To determine the influence of modifiable lifestyle factors on the risk of cardiovascular disease after hematopoietic cell transplantation (HCT).
Patients and Methods
HCT survivors of ≥ 1 year treated from 1970 to 2010 (n = 3,833) were surveyed from 2010 to 2011 on current cardiovascular health and related lifestyle factors (smoking, diet, recreational physical activity). Responses (n = 2,362) were compared with those from a matched general population sample (National Health and Nutrition Examination Survey [NHANES]; n = 1,192).
Compared with NHANES participants, HCT survivors (median age, 55.9 years; median 10.8 years since HCT; 71.3% allogeneic) had higher rates of cardiomyopathy (4.0% v 2.6%), stroke (4.8% v 3.3%), dyslipidemia (33.9% v 22.3%), and diabetes (14.3% v 11.7%; P < .05 for all comparisons). Prevalence of hypertension was similar (27.9% v 30.0%), and survivors were less likely to have ischemic heart disease (6.1% v 8.9%; P < .01). Among HCT survivors, hypertension, dyslipidemia, and diabetes were independent risk factors for ischemic heart disease and cardiomyopathy, and smoking was associated with ischemic heart disease and diabetes (odds ratios [ORs], 1.8 to 2.1; P = .02). Obesity was a risk factor for post-transplantation hypertension, dyslipidemia, and diabetes (ORs ≥ 2.0; P < .001). In contrast, lower fruit/vegetable intake was associated with greater risk of dyslipidemia and diabetes (ORs, 1.4 to 1.8; P ≤ .01), and lower physical activity level was associated with greater risk of hypertension and diabetes (ORs, 1.4 to 1.5; P < .05). Healthier lifestyle characteristics among HCT survivors attenuated risk of all cardiovascular conditions assessed.
Attention of clinicians to conventional cardiovascular risk factors and modifiable lifestyle characteristics offers hope of reducing serious cardiovascular morbidity after HCT.
To evaluate the relative contribution of modifiable cardiovascular risk factors on the development of major cardiac events in aging adult survivors of childhood cancer.
Patients and Methods
Among 10,724 5-year survivors (median age, 33.7 years) and 3,159 siblings in the Childhood Cancer Survivor Study, the prevalence of hypertension, diabetes mellitus, dyslipidemia, and obesity was determined, along with the incidence and severity of major cardiac events such as coronary artery disease, heart failure, valvular disease, and arrhythmia. On longitudinal follow-up, rate ratios (RRs) of subsequent cardiac events associated with cardiovascular risk factors and cardiotoxic therapy were assessed in multivariable Poisson regression models.
Among survivors, the cumulative incidence of coronary artery disease, heart failure, valvular disease, and arrhythmia by 45 years of age was 5.3%, 4.8%, 1.5%, and 1.3%, respectively. Two or more cardiovascular risk factors were reported by 10.3% of survivors and 7.9% of siblings. The risk for each cardiac event increased with increasing number of cardiovascular risk factors (all Ptrend < .001). Hypertension significantly increased risk for coronary artery disease (RR, 6.1), heart failure (RR, 19.4), valvular disease (RR, 13.6), and arrhythmia (RR, 6.0; all P values < .01). The combined effect of chest-directed radiotherapy plus hypertension resulted in potentiation of risk for each of the major cardiac events beyond that anticipated on the basis of an additive expectation. Hypertension was independently associated with risk of cardiac death (RR, 5.6; 95% CI, 3.2 to 9.7).
Modifiable cardiovascular risk factors, particularly hypertension, potentiate therapy-associated risk for major cardiac events in this population and should be the focus of future interventional studies.
To better understand the combined effects of pre-transplant, transplant, and post-transplant factors in determining risks of serious cardiovascular disease following hematopoietic cell transplantation (HCT).
Hospitalizations and deaths associated with serious cardiovascular outcomes were identified among 1,379 Washington State residents who received HCT (57% allogeneic; 43% autologous) at a single center from 1985–2005, survived ≥2 years, and followed through 2008. Using a nested-case-cohort design, relationships (hazard ratios, HR) between potential risk factors and outcomes were examined among affected survivors and a randomly selected sub-cohort (n=509).
After 7.0 years median follow-up (range 2.0–23.7), the 10-year cumulative incidence of ischemic heart disease, cardiomyopathy, stroke, and all-cause cardiovascular death was 3.8%, 6.0%, 3.5%, and 3.7%, respectively. In multivariable analysis, increased pre-transplant anthracyclines was associated with cardiomyopathy. Active chronic graft vs. host disease was associated with cardiovascular death (HR 4.0, 95% CI 1.1–14.7); risk was otherwise similar between autologous vs. allogeneic HCT recipients. Independent of therapeutic exposures, pre-transplant smoking, hypertension, dyslipidemia, diabetes, and obesity conferred additional risk of all outcomes except stroke (HR ≥1.5 for each additional risk factor, p<0.03). Hypertension and dyslipidemia at one year with persistence of these conditions two or more years following HCT also were associated with independent risks of multiple outcomes.
Hematopoietic cell transplant survivors with pre-existing or newly developed and persistent cardiovascular risk factors remain at greater risk of subsequent serious cardiovascular disease compared with other survivors, independent of chemo- and radiotherapy exposures. These survivors should receive appropriate follow-up and be considered for primary intervention.
In the US, children diagnosed with cancer are living longer, but not without consequences from the same drugs that cured their cancer. In these patients, cardiovascular disease is the leading cause of non-cancer-related morbidity and mortality. Although this review focuses on anthracycline-related cardiomyopathy in childhood cancer survivors, the global lifetime risk of other cardiovascular diseases such as atherosclerosis, arrhythmias and intracardiac conduction abnormalities, hypertension, and stroke also are increased. Besides anthracyclines, newer molecularly targeted agents, such as vascular endothelial growth factor receptor and tyrosine kinase inhibitors, also have been associated with acute hypertension, cardiomyopathy, increased risk of ischemic cardiac events and arrhythmias, and are summarized here. This review also covers other risk factors for chemotherapy-related cardiotoxicity (including both modifiable and non-modifiable factors), monitoring strategies (including both blood and imaging-based biomarkers) during and following cancer treatment, and discusses the management of cardiotoxicity (including prevention strategies such as cardioprotection by use of dexrazoxane).
Hematopoietic cell transplantation (HCT) is increasingly offered as a curative option for many patients with hematologic malignancies. Improvements in HCT strategies and supportive care have resulted in a growing number of long-term survivors. However, these survivors are at increased risk of developing long-term debilitating chronic health conditions, including premature cardiovascular disease. These complications are more common than in the general population, and there are well-described associations between therapeutic exposures, traditional cardiovascular risk factors and subsequent cardiovascular disease risk. We present here an overview of the current state of knowledge regarding pathogenesis and risk factors for some of the more commonly occurring cardiovascular complications following HCT, highlighting existing surveillance recommendations and future directions for research to minimize cardiovascular morbidity in these survivors.
Hematopoietic cell transplantation; cardiovascular disease; late effects; cancer survivors; screening
Survivors of childhood acute lymphoblastic leukemia (ALL) may face an increased risk of metabolic and cardiovascular late effects. In order to determine the prevalence of and risk factors for adverse cardiometabolic traits in a contemporary cohort of pediatric ALL survivors, we recruited 48 off-therapy patients in remission treated with conventional chemotherapy and 26 treated with total body irradiation (TBI) based hematopoietic cell transplantation (HCT) in this cross-sectional pilot study. At a median age of 15 (range 8–21 years), HCT survivors were significantly more likely than non-HCT survivors to manifest multiple cardiometabolic traits including central adiposity, hypertension, insulin resistance, and dyslipidemia. Overall, 23.1% of HCT survivors met criteria for metabolic syndrome (≥3 traits) compared with 4.2% of non-HCT survivors (p=0.02). HCT survivors also had increased C-reactive protein and leptin levels and decreased adiponectin, suggestive of underlying inflammation and increased visceral fat. In multivariate analyses, history of HCT remained associated with ≥2 (OR 5.13, 95% CI 1.54, 17.15) as well as ≥3 (OR 16.72, 95% CI 1.66, 168.80) traits. Other risk factors included any cranial radiation exposure and family history of cardiometabolic disease. In summary, pediatric ALL survivors exposed to TBI-based HCT as well as any cranial radiation may manifest cardiometabolic traits at an early age and should be screened accordingly.
acute lymphoblastic leukemia; hematopoietic cell transplantation; metabolic syndrome; radiotherapy; survivor
Children of different racial/ethnic backgrounds have varying risks of cancer. However, few studies have examined cancer occurrence in mixed ancestry children.
Population-based case-control study examining cancer among children age <15 years using linked cancer and birth-registry data from 5 U.S. states from 1978 to 2004. Data were available for 13,249 cancer cases and 36,996 controls selected from birth records. Parental race/ethnicity was determined from birth records. Logistic regression was used to examine the association of cancer with different racial/ethnic groups.
Relative to Whites, Blacks had a 28% decreased risk of cancer (odds ratio (OR) 0.72, 95% CI 0.65–0.80), while both Asians and Hispanics had an approximate 15% decrease. Children of mixed White/Black ancestry also were at decreased risk (OR 0.71, 95% CI 0.56–0.90), but estimates for mixed White/Asian and White/Hispanic children did not differ from those of Whites. Relative to Whites: 1.) Black and mixed White/Black children had decreased ORs for acute lymphoblastic leukemia, (0.39, 95% CI 0.31–0.49) and (0.58, 95% CI 0.37–0.91), respectively; 2.) Asian and mixed White/Asian children had decreased ORs for brain tumors, (0.51, 95% CI 0.39–0.68) and (0.79, 95% CI 0.54–1.16), respectively; and 3.) Hispanic and mixed White/Hispanic children had decreased ORs for neuroblastoma (0.51, 95% CI 0.42–0.61) and (0.67, 95% CI 0.50–0.90), respectively.
The tendency of mixed ancestry children to have risks more similar to racial/ethnic minority children than the White majority group may help formulate etiologic studies designed to more directly study possible genetic and environmental differences.
child; ethnicity; neoplasms/epidemiology; race; risk factors
Childhood cancer survivors (CCS) are more insulin resistant (IR) and have higher levels of several cardiovascular (CV) risk factors even while still children. This study examines specific treatment exposures associated with CV risk factors and IR.
CCS age 9–18 years at study entry and in remission ≥5 years from diagnosis (n=319) and 208 sibling controls were recruited into this cross-sectional study that included physiologic assessment of IR (hyperinsulinemic euglycemic clamp) and assessment of CV risk factors.. Regression and recursive tree modeling were used to ascertain treatment combinations associated with IR and CV risk.
Mean current age of CCS was 14.5yr, 54% were male (siblings 13.6yr, 54% male). Diagnoses included leukemia (35%), brain tumors (36%), solid tumors (33%) or lymphoma (6%). Among CCS, analysis of individual chemotherapy agents failed to find associations with CV risk factors or IR. Compared to siblings, IR was significantly higher in CCS who received platinum plus cranial radiation (CRT, 92% brain tumors) and in those who received steroids but no platinum (majority leukemia). IR did not differ between CCS who received surgery alone vs. siblings. Within survivor comparisons failed to elucidate treatment combinations that increased IR compared to those who received surgery only.
Exposure to platinum, CRT or steroids is associated with IR and CV risk factors and should be taken into consideration in the development of screening recommendations for CV risk.
Earlier identification of CCS who may benefit from targeted prevention efforts may reduce their future risk of CV disease.
cancer survivor; cardiovascular risk; insulin resistance; late effects
Compare the risk of reproductive and infant outcomes between male childhood cancer survivors and a population-based comparison group.
Retrospective cohort study.
4 U.S. regions.
Cancer registries identified males <20 years old diagnosed with cancer 1973−2000. Linked birth certificates identified first subsequent live offspring (n=470). Comparison subjects were identified from remaining birth certificates, frequency-matched on year and age at fatherhood, and race/ethnicity (n=4150).
Cancer diagnosis prior to age 20.
Pregnancy and infant outcomes identified from birth certificates.
Compared with infants born to unaffected males, offspring of cancer survivors had a borderline risk of birth weight <2500 g (RR 1.43, 95% CI 0.99−2.05), with risk associated most strongly with younger age of cancer diagnosis and exposure to any chemotherapy (RR 1.96, 95% CI 1.22−3.17) or radiotherapy (RR 1.95, 95% CI 1.14−3.35). However, they were not at risk of being born prematurely, small for gestational age, having malformations or an altered male:female sex ratio. Overall, female partners of male survivors were not more likely to have maternal complications recorded on birth records versus the comparison group. However, preeclampsia was associated with some cancers, especially central nervous system tumors (RR 3.36, 95% CI 1.63−6.90).
Most pregnancies resulting in live births among partners of male childhood cancer survivors were not at significantly greater risk of complications versus comparison subjects. The possibility of a paternal component affected by prior cancer history influencing predisposition towards some adverse perinatal outcomes merits further investigation.
male; cancer survivors; pregnancy outcome; low birth weight
To compare birth outcomes among childhood and adolescent female cancer survivors who subsequently bear children, relative to those of women without cancer history.
Retrospective cohort study.
4 U.S. regions.
Cancer registries identified girls <20 years, diagnosed with cancer 1973-2000. Linked birth records identified first live births after diagnosis (n=1898). Comparison subjects were selected from birth records (n=14278). Cervical/genital tract cancer cases were analyzed separately.
Cancer diagnosis <20 years.
Infant low birth weight, preterm delivery, sex ratio, malformations, mortality, delivery method; maternal diabetes, anemia, preeclampsia.
Childhood cancer survivors' infants were more likely to be preterm (relative risk [RR] 1.54, 95% CI 1.30-1.83) and weigh <2500 g (RR 1.31, 95% CI 1.10-1.57). For cervical/genital cancer patients' offspring, estimates were 1.33 (95% CI 1.13, 1.56), and 1.29 (95% CI 1.10-1.53), respectively. There were no increased risks of malformations, infant death, or altered sex ratio, suggesting no increased germ cell mutagenicity. In exploratory analysis, bone cancer survivors had an increased risk of diabetes (RR 4.92, 95% CI 1.60-15.13), and anemia was more common among brain tumor survivors (RR 3.05, 95% CI 1.16-7.98) and childhood cancer survivors with initial treatment of chemotherapy only (RR 2.45, 95% CI 1.16-5.17).
Infants of female childhood and adolescent cancer patients were not at increased risk of malformations or death. Increased occurrence of preterm delivery and low birth weight suggest close monitoring is warranted. Increased diabetes and anemia among sub-groups have not been reported, suggesting areas for study.
cancer survivors; pregnancy outcome; low birth weight; premature birth; congenital abnormalities
To determine the risk of thyroid dysfunction and subsequent thyroid cancer among childhood acute lymphoblastic leukemia (ALL) survivors.
Rates of self-reported thyroid dysfunction and thyroid cancer were determined among 3,579 ALL survivors participating in the Childhood Cancer Survivor Study, a cohort of 5-year survivors of pediatric cancers diagnosed from 1970–1986, and compared with 3,846 siblings and population rates, respectively.
The cumulative incidence of hypo- and hyperthyroidism among survivors 15 years following leukemia diagnosis was 1.6% (95% CI 1.1, 2.1) and 0.6% (95% CI 0.3, 1.1), respectively, both significantly increased compared with siblings. In multivariate analysis, survivors who received ≥20 Gy cranial radiotherapy plus any spinal radiotherapy had the highest risk of subsequent hypothyroidism (HR 8.3, 95% CI 3.3, 20.5) compared with those treated with chemotherapy alone. Craniospinal radiotherapy also was associated with an increased risk of subsequent hyperthyroidism (HR 6.1, 95% CI 1.1, 34.2) compared with chemotherapy alone, as well as an increased risk of subsequent thyroid cancers (SIR 30.3, 95% CI 14.5, 55.7) compared with population rates. In radiation dosimetry analysis, pituitary doses ≥20 Gy combined with thyroid doses ≥10 Gy were associated with hypothyroidism, whereas pituitary doses ≥20 Gy combined with thyroid doses ≥15 Gy were associated with hyperthyroidism.
The risk of thyroid dysfunction and thyroid cancer was increased among childhood ALL survivors treated with craniospinal radiotherapy. In these individuals, long-term surveillance is warranted as no obvious plateau in risk was seen, even after 25 years of follow-up.
late effects; leukemia; radiation; hypothyroidism; hyperthyroidism; thyroid cancer
To determine risk factors associated with reduced adult height in survivors of childhood acute lymphoblastic leukemia (ALL).
Cross-sectional study. Attained adult height was determined among 2,434 ALL survivors participating in the Childhood Cancer Survivor Study, a cohort of five-year survivors of common pediatric cancers diagnosed from 1970–1986, and compared with 3,009 siblings.
All survivor treatment exposure groups (chemotherapy alone, chemotherapy with cranial or craniospinal radiotherapy) had decreased adult heights and an increased risk of adult short stature (height standard deviation score < −2) compared with siblings (p<0.001). Compared with siblings, the risk of short stature for survivors treated with chemotherapy alone was elevated (OR 3.4, 95% CI 1.9, 6.0). Among survivors, significant risk factors for short stature included diagnosis of ALL prior to puberty, higher dose cranial radiotherapy (≥20 Gy versus <20 Gy), any radiotherapy to the spine, and female sex.
Survivors of childhood ALL are at increased risk of adult short stature, including those treated with chemotherapy alone. Risk is highest for those treated with cranial and craniospinal radiotherapy at a young age.
chemotherapy; epidemiology; growth deficiency; late effects; radiation; survivorship
Children treated for acute lymphoblastic leukemia (ALL) are more likely to become overweight. Prolonged exposure to high-dose glucocorticoids may cause insulin resistance and facilitate development of this phenotype.
Body mass indices (BMI) and insulin resistance (HOMA-IR) were prospectively measured among on- (n=31) and off-therapy participants (n=29). On-therapy participants were assessed prior to and while on glucocorticoids (5 days of prednisone 40 mg/m2 or dexamethasone 6 mg/m2) given as part of routine maintenance chemotherapy, with a subset (n=10) receiving an intravenous glucose tolerance test (IVGTT) while on glucocorticoids.
Baseline HOMA-IR values among on- and off-therapy participants were similar, but among on-therapy participants, HOMA-IR increased significantly with glucocorticoid exposure (median 3.39 vs. 1.26; p<0.01) with 45.2% of participants having values >4.39 (upper 2.5th percentile among normal weight adolescents). Although baseline HOMA-IR was significantly correlated with current BMI (r=0.48, p<0.01), change in HOMA-IR following steroid exposure was not correlated with any demographic or treatment characteristic including current BMI. Among those with IVGTT data, HOMA estimates in general correlated with values derived from a minimal model analysis (r~0.7).
High-dose glucocorticoids given as part of routine chemotherapy were associated with a significantly increased insulin resistant state. Given the amount and duration of glucocorticoids children with ALL experience, these physiologic changes could be an important contributor to the development of therapy-related obesity.
acute lymphoblastic leukemia; glucocorticoid; insulin resistance; obesity; survivor
Physician practice variation may be a barrier to informing hematopoietic cell transplant (HCT) recipients about fertility preservation (FP) options. We surveyed HCT physicians in the United States to evaluate FP knowledge, practices, perceptions and barriers. Of the 1035 physicians invited, 185 completed a 29-item web-survey. Most respondents demonstrated knowledge of FP issues and discussed and felt comfortable discussing FP. However, only 55% referred patients to an infertility specialist. Most did not provide educational materials to patients and only 35% felt that available materials were relevant for HCT. Notable barriers to discussing FP included perception that patients were too ill to delay transplant (63%), patients were already infertile from prior therapy (92%) and time constraints (41%). Pediatric HCT physicians and physicians with access to an infertility specialist were more likely to discuss FP and to discuss FP even when prognosis was poor. On analyses that considered physician demographics, knowledge and perceptions as predictors of referral for FP, access to an infertility specialist and belief that patients were interested in FP were observed to be significant. We highlight variation in HCT physician perceptions and practices regarding FP. Physicians are generally interested in discussing fertility issues with their patients but lack educational materials.
Hematopoietic cell transplantation; autologous; allogeneic; fertility preservation; infertility; pregnancy; practice patterns
The differential effects of cranial (CRT), spinal (SRT), and total body irradiation (TBI) on growth and endocrine outcomes have rarely been examined in combination among childhood acute leukemia survivors.
Self-reported height/weight, hypothyroidism, and pregnancy/live birth were determined among acute lymphoblastic and myeloid leukemia survivors (n=3,467) participating in the Childhood Cancer Survivor Study, an ongoing cohort study of 5-year survivors of pediatric cancers diagnosed from 1970 to 1986.
Compared with no radiotherapy, risk estimates were consistent across outcomes (adult short stature, hypothyroidism, absence of pregnancy/live birth) with CRT treatment associated with 2–3 fold increased risks, TBI associated with 5–10 fold increased risks, and CRT+TBI associated with >10 fold increased risks. Exposure to any SRT further increased risk of these outcomes 2–3 fold. Changes in body composition were more nuanced as CRT only was associated with an increased risk of being overweight/obese (OR 1.6, 95% CI 1.3–1.9) whereas TBI only was associated with an increased risk of being underweight (OR 6.0, 95% CI 2.4–14.9).
Although patients treated with CRT+TBI were at greatest risk for short stature, hypothyroidism, and a reduced likelihood of pregnancy/live birth, those treated with either modality alone had significantly increased risks as well, including altered body composition. Any SRT exposure further increased risk in an independent fashion.
leukemia; childhood; survivor; growth; hypothyroidism; pregnancy
Cardiovascular complications are a leading cause of therapy-related morbidity and mortality in long-term survivors of childhood malignancy. In fact, childhood cancer survivors are at a 15-fold risk of developing CHF compared to age-matched controls. There is a strong dose-dependent association between anthracycline exposure and risk of CHF, and the incidence increases with longer followup. Outcome following diagnosis of CHF is generally poor, with overall survival less than 50% at 5 years. The growing number of childhood cancer survivors makes it imperative that strategies be developed to prevent symptomatic heart disease in this vulnerable population. We present here an overview of the current state of knowledge regarding primary, secondary, and tertiary prevention strategies for childhood cancer survivors at high risk for CHF, drawing on lessons learned from prevention studies in nononcology populations as well as from the more limited experience in cancer survivors.
Preventive care guidelines are available for hematopoietic cell transplantation (HCT) survivors. We assessed adherence to these guidelines and examined factors associated with lower adherence. A questionnaire was mailed to adult HCT survivors to collect information regarding survivor health, adherence to recommended guidelines and financial concerns. Multivariable models identified patient and transplant characteristics associated with lower adherence. Of 3066 survivors more than 2 years after HCT, 1549 (51%) responded. Median age of respondents was 54.5 years, and the median adherence to recommended preventive care based on age and gender-specific recommendations was 75%. Lower adherence was associated with autologous HCT, concerns about medical costs, non-white race, male gender, lower physical functioning, no chronic graft vs. host disease (cGVHD), longer time since HCT, and lack of knowledge about recommended tests. Although 98% of respondents had medical insurance, 26% endorsed concern about medical costs and reported efforts to limit medical costs. Concern about medical costs was associated with female gender, age younger than 65 years, no cGVHD and low physical and mental functional status. Future efforts to improve adherence should address concern about medical costs and lack of knowledge as they emerged as major modifiable predictors of lower adherence to preventive care practices in HCT survivors.
25-hydroxyvitamin D insufficiency is common in healthy children and adolescents. There have been limited studies of the 25-hydroxyvitamin D status of survivors of pediatric and adolescent acute lymphoblastic leukemia (ALL).
In a cohort of 78 ALL survivors (52 chemotherapy-treated and 26 HCT-treated), we determined the prevalence of, and host, treatment and environmental risk factors for 25-hydroxyvitamin D insufficiency and deficiency.
There were no differences in serum 25-hydroxyvitamin D levels between ALL survivors treated with conventional chemotherapy and those treated with HCT (median 26.0 vs 25.5 ng/ ml). Fifty-three percent of pediatric ALL survivors were 25-hydroxyvitamin D insufficient (15-29 ng/ dl), and 12% were deficient (<15 ng/ dl). Younger age, higher reported dietary vitamin D intake, use of vitamin D supplementation, and increased ambient ultraviolet light were associated with higher serum 25-hydroxyvitamin D levels. There was not enough evidence to suggest treatment type, gender, race, years since diagnosis or BMI were associated with serum 25-hydroxyvitamin D levels. Only 27% of conventional chemotherapy-treated ALL survivors and 8% of HCT-treated ALL survivors met RDA for dietary vitamin D intake.
The prevalence of vitamin D deficiency and insufficiency in ALL survivors is similar to that of the general pediatric population in the United States, and there is no difference in serum 25-hydroxyvitamin D status between chemotherapy-treated and HCT-treated ALL survivors. ALL survivors rarely meet the RDA requirements for vitamin D. Further studies are needed to determine whether dietary and behavioral interventions can improve the vitamin D status of ALL survivors.
vitamin D deficiency; acute lymphoblastic leukemia; cancer survivorship; late effects; vitamin D insufficiency
The causes of childhood cancers are largely unknown. Birth order has been used as a proxy for prenatal and postnatal exposures, such as frequency of infections and in utero hormone exposures. We investigated the association between birth order and childhood cancers in a pooled case-control dataset. The subjects were drawn from population-based registries of cancers and births in California, Minnesota, New York, Texas, and Washington. We included 17,672 cases less than 15 years of age who were diagnosed from1980-2004 and 57,966 randomly selected controls born 1970-2004, excluding children with Down syndrome. We calculated odds ratios and 95% confidence intervals using logistic regression, adjusted for sex, birth year, maternal race, maternal age, multiple birth, gestational age, and birth weight. Overall, we found an inverse relationship between childhood cancer risk and birth order. For children in the fourth or higher birth order category compared to first-born children, the adjusted OR was 0.87 (95% CI: 0.81, 0.93) for all cancers combined. When we examined risks by cancer type, a decreasing risk with increasing birth order was seen in the central nervous system (CNS) tumors, neuroblastoma, bilateral retinoblastoma, Wilms tumor, and rhabdomyosarcoma. We observed increased risks with increasing birth order for acute myeloid leukemia but a slight decrease in risk for acute lymphoid leukemia. These risk estimates were based on a very large sample size which allowed us to examine rare cancer types with greater statistical power than in most previous studies, however the biologic mechanisms remain to be elucidated.
birth order; case-control studies; child; epidemiology; neoplasms
Childhood cancer survivors are at higher risk of morbidity and mortality from cardiovascular (CV) disease compared with the general population.
8,599 survivors (52% male) and 2,936 siblings (46% male).from the Childhood Cancer Survivor Study (CCSS), a retrospectively ascertained – prospectively followed study of persons who survived 5 years after childhood cancer diagnosed from 1970–1986 were evaluated for BMI ≥30 kg/m2 based on self reported heights and weights and self-reported use of medications for hypertension, dyslipidemia, and impaired glucose metabolism. The presence of ≥3 of the above constituted Cardiovascular Risk Factor Cluster (CVRFC) a surrogate for Metabolic Syndrome
Survivors were more likely than siblings to take medications for hypertension (OR 1.9 95% CI 1.6–2.2), dyslipidemia (OR 1.6 95% CI 1.3–2.0) or diabetes (OR 1.7 95% CI 1.2–2.3). Among these young adults (mean age 32 years for survivors and 33 years for siblings) survivors were not more likely than siblings to be obese or have CVRFC. In a multivariable logistic regression analysis, factors associated with having CVRFC included: older age at interview (≥ 40 vs. < 30 years of age [OR 8.2 95% CI 3.5–19.9]), exposure to total body irradiation (OR 5.5 95% CI 1.5–15.8) or radiation to the chest and abdomen (OR 2.3 95% CI 1.2–2.4), and physical inactivity (OR 1.7 95% CI 1.1–2.6).
Among adult survivors of pediatric cancer, older attained age, exposure to TBI or abdominal plus chest radiation, and a sedentary lifestyle are associated with CVRFC.
survivor; cardiovascular risk factors; metabolic syndrome
Risk of hepatoblastoma is strongly increased among children with very low birth weight (VLBW: <1,500 grams). Because data on VLBW and other childhood cancers is sparse, we examined the risk of malignancy following VLBW in a large dataset.
We combined case-control datasets created by linking the cancer and birth registries of California, Minnesota, New York, Texas, and Washington states, which comprised 17,672 children diagnosed with cancer at 0-14 years of age and 57,966 randomly selected controls. Unconditional logistic regression was used to examine the association of cancer with VLBW and moderately low birth weights (1,500-1,999g and 2,000-2,499g) compared to moderate/high birth weight (≥2,500) adjusting for sex, gestational age, birth order, plurality, maternal age, maternal race, state, and year of birth.
Most childhood cancers were not associated with low birth weights. However, retinoblastoma and gliomas other than astrocytomas and ependymomas were possibly associated with VLBW, with respective odds ratios (OR) of 2.43 (95% Confidence Interval (CI): 1.00-5.89) and 2.13 (95% CI: 0.71-6.39). Risk of other gliomas was also increased among children weighing 1,500-1,999g at birth (OR = 3.58; 95% CI: 1.98-6.47). For hepatoblastoma the ORs associated with birth weights of 2,000-2,499g, 1,500-1999g, and 350-1,499g were 1.56 (95% CI: 0.81-2.98), 3.37 (95% CI: 1.44-7.88), and 17.18 (95% CI: 7.46-39.54), respectively
These data suggest no association between most cancers and VLBW with the exception of the known association with hepatoblastoma and possible moderately increased risks of other gliomas and retinoblastoma, which may warrant confirmation.
Infant; very low birth weight; cancer; case-control studies; registries
Few risk factors for childhood cancer are well-established. We investigated whether advancing parental age increases childhood cancer risk.
We assessed the relationship between parental age and childhood cancer in a case-control study using pooled population-based data. Our pooling was based on linked cancer and birth registry records from New York, Washington, Minnesota, Texas, and California. Subjects included 17,672 cancer cases diagnosed at ages 0–14 years during 1980–2004 and 57,966 controls born during 1970–2004. Persons with Down syndrome were excluded. Odds ratios and 95% confidence intervals were calculated by logistic regression for the association between parental age and childhood cancer after adjustment for sex, birth weight, gestational age, birth order, plurality, maternal race, birth year, and state.
Positive linear trends per 5-year maternal age increase were –observed for childhood cancers overall (odds ratio = 1.08 [95% confidence interval = 1.06–1.10]) and 7 of the 10 most frequent diagnostic groups: leukemia (1.08 [1.05–1.11]), lymphoma (1.06 [1.01–1.12]), central nervous system tumors (1.07 [1.03–1.10]), neuroblastoma (1.09 [1.04–1.15]), Wilms’ tumor (1.16 [1.09–1.22]), bone tumors (1.10 [ 1.00–1.20]), and soft tissue sarcomas (1.10 [1.04–1.17]). No maternal age effect was noted for retinoblastoma, germ cell tumors, or hepatoblastoma. Paternal age was not independently associated with most childhood cancers after adjustment for maternal age.
Our results suggest that older maternal age increases risk for most common childhood cancers. Investigation into possible mechanisms for this association is warranted.
Children who receive high dose radiation therapy to the hypothalamic-pituitary axis may be at risk for both early and late puberty. Data on risk of altered timing of menarche after higher dose RT, as used in the treatment of CNS tumors, are limited.
Patients & Methods
We evaluated 235 female survivors of CNS tumors, diagnosed between 1970-1986, and >1,000 sibling controls who were participants in the Childhood Cancer Survivor Study, and provided self-reported data on age at menarche.
Survivors of CNS tumors were more likely to have onset of menarche before age ten compared to their siblings (11.9% vs. 1.0%) (Odds Ratio [OR] =14.1, 95% confidence interval [95% CI] 7.0-30.9). Of the 138 survivors who received RT to the HP axis, 20 (14.5%) had onset of menarche before age 10, compared to 4.3% of those who did not receive RT (OR=3.8, 95% CI=1.2-16.5). Age ≤4 years at diagnosis was associated with an increased risk (OR=4.0, 95% CI=1.7-10.0) of early menarche. Additionally, survivors of CNS tumors were more likely than siblings to have onset of menarche after age 16 (10.6% vs. 1.9%) (OR=6.6, 95% CI=3.4-11.4). Doses of RT to the H-P axis >50 Gy (OR=9.0, 95% CI 2.3-59.5) and spinal RT conferred an increased risk of late menarche, as did older age (>10 years) at the time of diagnosis (OR = 3.0, 95% CI 1.3-7.0).
Survivors of CNS tumors are at significant risk of both early and late menarche associated with RT exposure and age at treatment.
menarche; puberty; late-effects; brain tumor; pediatric
Survival for childhood cancer has increased dramatically over the last 40 years with 5-year survival rates now approaching 80%. For many diagnostic groups, rapid increases in survival began in the 1970s with the broader introduction of multimodality approaches, often including combination chemotherapy with or without radiation therapy. With this increase in rates of survivorship has come the recognition that survivors are at risk for adverse health and quality-of-life outcomes, with risk being influenced by host-, disease-, and treatment-related factors. In 1994, the US National Cancer Institute funded the Childhood Cancer Survivor Study, a multi-institutional research initiative designed to establish a large and extensively characterized cohort of more than 14,000 5-year survivors of childhood and adolescent cancer diagnosed between 1970 and 1986. This ongoing study, which reflects the single most comprehensive body of information ever assembled on childhood and adolescent cancer survivors, provides a dynamic framework and resource to investigate current and future questions about childhood cancer survivors.