Five-year Survivors Of Childhood Cancer Research Articles

Treatments affecting splenic function as a risk factor for valvular heart disease in Childhood Cancer Survivors: A DCCSS-LATER study.

Splenectomy might be a risk factor for valvular heart disease (VHD) in adult Hodgkin lymphoma survivors. As this risk is still unclear for childhood cancer survivors (CCS), the aim of this study is to evaluate the association between treatments affecting splenic function (splenectomy and radiotherapy involving the spleen) and VHD in CCS. CCS were enrolled from the DCCSS-LATER cohort, consisting of 6,165 five-year CCS diagnosed between 1963 and 2002. Symptomatic VHD, defined as symptoms combined with a diagnostic test indicating VHD, was assessed from questionnaires and validated using medical records. Differences in the cumulative incidence of VHD between CCS who received treatments affecting splenic function and CCS who did not were assessed using the Gray test. Risk factors were analyzed in a multivariable Cox proportional hazards model. The study population consisted of 5,286 CCS, with a median follow-up of 22 years (5-50 years), of whom 59 (1.1%) had a splenectomy and 489 (9.2%) radiotherapy involving the spleen. VHD was present in 21 CCS (0.4%). The cumulative incidence of VHD at the age of 40 years was significantly higher in CCS who received treatments affecting splenic function (2.7%, 95% confidence interval (CI) 0.4%-4.9%) compared with CCS without (0.4%, 95% CI 0.1%-0.7%) (Gray's test, p=0.003). Splenectomy was significantly associated with VHD in a multivariable analysis (hazard ratio 8.6, 95% CI 3.1-24.1). Splenectomy was associated with VHD. Future research is needed to determine if CCS who had a splenectomy as part of cancer treatment might benefit from screening for VHD.

5 The Impact of Sex and Associations With Treatment Exposures on Neurocognitive Impairment in Pediatric Cancer Survivors: A report from the Childhood Cancer Survivor Study

Objective:Sexual dimorphism in human brain structure and behavior is influenced by exposure to sex hormones during critical developmental periods. In children, cancer and cancer treatments may alter hormone activity and brain development, impacting neurocognitive functions.Participants and Methods:Five-year survivors of childhood cancer (N=15,560) diagnosed at <21 years from 1970 to 1999, and 3,206 siblings from the Childhood Cancer Survivor Study completed the Neurocognitive Questionnaire (NCQ), a measure of self-reported task efficiency (TE), emotion regulation (ER), Organization, and working memory (WM). We compared rates of cognitive impairment (i.e., NCQ scores >90th percentile) in survivors and same-sex siblings, and sex differences in risk factors for cognitive impairment (i.e., treatment exposures, chronic health conditions (CHCs), cancer diagnosis, age at diagnosis) using modified Poisson regressions.Results:Survivors were more likely to report cognitive impairment than same-sex siblings (Males: TE OR=2.3, p<.001; ER OR=1.7, p=.008; Organization OR=1.5, p=.04; WM OR=2.3, p<.001. Females: TE OR=2.6, p<.001; ER OR=1.9, p<.001; Organization OR=1.5, p=.02; WM OR=2.6, p<.001). Within survivors, females were more likely than males to report impairment in TE (OR=1.2, p=.001), ER (OR=1.5, p<.001), and WM (OR=1.2, p<.001). There were no sex differences in symptom severity in siblings (all ps>.05). Risk factors for cognitive impairment in survivors included cranial radiation dose (TE <20Gy OR=1.5, p=.008, ≥20Gy OR=2.5, p<.001; ER OR=1.5, p<.001; Organization <20 Gy OR=1.4, p<.001; < WM 20 Gy OR=1.8, p<.001, ≥20Gy OR=2.7, p<.001), presence of moderate to severe CHCs (TE 1 CHC OR=1.9, p<.001, >1 CHC OR=3.6, p<.001; ER 1 CHC OR=1.7, p<.001, >1 CHC OR=2.2, p<.001; Organization 1 CHC OR=1.5, p=.001, >1 CHC OR=2.5, p<.001; WM 1 CHC OR=1.8, p<.001, >1 CHC OR=4.1, p<.001). There were sex differences in cognitive impairment risk factors in survivors. In females, cranial radiation dose (<20 Gy TE OR=1.6, p=.02; ≥20Gy TE OR=1.4, p=.01), leukemia diagnosis (TE OR=1.4, p=.02), or diagnosis age between 3-5 years (WM OR=1.4, p=.02) conferred higher risk for cognitive impairment compared to males with the same history. Females diagnosed with Hodgkin’s lymphoma (Organization OR=0.61, p=.05) or non-Hodgkin’s lymphoma (Organization OR=0.55, p=.03) were at lower risk for cognitive impairment compared to males.Conclusions:We found sex-specific differences in rates of, and risk factors for, neurocognitive impairment, suggesting a sex vulnerability. Future studies examining interactions between sex hormones and treatment exposures during brain development will enable tailoring treatments follow-up interventions to ensure that quality of life is maximized.

Assisted reproductive technology use and outcomes in childhood cancer survivors.

Treatment exposures for childhood cancer reduce ovarian reserve. However, the success of assisted reproductive technology (ART) among female survivors is not well established. Five-year survivors of childhood cancer in the Childhood Cancer Survivor Study were linked to the Society for Assisted Reproductive Technology Clinic Outcome Reporting System, which captures national ART outcomes. The authors assessed the live birth rate, the relative risk (RR) with 95% confidence intervals (95% CIs), and associations with treatment exposure using generalized estimating equations to account for multiple ovarian stimulations per individual. Siblings from a random sample of survivors were recruited to serve as a comparison group. Among 9885 female survivors, 137 (1.4%; median age at diagnosis, 10years [range, 0-20 years]; median years of follow-up after age 18 years, 11years [range, 2-11 years]) underwent 224 ovarian stimulations using autologous or donor eggs and/or gestational carriers (157 autologous ovarian stimulation cycles, 67 donor ovarian stimulation cycles). In siblings, 33 (1.4%) underwent 51 autologous or donor ovarian stimulations. Of those who used embryos from autologous eggs without using gestational carriers, 97 survivors underwent 155 stimulations, resulting in 49 live births, for a 31.6% chance of live birth per ovarian stimulation (vs. 38.3% for siblings; p=.39) and a 43.9% chance of live birth per transfer (vs. 50.0%; p=.33). Prior treatment with cranial radiation therapy (RR, 0.44; 95% CI, 0.20-0.97) and pelvic radiation therapy (RR, 0.33; 95% CI, 0.15-0.73) resulted in a reduced chance of live birth compared with siblings. The likelihood of live birth after ART treatment in survivors was not affected by alkylator exposure (cyclophosphamide-equivalent dose, ≥8000mg/m2 vs. none; RR, 1.04; 95% CI, 0.52-2.05). Childhood cancer survivors are as likely to undergo treatment using ART as sibling controls. The success of ART treatment was not reduced after alkylator exposure. The results from the current study provide needed guidance on the use of ART in this population.

Predictive factors of long-term follow-up attendance in very long-term childhood cancer survivors.

Long-term follow-up (LTFU) clinics have been developed but only some childhood cancer survivors (CCS) attend long-term follow-up (LTFU). To identify factors that influence LTFU attendance. Five-year CCS treated for a solid tumor or lymphoma in Gustave Roussy before 2000, included in the FCCSS cohort (French Childhood Cancer Survivor Study), aged >18years and alive at the date of the LTFU Clinic opening (January 2012) were invited to a LTFU visit. Factors associated with attendance at the LTFU clinic between 2012 and 2020 were estimated using logistic regression analyses. Analyses included different types of factors: clinical (tumor characteristics, cancer treatments, late effects), medical (medical expenses were used as a proxy of survivor's health status), social (deprivation index based on census-tract data relating to income, educational level, proportion of blue-collar workers, and unemployed people living in the area of residence), and spatial (distance to the LTFU clinic). Among 2341 CCS contacted (55% males, mean age at study,45years; SD±10years; mean age at diagnosis,6years; SD±5years), 779 (33%) attended at least one LTFU visit. Initial cancer-related factors associated with LTFU visit attendance were: treatment with both radiotherapy and chemotherapy (odds ratio [OR],4.02; 95% CI,2.11-7.70), bone sarcoma (OR,2.43; 95% CI,1.56-3.78), central nervous system primitive tumor (OR,1.65; 95% CI,1.02-2.67), and autologous hematopoietic cell transplant (OR,2.07; 95% CI,1.34-3.20). Late effects (OR,1.70; 95% CI,1.31-2.20), highest medical expenses (OR,1.65; 95% CI,1.22-2.22), living in the most advantaged area (OR vs. the most deprived area=1.60; 95% CI,1.15-2.22), and shorter distance from LTFU care center (<12miles) also increased attendance. Patients who are apparently healthy as well as socially disadvantaged and living far away from the center are less likely to attend LTFU care. Among 2341 adult childhood cancer survivors contacted between 2012 and 2020, 33% attended at least one long-term follow-up visit. Clinical factors related to attendance were multimodal treatment of first cancer (combining chemotherapy and radiotherapy), stem cell transplant, type of diagnosis (bone tumor and central nervous system primitive tumor), late effects (at least one disease among second malignancy, heart disease, or stroke), and highest medical expenses. In addition, the study identified social and spatial inequalities related to attendance, with independent negative effects of distance and social deprivation on attendance, even though the medical costs related to the long-term follow-up examinations are covered by the French social security system.

Risk of subsequent primary lymphoma in a cohort of 69,460 five-year survivors of childhood and adolescent cancer in Europe: The PanCareSurFup study.

Survivors of Hodgkin lymphoma (HL) are at risk of developing non-Hodgkin lymphoma (NHL) after treatment; however, the risks of developing subsequent primary lymphomas (SPLs), including HL and NHL, after different types of childhood cancer are unknown. The authors quantified the risk of SPLs using the largest cohort of childhood cancer survivors worldwide. The Pan-European Network for Care of Survivors After Childhood and Adolescent Cancer (PanCare) Survivor Care and Follow-Up Studies (PanCareSurFup) cohort includes 69,460 five-year survivors of childhood cancer, diagnosed during 1940 through 2008, from 12 European countries. Risks of SPLs were quantified by standardized incidence ratios (SIRs) and relative risks (RRs) using multivariable Poisson regression. Overall, 140 SPLs, including 104 NHLs and 36 HLs, were identified. Survivors were at 60% increased risk of an SPL compared with the general population (SIR, 1.6; 95% confidence interval [CI], 1.4-1.9). Survivors were twice as likely to develop NHL (SIR, 2.3; 95% CI, 1.9-2.8), with the greatest risks among survivors of HL (SIR, 7.1; 95% CI, 5.1-10.0), Wilms tumor (SIR, 3.1; 95% CI, 1.7-5.7), leukemia (SIR, 2.8; 95% CI, 1.8-4.4), and bone sarcoma (SIR, 2.7; 95% CI, 1.4-5.4). Treatment with chemotherapy for any cancer doubled the RR of NHL (RR, 2.1; 95% CI, 1.2-3.9), but treatment with radiotherapy did not (RR, 1.2; 95% CI, 0.7-2.0). Survivors were at similar risk of developing a subsequent HL as the general population (SIR, 1.1; 95% CI, 0.8-1.5). In addition to HL, the authors show here for the first time that survivors of Wilms tumor, leukemia, and bone sarcoma are at risk of NHL. Survivors and health care professionals should be aware of the risk of NHL in these survivors and in any survivors treated with chemotherapy.

Treatment exposure-based risk-stratification for care of survivors of childhood cancer: A report from the Childhood Cancer Survivor Study.

10056 Background: Treatment exposure-based risk-stratification oflong-term cancer survivors is needed to allocate tailored health care in survivorship clinics. Investigators from the United Kingdom (UK) developed a treatment exposure-based algorithm that stratifies survivors into low, medium, and high risk groups. Because this algorithm has not been validated, we sought to use the large, diverse population of the Childhood Cancer Survivor Study (CCSS) to validate risk for poor outcomes. Methods: Five-year survivors of childhood cancer (diagnosed between 1970-1999 at &lt; 21 years of age) were categorized into low, medium, and high risk groups based on treatment exposures and diagnoses (Table). Primary endpoints included cumulative health-related (i.e., non-recurrence, non-external) late mortality and cumulative incidence of grade 3-5 chronic conditions (CTCAEv4.03) conditional on reaching age 20 without the outcome. Siblings were a comparison group for chronic conditions. Cox proportional hazards models among survivors estimated hazard ratios (HRs) and 95% confidence intervals (CI) adjusted for sex and race. Results: A total of 21,504 survivors were analyzed with a median follow-up of 22 years. Application of the risk stratification algorithm resulted in 3,152 low risk, 6,443 medium risk, and 11,909 high risk survivors. Among those who survived to age 20 without any grade 3-5 conditions, the risk of developing one by age 35 was 12.2% (95% CI 1.0-14.7%), 14.2% (12.8-15.7%) and 25.4% (24.2-26.6%) for low, medium, and high-risk patients, respectively, and 6.9% (6.1-7.9%) for siblings. HRs of grade 3-5 conditions for medium (HR 1.8, 95% CI 1.6-2.1) and high (HR 3.9, 95% CI 3.5-4.4) risk relative to low risk survivors, respectively, were elevated. Cumulative health-related mortality was similarly associated with risk categories; conditional on being alive at age 20, survivors within low, medium, and high risk groups had cumulative incidences of 2.3% (95% CI 1.7-3.1%), 3.3% (2.8-3.9%) and 6.1% (5.6-6.6%), respectively, by age 35. Conclusions: Risk categorizations based on treatment exposures were effective at providing generalized risk stratification within the CCSS with respect to risk of grade 3-5 conditions and health related mortality, particularly for identifying high risk survivors. These risk groups may be useful to physicians in determining follow-up intervals and guiding management and long-term surveillance of these survivors. [Table: see text]

Modifiable risk factors for late mortality among five-year survivors of childhood cancer: A report from the Childhood Cancer Survivor Study.

10014 Background: The impact ofmodifiable lifestyle and cardiovascular risk factors (CVRFs) on risk for late mortality in adult survivors of childhood cancer is not well established. Methods: All-cause and health-related late (&gt;5 years from cancer diagnosis) mortality (HRM; excludes death from primary cancer and external causes) were evaluated in five-year survivors diagnosed &lt;21 years of age using the National Death Index through 2017. Modifiable lifestyle (smoking status, alcohol use, physical activity, body mass index [BMI]; combined to create a score [0-4] and categorized as unhealthy [0-2], moderate [2.5 or 3], healthy [3.5 or 4]) and CVRFs (hypertension [HTN], diabetes [DM], dyslipidemia) were assessed as time-varying covariates. Standardized mortality ratios (SMRs) and absolute excess risk of death per 1000 person-years (AER) with 95% confidence intervals (CIs) were estimated. Multivariable models estimated the relative risk (RR) of death adjusted for demographic and socioeconomic variables. Results: Among 20,051 adult survivors (median age 40.0 years, range 18.7 – 67.7), 19% reported ≥1 CVRF (13% HTN, 9% dyslipidemia, 5% DM) and few reported a healthy lifestyle (29% healthy, 40% moderate, 31% unhealthy). There were 1476 deaths due to health-related causes. While all survivors experienced an increased risk of HRM compared to the US population, risk was lower among those with a healthy vs. unhealthy lifestyle (SMR 3.5, 95% CI 3.1-3.9 vs. 6.2, 5.7-6.7) and very high among underweight survivors (11.1, 9.3-13.3) and those with both HTN and DM (13.0, 9.2-18.0). Stratified by lifestyle score, the excess risk of HRM was lowest in those with a healthy lifestyle across survival time (Table). Similar trends were seen when stratified by 0, 1 and 2 CVRFs. In multivariable models, compared to survivors with no CVRFs and healthy lifestyle, no CVRFs and unhealthy lifestyle was associated with a 50% increased risk of HRM (RR 1.5, 95% CI 1.2-1.8) and unhealthy lifestyle plus HTN a 2-fold increased risk of HRM (2.2, 1.6-2.8). Regardless of lifestyle group, ≥2 CVRF increased risk for HRM at least 2-fold (p-values &lt;0.001). Conclusions: A reduction in excess deaths is observed among adult survivors of childhood cancer with a healthy lifestyle and no CVRFs as they age. Interventions that target improved lifestyle choices and prevention or aggressive treatment of modifiable CVRFs may reduce risk for late mortality. [Table: see text]

Bone mineral density (BMD) deficits in adult survivors of childhood cancer: Attributable risks and long-term consequences.

e22021 Background: Survivors of childhood cancer are at risk for BMD deficits. Contributions of treatment, physical and lifestyle factors to overall risk are unknown as are long-term consequences of moderate and severe deficits. Methods: BMD deficits were evaluated in 3919 five-year childhood cancer survivors in the St. Jude Lifetime Cohort (median age 31.7 [range 18.0-69.9] years, 52.6% male, 80.4% non-Hispanic White) using lumbar quantitative computed tomography and classified by age- and sex-specific Z-scores as moderate (&lt;-1SD) or severe deficit (&lt;-2SD). Multivariable logistic regression estimated odds ratios (OR), risk factor attributable fractions (AF), and associations between BMD deficits and long-term outcomes (social/functional outcomes, fracture, mortality). Results: BMD deficits were moderate in 21.7% (95% CI 20.4%-23.0%) and severe in 6.9% (95% CI 6.1%-7.7%) of survivors. Risk factors for moderate deficit included age 5-9 years at diagnosis (OR 1.63, 95% CI 1.31-2.03), &gt;20Gy cranial radiotherapy (OR 1.75, 95% CI 1.41-2.18), &gt;3240 mg/m2 glucocorticoids (OR 1.34, 95% CI 1.09-1.66), and smoking (OR 1.55, 95% CI 1.27-1.90). AF were 7.2%, 0.7%, 5.9%, and 6.1% respectively; 80.1% of risk was unexplained. Risk factors for severe deficits included age 5-9 years at diagnosis (OR 1.95, 95% CI 1.36-2.80), BMI&lt;18.5 kg/m2 (OR 3.95, 95% CI 2.28-6.85), &gt;20Gy cranial radiotherapy (OR 5.22, 95% CI 3.74-7.30), testicular/pelvic radiation (OR 1.70, 95% CI 1.19-2.44), smoking (OR 1.71, 95% CI 1.21-2.43), and physical inactivity (OR 1.91, 95% CI 1.10-3.33). AFs were 10.9%, 7.0%, 2.9%, 11.5%, 6.7%, and 3.2% respectively; 57.8% of risk was unexplained. Those with deficits were less likely to live independently, to be employed, and more likely to require assistance with personal care needs (Table). Fracture risk was greatest among those with any BMD deficit, and mortality risk was greatest among those with severe deficits. Conclusions: Deficits in BMD among childhood cancer survivors are related not only to treatment, but also to modifiable health behaviors. In this population, children exposed to radiation or glucocorticoids are at greatest risk for poor bone quality and should be counselled to optimize health behaviors.[Table: see text]

Late Mortality in Childhood Cancer Survivors according to Pediatric Cancer Diagnosis and Treatment Era in the Dutch LATER Cohort

This multi-center cohort-study examined late mortality among 6,165 Dutch five-year childhood cancer survivors diagnosed 1963–2001. Clinical details and cause of death were based on medical records. Mortality was 12-fold that of the general population, with 51.3 additional deaths per 10,000 person-years (21.9 yrs median follow-up). Cumulative mortality 15 yrs post-diagnosis was 6.9%, predominantly from late recurrences; thereafter the absolute contribution of other health outcomes increased. Cumulative all-cause and recurrence-related mortality were highest for Central Nervous System and bone tumor survivors. All-cause, but not subsequent tumor and circulatory disease-related cumulative mortality, was highest for patients diagnosed 1963–1979 vs. later (p-trend <0.001).

Development and validation of a prediction model for kidney failure in long-term survivors of childhood cancer: A report from the Childhood Cancer Survivor Study (CCSS).

10047 Background: Kidney failure (need for dialysis or kidney transplantation, or death due to kidney disease) is a rare but serious late effect for survivors of childhood cancer. We aimed to develop a model using demographic and treatment characteristics to predict individual risk of kidney failure among five-year survivors of childhood cancer. Methods: CCSS survivors without kidney failure at five years after cancer diagnosis (n = 25,483) were assessed for subsequent kidney failure by age 40. Outcomes were self-reported and corroborated by the Organ Procurement and Transplantation Network and the National Death Index. A sibling cohort (n = 5045) served as a comparator. Piecewise exponential models with backward selection estimated the relationships between potential predictors and kidney failure and were converted to integer risk scores. Additional results from the St. Jude Lifetime Cohort Study (SJLIFE, n = 2490) and the National Wilms Tumor Study (NWTS, n = 6760) validated the models. Results: Among CCSS survivors, 204 developed late kidney failure. We developed a model with sex, race/ethnicity, age at cancer diagnosis, nephrectomy, exposure to specific chemotherapy, any abdominal radiation, presence of genitourinary anomalies, and early-onset hypertension (Table). Risk scores achieved an area under the curve (AUC) and concordance (C) statistic of 0.65 and 0.68 for kidney failure by age 40. Validation cohort AUC and C statistics were 0.83/0.86 for SJLIFE (8 cases) and 0.61/0.63 for NWTS (91 cases). An alternative model with specific chemotherapy doses and kidney-specific radiation dosimetry had similar AUC and C statistic (0.67/0.70). Integer risk scores were collapsed to form statistically distinct low (score &lt;3; 87 cases of 17,326), moderate (score 3-5; 63 cases of 4667), and high (score 6+; 18 cases of 401) risk groups. These groups corresponded to cumulative incidences in CCSS of kidney failure by age 40 of 0.6% (95% CI 0.4-0.7%), 2.3% (95% CI 1.6-3.2%), and 9.4% (95% CI 4.4-16.7%), compared with 0.2% (95% CI 0.1-0.5%) among siblings. Conclusions: Using readily available information, we were able to identify low, moderate, and high risk groups for developing kidney failure following treatment for childhood cancer. These prediction models may help guide screening and interventional strategies for higher risk survivors.[Table: see text]

Mortality among five-year survivors of childhood cancer: Results over five decades of follow-up in the Childhood Cancer Survivor Study.

10013 Background: Adult survivors of childhood cancer are at greater risk for late mortality compared to the general population due to cancer and its treatment. Risk factors, patterns and specific causes of late mortality across the lifespan are not well established. Methods: All-cause, cause-specific, and health-related late mortality (HRM; excludes death from primary cancer and external causes) &gt; 5 years from diagnosis were evaluated in survivors diagnosed &lt; 21 years of age between 1970-1999. Cause of death was based on ICD codes from the National Death Index through December 2017. Cumulative mortality, mortality rates and standardized mortality ratios (SMRs) with 95% confidence intervals (CIs) were estimated, overall and in 5- and 10-year survival periods. Results: Among 34,230 survivors (median time from diagnosis 29.1 years, range 5.0 - 48.0) the 40-year cumulative mortality was 23.3% (95% CI 22.7 - 24.0). Of 5,916 deaths, 3,061 (51.2%) were attributable to health-related causes including subsequent neoplasm (n = 1,458), cardiac (n = 504), and pulmonary causes (n = 238). All-cause mortality by time from diagnosis demonstrated a U-shaped distribution: 10.1 deaths/1000 person-years at 5-9 years, largely due to recurrence of the primary cancer, decreasing to 4.1 at 15-19 years before increasing to 18.5 at 40-48 years, attributable to an increasing mortality rate from HRM (2.3 at 5-9 years; 17.0 at 40-48 years). For the interval 5-9 years from diagnosis, survivors had an 18.1-fold (95% CI 17.3-18.9) higher risk of death from any cause, and a 13.1-fold (11.9-13.4) higher risk for HRM when compared to the general population. Although the SMRs declined with duration of follow-up, survivors had a 4-fold higher risk of death overall, attributable to a more than 4-fold increased risk of HRM. HRM 40-48 years from diagnosis was largely attributable to an increased risk of death due to subsequent neoplasm (SMR 6.0, 95% CI 4.9-7.2), cardiac (3.9, 2.9-5.0) and pulmonary (5.6, 3.6-8.4) causes. Cause-specific mortality remained markedly elevated at 40-48 years from diagnosis: CNS malignancy (SMR 11.7, 95% CI 5.4-22.3), benign meningioma (171.3, 34.4-500.5), valvular heart disease (39.8, 21.2-68.1), cardiomyopathy (10.4, 4.5-20.5), stroke (7.9, 4.6-12.6), and renal failure (5.6, 1.8-13.2). HRM was significantly higher among the youngest group of survivors (0-4 years at diagnosis), non-Hispanic blacks and those who received radiation to the brain, chest or total body, or who were exposed to anthracycline, alkylating or platinum chemotherapy. Conclusions: After five decades, aging survivors consistently remain at higher risk of all-cause mortality compared to the general, aging population, primarily due to a persistent 4-fold increased risk of HRM. Continued late-effects surveillance and reduction of therapies associated with long-term morbidity and increased mortality is essential.

Risk of digestive cancers in a cohort of 69 460 five-year survivors of childhood cancer in Europe: the PanCareSurFup study

BackgroundSurvivors of childhood cancer are at risk of subsequent primary neoplasms (SPNs), but the risk of developing specific digestive SPNs beyond age 40 years remains uncertain. We investigated risks of...

Abstract IA24: The lifetime impact of cancer and cancer therapy

Abstract Survival rates after childhood cancer have increased dramatically in the past 50 years. More than 80% of children diagnosed with a malignancy now survive five years, with most going on to become long-term survivors. This has resulted in a growing population of childhood cancer survivors in the U.S., estimated to exceed 420,000 in 2013 and to approach half a million by 2020. Unfortunately, the same curative treatments that enable long-term survival also cause toxicities that leave many survivors with a substantial burden of adverse health and quality-of-life outcomes. Survivors have a 13-fold higher mortality rate than the general population. Eighty percent of childhood cancer survivors develop at least one severe, disabling, life-threatening, or fatal chronic health condition by age 45 years, and the average survivor will experience four such conditions by age 50 years. Specifically, survivors have increased risk compared to the general population for diseases often associated with aging, such as heart disease, diminished pulmonary function, and second cancers. The substantial burden of morbidity experienced by survivors translates to a significantly reduced quality of life compared to those without a cancer history. Thus, there is a critical need to better understand which survivors have the highest risk of serious morbidity and mortality, identify those with subclinical dysfunction, and inform intervention strategies for mitigating the burden of these late effects. Unfortunately, however, as survivors age into adulthood, most are no longer followed at their primary treatment institution, but by their community primary care providers, limiting our knowledge of long-term follow and late outcomes, a similar problem to that seen when survivors of adult malignancies participate in clinical trials where systematic follow-up ends at the five-year time point. To address this knowledge gap, the Childhood Cancer Survivor Study (CCSS) was developed. The CCSS is a multi-institutional, multidisciplinary, NCI-funded collaborative resource (U24 CA55727; PI: Gregory Armstrong) established to evaluate long-term outcomes among survivors of childhood cancer, largely by self-reported outcomes. It is a retrospective cohort consisting of &amp;gt;25,000 five-year survivors of childhood cancer who were diagnosed between 1970-1999 at one of 31 participating centers in the U.S. and Canada. Self-reported outcomes across a spectrum of chronic health conditions, psychosocial and cognitive function, and physical function outcomes have informed over 350 publications to date enumerating risk for this aging population. The results of the CCSS have advanced knowledge of late effects among survivors of childhood cancer. CCSS investigators have demonstrated that 60-90% of adults treated for cancer during childhood develop one or more chronic health conditions. They have also shown that by age 50 years, the cumulative incidence of self-reported severe, disabling, life-threatening, or fatal health condition was 53.6% among survivors compared with 19.8% among sibling control group. Among childhood cancer survivors who reach age 35 years of age without a previous severe, disabling, life-threatening, or fatal health condition, 25.9% will experience a new severe, disabling, life-threatening or fatal condition within 10 years as compared to 6% of healthy siblings. In addition to the findings related to an increased risk of morbidity and mortality from subsequent neoplasms and cardiac disease, CCSS has shown that long-term survivors are at risk of developing a variety of adverse outcomes that include organ dysfunction (e.g., pulmonary, gonadal), impaired growth and development, impaired cognitive function, difficulties obtaining employment and insurance, and compromises in the quality of life. Recently, the CCSS provided evidence that survivors treated in more recent eras have a significant reduction in late mortality attributable to two things: fewer deaths from recurrence or progression of primary cancer but more importantly, fewer deaths from treatment-related causes such as subsequent malignancies and cardiopulmonary death. In conclusion, the now decades-long strategy of designing pediatric cancer treatment regimens with a focus on adult health and avoidance of late effects appears to have been successful. Taken along with promotion of early detection of late effects and improved treatment of late effects, this approach has now translated to extend the lifespan of many survivors of childhood cancer. Future directions include the need to: (1) assess the true impact of screening and early detection of late effects on morbidity and mortality and evaluate interventions that improve screening rates as well as alter health behaviors, (2) expand individual risk prediction for poor outcomes, (3) further understand genetic susceptibility for late effects, and (4) target studies for both primary and secondary prevention of late effects, so that we not only extend the lifespan of survivors, but their health span as well. Citation Format: Greg Armstrong. The lifetime impact of cancer and cancer therapy [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr IA24.

A detailed insight in the high risks of hospitalizations in long-term childhood cancer survivors-A Dutch LATER linkage study.

BackgroundInsight in hospitalizations in long-term childhood cancer survivors (CCS) is useful to understand the impact of long-term morbidity. We aimed to investigate hospitalization rates and underlying types of diagnoses in CCS compared to matched controls, and to investigate the determinants.MethodsWe linked 5,650 five-year CCS from the Dutch nationwide Dutch LATER cohort and 109,605 age- and sex-matched controls to the Dutch Hospital Discharge register, which contained detailed information on inpatient hospitalizations from 1995–2016. Relative hospitalization rates (RHRs) were calculated using a Poisson regression model. Adjusting for multiple hospitalizations per person via a Poisson model for generalized estimated equations, we investigated determinants for hospitalizations for all types of underlying diagnoses among CCS.ResultsCCS were twice as likely to be hospitalized as reference persons (hospitalization rate 178 and 78 per 1,000 person-years respectively; RHR 2.0, 95% confidence interval (CI) 1.9–2.2). Although CCS had more hospitalizations for 17 types of underlying diagnoses, they were especially more likely to be hospitalized for endocrine conditions (RHR: 6.0, 95% CI 4.6–7.7), subsequent neoplasms (RHR: 5.6, 95% CI 4.6–6.7) and symptoms without underlying diagnoses (RHR: 5.2, 95% CI 4.6–5.8). For those types of underlying diagnoses, female sex and radiotherapy were determinants.ConclusionThis study provides new insights in the high risk of hospitalizations for many types of underlying diagnoses in CCS and treatment related determinants. CCS are especially at high risk for hospitalizations for endocrine conditions, subsequent neoplasms and symptoms without an underlying diagnosis. This new knowledge is important for survivorship care and to identify possible preventable hospitalizations among CCS.

Association of Breast Cancer Risk After Childhood Cancer With Radiation Dose to the Breast and Anthracycline Use

Chest irradiation for childhood cancer is associated with increases in breast cancer risk. Growing evidence suggests that anthracyclines increase this risk, but the outcome of combined anthracycline use and radiotherapy has not been studied. To evaluate breast cancer risk in childhood cancer survivors following radiotherapy and chemotherapy and assess whether risks varied by estrogen receptor (ER) status. In a North American hospital-based nested case-control study, a retrospective cohort of 14 358 five-year survivors of childhood cancer, diagnosed from 1970 to 1986 and followed up through December 31, 2016, was analyzed. Cases (n = 271) were defined as women with subsequent breast cancer. Controls (n = 1044) were matched 4:1 to cases by age at first cancer and duration of follow-up (± 2 years). Data analysis was conducted from September 2017 to July 2018. Radiation dose to breast tumor site and ovaries and cumulative chemotherapy doses, including anthracyclines and alkylating agents. Odds ratios (ORs) for subsequent breast cancer by ER status. A total of 271 women served as breast cancer cases (median age at first cancer diagnosis, 15 years [range, 3-20]; median age at breast cancer diagnosis, 39 years [range, 20-57]): 201 invasive (113 ER positive [ER+], 41 ER negative [ER-], and 47 unknown) and 70 in situ breast cancers. The OR for breast cancer increased with increasing radiation dose to the breast (OR per 10 Gy, 3.9; 95% CI, 2.5-6.5) and was similar for ER+ (OR per 10 Gy, 5.5; 95% CI, 2.8-12.6) and ER- (OR per 10 Gy, 4.8; 95% CI, 1.7-22.3) cancers. For women who received ovarian doses less than 1 Gy, the OR per 10 Gy to the breast was higher (OR, 6.8; 95% CI, 3.9-12.5) than for women who received ovarian doses greater than or equal to 15 Gy (OR, 1.4; 95% CI, 1.0-6.4). The OR for breast cancer increased with cumulative anthracycline dose (OR per 100 mg/m2, 1.23; 95% CI, 1.09-1.39; P < .01 for trend), and was 1.49 (95% CI, 1.21-1.83) for ER+ cancer vs 1.10 (95% CI, 0.84-1.45) for ER- cancers (P value for heterogeneity = .47). There was an additive interaction between radiotherapy and anthracycline treatment (P = .04) with the OR for the combined association between anthracycline therapy and breast radiation dose of 10 Gy or more (compared with 0 to less than 1 Gy) of 19.1 (95% CI, 7.6-48.0) vs 9.6 (95% CI, 4.4-20.7) without anthracycline use. This study provides the first evidence to date that the combination of anthracyclines and radiotherapy may increase breast cancer risks compared with use of neither treatment with a similar radiation dose response for ER+ and ER- cancers and possibly higher anthracycline risks for ER+ cancers. These results might help inform surveillance guidelines for childhood cancer survivors.

Targeted Proteomics to Identify Early Diagnostic Biomarkers for Anthracycline-Induced Cardiomyopathy in Long-Term Survivors of Childhood Cancer

Introduction Plasma biomarkers may aid in the early diagnosis of anthracycline-induced cardiomyopathy in long-term childhood cancer survivors (CCS) and may provide insights into the underlying mechanisms involved. Natriuretic peptides and troponins are of limited value to diagnose left ventricular dysfunction in CCS >1 year after anthracycline treatment. To improve cardiomyopathy surveillance in long-term CCS, we aim to identify new plasma biomarkers for the early diagnosis of anthracycline-induced cardiomyopathy. Methods Five-year CCS treated with anthracyclines and ≥18 years at time of the study were identified from the ongoing Dutch Childhood Oncology Late Effects After Childhood Cancer (DCOG-LATER) study. Genetic cardiomyopathy cases were identified from a dilated cardiomyopathy cohort in the Amsterdam UMC (figure 1). Levels of 184 plasma proteins (from 32 different biological processes) were compared between three groups of 30 patients: anthracycline-induced cardiomyopathy cases (left ventricular ejection fraction (LVEF) Results The results will be available in August 2019 and will be presented during the congress. Conclusion Targeted proteomics in CCS treated with anthracyclines may identify new biomarkers for the early diagnosis of anthracycline-induced cardiomyopathy in CCS and may provide additional insights into the pathophysiology of anthracycline cardiomyopathy.

Risk of subsequent primary leukaemias among 69,460 five-year survivors of childhood cancer diagnosed from 1940 to 2008 in Europe: A cohort study within PanCareSurFup

BackgroundSurvivors of childhood cancers are at risk of developing subsequent primary leukaemias (SPLs), but the long-term risks beyond 20 years of treatment are still unclear. We investigated the risk of SPLs in five-year childhood cancer survivors using a large-scale pan-European (PanCareSurFup) cohort and evaluated variations in the risk by cancer and demographic factors. MethodsThis largest-ever assembled cohort comprises 69,460 five-year childhood cancer survivors from 12 European countries. Standardised incidence ratios (SIRs) and absolute excess risks (AERs) were calculated. ResultsOne hundred fifteen survivors developed an SPL including 86 myeloid leukaemias (subsequent primary myeloid leukaemias [SPMLs]), 17 lymphoid leukaemias and 12 other types of leukaemias; of these SPLs, 31 (27%) occurred beyond 20 years from the first childhood cancer diagnosis. Compared with the general population, childhood cancer survivors had a fourfold increased risk (SIR = 3.7, 95% confidence interval [CI]: 3.1 to 4.5) of developing leukaemia, and eight leukaemias per 100,000 person-years (AER = 7.5, 95% CI: 6.0 to 9.2) occurred in excess of that expected. The risks remained significantly elevated beyond 20 years from the first primary malignancy (SIR = 2.4, 95% CI: 1.6 to 3.4). Overall, the risk ratio for SPML (SIR = 5.8, 95% CI: 4.6 to 7.1) was higher than that for other SPLs. ConclusionsWe demonstrate that beyond 20 years after childhood cancer diagnosis, survivors experience an increased risk for SPLs compared with that expected from the general population. Our findings highlight the need for awareness by survivors and their healthcare providers for potential risk related to SPL.

Combined effect of radiotherapy and anthracyclines on risk of breast cancer among female childhood cancer survivors: A report from the Childhood Cancer Survivor Study (CCSS).

10053 Background: Breast cancer is a common late-effect for female childhood cancer survivors and chest radiotherapy is an established risk factor. Recent findings showed that treatment with anthracyclines also increases breast cancer risk. However, the risk from the combined effect of radiotherapy and anthracyclines is unknown. Methods: We conducted a matched case-control study of 271 subsequent breast cancer and 1044 controls nested within the CCSS - a North-American cohort of five-year survivors of childhood cancer, diagnosed from 1970-1986 and followed-up through 2016. Detailed treatment records were abstracted to estimate radiation dose (Gy) to the breast cancer location and ovaries and calculate cumulative chemotherapy doses (mg/m2). Multivariable conditional logistic regression was used to estimate Odds ratios (OR) and 95% confidence intervals (CI). Results: Breast cancer risk increased linearly with radiation dose to the breast (OR per 10Gy = 3.9, 95%CI:2.5-6.5) and decreased with increasing ovarian dose (p &lt; 0.01). Adjusted for radiation dose, the highest quartile of dose (455+mg/m2) of anthracyclines was associated with a 3.8-fold increased risk of breast cancer (95%CI:1.8-8.2) compared to no anthracyclines. This risk increased with cumulative anthracycline dose (p-trend &lt; 0.01) and was non-significantly higher for ER+ than ER- breast cancers. For a breast dose of 10+Gy, the OR was 19.1 (95%CI:7.6-48.0) with anthracyclines versus 9.6 (95%CI:4.4-20.7) without anthracyclines, compared to 0- &lt; 1Gy breast dose and no anthracyclines (p-additive interaction = 0.04). Conclusions: The combination of anthracyclines and radiotherapy doses to the breast can markedly increase breast cancer risk compared to those who receive neither treatment. Our results can be used to inform risk management for childhood cancer patients treated in the past, as well as project potential breast cancer risk from current treatment protocols.

The involvement of primary care physicians in care for childhood cancer survivors.

Childhood cancer survivors (CCS) are at risk of developing long-term morbidity, which is likely to be presented to a primary care physician (PCP). Therefore, insight into CCS's PCP-based health care use is needed. We investigated the volume and underlying health problems of PCP-based health care use and the determinants for PCP-based health care use in CCS. Data from a Dutch cohort of 6018 eligible five-year CCS were linked to the Nivel Primary Care database, which contains detailed data from a representative sample of 10% of all Dutch PCPs. Per CCS, two matched controls were selected. Negative binomial regression was performed to compare the annual number of contacts between CCS and controls, and to identify determinants for PCP-based care use among CCS. This study included 602 CCS and 1204 controls. CCS were 1.3 times more likely to contact their PCP than controls (95% CI, 1.2-1.5), up to 1.5 times at attained age over 40 years (95% CI, 1.2-1.8). CCS were 4.9 times more likely to contact their PCP for new malignancies, 3.1 for hematological conditions, and 2.8 for endocrine conditions. Female sex, higher attained age, and treatment with radiotherapy were determinants for having more PCP contacts. PCPs play an important role in care for CCS. CCS use more PCP-based care than matched controls, mainly for severe conditions such as malignancies, hematological, and endocrine conditions. Our results emphasize the importance of disseminating the current knowledge on long-term morbidity in CCS and on their optimal follow-up care among PCPs.

Communicating “cure” to pediatric oncology patients: A mixed‐methods study

Uncertainty about cure puts childhood cancer survivors at risk of mental distress. We asked survivors if they had been told they had been cured and investigated associated factors. We used nationwide registry data and a questionnaire survey for ≥five-year survivors of childhood cancer (n=301), followed by online focus groups with a purposive sample of Swiss pediatric oncologists (n=17). Discussions were coded by investigators using thematic analysis. Overall, 235 among 301 survivors (78%; 95% confidence interval, 73%-83%) reported having been told they were cured. The proportion was 89% (81%-97%) among lymphoma and 84% (77%-91%) among leukemia survivors, but only 49% (33%-65%) among central nervous system tumor survivors. Pediatric oncologists acknowledged that telling survivors they are cured may reassure them that their cancer lies behind them. However, many refrained from telling all patients. Reasons included the possibility of late effects (cure disrupted by a continued need for follow-up care) or late relapse (uncertainty of biological cure), case-by-case strategies (use of "cure" according to individual factors), and reluctance (substitution of noncommittal terms for "cure"; waiting for the patient to raise the topic). Not all physicians tell survivors they have been cured; their choices depend on the cancer type and risk of late effects.