3%) among comparisons (hazard ratio = 0.80, 95% CI = 0.75 to 0.86). A lower likelihood of pregnancy was associated with a brain tumor, alkylator chemotherapy, cranial radiation, and hematopoietic stem cell transplantation. Pregnant survivors were as likely as cancer-free women to carry a pregnancy >20 weeks (relative risk [RR] = 1.01, 95% CI = 0.98 to 1.04). Survivors had a higher relative risk of severe maternal morbidity (RR = 2.31, 95% CI = 1.59 to 3.37), cardiac morbidity (RR = 4.18, 95% CI = 1.89 to 9.24), and preterm birth (RR = 1.57, 95% CI = 1.29 to 1.92). Preterm birth was more likely in survivors treated with hematopoietic stem cell transplantation (allogenic: RR = 8.37, 95% CI = 4.83 to 14.48; autologous: RR = 3.72, 95% CI = 1.66 to 8.35). Conclusions Survivors of childhood or adolescent cancer are less likely to achieve a pregnancy and, once pregnant, are at higher risk for severe maternal morbidity and preterm birth.

Background: Prior studies have identified that survivors of childhood acute lymphoblastic leukemia (ALL) report poor health status. It is unknown how risk-stratified therapy impacts the health status of ALL survivors. Methods: We estimated and compared the prevalence of self-reported poor health status among adult (≥18 years) survivors of childhood ALL diagnosed at age Results: Among 5,119 survivors and 4,693 siblings, survivors were more likely to report poor health status in each domain including poor general health (13.5% vs. 7.4%; PR = 1.92; 95% CI, 1.69–2.19). Compared with 70s, 90sSR and 90sHR were less likely to report poor general health (90sSR: PR = 0.75; 95% CI, 0.57–0.98; 90sHR: PR = 0.58; 95% CI, 0.39–0.87), functional impairment (90sSR: PR = 0.56; 95% CI, 0.42–0.76; 90sHR: PR = 0.63; 95% CI, 0.42–0.95), and activity limitations (90sSR: 0.61; 95% CI, 0.45–0.83; 90sHR: PR = 0.59; 95% CI, 0.38–0.91). An added adjustment for chronic conditions in multivariable models partially attenuated 90sSR risk estimates. Conclusions: Risk-stratified ALL therapy has succeeded in reducing risk for poor general health, functional impairment, and activity limitations among more recent survivors of standard- and high-risk therapy. Impact: Future research into the relationship between risk-stratified therapy, health status, and late health outcomes may provide new opportunities to further improve late morbidity among survivors.

Background: Outcomes among Hodgkin lymphoma (HL) patients diagnosed between 22 and 39 years are worse than among those diagnosed Methods: We examined cancer-related expenditures among 22- to 39-year-old HL patients diagnosed between 2001 and 2016 using deidentified administrative claims data (OptumLabs Data Warehouse; CCC: n = 1,154; non-CCC: n = 643). Adjusting for sociodemographics, clinical characteristics, and months enrolled, multivariable general linear models modeled average monthly health-plan paid (HPP) expenditures, and incidence rate ratios compared CCC/non-CCC monthly visit rates. Results: In the year following diagnosis, CCC patients had higher HPP expenditures ($12,869 vs. $10,688, P = 0.001), driven by higher monthly rates of CCC nontreatment outpatient hospital visits (P = 0.001) and per-visit expenditures for outpatient hospital chemotherapy ($632 vs. $259); higher CCC inpatient expenditures ($1,813 vs. $1,091, P = 0.001) were driven by 3.1 times higher rates of chemotherapy admissions (P = 0.001). Out-of-pocket expenditures were comparable (P = 0.3). Conclusions: Young adults with HL at CCCs saw higher health-plan expenditures, but comparable out-of-pocket expenditures. Drivers of CCC expenditures included outpatient hospital utilization (monthly rates of non-therapy visits and per-visit expenditures for chemotherapy). Impact: Higher HPP expenditures at CCCs in the year following HL diagnosis likely reflect differences in facility structure and comprehensive care. For young adults, it is plausible to consider incentivizing CCC care to achieve superior outcomes while developing approaches to achieve long-term savings.

Purpose Adolescent and young adult cancer survivors require lifelong healthcare to address the late effects of therapy. We examined the impact of different provider models of long‐term follow‐up (LTFU) care on adherence to recommended surveillance. Methods We conducted a retrospective cohort study using administrative health databases in Ontario, Canada. Five‐year survivors were identified from IMPACT, a database of patients aged 15–20.9 years at diagnosis of six cancers between 1992 and 2010. We defined three models of LTFU care hierarchically: specialized survivor clinics (SCCs), general cancer clinics (GCCs), and family physician (FP). We assessed adherence to the Children's Oncology Group surveillance guidelines for cardiomyopathy and breast cancer. Multistate models assessed adherence transitions and impacts of LTFU attendance. Results A total of 1574 survivors were followed for a mean of 9.2 years (range 4.3–13.9 years) from index (5‐year survival). The highest level of LTFU attended in the first 2‐years post‐index was a GCC (47%); only 16.7% attended a SCC. By the end of study, 72% no longer attended any of the models of care and only 2% still attended an SCC. Among 188 survivors requiring breast cancer surveillance, 6.9% were adherent to their first required surveillance testing. Attendance at a SCC in the previous year and higher cumulative FP or GCC visits increased the rate of subsequently becoming adherent. Among 857 survivors requiring cardiomyopathy surveillance, 11% were adherent at study entry. Each subsequent SCC visit led to an 11.3% (95% CI: 1.05–1.18) increase in the rate of becoming adherent. Conclusion LTFU attendance and surveillance adherence are sub‐optimal. SCC follow‐up is associated with greater adherence, but few survivors receive such care, and this proportion diminished over time. Interventions are needed to improve LTFU attendance and promote surveillance adherence., Long‐term follow‐up care attendance and surveillance adherence are sub‐optimal among adolescent and young adult cancer survivors. Specialized survivor clinic follow‐up is associated with greater adherence, but few survivors receive such care, and this proportion diminished over time. Interventions are needed to improve the long‐term follow‐up care attendance and promote surveillance adherence.

PURPOSE To determine the incidence of serious chronic health conditions among survivors of pediatric Hodgkin lymphoma (HL), compare by era of therapy and by selected cancer therapies, and provide estimates of risks associated with contemporary therapy. METHODS Assessing 2,996 5-year HL survivors in the Childhood Cancer Survivor Study diagnosed from 1970 to 1999, we examined the cumulative incidence of severe to fatal chronic conditions (grades 3-5) using self-report conditions, medically confirmed subsequent malignant neoplasms, and cause of death based on the National Death Index. We used multivariable regression models to estimate hazard ratios (HRs) per decade and by key treatment exposures. RESULTS HL survivors were of a mean age of 35.6 years (range, 12-58 years). The cumulative incidence of any grade 3-5 condition by 35 years of age was 31.4% (95% CI, 29.2 to 33.5). Females were twice as likely (HR, 2.1; 95% CI, 1.8 to 2.4) to have a grade 3-5 condition compared with males. From the 1970s to the 1990s, there was a 20% reduction (HR, 0.8; 95% CI, 0.7 to 0.9) in decade-specific risk of a grade 3-5 condition ( P trend = .002). In survivors who had a recurrence and/or hematopoietic cell transplant, the risk of a grade 3-5 condition was substantially elevated, similar to that of survivors treated with high-dose, extended-field radiotherapy (HR, 1.2; 95% CI, 0.9 to 1.5). Compared with survivors treated with chest radiotherapy ≥ 35 Gy in combination with an anthracycline or alkylator, a contemporary regimen for low-intermediate risk HL was estimated to lead to a 40% reduction in risk of a grade 3-5 condition (HR, 0.6; 95% CI, 0.4 to 0.8). CONCLUSION This study demonstrates that risk-adapted therapy for pediatric HL has resulted in a significant reduction in serious long-term outcomes.

Risk prediction models are important to identify survivors of childhood cancer who are at risk of experiencing poor health-related quality of life (HRQOL) as they age.To develop and validate prediction models for a decline in HRQOL among adult survivors of childhood cancer.This prognostic study included 4755 adults from the Childhood Cancer Survivor Study (CCSS) diagnosed between January 5, 1970, and December 31, 1986, who completed baseline (time 0 [November 3, 1992, to August 28, 2003]) and 2 follow-up (time 1 [February 12, 2002, to May 21, 2005] and time 2 [January 6, 2014, to November 30, 2016]) surveys. Data were analyzed from June 19, 2019, to February 2, 2022.Sociodemographic, lifestyle, and emotional factors, and chronic health conditions (CHCs) were assessed at time 0 and time 1, and neurocognitive factors were assessed at time 1 to predict HRQOL at time 2 and a decline in HRQOL between time 1 and time 2. Impaired health states were defined as CHC grades 2 to 4 using the modified Common Terminology Criteria for Adverse Events, version 4.03, and mental and neurocognitive status as 1 SD or more below reference levels.Health-related quality of life was operationalized using the Medical Outcomes Study 36-Item Short Form Health Survey Physical (PCS) and Mental (MCS) Component Summary and classified by optimal (≥40) or suboptimal (40) at each point (main outcome). A decline in HRQOL was defined as a change from optimal to suboptimal between time 1 and time 2. Multivariable logistic regression identified factors associated with HRQOL decline. The cohort was randomly split into training (80%) and test (20%) data sets for model development and validation; the area under the receiver operating characteristic curve was used to evaluate prediction performance.A total of 4755 adults (mean [SD] age at time 0, 24.3 [7.6] years; 2623 [55.2%] women) were included in the analysis. Between time 1 and time 2, 285 of 3294 survivors (8.7%) had declining PCS and 278 of 3294 (8.4%) had declining MCS. Risk factors associated with PCS decline included female sex (odds ratio [OR], 1.67 [95% CI, 1.25-2.24]), family income less than $20 000 vs $80 000 or more (OR, 2.00 [95% CI, 1.21-3.30]), presence of CHCs (OR for neurological, 2.16 [95% CI, 1.51-3.10]; OR for endocrine, 2.25 [95% CI, 1.44-3.52]; OR for gastrointestinal tract, 1.89 [95% CI, 1.32-2.69]; OR for respiratory, 1.66 [95% CI, 1.06-2.59]; OR for cardiovascular, 1.53 [95% CI, 1.14-2.06]), and depression (OR, 1.79 [95% CI, 1.20-2.67]). Risk factors associated with MCS decline included unemployment vs full-time employment (OR, 1.68; [95% CI, 1.19-2.38]), current vs never cigarette smoking (OR, 2.03 [95% CI, 1.37-3.00]), depression (OR, 4.29 [95% CI, 2.44-7.55]), somatization (OR, 1.63 [95% CI, 1.05-2.53]), impaired task efficiency (OR, 1.90 [95% CI, 1.34-2.68]), and impaired organization (OR, 1.67 [95% CI, 1.12-2.48]). The areas under the receiver operating characteristic curve for the test models were 0.74 (95% CI, 0.67-0.81) for declining PCS and 0.68 (95% CI, 0.60-0.75) for declining MCS.In this prognostic study of adult survivors of childhood cancer who experienced declining HRQOL, CHCs were associated with a decline in physical HRQOL, whereas current smoking and emotional and neurocognitive impairment were associated with a decline in mental HRQOL. These findings suggest that interventions targeting modifiable risk factors are needed to prevent poor HRQOL in this population.

BACKGROUND: Retrospective multicenter research using echocardiograms obtained for routine clinical care can be hampered by issues of individual center quality, thus limiting the application of post-hoc research analytics. We sought to evaluate imaging and patient characteristics associated with poorer quality of archived echocardiograms from a cohort of childhood cancer survivors. METHODS: A single blinded reviewer at a central core lab graded quality of clinical echocardiograms from 5 contributing centers focusing on images to derive 2D and M-mode fractional shortening (FS), biplane Simpson ejection fraction (EF), myocardial performance index (MPI), tissue Doppler imaging (TDI) derived velocities and global longitudinal strain (GLS). RESULTS: Of 535 studies analyzed in 102 subjects from 2004 to 2017, all measures of cardiac function could be assessed in only 7%. While FS by 2D or M-mode, MPI and septal E/E’ could be measured in >80% studies, mitral E/E’ was less consistent (69%), but better than EF (52%) and GLS (10%). At least one quality issue was identified in 66% studies, with technical issues (ex. lung artifact, poor endocardial definition) being the most common (33%). Lack of 2- and 3-chamber views was associated with the performing center. Patients < 5 years had a higher chance of apex cut-off in 4-chamber views compared to 16–35 year old (RR 1.99 (1.07–3.72), p = 0.03). Overall, for any quality issue, earlier era of echo and center were the only significant risk factors. CONCLUSION: Assessment of cardiac function using pooled multicenter archived echocardiograms was significantly limited. Efforts to standardize clinical echocardiographic protocols to include apical 2- and 3-chamber views and TDI will improve the ability to quantitate LV function.

As treatment evolves and the population who survive childhood cancer ages and increases in number, researchers must use novel approaches to prevent, identify and mitigate adverse effects of treatment. Future priorities include collaborative efforts to pool large cohort data to improve detection of late effects, identify late effects of novel therapies, and determine the contribution of genetic factors along with physiologic and accelerated aging among survivors. This knowledge should translate to individual risk prediction and prevention strategies. Finally, we must utilize health services research and implementation science to improve adoption of survivorship care recommendations outside of specialized pediatric oncology centers.

The authors' objective is to provide a brief update on recent advances in knowledge relating to subsequent primary neoplasms developing in survivors of childhood cancer. This includes a summary of established large-scale cohorts, risks reported, and contrasts with results from recently established large-scale cohorts of survivors of adolescent and young adult cancer. Recent evidence is summarized concerning the role of radiotherapy and chemotherapy for childhood cancer and survivor genomics in determining the risk of subsequent primary neoplasms. Progress with surveillance, screening, and clinical follow-up guidelines is addressed. Finally, priorities for future research are outlined.

Background Despite known clinical risk factors, predicting anthracycline cardiotoxicity remains challenging. Objectives This study sought to develop a clinical and genetic risk prediction model for anthracycline cardiotoxicity in childhood cancer survivors. Methods We performed exome sequencing in 289 childhood cancer survivors at least 3 years from anthracycline exposure. In a nested case-control design, 183 case patients with reduced left ventricular ejection fraction despite low-dose doxorubicin (≤250 mg/m2), and 106 control patients with preserved left ventricular ejection fraction despite doxorubicin >250 mg/m2 were selected as extreme phenotypes. Rare/low-frequency variants were collapsed to identify genes differentially enriched for variants between case patients and control patients. The expression levels of 5 top-ranked genes were evaluated in human induced pluripotent stem cell–derived cardiomyocytes, and variant enrichment was confirmed in a replication cohort. Using random forest, a risk prediction model that included genetic and clinical predictors was developed. Results Thirty-one genes were differentially enriched for variants between case patients and control patients (p < 0.001). Only 42.6% case patients harbored a variant in these genes compared to 89.6% control patients (odds ratio: 0.09; 95% confidence interval: 0.04 to 0.17; p = 3.98 × 10–15). A risk prediction model for cardiotoxicity that included clinical and genetic factors had a higher prediction accuracy and lower misclassification rate compared to the clinical-only model. In vitro inhibition of gene-associated pathways (PI3KR2, ZNF827) provided protection from cardiotoxicity in cardiomyocytes. Conclusions Our study identified variants in cardiac injury pathway genes that protect against cardiotoxicity and informed the development of a prediction model for delayed anthracycline cardiotoxicity, and it also provided new targets in autophagy genes for the development of cardio-protective drugs. (Preventing Cardiac Sequelae in Pediatric Cancer Survivors [PCS2]; NCT01805778), Central Illustration

PURPOSE Survivors of childhood cancer treated with anthracyclines and/or chest-directed radiation are at increased risk for heart failure (HF). The International Late Effects of Childhood Cancer Guideline Harmonization Group (IGHG) recommends risk-based screening echocardiograms, but evidence supporting its frequency and cost-effectiveness is limited. PATIENTS AND METHODS Using the Childhood Cancer Survivor Study and St Jude Lifetime Cohort, we developed a microsimulation model of the clinical course of HF. We estimated long-term health outcomes and economic impact of screening according to IGHG-defined risk groups (low [doxorubicin-equivalent anthracycline dose of 1-99 mg/m2 and/or radiotherapy < 15 Gy], moderate [100 to < 250 mg/m2 or 15 to < 35 Gy], or high [≥ 250 mg/m2 or ≥ 35 Gy or both ≥ 100 mg/m2 and ≥ 15 Gy]). We compared 1-, 2-, 5-, and 10-year interval-based screening with no screening. Screening performance and treatment effectiveness were estimated based on published studies. Costs and quality-of-life weights were based on national averages and published reports. Outcomes included lifetime HF risk, quality-adjusted life-years (QALYs), lifetime costs, and incremental cost-effectiveness ratios (ICERs). Strategies with ICERs < $100,000 per QALY gained were considered cost-effective. RESULTS Among the IGHG risk groups, cumulative lifetime risks of HF without screening were 36.7% (high risk), 24.7% (moderate risk), and 16.9% (low risk). Routine screening reduced this risk by 4% to 11%, depending on frequency. Screening every 2, 5, and 10 years was cost-effective for high-risk survivors, and every 5 and 10 years for moderate-risk survivors. In contrast, ICERs were > $175,000 per QALY gained for all strategies for low-risk survivors, representing approximately 40% of those for whom screening is currently recommended. CONCLUSION Our findings suggest that refinement of recommended screening strategies for IGHG high- and low-risk survivors is needed, including careful reconsideration of discontinuing asymptomatic left ventricular dysfunction and HF screening in low-risk survivors.

Objectives. We had two aims: (1) identify and analyze models of survivorship care for adult survivors of childhood cancer that include primary care, and (2) identify available tools, training, and other resources for adult survivors of childhood cancer. Methods. For each aim, we used realist synthesis to provide insights on how and for whom, in what contexts, and via what mechanisms the models of care and resources we identified can be effective for adult survivors of childhood cancer. We developed an initial program theory through searches of the literature and discussions with Stakeholders. We then identified and summarized quantitative evidence that supported or refuted the theory and developed specific hypotheses about how contexts and mechanisms may interact to produce outcomes (i.e., “CMO” hypotheses). The final program theory and CMO hypotheses were presented to Stakeholders for feedback. Results. Our final refined theory describes how, within the overall environment, survivor and provider characteristics and facilitators/barriers interact to produce intermediate and final outcomes. We focus on the role of models of care and resources (e.g., care plans) in these interactions. The program theory variables seen most consistently in the literature include oncology care versus primary care, survivor and provider knowledge (i.e., survivor risks and needs), provider comfort treating childhood cancer survivors, communication and coordination between and among providers and survivors, and delivery/receipt of prevention and surveillance of late effects of original cancer treatment. In turn, these variables played the most prominent role in the seven CMO hypotheses (4 focused on survivors and 3 focused on providers) regarding what works for whom and in what circumstances. Conclusions. To enable models of care that include primary care for adult survivors of childhood cancer, there needs to be communication of knowledge to both survivors and primary care providers. Our program theory provides guidance on the ways this knowledge could be shared, including the role of resources in doing so, and our CMO hypotheses suggest how the relationships illustrated in our theory could be associated with survivors living longer and feeling better through high-value care.

Background Early initiation of breast cancer screening is recommended for high-risk women, including survivors of childhood cancer treated with chest radiation. Recent studies suggest that female survivors of childhood leukemia or sarcoma treated without chest radiation are also at elevated early onset breast cancer risk. However, the potential clinical benefits and cost-effectiveness of early breast cancer screening among these women are uncertain. Methods Using data from the Childhood Cancer Survivor Study, we adapted 2 Cancer Intervention and Surveillance Modeling Network simulation models to reflect the elevated risks of breast cancer and competing mortality among leukemia and sarcoma survivors. Costs and utility weights were based on published studies and databases. Outcomes included breast cancer deaths averted, false-positive screening results, benign biopsies, and incremental cost-effectiveness ratios. Results In the absence of screening, the lifetime risk of dying from breast cancer among survivors was 6.8% to 7.0% across models. Early initiation of annual mammography with breast magnetic resonance imaging screening between ages 25 and 40 years would avert 52.6% to 64.3% of breast cancer deaths. When costs and quality-of-life impacts were considered, screening starting at age 40 years was the only strategy with an incremental cost-effectiveness ratio below the $100 000 per quality-adjusted life-year (QALY) gained cost-effectiveness threshold ($27 680 to $44 380 per QALY gained across models). Conclusions Among survivors of childhood leukemia or sarcoma, early initiation of breast cancer screening at age 40 years may reduce breast cancer deaths by half and is cost-effective. These findings could help inform screening guidelines for survivors treated without chest radiation.

Background Prognostic factors in adolescent and young adult (AYA) glioma are not well understood. Though clinical and molecular differences between pediatric and adult glioma have been characterized, their application to AYA populations is less clear. There is a major need to develop more robust evidence-based practices for managing AYA glioma patients. Methods A systematic review using PRISMA methodology was conducted using multiple databases with the objective of identifying demographic, clinical, molecular and treatment factors influencing AYA glioma outcomes. Results 40 Studies met inclusion criteria. Overall survival was highly variable across studies depending on glioma grade, anatomic compartment and cohort characteristics. Thirty-five studies suffered from high risk of bias in at least one domain. Several studies included older adults within their cohorts; few captured purely AYA groups. Despite study heterogeneity, identified favorable prognosticators included younger age, higher functional status at diagnosis, low-grade pathology, oligodendroglioma histology and increased extent of surgical resection. Though isocitrate dehydrogenase (IDH) mutant status was associated with favorable prognosis, validity of this finding within AYA was compromised though may studies including older adults. The prognostic influence of chemotherapy and radiotherapy on overall survival varied across studies with conflicting evidence. Conclusion Existing literature is heterogenous, at high risk of bias, and rarely focused solely on AYA patients. Many included studies did not reflect updated pathological and molecular AYA glioma classification. The optimal role of chemotherapy, radiotherapy, and targeted agents cannot be determined from existing literature and should be the focus of future studies.

Objectives: The purpose of this study was to assess the timing of changes in serial echocardiographic parameters in pediatric cancer survivors and to evaluate their associations with cardiomyopathy development. Background: Pediatric cancer survivors undergo serial echocardiograms to screen for cardiotoxicity. It is not clear whether small longitudinal changes in functional or structural parameters over time have clinical significance. Methods: This is a multicenter, retrospective, case-control study of ≥1-year survivors following the end of cancer therapy. Cardiomyopathy cases (fractional shortening [FS] ≤28% or ejection fraction [EF] ≤50% on ≥2 occasions) were matched to control subjects (FS ≥30%, EF ≥55%, not on cardiac medications) by cumulative anthracycline and chest radiation dose, follow-up duration, and age at diagnosis. Digitally archived clinical surveillance echocardiograms were quantified in a central core laboratory, blinded to patient characteristics. Using mixed models with interaction terms between time and case status, we estimated the least square mean differences of 2-dimensional, M-mode, pulsed wave Doppler, and tissue Doppler imaging–derived parameters over time between cases and control subjects. Results: We identified 50 matched case-control pairs from 5 centers. Analysis of 412 echocardiograms (cases, n = 181; control subjects, n = 231) determined that indices of left ventricular systolic function (FS, biplane EF), diastolic function (mitral E/A ratio), and left ventricular size (end-diastolic dimension z-scores) were significantly different between cases and control subjects, even 4 years prior to the development of cardiomyopathy. Conclusions: Longitudinal changes in cardiac functional parameters can occur relatively early in pediatric cancer survivors and are associated with the development of cardiomyopathy.

Background: Cancer in children presents unique issues for diagnosis, treatment and survivorship care. Phase-specific comparative cost estimates are important for informing healthcare planning. Objectives: The aim of this paper is to compare direct medical costs of childhood cancer by phase of care in British Columbia (BC) and Ontario (ON). Methods: For cancer patients diagnosed at 50% higher in ON. Phase-specific in-patient hospital costs (the major cost category) represented 63%–82% of ON costs, versus 43%–73% of BC costs. Phase-specific diagnostic tests and procedures accounted for 1.0%–3.4% of ON costs and 2.8%–13.0% of BC costs. Conclusions: There are substantial cost differences between these two Canadian provinces, BC and ON, possibly identifying opportunities for healthcare planning improvement.

With the widespread adoption of multimodality treatment, 5-year survival of children diagnosed with cancer has improved dramatically in the past several decades from approximately 60% in 1970 to greater than 85% currently. As a result, there are an estimated nearly half a million long-term survivors of childhood cancer living in the United States today. However, survivors have, on average, significantly greater serious medical and psychosocial late effects compared with the general population. In this review, we will discuss the current epidemiology of childhood cancer survivorship, including new methods to estimate the burden of late effects and genetic susceptibility toward late effects. We will also review the development of surveillance guidelines for childhood cancer survivors and early toxicity signals from novel agents now being tested and used increasingly to treat pediatric and adult cancers. We conclude with an overview of current models of survivorship care and areas for future research.

PURPOSE To estimate the prevalence of frailty among childhood cancer survivors and to determine the direct and indirect effects of treatment exposures, lifestyle factors, and severe, disabling, and life-threatening chronic condition on frailty. METHODS Childhood cancer survivors (≥ 5 years since diagnosis), treated between 1970 and 1999 when < 21 years old (n = 10,899; mean age, 37.6 ± 9.4 years; 48% male, 86% white) and siblings were included (n = 2,097; mean age, 42.9 ± 9.4 years). Frailty was defined as ≥ 3 of the following: low lean mass, exhaustion, low energy expenditure, walking limitations, and weakness. Generalized linear models were used to evaluate direct and indirect associations between frailty and treatment exposures, sociodemographic characteristics, lifestyle factors, and chronic condition. RESULTS The overall prevalence of frailty among survivors was 3 times higher compared with siblings (6.4%; 95% CI, 4.1% to 8.7%; v 2.2%; 95% CI, 1.2% to 3.2%). Survivors of CNS tumors (9.5%; 95% CI, 5.2% to 13.8%) and bone tumors (8.1%; 95% CI, 5.1% to 11.1%) had the highest prevalence of frailty. Survivors exposed to cranial radiation, pelvic radiation ≥ 34 Gy, abdominal radiation > 40 Gy, cisplatin ≥ 600 mg/m2, amputation, or lung surgery had increased risk for frailty. These associations were partially but not completely attenuated when sociodemographic characteristics, lifestyle factors, and chronic conditions were added to multivariable models. Cranial radiation (prevalence ratio [PR], 1.47; 95% CI, 1.20 to 1.76), pelvic radiation ≥ 34 Gy (PR, 1.46; 95% CI, 1.01 to 2.11), and lung surgery (PR, 1.75; 95% CI, 1.28 to 2.38) remained significant after sociodemographic, lifestyle, and chronic conditions were accounted for. CONCLUSION Childhood cancer survivors reported a higher prevalence of frailty compared with siblings. Radiation and lung surgery exposures were associated with increased risk for frailty. Interventions to prevent, delay onset, or remediate chronic disease and/or promote healthy lifestyle are needed to decrease the prevalence of frailty and preserve function in this at-risk population.

PURPOSE Although a diagnosis of childhood cancer can have a profound effect on the entire family unit, its impact on the long-term mental health of family members is not well characterized. METHODS A provincial childhood cancer registry in Ontario, Canada, was linked to birth records to identify separate population-based cohorts of mothers and siblings of children diagnosed with cancer between 1998 and 2014. The mother and sibling cohorts were matched to corresponding population controls and linked to health services data. The rate of mental health–related outpatient visits (family physician, psychiatrist) and the incidence of severe psychiatric events (psychiatric emergency department visit, psychiatric hospitalization, suicide) were compared between mothers and siblings and their controls. Possible predictors of mental health outcomes were examined, including demographics, characteristics of the cancer-affected child, and cancer treatment. RESULTS We identified 4,773 mothers and 7,897 siblings of children diagnosed with cancer during the study period. Compared with controls, both groups experienced elevated rates of outpatient visits (mothers: rate ratio [RR], 1.4; P < .0001; siblings: RR, 1.1; P < .0001). The risk of severe psychiatric events was not increased in either cohort. Mother and sibling demographic factors associated with increased risk of adverse mental health included younger maternal age at cancer diagnosis, low socioeconomic status, and rural residence among mothers and older sibling age among siblings. Treatment-related variables pertaining to the cancer-affected child were not associated with mental health outcomes. Mental health outcomes clustered within families. CONCLUSION Both mothers and siblings experience elevated and prolonged need for mental health–related health care as compared with the general population. Demographic risk factors predict subpopulations at highest risk. Increased psychosocial support for family members during and after cancer therapy is warranted.

Appropriate models of survivorship care for the growing number of adult survivors of childhood cancer are unclear. We conducted a realist review to describe how models of care that include primary care and relevant resources (eg, tools, training) could be effective for adult survivors of childhood cancer. We first developed an initial program theory based on qualitative literature (studies, commentaries, opinion pieces) and stakeholder consultations. We then reviewed quantitative evidence and consulted stakeholders to refine the program theory and develop and refine context-mechanism-outcome hypotheses regarding how models of care that include primary care could be effective for adult survivors of childhood cancer. Effectiveness for both resources and models is defined by survivors living longer and feeling better through high-value care. Intermediate measures of effectiveness evaluate the extent to which survivors and providers understand the survivor’s history, risks, symptoms and problems, health-care needs, and available resources. Thus, the models of care and resources are intended to provide information to survivors and/or primary care providers to enable them to obtain/deliver appropriate care. The variables from our program theory found most consistently in the literature include oncology vs primary care specialty, survivor and provider knowledge, provider comfort treating childhood cancer survivors, communication and coordination between and among providers and survivors, and delivery/receipt of prevention and surveillance of late effects. In turn, these variables were prominent in our context-mechanism-outcome hypotheses. The findings from this realist review can inform future research to improve childhood cancer survivorship care and outcomes.

Importance Prompt recognition of a child with a cancer predisposition syndrome (CPS) has implications for cancer management, surveillance, genetic counseling, and cascade testing of relatives. Diagnosis of CPS requires practitioner expertise, access to genetic testing, and test result interpretation. This diagnostic process is not accessible in all institutions worldwide, leading to missed CPS diagnoses. Advances in electronic health technology can facilitate CPS risk assessment. Objective To evaluate the diagnostic accuracy of a CPS prediction tool (McGill Interactive Pediatric OncoGenetic Guidelines [MIPOGG]) in identifying children with cancer who have a low or high likelihood of having a CPS. Design, Setting, and Participants In this international, multicenter diagnostic accuracy study, 1071 pediatric (

Since the inception of the Journal of Cancer Survivorship (JCSU), the founding editor-in-chief, the associate editors, editorial board members, and peer reviewers have played important roles in influencing the knowledge base published in JCSU. The journal editors represent key disciplines, practice areas, and research expertise in cancer survivorship, which includes oncology and hematology, pediatric oncology, health psychology/behavior medicine, primary care, oncology nursing, exercise oncology, epidemiology, rehabilitation sciences, health services research, health policy, public health, and sociology. Over the years, the journal editors have worked to facilitate peer review and provide quality reviews to prospective authors. Earlier this year, Chan et al. [1] provided an overview of the evolution of JCSU since its inception in 2007 to 2020. Chan et al.’s [1] paper included a comprehensive description of the content, impact metrics, and top cited papers. In addition, they created a neural network using the key terms of published articles (Fig. 1) that depicted both minor and major themes published since the inception of JCSU.

Background Human papillomavirus (HPV)-associated subsequent malignant neoplasms (SMNHPV ) in childhood cancer survivors are poorly understood. Methods The cumulative risk of SMNHPV was assessed among 24,363 Childhood Cancer Survivor Study participants. Standardized incidence ratios (SIRs) and absolute excess risk were calculated using age-matched, sex-matched, and calendar year rates from the Surveillance, Epidemiology, and End Results program. Poisson regression models identified SMNHPV risk factors, evaluating relative SIRs (rSIR) and 95% confidence intervals (95% CIs). Results In total, 46 survivors developed an SMNHPV (median age, 31 years [range, 10-56 years]; median time from primary cancer, 21 years [range, 9-35 years]). SMNHPV sites included oropharynx (N = 44), anorectum (N = 6), uterine cervix (N = 2), and vulva (N = 2). The 33-year cumulative incidence was 0.3% (95% CI, 0.2%-0.4%), and the SIR was nearly 3-fold that of the general population (SIR, 2.86; 95% CI, 2.05-4.00). Female survivors were not at increased risk of cervical or vulvar cancers compared with the general population. All survivors had an elevated risk of oropharyngeal SMNHPV (males: SIR, 4.06; 95% CI, 2.37-6.97; females: SIR, 8.44; 95% CI 4.88-14.61) and anorectal SMNHPV (males: SIR, 13.56; 95% CI, 5.09-36.13; females: SIR, 9.15; 95% CI, 2.29-36.61). Males (vs females: rSIR, 1.99; 95% CI, 1.00-3.94); head, neck, and pelvic radiotherapy doses >3000 centigray (vs none: rSIR, 2.35; 95% CI, 1.11-4.97); and cisplatin-equivalent doses >400 mg/m2 (vs none: rSIR, 4.51; 95% CI, 1.78-11.43) were associated with increased SMNHPV SIRs in multivariable analysis. Conclusions Childhood cancer survivors are at increased risk for SMN in sites susceptible to HPV-associated malignancies. Further research examining HPV in the etiology of SMN and the promotion of HPV vaccination and surveillance guidelines for SMNHPV in cancer survivors is warranted.

Background: The European Organisation for Research and Treatment of Cancer (EORTC) 1325/KEYNOTE-054 trial assessed pembrolizumab versus placebo in patients with resected high-risk stage III melanoma. At 15-month median follow-up, pembrolizumab improved recurrence-free survival (hazard ratio [HR] 0·57 [98·4% CI 0·43–0·74], p1 mm), IIIB, or IIIC (without in-transit metastasis), and with an Eastern Cooperative Oncology Group performance status of 0 or 1 were eligible. Patients were randomly assigned (1:1) via a central interactive voice response system to receive intravenous pembrolizumab 200 mg or placebo every 3 weeks for up to 18 doses or until disease recurrence or unacceptable toxicity. Randomisation was stratified according to disease stage and region, using a minimisation technique, and clinical investigators, patients, and those collecting or analysing the data were masked to treatment assignment. The two coprimary endpoints were recurrence-free survival in the intention-to-treat (ITT) population and in patients with PD-L1-positive tumours. The secondary endpoint reported here was distant metastasis-free survival in the ITT and PD-L1-positive populations. This study is registered with ClinicalTrials.gov, NCT02362594, and EudraCT, 2014-004944-37. Findings: Between Aug 26, 2015, and Nov 14, 2016, 1019 patients were assigned to receive either pembrolizumab (n=514) or placebo (n=505). At an overall median follow-up of 42·3 months (IQR 40·5–45·9), 3·5-year distant metastasis-free survival was higher in the pembrolizumab group than in the placebo group in the ITT population (65·3% [95% CI 60·9–69·5] in the pembrolizumab group vs 49·4% [44·8–53·8] in the placebo group; HR 0·60 [95% CI 0·49–0·73]; p

Context Childhood cancer survivors experience chronic health conditions that impact health-related quality of life (HRQOL) and participation in optimal physical activity. Objective The study aimed to determine independent effects of endocrine and metabolic disorders on HRQOL and physical activity. Design, Setting, and Patients Retrospective cohort with longitudinal follow-up of survivors of childhood cancer enrolled in the North American Childhood Cancer Survivor Study. Main Outcome Measures Medical Outcomes Short Form-36 estimated HRQOL, and participation in physical activity was dichotomized as meeting or not meeting recommendations from the Centers for Disease Control and Prevention. Log binomial regression evaluated the association of each endocrine/metabolic disorder with HRQOL scales and physical activity. Results Of 7287 survivors, with a median age of 32 years (range, 18 to 54 years) at their last follow-up survey, 4884 (67%) reported one or more endocrine/metabolic disorders. Survivors with either disorder were significantly more likely to be male, older, have received radiation treatment, and have experienced other chronic health conditions. After controlling for covariates, survivors with any endocrine/metabolic disorder were more likely to report poor physical function risk ratio (RR, 1.25; 95% CI, 1.05 to 1.48), increased bodily pain (RR, 1.27; 95% CI, 1.12 to 1.44), poor general health (RR, 1.49; 95% CI, 1.32 to 1.68), and lower vitality (RR, 1.21; 95% CI, 1.09 to 1.34) compared with survivors without. The likelihood of meeting recommended physical activity was lower among survivors with growth disorders (RR, 0.90; 95% CI, 0.83 to 0.97), osteoporosis (RR, 0.87; 95% CI, 0.76 to 0.99), and overweight/obesity (RR, 0.92; 95% CI, 0.88 to 0.96). Conclusion Endocrine and metabolic disorders are independently associated with poor HRQOL and suboptimal physical activity among childhood cancer survivors.

Background Adolescent women treated for Hodgkin lymphoma (HL) are at increased risk of breast cancer (BC). We evaluate the cost-utility of eight high-risk BC surveillance strategies for this population, including the Children’s Oncology Group guideline of same-day annual mammography and magnetic resonance imaging (MRI) beginning at age 25 years. Methods A discrete event simulation model was used to simulate the life histories of a cohort of 500 000 25-year-old women treated for HL at age 15 years. We estimated BC incidence and mortality, life expectancy, quality-adjusted life-years (QALYs), health-care costs, and the relative cost-utility (incremental cost-utility ratio [ICUR]) under the eight assessed surveillance strategies. One-way sensitivity analysis enabled modeling of uncertainty evaluation. A publicly funded health-care payer perspective was adopted. Results Costs across the eight screening strategies ranged from $32 643 to $43 739, whereas QALYs ranged from 24.419 to 24.480. In an incremental cost-effectiveness analysis, annual mammography beginning at age 25 years was associated with an ICUR of $43 000/QALY gained, annual MRI beginning at age 25 years with a switch to annual mammography at age 50 years had an ICUR of $148 000/QALY, and annual MRI beginning at age 25 years had an ICUR of $227 222/QALY. Among all assessed surveillance strategies, the differences in life expectancy were small. Conclusions Current high-risk BC surveillance guidelines do not reflect the most cost-effective strategy in survivors of adolescent HL. The results suggest that groups at high risk of BC may require high-risk surveillance guidelines that reflect their specific risk profile.

Background Retrospective studies have shown adolescents and young adults (AYA) with acute lymphoblastic leukemia (ALL) have superior survival when treated in pediatric versus adult centers (locus of care; LOC). Several adult centers recently adopted pediatric protocols. Whether this has narrowed LOC disparities in real-world settings is unknown. Methods The IMPACT Cohort is an Ontario population-based cohort that captured demographic, disease and treatment (treatment protocol, chemotherapy doses) data for all 15-21 year olds diagnosed with ALL 1992-2011. Cancer outcomes were determined by chart abstraction and linkage to provincial healthcare databases. Treatment protocols were classified as pediatric- or adult-based. We examined predictors of outcome, including LOC, protocol, disease biology, and time period. Results Of 271 patients, 152 (56%) received therapy at adult centers. 5-year event-free survival (EFS +/- SE) among AYA at pediatric vs adult centers was 72% +/- 4% vs 56% +/- 4% (P = 0.03); 5-year overall survival (OS) was 82% +/- 4% vs 64% +/- 4% (P < 0.001). After adjustment, OS remained inferior at adult centers (hazard ratio 2.5; 95% confidence interval 1.1-6.1; P = 0.04). In the most recent period (2006-2011), 39/59 (66%) AYA treated at adult centers received pediatric protocols. These AYA had outcomes superior to the 20 AYA treated on adult protocols, but inferior to the 44 AYA treated at pediatric centers (EFS 72% +/- 5% vs 60% +/- 9% vs 81% +/- 6%; P = 0.02; OS 77% +/- 7% vs 65% +/- 11% vs 91% +/- 4%; P = 0.004). Induction deaths and treatment-related mortality did not vary by LOC. Conclusions Survival disparities between AYA with ALL treated in pediatric vs adult centers have persisted over time, partially attributable to incomplete adoption of pediatric protocols by adult centers. Although pediatric protocol use has improved survival, residual disparities remain, perhaps due to other differences in care between adult and pediatric centers.