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1.  Psychological Status in Childhood Cancer Survivors: A Report From the Childhood Cancer Survivor Study 
Journal of Clinical Oncology  2009;27(14):2396-2404.
Psychological quality of life (QOL), health-related QOL (HRQOL), and life satisfaction outcomes and their associated risk factors are reviewed for the large cohort of survivors and siblings in the Childhood Cancer Survivor Study (CCSS). This review includes previously published manuscripts that used CCSS data focused on psychological outcome measures, including the Brief Symptom Inventory (BSI-18), the Medical Outcomes Survey Short Form-36 (SF-36), the Cantril Ladder of Life, and other self-report questionnaires. Comparisons and contrasts are made between siblings and survivors, and to normative data when available, in light of demographic/health information and abstracted data from the medical record. These studies demonstrate that a significant proportion of survivors report more symptoms of global distress and poorer physical, but not emotional, domains of HRQOL. Other than brain tumor survivors, most survivors report both good present and expected future life satisfaction. Risk factors for psychological distress and poor HRQOL are female sex, lower educational attainment, unmarried status, annual household income less than $20,000, unemployment, lack of health insurance, presence of a major medical condition, and treatment with cranial radiation and/or surgery. Cranial irradiation impacted neurocognitive outcomes, especially in brain tumor survivors. Psychological distress also predicted poor health behaviors, including smoking, alcohol use, fatigue, and altered sleep. Psychological distress and pain predicted use of complementary and alternative medicine. Overall, most survivors are psychologically healthy and report satisfaction with their lives. However, certain groups of childhood cancer survivors are at high risk for psychological distress, neurocognitive dysfunction, and poor HRQOL, especially in physical domains. These findings suggest targeting interventions for groups at highest risk for adverse outcomes and examining the positive growth that remains despite the trauma of childhood cancer.
doi:10.1200/JCO.2008.21.1433
PMCID: PMC2677925  PMID: 19255309
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.  Cancer Prevention and Screening Practices of Siblings of Childhood Cancer Survivors: A Report from the Childhood Cancer Survivor Study 
Objective
To compare the skin and breast/cervical cancer prevention/screening practices of adult siblings of childhood cancer survivors with controls and to identify modifying factors for these practices.
Methods
Cross-sectional, self-report data from 2,588 adult siblings of 5+ year survivors of childhood cancer were analyzed to assess cancer prevention/screening practices. Two age, sex and race/ethnicity-matched samples (n=5,915 and n=37,789) of the Behavioral Risk Factor Surveillance System participants served as the comparison populations. Sociodemographic and cancer-related data were explored as modifying factors for sibling cancer prevention/screening practices through multivariable logistic regression.
Results
Compared to controls, siblings were more likely to practice skin cancer prevention behaviors: use of protective clothing (OR 2.85, 95% 2.39-3.39), use of shade (OR 2. 11, 95% 1.88-2.36), use of sunscreen (OR 1.27, 95% 1.14-1.40), and wearing a hat (OR 1.77, 95% 1.58-1.98). No differences were noted for breast/cervical cancer screening including mammography and Pap testing. Having less than a high school education and lack of health insurance were associated with diminished cancer prevention/screening behaviors. Survivor diagnosis, treatment intensity, adverse health, chronic health conditions, and second cancers were not associated with sibling cancer prevention/screening behaviors.
Conclusions
Siblings of cancer survivors report greater skin cancer prevention practices when compared with controls; however, no differences were noted for breast/cervical cancer screening practices. Access to care and lack of education may be associated with decreased cancer prevention/screening behaviors. Interventions are needed to address these barriers.
Impact
Research should be directed at understanding the impact of the cancer experience on sibling health behaviors.
doi:10.1158/1055-9965.EPI-11-1095
PMCID: PMC3392493  PMID: 22576363
Siblings; survivor; childhood cancer; prevention; screening
4.  Late-Occurring Neurologic Sequelae in Adult Survivors of Childhood Acute Lymphoblastic Leukemia: A Report From the Childhood Cancer Survivor Study 
Journal of Clinical Oncology  2009;28(2):324-331.
Purpose
Children with acute lymphoblastic leukemia (ALL) are often cured, but the therapies they receive may be neurotoxic. Little is known about the incidence and severity of late-occurring neurologic sequelae in ALL survivors. Data were analyzed to determine the incidence of adverse long-term neurologic outcomes and treatment-related risk factors.
Patients and Methods
We analyzed adverse neurologic outcomes that occurred after diagnosis in 4,151 adult survivors of childhood ALL who participated in the Childhood Cancer Survivor Study (CCSS), a retrospective cohort of 5-year survivors of childhood cancer diagnosed between 1970 and 1986. A randomly selected cohort of the survivors' siblings served as a comparison group. Self-reported auditory-vestibular-visual sensory deficits, focal neurologic dysfunction, seizures, and serious headaches were assessed.
Results
The median age at outcome assessment was 20.2 years for survivors. The median follow-up time to death or last survey since ALL diagnosis was 14.1 years. Of the survivors, 64.5% received cranial radiation and 94% received intrathecal chemotherapy. Compared with the sibling cohort, survivors were at elevated risk for late-onset auditory-vestibular-visual sensory deficits (rate ratio [RR], 1.8; 95% CI, 1.5 to 2.2), coordination problems (RR, 4.1; 95% CI, 3.1 to 5.3), motor problems (RR, 5.0; 95% CI, 3.8 to 6.7), seizures (RR, 4.6; 95% CI, 3.4 to 6.2), and headaches (RR, 1.6; 95% CI, 1.4 to 1.7). In multivariable analysis, relapse was the most influential factor that increased risk of late neurologic complications.
Conclusion
Children treated with regimens that include cranial radiation for ALL and those who suffer a relapse are at increased risk for late-onset neurologic sequelae.
doi:10.1200/JCO.2009.22.5060
PMCID: PMC2815720  PMID: 19917844
5.  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
6.  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
7.  Neurocognitive Functioning in Adult Survivors of Childhood Non-Central Nervous System Cancers 
Background
We sought to measure self-reported neurocognitive functioning among survivors of non-central nervous system (CNS) childhood cancers, overall and compared with a sibling cohort, and to identify factors associated with worse functioning.
Methods
In a retrospective cohort study, 5937 adult survivors of non-CNS cancers and 382 siblings completed a validated neuropsychological instrument with subscales in task efficiency, emotional regulation, organization, and memory. Scores were converted to T scores; scores in the worst 10% of siblings’ scores (ie, T score ≥63) were defined as impaired. Non-CNS cancer survivors and siblings were compared with multivariable linear regression and log-binomial regression. Among survivors, log-binomial models assessed the association of patient and treatment factors with neurocognitive dysfunction. All statistical tests were two-sided.
Results
Non-CNS cancer survivors had similar or slightly worse (<0.5 standard deviation) mean test scores for all four subscales than siblings. However, frequencies of impaired survivors were approximately 50% higher than siblings in task efficiency (13.0% of survivors vs 7.3% of siblings), memory (12.5% vs 7.6%), and emotional regulation (21.2% vs 14.4%). Impaired task efficiency was most often identified in patients with acute lymphoblastic leukemia who received cranial radiation therapy (18.1% with impairment), myeloid leukemia who received cranial radiation therapy (21.2%), and non-Hodgkin lymphoma (13.9%). In adjusted analysis, diagnosis age of younger than 6 years, female sex, cranial radiation therapy, and hearing impairment were associated with impairment.
Conclusion
A statistically and clinically significantly higher percentage of self-reported neurocognitive impairment was found among survivors of non-CNS cancers than among siblings.
doi:10.1093/jnci/djq156
PMCID: PMC2886093  PMID: 20458059
8.  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
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.  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
11.  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
12.  Pain in Long-Term Adult Survivors of Childhood Cancers and Their Siblings: A Report from the Childhood Cancer Survivor Study 
Pain  2011;152(11):2616-2624.
Little is known about pain among long-term adult survivors of childhood cancers. The study investigated pain prevalence in this population compared with sibling controls and examined pain-related risk factors. Three self-reported pain outcomes including pain conditions, prescription analgesics used, and pain attributed to cancer and treatment were assessed among 10,397 cancer survivors and 3,034 sibling controls from the Childhood Cancer Survivor Study (CCSS). Pain conditions (pain/abnormal sensation, migraines, and other headaches) were reported by 12.3%, 15.5%, and 20.5% of survivors respectively; 16.7% of survivors reported use of prescription analgesics, and 21% attributed pain to cancer and treatment. Risks of reporting pain conditions and using prescription analgesics were higher among survivors than siblings adjusting for sociodemographic factors. Younger age at diagnosis and a history of non-Hodgkin lymphoma, Wilms tumor, or neuroblastoma (compared to leukemia) were associated with greater risk of reporting pain conditions. A history of bone cancer or soft tissue sarcoma (compared to leukemia) was associated with greater risks of using prescription analgesics and cancer-related pain attribution. Non-brain directed scatter irradiation was associated with elevated risk for migraines and cancer-related pain attribution. Female gender and lower educational attainment were associated with increased reports of all three pain outcomes; minority status, unemployment, and being single were associated with greater risks for reporting pain conditions. These findings contribute to the understanding of pain and associated risk factors among adult survivors of childhood cancer and suggest areas of focus for pain intervention.
doi:10.1016/j.pain.2011.08.006
PMCID: PMC3304496  PMID: 21907493
Long-term adult survivors of childhood cancer; Self-reported pain; Pain attribution; Risk factors
13.  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
14.  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
15.  Risk of Thyroid Dysfunction and Subsequent Thyroid Cancer Among Survivors of Acute Lymphoblastic Leukemia: A Report from the Childhood Cancer Survivor Study 
Pediatric blood & cancer  2009;53(3):432-437.
Background
To determine the risk of thyroid dysfunction and subsequent thyroid cancer among childhood acute lymphoblastic leukemia (ALL) survivors.
Procedure
Rates of self-reported thyroid dysfunction and thyroid cancer were determined among 3,579 ALL survivors participating in the Childhood Cancer Survivor Study, a cohort of 5-year survivors of pediatric cancers diagnosed from 1970–1986, and compared with 3,846 siblings and population rates, respectively.
Results
The cumulative incidence of hypo- and hyperthyroidism among survivors 15 years following leukemia diagnosis was 1.6% (95% CI 1.1, 2.1) and 0.6% (95% CI 0.3, 1.1), respectively, both significantly increased compared with siblings. In multivariate analysis, survivors who received ≥20 Gy cranial radiotherapy plus any spinal radiotherapy had the highest risk of subsequent hypothyroidism (HR 8.3, 95% CI 3.3, 20.5) compared with those treated with chemotherapy alone. Craniospinal radiotherapy also was associated with an increased risk of subsequent hyperthyroidism (HR 6.1, 95% CI 1.1, 34.2) compared with chemotherapy alone, as well as an increased risk of subsequent thyroid cancers (SIR 30.3, 95% CI 14.5, 55.7) compared with population rates. In radiation dosimetry analysis, pituitary doses ≥20 Gy combined with thyroid doses ≥10 Gy were associated with hypothyroidism, whereas pituitary doses ≥20 Gy combined with thyroid doses ≥15 Gy were associated with hyperthyroidism.
Conclusions
The risk of thyroid dysfunction and thyroid cancer was increased among childhood ALL survivors treated with craniospinal radiotherapy. In these individuals, long-term surveillance is warranted as no obvious plateau in risk was seen, even after 25 years of follow-up.
doi:10.1002/pbc.22082
PMCID: PMC2713362  PMID: 19459201
late effects; leukemia; radiation; hypothyroidism; hyperthyroidism; thyroid cancer
16.  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
17.  Auditory Complications in Childhood Cancer Survivors: A Report from the Childhood Cancer Survivor Studya 
Pediatric blood & cancer  2011;57(1):126-134.
Background
Studies have found associations between cancer therapies and auditory complications, but data are limited on long-term outcomes and risks associated with multiple exposures.
Procedure
The Childhood Cancer Survivor Study is a retrospective cohort investigating health outcomes of long-term survivors (5+ years) diagnosed and treated between 1970 and 1986 compared to a randomly selected sibling cohort. Questionnaires were completed by 14,358 survivors of childhood cancer and 4,023 sibling controls. Analysis determined the first occurrence of four auditory conditions in two time periods: diagnosis to ≥ 5 years post diagnosis, and > 5 years post diagnosis. Multivariable analyses determined the relative risks (RR) and 95% confidence interval (CI) of auditory conditions by treatment exposure.
Results
Five or more years from cancer diagnosis, survivors were at increased risk of problems hearing sounds (RR=2.3; 95% CI: 1.8–2.8), tinnitus (RR=1.7; 95% CI: 1.4–2.1), hearing loss requiring an aid (RR=4.4; 95% CI: 2.8–6.9), and hearing loss in 1 or both ears not corrected by a hearing aid (RR=5.2; 95% CI: 2.8–9.5), when compared to siblings. Temporal lobe and posterior fossa radiation was associated with these outcomes in a dose-dependent fashion. Exposure to platinum compounds was associated with an increased risk of problems hearing sounds (RR=2.1; 95% CI: 1.3–3.2), tinnitus (RR=2.8; 95% CI: 1.9–4.2), and hearing loss requiring an aid (RR=4.1; 95% CI:2.5–6.7)
Conclusions
Childhood cancer survivors are at risk of developing auditory complications. Radiation and platinum compounds are determinants of this risk. Follow-up is needed to evaluate the impact of auditory conditions on quality of life.
doi:10.1002/pbc.23025
PMCID: PMC3091978  PMID: 21328523
late effects of therapy; radiation therapy
18.  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
19.  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
20.  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
21.  Fractures among long-term survivors of childhood cancer: A report from the Childhood Cancer Survivor Study 
Cancer  2012;118(23):5920-5928.
Background
Although reductions in bone mineral density are well-documented among children during treatment for cancer and among childhood cancer survivors, little is known about the long-term risk of fracture. The aim of this study was to ascertain the prevalence of and risk factors for fractures among individuals participating in the Childhood Cancer Survivor Study (CCSS).
Methods
Analyses included 7414 5+ year survivors of childhood cancer diagnosed between 1970-86 who completed the 2007 CCSS follow-up questionnaire and a comparison group of 2374 siblings. Generalized linear models stratified by sex were used to compare the prevalence of reported fractures between survivors and siblings.
Results
The median ages at follow-up among survivors and siblings were 36.2, (range: 21.2-58.8) and 38.1 years (range: 18.4-62.6), respectively with a median 22.7 years of follow-up after cancer diagnosis for survivors. Approximately 35% of survivors and 39% of siblings reported ≥1 fractures during their lifetime. The prevalence of fractures was lower among survivors than siblings, both in males (prevalence ratio=0.87, 95%CI=0.81-0.94, p<0.001) and females (prevalence ratio=0.94, 95%CI=0.86-1.04, p=0.22). In multivariable analyses, increasing age at follow-up, white race, methotrexate treatment and balance difficulties were associated with increased prevalence of fractures among female survivors (p=0.05). Among males, only smoking history and white race were associated with an increased prevalence of fracture (p<0.001).
Conclusions
Findings from this study indicate that the prevalence of fractures among adult survivors is not increased compared to that of siblings. Additional studies of bone health among aging female cancer survivors may be warranted.
doi:10.1002/cncr.27626
PMCID: PMC3439597  PMID: 22605509
22.  ALCOHOL CONSUMPTION PATTERNS AND RISK FACTORS AMONG CHILDHOOD CANCER SURVIVORS COMPARED TO SIBLINGS AND GENERAL POPULATION PEERS 
Addiction (Abingdon, England)  2008;103(7):1139-1148.
Aims
This study describes alcohol consumption among adult survivors of pediatric cancer compared to sibling controls and a national sample of healthy peers. Risk factors for heavy drinking among survivors are described.
Design, Setting and Participants
Cross-sectional data were utilized from the Childhood Cancer Survivor Study including adult survivors of pediatric cancer (N=10,398), and a sibling cohort (n=3,034). Comparison data were drawn from the National Alcohol Survey (n=4,774).
Measurement
Alcohol consumption, demographic, cancer diagnosis, treatment and psychosocial factors were measured.
Findings
Compared to peers, survivors were slightly less likely to be risky (ORadj=0.9; CI 0.8-1.0) and heavy drinkers (ORadj=0.8; CI 0.7-0.9) and more likely to be current drinkers. Compared to siblings, survivors were less likely to be current, risky and heavy drinkers. Risk factors for survivors’ heavy drinking included being age 18-21 (ORadj=2.0; 95% CI 1.5-2.6), male (ORadj=2.1; 95% CI 1.8-2.6), having high school education or less (ORadj=3.4; 95% CI 2.7-4.4), and drinking initiation before age 14 (ORadj=6.9; 95% CI 4.4-10.8). Among survivors, symptoms of depression, anxiety, or somatization, activity limitations and anxiety about cancer were associated with heavy drinking. Cognitively compromising treatment, brain tumors and older age at diagnosis were protective.
Conclusions
Adult survivors of childhood cancer show only a modest reduction in alcohol consumption compared to peers despite their more vulnerable health status. Distress and poorer health are associated with survivor heavy drinking. Screening for alcohol consumption should be instituted in long-term follow-up care and interventions among survivors and siblings should be established to reduce risk for early drinking.
doi:10.1111/j.1360-0443.2008.02242.x
PMCID: PMC2791534  PMID: 18554347
childhood cancer survivor; alcohol consumption; late-effects; risky drinking; long-term follow-up care
23.  Prevalence and Predictors of Posttraumatic Stress Disorder in Adult Survivors of Childhood Cancer: a report from the Childhood Cancer Survivor Study 
Pediatrics  2010;125(5):e1124-e1134.
Objective
Recent studies have found that a subset of young adult survivors of childhood cancer report posttraumatic stress symptoms in response to their diagnosis and treatment. However, it is unclear if these symptoms are associated with impairment in daily functions and/or significant distress, thereby resulting in a clinical disorder. Furthermore, it is unknown whether this disorder continues into very long-term survivorship, including the 3rd and 4th decades of life. This study hypothesized that very long-term survivors of childhood cancer would be more likely to report symptoms of posttraumatic stress disorder, with functional impairment and/or clinical distress, compared to a group of healthy siblings.
Patients and Methods
6,542 childhood cancer survivors over the age of 18 who were diagnosed between 1970 and 1986 and 368 siblings of cancer survivors completed a comprehensive demographic and health survey.
Results
589 survivors (9%) and 8 siblings (2%) reported functional impairment and/or clinical distress in addition to the set of symptoms consistent with a full diagnosis of Posttraumatic Stress Disorder (PTSD). Survivors had more than a four-fold risk of PTSD compared to siblings (OR=4.14, 95%CI: 2.08-8.25). Controlling for demographic and treatment variables, increased risk of PTSD was associated with educational level of high school or less (OR=1.51, 95% CI=1.16-1.98), being unmarried (OR=1.99, 95% CI=1.58-2.50), annual income less than $20,000 (OR=1.63, 95% CI=1.21-2.20), and being unemployed (OR=2.01, 95% CI=1.62-2.51). Intensive treatment was also associated with increased risk of full PTSD (OR=1.36, 95% CI 1.06 -1.74).
Conclusions
Posttraumatic stress disorder is reported significantly more often by childhood cancer survivors than by sibling controls. Although most survivors are apparently doing well, a subset report significant impairment that may warrant targeted intervention.
doi:10.1542/peds.2009-2308
PMCID: PMC3098501  PMID: 20435702
childhood cancer; young adult
24.  Behaviors Associated with Ultraviolet Radiation Exposure in a Cohort of Adult Survivors of Childhood and Adolescent Cancer. A Report from the Childhood Cancer Survivor Study1 
Cancer  2009;115(18 Suppl):4374-4384.
Background
Previous research from the Childhood Cancer Survivor Study (CCSS) has shown that risk of skin cancer is strongly associated with exposure to radiation therapy. The potential role of ultraviolet radiation exposure in survivors has not been described.
Participants Methods
The CCSS is a retrospective cohort study designed to investigate late effects among 5-year survivors of children and adolescents diagnosed with cancer between 1970–1986. Data regarding current sun protection behavior were collected on 9,298 survivors and 2,950 sibling controls. Median age at follow-up was 31 years (range: 17–54).
Results
In this cohort, childhood cancer survivors and siblings showed similar patterns of sunscreen use (67% vs. 66%). Survivors were significantly less likely to report having sunbathed in the previous year (none vs. any in previous year: RR=0.92, 95%CI=0.89–0.95) or use artificial tanning (none vs. any in previous year: RR=0.76, 95%CI=0.70–0.83). Compared to survivors without radiation therapy, survivors with radiation exposure showed increased use of sunscreen (RR=1.06, 95%CI=1.03–1.10), and less sunbathing (none vs. any in previous year; RR=0.89, 95%CI=0.86–0.92) or artificial tanning (none vs. any in previous year; RR=0.62, 95%CI=0.56–0.69). In adjusted multivariable analysis, statistically significant factors for regular sunscreen use in the past summer (vs. never/rarely) in the survivor population were being female, having lighter skin complexions, having previously been examined for skin cancer, and having skin that burned when in the sun unprotected.
Conclusions
Survivors of childhood cancer self-reported lower tanning practices than siblings. However, because of the potential increased risk of skin cancer from therapy-related exposures, future research should be directed at intervention studies to further reduce UV exposures.
doi:10.1002/cncr.24581
PMCID: PMC2778206  PMID: 19731349
Skin cancer; sun protection behaviors; survivor; radiation; siblings
25.  Perceived Positive Impact of Cancer Among Long-term Survivors of Childhood Cancer: a report from the Childhood Cancer Survivor Study 
Psycho-oncology  2011;21(6):630-639.
Background
Investigations examining psychosocial adjustment among childhood cancer survivors have focused primarily on negative effects and psychopathology. Emergent literature suggests the existence of positive impact or adjustment experienced after cancer, as well. The purpose of this study is to examine the distribution of Perceived Positive Impact (PPI) and its correlates in young adult survivors of childhood cancer.
Methods
6,425 survivors and 360 siblings completed a comprehensive health survey, inclusive of a modified version of the Posttraumatic Growth Inventory (PTGI) as a measure of PPI. Linear regression models were used to examine demographic, disease and treatment characteristics associated with PPI.
Results
Survivors were significantly more likely than siblings to report PPI. Endorsement of PPI was significantly greater among female and non-white survivors, and among survivors exposed to at least one intense therapy, a second malignancy or cancer recurrence. Survivors diagnosed at older ages and fewer years since diagnosis were more likely to report PPI. Income, education and marital/relationship status appeared to have varied relationships to PPI depending upon the subscale being evaluated.
Conclusions
The existence and variability of PPI in survivors in this study suggest that individual characteristics, inclusive of race, gender, cancer type, intensity of treatment, age at diagnosis and time since diagnosis, have unique and specific associations with different aspects of perceived positive outcomes of childhood cancer.
doi:10.1002/pon.1959
PMCID: PMC3697081  PMID: 21425388
Psychosocial; childhood cancer; trauma; event centrality; survivors

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