Abstract
Background
Childhood cancer survivors have an increased risk of heart failure, ischemic heart disease, and stroke. They may benefit from prediction models that account for cardiotoxic cancer ...treatment exposures combined with information on traditional cardiovascular risk factors such as hypertension, dyslipidemia, and diabetes.
Methods
Childhood Cancer Survivor Study participants (n = 22 643) were followed through age 50 years for incident heart failure, ischemic heart disease, and stroke. Siblings (n = 5056) served as a comparator. Participants were assessed longitudinally for hypertension, dyslipidemia, and diabetes based on self-reported prescription medication use. Half the cohort was used for discovery; the remainder for replication. Models for each outcome were created for survivors ages 20, 25, 30, and 35 years at the time of prediction (n = 12 models).
Results
For discovery, risk scores based on demographic, cancer treatment, hypertension, dyslipidemia, and diabetes information achieved areas under the receiver operating characteristic curve and concordance statistics 0.70 or greater in 9 and 10 of the 12 models, respectively. For replication, achieved areas under the receiver operating characteristic curve and concordance statistics 0.70 or greater were observed in 7 and 9 of the models, respectively. Across outcomes, the most influential exposures were anthracycline chemotherapy, radiotherapy, diabetes, and hypertension. Survivors were then assigned to statistically distinct risk groups corresponding to cumulative incidences at age 50 years of each target outcome of less than 3% (moderate-risk) or approximately 10% or greater (high-risk). Cumulative incidence of all outcomes was 1% or less among siblings.
Conclusions
Traditional cardiovascular risk factors remain important for predicting risk of cardiovascular disease among adult-age survivors of childhood cancer. These prediction models provide a framework on which to base future surveillance strategies and interventions.
The effect that long-term use of suppressive acyclovir (ACV) has on both overall herpes simplex virus (HSV) disease and ACV-resistant HSV disease was examined in 3 consecutive cohorts of ...hematopoietic stem-cell transplant (HCT) recipients (n=2049); cohort 1 received ACV for 30 days after HCT, cohort 2 received it for 1 year after HCT, and cohort 3 received it for an extended period (i.e., >1 year) if the patient's immunosuppression continued after 1 year. The 2-year probability of HSV disease was 31.6% (95% confidence interval CI, 28.0%–35%) in cohort 1, 3.9% (95% CI, 2.7%–5.2%) in cohort 2, and 0% in cohort 3 (P<.001). ACV-resistant HSV disease developed in 10 patients in cohort 1 (2-year probability, 1.3% 95% CI, 0.8%–2.7%), in 2 patients in cohort 2 (2-year probability, 0.2% 95% CI, 0%–0.8%; P=.006), and in 0 patients in cohort 3 (cohort 2 vs. cohort 3, P=.3). Long-term use of suppressive prophylactic ACV appears to prevent the emergence of drug-resistant HSV disease in HCT.
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.
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.
The overall prevalence of frailty among survivors was 3 times higher compared with siblings (6.4%; 95% CI, 4.1% to 8.7%;
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/m
, 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.
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.
•Radiation-related late cardiac disease risk is updated for the Childhood Cancer Survivor Study using enhanced dosimetry.•Consistent with previous findings, late cardiac disease risk increases with ...Dm ≥ 10 Gy, V20 ≥ 0.1%, and V5,V20=0% ≥ 50%.•Risks are significantly (P < 0.05) higher than previously estimated for survivors with Dm in the range of 20–29.9 Gy.•Risks are significantly (P < 0.05) higher than previously estimated for survivors with V20 in the range of 30–79.9%.
We previously evaluated late cardiac disease in long-term survivors in the Childhood Cancer Survivor Study (CCSS) based on heart radiation therapy (RT) doses estimated from an age-scaled phantom with a simple atlas-based heart model (HAtlas). We enhanced our phantom with a high-resolution CT-based anatomically realistic and validated age-scalable cardiac model (HHybrid). We aimed to evaluate how this update would impact our prior estimates of RT-related late cardiac disease risk in the CCSS cohort.
We evaluated 24,214 survivors from the CCSS diagnosed from 1970 to 1999. RT fields were reconstructed on an age-scaled phantom with HHybrid and mean heart dose (Dm), percent volume receiving ≥ 20 Gy (V20) and ≥ 5 Gy with V20 = 0 (V5,V20=0%) were calculated. We reevaluated cumulative incidences and adjusted relative rates of grade 3–5 Common Terminology Criteria for Adverse Events outcomes for any cardiac disease, coronary artery disease (CAD), and heart failure (HF) in association with Dm, V20, and V5,V20=0% (as categorical variables). Dose-response relationships were evaluated using piecewise-exponential models, adjusting for attained age, sex, cancer diagnosis age, race/ethnicity, time-dependent smoking history, diagnosis year, and chemotherapy exposure and doses. For relative rates, Dm was also considered as a continuous variable.
Consistent with previous findings with HAtlas, reevaluation using HHybrid dosimetry found that, Dm ≥ 10 Gy, V20 ≥ 0.1%, and V5,V20=0% ≥ 50% were all associated with increased cumulative incidences and relative rates for any cardiac disease, CAD, and HF. While updated risk estimates were consistent with previous estimates overall without statistically significant changes, there were some important and significant (P < 0.05) increases in risk with updated dosimetry for Dm in the category of 20 to 29.9 Gy and V20 in the category of 30% to 79.9%. When changes in the linear dose–response relationship for Dm were assessed, the slopes of the dose response were steeper (P < 0.001) with updated dosimetry. Changes were primarily observed among individuals with chest-directed RT with prescribed doses ≥ 20 Gy.
These findings present a methodological advancement in heart RT dosimetry with improved estimates of RT-related late cardiac disease risk. While results are broadly consistent with our prior study, we report that, with updated cardiac dosimetry, risks of cardiac disease are significantly higher in two dose and volume categories and slopes of the Dm-specific RT-response relationships are steeper. These data support the use of contemporary RT to achieve lower heart doses for pediatric patients, particularly those requiring chest-directed RT.
Childhood cancer survivors carry a high burden of treatment-related morbidity; however, race/ethnicity-specific risks of adverse outcomes are not well understood.
Data from the Childhood Cancer ...Survivor Study, a cohort of survivors of at least 5 years, were used to compare Hispanic (n = 750, 5.4%) and non-Hispanic black (NHB: n = 694, 5.0%) survivors to non-Hispanic white patients (NHW: n = 12,397, 89.6%) for late mortality, subsequent neoplasms, and chronic health conditions.
NHBs and Hispanics reported lower socioeconomic status (SES) and higher prevalence of obesity, and NHBs reported higher prevalence of hypertension. NHBs had higher rate of all-cause mortality (relative rate RR, 1.4; 95% CI, 1.1 to 1.9; P = .008), which was abrogated (RR, 1.0; 95% CI, 0.8 to 1.4; P = .9) after adjusting for SES. Nonmelanoma skin cancer was not observed among irradiated NHBs, and the risk was lower among Hispanic survivors (RR, 0.3; 95% CI, 0.1 to 0.7) compared with NHWs. Both NHBs and Hispanics demonstrated elevated risks for diabetes; these risks persisted after adjusting for SES and obesity (NHBs: RR, 2.8; 95% CI, 1.1 to 6.7; Hispanics: RR, 3.1; 95% CI, 1.5 to 6.4). NHBs were more likely to report cardiac conditions (RR, 1.8; 95% CI, 1.1 to 2.7), but the risk was attenuated after adjusting for cardiovascular risk factors. Therapeutic exposures did not affect racial/ethnic differences in mortality (all cause or cause specific), chronic health conditions, or subsequent neoplasms.
By and large, NHB and Hispanic childhood cancer survivors experience a comparable burden of morbidity and mortality to their NHW counterparts. The few differences in risk were explained by the racial/ethnic differences in socioeconomic status and/or cardiovascular risk factors.
Cumulative incidence has been widely used to estimate the cumulative probability of developing an event of interest by a given time, in the presence of competing risks. When it is of interest to ...measure the total burden of recurrent events in a population, however, the cumulative incidence method is not appropriate because it considers only the first occurrence of the event of interest for each individual in the analysis: Subsequent occurrences are not included. Here, we discuss a straightforward and intuitive method termed "mean cumulative count," which reflects a summarization of all events that occur in the population by a given time, not just the first event for each subject. We explore the mathematical relationship between mean cumulative count and cumulative incidence. Detailed calculation of mean cumulative count is described by using a simple hypothetical example, and the computation code with an illustrative example is provided. Using follow-up data from January 1975 to August 2009 collected in the Childhood Cancer Survivor Study, we show applications of mean cumulative count and cumulative incidence for the outcome of subsequent neoplasms to demonstrate different but complementary information obtained from the 2 approaches and the specific utility of the former.
Limited understanding of the immunopathogenesis of human herpesvirus 6B (HHV-6B) has prevented its acceptance as a pulmonary pathogen after hematopoietic cell transplant (HCT). In this prospective ...multicenter study of patients undergoing bronchoalveolar lavage (BAL) for pneumonia after allogeneic HCT, we test blood and BAL fluid (BALF) for HHV-6B DNA and mRNA transcripts associated with lytic infection and perform RNA-seq on paired blood. Among 116 participants, HHV-6B DNA is detected in 37% of BALs, 49% of which also have HHV-6B mRNA detection. We establish HHV-6B DNA viral load thresholds in BALF that are highly predictive of HHV-6B mRNA detection and associated with increased risk for overall mortality and death from respiratory failure. Participants with HHV-6B DNA in BALF exhibit distinct host gene expression signatures, notable for enriched interferon signaling pathways in participants clinically diagnosed with idiopathic pneumonia. These data implicate HHV-6B as a pulmonary pathogen after allogeneic HCT.
Purpose To compare the risks of serious health outcomes among hematopoietic cell transplantation (HCT) survivors versus a matched population of patients with cancer who did not undergo HCT, where the ...primary difference may be exposure to HCT. Methods Two-year HCT survivors treated at a comprehensive cancer center from 1992 through 2009 who were Washington State residents (n = 1,792; 52% allogeneic and 90% hematologic malignancies) were frequency matched by demographic characteristics and underlying cancer diagnosis (as applicable) to non-HCT 2-year cancer survivors, using the state cancer registry (n = 5,455) and the general population (n = 16,340) using driver's license files. Late outcomes for all three cohorts were ascertained from the state hospital discharge and death registries; subsequent cancers were ascertained from the state cancer registry. Results After median follow-up of 7.1 years, HCT survivors experienced significantly greater rates of hospitalization compared with matched non-HCT cancer survivors (280 v 173 episodes per 1,000 person-years, P < .001) and greater all-cause mortality (hazard ratio HR, 1.1; 95% CI, 1.01 to 1.3). HCT survivors had more hospitalizations or death with infections (10-year cumulative incidence, 31% v 22%; HR, 1.4; 95% CI, 1.3 to 1.6) and respiratory complications (cumulative incidence, 27% v 20%; HR, 1.4; 95% CI, 1.2 to 1.5). Risks of digestive, skin, and musculoskeletal complications also were greater among HCT versus non-HCT cancer survivors. The two groups had similar risks of circulatory complications and second cancers. Both HCT and non-HCT cancer survivors had significantly greater 10-year cumulative incidences of all major organ-system outcomes versus the general population. Conclusion History of HCT was associated with late morbidity and mortality among cancer survivors. In particular, clinicians who care for HCT survivors should be aware of their high rates of late respiratory and infectious complications.
SummaryBackgroundSerious chronic medical conditions occur in childhood cancer survivors. We aimed to investigate incidence of and risk factors for end-organ damage resulting in registration on a ...waiting list for or receiving a solid organ transplantation and 5-year survival following these procedures. MethodsThe Childhood Cancer Survivor Study (CCSS) is a retrospective cohort of individuals who survived at least 5 years after childhood cancer diagnosed at younger than 21 years of age, between Jan 1, 1970, and Dec 31, 1986, at one of 25 institutions in the USA. We linked data from CCSS participants treated in the USA diagnosed between Jan 1, 1970, and Dec 31, 1986 (without solid organ transplantation before cohort entry) to the Organ Procurement and Transplantation Network—a database of all US organ transplants. Eligible participants had been diagnosed with leukaemia, lymphoma, malignant CNS tumours, neuroblastoma, Wilms' tumours, and bone and soft tissue sarcomas. The two primary endpoints for each type of organ transplant were date of first registration of a transplant candidate on the waiting list for an organ and the date of the first transplant received. We also calculated the cumulative incidence of being placed on a waiting list or receiving a solid organ transplantation, hazard ratios (HRs) for identified risk factors, and 5-year survival following transplantation. FindingsOf 13 318 eligible survivors, 100 had 103 solid organ transplantations (50 kidney, 37 heart, nine liver, seven lung) and 67 were registered on a waiting list without receiving a transplant (21 kidney, 25 heart, 15 liver, six lung). At 35 years after cancer diagnosis, the cumulative incidence of transplantation or being on a waiting list was 0·54% (95% CI 0·40–0·67) for kidney transplantation, 0·49% (0·36–0·62) for heart, 0·19% (0·10–0·27) for liver, and 0·10% (0·04–0·16) for lung. Risk factors for kidney transplantation were unilateral nephrectomy (HR 4·2, 95% CI 2·3–7·7), ifosfamide (24·9, 7·4–83·5), total body irradiation (6·9, 2·3–21·1), and mean kidney radiation of greater than 15 Gy (>15–20 Gy, 3·6 1·5–8·5; >20 Gy 4·6 1·1–19·6); for heart transplantation, anthracycline and mean heart radiation of greater than 20 Gy (dose-dependent, both p<0·0001); for liver transplantation, dactinomycin (3·8, 1·3–11·3) and methotrexate (3·3, 1·0–10·2); for lung transplantation, carmustine (12·3, 3·1–48·9) and mean lung radiation of greater than 10 Gy (15·6, 2·6–92·7). 5-year overall survival after solid organ transplantation was 93·5% (95% CI 81·0–97·9) for kidney transplantation, 80·6% (63·6–90·3) for heart, 27·8% (4·4–59·1) for liver, and 34·3% (4·8–68·6) for lung. InterpretationSolid organ transplantation is uncommon in ageing childhood cancer survivors. Organ-specific exposures were associated with increased solid organ transplantation incidence. Survival outcomes showed that solid organ transplantation should be considered for 5-year childhood cancer survivors with severe end-organ failure. FundingUS National Institute of Health, American Lebanese Syrian Associated Charities, US Health Resources and Services Administration.
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