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1.  Physical activity among adult survivors of childhood lower extremity sarcoma 
INTRODUCTION
Adult survivors of childhood lower-extremity sarcoma are largely physically inactive, a behavior which potentially compounds their health burden. Altering this behavior requires understanding those factors that contribute to their physical inactivity. Therefore, this investigation sought to identify factors associated with inactivity in this subpopulation of cancer survivors.
METHODS
Demographic, personal, treatment and physical activity information from adult survivors of childhood lower-extremity sarcomas was obtained from the Childhood Cancer Survivor Study (CCSS) cohort. Generalized linear models were used to identify variables that best identified those individuals who were physically inactive.
RESULTS
Only 41% of survivors met Center for Disease Control (CDC) activity guidelines. Survivors were 1.20 (95% CI 1.11–1.30) more likely compared to CCSS sibling cohort and 1.12 (95% CI 1.10–1.15) times more likely than the general population to fail to meet CDC guidelines. Significant predictors of physical inactivity included female sex, hemipelvectomy surgery, and platinum and vinca alkaloid chemotherapy.
CONCLUSIONS
The primary findings of this study are that survivors of childhood onset lower-extremity sarcoma are 1) highly likely to be physically inactive and 2) less likely than their siblings or the general population to regularly exercise. This study has identified treatment related risk factors associated with inactivity that will help health and wellness practitioners develop successful exercise interventions to help these survivors achieve recommended levels of physical activity for health.
IMPLICATIONS FOR CANCER SURVIVORS
These results suggest that physical activity interventions for adult survivors of childhood lower-extremity sarcomas should be sex specific and responsive to unique physical late effects experienced by these survivors.
doi:10.1007/s11764-011-0187-5
PMCID: PMC3248971  PMID: 21681405
Childhood cancer; physical activity; exercise; late-effects; sedentary
2.  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.
Purpose
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).
Results
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.
Conclusion
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.
doi:10.1200/JCO.2010.34.4267
PMCID: PMC3269951  PMID: 22184380
3.  Occupational outcomes of adult childhood cancer survivors: A report from the Childhood Cancer Survivor Study 
Cancer  2011;117(13):3033-3044.
Background
We examined whether survivors from the Childhood Cancer Survivor Study were less likely to be in higher skill occupations than a sibling comparison and whether certain survivors were at higher risk.
Methods
We created three mutually-exclusive occupational categories for participants aged ≥25 years: Managerial/Professional and Non-Physical and Physical Service/Blue Collar. We examined currently employed survivors (N=4845) and siblings (N=1727) in multivariable generalized linear models to evaluate the likelihood of being in the three occupational categories. Among all participants, we used multinomial logistic regression to examine the likelihood of these outcomes in comparison to being unemployed (survivors N=6671; siblings N=2129). Multivariable linear models were used to assess survivor occupational differences by cancer and treatment variables. Personal income was compared by occupation.
Results
Employed survivors were less often in higher skilled Managerial/Professional occupations (Relative Risk=0.93, 95% Confidence Interval 0.89–0.98) than siblings. Survivors who were Black, were diagnosed at a younger age, or had high-dose cranial radiation were less likely to hold Professional occupations than other survivors. In multinomial models, female survivors’ likelihood of being in full-time Professional occupations (27%) was lower than male survivors (42%) and female (41%) and male (50%) siblings. Survivors’ personal income was lower than siblings within each of the three occupational categories in models adjusted for sociodemographic variables.
Conclusions
Adult childhood cancer survivors are employed in lower skill jobs than siblings. Survivors with certain treatment histories are at higher risk and may require vocational assistance throughout adulthood.
doi:10.1002/cncr.25867
PMCID: PMC3547616  PMID: 21246530
Neoplasms; Occupations; Survivors; Socioeconomic Factors; Late Effects; Female
4.  Adipokines, Body Fatness, and Insulin Resistance Among Survivors of Childhood Leukemia 
Pediatric blood & cancer  2011;58(1):31-36.
Background
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.
Methods
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.
Results
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).
Conclusions
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.
doi:10.1002/pbc.22964
PMCID: PMC3520427  PMID: 21254377
ALL; adiponectin; insulin resistance; leptin; leukemia
5.  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.
Background
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.
Methods
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.
Results
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).
Conclusions
Childhood cancer survivors treated with total body or abdominal irradiation have an increased risk of diabetes that appears unrelated to BMI or physical inactivity.
doi:10.1001/archinternmed.2009.209
PMCID: PMC3529471  PMID: 19667301
Childhood cancer survivor; diabetes mellitus; abdominal radiation; total body irradiation
6.  Impact of Insurance Type on Survivor-Focused and General Preventive Health Care Utilization in Adult Survivors of Childhood Cancer: The Childhood Cancer Survivor Study (CCSS) 
Cancer  2010;117(9):1966-1975.
Background
Lack of health insurance is a key barrier to accessing care for chronic conditions and cancer screening. We examined the influence of insurance type (private, public, none) on survivor-focused and general preventive health care in adult survivors of childhood cancer.
Methods
The Childhood Cancer Survivor Study is a retrospective cohort study of childhood cancer survivors diagnosed between 1970–1986. Among 8425 adult survivors, the Relative Risk (RR), 95% confidence interval (CI) of receiving survivor-focused and general preventive health care were estimated for uninsured (n=1390) and publicly insured (n=640), comparing to privately insured (n=6395).
Results
Uninsured survivors were less likely than privately insured to report a cancer-related (adjusted RR=0.83, 95% CI, 0.75–0.91) or a cancer center visit (adjusted RR=0.83, 95% CI, 0.71–0.98). Uninsured survivors had lower levels of utilization in all measures of care in comparison with privately insured. In contrast, publicly insured survivors were more likely to report a cancer-related (adjusted RR=1.22, 95% CI, 1.11–1.35) or a cancer center visit (adjusted RR=1.41, 95% CI, 1.18–1.70) than privately insured. While having a similar utilization level of general health examinations, publicly insured survivors were less likely to report Papanicolaou smear or dental examinations.
Conclusion
Among this large, socioeconomically diverse cohort, publicly insured survivors utilize survivor-focused health care at rates at least as high as survivors with private insurance. Uninsured survivors have lower utilization to both survivor-focused and general preventive health care.
doi:10.1002/cncr.25688
PMCID: PMC3433164  PMID: 21509774
Childhood Cancer Survivors; Health Insurance; Health Care Access; Survivorship; Delivery of Health Care
7.  Response to a Treatment Summary and Care Plan Among Adult Survivors of Pediatric and Young Adult Cancer 
Journal of Oncology Practice  2012;8(3):196-202.
The authors found that a one-page treatment summary and care plan was accepted and retained by adult survivors of pediatric and young adult cancers, and did not result in undue worry or concern for most participants.
Purpose:
Survivors of pediatric and young adult cancer are at increased risk for treatment-related problems. Yet, few survivors receive risk-based care. The treatment summary and care plan are recommended to improve understanding of cancer treatment, potential late effects, and recommended screening. It is unknown whether survivors retain, understand, value, and disseminate the document, and whether it causes worry.
Methods:
We surveyed 111 adult survivors of pediatric and young adult cancer 1 to 6 weeks after receipt of a one-page treatment summary and care plan (response rate, 96%). Participants answered questions regarding retention, understanding, value, dissemination, concern, and preferences.
Results:
Participants were majority female (58%), college-educated (60%), diagnosed with cancer before age 21 (76%), on average 18 years from diagnosis (range, 2 to 50 years), and treated with radiation and chemotherapy (61%). Median age was 30 years (range, 18 to 65 years). A majority of participants stated that they understood the treatment summary (95%), retained the document (95%), and valued it (92%). A minority reported that the document caused concern (14%) or wanted more information than the form provided (20%). Although the time between receipt of the document and survey was brief, many described dissemination of the document to their personal circle (44%) or an outside provider (10 [33%] of 30 who saw an outside doctor).
Conclusion:
A one-page treatment summary and care plan was well-received and did not cause report of undue concern. Additional health-related information was requested by some, and dissemination to outside providers could be improved.
doi:10.1200/JOP.2011.000345
PMCID: PMC3396810  PMID: 22942816
8.  Unemployment among Adult Survivors of Childhood Cancer: A report from the Childhood Cancer Survivors Study 
Medical care  2010;48(11):1015-1025.
Background
Adult childhood cancer survivors report high levels of unemployment although it is unknown whether this is due to health or employability limitations.
Objectives
We examined two employment outcomes from 2002–2005 in the Childhood Cancer Survivor Study (CCSS): 1. health-related unemployment and 2. unemployed but seeking work. We compared survivors to a nearest-age CCSS sibling cohort and examined demographic and treatment-related risk groups for each outcome.
Methods
We studied 6339 survivors and 2280 siblings aged ≥25 years excluding those unemployed by choice. Multivariable generalized linear models evaluated whether survivors were more likely to be unemployed than siblings and whether certain survivors were at a higher risk for unemployment.
Results
Survivors (10.4%) reported health-related unemployment more often than siblings (1.8%; Relative Risk [RR] 6.07, 95% Confidence Interval [CI] 4.32–8.53). Survivors (5.0%) were more likely to report being unemployed but seeking work than siblings (2.7%; RR 1.90, 95% CI 1.43–2.54). Health-related unemployment was more common in female survivors than males (Odds Ratio [OR] 1.73, 95% CI 1.43–2.08). Cranial radiotherapy doses ≥25 Gy were associated with higher odds of unemployment (health-related: OR 3.47, 95% CI 2.54–4.74; seeking work: OR 1.77, 95% CI 1.15–2.71). Unemployed survivors reported higher levels of poor physical functioning than employed survivors, and had lower education and income and were more likely to be publicly insured than unemployed siblings.
Conclusions
Childhood cancer survivors have higher levels of unemployment due to health or being between jobs. High-risk survivors may need vocational assistance.
doi:10.1097/MLR.0b013e3181eaf880
PMCID: PMC3428202  PMID: 20940653
9.  PHYSICAL THERAPY AND CHIROPRACTIC USE AMONG CHILDHOOD CANCER SURVIVORS WITH CHRONIC DISEASE: IMPACT ON HEALTH-RELATED QUALITY OF LIFE 
Introduction
The use of rehabilitation services to address musculoskeletal, neurological and cardiovascular late effects among childhood cancer survivors could improve physical function and health-related quality-of-life (HRQL). We describe physical therapy (PT) and chiropractic utilization among childhood cancer survivors and their association with HRQL.
Methods
The sample included 5+ year survivors from the Childhood Cancer Survivor Study (N=9,289). Questions addressing use of PT or chiropractic services and HRQL (Medical Outcomes Survey Short Form (SF-36)) were evaluated. Multivariable regression models compared PT and/or chiropractic utilization between survivors and siblings, and by diagnosis, treatment and demographic characteristics; associations between chronic disease, PT/chiropractic use, and HRQL were similarly evaluated.
Results
Survivors were not more likely to use PT (OR 1.0; 95% CI 0.8-1.2) or chiropractic (OR 0.8; 95% CI 0.7-1.0) services than siblings. More survivors reported using chiropractic (12.4%) than PT (9.2%) services. Older age and having health insurance were associated with utilization of either PT or chiropractic services. Grade 3-4 chronic conditions and a CNS tumor or sarcoma history were associated with PT but not with chiropractic service utilization. Survivors with musculoskeletal (OR 1.8; 95% CI 1.1-2.9), neurological (OR 3.4; 95% CI 1.6-6.9), or cardiovascular (OR 3.3; 95% CI 1.6-6.9) chronic conditions who used PT/chiropractic services were more likely to report poor physical health than survivors who did not use services.
Conclusions
The reported prevalence of PT/chiropractic among survivors is consistent with that reported by siblings. Severity of late effects is associated with service use and with reporting poor physical health.
Implications for Cancer Survivors
Long-term childhood cancer survivors do not appear to utilize rehabilitation services to optimize physical function and support increased HRQL.
doi:10.1007/s11764-010-0151-9
PMCID: PMC3062253  PMID: 20922492
Physical therapy; chiropractic; childhood cancer survivor; health related quality of life
10.  Long-term Survivors of Childhood Ewing Sarcoma: Report From the Childhood Cancer Survivor Study 
Background
The survival of Ewing sarcoma (ES) patients has improved since the 1970s but is associated with considerable future health risks.
Methods
The study population consisted of long-term (≥5-year) survivors of childhood ES diagnosed before age 21 from 1970 to 1986. Cause-specific mortality was evaluated in eligible survivors (n = 568), and subsequent malignant neoplasms, chronic health conditions, infertility, and health status were evaluated in the subset participating in the Childhood Cancer Survivor Study (n = 403). Outcomes were compared with the US population and sibling control subjects (n = 3899). Logistic, Poisson, or Cox proportional hazards models, with adjustments for sex, age, race/ethnicity, and potential intrafamily correlation, were used. Statistical tests were two-sided.
Results
Cumulative mortality of ES survivors was 25.0% (95% confidence interval [CI] = 21.1 to 28.9) 25 years after diagnosis. The all-cause standardized mortality ratio was 13.3 (95% CI = 11.2 to 15.8) overall, 23.1 (95% CI = 17.6 to 29.7) for women, and 10.0 (95% CI = 7.9 to 12.5) for men. The nonrecurrence-progression non-external cause standardized mortality ratio (subsequent non-ES malignant neoplasms and cardiac and pulmonary causes potentially attributable to ES treatment) was 8.7 (95% CI = 6.2 to 12.0). Twenty-five years after ES diagnosis, cumulative incidence of subsequent malignant neoplasms, excluding nonmelanoma skin cancers, was 9.0% (95% CI = 5.8 to 12.2). Compared with siblings, survivors had an increased risk of severe, life-threatening, or disabling chronic health conditions (relative risk = 6.0, 95% CI = 4.1 to 9.0). Survivors had lower fertility rates (women: P = .005; men: P < .001) and higher rates of moderate to extreme adverse health status (P < .001).
Conclusion
Long-term survivors of childhood ES exhibit excess mortality and morbidity.
doi:10.1093/jnci/djq278
PMCID: PMC2948841  PMID: 20656964
11.  Testicular Cancer Survivorship: Research Strategies and Recommendations 
Testicular cancer represents the most curable solid tumor, with a 10-year survival rate of more than 95%. Given the young average age at diagnosis, it is estimated that effective treatment approaches, in particular, platinum-based chemotherapy, have resulted in an average gain of several decades of life. This success, however, is offset by the emergence of considerable long-term morbidity, including second malignant neoplasms, cardiovascular disease, neurotoxicity, nephrotoxicity, pulmonary toxicity, hypogonadism, decreased fertility, and psychosocial problems. Data on underlying genetic or molecular factors that might identify those patients at highest risk for late sequelae are sparse. Genome-wide association studies and other translational molecular approaches now provide opportunities to identify testicular cancer survivors at greatest risk for therapy-related complications to develop evidence-based long-term follow-up guidelines and interventional strategies. We review research priorities identified during an international workshop devoted to testicular cancer survivors. Recommendations include 1) institution of lifelong follow-up of testicular cancer survivors within a large cohort setting to ascertain risks of emerging toxicities and the evolution of known late sequelae, 2) development of comprehensive risk prediction models that include treatment factors and genetic modifiers of late sequelae, 3) elucidation of the effect(s) of decades-long exposure to low serum levels of platinum, 4) assessment of the overall burden of medical and psychosocial morbidity, and 5) the eventual formulation of evidence-based long-term follow-up guidelines and interventions. Just as testicular cancer once served as the paradigm of a curable malignancy, comprehensive follow-up studies of testicular cancer survivors can pioneer new methodologies in survivorship research for all adult-onset cancer.
doi:10.1093/jnci/djq216
PMCID: PMC2914759  PMID: 20585105
12.  Knowledge of Hepatitis C Virus Screening in Long-Term Pediatric Cancer Survivors: A Report from the Childhood Cancer Survivor Study 
Cancer  2010;116(4):974-982.
Background
Pediatric cancer survivors who were treated before routine hepatitis C virus (HCV) screening of blood donors in 1992 have an elevated risk of transfusion-acquired HCV.
Methods
To assess long-term pediatric cancer survivors’ knowledge of HCV testing and blood transfusion history, a questionnaire was administered to 9,242 participants in the Childhood Cancer Survivor Study (CCSS) who are at risk for transfusion-acquired HCV following cancer therapy from 1970–1986.
Results
More than 70% of survivors reported either no prior HCV testing (41%) or uncertainty about testing (31%), with only 29% reporting prior testing. One-half recalled having a treatment-related blood transfusion; those who recalled a transfusion were more likely to report HCV testing (39%) than those who did not (18%) or were unsure (20%). In multivariate models, survivors who reported no prior HCV testing were more likely to be older (odds ratio [OR] per five-year increase, 1.1; 95% confidence interval [95% CI], 1.0–1.1) and to report no care at a cancer center within the past two years (OR, 1.2; 95% CI, 1.0–1.4), no cancer treatment summary (OR, 1.3; 95% CI, 1.2–1.5), and no transfusions (OR, 2.6; 95% CI, 2.3–3.0) or uncertainty about transfusions (OR, 2.2; 95% CI, 1.9–2.6), and less likely to be racial/ethnic minorities (OR, 0.9; 95% CI, 0.8–1.0) or survivors of acute myeloid leukemia (OR, 0.7; 95% CI, 0.5–1.0).
Conclusions
Many pediatric cancer survivors at risk for transfusion-acquired HCV are unaware of their transfusion history and prior testing for HCV and would benefit from programs to increase HCV knowledge and screening.
doi:10.1002/cncr.24810
PMCID: PMC2819650  PMID: 20041485
cancer screening; late effects; survivorship; adverse treatment effects; chronic disease
13.  Cardiovascular Risk Factors in Adult Survivors of Pediatric Cancer – a report from the Childhood Cancer Survivor Study 
Background
Childhood cancer survivors are at higher risk of morbidity and mortality from cardiovascular (CV) disease compared with the general population.
Methods
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
Results
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).
Conclusions
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.
doi:10.1158/1055-9965.EPI-09-0555
PMCID: PMC2805162  PMID: 20056636
survivor; cardiovascular risk factors; metabolic syndrome
14.  Insulin Resistance and Risk Factors for Cardiovascular Disease in Young Adult Survivors of Childhood Acute Lymphoblastic Leukemia 
Journal of Clinical Oncology  2009;27(22):3698-3704.
Purpose
To determine the prevalence of insulin resistance and other risk factors for cardiovascular disease (CVD) in young adult survivors of childhood acute lymphoblastic leukemia (ALL).
Patients and Methods
In this cross-sectional evaluation of 118 survivors of childhood ALL (median age, 23.0 years; range, 18 to 37 years), insulin resistance was estimated using the homeostasis model for assessment of insulin resistance (HOMA-IR). Sex-specific comparisons were made with a cohort of 30- to 37-year-old individuals from the same region participating in the Dallas Heart Study (DHS, N = 782). ALL survivors were stratified by treatment with and without cranial radiotherapy (CRT).
Results
Female ALL survivors had a significantly higher HOMA-IR (CRT, mean 4.6, 95% CI, 3.6 to 5.7; no CRT, mean 3.3, 95% CI, 2.8 to 3.8) in comparison with DHS women (mean 2.4, 95% CI, 2.2 to 2.7). Eighty percent of women treated with CRT had at least three of six CVD risk factors, and they were significantly more likely to have three or more risk factors compared with DHS women (odds ratio [OR], 5.96; 95% CI, 2.15 to 16.47). Male ALL survivors had a significantly higher HOMA-IR (CRT, mean 4.0, 95% CI, 2.8 to 5.6; no CRT, mean 3.4, 95% CI, 2.9 to 3.9) in comparison with DHS men (mean 2.3, 95% CI, 2.1 to 2.6), but were not more likely to have multiple CVD risk factors.
Conclusion
ALL survivors had an increased prevalence of insulin resistance in comparison with a cohort of older individuals from the same community. Importantly, women treated with CRT seem to have an increased prevalence of multiple CVD risk factors, warranting close monitoring and risk-reducing strategies.
doi:10.1200/JCO.2008.19.7251
PMCID: PMC2720083  PMID: 19564534
16.  High-Risk Populations Identified in Childhood Cancer Survivor Study Investigations: Implications for Risk-Based Surveillance 
Journal of Clinical Oncology  2009;27(14):2405-2414.
Childhood cancer survivors often experience complications related to cancer and its treatment that may adversely affect quality of life and increase the risk of premature death. The purpose of this manuscript is to review how data derived from Childhood Cancer Survivor Study (CCSS) investigations have facilitated identification of childhood cancer survivor populations at high risk for specific organ toxicity and secondary carcinogenesis and how this has informed clinical screening practices. Articles previously published that used the resource of the CCSS to identify risk factors for specific organ toxicity and subsequent cancers were reviewed and results summarized. CCSS investigations have characterized specific groups to be at highest risk of morbidity related to endocrine and reproductive dysfunction, pulmonary toxicity, cerebrovascular injury, neurologic and neurosensory sequelae, and subsequent neoplasms. Factors influencing risk for specific outcomes related to the individual survivor (eg, sex, race/ethnicity, age at diagnosis, attained age), sociodemographic status (eg, education, household income, health insurance) and cancer history (eg, diagnosis, treatment, time from diagnosis) have been consistently identified. These CCSS investigations that clarify risk for treatment complications related to specific treatment modalities, cumulative dose exposures, and sociodemographic factors identify profiles of survivors at high risk for cancer-related morbidity who deserve heightened surveillance to optimize outcomes after treatment for childhood cancer.
doi:10.1200/JCO.2008.21.1516
PMCID: PMC2677926  PMID: 19289611
17.  Health Behaviors, Medical Care, and Interventions to Promote Healthy Living in the Childhood Cancer Survivor Study Cohort 
Journal of Clinical Oncology  2009;27(14):2363-2373.
Childhood cancer survivors are at risk for medical and psychosocial late effects as a result of their cancer and its therapy. Promotion of healthy lifestyle behaviors and provision of regular risk-based medical care and surveillance may modify the evolution of these late effects. This manuscript summarizes publications from the Childhood Cancer Survivor Study (CCSS) that have examined health behaviors, risk-based health care, and interventions to promote healthy lifestyle practices. Long-term survivors use tobacco and alcohol and have inactive lifestyles at higher rates than is ideal given their increased risk of cardiac, pulmonary, and metabolic late effects. Nearly 90% of survivors report receiving some form of medical care. However, only 18% report medical visits related to their prior cancer that include discussion or ordering of screening tests or counseling on how to reduce the specific risks arising from their cancer. One low-cost, peer-driven intervention trial has been successful in improving smoking cessation within the CCSS cohort. On the basis of data from CCSS investigations, several trials to promote improved medical surveillance among high-risk groups within the cohort are underway. Despite their long-term risks, many survivors of childhood cancer engage in risky health behaviors and do not receive adequate risk-based medical care.
doi:10.1200/JCO.2008.21.1441
PMCID: PMC2738646  PMID: 19255308
18.  Predictors of inactive lifestyle among adult survivors of childhood cancer: A report from the Childhood Cancer Survivor Study 
Cancer  2009;115(9):1984-1994.
Background
Participation in physical activity is important for childhood cancer survivors because inactivity may compound cancer/treatment-related late-effects. However, some survivors may have difficulty participating physical activity and these individuals need to be identified so that risk-based guidelines for physical activity, tailored to specific needs, can be developed and implemented.
Purpose
To document physical activity patterns in the Childhood Cancer Survivor Study (CCSS) cohort, compare physical activity patterns to siblings in CCSS and a population based sample from the Behavioral Risk Factor Surveillance System, and evaluate associations between diagnosis, treatment, and personal factors and risk for inactive lifestyle.
Methods
Percentages of participation in recommended physical activity were compared among survivors, siblings and population norms. Generalized linear models were used to evaluate associations between cancer diagnosis and therapy, sociodemographics and risk for inactive lifestyle.
Results
Participants included 9301 adult survivors of childhood cancer and 2886 siblings. Survivors were less likely than siblings (46% vs. 52%) to meet physical activity guidelines and more likely than siblings to report inactive lifestyle (23% vs. 14%). Medulloblastoma (35%) and osteosarcoma (27%) survivors reported highest levels of inactive lifestyle. Treatments with cranial radiation or amputation was associated with an inactive lifestyle as were female gender, black race, older age, lower educational attainment, underweight or obese status, smoking, and depression.
Conclusion
Childhood cancer survivors are less active than a sibling comparison group or an age and gender-matched population sample. Survivors at risk for inactive lifestyle should be considered high priority for developing and testing of intervention approaches.
doi:10.1002/cncr.24209
PMCID: PMC2692052  PMID: 19224548
Childhood Cancer; Physical Activity; Survivorship
19.  Assessment of Selection Bias in Clinic-Based Populations of Childhood Cancer Survivors 
Pediatric blood & cancer  2009;52(3):379-386.
Background
It is not known to what extent prevalence estimates of late effects among childhood cancer survivors derived from clinic based samples represent the actual estimates that would be derived if the entire population of childhood cancer survivors was recruited and evaluated for a particular outcome.
Procedure
In a large retrospective cohort study of childhood cancer survivors, the Childhood Cancer Survivor Study (CCSS), the prevalence of chronic health conditions among participants who reported being seen in a cancer center or long-term follow-up clinic was compared to the prevalence of chronic conditions in the entire cohort.
Results
When compared to survivors who had no medical care in the previous two years, survivors accessing medical follow-up were significantly more likely to have chronic health conditions. Relative risks of reporting a chronic health condition were 1.4 (95% CI 1.3 – 1.5) if seen in a cancer center or long-term follow-up clinic and 1.2 (95% CI 1.1-1.3) if seen in a general medical care setting. Estimates derived from only those childhood cancer survivors who were seen in a cancer center or long term follow-up clinic overestimate the prevalence of any chronic disease by 9.3% (95% CI: 7.0-11.6%).
Conclusions
Applying chronic condition prevalence estimates from a clinical population to the general population of childhood cancer survivors must be undertaken with caution. Survivorship research must maintain a high level of scientific rigor to ensure that results reported in the literature are interpreted within the appropriate context.
doi:10.1002/pbc.21829
PMCID: PMC2628420  PMID: 18989878
20.  Longitudinal Changes in Obesity and Body Mass Index Among Adult Survivors of Childhood Acute Lymphoblastic Leukemia: A Report From the Childhood Cancer Survivor Study 
Journal of Clinical Oncology  2008;26(28):4639-4645.
Purpose
We examined the rate of increase in the body mass index (BMI; kg/m2) after final height attainment in survivors of acute lymphoblastic leukemia (ALL) and a noncancer comparison group.
Methods
Childhood Cancer Survivor Study (CCSS) is a retrospectively ascertained cohort study that prospectively tracks the health status of adults who were diagnosed with childhood cancer between 1970 and 1986 and a comparison group of siblings. Changes in BMI from baseline enrollment to time of completion of follow-up (mean interval, 7.8 years) were calculated for 1,451 ALL survivors (mean age, 32.3 years at follow-up) and 2,167 siblings of childhood cancer survivors (mean age, 35.9 years).
Results
The mean BMI of the CCSS sibling comparison group increased with age (women, 0.25 units/yr, 95% CI, 0.22 to 0.28 units; men, 0.23 units/yr, 95% CI, 0.20 to 0.25 units). Compared with CCSS siblings, ALL survivors who were treated with cranial radiation therapy (CRT) had a significantly greater increase in BMI (women, 0.41 units/yr, 95% CI, 0.37 to 0.45 units; men, 0.29 units/yr; 95% CI, 0.26 to 0.32 units). The rate of BMI increase was not significantly increased for ALL survivors who were treated with chemotherapy alone. Younger age at CRT exposure significantly modified risk.
Conclusion
CRT used in the treatment of childhood ALL is associated with a greater rate of increasing BMI, particularly among women treated with CRT during the first decade of life. Health care professionals should be aware of this risk and interventions to reduce or manage weight gain are essential in this high-risk population.
doi:10.1200/JCO.2008.16.3527
PMCID: PMC2653124  PMID: 18824710
21.  Medical Care in Long-Term Survivors of Childhood Cancer: A Report From the Childhood Cancer Survivor Study 
Journal of Clinical Oncology  2008;26(27):4401-4409.
Purpose
To evaluate whether childhood cancer survivors receive regular medical care focused on the specific morbidities that can arise from their therapy.
Patients and Methods
We conducted a cross-sectional survey of health care use in 8,522 participants in the Childhood Cancer Survivor Study, a multi-institutional cohort of childhood cancer survivors. We assessed medical visits in the preceding 2 years, whether these visits were related to the prior cancer, whether survivors received advice about how to reduce their long-term risks, and whether screening tests were discussed or ordered. Completion of echocardiograms and mammograms were assessed in patients at high risk for cardiomyopathy or breast cancer. We examined the relationship between demographics, treatment, health status, chronic medical conditions, and health care use.
Results
Median age at cancer diagnosis was 6.8 years (range, 0 to 20.9 years) and at interview was 31.4 years (range, 17.5 to 54.1 years). Although 88.8% of survivors reported receiving some form of medical care, only 31.5% reported care that focused on their prior cancer (survivor-focused care), and 17.8% reported survivor-focused care that included advice about risk reduction or discussion or ordering of screening tests. Among survivors who received medical care, those who were black, older at interview, or uninsured were less likely to have received risk-based, survivor-focused care. Among patients at increased risk for cardiomyopathy or breast cancer, 511 (28.2%) of 1,810 and 169 (40.8%) of 414 had undergone a recommended echocardiogram or mammogram, respectively.
Conclusion
Despite a significant risk of late effects after cancer therapy, the majority of childhood cancer survivors do not receive recommended risk-based care.
doi:10.1200/JCO.2008.16.9607
PMCID: PMC2653112  PMID: 18802152
22.  Breast Cancer Surveillance Practices Among Women Previously Treated With Chest Radiation for a Childhood Cancer 
Context
Women treated with chest radiation for a pediatric malignancy have a significantly increased risk of breast cancer at a young age and are recommended to have an annual screening mammogram starting at age 25 or 8 years after radiation, whichever occurs last.
Objective
Characterize the breast cancer surveillance practices among female pediatric cancer survivors who were treated with chest radiation and identify correlates of screening.
Design, Setting, Participants
Between June 2005 and August 2006, a 114-item questionnaire was administered to a random sample of 625 female pediatric cancer survivors who had been treated with chest radiation and were age 25–50 and participating in the Childhood Cancer Survivor Study (CCSS), a North American cohort of long-term survivors diagnosed from 1970–1986. Comparisons were made with similarly aged pediatric cancer survivors not treated with chest radiation (N=639) and the CCSS siblings cohort (N=712).
Main Outcome Measure
Screening mammogram within the previous two years.
Results
Of 1976 cancer survivors and siblings who were contacted, 87.9% participated. Among the 551 women with a history of chest radiation, 55% reported a screening mammogram in the past two years (ages 25–39, 36.5%; 95% confidence interval [CI], 31.0%–42.0%; ages 40–50, 76.5%; 95% CI, 71.3%–81.7%). In comparison, 40.5% of survivors without chest radiation and 37.0% of CCSS siblings reported a screening mammogram in the same time interval. Notably, among women with a history of chest radiation, 47.3% (95% CI, 41.6%–53.0%) of those under age 40 had never had a mammogram and only 52.6% (95% CI, 46.4%–58.8%) of women ages 40–50 were being regularly screened (two mammograms within four years). Screening rates were higher among women who reported a physician recommendation compared to those who did not (ages 25–39, 76.0% vs. 17.6%; ages 40–50, 87.3% vs. 58.3%). In multivariable models, the association was particularly strong for younger women (ages 25–39, prevalence ratio [PR] = 3.0, 95% CI, 2.0–4.0; ages 40–50, PR = 1.3, 95% CI, 1.1–1.6).
Conclusions
In this study cohort of women who had childhood cancer treated with chest radiation, 63.5% of those aged 25–39 years and 23.5% of those aged 40–50 years had not undergone mammography screening for breast cancer, as recommended by current guidelines for survivors of childhood cancer.
doi:10.1001/jama.2008.1039
PMCID: PMC2676434  PMID: 19176442
23.  Promoting Physical Activity in Childhood Cancer Survivors: Targets for Intervention 
Cancer  2009;115(3):642-654.
Purpose
Although physical activity may modify the late effects of childhood cancer treatment, 20%-52% of adult survivors are sedentary. We sought to identify modifiable factors that influence survivors' participation in physical activity.
Methods
Structural equation modeling of data from the Childhood Cancer Survivors Study of adult survivors (current mean age, 30.98 years; mean years since diagnosis, 23.74; mean age at diagnosis, 9.25 years) diagnosed between 1970 and 1986.
Results
Forty percent of the variance in male survivors' recent participation vs. nonparticipation in physical activity was explained directly and/or indirectly by self-reported health fears (P=0.01), perceived primary-care physician (PCP) expertise (P=0.01), baseline exercise frequency (P=<0.001), education level (P=0.01), self-reported stamina (P=0.01), cancer-related pain (P=<0.001), fatigue (P=<0.001), age at diagnosis (P=0.01), cancer-related anxiety (P=<0.001), motivation (P=0.01), affect (P=0.01), and discussion of subsequent cancer risk with the PCP (P=<0.001) (N=256; X2=53.38, df=51, P=0.38, CFI=1.000, TLI=1.000, RMSEA=0.014,WRMR=0.76). Thirty-one percent of the variance in females' recent physical activity participation was explained directly and/or indirectly by self-reported stamina (P=<0.001), fatigue (P=0.01), baseline exercise frequency (P=0.01), cancer-related pain (P=<0.001), cancer-related anxiety (P=0.01), recency of visits with PCP (<0.001), quality of interaction with the PCP (P=0.01), and motivation (P=<0.001) (N=366; X2=67.52 df=55, P=0.12, CFI=0.98, TLI=0.98, RMSEA=0.025, WRMR=0.76).
Conclusions
Gender-tailored intervention strategies in which providers specifically target motivation, fear, and affect may support physical activity in childhood cancer survivors.
doi:10.1002/cncr.24043
PMCID: PMC2653221  PMID: 19117349
childhood cancer survivors; sedentary lifestyle
24.  Inconsistent mammography perceptions and practices among women at risk of breast cancer following a pediatric malignancy: a report from the Childhood Cancer Survivor Study 
Cancer causes & control : CCC  2010;21(10):1585-1595.
Women treated with chest radiation for a pediatric cancer have low mammography screening rates despite their high risk for breast cancer. This study characterized the relationship between perceptions of mammography and screening practices. A cross-sectional survey was administered to 523 women in North America who were treated with chest radiation before 21 years of age. Women with inconsistent mammography perceptions and practices were identified using the Pros and Cons of Mammography for perceptions and Transtheoretical Model stages of adoption for prior and intended screening practices. Classification and regression tree (CART) analysis was used to identify barriers to and facilitators of screening among women with positive and negative perceptions. Nearly one-third of the cohort had inconsistent perceptions and practices: 37.4% had positive perceptions and were not having mammograms; 27.6% had negative/neutral perceptions and were having mammograms. Regardless of perceptions, a recent physician’s recommendation for mammography, age ≥ 40, and interest in routine health care were universally associated with mammography practices. For women with positive perceptions and a physician’s recommendation, barriers to screening included high acceptance coping, low active-planning coping, and high internal health locus of control. For women with negative perceptions, acknowledging the importance of asymptomatic screening was associated with mammography.
doi:10.1007/s10552-010-9587-5
PMCID: PMC2941535  PMID: 20506037
Cancer survivorship; Late effects; Screening; Transtheoretical model; Stages of adoption
25.  Surveillance for Breast Cancer in Women Treated with Chest Radiation for a Childhood, Adolescent or Young Adult Cancer: A Report from the Children's Oncology Group 
Annals of internal medicine  2010;152(7):444-W154.
Background
Women treated with therapeutic chest radiation may develop breast cancer.
Purpose
Summarize breast cancer risk and breast cancer surveillance in women following chest radiation for a pediatric or young adult cancer.
Data Sources
Studies from MEDLINE, EMBASE, Cochrane Library, and CINAHL (1966 through December 2008).
Study Selection
Articles selected to answer any of 3 questions: 1) What is the incidence and excess risk of breast cancer in women following chest radiation for a pediatric or young adult cancer? 2) For these women, are the clinical characteristics of the breast cancer and the outcomes following therapy different than for women with sporadic breast cancer in the general population? 3) What are the potential benefits and harms associated with breast cancer surveillance among women exposed to chest radiation?
Data Extraction
Three investigators independently extracted data and assessed study quality.
Data Synthesis
Standardized incidence ratios ranged from 13.3 to 55.5; cumulative incidence of breast cancer by 40–45 years of age ranged from 13–20%. Risk of breast cancer increased linearly with chest radiation dose. Available limited evidence suggests that the characteristics of the breast cancers in these women and the outcomes following diagnosis are similar to those in the general population; these breast cancers can be detected by mammography, though sensitivity is limited.
Limitations
Limitations include study heterogeneity, design and small sample size.
Conclusions
Women treated with chest radiation have a substantially elevated risk of breast cancer at a young age, which does not appear to plateau. Among this high risk population, there appears to be a benefit associated with early detection. Further research is required to better define the harms and benefits of lifelong surveillance.
doi:10.1059/0003-4819-152-7-201004060-00009
PMCID: PMC2857928  PMID: 20368650

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