Long-term Survivors Of Pediatric Cancer Research Articles

Risk of low bone mineral density in young pediatric cancer survivors with sarcopenia.

10070 Background: Required treatments to cure pediatric cancer at such a young age increase the risk of later health-related complications. Early exposure to DNA damaging agents, during a vital period of active skeletal growth, interferes with accrual of bone mass. Treatments not only impair bone health, but also affect skeletal muscle function and mass. Long-term pediatric cancer survivors present these limitations due to myofibrillary atrophy caused by degradation of myosin heavy chain and decrease in myosin synthesis death. Muscle weakness (both muscle strength deficits and low lean mass hereafter referred to as sarcopenia) and low areal bone mineral density (aBMD) have been observed to coexist in adult survivors of paediatric cancer. However, in young pediatric cancers survivors, associations between sarcopenia and low aBMD are not well described. Therefore, this study aimed to examine the risk of low aBMD in young pediatric cancer survivors with sarcopenia confirmed/probable, compared to not having sarcopenia. Methods: This cross-sectional study included 116 pediatric cancer survivors (12.1±3.3 years old; 42% female) enrolled on a randomized controlled trial designed to improve bone health (iBoneFIT project). Handgrip strength was used to assessed muscle strength. Dual-energy X-ray absorptiometry estimated aBMD (g/cm2) at the total body (less head), lumbar spine, total hip and femoral neck, and appendicular lean mass index (ALMI, kg/m2). Sarcopenia status was determined using age and sex specific international reference data from a healthy population. “No sarcopenia” was defined when muscle strength was >decile 2. “Sarcopenia probable” was defined when muscle strength was ≤decile 2 and ALMI Z-score was > -1.5 standard deviation (SD). “Sarcopenia confirmed” was defined when muscle strength was ≤decile 2 and ALMI Z-score ≤-1.5 SD. Logistic regression, adjusted for time from treatment completion and radiation exposure, was used to evaluate the risk of low aBMD (age-, sex- and race-specific aBMD Z-score < -1.0) by sarcopenia status. Results: More than one-third of survivors met criteria for sarcopenia confirmed (37.9%); 19.0% met criteria for sarcopenia probable. Survivors with sarcopenia confirmed had higher risk of low aBMD at the total body (odd ratio [OR]: 6.91, 95% confidence interval [CI]: 2.31-24.15), total hip (OR: 2.98, 95% CI: 1.02-9.54) and femoral neck (OR: 4.72, 95% CI: 1.72-14.19) than those without sarcopenia. Survivors with sarcopenia probable had higher risk of having low aBMD only at the total body (OR: 4.13, 95% CI: 1.04-17.60) than those without sarcopenia. Conclusions: Over one-third of young paediatric cancer survivors presented sarcopenia confirmed with higher risk of low aBMD. These findings suggest that interventions to mitigate osteosarcopenia in this population should be implemented at early stages after treatment completion.

Longitudinal associations between peripheral neuropathy and neurocognitive decline in long-term survivors of pediatric cancer treated without central nervous system (CNS) directed therapy.

10054 Background: Survivors of pediatric cancer treated without CNS-directed therapy are at risk of neurocognitive impairment and peripheral neuropathies. Using the St. Jude Lifetime Cohort, we investigated longitudinal associations with neuropathy to inform contributors to long-term cancer-related neurocognitive decline. Methods: Survivors of pediatric cancer (N=899 mean age 32 [SD 12], 24[10] years from diagnosis) treated without CNS-directed therapy completed neurocognitive testing and medical assessments at two timepoints (T1, T2 4.4[2.3] years apart). Peripheral sensory and motor neuropathy subscales combined with functional tasks were severity graded using a modified CTCAE (no neuropathy = none or grade 1 at T1 and T2; new onset = new grade 2 or 3 at T2; persistent = grade 2 or 3 at T1 & T2). Linear regression models estimated change in neurocognitive Z-score associated with neuropathy groups, adjusted for diagnosis age, time between visits, sex, race/ethnicity, high-dose intravenous methotrexate & baseline neurocognitive Z-score. Results: New onset sensory (n=33, 3.6%) and motor (n=35, 3.9%) neuropathy was associated with a 0.33 standard deviation (SD) decline in visual-motor processing speed (Table). New onset motor neuropathy was associated with a 0.50 SD decline in sustained attention as well as significant declines in verbal recall, working memory, and cognitive flexibility (p’s<0.05). Persistent sensory neuropathy (n=25, 2.8%) was associated with large declines in focused attention and cognitive flexibility (p’s<0.05). Persistent motor neuropathy (n=18, 2.0%) was associated with a 0.50 SD decline in sustained attention, verbal recall, and working memory (p’s<0.05). Conclusions: Peripheral neuropathies are associated with future neurocognitive decline in adult survivors of pediatric cancer. Research is needed to understand shared mechanisms (e.g. pain, inflammation) to inform targeted interventions to improve neuropathic symptoms and neurocognitive function. [Table: see text]

Dynamics of Age- versus Therapy-Related Clonal Hematopoiesis in Long-term Survivors of Pediatric Cancer.

This first comprehensive CH analysis in long-term survivors of pediatric cancer presents the elevated prevalence and therapy exposures/diagnostic spectrum associated with CH. Due to the contrasting dynamics of clonal expansion for age-related versus therapy-related CH, longitudinal monitoring is recommended to ascertain the long-term effects of therapy-induced CH in pediatric cancer survivors. See related commentary by Collord and Behjati, p. 811. This article is highlighted in the In This Issue feature, p. 799.

Incidence and risk factors of anthracycline-induced cardiotoxicity in long-term survivors of pediatric cancer: A population based cohort study

BackgroundPopulation-based data on the incidence of anthracycline-induced cardiotoxicity (AIC) in long-term survivors of childhood cancer is limited. This study will report the incidence and risk factors for AIC in long term survivors of pediatric cancer. Material and methodsA retrospective population-based study was conducted using (i) patient charts (ii) oncology database at the IWK Health Centre. All pediatric oncology patients treated with anthracycline on or before December 2014 and followed in the long-term follow up were included. Cardiotoxicity was defined as an ejection fraction (EF) < 50% and/or a fractional shortening (FS) < 27% in any echocardiogram or comparable cardiac imaging and/or symptomatic cardiotoxicity. Pearson's Chi-Square and Fisher's exact were used to determine the relationship of cardiac changes to various risk factors. ResultsIn 184 patients, we found an incidence of AIC of 5.98%. AIC with long-term complications had a low incidence (2.17%). The mean age at diagnosis for patients with AIC was 5.55 ± 4.97 years. The follow-up time ranged from 5 to 25 years (mean = 9.06). The time from treatment to a cardiac event ranged from 0 to 15 years (mean = 3.82). Our study found that bone marrow transplant (p = 0.025) and cancer diagnosis (p = 0.039) were significantly associated with AIC. However, when only symptomatic patients were analyzed, only a cumulative dose of anthracycline ≥300 mg/m2 had a significant relationship with AIC (p = 0.017). ConclusionThe present study confirms the dose dependent AIC in long term oncology follow up patients.

Neuropathy and neurocognitive impairment in long-term survivors of pediatric cancer treated without central nervous system (CNS) directed therapy.

10020 Background: Survivors of pediatric cancer, including those without CNS-directed treatment, are at risk of neurocognitive impairment and peripheral or autonomic neuropathies; conditions that co-occur in non-cancer populations. Using the St. Jude Lifetime Cohort, we investigated associations between these sequelae to inform contributors to long-term cancer-related neurocognitive impairment. Methods: Clinically assessed survivors of pediatric cancer (N=2,138, mean age 31 [SD 13], 23[11] years from diagnosis, 51% male) not treated with CNS-directed therapy completed neurocognitive testing. Modified total neuropathy score peripheral sensory and motor subscales were combined with functional tasks and severity graded using a modified NCI CTCAE. Cardiac autonomic neuropathy was defined as impaired heart rate reserve (&lt;80% age- sex-predicted or ≤62% with beta blocker). Separate log binomial regression models estimated risk of neurocognitive impairment (age adjusted z-score &lt;10th percentile) associated with grade 2+ sensory, motor or autonomic neuropathy. Path analysis examined if pain with daily interference mediated associations between motor or sensory neuropathy and neurocognitive impairment. Results: 838 (39%) survivors had autonomic, 115 (5.4%) had motor and 162 (7.6%) had sensory neuropathy. Compared to those with no neuropathy, survivors with motor or sensory neuropathy had a higher risk of impairment in sustained attention, visual-motor processing speed, short- and long-term memory, and executive function (Table, p’s&lt;0.01). Autonomic neuropathy was associated with a higher risk of impairment in visuo-motor processing speed (p=0.03). Pain partially mediated associations between sensory neuropathy and sustained attention (10% mediated, p=0.04), visual-motor processing speed (8% p=0.02), and executive function (14% p=0.02). Pain was not related to motor neuropathy. Conclusions: Peripheral and autonomic neuropathies are associated with significant risk of neurocognitive impairment in adult survivors of pediatric cancer. Research is needed to further understand shared mechanisms (e.g., pain, inflammation) to design targeted interventions to improve neuropathic symptoms and neurocognitive function. [Table: see text]

Fecal microbiota of adolescent and young adult cancer survivors and metabolic syndrome: an exploratory study

Metabolic syndrome and obesity occur commonly in long-term pediatric cancer survivors. The intestinal microbiome is associated with metabolic syndrome and obesity in the general population, and is perturbed during cancer therapy. We aimed to determine if long-term survivors of pediatric cancer would have reduced bacterial microbiome diversity, and if these findings would be associated with components of the metabolic syndrome, obesity, and chronic inflammation. We performed a cross-sectional exploratory study examining the intestinal microbiome via 16S amplicon sequencing, treatment history, clinical measurements (blood pressure, body mass index) and biomarkers (hemoglobin A1c, lipoproteins, adiponectin: leptin ratio, C-reactive protein, TNFα, Interleukin-6, and Interleukin-10) between 35 long-term survivors and 32 age, sex, and race matched controls. All subjects were aged 10–40 years, and survivors were at least five years from therapy completion. Survivors had lower alpha diversity compared to controls (Shannon index p = .001, Simpson index p = .032) and differently abundant bacterial taxa. Further, among survivors, those who received radiation (18/35) to the central nervous system or abdomen/pelvis had decreased alpha diversity compared to those who did not receive radiation (Shannon and Simpson p < .05 for both). Although, no specific component of metabolic syndrome or cytokine was associated with measures of alpha diversity, survivors with low adiponectin–lectin ratio, elevated body mass index, and elevated C-reactive protein had differently abundant taxa compared to those with normal measures. The microbiome of cancer survivors remains less diverse than controls even many years after diagnosis, and exposure to radiation may lead to further loss of diversity in survivors. Supplemental data for this article is available online at https://doi.org/10.1080/08880018.2022.2049937

Cardiac Surveillance for Early Detection of Late Subclinical Cardiac Dysfunction in Childhood Cancer Survivors After Anthracycline Therapy.

BackgroundIn childhood cancer survivors (CCSs) anthracycline-related cardiotoxicity is an important cause of morbidity and late mortality, but the optimal modality of cardiac surveillance still remains to be defined. The aim of this study was to assess whether non-invasive echocardiography-based functional cardiac measures can detect early subclinical myocardial changes in long-term pediatric cancer survivors who received anthracycline therapy.MethodsTwenty anthracycline-treated long-term CCSs and 20 age, sex, and body surface area matched healthy controls were enrolled in this study. Among cancer survivors, mean age at diagnosis was 6.5 ± 4.4 years, and the mean cumulative anthracycline dose was 234.5 ± 87.4 mg/m2. All subjects underwent a comprehensive functional echocardiographic protocol study including two-dimensional echocardiography (2D Echo), tissue Doppler imaging (TDI), speckle tracking (STE) and three-dimensional echocardiography (3D Echo). Patients were studied at a mean follow-up time of 6.5 ± 2.8 years from the end of therapy.ResultsNo significant differences in two-dimensional left ventricle ejection fraction (LVEF), diastolic parameters and speckle tracking (STE)-derived myocardial strain were observed between patients treated with anthracyclines and controls. Myocardial performance index was significantly prolonged (p = 0.005) and three-dimensional LVEF was significantly reduced (p = 0.002) in CCSs compared to controls, even though most values were within the normal range. There were no significant correlations between 2D, STE, and 3D echocardiographic parameters and age at diagnosis or duration of follow-up. No significant differences in echocardiographic parameters were found when stratifying cancer patients according to established risk factors for anthracycline cardiomyopathy.ConclusionsThis study found significantly reduced three-dimensional LVEF in CCSs compared with controls, despite no significant differences in two-dimensional LVEF and longitudinal strain values. These findings suggest that long-term CCSs who had received anthracycline therapy may be found to have subclinical features of myocardial dysfunction. However, further studies are needed to demonstrate the validity of new imaging techniques, including STE and 3D Echo, to identify patients at risk for cardiomyopathy in the long-term follow-up of CCSs.

A crosscut survey on reproductive health in Lithuanian childhood cancer survivors

Sexual dysfunction was reported to compromise the quality of life in childhood cancer survivors. The aim of our study was to evaluate the reproductive health in long-term pediatric cancer survivors by conducting a crosscut survey. Childhood cancer survivors over 18 years of age, who were in remission for more than 5 years, were invited to complete a gender-specific questionnaire surveying on their reproductive health. Demographic and treatment data were retrieved from their medical records. Treatment modalities were reviewed for its potential gonadotoxicity. 34 (17 males and 17 females, respectively) from 346 addressed survivors (9.8%) completed the questionnaire. Median age and follow-up after diagnosis was 27 (18-35) and 14 (3-25) years, respectively. Some respondents reported sexual concerns: 11.8% males experienced problems with penetration, two males (11.8%) who underwent semen analysis were found to be azoospermic. Similarly, 11.8% females reported delayed puberty, the average age of menarche was 14 (12-17) years, 29.4% females reported irregular menstrual cycles. Cyclophosphamide equivalent dose (CED) differed significantly between the patients treated for leukemia, lymphoma and solid tumors (3000 vs 4352 vs 6660 mg/m2, respectively, p = 0.014). Low prevalence of sexual dysfunction, fertility related disorders or delayed puberty in childhood cancer survivors was found. However, the results should be interpreted with caution taking into account a low response rate.

Abstract IA-18: Big pediatric cancer genomic data: Discovery, precision medicine, and data sharing

Abstract High throughput next generation sequencing (NGS) has enabled tremendous advances in our understanding of the genomic landscape of pediatric cancer, leading to discoveries of new mechanisms of tumor initiation and progression, novel targets, and diagnostic and prognostic markers. By focusing on the development of innovative computational analysis tools, we have investigated the genomic variants in pediatric cancer in the following areas: 1) genomic landscapes of &amp;gt;20 subtypes of pediatric cancer; 2) a pan-cancer study of genomes and transcriptomes of pediatric cancer which unveiled that &amp;gt;50% of the driver genes are absent in adult cancer; 3) clonal evolution of relapsed pediatric leukemia driven by therapy-induced variants bearing novel mutational signature; and 4) pathogenic germline mutations in cancer predisposition genes. These insights led to implementation of clinical cancer genomic profiling by three-platform of whole genome, whole exome and transcriptome sequencing for all eligible pediatric cancer patients at St Jude. Use of these data sets improved molecular diagnosis of pediatric cancer. Since 2015, we have analyzed &amp;gt;1,200 pediatric oncology patients providing critical data that may affect patient care. The omics data generated from our research and clinical programs can be accessed on St. Jude Cloud (https://www.stjude.cloud), a cloud-based data sharing ecosystem for accessing, analyzing and visualizing genomic data generated from &amp;gt;10,000 pediatric cancer patients, long-term survivors of pediatric cancer and &amp;gt;800 pediatric sickle cell patients. Access to three interconnected Apps on St. Jude Cloud, i.e. Genomics Platform, Pediatric Cancer (PeCan) Knowledgebase and Visualization Community, provides a unique experience for simultaneously performing advanced data analysis and enhancing the knowledgebase for pediatric cancer. Citation Format: Jinghui Zhang. Big pediatric cancer genomic data: Discovery, precision medicine, and data sharing [abstract]. In: Proceedings of the AACR Virtual Special Conference on Artificial Intelligence, Diagnosis, and Imaging; 2021 Jan 13-14. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(5_Suppl):Abstract nr IA-18.

Frequency of Pathogenic Germline Variants in Cancer-Susceptibility Genes in the Childhood Cancer Survivor Study.

Pediatric cancers are the leading cause of death by disease in children despite improved survival rates overall. The contribution of germline genetic susceptibility to pediatric cancer survivors has not been extensively characterized. We assessed the frequency of pathogenic or likely pathogenic (P/LP) variants in 5451 long-term pediatric cancer survivors from the Childhood Cancer Survivor Study. Exome sequencing was conducted on germline DNA from 5451 pediatric cancer survivors (cases who survived ≥5 years from diagnosis; n = 5105 European) and 597 European cancer-free adults (controls). Analyses focused on comparing the frequency of rare P/LP variants in 237 cancer-susceptibility genes and a subset of 60 autosomal dominant high-to-moderate penetrance genes, for both case-case and case-control comparisons. Of European cases, 4.1% harbored a P/LP variant in high-to-moderate penetrance autosomal dominant genes compared with 1.3% in controls (2-sided P = 3 × 10-4). The highest frequency of P/LP variants was in genes typically associated with adult onset rather than pediatric cancers, including BRCA1/2, FH, PALB2, PMS2, and CDKN2A. A statistically significant excess of P/LP variants, after correction for multiple tests, was detected in patients with central nervous system cancers (NF1, SUFU, TSC1, PTCH2), Wilms tumor (WT1, REST), non-Hodgkin lymphoma (PMS2), and soft tissue sarcomas (SDHB, DICER1, TP53, ERCC4, FGFR3) compared with other pediatric cancers. In long-term pediatric cancer survivors, we identified P/LP variants in cancer-susceptibility genes not previously associated with pediatric cancer as well as confirmed known associations. Further characterization of variants in these genes in pediatric cancer will be important to provide optimal genetic counseling for patients and their families.

Safety Of Exercise Testing In Long Term Survivors Of Pediatric Cancer Exposed To Anthracyclines

Survivors of pediatric cancers are at risk for long-term cardiac complications, often due to a history of treatment with anthracyclines. Current recommendations for these survivors include significant exercise restriction, despite a lack of data on exercise safety. PURPOSE: Determine the burden of arrhythmia and/or evidence of ischemia provoked by standardized exercise stress testing in long-term survivors of pediatric cancer treated with anthracyclines. METHODS: Cardiopulmonary exercise testing (CPET) was performed in 20 subjects (mean age 23.0 +/- 9 yrs; mean BMI 26.3 +/- 7; 55% male). The 12-lead exercise EKG was evaluated for arrhythmia and ischemia at baseline, exercise, and recovery segments of the CPET. Anthracyclines mean dose was 266 +/- 119 mg/m2 with last dose of chemotherapy occurring 5 years ago or later. RESULTS: Subjects had normal left ventricular function determined by cardiac MRI (mean ejection fraction 56% +/- 8). Mean VO2 was 32.6 +/- 9 mL/Kg/min. No sustained atrial or ventricular arrhythmias or ischemic changes were observed in this sample. Isolated premature atrial contractions (PACs) and premature ventricular contractions (PVCs) existed in 8 of the 20 subjects with 1 demonstrating PVCs at baseline, 6 with PVCs or PACs late in exercise, and 4 with PVCs or PACs in recovery. CONCLUSION: CPET revealed safe in a small sample of long-term survivors of pediatric cancer exposed to high-dose anthracyclines with normal heart function. A greater sample size with consistent results could help providers promote physical activity in this population.

Genome-wide association study using whole-genome sequencing to identify a novel locus associated with cardiomyopathy risk in adult survivors of childhood cancer: Utility of a two-stage analytic approach.

1516 Background: Survivors of childhood cancer are at increased risk of treatment-related cardiomyopathy, found to be modified by genetic factors. To further investigate genetic risks of cardiomyopathy, we utilized whole-genome sequencing (WGS) in a clinically phenotyped cohort of long-term survivors of pediatric cancer. Methods: Utilizing a novel 2-stage analytic approach, we first performed association analysis for ejection fraction (EF) using WGS data in European-descent childhood cancer survivors from the St. Jude Lifetime Cohort (SJLIFE). EF was analyzed as a continuous variable to increase statistical power for genetic discovery. Common variants (minor allele frequency (MAF) &gt; 0.05) were analyzed using linear regression, adjusting for age at diagnosis, sex, age at follow-up, doses of anthracycline and average radiation dose to the heart, and eigenvectors. Rare/low-frequency variants were aggregated by different functional annotations and agnostic 4-kb sliding windows, testing jointly using Burden/SKAT test. In the second stage, only the variant showing genome-wide significance with EF was tested for its association with cardiomyopathy risk. Results: Among the 2,015 SJLIFE survivors with WGS data, a locus on 6p21.2 near KCNK17achieved genome-wide significance with EF (rs2815063; MAF = 0.13; per allele beta = -0.016; P = 2.10´10-8), which replicated in 320 SJLIFE African survivors (MAF = 0.48; beta = -0.015; P = 0.004). In SJLIFE Europeans, 282 had a CTCAE Grade 2-5 cardiomyopathy. rs2815063 was significantly associated with increased risk of cardiomyopathy [per allele odds ratio (OR) = 1.38; P = 0.02], which replicated in 3,957 European survivors from the Childhood Cancer Survivor Study (163 CTCAE Grade 3-5 self-reported cases; per allele OR = 1.39; P = 0.038). rs2815063 alters DNA binding motif of EWSR1-FLI1, whose expression was found to lead to cardiomyopathy and death due to chronic cardiac failure in mice. Conclusions: Using a 2-stage approach, we report a novel locus for cardiomyopathy in childhood cancer survivors, which warrants additional work to gain mechanistic insights.

Prevalence of mental distress among adult survivors of childhood cancer in Germany-Compared to the general population.

BackgroundIncreasing survival rates after childhood cancer have raised the issue of long‐term mental health consequences in adulthood. This study determines mental health distress among long‐term survivors of pediatric cancer and compares it to control groups.MethodsChildhood cancer survivors (CCS; N = 951, aged 24‐49 years) were compared to three age‐matched control groups from the general population collected at three time points. The study compared the prevalence of clinically relevant symptoms of a wide range of common mental disorders (depression, somatic distress, suicidal ideation, generalized anxiety, panic, social anxiety, and sleep disturbances) using identical, validated questionnaires. CCS were identified by the German Childhood Cancer Registry. Controls were approached by a demographic consultation company (USUMA) which assured that the three samples were nationally representative.ResultsChildhood cancer survivors reported higher education than controls and were less often married. All forms of common mental distress were increased among survivors. Twenty‐four percent of male (N = 526) and 41% of female survivors (N = 425) reported some form of clinically relevant mental health symptoms. Somatic distress as the leading complaint was highly frequent among CCS (OR: 10.98, CI 95%: 7.24‐16.64). Complaints by generalized anxiety (OR: 5.04, CI 95%: 2.61‐9.70), panic (OR: 3.28, CI 95%: 1.60‐6.70), depression (OR: 3.36, CI 95%: 2.22‐5.09), and suicidality (OR = 2.22; CI 95%: 1.38‐3.57) were also strongly increased. Female sex, low education, low income, and unemployment were associated with increased distress.ConclusionsFindings indicate a need to integrate psycho‐oncological screening and care into long‐term aftercare. Somatic distress, as cause and indicator of psychological distress, should receive stronger attention, especially tiredness, low energy, and pain.

Modeling Radiation Therapy-Related Risk of Heart Failure in Survivors of Pediatric Malignancy: Early Results from the Pediatric Normal Tissue Effects in the Clinic (PENTEC) Group

Cardiac disease is the most common cause of non-cancer mortality among long-term survivors of pediatric cancer; radiation therapy (RT) is a risk factor for late cardiotoxicity. The PENTEC cardiovascular task force aims to quantify radiation dose effects and the impact of critical risk factors. Through systemic review, including a meta-analysis of the available literature, we describe the relationships between heart failure (HF) and RT, as well as the influence of anthracycline chemotherapy, age, and gender. We conducted PubMed searches of peer-reviewed manuscripts published January 1, 1995, to October 2, 2017, evaluating HF among survivors of childhood cancer who received RT. Overall, 1,496 reports were identified, 148 were fully reviewed, and 5 had adequate data for modelling as described herein (Table). Patients were treated between 1966 and 1998, before the age of 18 years. HF diagnosis was based on CTCAE criteria, physician diagnosis, or patient reporting; all patients diagnosed were symptomatic. Heart dose was determined by either dose reconstruction or prescribed dose to an RT field including the heart. Meta-analysis hazard ratios for RT dose, anthracycline dose, gender, and age were determined using the inverse variance method based on multivariate, mutually adjusted models in the contributing reports. The population analyzed included 32,395 survivors; 614 events of HF were identified. The population-weighted mean incidence of HF at 20 years was 2.2%. For each 10 Gy increase in mean cardiac dose, the relative increase in HF risk was 50% (hazard ratio [HR] = 1.50; 95% CI = 1.41 – 1.60). Similarly, for each 100 mg/m2 increase in cumulative anthracycline dose, relative HF risk increased by 60% (HR = 1.60; 95% CI = 1.55 – 1.66). Younger age at diagnosis was associated with increased HF risk; every 5 years below 15 years of age increased the relative HF risk by 83% (HR = 1.83; 95% CI = 1.52 – 2.20). Female gender also increased HF risk (HR = 1.61; 95% CI = 1.35 – 1.93). This meta-analysis quantifies the dose relationship between cardiac RT and late HF, and identifies anthracycline dose, young age, and female gender as risk factors. Each 10 Gy of mean cardiac RT and each 100 mg/m2 of cumulative anthracycline dose results in a similar increase in the risk of HF. Further knowledge of the impact of these variables, especially the age-related vulnerabilities, helps inform clinical shared decision-making between providers, patients, and their families. This information will also inform future treatment protocols to minimize the late cardiac toxicity of cancer therapies.Abstract 105; TableIncluded StudiesCalculated HR per 10 Gy RT95% CIMulrooney, et al (2009)1.51.3 – 1.6Van der Pal, et al (2012)1.41.1 – 2.0Green, et al (2001)1.81.1 – 2.7Chow, et al (2015)1.71.5 – 1.9Schellong, et al (2010)––Meta-Value1.51.4 – 1.6 Open table in a new tab

Psychological risk in long-term survivors of childhood acute lymphoblastic leukemia and its association with functional health status: A PETALE cohort study.

Recent research has suggested that long-term pediatric cancer survivors were at risk of important physical and psychological morbidities. To date, we do not know to what extent functional health status contributes to psychological risk and which domains are most important. The aim of this study was to systematically explore which functional domain could explain anxiety, depression, and distress symptoms. We used data available for 105 adolescents and 182 adults successfully treated for childhood acute lymphoblastic leukemia at two Canadian sites part of the PETALE cohort. Participants were ≥5 years postdiagnosis, aged 22 ± 6 years, 52% female, and 49% acute lymphoblastic leukemia high-risk status. The contribution of health functional status (15D/16D questionnaires) to self-reported anxiety, depression, and distress (Beck scales and distress thermometer) was evaluated using adjusted logistic regression models. Prevalence rates found for mild-severe anxiety, depression, and distress were 14%, 21%, and 30% among adolescents and 27%, 20%, and 19% among adults. Frequent health domains associated with psychological risk were sleeping and breathing in adolescents, and vitality/fatigue, discomfort/symptoms, mental function, and sleeping in adults. Mental function was systematically associated with psychological risk across age groups (median OR=10.00, 95% CI 3.01-33.71). Exploratory mediation bootstrapping analyses suggested that the effect on psychological risk of overall health status and mental function problems was partly explained by social/work/school functioning. The results identified important functional health domains that could be targeted for interventions preventing psychological risk: vitality/fatigue, discomfort/symptoms, sleeping, and mental function issues. Health domains probably affect mood partly by limiting social/work/school functioning.

Topical Review: Pain in Survivors of Pediatric Cancer: Applying a Prevention Framework

To apply a biopsychosocial framework to understand factors influencing pain in survivors of pediatric cancer to inform pain prevention efforts and highlight the need for interdisciplinary care. This topical review draws from both pediatric cancer survivorship research and chronic noncancer pain research to illustrate how components of a preventative model can be applied to pain in survivorship. Pain is a common experience among long-term survivors of pediatric cancer. The pain experience in survivorship can be conceptualized in terms of biological disease and treatment factors, cognitive and affective factors, and social and contextual factors. We review literature pertinent to each of these biopsychosocial factors and tailor an existing public health prevention framework for pain in survivors of pediatric cancer. Classifying survivors of pediatric cancer into pain risk categories based on their daily experiences of pain, pain-related functional impairment, and distress could help guide the implementation of pain-related prevention and intervention strategies in this population. Future research is needed to establish the efficacy of screening measures to identify patients in need of psychosocial pain and pain-related fear management services, and interdisciplinary pediatric chronic pain management programs in survivors of pediatric cancer.

Age-associated vulnerability to treatment-related late cardiotoxicity: A report from the Childhood Cancer Survivor Study (CCSS).

10501 Background: Cardiovascular disease (CVD) is the most common non-cancer cause of death in long-term survivors of pediatric cancer. We investigated the role of age at diagnosis in modifying treatment-related late CVD risk in the CCSS population. Methods: We evaluated CTCAE grade 3 – 5 CVD events occurring ≥5 years after diagnosis in 23,465 5-year survivors of pediatric cancer diagnosed 1970-1999. We estimated the rates of developing any CVD, including coronary artery disease (CAD) or heart failure (HF). Modifications of treatment effects by age at diagnosis were analyzed using piecewise exponential models adjusting for current age, race, and smoking. Results: At a median age of 28.4 years (range 5.6 –58.3) and follow up of 20.2 years (5 – 39.3), 239 CAD and 359 HF events occurred. The cumulative incidence of CVD, CAD, and HF were 4.8% (95% CI: 4.3-5.3), 2.4% (95% CI: 2.2-2.9), and 2.5% (95% CI: 2.2-2.9) by 30 years from diagnosis. Mean cardiac radiotherapy (CRT) doses of ≥10 Gy were associated with a progressively increasing risk of CVD (10 - &lt; 20 Gy: RR 3.6, 95% CI 2.1 – 6.2, p &lt; 0.01; 20 - &lt; 30 Gy: RR 4.4, 95% CI 2.7 – 7.2, p &lt; 0.01; ≥30 Gy: RR 7.5, 95% CI 4.9 – 11.5, p &lt; 0.01) relative to those receiving no CRT. In those receiving a low mean CRT dose (0.1 - &lt; 10 Gy), younger children had higher rates of CVD (0 – 4 years: RR = 2.2, 95% CI = 1.0 – 4.6, p = 0.04; &gt; 4 - ≤13 years: RR = 2.1, 95% CI = 1.1 – 4.1, p = 0.03) compared to those &gt; 13 years, an effect not seen at higher doses. Among survivors exposed to anthracycline doses ≥250 mg/m2, those age 0 – 4 at diagnosis had increased risk of both CAD (RR = 4.9, 95% CI 1.5 – 16.3, p = 0.01) and HF (RR = 3.0, 95% CI 1.6 – 5.0, p &lt; 0.01). Cisplatin exposure ≥300 mg/m2 was associated with increased risk of any CVD (RR = 1.8, CI = 1.2 – 2.6, p &lt; 0.01), primarily attributable to increased risk of HF (RR = 2.3, 95% CI = 1.5 - 3.5, p &lt; 0.01). Conclusions: Among long-term survivors of pediatric cancer, increasing CRT dose is associated with increased risk for CVD in a dose-response relationship. Young children are at higher risk for CVD after low-dose CRT or high-dose anthracycline exposure. Cisplatin exposure significantly increases risk for CVD. These findings should inform future treatment and surveillance protocols.

Psychosocial Late Effects in Pediatric Cancer Survivors: A Report From the Children's Oncology Group.

This review was conducted to update the Children's Oncology Group (COG) Long-Term Follow-Up Guidelines (COG-LTFU Guidelines, version 4.0) regarding screening for psychosocial late effects of pediatric cancer. Articles published between August 2009 and January 2011 that addressed psychosocial late effects of long-term survivors of pediatric cancer (n = 35) were reviewed by a multidisciplinary team of COG late effect experts. The majority of studies in this time period indicate that survivors experience few psychosocial problems in long-term survivorship. A critical subset, however, is at increased risk for psychosocial late effects secondary to the treatment. Highlighted findings from this review include increased rates of suicidal ideation (SI), and health beliefs as robust predictors of SI, anxiety, and global distress. Survivors' health beliefs were associated with their perceptions of physical limitations, overall late effects, and cancer-related pain. While many survivorship studies continue to specify risk factors for anxiety and posttraumatic stress symptoms/posttraumatic stress disorder, others outcomes (e.g., developmental, interpersonal, and familial factors) appear to be emerging in importance. Although the majority of childhood cancer survivors do not experience psychosocial problems, a subset will. The recent research findings have been included in the new COG-LTFU Guidelines that will assist in the targeted assessment and the treatment of survivors' psychosocial health.

Development of a Primary Care-Based Clinic to Support Adults With a History of Childhood Cancer: The Tactic Clinic

Describe the development and evolution of a primary-care-based, multidisciplinary clinic to support the ongoing care of adult survivors of childhood cancer. A consultative clinic for adult survivors of childhood cancer has been developed that is located in an adult, academic internal medicine setting and is based on a long-term follow-up clinic model available at Children's Hospital Colorado. The clinic opened in July 2008. One hundred thirty-five patients have been seen as of April 2014. Referrals and clinic capacity have gradually increased over time, and a template has been developed in the electronic medical record to help facilitate completion of individualized care plan letters. A primary care-based, multidisciplinary consultative clinic for adults with a history of childhood cancer survivor is feasible and actively engages adult primary care resources to provide risk-based care for long-term pediatric cancer survivors. This model of care planning can help support adult survivors of pediatric cancer and their primary care providers in non-academic, community settings as well.

Conditional survival in pediatric malignancies: analysis of data from the Childhood Cancer Survivor Study and the Surveillance, Epidemiology, and End Results Program.

Long-term survivors of pediatric cancer are at risk of life-threatening late effects of their cancer. Previous studies have shown excesses in long-term mortality within high-risk groups defined by demographic and treatment characteristics. To investigate conditional survival in a pediatric cancer population, the authors performed an analysis of conditional survival in the original Childhood Cancer Survivor Study (CCSS) cohort and the Surveillance, Epidemiology, and End Results (SEER) database registry. The overall probability of death for patients at 5 years and 10 years after they survived 5, 10, 15, and 20 years since cancer diagnosis and cause-specific death in 10 years for 5-year survivors were estimated using the cumulative incidence method. Among patients in the CCSS and SEER cohorts who were alive 5 years after their cancer diagnosis, within each diagnosis group at least 92% were alive in the subsequent 5 years, except for patients with leukemia, of whom only 88% of 5-year survivors remained alive in the subsequent 5 years. The probability of all-cause mortality in the next 10 years among patients who survived at least 5 years after diagnosis was 8.8% in CCSS and 10.6% in SEER, approximately 75% of which was due to neoplasms as the cause of death. The risk of death among survivors of pediatric cancer in 10 years can vary between diagnosis groups by at most 12%, even up to 20 years after diagnosis. This information is clinically significant when counseling patients regarding their conditional survival, particularly when survivors are seen in long-term follow-up.