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1.  Correlates of continued smoking versus cessation among survivors of smoking-related cancers 
Psycho-oncology  2012;22(4):799-806.
Objective
We examined correlates of continued smoking versus cessation among a sample of survivors of smoking-related cancers who were actively smoking at the time of cancer diagnosis.
Methods
Participants with a history of smoking and a smoking-related cancer diagnosis (lung, oral, pharynx, larynx, esophagus, bladder, stomach, cervix, kidney, pancreas, acute myeloid leukemia) within the past four years were identified in the electronic medical record. We recruited 613 individuals to complete a mail-based survey and received 139 completed surveys (22.7% response rate). We focused on 105 participants who smoked at the time of diagnosis and dichotomized them to having either quit since diagnosis (48.6%; n=51) or continued smoking (51.4%; n=54). We assessed sociodemographics, type of cancer and treatment(s), and psychosocial factors (depressive symptoms, social support, hope, quality of life). We then conducted structured interviews with a subset of 21 survey respondents.
Results
Binary logistic regression indicated that, controlling for age, gender, ethnicity, marital status, and income, factors associated with continued smoking versus cessation included being diagnosed with other smoking-related cancers versus lung or head and neck cancer (OR=11.21, CI 2.85, 44.02) and having significant depressive symptoms (OR=1.25, CI 1.08, 1.45). Qualitative findings highlighted motivators for cessation (impact of being diagnosed with cancer, doctor advice to quit, social influences) and barriers to cessation (hopelessness, stress, addiction).
Conclusions
These findings highlight the need to address depressive symptoms among cancer survivors, particularly those continuing to smoke, and the importance of exploring messages cancer survivors are given regarding the need for cessation post cancer diagnosis.
doi:10.1002/pon.3077
PMCID: PMC3425712  PMID: 22488864
Smoking; smoking cessation; survivors; depression; cancer; oncology
2.  Risk of Salivary Gland Cancer Following Childhood Cancer: A Report From The Childhood Cancer Survivor Study 
Purpose
To evaluate effects of radiotherapy, chemotherapy, cigarette smoking and alcohol consumption on the risk of second primary salivary gland cancer (SGC) in the Childhood Cancer Survivor Study (CCSS).
Methods
Standardized incidence ratios (SIR) and excess absolute risks (EAR) of SGC in the CCSS were calculated using incidence rates from Surveillance, Epidemiology and End Results population-based cancer registries. Radiation dose to the salivary glands was estimated based on medical records. Poisson regression was used to assess risks with respect to radiation dose, chemotherapy, smoking and alcohol consumption.
Results
During the time period of the study, 23 cases of SGC were diagnosed among 14,135 childhood cancer survivors. The mean age at diagnosis of the first primary cancer was 8.3 years, and the mean age at SGC diagnosis was 24.8 years. The incidence of SGC was 39-fold higher in the cohort than in the general population (SIR=39.4; 95% CI: 25.4–7.8). The EAR was 9.8 per 100,000 person years. Risk increased linearly with radiation dose (excess relative risk=0.36 per gray; 95% CI: 0.06 to 2.5) and remained elevated after 20 years. There was no significant trend of increasing risk with increasing dose of chemotherapeutic agents, pack-years of cigarette smoking or alcohol intake.
Conclusion
While the cumulative incidence of SGC was low, childhood cancer survivors treated with radiation experienced significantly increased risk for at least two decades following exposure, and risk was positively associated with radiation dose. Results underscore the importance of long-term follow up of childhood cancer survivors for the development of new malignancies.
doi:10.1016/j.ijrobp.2012.06.006
PMCID: PMC3500417  PMID: 22836059
3.  Absolute Risk Prediction of Second Primary Thyroid Cancer Among 5-Year Survivors of Childhood Cancer 
Journal of Clinical Oncology  2012;31(1):119-127.
Purpose
We developed three absolute risk models for second primary thyroid cancer to assist with long-term clinical monitoring of childhood cancer survivors.
Patients and Methods
We used data from the Childhood Cancer Survivor Study (CCSS) and two nested case-control studies (Nordic CCSS; Late Effects Study Group). Model M1 included self-reported risk factors, model M2 added basic radiation and chemotherapy treatment information abstracted from medical records, and model M3 refined M2 by incorporating reconstructed radiation absorbed dose to the thyroid. All models were validated in an independent cohort of French childhood cancer survivors.
Results
M1 included birth year, initial cancer type, age at diagnosis, sex, and past thyroid nodule diagnosis. M2 added radiation (yes/no), radiation to the neck (yes/no), and alkylating agent (yes/no). Past thyroid nodule was consistently the strongest risk factor (M1 relative risk [RR], 10.8; M2 RR, 6.8; M3 RR, 8.2). In the validation cohort, 20-year absolute risk predictions for second primary thyroid cancer ranged from 0.04% to 7.4% for M2. Expected events agreed well with observed events for each model, indicating good calibration. All models had good discriminatory ability (M1 area under the receiver operating characteristics curve [AUC], 0.71; 95% CI, 0.64 to 0.77; M2 AUC, 0.80; 95% CI, 0.73 to 0.86; M3 AUC, 0.75; 95% CI, 0.69 to 0.82).
Conclusion
We developed and validated three absolute risk models for second primary thyroid cancer. Model M2, with basic prior treatment information, could be useful for monitoring thyroid cancer risk in childhood cancer survivors.
doi:10.1200/JCO.2012.41.8996
PMCID: PMC3530689  PMID: 23169509
4.  Increasing Rates of Breast Cancer and Cardiac Surveillance Among High Risk Survivors of Childhood Hodgkin Lymphoma Following a Mailed, One-Page Survivorship Care Plan 
Pediatric blood & cancer  2010;56(5):818-824.
Background
Hodgkin lymphoma (HL) survivors face substantially elevated risks of breast cancer and cardiovascular disease. They and their physicians are often unaware of these risks and surveillance recommendations.
Procedure
A prospective one-arm study was conducted among a random sample of 72 HL survivors, ages 27 to 55, participating in the Childhood Cancer Survivor Study (CCSS) who were at increased risk for breast cancer and/or cardiomyopathy and had not had a screening mammogram or echocardiogram, respectively, within the prior two years. A one-page survivorship care plan with recommendations for surveillance was mailed to participants. In addition, survivors’ primary physicians were contacted and provided patient-specific information and a web-based Virtual Information Center was made available for both survivors and physicians. Outcomes were assessed by telephone six months after the intervention.
Results
The survivor participation (62/72; 86%) and six-month retention (56/61; 92%) rates were high. Tension and anxiety, measured by the Profile of Mood States, did not increase following risk notification; 91% of survivors described their reactions to receiving the information in positive terms. At six months, 41% of survivors reported having completed the recommended mammogram; 20% reported having an echocardiogram (females 30%, males 10%). Only 29% of survivors visited the website. Nine physicians enrolled, and none used the study resources.
Conclusion
A mailed, personalized survivorship care plan was effective in communicating risk and increasing compliance with recommended medical surveillance. Internet- and telephone-based strategies to communicate risk were not utilized by survivors or physicians.
doi:10.1002/pbc.22696
PMCID: PMC3749088  PMID: 21370417
cancer survivor; late effects; survivorship care plan
5.  Radiation-Related Risk of Basal Cell Carcinoma: A Report From the Childhood Cancer Survivor Study 
Background
Basal cell carcinoma (BCC) is the most common malignancy in the United States. Ionizing radiation is an established risk factor in certain populations, including cancer survivors. We quantified the association between ionizing radiation dose and the risk of BCC in childhood cancer survivors.
Methods
Participants in the Childhood Cancer Survivor Study who reported a BCC (case subjects, n = 199) were matched on age and length of follow-up to three study participants who had not developed a BCC (control subjects, n = 597). The radiation-absorbed dose (in Gy) to the BCC location was calculated based on individual radiotherapy records using a custom-designed dosimetry program. Conditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for associations between demographic and treatment factors, therapeutic radiation dose, and surrogate markers of sun sensitivity (skin and hair color) and the risk of BCC. A linear dose–response model was fitted to evaluate the excess odds ratio per Gy of radiation dose.
Results
Among case subjects, 83% developed BCC between the ages of 20 and 39 years. Radiation therapy, either alone or in combination with chemotherapy, was associated with an increased risk of BCC compared with no chemotherapy or radiation. The odds ratio for subjects who received 35 Gy or more to the skin site vs no radiation therapy was 39.8 (95% CI = 8.6 to 185). Results were consistent with a linear dose–response relationship, with an excess odds ratio per Gy of 1.09 (95% CI = 0.49 to 2.64). No other treatment variables were statistically significantly associated with an increased risk of BCC.
Conclusions
Radiation doses to the skin of more than 1 Gy are associated with an increased risk of BCC.
doi:10.1093/jnci/djs298
PMCID: PMC3611815  PMID: 22835387
6.  Risky Health Behavior Among Adolescents in the Childhood Cancer Survivor Study Cohort 
Journal of Pediatric Psychology  2012;37(6):634-646.
Objective To report the prevalence and comparison of cancer-linked health behaviors and identify risk factors associated with unhealthy behavior among adolescent siblings and cancer survivors. Methods The Child Health and Illness Profile—Adolescent Edition (CHIP—AE) was completed by 307 survivors and 97 sibling controls 14–20 years of age. Results Risky behavior ranged from 0.7% to 35.8% for survivors and 1.0% to 41.2% for siblings. Comparisons of sexual behavior, tobacco, alcohol, or illicit drug use utilizing continuous data revealed no differences between groups. Categorically, survivors were less likely to report past smokeless tobacco use or current use of beer/wine or binge drinking (p-values range from .01 to .04). Survivors with better mental health were at lower risk for poor behavioral outcomes. Conclusions Adolescent survivors engage in risky health behaviors at rates generally equivalent to their siblings. Aggressive health education efforts should be directed toward this high-risk population.
doi:10.1093/jpepsy/jss046
PMCID: PMC3381714  PMID: 22427699
adolescents; childhood cancer; risky health behavior; survivors
7.  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
8.  Risk Factors for Smoking among Adolescent Survivors of Childhood Cancer: A Report from the Childhood Cancer Survivor Study 
Pediatric blood & cancer  2011;58(3):428-434.
Background
Few studies have examined risk factors for smoking among adolescent survivors of childhood cancer. The present study reports on the rate of smoking and identifies factors associated with smoking in a sample of adolescent survivors from the Childhood Cancer Survivor Study (CCSS).
Procedure
Participants included 307 adolescent survivors and 97 healthy siblings (ages 14-20) who completed a self-report survey of health, quality of life, and health behaviors.
Results
Smoking rates did not differ significantly between survivor and sibling groups (Ever Smokers: 28% vs. 33%, Recent Smokers: 10% vs. 9%, respectively). Ever smoking was significantly associated with peer smoking, smokers in the household, binging, suicidal behavior, and no history of CRT. There were significant interactions of peer smoking with gender and CRT for ever smoking and with binging for recent smoking. Recent smoking was more likely for survivors with other household smokers (RR=2.24, CI=1.21-4.16), past suicidality (RR=1.89, CI=1.00-3.56), and no CRT (RR=2.40, CI=1.12-5.17). Among survivors with few smoking friends, ever smoking was more likely for survivors with no CRT (RR=4.47, CI=1.43-13.9), and recent smoking was more likely among survivors who binged (RR=3.37, CI=1.17-9.71).
Conclusions
Despite the health risks associated with survivorship, nearly one in three adolescent survivors of childhood cancer has smoked. Exposure to other smokers, in particular, appears to increase the likelihood of smoking for some survivors. Providing smoking cessation programs targeted to family members, helping survivors choose nonsmoking friends, and teaching ways to resist smoking influences from peers may be important pathways for smoking prevention with adolescent survivors.
doi:10.1002/pbc.23139
PMCID: PMC3165077  PMID: 21618409
adolescents; childhood cancer; survivors; smoking
9.  Congenital Anomalies in the Children of Cancer Survivors: A Report From the Childhood Cancer Survivor Study 
Journal of Clinical Oncology  2011;30(3):239-245.
Purpose
Children with cancer receive mutagenic treatments, which raises concern about the potential transmissibility of germline damage to their offspring. This question has been inadequately studied to date because of a lack of detailed individual treatment exposure assessment such as gonadal radiation doses.
Methods
Within the Childhood Cancer Survivor Study, we performed a retrospective cohort analysis of validated cases of congenital anomalies among 4,699 children of 1,128 male and 1,627 female childhood cancer survivors. We quantified chemotherapy with alkylating agents and radiotherapy doses to the testes and ovaries and related these exposures to risk of congenital anomalies using logistic regression.
Results
One hundred twenty-nine children had at least one anomaly (prevalence = 2.7%). For children whose mothers were exposed to radiation or alkylating agents versus neither, the prevalence of anomalies was 3.0% versus 3.5% (P = .51); corresponding figures were 1.9% versus 1.7% (P = .79) for the children of male survivors. Neither ovarian radiation dose (mean, 1.19 Gy; odds ratio [OR] = 0.59; 95% CI, 0.20 to 1.75 for 2.50+ Gy) nor testicular radiation dose (mean, 0.48 Gy; OR = 1.01; 95% CI, 0.36 to 2.83 for 0.50+ Gy) was related to risk of congenital anomalies. Treatment with alkylating agents also was not significantly associated with anomalies in the children of male or female survivors.
Conclusion
Our findings offer strong evidence that the children of cancer survivors are not at significantly increased risk for congenital anomalies stemming from their parent's exposure to mutagenic cancer treatments. This information is important for counseling cancer survivors planning to have children.
doi:10.1200/JCO.2011.37.2938
PMCID: PMC3269950  PMID: 22162566
10.  Chemotherapy and thyroid cancer risk: A report from the Childhood Cancer Survivor Study 
Background
While ionizing radiation is an established environmental risk factor for thyroid cancer, the effect of chemotherapy drugs on thyroid cancer risk remains unclear. We evaluated the chemotherapy-related risk of thyroid cancer in childhood cancer survivors, and the possible joint effects of chemotherapy and radiotherapy.
Methods
The study included 12,547 five-year survivors of childhood cancer diagnosed during 1970 through 1986. Chemotherapy and radiotherapy information was obtained from medical records, and radiation dose was estimated to the thyroid gland. Cumulative incidence and relative risks were calculated using life-table methods and Poisson regression. Chemotherapy-related risks were evaluated separately by categories of radiation dose.
Results
Histologically confirmed thyroid cancer occurred in 119 patients. Thirty years after the first childhood cancer treatment, the cumulative incidence of thyroid cancer was 1.3% (95% CI, 1.0–1.6) for females and 0.6% (0.4–0.8) for males. Among patients with thyroid radiation doses ≤ 20 Gy, treatment with alkylating agents was associated with a significant 2.4-fold increased risk of thyroid cancer (95% CI, 1.3–4.5; P = 0.002). Chemotherapy risks decreased as radiation dose increased, with a significant decrease for patients treated with alkylating agents (P-trend = 0.03). No chemotherapy-related risk was evident for thyroid radiation doses >20 Gy.
Conclusions
Treatments with alkylating agents increased thyroid cancer risk, but only in the radiation dose range under 20 Gy, where cell sparing likely predominates over cell killing.
Impact
Our study adds to the evidence for chemotherapy agent-specific increased risks of thyroid cancer, which to date, were mainly thought to be related to prior radiotherapy.
doi:10.1158/1055-9965.EPI-11-0576
PMCID: PMC3253948  PMID: 22028399
Thyroid cancer; second cancer; chemotherapy; radiation risk; cohort study
11.  Impact of Insurance Type on Survivor-Focused and General Preventive Health Care Utilization in Adult Survivors of Childhood Cancer: The Childhood Cancer Survivor Study (CCSS) 
Cancer  2010;117(9):1966-1975.
Background
Lack of health insurance is a key barrier to accessing care for chronic conditions and cancer screening. We examined the influence of insurance type (private, public, none) on survivor-focused and general preventive health care in adult survivors of childhood cancer.
Methods
The Childhood Cancer Survivor Study is a retrospective cohort study of childhood cancer survivors diagnosed between 1970–1986. Among 8425 adult survivors, the Relative Risk (RR), 95% confidence interval (CI) of receiving survivor-focused and general preventive health care were estimated for uninsured (n=1390) and publicly insured (n=640), comparing to privately insured (n=6395).
Results
Uninsured survivors were less likely than privately insured to report a cancer-related (adjusted RR=0.83, 95% CI, 0.75–0.91) or a cancer center visit (adjusted RR=0.83, 95% CI, 0.71–0.98). Uninsured survivors had lower levels of utilization in all measures of care in comparison with privately insured. In contrast, publicly insured survivors were more likely to report a cancer-related (adjusted RR=1.22, 95% CI, 1.11–1.35) or a cancer center visit (adjusted RR=1.41, 95% CI, 1.18–1.70) than privately insured. While having a similar utilization level of general health examinations, publicly insured survivors were less likely to report Papanicolaou smear or dental examinations.
Conclusion
Among this large, socioeconomically diverse cohort, publicly insured survivors utilize survivor-focused health care at rates at least as high as survivors with private insurance. Uninsured survivors have lower utilization to both survivor-focused and general preventive health care.
doi:10.1002/cncr.25688
PMCID: PMC3433164  PMID: 21509774
Childhood Cancer Survivors; Health Insurance; Health Care Access; Survivorship; Delivery of Health Care
12.  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
14.  Cardiac outcomes in a cohort of adult survivors of childhood and adolescent cancer: retrospective analysis of the Childhood Cancer Survivor Study cohort 
Objectives To assess the incidence of and risks for congestive heart failure, myocardial infarction, pericardial disease, and valvular abnormalities among adult survivors of childhood and adolescent cancers.
Design Retrospective cohort study.
Setting 26 institutions that participated in the Childhood Cancer Survivor Study.
Participants 14 358 five year survivors of cancer diagnosed under the age of 21 with leukaemia, brain cancer, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, kidney cancer, neuroblastoma, soft tissue sarcoma, or bone cancer between 1970 and 1986. Comparison group included 3899 siblings of cancer survivors.
Main outcome measures Participants or their parents (in participants aged less than 18 years) completed a questionnaire collecting information on demographic characteristics, height, weight, health habits, medical conditions, and surgical procedures occurring since diagnosis. The main outcome measures were the incidence of and risk factors for congestive heart failure, myocardial infarction, pericardial disease, and valvular abnormalities in survivors of cancer compared with siblings.
Results Survivors of cancer were significantly more likely than siblings to report congestive heart failure (hazard ratio (HR) 5.9, 95% confidence interval 3.4 to 9.6; P<0.001), myocardial infarction (HR 5.0, 95% CI 2.3 to 10.4; P<0.001), pericardial disease (HR 6.3, 95% CI 3.3 to 11.9; P<0.001), or valvular abnormalities (HR 4.8, 95% CI 3.0 to 7.6; P<0.001). Exposure to 250 mg/m2 or more of anthracyclines increased the relative hazard of congestive heart failure, pericardial disease, and valvular abnormalities by two to five times compared with survivors who had not been exposed to anthracyclines. Cardiac radiation exposure of 1500 centigray or more increased the relative hazard of congestive heart failure, myocardial infarction, pericardial disease, and valvular abnormalities by twofold to sixfold compared to non-irradiated survivors. The cumulative incidence of adverse cardiac outcomes in cancer survivors continued to increase up to 30 years after diagnosis.
Conclusion Survivors of childhood and adolescent cancer are at substantial risk for cardiovascular disease. Healthcare professionals must be aware of these risks when caring for this growing population.
doi:10.1136/bmj.b4606
PMCID: PMC3266843  PMID: 19996459
15.  Risk of Second Primary Thyroid Cancer after Radiotherapy for a Childhood Cancer in a Large Cohort Study: An Update from the Childhood Cancer Survivor Study 
Radiation research  2010;174(6):741-752.
Previous studies have indicated that thyroid cancer risk after a first childhood malignancy is curvilinear with radiation dose, increasing at low to moderate doses and decreasing at high doses. Understanding factors that modify the radiation dose response over the entire therapeutic dose range is challenging and requires large numbers of subjects. We quantified the long-term risk of thyroid cancer associated with radiation treatment among 12,547 5-year survivors of a childhood cancer (leukemia, Hodgkin lymphoma and non-Hodgkin lymphoma, central nervous system cancer, soft tissue sarcoma, kidney cancer, bone cancer, neuroblastoma) diagnosed between 1970 and 1986 in the Childhood Cancer Survivor Study using the most current cohort follow-up to 2005. There were 119 subsequent pathologically confirmed thyroid cancer cases, and individual radiation doses to the thyroid gland were estimated for the entire cohort. This cohort study builds on the previous case-control study in this population (69 thyroid cancer cases with follow-up to 2000) by allowing the evaluation of both relative and absolute risks. Poisson regression analyses were used to calculate standardized incidence ratios (SIR), excess relative risks (ERR) and excess absolute risks (EAR) of thyroid cancer associated with radiation dose. Other factors such as sex, type of first cancer, attained age, age at exposure to radiation, time since exposure to radiation, and chemotherapy (yes/no) were assessed for their effect on the linear and exponential quadratic terms describing the dose–response relationship. Similar to the previous analysis, thyroid cancer risk increased linearly with radiation dose up to approximately 20 Gy, where the relative risk peaked at 14.6-fold (95% CI, 6.8–31.5). At thyroid radiation doses >20 Gy, a downturn in the dose–response relationship was observed. The ERR model that best fit the data was linear-exponential quadratic. We found that age at exposure modified the ERR linear dose term (higher radiation risk with younger age) (P < 0.001) and that sex (higher radiation risk among females) (P = 0.008) and time since exposure (higher radiation risk with longer time) (P < 0.001) modified the EAR linear dose term. None of these factors modified the exponential quadratic (high dose) term. Sex, age at exposure and time since exposure were found to be significant modifiers of the radiation-related risk of thyroid cancer and as such are important factors to account for in clinical follow-up and thyroid cancer risk estimation among childhood cancer survivors.
doi:10.1667/RR2240.1
PMCID: PMC3080023  PMID: 21128798
16.  Subsequent Neoplasms in 5-Year Survivors of Childhood Cancer: The Childhood Cancer Survivor Study 
Background
The occurrence of subsequent neoplasms has direct impact on the quantity and quality of life in cancer survivors. We have expanded our analysis of these events in the Childhood Cancer Survivor Study (CCSS) to better understand the occurrence of these events as the survivor population ages.
Methods
The incidence of and risk for subsequent neoplasms occurring 5 years or more after the childhood cancer diagnosis were determined among 14 359 5-year survivors in the CCSS who were treated from 1970 through 1986 and who were at a median age of 30 years (range = 5–56 years) for this analysis. At 30 years after childhood cancer diagnosis, we calculated cumulative incidence at 30 years of subsequent neoplasms and calculated standardized incidence ratios (SIRs), excess absolute risks (EARs) for invasive second malignant neoplasms, and relative risks for subsequent neoplasms by use of multivariable Poisson regression.
Results
Among 14 359 5-year survivors, 1402 subsequently developed 2703 neoplasms. Cumulative incidence at 30 years after the childhood cancer diagnosis was 20.5% (95% confidence interval [CI] = 19.1% to 21.8%) for all subsequent neoplasms, 7.9% (95% CI = 7.2% to 8.5%) for second malignant neoplasms (excluding nonmelanoma skin cancer), 9.1% (95% CI = 8.1% to 10.1%) for nonmelanoma skin cancer, and 3.1% (95% CI = 2.5% to 3.8%) for meningioma. Excess risk was evident for all primary diagnoses (EAR = 2.6 per 1000 person-years, 95% CI = 2.4 to 2.9 per 1000 person-years; SIR = 6.0, 95% CI = 5.5 to 6.4), with the highest being for Hodgkin lymphoma (SIR = 8.7, 95% CI = 7.7 to 9.8) and Ewing sarcoma (SIR = 8.5, 95% CI = 6.2 to 11.7). In the Poisson multivariable analysis, female sex, older age at diagnosis, earlier treatment era, diagnosis of Hodgkin lymphoma, and treatment with radiation therapy were associated with increased risk of subsequent neoplasm.
Conclusions
As childhood cancer survivors progress through adulthood, risk of subsequent neoplasms increases. Patients surviving Hodgkin lymphoma are at greatest risk. There is no evidence of risk reduction with increasing duration of follow-up.
doi:10.1093/jnci/djq238
PMCID: PMC2907408  PMID: 20634481
17.  Characteristics of Responders to a Request for a Buccal Cell Specimen Among Survivors of Childhood Cancer and Their Siblings 
Pediatric blood & cancer  2010;55(1):165-170.
Purpose
Analysis of biological samples in large cohort studies may provide insight into the mechanism of, and risk factors for, disease onset and progression.
Methods
This study describes the methods used to collect biological samples from a large multi-center cohort of childhood cancer survivors and siblings of childhood cancer survivors, and evaluates the predictors of a positive response among these individuals.
Results
Among survivors, female sex, white race/ethnicity, college graduation, never smoking, accessing the health care system in the past two years, and having a second malignant neoplasm were the strongest predictors of returning a sample. Among siblings, a similar demographic profile defined those likely to submit the requested sample.
Conclusion
To reduce selection bias and increase the value of these samples for future analysis, additional phone calls and reminders targeting non-responders are needed to improve response rates among those least likely to respond to a single mailed request.
doi:10.1002/pbc.22513
PMCID: PMC2909600  PMID: 20486182
neoplasm; pediatric; buccal mucosa; cohort study; DNA
18.  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
19.  A Model-Based Estimate of Cumulative Excess Mortality in Survivors of Childhood Cancer 
Annals of internal medicine  2010;152(7):409-W138.
Background
Although childhood cancer survival rates have dramatically increased, survivors continue to face elevated risks for life-threatening late-effects, including secondary cancers.
Objective
We sought to estimate the cumulative impact of disease- and treatment-related mortality risks on survivor life expectancy.
Design
State-transition model.
Setting
To simulate the lifetime clinical course of childhood cancer survivors, we estimated probabilities for the following competing risks from published studies: (1) risk of dying from original cancer diagnosis; (2) excess mortality from non-recurrence late-effects; and (3) background mortality.
Patients
Five-year childhood cancer survivors.
Measurements
Lifetime cause-specific mortality, life expectancy, cause-specific attributable proportion of overall mortality risk, conditional ten-year mortality probabilities.
Results
For a cohort of 15-year-old five-year survivors, diagnosed with cancer at age 10, the average lifetime probability of mortality was 0.10 for late-recurrence, 0.15 for treatment-related subsequent cancers, cardiac, pulmonary, and external causes, and 0.05 for other excess risk. Life expectancy for the cohort of 15-year-olds was 50.6 years, a loss of 10.4 years (17.1%) compared to the general population. Reduction in life expectancy varied by diagnosis, ranging from 4.0 years (6.0%) for kidney tumors to more than 17.8 years (>28.2%) for brain and bone tumor survivors, and was sensitive to late-recurrence mortality risk and duration of excess mortality risks.
Limitations
Estimates are based on data for survivors treated 20–40 years ago; patients treated more recently may have more favorable outcomes.
Conclusions
Despite surviving their initial cancer, childhood cancer survivors face considerable mortality during adulthood, with excess risks reducing life expectancy by as much as 28%. Our findings underscore the need to monitor the health of current survivors and carefully evaluate therapies with known late toxicities in newly diagnosed patients.
doi:10.1059/0003-4819-152-7-201004060-00005
PMCID: PMC3086591  PMID: 20368646
20.  Attentional and executive dysfunction as predictors of smoking within the Childhood Cancer Survivor Study cohort 
Nicotine & Tobacco Research  2010;12(4):344-354.
Introduction:
Previous research has suggested that childhood cancer survivors initiate smoking at rates approaching those of healthy individuals, even though smoking presents unique risks to survivors. The present study explores whether the attentional and executive functioning (EF) deficits associated with cancer and treatment place survivors of childhood cancer at increased risk for smoking.
Methods:
Data from the Childhood Cancer Survivor Study were examined to identify concurrent and longitudinal correlates of tobacco use. We explored whether childhood attention problems and adulthood executive dysfunction were associated with smoking among adult survivors of childhood cancer.
Results:
Childhood attention problems emerged as a striking predictor of adult smoking nearly a decade later on average. Nearly half (40.4%) of survivors who experienced attention problems in childhood reported a history of smoking, a significantly higher rate of ever smoking, than reported by those without childhood attention problems (relative risk [RR] = 1.53, 95% CI = 1.31–1.79). Furthermore, they were nearly twice as likely to be current smokers in adulthood compared with those without childhood attention problems (RR = 1.71, 95% CI = 1.38–2.11). Similar associations were found between components of adult executive dysfunction and adult smoking.
Discussion:
Childhood cancer and treatment are associated with subsequent deficits in attention and EF. Early detection of these deficits will allow clinicians to identify patients who are at increased risk for smoking, an important step in promoting and maintaining health in this medically vulnerable population.
doi:10.1093/ntr/ntq004
PMCID: PMC2847073  PMID: 20154054
21.  Knowledge of Hepatitis C Virus Screening in Long-Term Pediatric Cancer Survivors: A Report from the Childhood Cancer Survivor Study 
Cancer  2010;116(4):974-982.
Background
Pediatric cancer survivors who were treated before routine hepatitis C virus (HCV) screening of blood donors in 1992 have an elevated risk of transfusion-acquired HCV.
Methods
To assess long-term pediatric cancer survivors’ knowledge of HCV testing and blood transfusion history, a questionnaire was administered to 9,242 participants in the Childhood Cancer Survivor Study (CCSS) who are at risk for transfusion-acquired HCV following cancer therapy from 1970–1986.
Results
More than 70% of survivors reported either no prior HCV testing (41%) or uncertainty about testing (31%), with only 29% reporting prior testing. One-half recalled having a treatment-related blood transfusion; those who recalled a transfusion were more likely to report HCV testing (39%) than those who did not (18%) or were unsure (20%). In multivariate models, survivors who reported no prior HCV testing were more likely to be older (odds ratio [OR] per five-year increase, 1.1; 95% confidence interval [95% CI], 1.0–1.1) and to report no care at a cancer center within the past two years (OR, 1.2; 95% CI, 1.0–1.4), no cancer treatment summary (OR, 1.3; 95% CI, 1.2–1.5), and no transfusions (OR, 2.6; 95% CI, 2.3–3.0) or uncertainty about transfusions (OR, 2.2; 95% CI, 1.9–2.6), and less likely to be racial/ethnic minorities (OR, 0.9; 95% CI, 0.8–1.0) or survivors of acute myeloid leukemia (OR, 0.7; 95% CI, 0.5–1.0).
Conclusions
Many pediatric cancer survivors at risk for transfusion-acquired HCV are unaware of their transfusion history and prior testing for HCV and would benefit from programs to increase HCV knowledge and screening.
doi:10.1002/cncr.24810
PMCID: PMC2819650  PMID: 20041485
cancer screening; late effects; survivorship; adverse treatment effects; chronic disease
22.  Fertility of Male Survivors of Childhood Cancer: A Report From the Childhood Cancer Survivor Study 
Journal of Clinical Oncology  2009;28(2):332-339.
Purpose
This study was undertaken to determine the effect of treatment for childhood cancer on male fertility.
Patients and Methods
We reviewed the fertility of male Childhood Cancer Survivor Study survivor and sibling cohorts who completed a questionnaire. We abstracted the chemotherapeutic agents administered, the cumulative dose of drug administered for selected drugs, and the doses and volumes of all radiation therapy from medical records. Risk factors for siring a pregnancy were evaluated using Cox proportional hazards models.
Results
The 6,224 survivors age 15 to 44 years who were not surgically sterile were less likely to sire a pregnancy than siblings (hazard ratio [HR], 0.56; 95% CI, −0.49 to 0.63). Among survivors, the HR of siring a pregnancy was decreased by radiation therapy of more than 7.5 Gy to the testes (HR, 0.12; 95% CI, −0.02 to 0.64), higher cumulative alkylating agent dose (AAD) score or treatment with cyclophosphamide (third tertile HR, 0.42; 95% CI, −0.31 to 0.57) or procarbazine (second tertile HR, 0.48; 95% CI, −0.26 to 0.87; third tertile HR, 0.17; 95% CI, −0.07 to 0.41). Compared with siblings, the HR for ever siring a pregnancy for survivors who had an AAD score = 0, a hypothalamic/pituitary radiation dose = 0 Gy, and a testes radiation dose = 0 Gy was 0.91 (95% CI, 0.73 to 1.14; P = .41).
Conclusion
This large study identified risk factors for decreased fertility that may be used for counseling male cancer patients.
doi:10.1200/JCO.2009.24.9037
PMCID: PMC2815721  PMID: 19949008
23.  Ocular Late Effects in Childhood and Adolescent Cancer Survivors: A Report from the Childhood Cancer Survivor Studya 
Pediatric blood & cancer  2010;54(1):103-109.
Introduction
Approximately 80% of children currently survive 5 years following diagnosis of their cancer. Studies based on limited data have implicated certain cancer therapies in the development of ocular sequelae in these survivors.
Procedure
The Childhood Cancer Survivor Study (CCSS) is a retrospective cohort study investigating health outcomes of 5+ year survivors diagnosed and treated between 1970 and 1986 compared to a sibling cohort. The baseline questionnaire included questions about the first occurrence of 6 ocular conditions. Relative risks (RR) and 95% confidence intervals (CI) were calculated from responses of 14,362 survivors and 3,901 siblings.
Results
Five or more years from the diagnosis, survivors were at increased risk of cataracts (RR:10.8; 95% CI: 6.2–18.9), glaucoma (RR: 2.5; 95% CI: 1.1–5.7), legal blindness (RR: 2.6; 95% CI: 1.7–4.0), double vision (RR:4.1; 95% CI: 2.7–6.1), and dry eyes (RR: 1.9; 95% CI: 1.6–2.4), when compared to siblings. Dose of radiation to the eye was significantly associated with risk of cataracts, legal blindness, double vision, and dry eyes, in a dose-dependent fashion. Risk of cataracts were also associated with radiation 3000+ cGy to the posterior fossa (RR: 8.4; 95% CI: 5.0–14.3), temporal lobe (RR: 9.4; 95% CI: 5.6–15.6), and exposure to prednisone (RR:2.3; 95% CI:.1.6–3.4)
Conclusions
Childhood cancer survivors are at risk of developing late occurring ocular complications, with exposure to glucocorticoids and cranial radiation being important determinants of increased risk. Long-term follow-up is needed to evaluate potential progression of ocular deficits and impact on quality of life.
doi:10.1002/pbc.22277
PMCID: PMC2783513  PMID: 19774634
late effects of cancer therapy; radiation therapy; chemotherapy
24.  Late Recurrence in Pediatric Cancer: A Report From the Childhood Cancer Survivor Study 
Background
An increasing percentage of childhood cancer patients are surviving their disease, but there is limited research on late recurrence. We sought to estimate late recurrence rates for the most common pediatric cancers and to determine risk factors for late recurrence.
Methods
The incidence of late recurrences, or first recurrences that occurred more than 5 years after diagnosis, was analyzed for the most common pediatric cancers using data from the Childhood Cancer Survivor Study, a retrospective cohort of 5-year survivors of childhood and adolescent cancers who were diagnosed between 1970 and 1986. A total of 12 795 survivors with no history of recurrence within 5 years after their original cancer diagnosis were included in the analysis, with a total of 217 127 person-years of follow-up. Cumulative incidence of late recurrence at 5, 10, 15, and 20 years after diagnosis was calculated using death as a competing risk. Adjusted relative rates of late recurrence were obtained using multivariable Poisson regression. All statistical tests were two-sided.
Results
Overall, 5-year survivors of pediatric cancers experienced a cumulative incidence of recurrent disease of 4.4%, 5.6%, and 6.2% at 10, 15, and 20 years, respectively. Cumulative incidence varied by diagnosis: Survivors of Ewing sarcoma and astrocytoma had the highest 20-year cumulative incidences at 13.0% (95% confidence interval [CI] = 9.4 to 16.5) and 14.4% (95% CI = 12.3 to 16.6), respectively. In multivariable analysis, the greatest risk factors for late recurrence included diagnosis, combination treatment with chemotherapy and radiation, earlier treatment era, and fewer years since diagnosis (P < .001 for all).
Conclusion
Late recurrence is a risk for some pediatric cancers. By understanding diagnosis-specific risks, patients, families, and their medical providers can be better informed of the probability of cure.
doi:10.1093/jnci/djp417
PMCID: PMC2800799  PMID: 19966206
25.  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

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