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1.  Prevalence and Predictors of Prescription Psychoactive Medication Use in Adult Survivors of Childhood Cancer: A Report from the Childhood Cancer Survivor Study 
Purpose
Childhood cancer survivors are at-risk for late effects which may be managed pharmacologically. The purpose of this study was to estimate and compare the prevalence of psychoactive medication use of adult survivors of childhood cancer and sibling controls, identify predictors of medication use in survivors, and investigate associations between psychoactive medications and health-related quality of life (HRQOL).
Methods
Psychoactive medication use from 1994 to 2010 was evaluated in 10,378 adult survivors from the Childhood Cancer Survivor Study. A randomly selected subset of 3,206 siblings served as a comparison group. Multivariable logistic regression models were used to calculate odds ratios (OR) for baseline and new onset of self-reported psychoactive medication use and HRQOL.
Results
Survivors were significantly more likely to report baseline (22% vs. 15%, p<0.001) and new onset (31% vs. 25%, p<0.001) psychoactive medication use compared to siblings, as well as use of multiple medications (p<0.001). In multivariable models, controlling for pain and psychological distress, female survivors were significantly more likely to report baseline and new onset use of antidepressants (OR=2.66; 95% CI=2.01–3.52; OR=2.02; 95% CI=1.72–2.38, respectively) and multiple medications (OR=1.80; 95% CI=1.48–2.19; OR=1.77; 95% CI=1.48–2.13, respectively). Non-cranial radiation and amputation predicted incident use of analgesics >15 years following diagnosis. Antidepressants were associated with impairment across all domains of HRQOL, with the exception of physical function.
Conclusions
Prevalence of psychoactive medication use was higher among survivors for most medication classes, as was the use of multiple medications. Clinicians should be aware of the possible contribution of psychoactive medications to HRQOL.
doi:10.1007/s11764-012-0250-x
PMCID: PMC3568188  PMID: 23224753
psychoactive medication; quality of life; survivorship
2.  Scarring, Disfigurement, and Quality of Life in Long-Term Survivors of Childhood Cancer: A Report From the Childhood Cancer Survivor Study 
Journal of Clinical Oncology  2012;30(20):2466-2474.
Purpose
Childhood cancer survivors are at increased risk for adverse outcomes and chronic medical conditions. Treatment-related scarring, disfigurement, and persistent hair loss, in addition to their long-term impact on psychological distress or health-related quality of life (HRQOL), have received little attention.
Patients and Methods
Self-reported scarring/disfigurement and persistent hair loss were examined in 14,358 survivors and 4,023 siblings from the Childhood Cancer Survivor Study. Multivariable models were used to examine associations with demographic and cancer treatment. The impact of disfigurement and hair loss on HRQOL (ie, Medical Outcomes Short Form–36) and emotional distress (ie, Brief Symptom Inventory–18) was examined.
Results
Survivors reported a significantly higher rate of scarring/disfigurement compared with siblings for head/neck (25.1% v 8.4%), arms/legs (18.2% v 10.2%), and chest/abdomen (38.1% v 9.1%), as well as hair loss (14.0% v 6.3%). In age-, sex-, and race-adjusted models, cranial radiation exposure ≥ 36 Gy increased risk for head/neck disfigurement (relative risk [RR], 2.42; 95% CI, 2.22 to 2.65) and hair loss (RR, 4.24; 95% CI, 3.63 to 4.95). Adjusting for cranial radiation, age, sex, race, education, and marital status, survivor hair loss increased risk of anxiety (RR, 1.60; 95% CI, 1.23 to 2.07), whereas head/neck disfigurement increased risk of depression (RR, 1.19; 95% CI, 1.01 to 1.41). Limitations due to emotional symptoms were associated with head/neck disfigurement (RR, 1.24; 95% CI, 1.10 to 1.41), arm/leg disfigurement (RR, 1.19; 95% CI, 1.05 to 1.35), and hair loss (RR, 1.26; 95% CI, 1.09 to 1.47).
Conclusion
Survivors of childhood cancer are at increased risk for disfigurement and persistent hair loss, which is associated with future emotional distress and reduced quality of life. Future studies are needed to better identify and manage functional outcomes in these patients.
doi:10.1200/JCO.2011.39.3611
PMCID: PMC3397782  PMID: 22614987
3.  Neurocognitive Status in Long-Term Survivors of Childhood CNS Malignancies: A Report from the Childhood Cancer Survivor Study 
Neuropsychology  2009;23(6):705-717.
Background
Among survivors of childhood cancer, those with Central Nervous System (CNS) malignancies have been found to be at greatest risk for neuropsychological dysfunction in the first few years following diagnosis and treatment. This study follows survivors to adulthood to assess the long term impact of childhood CNS malignancy and its treatment on neurocognitive functioning.
Participants & Methods
As part of the Childhood Cancer Survivor Study (CCSS), 802 survivors of childhood CNS malignancy, 5937 survivors of non-CNS malignancy and 382 siblings without cancer completed a 25 item Neurocognitive Questionnaire (CCSS-NCQ) at least 16 years post cancer diagnosis assessing task efficiency, emotional regulation, organizational skills and memory. Neurocognitive functioning in survivors of CNS malignancy was compared to that of non-CNS malignancy survivors and a sibling cohort. Within the group of CNS malignancy survivors, multiple linear regression was used to assess the contribution of demographic, illness and treatment variables to reported neurocognitive functioning and the relationship of reported neurocognitive functioning to educational, employment and income status.
Results
Survivors of CNS malignancy reported significantly greater neurocognitive impairment on all factors assessed by the CCSS-NCQ than non-CNS cancer survivors or siblings (p<.01), with mean T scores of CNS malignancy survivors substantially more impaired that those of the sibling cohort (p<.001), with a large effect size for Task Efficiency (1.16) and a medium effect size for Memory (.68). Within the CNS malignancy group, medical complications, including hearing deficits, paralysis and cerebrovascular incidents resulted in a greater likelihood of reported deficits on all of the CCSS-NCQ factors, with generally small effect sizes (.22-.50). Total brain irradiation predicted greater impairment on Task Efficiency and Memory (Effect sizes: .65 and .63, respectively), as did partial brain irradiation, with smaller effect sizes (.49 and .43, respectively). Ventriculoperitoneal (VP) shunt placement was associated with small deficits on the same scales (Effect sizes: Task Efficiency .26, Memory .32). Female gender predicted a greater likelihood of impaired scores on 2 scales, with small effect sizes (Task Efficiency .38, Emotional Regulation .45), while diagnosis before age 2 years resulted in less likelihood of reported impairment on the Memory factor with a moderate effect size (.64). CNS malignancy survivors with more impaired CCSS-NCQ scores demonstrated significantly lower educational attainment (p<.01), less household income (p<.001) and less full time employment (p<.001).
Conclusions
Survivors of childhood CNS malignancy are at significant risk for impairment in neurocognitive functioning in adulthood, particularly if they have received cranial radiation, had a VP shunt placed, suffered a cerebrovascular incident or are left with hearing or motor impairments. Reported neurocognitive impairment adversely affected important adult outcomes, including education, employment, income and marital status.
doi:10.1037/a0016674
PMCID: PMC2796110  PMID: 19899829
Neurocognitive functioning; brain tumors; CNS malignancies; Childhood Cancer Survivor Study
4.  Psychological Outcomes of Siblings of Cancer Survivors: A Report from the Childhood Cancer Survivor Study 
Psycho-oncology  2010;20(12):1259-1268.
Objective
To identify risk factors for adverse psychological outcomes among adult siblings of long-term survivors of childhood cancer.
Methods
Cross-sectional, self-report data from 3,083 adult siblings (mean age 29 years, range 18-56 years) of 5+ year survivors of childhood cancer were analyzed to assess psychological outcomes as measured by the Brief Symptom Inventory-18 (BSI-18). Sociodemographic and health data, reported by both the siblings and their matched cancer survivors were explored as risk factors for adverse sibling psychological outcomes through multivariable logistic regression.
Results
Self-reported symptoms of psychological distress, as measured by the global severity index of the BSI-18, were reported by 3.8% of the sibling sample. Less than 1.5% of siblings reported elevated scores on two or more of the subscales of the BSI-18. Risk factors for sibling depression included having a survivor brother (OR 2.22, 95% CI 1.42-3.55), and having a survivor with impaired general health (OR 2.15, 95% CI 1.18-3.78). Siblings who were younger than the survivor reported increased global psychological distress (OR 1.81, 95% CI 1.05-3.12), as did siblings of survivors reporting global psychological distress (OR 2.32, 95% CI 1.08-4.59). Siblings of sarcoma survivors reported more somatization than did siblings of leukemia survivors (OR 2.07, 95% CI 1.05-3.98).
Conclusions
These findings suggest that siblings of long-term childhood cancer survivors are psychologically healthy in general. There are, however, small subgroups of siblings at risk for long-term psychological impairment who may benefit from preventive risk-reduction strategies during childhood while their sibling with cancer is undergoing treatment.
doi:10.1002/pon.1848
PMCID: PMC3223600  PMID: 22114043
5.  Health Related Quality of Life, Lifestyle Behaviors, and Intervention Preferences of Survivors of Childhood Cancer 
Journal of cancer survivorship : research and practice  2013;7(4):10.1007/s11764-013-0289-3.
PURPOSE
Childhood cancer survivors (CCSs) are at increased risk for poor health-related quality of life (HRQOL) and chronic health conditions -- both of which can be exacerbated by unhealthy lifestyle behaviors. Developing a clearer understanding of the associations between HRQOL, lifestyle behaviors, and medical and demographic variables (e.g., age/developmental stage at time of diagnosis) is an important step toward developing more targeted behavioral interventions for this population.
METHOD
Cross-sectional questionnaires were completed by 170 CCSs who were diagnosed with leukemia, lymphoma, sarcoma, or a cancer of the central nervous system (CNS) and treated at a comprehensive cancer center between 1992 and 2007. Questionnaires addressed weight status, lifestyle behaviors, aspects of HRQOL, and intervention preferences.
RESULTS
Adolescent and young adult survivors (AYAs) and survivors of CNS tumors or lymphoma reported significantly (p<.05) poorer HRQOL across multiple domains compared to those diagnosed at an earlier age, survivors of leukemia or sarcoma, and healthy populations. A significant proportion also failed to meet national recommendations for dietary intakes (39–94%) and physical activity (65%). Female survivors reported poorer physical functioning and consumed less dietary fiber and fruits and vegetables than did male survivors. They also expressed the strongest interest in participating in diet and exercise interventions.
CONCLUSION
Findings support the premise that females, AYAs, and survivors of cancers of the CNS or lymphoma are “at risk” subgroups within the CCS population for poor dietary practices, sedentary behaviors, and poor HRQOL. Future research should focus on developing diet and PA interventions to improve HRQOL that target these groups.
IMPLICATIONS FOR SURVIVORS
Greater consideration of the role of gender, developmental stage, and the HRQOL challenges facing CCSs may help researchers to develop targeted behavioral interventions for those who stand to benefit the most.
doi:10.1007/s11764-013-0289-3
PMCID: PMC3825822  PMID: 23749663
childhood cancer; diet; physical activity; health related quality of life; intervention preferences
6.  Sexual Functioning in Young Adult Survivors of Childhood Cancer 
Psycho-oncology  2010;19(8):814-822.
Background
Studies of sexuality or sexual behavior in childhood cancer survivors tend to examine relationships or achievement of developmental milestones but not physiological response to cancer or treatment. The purpose of this study is to (1) identify prevalence and risk factors for sexual dysfunction in childhood cancer survivors, and (2) examine the extent to which sexual dysfunction may be associated with health-related quality of life (HRQOL) and psychosocial outcomes.
Methods
Five hundred ninety-nine survivors age 18-39 years completed standardized measures of sexual functioning, HRQOL, psychological distress and life satisfaction. Descriptive statistics assessed prevalence of sexual symptoms. Bivariate analyses identified correlates of sexual symptoms and examined associations between symptoms and HRQOL/psychosocial outcomes.
Results
Most survivors appear to be doing well, although 52% of female survivors and 32% of male survivors reported at least “a little of a problem” in one or more areas of sexual functioning. Mean symptom score for females was more than twice that of males. Sexual symptoms were associated with reporting health problems. Significant associations between sexual functioning and HRQOL outcomes were observed, with gender differences in strengths of association suggesting that males find sexual symptoms more distressing than do females.
Conclusions
While most survivors appear to be doing well in this important life domain, some young adult survivors report sexual concerns. While female survivors may report more sexual symptoms than male survivors, males may experience more distress associated with sexual difficulties. Better specified measures of sexual function, behavior and outcomes are needed for this young adult population.
doi:10.1002/pon.1641
PMCID: PMC2888926  PMID: 19862693
Sexual functioning; cancer survivor; childhood cancer; quality of life; psychosocial; gender
7.  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
8.  Longitudinal patterns of psychological distress in adult survivors of childhood cancer 
British Journal of Cancer  2013;109(5):1373-1381.
Background:
This study investigated longitudinal patterns of psychological distress in adult survivors of childhood cancer.
Methods:
Participants included 4569 adult survivors in the Childhood Cancer Survivor Study Cohort (CCSS) who completed the Brief Symptom Inventory-18 on three occasions between 1994 and 2010. Longitudinal latent class analysis was used to identify discrete classes of psychological distress. Predictors of class membership were examined through logistic regression modelling with odds ratios (ORs) and 95% confidence intervals (CIs) reported.
Results:
Survivors were a median of 39 years of age and 30 years from diagnosis at the most recent follow-up. Most survivors reported few or no symptoms of distress over time, although subsets of survivors reported persistently elevated (depression: 8.9% anxiety: 4.8% somatisation: 7.2%) or significant increases in distress symptoms over the follow-up period (depression: 10.2% anxiety: 11.8% somatisation: 13.0%). Increasing distress symptoms were predicted by survivor perception of worsening physical health over time (depression: OR=3.3; 95% CI=2.4–4.5; anxiety: OR=3.0; 95% CI=2.2–4.0; somatisation: OR=5.3; 95% CI=3.9–7.4). Persistent distress symptoms were also predicted by survivor perception of worsening physical health over time, as well as by worsening pain and ending analgesic use.
Conclusion:
Subgroups of adult survivors are at-risk for chronic distress or significant increases in distress decades following their original cancer diagnosis. Routine screening of psychological distress in adult survivors of childhood cancer is warranted, especially for survivors who experience physical health morbidities.
doi:10.1038/bjc.2013.428
PMCID: PMC3778287  PMID: 23880828
psychological distress; survivorship; childhood cancer
9.  Predictors of Marriage and Divorce in Adult Survivors of Childhood Cancers: A Report from the Childhood Cancer Survivor Study 
Background/Objective
Adult survivors of childhood cancer can have altered social functioning. We sought to identify factors that predict marriage and divorce outcomes in this growing population.
Methods
Retrospective cohort study of 8,928 ≥ five-year adult survivors of childhood malignancy and 2,879 random sibling controls participating in the Childhood Cancer Survivor Study. Marital status, current health, psychological status, and neurocognitive functioning were determined from surveys and validated instruments.
Results
Survivors were more likely to be never-married than siblings (relative risk (RR) = 1.21; 95% confidence interval (CI) 1.15–1.26) and the U.S. population (RR=1.25; 95% CI= 1.21 – 1.29), after adjusting for age, gender, and race. Patients with central nervous system (CNS) tumors were at greatest risk for not marrying (RR=1.50; 95% CI= 1.41–1.59). Married survivors divorced at frequencies similar to controls. In multivariable regression analysis, non-marriage was most associated with cranial radiation (RR=1.15; 95% CI=1.02–1.31 for >2400 centigray). In analysis of neurobehavioral functioning, non-marriage was associated with worse task efficiency (RR=1.27; 95% CI=1.20–1.35), but not with emotional distress, or problems with emotional regulation, memory, or organization. Physical conditions predictive of non-marriage included short stature (RR=1.27; 95% CI=1.20–1.34) and poor physical function (RR=1.08; 95% CI=1.00–1.18). Structural equation modeling suggested that cranial radiation influenced marriage status through short stature, cognitive problems, and poor physical function.
Conclusions
Childhood cancer survivors married at lower frequencies compared to peers. Patients with CNS tumors, cranial radiation, impaired processing efficiency, and short stature were more likely to never marry. Divorce patterns in survivors were similar to peers.
doi:10.1158/1055-9965.EPI-08-0959
PMCID: PMC2768276  PMID: 19815636
Survivorship; Cancer; Predictors; Marriage; Divorce
10.  Physical and Mental Health Status and Health Behaviors of Childhood Cancer Survivors: Findings from the 2009 BRFSS Survey 
Pediatric blood & cancer  2011;58(6):964-970.
Background
The growing number of childhood cancer survivors makes examination of their current physical and mental health status and health behaviors an important concern. Much of what is known about the long-term outcomes of childhood cancer survivors comes from the Childhood Cancer Cohort Study (CCSS) which uses sibling controls.
Procedure
Using data from the 2009 Behavioral Risk Factor Surveillance System survey, 651 childhood cancer survivors and 142,932 non-cancer peer controls were identified. The two groups were compared on a variety of physical and mental health status and health behavior variables using ANCOVA and binary logistic regression.
Results
While controlling for differences in age, sex, and minority status, survivors significantly (p ≤0.001) had poorer socioeconomic outcomes, more comorbid conditions, lower life satisfaction, less social and emotional support, poorer general health, and reported more days per month of poor physical and mental health than non-cancer individuals. Survivors were more likely to report being a current smoker (odds ratio [OR] = 2.33; 95% confidence interval [CI], 1.98 to 2.73; p<0.001); tested for human immunodeficiency virus (HIV) (OR = 1.79; 95% CI, 1.52 to 2.11; p<0.001); and that at least one HIV situation applied to them (OR = 2.06; 95% CI, 1.55 to 2.74; p<0.001). No significant differences were found between groups in regards alcohol use and diet.
Conclusions
Results support and extend previous findings reported by the CCSS. New findings regarding survivors’ increased likelihood to engage in risky behaviors proposes new directions for future research.
doi:10.1002/pbc.23359
PMCID: PMC3332525  PMID: 22012636
childhood cancer survivors; physical health; mental health; health behaviors
11.  Twenty Years of Follow-Up of Survivors of Childhood Osteosarcoma: A Report from the Childhood Cancer Survivor Study (CCSS) 
Cancer  2010;117(3):625-634.
BACKGROUND
Osteosarcoma survivors have received significant chemotherapy and have undergone substantial surgeries. Their very long term outcomes (20 year) are reported here.
METHODS
We assessed the long-term outcomes of 733 five-year survivors of childhood osteosarcoma diagnosed from 1970-1986 to provide a comprehensive evaluation of medical and psychosocial outcomes for survivors enrolled on the Childhood Cancer Survivor Study (CCSS). Outcomes evaluated included overall survival, second malignant neoplasms (SMNs), recurrent osteosarcoma, chronic health conditions, health status(general and mental health and functional limitations), and psycho-social factors. Outcomes of osteosarcoma survivors were compared to general-population statistics, other CCSS survivors, and CCSS siblings.
RESULTS
Survivors had a mean follow-up of 21.6 years. The overall survival of children diagnosed with osteosarcoma who survived 5-years at 20 years from original diagnosis was 88.6% (95% CI: 86.6-90.5%). The cumulative incidence of SMNs at 25 years was 5.4% with a Standardized Incidence Ratio of 4.79 (95% CI: 3.54-6.33, p<0.01). Overall, 86.9% of osteosarcoma survivors experienced at least one chronic medical condition and over 50% experienced two or more conditions. Compared to survivors of other cancers, osteosarcoma survivors did not differ in their reported general health status (OR=0.9, 95% CI: 0.7-1.2), but were more likely to report an adverse health status in at least one domain (OR=1.9, 95% CI: 1.6-2.2) with activity limitations (29.1%) being the most common.
CONCLUSIONS
Childhood osteosarcoma survivors in this cohort did relatively well considering their extensive treatment; but are at risk to experience chronic medical conditions and adverse health status. Survivors warrant life-long follow-up.
doi:10.1002/cncr.25446
PMCID: PMC3025070  PMID: 20922787
Osteosarcoma; childhood cancer; survivorship; outcomes; bone sarcoma
12.  Psychoactive Medication Use and Neurocognitive Function in Adult Survivors of Childhood Cancer: A Report from the Childhood Cancer Survivor Study 
Pediatric blood & cancer  2012;60(3):486-493.
Background
Adult survivors of childhood cancer are at risk for long-term morbidities, which may be managed pharmacologically. Psychoactive medication treatment has been associated with adverse effects on specific neurocognitive processes in non-cancer populations, yet these associations have not been examined in adult survivors of childhood cancer.
Procedure
Outcomes were evaluated in 7,080 adult survivors from the Childhood Cancer Survivor Study using a validated self-report Neurocognitive Questionnaire. Multivariable logistic regression models were used to calculate odds ratios (OR) and 95% confidence intervals (CI) for neurocognitive impairment using demographic and treatment factors and survivors’ report of prescription medication use.
Results
Controlling for cranial radiation, pain, psychological distress, and stroke/seizure, use of antidepressant medications was associated with impaired task efficiency (OR=1.80, 95% CI=1.47–2.21), organization (OR=1.83, 95% CI=1.48–2.25), memory (OR=1.53, 95% CI=1.27–1.84) and emotional regulation (OR=2.06, 95% CI=1.70–2.51). Neuroleptics and stimulants were associated with impaired task efficiency (OR=2.46, 95% CI=1.29–4.69; OR=2.82, 95% CI=1.61–4.93, respectively) and memory (OR=2.08, 95% CI=1.13–3.82; OR=2.69, 95% CI=1.59–4.54, respectively). Anticonvulsants were associated with impaired task efficiency, memory and emotional regulation, although survivors who use these medications may be at risk for neurocognitive impairment on the basis of seizure disorder and/or underlying tumor location (CNS).
Conclusions
These findings suggest that specific psychoactive medications and/or mental health conditions may be associated with neurocognitive function in adult survivors of childhood cancer. The extent to which these associations are causal or indicative of underlying neurological impairment for which the medications are prescribed remains to be ascertained.
doi:10.1002/pbc.24255
PMCID: PMC3494805  PMID: 22848025
psychoactive medication; neurocognition; survivorship
13.  Suicide Ideation and Associated Mortality in Adult Survivors of Childhood Cancer 
Cancer  2013;120(2):271-277.
Background
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.
Methods
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.
Results
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).
Conclusion
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.
doi:10.1002/cncr.28385
PMCID: PMC3947253  PMID: 24122148
childhood cancer; survivorship; suicide; mortality; late effects
14.  Antioxidant enzyme polymorphisms and neuropsychological outcomes in medulloblastoma survivors: a report from the Childhood Cancer Survivor Study 
Neuro-Oncology  2012;14(8):1018-1025.
Psychological or neurocognitive impairment is often seen in medulloblastoma survivors after craniospinal radiation; however, significant variability in outcomes exists. This study investigated the role of antioxidant enzyme polymorphisms in moderating this outcome and hypothesized that patients who had polymorphisms associated with lower antioxidant enzyme function would have a higher occurrence of impairment. From the Childhood Cancer Survivor Study (CCSS) cohort, 109 medulloblastoma survivors and 143 siblings were identified who completed the CCSS Neurocognitive Questionnaire (NCQ) and the Brief Symptom Inventory-18 (BSI-18) and who provided buccal DNA samples. Real-time polymerase chain reaction (PCR) allelic discrimination was used for SOD2 (rs4880), GPX1 (rs1050450), and GSTP1 (rs1695 and rs1138272) genotyping and PCR for GSTM1 and GSTT1 gene deletions. Outcomes on NCQ and BSI-18 subscale scores were examined in association with genotypes and clinical factors, including age at diagnosis, sex, and radiation dose, using univariate and multivariate analysis of variance. Patients <7 years of age at diagnosis displayed more problems with task efficiency (P < .001) and fewer problems with somatic complaints (P = .004) than did patients ≥7 years of age. Female patients reported more organization problems than did male patients (P = .02). Patients with homozygous GSTM1 gene deletion reported higher anxiety (mean null genotype = 47.3 ± 9.2, non-null = 43.9 ± 7.8; P = .04), more depression (null = 51.0 ± 9.8, non-null = 47.0 ± 9.4; P = .03), and more global distress (null = 50.2 ± 9.7, non-null = 45.2 ± 9.9; P = .01). All associations for the GSTM1 polymorphism remained statistically significant in a multivariate model controlling for age, sex, and radiation dose. Homozygous GSTM1 gene deletion was consistently associated with greater psychological distress in medulloblastoma survivors across multiple domains, suggesting that this genotype may predispose patients for increased emotional late effects.
doi:10.1093/neuonc/nos123
PMCID: PMC3408256  PMID: 22661588
Childhood Cancer Survivor Study; glutathione S-transferase polymorphisms; medulloblastoma; neuropsychological impairment; radiation therapy
15.  Mental and Physical Health-Related Quality of Life among US Cancer Survivors: Population Estimates from the 2010 National Health Interview Survey 
Background
Despite extensive data on health-related quality of life (HRQOL) among cancer survivors, we do not yet have an estimate of the percent of survivors with poor mental and physical HRQOL compared to population norms. HRQOL population means for adult-onset cancer survivors of all ages and across the survivorship trajectory also have not been published.
Methods
Survivors (n=1,822) and adults with no cancer history (n=24,804) were identified from the 2010 National Health Interview Survey. The PROMIS® Global Health Scale was used to assess HRQOL. Poor HRQOL was defined as one standard deviation or more below the PROMIS population norm.
Results
Poor physical and mental HRQOL were reported by 24.5% and 10.1% of survivors, respectively, compared to 10.2% and 5.9% of adults without cancer (both p<.0001). This represents a population of approximately 3.3 million and 1.4 million US survivors with poor physical and mental HRQOL. Adjusted mean mental and physical HRQOL scores were similar for breast, prostate, and melanoma survivors compared to adults without cancer. Survivors of cervical, colorectal, hematologic, short-survival, and other cancers had worse physical HRQOL; cervical and short-survival cancer survivors reported worse mental HRQOL.
Conclusion
These data elucidate the burden of cancer diagnosis and treatment among US survivors and can be used to monitor the impact of national efforts to improve survivorship care and outcomes.
Impact
We present novel data on the number of US survivors with poor HRQOL. Interventions for high-risk groups that can be easily implemented are needed to improve survivor health at a population level.
doi:10.1158/1055-9965.EPI-12-0740
PMCID: PMC3645867  PMID: 23112268
cancer; survivors; health-related quality of life; pain; fatigue
16.  Neurocognitive functioning and health-related behaviors in adult survivors of childhood cancer: A report from the Childhood Cancer Survivor Study 
SUMMARY
Background
Positive health-related behaviors are essential for the future wellbeing of childhood cancer survivors, though relatively few maintain healthy behaviors into adulthood.
Methods
Neurocognitive function and emotional distress were examined in 6,440 adult survivors from the Childhood Cancer Survivor Study, and used to predict rates of expected health-related behaviors. Covariates included cancer diagnosis, age, sex, body mass index, insurance status, income, and antidepressant medication use, and multivariable models were constructed adjusting for these factors.
Findings
In multivariable regression models, survivors with neurocognitive problems in task efficiency (RR=0.77, 95% CI=0.72–0.84) were less likely to meet the Centers for Disease Control guidelines for weekly physical activity. Survivors with neurocognitive impairment were more likely to engage in general survivor care (RR=1.20, 95% CI=1.10–1.30), and less likely to engage in dental care (RR=0.92, 95% CI=0.88–0.97). Obese survivors were less likely to report receiving a bone density exam (RR=0.67, 95% CI=0.54–0.82), a mammogram (RR=0.71, 95% CI=0.57–0.89), and a skin exam (RR=0.78, 95% CI = 0.68–0.89). Survivors reporting somatization, i.e. vague physical symptoms associated with anxiety, were more likely to report receiving echocardiograms (RR=1.53, 95% CI = 1.32–1.77).
Interpretation
These results support the link between neurocognitive and emotional problems and health-related behaviors in adult survivors of childhood cancer. Monitoring neurocognitive and emotional outcomes may help to identify survivors at risk for poor adherence to prescribed health behaviors and health screening exams.
doi:10.1016/j.ejca.2011.03.001
PMCID: PMC3103640  PMID: 21458986
17.  Region-specific radiotherapy and neuropsychological outcomes in adult survivors of childhood CNS malignancies 
Neuro-Oncology  2010;12(11):1173-1186.
Childhood cancer survivors exposed to CNS irradiation are at increased risk for neurocognitive deficits; however, limited data exist linking outcomes with region-specific exposure to CNS irradiation. We report associations between region-specific radiation dose and self-reported neurocognitive and health-related quality of life (HRQOL) outcomes in 818 adult survivors of childhood central nervous system (CNS) malignancies from the Childhood Cancer Survivor Study. Survivors were compared with a sibling group and national normative samples to calculate standardized scores. Cumulative radiation dose was calculated for 4 specific brain regions. Logistic regression was used to estimate the association between radiation dose to specific brain regions and outcome measures of functional impairment adjusted for clinical and demographic factors, including sex and age at diagnosis. High radiation dose levels to temporal regions were associated with a higher risk for memory impairment (radiation doses ≥30 to <50 Gy: OR, 1.95; 95% CI, 1.01–3.78; dose ≥50 Gy: OR, 2.34; 95% CI, 1.25–4.39) compared with those with no radiation exposure. No such association was seen with radiation exposure to other regions. Exposure to temporal regions was associated with more social and general health problems, whereas exposure to frontal regions was associated with general health problems and physical performance limitations. Adult survivors of childhood CNS malignancies report higher rates of neuropsychological and HRQOL outcomes, which vary as a function of dose to specific neuroanatomical regions. Survivors with a history of radiation exposure to temporal brain regions are at increased risk for impairment in memory and social functioning.
doi:10.1093/neuonc/noq104
PMCID: PMC3098024  PMID: 20716593
CNS malignancies; Childhood Cancer Survivor Study (CCSS); health-related quality of life; neuropsychological functioning; radiation therapy
18.  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
19.  Psychological Outcomes and Health Beliefs in Adolescent and Young Adult Survivors of Childhood Cancer and Controls 
Journal of Clinical Oncology  2010;28(12):2002-2007.
Purpose
The purpose of this study was to compare adolescent and young adult (AYA) pediatric cancer survivors and peers without a history of serious illness on psychological distress, health-related quality of life (HRQOL), health beliefs; examine age at diagnosis and cancer treatment intensity on these outcomes; and examine relationships between number of health problems and the outcomes.
Patients and Methods
AYA cancer survivors (n = 167) and controls (n = 170), recruited during visits to a cancer survivorship clinic and primary care, completed self-report questionnaires of distress, health problems, and health beliefs. For survivors, providers rated treatment intensity and health problems.
Results
There were no statistically significant differences between survivors and controls in psychological distress or HRQOL. Cancer survivors had less positive health beliefs. Survivors diagnosed as adolescents had significantly greater psychological distress and fewer positive health beliefs than those diagnosed earlier. Survivors with the highest level of treatment intensity had greater anxiety and fewer positive health beliefs than those with less intense treatments. Provider report of current health problems related to survivors' beliefs and mental HRQOL only, whereas patient report of health problems correlated significantly with most psychosocial outcomes and beliefs.
Conclusion
AYA cancer survivors did not differ from peers in psychological adjustment but did endorse less adaptive health beliefs. Survivors diagnosed during adolescence and who had more intensive cancer treatments evidenced poorer psychosocial outcomes. Beliefs about health may be identified and targeted for intervention to improve quality of life, particularly when patient perceptions of current health problems are considered.
doi:10.1200/JCO.2009.25.9564
PMCID: PMC2860405  PMID: 20231679
20.  Predictors of Independent Living Status in Adult Survivors of Childhood Cancer: A Report from the Childhood Cancer Survivor Study 
Pediatric blood & cancer  2011;57(7):1197-1203.
Background
Adult survivors of childhood cancer and their siblings are compared on one of the most salient developmental milestones of adulthood, the ability to live independently.
Procedure
Adult survivors of childhood cancers (n=6,047) and siblings (n=2,326), all 25 years of age and older, completed a long-term follow-up questionnaire that assessed adaptive, neurocognitive, and psychological functioning, as well as demographic and health status. Multivariable logistic regression analyses and structural equation modeling (SEM) were used to identify predictors of independent living.
Results
Compared to siblings (n=206, 8.7%), survivors (n=1063; 17.7%) were more than twice as likely to live dependently (OR 2.07; 95% confidence interval [CI] 1.77–2.42). Survivors diagnosed with CNS tumors (OR 0.13, 95% CI 0.10–0.18) or leukemia (OR 0.29, 95% CI 0.23–0.27) were significantly less likely to live independently compared to those diagnosed with Hodgkin Lymphoma. Other risk factors for reduced independent living included cranial radiation (≤24Gy OR 0.76, 95% CI 0.62–0.93; >24Gy OR 0.31, 95% CI 0.24–0.41), use of neuroleptic, anticonvulsant, or psychostimulant medication (OR 0.32, 95% CI 0.24–0.43), attention and processing speed problems (OR 0.58, 95% CI 0.47–0.71), poor physical functioning (OR 0.49, 95% CI 0.38–0.63), depression (OR 0.68, 95% CI 0.53–0.88), and racial/ethnic minority status (OR 0.39, 95% CI 0.30–0.51). SEM demonstrated that neurocognitive functioning had both direct effects on independent living status, and indirect effects through use of neurologically-directed medication, depression, and poor mental health.
Conclusion
Adult survivors of childhood cancer who experience neurocognitive, psychological or physical late effects are less likely to live independently as adults.
doi:10.1002/pbc.22982
PMCID: PMC3139702  PMID: 21294244
Pediatric oncology; psychosocial; late effects; outcomes research
21.  Adolescent behavior and adult health status in childhood cancer survivors 
Introduction
This study examined the longitudinal association between adolescent psychological problems following cancer treatment and obesity, limited exercise, smoking, and excess sun exposure during adulthood in the Childhood Cancer Survivor Study cohort.
Methods
Participants included 1,652 adolescent survivors of childhood cancer and 406 siblings of cancer survivors, initially evaluated at 12-17 years of age and ≥ 5 years post-diagnosis. A follow-up survey of these participants was conducted roughly 7 years later and included assessment of health status and health behaviors. Logistic regression models were used to assess the association between adolescent psychological problems and adult health behavior outcomes.
Results
During adolescence, survivors demonstrated higher rates of attention deficits, emotional problems, externalizing behavior and social withdrawal compared to sibling controls. Social withdrawal was associated with adult obesity (OR = 1.5, 95% CI = 1.1 - 2.1) and physical inactivity (OR = 1.7, 1.1 - 2.5). Use of stimulant medication during adolescence was also associated with adult obesity (OR = 1.9, 1.1 – 3.2), while antidepressant use was associated with physical inactivity (OR = 3.2, 1.2 – 8.2).
Discussion/Conclusions
Adolescent survivors of childhood cancer display higher rates of psychological problems compared to siblings of cancer survivors. These psychological problems are associated with an increased risk for obesity and poor heath behavior in adulthood, which may increase future risk for chronic health conditions and secondary neoplasms.
Implications
In order to decrease risk of future health problems, adolescent survivors of childhood cancer should be routinely screened and treated for psychological problems following cancer therapy.
doi:10.1007/s11764-010-0123-0
PMCID: PMC3098531  PMID: 20383785
Adolescence; Cancer; Psychological problems; Obesity; Oncology; Childhood Cancer Survivor Study
22.  Suicide Ideation in Adult Survivors of Childhood Cancer: A Report From the Childhood Cancer Survivor Study 
Journal of Clinical Oncology  2009;28(4):655-661.
Purpose
To evaluate risk of suicide ideation (SI) after childhood cancer, prevalence of SI in a cohort of adult survivors of pediatric cancers was compared with prevalence in a sibling comparison group. The relationship of SI to cancer treatment and current health was examined, and the hypothesis that poor physical health is significantly associated with suicidality, after adjusting for depression, was specifically tested.
Methods
Nine thousand one hundred twenty-six adult survivors of childhood cancer and 2,968 siblings enrolled onto the Childhood Cancer Survivor Study completed a survey describing their demographics and medical and psychological functioning, including SI in the prior week.
Results
Of survivors, 7.8% reported SI compared with 4.6% of controls (odds ratio = 1.79; 95% CI, 1.4 to 2.4). Suicidality was unrelated to age, age at diagnosis, sex, cancer therapy, recurrence, time since diagnosis, or second malignancy. SI was associated with primary CNS cancer diagnosis, depression, and poor health outcomes including chronic conditions, pain, and poor global health rating. A logistic regression analysis showed that poor current physical health was significantly associated with SI even after adjusting for cancer diagnosis and depression.
Conclusion
Adult survivors of childhood cancers are at increased risk for SI. Risk of SI is related to cancer diagnosis and post-treatment mental and physical health, even many years after completion of therapy. The association of suicidal symptoms with physical health problems is important because these may be treatable conditions for which survivors seek follow-up care and underscores the need for a multidisciplinary approach to survivor care.
doi:10.1200/JCO.2009.22.8635
PMCID: PMC2816000  PMID: 19841325
23.  Self-reported global function among adult survivors of childhood lower-extremity bone tumors 
Introduction
Adult survivors of childhood lower-extremity bone tumors may experience physical and psychosocial late effects that impact physical performance, global function and quality of life. The identification of survivors at greatest risk for poor outcomes will inform potential intervention targets.
Methods
Study participants were selected from the Childhood Cancer Survivor Study (CCSS), a multi-institutional study of childhood cancer survivors. Adult survivors (n=629) of either childhood onset osteosarcoma or Ewing’s sarcoma, with a primary tumor location in the lower-extremity were identified and contacted via mail to complete an additional questionnaire. Participants completed the Reintegration into Normal Living Index (RNL) to evaluate global function (maximum score of 22), daily function (maximum score of 16) and self perception (maximum score of 6).
Results
Survivors reported high levels of global function with an adjusted mean overall RNL index score of 20.6 (SE 0.14), mean daily function score of 15.0 (SD 0.10) and mean self perception score of 5.6 (SE 0.05). While female gender and increasing age were associated with lower RNL scores, the magnitude of difference is of questionable clinical significance. Global function was only moderately correlated with physical performance (r=0.56) and QOL (r=0.59).
Discussion
Based upon the RNL index, the vast majority of long-term survivors of childhood lower extremity bone tumors adapt well to their environment.
Implications for cancer survivors
While some long-term survivor of lower-extremity bone tumors may report measurable limitations in physical performance and quality of life, the majority do not report moderate or severe difficulties with social integration.
doi:10.1007/s11764-008-0073-y
PMCID: PMC2657188  PMID: 19030995
Bone sarcoma; Global function; Physical performance; Quality of life; Childhood cancer survivor
24.  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
25.  Health-Related Quality of Life in Long-Term Survivors of Relapsed Childhood Acute Lymphoblastic Leukemia 
PLoS ONE  2012;7(5):e38015.
Background
Relapses occur in about 20% of children with acute lymphoblastic leukemia (ALL). Approximately one-third of these children can be cured. Their risk for late effects is high because of intensified treatment, but their health-related quality of life (HRQOL) was largely unmeasured. Our aim was to compare HRQOL of ALL survivors with the general population, and of relapsed with non-relapsed ALL survivors.
Methodology/Principal Findings
As part of the Swiss Childhood Cancer Survivor Study (SCCSS) we sent a questionnaire to all ALL survivors in Switzerland who had been diagnosed between 1976–2003 at age <16 years, survived ≥5 years, and were currently aged ≥16 years. HRQOL was assessed with the Short Form-36 (SF-36), which measures four aspects of physical health and four aspects of mental health. A score of 50 corresponded to the mean of a healthy reference population. We analyzed data from 457 ALL survivors (response: 79%). Sixty-one survivors had suffered a relapse. Compared to the general population, ALL survivors reported similar or higher HRQOL scores on all scales. Survivors with a relapse scored lower in general health perceptions (51.6) compared to those without (55.8;p=0.005), but after adjusting for self-reported late effects, this difference disappeared.
Conclusion/Significance
Compared to population norms, ALL survivors reported good HRQOL, even after a relapse. However, relapsed ALL survivors reported poorer general health than non-relapsed. Therefore, we encourage specialists to screen for poor general health in survivors after a relapse and, when appropriate, specifically seek and treat underlying late effects. This will help to improve patients’ HRQOL.
doi:10.1371/journal.pone.0038015
PMCID: PMC3360640  PMID: 22662262

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