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1.  Suicide Ideation and Associated Mortality in Adult Survivors of Childhood Cancer 
Cancer  2013;120(2):271-277.
Adult survivors of childhood cancer are at-risk for suicide ideation, though longitudinal patterns and rates of recurrent suicide ideation are unknown. We investigated the prevalence of late report (i.e. post-initial assessment) and recurrent suicide ideation in adult survivors of childhood cancer, identified predictors of suicide ideation, and examined associations among suicide ideation and mortality.
Participants included 9,128 adult survivors of childhood cancer and 3,082 sibling controls enrolled in the Childhood Cancer Survivor Study who completed a survey question assessing suicide ideation on one or more occasions between 1994 and 2010. Suicide ideation was assessed using the Brief Symptom Inventory-18. Mortality data was ascertained from the National Death Index.
Survivors were more likely to report late (Odds Ratio (OR) =1.9; 95% Confidence Interval (CI) =1.5–2.5) and recurrent suicide ideation (OR=2.6, 95% CI=1.8–3.8) compared to siblings. Poor physical health status was associated with increased risk of suicide ideation in survivors (late report: OR=1.9, 95% CI=1.3–2.7; recurrent: OR=1.9, 95% CI=1.2–2.9). Suicide ideation was associated with increased risk for all-cause mortality (Hazard Ratio (HR) =1.3, 95% CI=1.03–1.6) and death by external causes (HR=2.4, 95% CI=1.4–4.1).
Adult survivors of childhood cancer are at-risk for late report and recurrent suicide ideation, which is associated with increased risk of mortality. Routine screening for psychological distress in adult survivors appears warranted, especially for survivors who develop chronic physical health conditions.
PMCID: PMC3947253  PMID: 24122148
childhood cancer; survivorship; suicide; mortality; late effects
2.  The Cyclophosphamide Equivalent Dose as an Approach for Quantifying Alkylating Agent Exposure. A Report from the Childhood Cancer Survivor Study 
Pediatric blood & cancer  2013;61(1):53-67.
Estimation of the risk of adverse long-term outcomes such as second malignant neoplasms and infertility often requires reproducible quantification of exposures. The method for quantification should be easily utilized and valid across different study populations. The widely used Alkylating Agent Dose (AAD) score is derived from the drug dose distribution of the study population and thus cannot be used for comparisons across populations as each will have a unique distribution of drug doses.
We compared the performance of the Cyclophosphamide Equivalent Dose (CED), a unit for quantifying alkylating agent exposure independent of study population, to the AAD. Comparisons included associations from three Childhood Cancer Survivor Study (CCSS)outcome analyses, receiver operator characteristic (ROC) curves and goodness of fit based on the Akaike’s Information Criterion (AIC).
The CED and AAD performed essentially identically in analyses of risk for pregnancy among the partners of male CCSS participants, risk for adverse dental outcomes among all CCSS participants and risk for premature menopause among female CCSS participants, based on similar associations, lack of statistically significant differences between the areas under the ROC curves and similar model fit values for the AIC between models including the two measures of exposure.
The CED is easily calculated, facilitating its use for patient counseling. It is independent of the drug dose distribution of a particular patient population, a characteristic that will allow direct comparisons of outcomes among epidemiological cohorts. We recommend the use of the CED in future research assessing cumulative alkylating agent exposure.
PMCID: PMC3933293  PMID: 23940101
late effects of cancer treatment; chemotherapy; long term survival; cyclophosphamide; alkylating agent; alkylating agent dose score
3.  Abdominal radiation and diabetes: one more piece in the puzzle 
The Lancet. Oncology  2012;13(10):961-962.
PMCID: PMC4280844  PMID: 22921662
4.  Physiologic Frailty As a Sign of Accelerated Aging Among Adult Survivors of Childhood Cancer: A Report From the St Jude Lifetime Cohort Study 
Journal of Clinical Oncology  2013;31(36):4496-4503.
Frailty, a phenotype reported among 9.9% of individuals 65 years old and older (9.6% of women; 5.2% of men), has not been assessed among adult childhood cancer survivors (CCS). We estimated the prevalence of frailty and examined associations with morbidity and mortality.
Participants included 1,922 CCS at least 10 years from original cancer diagnosis (men, 50.3%; mean age, 33.6 ± 8.1 years) and a comparison population of 341 participants without cancer histories. Prefrailty and frailty were defined as two and ≥ three of the following conditions: low muscle mass, self-reported exhaustion, low energy expenditure, slow walking speed, and weakness. Morbidity was defined as grade 3 to 4 chronic conditions (Common Terminology Criteria for Adverse Events version 4.0). Fisher's exact tests were used to compare, by frailty status, percentages of those with morbidity. In a subset of 162 CCS who returned for a second visit, Poisson regression was used to evaluate associations between frailty and new onset morbidity. Cox proportional hazards regression was used to evaluate associations between frailty and death.
The prevalence of prefrailty and frailty were 31.5% and 13.1% among women and 12.9% and 2.7% among men, respectively, with prevalence increasing with age. Frail CCS were more likely than nonfrail survivors to have a chronic condition (82.1% v 73.8%). In models adjusted for existing chronic conditions, baseline frailty was associated with risk of death (hazard ratio, 2.6; 95% CI, 1.2 to 6.2) and chronic condition onset (relative risk, 2.2; 95% CI, 1.2 to 4.2).
The prevalence of frailty among young adult CCS is similar to that among adults 65 years old and older, suggesting accelerated aging.
PMCID: PMC3871511  PMID: 24248696
5.  Modifiable Risk Factors and Major Cardiac Events Among Adult Survivors of Childhood Cancer 
Journal of Clinical Oncology  2013;31(29):3673-3680.
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.
PMCID: PMC3804290  PMID: 24002505
6.  Infertility, infertility treatment, and achievement of pregnancy in female survivors of childhood cancer: a report from the Childhood Cancer Survivor Study cohort 
The lancet oncology  2013;14(9):10.1016/S1470-2045(13)70251-1.
Prior studies have documented decreased pregnancy rates and early menopause in female cancer survivors; however, infertility rates and reproductive interventions have not been studied. This study investigates infertility and time to pregnancy among female childhood cancer survivors, and analyzes treatment characteristics associated with infertility and subsequent pregnancy.
The Childhood Cancer Survivor Study (CCSS) is a cohort study including five-year cancer survivors from 26 institutions who were <21 years old at the time of diagnosis between January 1, 1970, and December 31, 1986, and a sibling control group. CCSS females ages 18–39 years reporting they had ever been sexually active (3,531 survivors and 1,366 female controls) were studied. Self-reported infertility, medical treatment for infertility, the time to first pregnancy in survivors and siblings, and the risk of infertility in survivors by demographic, disease, and treatment variables were analyzed.
Survivors had an increased risk of clinical infertility (>1 year of attempts at conception without success) compared to siblings which was most pronounced at early reproductive ages (≤24 years Relative Risk (RR)=2·92, 95% Confidence Interval (CI) 1·18–7·20; 25–29 years RR=1·61, 95% CI 1·05–2·48; 30–39 years RR=1·37, 95% CI 1·11–1·69). Despite being equally likely to seek treatment for infertility, survivors were less likely to be prescribed medication for treatment of infertility (RR=0·57, 95% CI 0·46–0·70). Increasing doses of uterine radiation and alkylating agent chemotherapy were most strongly associated with infertility. Although survivors had an increased time to pregnancy interval (p=0·032), 64·2% (292/455) with infertility achieved a pregnancy.
A more comprehensive understanding of infertility after cancer is critical for counseling and decision-making regarding future attempts at conception as well as fertility preservation.
PMCID: PMC3845882  PMID: 23856401
7.  Whole-body magnetic resonance imaging (WB-MRI) as surveillance for subsequent malignancies in survivors of hereditary retinoblastoma: a pilot study 
Pediatric blood & cancer  2013;61(8):1440-1444.
Individuals with hereditary retinoblastoma (RB) are at very high risk of developing subsequent malignant neoplasms (SMN) of which osteosarcoma (OS) is one of the most common. We hypothesized that annual surveillance using whole-body magnetic resonance imaging (WB-MRI) in asymptomatic survivors of hereditary RB would detect SMN of the bone and soft tissues at an early stage.
Retrospective review of the results of a WB-MRI screening program in hereditary RB survivors from February 2008 – August 2012. The primary outcome was to determine the sensitivity and specificity of WB-MRI in detecting SMNs.
Twenty-five patients had at least one WB-MRI performed (range: 1 – 5). First WB- MRI was performed at a median age of 16 years (range: 8 – 25 years). WB-MRI detected new osseous abnormalities suspicious for malignancy in 5 patients: 2 were diagnosed with localized high-grade OS of the extremity and 3 were found to have benign osseous abnormalities after dedicated imaging (n=5/5) and/or biopsy (n=3/5). One patient was diagnosed with secondary OS three months after a normal screening WB- MRI exam. Among a total of 41 WB-MRI screening tests performed in survivors of hereditary RB, the sensitivity of detecting SMN was 66.7% and the specificity was 92.1%.
Preliminary results suggest that annual WB-MRI surveillance detects SMN in survivors of hereditary RB, but with modest sensitivity. Further study is needed to assess the performance of annual surveillance WB-MRIs and whether this modality decreases SMN-related mortality in RB survivors.
PMCID: PMC4007376  PMID: 24402721
Retinoblastoma; survivors; screening; whole-body MRI; pediatric oncology
8.  Radiation, Atherosclerotic Risk Factors and Stroke Risk in Survivors of Pediatric Cancer: a Report from the Childhood Cancer Survivor Study 
The impact of childhood cranial radiation therapy (CRT) on stroke risk in adulthood, and the role of modifiable atherosclerotic risk factors, remains poorly defined. We assessed long-term incidence rates and stroke risk factors in survivors of childhood cancer followed by the Childhood Cancer Survivor Study (CCSS).
Patients and Methods
CCSS is a multi-institutional retrospective cohort study of 14,358 five-year survivors of childhood cancer and 4,023 randomly selected sibling controls with longitudinal follow up. Age-adjusted incidence rates of self-reported late-occurring (≥ 5 years after diagnosis) first-stroke were calculated. Multivariable Cox Proportional Hazards models were used to identify independent stroke predictors.
During a mean follow-up of 23.3 years, 292 survivors reported a late-occurring stroke. The age-adjusted stroke rate per 100,000 person-years was 77 (95% Confidence Interval [CI] 62–96) compared to 9.3 (95% CI 4–23) for siblings. Treatment with CRT increased stroke risk in a dose dependent manner: hazard ratio (HR) 5.9 (95% CI 3.5–9.9) for 30–49 Gy CRT, and 11.0 (7.4–17.0) for 50+ Gy CRT. The cumulative stroke incidence in survivors treated with 50+ Gy CRT was 1.1% (95% CI 0.4–1.8) at 10 years post-diagnosis and 12% (95% CI 8.9–15.0) at 30 years. Hypertension (HTN) increased stroke hazard by 4-fold (95% CI 2.8–5.5) and in black survivors by 16-fold (95% CI 6.9–36.6).
Young adult pediatric cancer survivors have an increased stroke risk that is associated with CRT in a dose dependent manner. Atherosclerotic risk factors enhanced this risk and should be treated aggressively.
PMCID: PMC3696633  PMID: 23680033
9.  Prevalence of Vitamin D Insufficiency in Survivors of Childhood Cancer 
Pediatric blood & cancer  2012;60(7):1237-1239.
Data on 25-hydroxyvitamin D (25-OH D) status among survivors of childhood cancer are limited. Our aim was to determine the prevalence of and risk factors for 25-OH D insufficiency in a large, diverse population of cancer survivors being followed in a childhood cancer survivor clinic.
Retrospective chart review in survivors seen for routine long-term follow-up, who underwent routine screening blood studies including 25-OH D levels. Vitamin D insufficiency was defined as 25-OH D <20 ng/ml.
Four hundred eighty-four subjects (234 males) were evaluable for this analysis. Median age at 25-OH D testing was 12.3 years (2.05–36.4) and median age at cancer diagnosis was 3.9 years (0–18). Diagnoses included brain tumors (23.6%), neuroblastoma (21%), and leukemia (17.6%). Mean 25-OH D level was 25.2 ng/ml (SD = 10.37); 29% of subjects were 25-OH D insufficient. In univariate analysis, race, pubertal status, and age at cancer diagnosis were associated with 25-OH D insufficiency (P < 0.05). In multivariate analysis, a model including race and pubertal status provided a good fit for the data.
The prevalence of 25-OH D insufficiency in these cancer survivors was high but similar to what has been described in the general population. No cancer specific variables were associated with 25-OH D insufficiency. Since cancer survivors are at a higher risk for subsequent malignancies, cardiovascular disease, and low bone mineral density, all of which may be affected by 25-OH D levels, interventions to improve 25-OH D status in this vulnerable population are needed.
PMCID: PMC4006112  PMID: 23192881
cancer survivors; prevalence; vitamin D
10.  Lack of Specificity of Plasma Concentrations of Inhibin B and Follicle-Stimulating Hormone for Identification of Azoospermic Survivors of Childhood Cancer: A Report From the St Jude Lifetime Cohort Study 
Journal of Clinical Oncology  2013;31(10):1324-1328.
Many male survivors of childhood cancer are at risk for azoospermia. Although both the levels of follicle-stimulating hormone (FSH) and inhibin B are correlated with sperm concentration, their ability to predict azoospermia in survivors of childhood cancer remains uncertain.
Patients and Methods
Semen analysis was performed and serum levels of FSH and inhibin B were measured in 275 adult male survivors of childhood cancer who had received gonadotoxic therapy. Receiver operating characteristic (ROC) analysis was performed to determine the optimal inhibin B and FSH values for identifying patients with azoospermia. The patient sample was divided into a learning set and a validation set. Sensitivity, specificity, and positive and negative predictive value were calculated.
Inhibin B was dichotomized as ≤ 31 ng/L or more than 31 ng/L and FSH was dichotomized as ≤ 11.5 mIU/mL or more than 11.5 mIU/mL based on results of the ROC analysis. Using these values, the specificity of the serum level of inhibin B for identifying azoospermic survivors was 45.0%, and the positive predictive value was 52.1%. The specificity for FSH was 74.1%, and the positive predictive value was 65.1%.
Neither serum inhibin B nor FSH is a suitable surrogate for determination of sperm concentration in a semen sample. Young men and their physicians should be aware of the limitations of these measures for assessment of fertility potential.
PMCID: PMC3607671  PMID: 23423746
11.  Differential Effects of Radiotherapy on Growth and Endocrine Function Among Acute Leukemia Survivors: A Childhood Cancer Survivor Study Report 
Pediatric blood & cancer  2012;60(1):110-115.
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.
PMCID: PMC3436954  PMID: 22628201
leukemia; childhood; survivor; growth; hypothyroidism; pregnancy
12.  Absolute Risk Prediction of Second Primary Thyroid Cancer Among 5-Year Survivors of Childhood Cancer 
Journal of Clinical Oncology  2012;31(1):119-127.
We developed three absolute risk models for second primary thyroid cancer to assist with long-term clinical monitoring of childhood cancer survivors.
Patients and Methods
We used data from the Childhood Cancer Survivor Study (CCSS) and two nested case-control studies (Nordic CCSS; Late Effects Study Group). Model M1 included self-reported risk factors, model M2 added basic radiation and chemotherapy treatment information abstracted from medical records, and model M3 refined M2 by incorporating reconstructed radiation absorbed dose to the thyroid. All models were validated in an independent cohort of French childhood cancer survivors.
M1 included birth year, initial cancer type, age at diagnosis, sex, and past thyroid nodule diagnosis. M2 added radiation (yes/no), radiation to the neck (yes/no), and alkylating agent (yes/no). Past thyroid nodule was consistently the strongest risk factor (M1 relative risk [RR], 10.8; M2 RR, 6.8; M3 RR, 8.2). In the validation cohort, 20-year absolute risk predictions for second primary thyroid cancer ranged from 0.04% to 7.4% for M2. Expected events agreed well with observed events for each model, indicating good calibration. All models had good discriminatory ability (M1 area under the receiver operating characteristics curve [AUC], 0.71; 95% CI, 0.64 to 0.77; M2 AUC, 0.80; 95% CI, 0.73 to 0.86; M3 AUC, 0.75; 95% CI, 0.69 to 0.82).
We developed and validated three absolute risk models for second primary thyroid cancer. Model M2, with basic prior treatment information, could be useful for monitoring thyroid cancer risk in childhood cancer survivors.
PMCID: PMC3530689  PMID: 23169509
13.  Fractures among long-term survivors of childhood cancer: A report from the Childhood Cancer Survivor Study 
Cancer  2012;118(23):5920-5928.
Although reductions in bone mineral density are well-documented among children during treatment for cancer and among childhood cancer survivors, little is known about the long-term risk of fracture. The aim of this study was to ascertain the prevalence of and risk factors for fractures among individuals participating in the Childhood Cancer Survivor Study (CCSS).
Analyses included 7414 5+ year survivors of childhood cancer diagnosed between 1970-86 who completed the 2007 CCSS follow-up questionnaire and a comparison group of 2374 siblings. Generalized linear models stratified by sex were used to compare the prevalence of reported fractures between survivors and siblings.
The median ages at follow-up among survivors and siblings were 36.2, (range: 21.2-58.8) and 38.1 years (range: 18.4-62.6), respectively with a median 22.7 years of follow-up after cancer diagnosis for survivors. Approximately 35% of survivors and 39% of siblings reported ≥1 fractures during their lifetime. The prevalence of fractures was lower among survivors than siblings, both in males (prevalence ratio=0.87, 95%CI=0.81-0.94, p<0.001) and females (prevalence ratio=0.94, 95%CI=0.86-1.04, p=0.22). In multivariable analyses, increasing age at follow-up, white race, methotrexate treatment and balance difficulties were associated with increased prevalence of fractures among female survivors (p=0.05). Among males, only smoking history and white race were associated with an increased prevalence of fracture (p<0.001).
Findings from this study indicate that the prevalence of fractures among adult survivors is not increased compared to that of siblings. Additional studies of bone health among aging female cancer survivors may be warranted.
PMCID: PMC3439597  PMID: 22605509
14.  Clinical Ascertainment of Health Outcomes among Adults Treated for Childhood Cancer: A Report from the St. Jude Lifetime Cohort Study 
Adult survivors of childhood cancer are known to be at risk for treatment-related adverse health outcomes. A large population of survivors has not been evaluated using a comprehensive systematic clinical assessment to determine the prevalence of chronic health conditions.
Following systematic exposure-based medical assessments of a large cohort of adult survivors of childhood cancer, determine the prevalence of adverse health outcomes and the proportion associated with treatment-related exposures.
Design, Setting, and Participants
Presence of health outcomes was ascertained among 1713 adult (median age 32 years, range 18-60) survivors of childhood cancer (median time from diagnosis 25 years, range 10-47) enrolled in the St. Jude Lifetime Cohort Study since 10/1/2007 and followed through 10/31/2012.
Main Outcome Measures
Age-specific cumulative prevalence of adverse outcomes by organ system and sex-adjusted attributable fraction percentages with 95% confidence intervals were calculated.
Using clinical criteria, the crude prevalence of adverse health outcomes was highest for pulmonary [65.2%(95% CI, 60.4-69.8%)], auditory [62.1%(95% CI, 55.8-68.2%)], endocrine-reproductive [62.0%(95% CI, 59.5-64.6%)], cardiac [56.4(95% CI, 53.5-59.2%)] and neurocognitive [48.0%(95%CI, 44.9-51.0%)] function, whereas abnormalities impacting hepatic [13.0%(95% CI, 10.8-15.3%)], skeletal [9.6%(95% CI, 8.0-11.5%)], renal [5.0%(95% CI, 4.0-6.3%)] and hematopoietic [3.0%(95% CI: 2.1-3.9%)] function were less common. Attributable fractions were highest for endocrine-reproductive disorders [88.4%(95% CI, 80.1-93.3%)] to 100%, but considerably lower for conditions highly prevalent in the general population such as hypertension [9.3%(95%CI, −16.3-29.2%)], dyslipidemia [15.5%(95% CI, 10.2-20.5%)], and obesity [42.1%(95% CI, 34.4-48.9%)]. Among survivors at risk for adverse outcomes following specific cancer treatment modalities, the estimated cumulative prevalence at 50 years of age was 21.6%(95% CI, 19.3-23.9%) for cardiomyopathy, 83.5%(95% CI, 80.2-86.8%) for heart valve disorder, 76.8%(95% CI, 73.6-80.0%) for pituitary dysfunction, 81.3%(95% CI, 77.6-85.0%) for pulmonary dysfunction, 86.5%(95% CI, 82.3-90.7%) for hearing loss, 40.9%(95% CI, 32.0-49.8%) for breast cancer, 31.1%(95% CI, 27.3-34.9%) for Leydig cell failure, and 31.9%(95% CI, 28.0-35.8%) for primary ovarian failure. At age 45 years, the estimated cumulative prevalence of any chronic health condition is 95.2% (95% CI 94.8-98.6%) and 80% (95% CI 73.0-86.6%) for a serious, life-threatening or disabling chronic condition.
Conclusion and Relevance
Systematic risk-based medical assessments of adults treated for childhood cancer identified a substantial number of previously undiagnosed problems that are typically prevalent in an older population underscoring the need for ongoing health monitoring and intervention of this population.
PMCID: PMC3771083  PMID: 23757085
Childhood cancer; late effects; long-term follow-up; health screening
15.  Impact of Radiation and Chemotherapy on Risk of Dental Abnormalities: A Report from the Childhood Cancer Survivor Study 
Cancer  2009;115(24):5817-5827.
Describe frequencies and risk factors of altered oral health and odontogenesis in childhood cancer survivors.
Patients and Methods
9308 survivors, diagnosed between 1970–1986, and 2951 siblings from Childhood Cancer Survivor Study completed a survey containing oral-dental health information. We analyzed treatment impact, socioeconomic data and patient demographics on dental outcomes using univariate and multivariate logistic regression models to estimate odds ratios (OR).
In multivariate analysis, survivors more likely reported microdontia (OR 3.0, 95% confidence interval [CI] 2.4–3.8), hypodontia (OR 1.7, 95% CI 1.4–2.0), root abnormalities (OR 3.0, 95% CI 2.2–4.0), abnormal enamel (OR 2.4, 95% CI 2.0–2.9), teeth loss ≥6 (OR 2.6, 95% CI 1.9–3.6), severe gingivitis (OR 1.2, 95% CI 1.0–1.5), xerostomia (OR 9.7, 95% CI 4.8–19.7). Controlling for chemotherapy and socio-economic factors, radiation exposure of ≥20Gy to dentition was significantly associated with increased risk of ≥1 dental abnormality. Dose-dependent alkylating agent therapy significantly increased risk ≥1 anatomic/developmental dental abnormalities in survivors diagnosed <5 years of age (OR 1.7, 2.7, 3.3 for alkylating agent score of 1, 2, 3, respectively).
Radiation and chemotherapy are independent risk factors for adverse oral-dental sequelae among childhood cancer survivors. Patients receiving alkylating agents at < 5 years should be closely monitored.
PMCID: PMC3754878  PMID: 19834960
radiation; chemotherapy; pediatric oncology; dental abnormalities
16.  A Cross-Sectional Study of the Psychosexual Impact of Cancer-Related Infertility in Women: Third-Party Reproductive Assistance 
This study empirically assessed emotional and sexual functioning, reproductive concerns, and quality of life (QOL) of cancer-related infertile women in comparison to those without a cancer history and explored awareness of third-party reproduction options in cancer survivors.
One hundred twenty-two cancer survivors (Gynecologic and Bone Marrow/Stem Cell Transplant) with cancer-related infertility and 50 non-cancer infertile women completed a self-report survey assessing: reproductive concerns(RCS), mood(CES-D), distress(IES), sexual function(FSFI), menopause(SCL), QOL(SF-12), relationships(ADAS), and exploratory (reproductive options) items.
Cancer survivors exhibited greater sexual dysfunction and lower physical QOL than non-cancer infertile women (P<0.001). No significant group differences were identified for mood (CES-D), mental health QOL (SF-12), reproductive concerns (RCS), and relationship satisfaction (ADAS). All groups scored in the FSFI range of sexual dysfunction, and with RCS scores above published means. Multivariate comparisons showed comparable depression and distress levels for all groups, but cancer survivors had poorer physical QOL [F(5,146)=4.22, P<0.01]. A significant effect was also found for knowledge of third-party reproductive options on depression and distress levels [F(3,97)=4.62, P<0.01]. Adjusted means demonstrated higher depression and distress scores for women with perceived unmet informational needs.
Overall, loss of fertility was an emotionally challenging experience for women regardless of its cause. Cancer survivors were found to have lower scores of physical QOL and sexual function than non-cancer infertile women. Unmet informational needs about reproductive options appeared to be associated with negative mood and increased distress in cancer survivors.
Implications for Cancer Survivors
Targeted interventions to increase knowledge about reproductive options could be of great assistance to women pursuing parenthood in cancer survivorship. Additionally, intervention studies to improve sexual functioning and QOL in women with cancer-related infertility should be a priority of future research.
PMCID: PMC3701949  PMID: 20373042
cancer; infertility; survivorship; quality of life; third-party parenting
17.  Long-Term Follow-Up of Children Treated for High-Grade Gliomas: Children's Oncology Group L991 Final Study Report 
Journal of Clinical Oncology  2012;30(9):943-949.
High-grade gliomas of the CNS are characterized by poor treatment response and prognosis for long-term survival. The Children's Oncology Group (COG) L991 study investigated the neuropsychological, behavioral, and quality of life (QoL) outcomes after treatment on the Children's Cancer Group (CCG) trial for high-grade gliomas (CCG-945).
Patients and Methods
Fifty-four patients (29 males, 25 females) with a median age of 8.8 years at diagnosis (range, 0.2 to 19.5 years) were enrolled at 25 institutions in North America, representing 81% of available survivors; median length of follow-up was 15.1 years (range, 9.5 to 19.2 years), and median age at study evaluation was 23.6 years (range, 11.3 to 36 years). Standardized tests of neuropsychological functioning and QoL were performed. Descriptive statistics summarized principal findings, and one-way analysis of variance identified potential predictors of outcomes.
With an average follow-up time of 15 years, survivors demonstrated intellectual functioning within the low-average range. Executive functioning and verbal memory were between the low-average and borderline ranges. In contrast, visual memory and psychomotor processing speed were between the borderline and impaired ranges, respectively. Approximately 75% of patient reported overall QoL within or above normal limits for both physical and psychosocial domains. Nonhemispheric tumor location (midline or cerebellum), female sex, and younger age at treatment emerged as independent risk factors.
These results serve as a benchmark for comparison with future pediatric high-grade glioma studies, in addition to identifying at-risk cohorts that warrant further research and proactive interventions to minimize late effects while striving to ensure survival.
PMCID: PMC3341107  PMID: 22355055
18.  Risk Factors for Obesity in Adult Survivors of Childhood Cancer: A Report From the Childhood Cancer Survivor Study 
Journal of Clinical Oncology  2011;30(3):246-255.
Many Childhood Cancer Survivor Study (CCSS) participants are at increased risk for obesity. The etiology of their obesity is likely multifactorial but not well understood.
Patients and Methods
We evaluated the potential contribution of demographic, lifestyle, treatment, and intrapersonal factors and self-reported pharmaceutical use to obesity (body mass index ≥ 30 kg/m2) among 9,284 adult (> 18 years of age) CCSS participants. Independent predictors were identified using multivariable regression models. Interrelationships were determined using structural equation modeling (SEM).
Independent risk factors for obesity included cancer diagnosed at 5 to 9 years of age (relative risk [RR], 1.12; 95% CI, 1.01 to 1.24; P = .03), abnormal Short Form–36 physical function (RR, 1.19; 95% CI, 1.06 to 1.33; P < .001), hypothalamic/pituitary radiation doses of 20 to 30 Gy (RR, 1.17; 95% CI, 1.05 to 1.30; P = .01), and paroxetine use (RR, 1.29; 95% CI, 1.08 to 1.54; P = .01). Meeting US Centers for Disease Control and Prevention guidelines for vigorous physical activity (RR, 0.90; 95% CI, 0.82 to 0.97; P = .01) and a medium amount of anxiety (RR, 0.86; 95% CI, 0.75 to 0.99; P = .04) reduced the risk of obesity. Results of SEM (N = 8,244; comparative fit index = 0.999; Tucker Lewis index = 0.999; root mean square error of approximation = 0.014; weighted root mean square residual = 0.749) described the hierarchical impact of the direct predictors, moderators, and mediators of obesity.
Treatment, lifestyle, and intrapersonal factors, as well as the use of specific antidepressants, may contribute to obesity among survivors. A multifaceted intervention, including alternative drug and other therapies for depression and anxiety, may be required to reduce risk.
PMCID: PMC3269951  PMID: 22184380
19.  Chemotherapy and thyroid cancer risk: A report from the Childhood Cancer Survivor Study 
While ionizing radiation is an established environmental risk factor for thyroid cancer, the effect of chemotherapy drugs on thyroid cancer risk remains unclear. We evaluated the chemotherapy-related risk of thyroid cancer in childhood cancer survivors, and the possible joint effects of chemotherapy and radiotherapy.
The study included 12,547 five-year survivors of childhood cancer diagnosed during 1970 through 1986. Chemotherapy and radiotherapy information was obtained from medical records, and radiation dose was estimated to the thyroid gland. Cumulative incidence and relative risks were calculated using life-table methods and Poisson regression. Chemotherapy-related risks were evaluated separately by categories of radiation dose.
Histologically confirmed thyroid cancer occurred in 119 patients. Thirty years after the first childhood cancer treatment, the cumulative incidence of thyroid cancer was 1.3% (95% CI, 1.0–1.6) for females and 0.6% (0.4–0.8) for males. Among patients with thyroid radiation doses ≤ 20 Gy, treatment with alkylating agents was associated with a significant 2.4-fold increased risk of thyroid cancer (95% CI, 1.3–4.5; P = 0.002). Chemotherapy risks decreased as radiation dose increased, with a significant decrease for patients treated with alkylating agents (P-trend = 0.03). No chemotherapy-related risk was evident for thyroid radiation doses >20 Gy.
Treatments with alkylating agents increased thyroid cancer risk, but only in the radiation dose range under 20 Gy, where cell sparing likely predominates over cell killing.
Our study adds to the evidence for chemotherapy agent-specific increased risks of thyroid cancer, which to date, were mainly thought to be related to prior radiotherapy.
PMCID: PMC3253948  PMID: 22028399
Thyroid cancer; second cancer; chemotherapy; radiation risk; cohort study
20.  Adipokines, Body Fatness, and Insulin Resistance Among Survivors of Childhood Leukemia 
Pediatric blood & cancer  2011;58(1):31-36.
Following our previous reports of an increased prevalence of insulin resistance and adiposity among acute lymphoblastic leukemia (ALL) survivors, particularly women treated with cranial radiotherapy (CRT), we aimed to (1) assess the relationships between adipokines (leptin and adiponectin), CRT, and measures of body fatness, and (2) determine correlates of insulin resistance, by gender.
We conducted cross-sectional evaluation of 116 ALL survivors (median age, 23.0 years; range, 18–37; average time from treatment: 17.5 years), including fasting laboratory testing (adiponectin, leptin, insulin, glucose), anthropometric measurements (weight, height, waist circumference), DXA (total body fat, truncal-to-lower-body-fat ratio), and abdominal CT (visceral fat). We estimated insulin resistance using the homeostasis model for assessment of insulin resistance (HOMA-IR). Analytic approaches included regression models and Wilcoxon rank sum testing.
Mean leptin per kilogram fat mass was higher for females (0.7 ng/mL/kg) than males (0.4 ng/mL/kg, P<0.01), and among subjects who had received CRT compared to those who had not received CRT (females CRT =0.9 ng/mL/kg, no CRT=0.7 ng/mL/kg; P=0.1; males CRT=0.5 ng/mL/kg, no CRT=0.3 ng/mL/kg; P<0.01). Elevated HOMA-IR was nearly uniformly present, even among subjects with BMI<25 kg/m2, and was associated with higher leptin:adiponectin ratio (P<0.01).
Among survivors of childhood leukemia, higher leptin levels were associated with measures of body fat and insulin resistance. Anthropomorphic and metabolic changes many years after ALL treatment remain a major health problem facing survivors and may be related to central leptin resistance.
PMCID: PMC3520427  PMID: 21254377
ALL; adiponectin; insulin resistance; leptin; leukemia
21.  Diabetes Mellitus in Long-Term Survivors of Childhood Cancer: Increased Risk Associated with Radiation Therapy A Report for the Childhood Cancer Survivor Study (CCSS) 
Archives of internal medicine  2009;169(15):1381-1388.
Childhood cancer survivors are at increased risk of morbidity and mortality. To further characterize this risk, this study aimed to compare the prevalence of diabetes mellitus (DM) in childhood cancer survivors and their siblings.
Participants included 8599 survivors in the Childhood Cancer Survivor Study (CCSS), a retrospectively ascertained North American cohort of long-term survivors who were diagnosed 1970–1986, and 2936 randomly selected siblings of CCSS survivors. The main outcome was self-reported DM.
Survivors and siblings had mean ages of 31.5 years (range, 17.0–54.1) and 33.4 years (range, 9.6–58.4), respectively. DM was reported in 2.5% of survivors and 1.7% of siblings. Adjusting for body mass index (BMI), age, sex, race/ethnicity, household income, and insurance, survivors were 1.8 times more likely to report DM (95% confidence interval [CI], 1.3–2.5; P<0.001) than siblings, with survivors who received total body irradiation (odds ratio [OR], 12.6; 95% CI, 6.2–25.3; P<0.001), abdominal irradiation (OR, 3.4; 95% CI, 2.3–5.0; P<0.001) and cranial irradiation (OR, 1.6; 95% CI 1.0–2.3; P=0.03) at increased risk. In adjusted models, increased risk of DM was associated with: total body irradiation (OR 7.2; 95% CI, 3.4–15.0; P<0.001); abdominal irradiation (OR 2.7; 95% CI, 1.9–3.8; P<0.001); alkylating agents (OR 1.7; 95% CI, 1.2–2.3; P<0.01); and younger age at diagnosis (0–4 years; OR 2.4; 95% CI 1.3–4.6; P<0.01).
Childhood cancer survivors treated with total body or abdominal irradiation have an increased risk of diabetes that appears unrelated to BMI or physical inactivity.
PMCID: PMC3529471  PMID: 19667301
Childhood cancer survivor; diabetes mellitus; abdominal radiation; total body irradiation
22.  Case-parent analysis of variation in pubertal hormone genes and pediatric osteosarcoma: a Children’s Oncology Group (COG) study 
Osteosarcoma (OS) is a rare malignant bone tumor with an overall incidence rate of 4.6 cases per million children aged 0-19 years in the United States. While the etiology of OS is largely unknown, its distinctive age-incidence pattern suggests that growth and development is crucial in genesis. Prior studies have suggested that variants in genes in the estrogen metabolism (ESTR) and insulin-like growth factor/growth hormone (IGF/GH) pathways are associated with OS. We examined 798 single nucleotide polymorphisms (SNPs) in 42 genes from these pathways in a case-parent study (229 complete triads and 56 dyads) using buccal cell samples. Relative risks (RR) and 95% confidence intervals (CI) associated with transmitting one or two copies of the variant were estimated using log-linear models. After Bonferroni correction, 1 SNP within the ESTR pathway (rs1415270: RR = 0.50 and 8.37 for 1 and 2 vs. 0 copies, respectively; p = 0.010), and two SNPs in the IGF/GH pathway (rs1003737: RR = 0.91 and 0.0001 for 1 and 2 vs. 0 copies, respectively; p <0.0001 and rs2575352: RR = 2.62 and 0.22 for 1 and 2 vs. 0 copies; p < 0.0001) were significantly associated with OS incidence. These results confirm previous findings that variation in the estrogen metabolism and bone growth pathways influence OS risk and further support a biologically and epidemiologically plausible role in OS development.
PMCID: PMC3508538  PMID: 23205180
Osteosarcoma; case-parent study; growth and development; insulin-like growth factor pathway; estrogen metabolism pathway
23.  Auditory Complications in Childhood Cancer Survivors: A Report from the Childhood Cancer Survivor Studya 
Pediatric blood & cancer  2011;57(1):126-134.
Studies have found associations between cancer therapies and auditory complications, but data are limited on long-term outcomes and risks associated with multiple exposures.
The Childhood Cancer Survivor Study is a retrospective cohort investigating health outcomes of long-term survivors (5+ years) diagnosed and treated between 1970 and 1986 compared to a randomly selected sibling cohort. Questionnaires were completed by 14,358 survivors of childhood cancer and 4,023 sibling controls. Analysis determined the first occurrence of four auditory conditions in two time periods: diagnosis to ≥ 5 years post diagnosis, and > 5 years post diagnosis. Multivariable analyses determined the relative risks (RR) and 95% confidence interval (CI) of auditory conditions by treatment exposure.
Five or more years from cancer diagnosis, survivors were at increased risk of problems hearing sounds (RR=2.3; 95% CI: 1.8–2.8), tinnitus (RR=1.7; 95% CI: 1.4–2.1), hearing loss requiring an aid (RR=4.4; 95% CI: 2.8–6.9), and hearing loss in 1 or both ears not corrected by a hearing aid (RR=5.2; 95% CI: 2.8–9.5), when compared to siblings. Temporal lobe and posterior fossa radiation was associated with these outcomes in a dose-dependent fashion. Exposure to platinum compounds was associated with an increased risk of problems hearing sounds (RR=2.1; 95% CI: 1.3–3.2), tinnitus (RR=2.8; 95% CI: 1.9–4.2), and hearing loss requiring an aid (RR=4.1; 95% CI:2.5–6.7)
Childhood cancer survivors are at risk of developing auditory complications. Radiation and platinum compounds are determinants of this risk. Follow-up is needed to evaluate the impact of auditory conditions on quality of life.
PMCID: PMC3091978  PMID: 21328523
late effects of therapy; radiation therapy
Fertility and sterility  2011;95(6):1922-1927.e1.
To evaluate the effect of hypothalamic/pituitary radiation dose on the occurrence of first pregnancy
Retrospective cohort study of childhood cancer five-year survivors (CCS) diagnosed between 1970 and 1986 prior to 21 years of age at one of 26 North American pediatric cancer treatment centers
Self-administered questionnaire
3619 female CCS who participated in the Childhood Cancer Survivor Study and received no/scatter (≤ 0.1 Gy) radiation to the ovaries and 2081 female siblings (Sibs) of the participants
Main Outcome Measure(s)
Self-reported pregnancy events
As a group CCS were as likely to report being pregnant as Sibs (Hazard Ratio (HR), 1.07; 95% Confidence Interval (95%CI), 0.97 to 1.19). Multivariable models showed a significant decrease in the risk of pregnancy with HPT RT doses ≥ 22 Gy compared with those CCS receiving no HPT RT.
These results support the hypothesis that exposures of 22 to 27 Gy HPT RT may be a contributing factor to infertility among female CCS.
PMCID: PMC3080448  PMID: 21376314
childhood cancer survivor; hypothalamic irradiation; pituitary irradiation; alkylating agent; pregnancy
25.  Survivors of Childhood Cancer Have Increased Risk for Gastrointestinal Complications Later in Life 
Gastroenterology  2011;140(5):1464-1471.e1.
Background & Aims
Children who receive cancer therapy experience numerous acute gastrointestinal (GI) toxicities. However, the long-term GI consequences have not been extensively studied. We evaluated the incidence of adverse long-term GI outcomes and identified treatment-related risk factors.
Upper GI, hepatic, and lower GI adverse outcomes were assessed in cases randomly selected from participants in the Childhood Cancer Survivor Study, a study of 14,358 survivors of childhood cancer who were diagnosed between 1970 and 1986; data were compared with those from siblings. The median age at cancer diagnosis was 6.8 years (0–21.0 years), the median age at outcome assessment was 23.2 years (5.6–48.9 years) for survivors and 26.6 years (1.8–56.2 years) for siblings. Rates of self-reported, late complications of the GI tract (occurred 5 or more years after cancer diagnosis) were determined and associated with patient characteristics and cancer treatments, adjusting for age, sex, and race; data were compared with those from siblings.
Compared with siblings, survivors had increased risk for late-onset complications of the upper GI tract (relative risk [RR]=1.8; 95% confidence interval [CI], 1.6–2.0), liver (RR=2.1; 95% CI, 1.8–2.5), and lower GI tract (RR=1.9; 1.7–2.2). The RR for requiring colostomy, ileostomy, or liver biopsy, or for developing liver cirrhosis were 5.6 (95% CI, 2.4–13.1), 24.1 (95% CI, 7.5–77.8), and 8.9 (95% CI, 2.0–40.0), respectively. Older age at diagnosis, intensified therapy, abdominal radiation, and abdominal surgery increased the risk of certain GI complications.
Individuals who received therapy for cancer during childhood have an increased risk of developing GI complications later in life.
PMCID: PMC3081911  PMID: 21315721
tumor; chemotherapy; side effect; toxicity; pediatric

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