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1.  Suicide Ideation and Associated Mortality in Adult Survivors of Childhood Cancer 
Cancer  2013;120(2):271-277.
Adult survivors of childhood cancer are at-risk for suicide ideation, though longitudinal patterns and rates of recurrent suicide ideation are unknown. We investigated the prevalence of late report (i.e. post-initial assessment) and recurrent suicide ideation in adult survivors of childhood cancer, identified predictors of suicide ideation, and examined associations among suicide ideation and mortality.
Participants included 9,128 adult survivors of childhood cancer and 3,082 sibling controls enrolled in the Childhood Cancer Survivor Study who completed a survey question assessing suicide ideation on one or more occasions between 1994 and 2010. Suicide ideation was assessed using the Brief Symptom Inventory-18. Mortality data was ascertained from the National Death Index.
Survivors were more likely to report late (Odds Ratio (OR) =1.9; 95% Confidence Interval (CI) =1.5–2.5) and recurrent suicide ideation (OR=2.6, 95% CI=1.8–3.8) compared to siblings. Poor physical health status was associated with increased risk of suicide ideation in survivors (late report: OR=1.9, 95% CI=1.3–2.7; recurrent: OR=1.9, 95% CI=1.2–2.9). Suicide ideation was associated with increased risk for all-cause mortality (Hazard Ratio (HR) =1.3, 95% CI=1.03–1.6) and death by external causes (HR=2.4, 95% CI=1.4–4.1).
Adult survivors of childhood cancer are at-risk for late report and recurrent suicide ideation, which is associated with increased risk of mortality. Routine screening for psychological distress in adult survivors appears warranted, especially for survivors who develop chronic physical health conditions.
PMCID: PMC3947253  PMID: 24122148
childhood cancer; survivorship; suicide; mortality; late effects
2.  The Cyclophosphamide Equivalent Dose as an Approach for Quantifying Alkylating Agent Exposure. A Report from the Childhood Cancer Survivor Study 
Pediatric blood & cancer  2013;61(1):53-67.
Estimation of the risk of adverse long-term outcomes such as second malignant neoplasms and infertility often requires reproducible quantification of exposures. The method for quantification should be easily utilized and valid across different study populations. The widely used Alkylating Agent Dose (AAD) score is derived from the drug dose distribution of the study population and thus cannot be used for comparisons across populations as each will have a unique distribution of drug doses.
We compared the performance of the Cyclophosphamide Equivalent Dose (CED), a unit for quantifying alkylating agent exposure independent of study population, to the AAD. Comparisons included associations from three Childhood Cancer Survivor Study (CCSS)outcome analyses, receiver operator characteristic (ROC) curves and goodness of fit based on the Akaike’s Information Criterion (AIC).
The CED and AAD performed essentially identically in analyses of risk for pregnancy among the partners of male CCSS participants, risk for adverse dental outcomes among all CCSS participants and risk for premature menopause among female CCSS participants, based on similar associations, lack of statistically significant differences between the areas under the ROC curves and similar model fit values for the AIC between models including the two measures of exposure.
The CED is easily calculated, facilitating its use for patient counseling. It is independent of the drug dose distribution of a particular patient population, a characteristic that will allow direct comparisons of outcomes among epidemiological cohorts. We recommend the use of the CED in future research assessing cumulative alkylating agent exposure.
PMCID: PMC3933293  PMID: 23940101
late effects of cancer treatment; chemotherapy; long term survival; cyclophosphamide; alkylating agent; alkylating agent dose score
3.  Modifiable Risk Factors and Major Cardiac Events Among Adult Survivors of Childhood Cancer 
Journal of Clinical Oncology  2013;31(29):3673-3680.
To evaluate the relative contribution of modifiable cardiovascular risk factors on the development of major cardiac events in aging adult survivors of childhood cancer.
Patients and Methods
Among 10,724 5-year survivors (median age, 33.7 years) and 3,159 siblings in the Childhood Cancer Survivor Study, the prevalence of hypertension, diabetes mellitus, dyslipidemia, and obesity was determined, along with the incidence and severity of major cardiac events such as coronary artery disease, heart failure, valvular disease, and arrhythmia. On longitudinal follow-up, rate ratios (RRs) of subsequent cardiac events associated with cardiovascular risk factors and cardiotoxic therapy were assessed in multivariable Poisson regression models.
Among survivors, the cumulative incidence of coronary artery disease, heart failure, valvular disease, and arrhythmia by 45 years of age was 5.3%, 4.8%, 1.5%, and 1.3%, respectively. Two or more cardiovascular risk factors were reported by 10.3% of survivors and 7.9% of siblings. The risk for each cardiac event increased with increasing number of cardiovascular risk factors (all Ptrend < .001). Hypertension significantly increased risk for coronary artery disease (RR, 6.1), heart failure (RR, 19.4), valvular disease (RR, 13.6), and arrhythmia (RR, 6.0; all P values < .01). The combined effect of chest-directed radiotherapy plus hypertension resulted in potentiation of risk for each of the major cardiac events beyond that anticipated on the basis of an additive expectation. Hypertension was independently associated with risk of cardiac death (RR, 5.6; 95% CI, 3.2 to 9.7).
Modifiable cardiovascular risk factors, particularly hypertension, potentiate therapy-associated risk for major cardiac events in this population and should be the focus of future interventional studies.
PMCID: PMC3804290  PMID: 24002505
4.  Stomach Cancer Risk After Treatment for Hodgkin Lymphoma 
Journal of Clinical Oncology  2013;31(27):3369-3377.
Treatment-related stomach cancer is an important cause of morbidity and mortality among the growing number of Hodgkin lymphoma (HL) survivors, but risks associated with specific HL treatments are unclear.
Patients and Methods
We conducted an international case-control study of stomach cancer nested in a cohort of 19,882 HL survivors diagnosed from 1953 to 2003, including 89 cases and 190 matched controls. For each patient, we quantified cumulative doses of specific alkylating agents (AAs) and reconstructed radiation dose to the stomach tumor location.
Stomach cancer risk increased with increasing radiation dose to the stomach (Ptrend < .001) and with increasing number of AA-containing chemotherapy cycles (Ptrend = .02). Patients who received both radiation to the stomach ≥ 25 Gy and high-dose procarbazine (≥ 5,600 mg/m2) had strikingly elevated stomach cancer risk (25 cases, two controls; odds ratio [OR], 77.5; 95% CI, 14.7 to 1452) compared with those who received radiation < 25 Gy and procarbazine < 5,600 mg/m2 (Pinteraction < .001). Risk was also elevated (OR, 2.8; 95% CI, 1.3 to 6.4) among patients who received radiation to the stomach ≥ 25 Gy but procarbazine < 5,600 mg/m2; however, no procarbazine-related risk was evident with radiation < 25 Gy. Treatment with dacarbazine also increased stomach cancer risk (12 cases, nine controls; OR, 8.8; 95% CI, 2.1 to 46.6), after adjustment for radiation and procarbazine doses.
Patients with HL who received subdiaphragmatic radiotherapy had dose-dependent increased risk of stomach cancer, with marked risks for patients who also received chemotherapy containing high-dose procarbazine. For current patients, risks and benefits of exposure to both procarbazine and subdiaphragmatic radiotherapy should be weighed carefully. For patients treated previously, GI symptoms should be evaluated promptly.
PMCID: PMC3770865  PMID: 23980092
5.  Contralateral Breast Cancer after Radiotherapy among BRCA1 and BRCA2 Mutation Carriers: A WECARE Study Report 
Women with germline BRCA1 or BRCA2 (BRCA1/BRCA2) mutations are at very high risk of developing breast cancer, including asynchronous contralateral breast cancer (CBC). BRCA1/BRCA2 genes help maintain genome stability and assist in DNA repair. We examined whether the risk of CBC associated with radiation treatment was higher among women with germline BRCA1/BRCA2 mutations than among non-carriers.
A population-based, nested case-control study was conducted within a cohort of 52,536 survivors of unilateral breast cancer (UBC). Cases were 603 women with CBC and controls were 1199 women with UBC individually matched on age at diagnosis, race, year of first diagnosis and cancer registry. All women were tested for BRCA1 and BRCA2 mutations. Radiation absorbed dose from the initial radiotherapy (RT) to the CBC location within the contralateral breast was reconstructed from measurements in a tissue-equivalent phantom and details available in the therapy records.
Among women treated with radiation, the mean radiation dose was 1.1 Gy (range=0.02-6.2 Gy). Risk of developing CBC was elevated among women who carried a deleterious BRCA1/BRCA2 mutation (rate ratio, RR=4.5, confidence interval, CI=3.0-6.8), and also among those treated with RT (RR=1.2, CI=1.0-1.6). However, among mutation carriers, an incremental increase in risk associated with radiation dose was not statistically significant.
Multiplicative interaction of RT with mutation status would be reflected by a larger association of RT with CBC among carriers than among non-carriers, but this was not apparent. Accordingly, there was no clear indication that carriers of deleterious BRCA/BRCA2 mutations were more susceptible to the carcinogenic effects of radiation than non-carriers. These findings are reassuring and have important clinical implications for treatment decisions and the clinical management of patients harboring deleterious BRCA1/BRCA2 mutations.
All work associated with this study was supported by the U.S. National Cancer Institute [R01CA097397, U01CA083178].
PMCID: PMC3755053  PMID: 23706288
Contralateral Breast Cancer; Radiotherapy; BRCA1/BRCA2
6.  The risk of developing a second cancer after receiving craniospinal proton irradiation 
Physics in medicine and biology  2009;54(8):2277-2291.
The purpose of this work was to compare the risk of developing a second cancer after craniospinal irradiation using photon versus proton radiotherapy by means of simulation studies designed to account for the effects of neutron exposures. Craniospinal irradiation of a male phantom was calculated for passively-scattered and scanned-beam proton treatment units. Organ doses were estimated from treatment plans; for the proton treatments, the amount of stray radiation was calculated separately using the Monte Carlo method. The organ doses were converted to risk of cancer incidence using a standard formalism developed for radiation protection purposes. The total lifetime risk of second cancer due exclusively to stray radiation was 1.5% for the passively scattered treatment versus 0.8% for the scanned proton beam treatment. Taking into account the therapeutic and stray radiation fields, the risk of second cancer from intensity-modulated radiation therapy and conventional radiotherapy photon treatments were 7 and 12 times higher than the risk associated with scanned-beam proton therapy, respectively, and 6 and 11 times higher than with passively scattered proton therapy, respectively. Simulations revealed that both passively scattered and scanned-beam proton therapies confer significantly lower risks of second cancers than 6MV conventional and intensity-modulated photon therapies.
PMCID: PMC4144016  PMID: 19305036
7.  Infertility, infertility treatment, and achievement of pregnancy in female survivors of childhood cancer: a report from the Childhood Cancer Survivor Study cohort 
The lancet oncology  2013;14(9):10.1016/S1470-2045(13)70251-1.
Prior studies have documented decreased pregnancy rates and early menopause in female cancer survivors; however, infertility rates and reproductive interventions have not been studied. This study investigates infertility and time to pregnancy among female childhood cancer survivors, and analyzes treatment characteristics associated with infertility and subsequent pregnancy.
The Childhood Cancer Survivor Study (CCSS) is a cohort study including five-year cancer survivors from 26 institutions who were <21 years old at the time of diagnosis between January 1, 1970, and December 31, 1986, and a sibling control group. CCSS females ages 18–39 years reporting they had ever been sexually active (3,531 survivors and 1,366 female controls) were studied. Self-reported infertility, medical treatment for infertility, the time to first pregnancy in survivors and siblings, and the risk of infertility in survivors by demographic, disease, and treatment variables were analyzed.
Survivors had an increased risk of clinical infertility (>1 year of attempts at conception without success) compared to siblings which was most pronounced at early reproductive ages (≤24 years Relative Risk (RR)=2·92, 95% Confidence Interval (CI) 1·18–7·20; 25–29 years RR=1·61, 95% CI 1·05–2·48; 30–39 years RR=1·37, 95% CI 1·11–1·69). Despite being equally likely to seek treatment for infertility, survivors were less likely to be prescribed medication for treatment of infertility (RR=0·57, 95% CI 0·46–0·70). Increasing doses of uterine radiation and alkylating agent chemotherapy were most strongly associated with infertility. Although survivors had an increased time to pregnancy interval (p=0·032), 64·2% (292/455) with infertility achieved a pregnancy.
A more comprehensive understanding of infertility after cancer is critical for counseling and decision-making regarding future attempts at conception as well as fertility preservation.
PMCID: PMC3845882  PMID: 23856401
8.  Radiation dose and subsequent risk for stomach cancer in long-term survivors of cervical cancer 
International journal of radiation oncology, biology, physics  2013;86(5):10.1016/j.ijrobp.2013.04.010.
To assess the dose-response relationship for stomach cancer following radiotherapy for cervical cancer.
Methods and Materials
We conducted a nested, matched case-control study of 201 cases and 378 controls among 53,547 5-year survivors of cervical cancer diagnosed from 1943–1995, from five international, population-based cancer registries. We estimated individual radiation doses to the site of the stomach cancer for all cases and to corresponding sites for the matched controls (overall mean stomach tumor dose, 2.56 gray [Gy], range 0.03–46.1 and following parallel opposed pelvic fields, 1.63 Gy, range 0.12–6.3).
Over 90% of women received radiotherapy, mostly with external beam therapy in combination with brachytherapy. Stomach cancer risk was non-significantly increased (odds ratios [ORs] 1.27–2.28) for women receiving between 0.5–4.9 Gy to the stomach cancer site and significantly increased at doses ≥5 Gy (OR=4.20, 95% confidence interval, 1.41–13.4, Ptrend=0.047) compared to non-irradiated women. A highly significant radiation dose-response relationship was evident when analyses were restricted to the 131 cases (251 controls) whose stomach cancer was located in the middle and lower portions of the stomach (Ptrend=0.003), whereas there was no indication of increasing risk with increasing dose for 30 cases (57 controls) whose cancer was located in the upper stomach (Ptrend=0.23).
Our findings showed for the first time a significant linear dose-response relationship for risk of stomach cancer in long-term survivors of cervical cancer.
PMCID: PMC3831516  PMID: 23707149
cervical cancer; stomach cancer; radiotherapy; case-control; second primary cancer
9.  Radiation, Atherosclerotic Risk Factors and Stroke Risk in Survivors of Pediatric Cancer: a Report from the Childhood Cancer Survivor Study 
The impact of childhood cranial radiation therapy (CRT) on stroke risk in adulthood, and the role of modifiable atherosclerotic risk factors, remains poorly defined. We assessed long-term incidence rates and stroke risk factors in survivors of childhood cancer followed by the Childhood Cancer Survivor Study (CCSS).
Patients and Methods
CCSS is a multi-institutional retrospective cohort study of 14,358 five-year survivors of childhood cancer and 4,023 randomly selected sibling controls with longitudinal follow up. Age-adjusted incidence rates of self-reported late-occurring (≥ 5 years after diagnosis) first-stroke were calculated. Multivariable Cox Proportional Hazards models were used to identify independent stroke predictors.
During a mean follow-up of 23.3 years, 292 survivors reported a late-occurring stroke. The age-adjusted stroke rate per 100,000 person-years was 77 (95% Confidence Interval [CI] 62–96) compared to 9.3 (95% CI 4–23) for siblings. Treatment with CRT increased stroke risk in a dose dependent manner: hazard ratio (HR) 5.9 (95% CI 3.5–9.9) for 30–49 Gy CRT, and 11.0 (7.4–17.0) for 50+ Gy CRT. The cumulative stroke incidence in survivors treated with 50+ Gy CRT was 1.1% (95% CI 0.4–1.8) at 10 years post-diagnosis and 12% (95% CI 8.9–15.0) at 30 years. Hypertension (HTN) increased stroke hazard by 4-fold (95% CI 2.8–5.5) and in black survivors by 16-fold (95% CI 6.9–36.6).
Young adult pediatric cancer survivors have an increased stroke risk that is associated with CRT in a dose dependent manner. Atherosclerotic risk factors enhanced this risk and should be treated aggressively.
PMCID: PMC3696633  PMID: 23680033
10.  Smokeless and Dual Tobacco Use among Males Surviving Childhood Cancer: A report from the Childhood Cancer Survivor Study 
Cancer survivors experience treatment-related complications that can be exacerbated by tobacco use. This study reports the prevalence of smokeless (ST) and dual tobacco (DT) use, compares these rates to the US population, and examines tobacco risk factors among males surviving childhood cancer. Data from the Childhood Cancer Survivor Study (CCSS) 2007 survey were used (N = 3378). Standardized incidence ratios (SIR) were obtained by comparing CCSS data to the National Survey on Drug Use and Health. Logistic regression was used to evaluate associations between risk factors and tobacco use. Among male survivors, 8.3% and 2.3% were current ST and DT users, respectively. Survivors were less likely than population males to report ST (SIR = 0.64, 95% CI = 0.57 – 0.72) or DT (SIR = 0.37, CI = 0.29 – 0.46) use; however, non-white survivors aged 35–49 years were more likely to use ST (SIR = 2.32, CI = 1.27 – 3.90). ST use was associated (p < 0.05) with younger age at diagnosis, lower education, being married or divorced/separated, and not living in the Northeastern US, while history of cardiovascular- and/or pulmonary-toxic treatment was protective. DT use was associated with younger age at diagnosis, lower education, divorce/separation, and high psychological distress. Having active heart or circulatory conditions was protective. Although ST/DT use is generally low among childhood cancer survivors, these findings suggest that tobacco use screening should be expanded to include ST use and that ST-specific education and cessation interventions should be provided to users. Screening and intervening for ST/DT use in childhood cancer survivors will reduce tobacco-related morbidity and mortality.
PMCID: PMC3681858  PMID: 23580700
smokeless tobacco; dual tobacco; cancer survivors; health behaviors
11.  Changes in Health Status Among Aging Survivors of Pediatric Upper and Lower Extremity Sarcoma: A Report from the Childhood Cancer Survivor Study (CCSS) 
To evaluate health status and participation restrictions in childhood extremity sarcoma survivors.
Members of the CCSS cohort with extremity sarcomas, who completed 1995, 2003 or 2007 questionnaires, were included.
Cohort Study of extremity sarcomas survivors.
Childhood cancer survivors diagnosed and treated between 1970–1986.
Not applicable.
Main Outcome Measure
Prevalence rates for poor health status in six domains and five sub-optimal social participation categories were compared by tumor location and treatment exposure with generalized estimating equations adjusted for demographic/personal factors and time/age.
Among 1094 survivors, median age at diagnosis 13 years (range 0–20), current age 33 years (range 10–53), 49% were male, 87.5% Caucasian, and 75% had lower extremity tumors. In adjusted models, when compared to upper extremity survivors, lower extremity survivors had increased risk of activity limitations but lower risk of not completing college. Compared to those who did not have surgery, those with limb-sparing (LS) and upper extremity amputations (UEA) were 1.6 times more likely to report functional impairment; while those with an above the knee amputation (AKA) were 1.9 times more likely to report functional impairment. Survivors treated with LS were 1.5 times more likely to report activity limitations. Survivors undergoing LS were more likely to report inactivity, incomes < $20,000, unemployment and no college degree. Those with UEA more likely reported inactivity, unmarried status and no college degree. Lastly, those with AKA more likely reported no college degree. Treatment with abdominal irradiation was associated with increased risk of poor mental health, functional impairment and activity limitation.
Treatment for lower extremity sarcomas is associated with a 50% increased risk for activity limitations; upper extremity survivors are at 10% higher risk for not completing college. Type of local control influences health status and participation restrictions. Both these outcomes decline with age.
PMCID: PMC3913046  PMID: 23380347
upper extremity; lower extremity; sarcoma; survivors; childhood cancer
12.  Sleep Disturbances in Adult Survivors of Childhood Brain Tumors 
The aims of this study are to compare self-reported sleep quality in adult survivors of childhood brain tumors and a population-based comparison group, to identify treatment-related factors associated with sleep disturbances, and to identify the impact of post-treatment obesity and depression on sleep scores in adult survivors of childhood brain tumors.
Randomly selected adult survivors of childhood brain tumors (n = 78) and age, sex and zip code matched population-group members (n = 78) completed the Pittsburgh Sleep Quality Index and the Brief Symptom Inventory. Sleep quality and the effect of demographic, treatment, and post-treatment characteristics were evaluated with linear and logistic regression analyses.
Brain tumor survivors were 2.7 (95% CI: 1.1, 6.0) times more likely than the comparison group to take greater than 30 minutes to fall asleep. Females in both groups reported worse sleep quality and impaired daytime functioning. Among survivors, post-treatment obesity was associated with daytime dysfunction.
These results agree with previous studies associating sleep, sex and obesity and identified longer sleep latency as being a problem among childhood brain tumor survivors. Further study identifying factors contributing to sleep latency, and its impact on quality of life among adult survivors of childhood brain tumors is needed.
PMCID: PMC3442150  PMID: 22669471
Sleep quality; sleep latency; adult survivors; childhood brain tumors
13.  Restricted Access to the Environment and Quality of Life in Adult Survivors of Childhood Brain Tumors 
Journal of neuro-oncology  2012;111(2):195-203.
Survivors of pediatric brain tumors are at-risk for late effects which may affect mobility within and access to the physical environment. This study examined the prevalence of and risk factors for restricted environmental access in survivors of childhood brain tumors and investigated the associations between reduced environmental access, health-related quality of life (HRQOL), and survivors’ social functioning.
In-home evaluations were completed for 78 brain tumor survivors and 78 population-based controls matched on age, sex, and zip-code. Chi-square tests and multivariable logistic regression models were used to calculate odds ratios (OR) and 95% confidence intervals (CI) for poor environmental access and reduced HRQOL.
The median age of survivors was 22 years at the time of study. Compared to controls, survivors were more likely to report avoiding most dimensions of their physical environment, including a single flight of stairs (p<0.001), uneven surfaces (p<0.001), traveling alone (p=0.01), and traveling to unfamiliar places (p=0.001). Overall, survivors were 4.8 times more likely to report poor environmental access (95% CI, 2.0-11.5, p<0.001). In survivors, poor environmental access was associated with reduced physical function (OR=3.6, 95% CI, 1.0-12.8, p=0.04), general health (OR=6.0, 95% CI, 1.8-20.6, p=0.002), and social functioning (OR=4.3, 95% CI, 1.1-17.3, p=0.03).
Adult survivors of pediatric brain tumors were more likely to avoid their physical environment than matched controls. Restricted environmental access was associated with reduced HRQOL and diminished social functioning. Interventions directed at improving physical mobility may have significant impact on survivor quality of life.
PMCID: PMC3995451  PMID: 23143294
CNS malignancies; survivorship; quality of life; environmental access
14.  Nucleotide excision repair polymorphisms may modify ionizing radiation-related breast cancer risk in US radiologic technologists 
Exposure to ionizing radiation has been consistently associated with increased risk of female breast cancer. Although the majority of DNA damage caused by ionizing radiation is corrected by the base-excision repair pathway, certain types of multiple-base damage can only be repaired through the nucleotide excision repair pathway. In a nested case–control study of breast cancer in US radiologic technologists exposed to low levels of ionizing radiation (858 cases, 1,083 controls), we examined whether risk of breast cancer conferred by radiation was modified by nucleotide excision gene polymorphisms ERCC2 (XPD) rs13181, ERCC4 (XPF) rs1800067 and rs1800124, ERCC5 (XPG) rs1047769 and rs17655; and ERCC6 rs2228526. Of the 6 ERCC variants examined, only ERCC5 rs17655 showed a borderline main effect association with breast cancer risk (ORGC = 1.1, ORCC = 1.3; p-trend = 0.08), with some indication that individuals carrying the C allele variant were more susceptible to the effects of occupational radiation (EOR/GyGG = 1.0, 95% CI = <0, 6.0; EOR/GyGC/CC = 5.9, 95% CI = 0.9, 14.4; phet = 0.10). ERCC2 rs13181, although not associated with breast cancer risk overall, statistically significantly modified the effect of occupational radiation dose on risk of breast cancer (EOR/GyAA = 9.1, 95% CI = 2.1–21.3; EOR/GyAC/CC = 0.6, 95% CI = <0, 4.6; phet = 0.01). These results suggest that common variants in nucleotide excision repair genes may modify the association between occupational radiation exposure and breast cancer risk.
PMCID: PMC3984912  PMID: 18767034
15.  Cancer mortality among women frequently exposed to radiographic exams for spinal disorders 
Radiation research  2010;174(1):83-90.
We studied cancer mortality in a cohort of 5,573 women with scoliosis and other spine disorders diagnosed between 1912 and 1965, and who were exposed to frequent diagnostic X-ray procedures. Patients were identified from medical records in 14 orthopedic medical centers in the United States and followed for vital status and address through Dec 31, 2004, using publicly available regional, state, and nation-wide databases. Causes of death were obtained from death certificates or through linkage with the National Death Index (NDI). Statistical analyses included standardized mortality ratios (SMR=observed/expected) based on death rates for U.S. females, and internal comparisons using Cox regression models with attained age as the time scale. Diagnostic radiation exposure was estimated from radiology files for over 137,000 procedures; estimated average cumulative radiation doses to the breast, lung, thyroid and bone marrow were 10.9, 4.1, 7.4, and 1.0 cGy, respectively. After a median follow-up period of 47 years, 1527 women died including 355 from cancer. Cancer mortality was 8% higher than expected (95% CI=0.97–1.20). Mortality from breast cancer was significantly elevated (SMR=1.68; 95% CI: 1.38–2.02), whereas death rates from several other cancers were below expectation, in particular lung (SMR=0.77), cervical (SMR=0.31), and liver (SMR=0.17). The excess relative risk (ERR) for breast cancer mortality increased significantly with 10-yr lagged radiation dose to the breast (ERR/Gy=3.9; 95% CI: 1.0–9.3).
PMCID: PMC3982592  PMID: 20681802
breast neoplasms; radiation-induced; mortality; radiation; radiography; scoliosis; cohort study; epidemiology
16.  Renal Carcinoma After Childhood Cancer: A Report From the Childhood Cancer Survivor Study 
Adult survivors of childhood cancer are known to be at increased risk of subsequent malignancy, but only limited data exist describing the incidence and risk factors for secondary renal carcinoma. Among 14 358 5-year survivors diagnosed between 1970 and 1986, we estimated standardized incidence ratios (SIRs) for subsequent renal carcinoma and identified associations with primary cancer therapy using Poisson regression. Twenty-six survivors were diagnosed with renal carcinoma (median = 22.6 years from diagnosis; range = 6.3–35.7 years), reflecting a statistically significant excess (SIR = 8.0, 95% confidence interval [CI] = 5.2 to 11.7) compared with the general population. Highest risk was observed among neuroblastoma survivors (SIR = 85.8, 95% CI = 38.4 to 175.2) and, in multivariable analyses, with renal-directed radiotherapy of 5 Gy or greater (relative risk [RR] = 3.8, 95% CI = 1.6 to 9.3) and platinum-based chemotherapy (RR = 3.5, 95% CI = 1.0 to 11.2). To our knowledge, this is the first report of an association between cisplatin and subsequent renal carcinoma among survivors of childhood cancer.
PMCID: PMC3691945  PMID: 23515901
17.  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.
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.
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.
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).
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.
PMCID: PMC3494805  PMID: 22848025
psychoactive medication; neurocognition; survivorship
18.  Risk of Salivary Gland Cancer Following Childhood Cancer: A Report From The Childhood Cancer Survivor Study 
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).
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.
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.
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.
PMCID: PMC3500417  PMID: 22836059
19.  A reanalysis of curvature in the dose response for cancer and modifications by age at exposure following radiotherapy for benign disease 
To assess the shape of the dose response for various cancer endpoints, and modifiers by age and time.
Methods and Materials
Re-analysis of the US peptic ulcer data testing for heterogeneity of radiogenic risk by cancer endpoint (stomach, pancreas, lung, leukemia, all other).
There are statistically significant (p<0.05) excess risks for all cancer, and lung cancer, and borderline statistically significant risks for stomach cancer (p=0.07), and leukemia (p=0.06), with excess relative risks Gy−1 of 0.024 (95% CI 0.011, 0.039), 0.559 (95% CI 0.221, 1.021), 0.042 (95% CI −0.002, 0.119), and 1.087 (95% CI −0.018, 4.925), respectively. There is statistically significant (p=0.007) excess risk of pancreatic cancer when adjusted for dose-response curvature. General downward curvature is apparent in the dose response, statistically significant (p<0.05) for all cancers, pancreatic cancer and all other cancers (than stomach, pancreas, lung, leukemia). There are indications of reduction in risk with increasing age at exposure (for all cancers, pancreatic cancer), but no evidence for quadratic variations in relative risk with age at exposure. If a linear-exponential dose response is used there is no significant heterogeneity in the dose response between the five endpoints considered, or in the speed of variation of relative risk with age at exposure. The risks are generally consistent with those observed in the Japanese atomic bomb survivors and in groups of nuclear workers.
There are excess risks for various malignancies in this dataset. Generally there is marked downward curvature in the dose response, and significant reduction in relative risk with increasing age at exposure. The consistency of risks with those observed in the Japanese atomic bomb survivors, and in groups of nuclear workers, implies that there may be little sparing effect of fractionation of dose or low dose rate exposure.
PMCID: PMC3440544  PMID: 22682810
stomach cancer; lung cancer; pancreatic cancer; leukemia
20.  Risk of Asynchronous Contralateral Breast Cancer in Noncarriers of BRCA1 and BRCA2 Mutations With a Family History of Breast Cancer: A Report From the Women's Environmental Cancer and Radiation Epidemiology Study 
Journal of Clinical Oncology  2012;31(4):433-439.
To fully characterize the risk of contralateral breast cancer (CBC) in patients with breast cancer with a family history who test negative for BRCA1 and BRCA2 mutations.
Patients and Methods
From our population-based case-control study comparing women with CBC to women with unilateral breast cancer (UBC), we selected women who tested negative for BRCA1 and BRCA2 mutations (594 patients with CBC/1,119 control patients with UBC). Rate ratios (RRs) and 95% CIs were estimated to examine the association between family history of breast cancer and risk of asynchronous CBC. Age- and family history–specific 10-year cumulative absolute risks of CBC were estimated.
Family history of breast cancer was associated with increased CBC risk; risk was highest among young women (< 45 years) with first-degree relatives affected at young ages (< 45 years; RR, 2.5; 95% CI, 1.1 to 5.3) or women with first-degree relatives with bilateral disease (RR, 3.6; 95% CI, 2.0 to 6.4). Women diagnosed with UBC before age 55 years with a first-degree family history of CBC had a 10-year risk of CBC of 15.6%.
Young women with breast cancer who have a family history of breast cancer and who test negative for deleterious mutations in BRCA1 and BRCA2 are at significantly greater risk of CBC than other breast cancer survivors. This risk varies with diagnosis age, family history of CBC, and degree of relationship to an affected relative. Women with a first-degree family history of bilateral disease have risks of CBC similar to mutation carriers. This has important implications for the clinical management of patients with breast cancer with family history of the disease.
PMCID: PMC3731919  PMID: 23269995
21.  Differential Effects of Radiotherapy on Growth and Endocrine Function Among Acute Leukemia Survivors: A Childhood Cancer Survivor Study Report 
Pediatric blood & cancer  2012;60(1):110-115.
The differential effects of cranial (CRT), spinal (SRT), and total body irradiation (TBI) on growth and endocrine outcomes have rarely been examined in combination among childhood acute leukemia survivors.
Self-reported height/weight, hypothyroidism, and pregnancy/live birth were determined among acute lymphoblastic and myeloid leukemia survivors (n=3,467) participating in the Childhood Cancer Survivor Study, an ongoing cohort study of 5-year survivors of pediatric cancers diagnosed from 1970 to 1986.
Compared with no radiotherapy, risk estimates were consistent across outcomes (adult short stature, hypothyroidism, absence of pregnancy/live birth) with CRT treatment associated with 2–3 fold increased risks, TBI associated with 5–10 fold increased risks, and CRT+TBI associated with >10 fold increased risks. Exposure to any SRT further increased risk of these outcomes 2–3 fold. Changes in body composition were more nuanced as CRT only was associated with an increased risk of being overweight/obese (OR 1.6, 95% CI 1.3–1.9) whereas TBI only was associated with an increased risk of being underweight (OR 6.0, 95% CI 2.4–14.9).
Although patients treated with CRT+TBI were at greatest risk for short stature, hypothyroidism, and a reduced likelihood of pregnancy/live birth, those treated with either modality alone had significantly increased risks as well, including altered body composition. Any SRT exposure further increased risk in an independent fashion.
PMCID: PMC3436954  PMID: 22628201
leukemia; childhood; survivor; growth; hypothyroidism; pregnancy
22.  Absolute Risk Prediction of Second Primary Thyroid Cancer Among 5-Year Survivors of Childhood Cancer 
Journal of Clinical Oncology  2012;31(1):119-127.
We developed three absolute risk models for second primary thyroid cancer to assist with long-term clinical monitoring of childhood cancer survivors.
Patients and Methods
We used data from the Childhood Cancer Survivor Study (CCSS) and two nested case-control studies (Nordic CCSS; Late Effects Study Group). Model M1 included self-reported risk factors, model M2 added basic radiation and chemotherapy treatment information abstracted from medical records, and model M3 refined M2 by incorporating reconstructed radiation absorbed dose to the thyroid. All models were validated in an independent cohort of French childhood cancer survivors.
M1 included birth year, initial cancer type, age at diagnosis, sex, and past thyroid nodule diagnosis. M2 added radiation (yes/no), radiation to the neck (yes/no), and alkylating agent (yes/no). Past thyroid nodule was consistently the strongest risk factor (M1 relative risk [RR], 10.8; M2 RR, 6.8; M3 RR, 8.2). In the validation cohort, 20-year absolute risk predictions for second primary thyroid cancer ranged from 0.04% to 7.4% for M2. Expected events agreed well with observed events for each model, indicating good calibration. All models had good discriminatory ability (M1 area under the receiver operating characteristics curve [AUC], 0.71; 95% CI, 0.64 to 0.77; M2 AUC, 0.80; 95% CI, 0.73 to 0.86; M3 AUC, 0.75; 95% CI, 0.69 to 0.82).
We developed and validated three absolute risk models for second primary thyroid cancer. Model M2, with basic prior treatment information, could be useful for monitoring thyroid cancer risk in childhood cancer survivors.
PMCID: PMC3530689  PMID: 23169509
23.  Analysis of dose response for circulatory disease following radiotherapy for benign disease 
To assess the shape of the dose response for various circulatory disease endpoints, and modifiers by age and time since exposure.
Methods and Materials
Analysis of the US peptic ulcer data testing for heterogeneity of radiogenic risk by circulatory disease endpoint (ischemic heart, cerebrovascular, other circulatory disease).
There are significant excess risks for all circulatory disease, with an excess relative risk Gy−1 of 0.082 (95% CI 0.031, 0.140), and ischemic heart disease, with an excess relative risk Gy−1 of 0.102 (95% CI 0.039, 0.174) (both p<0.01), and indications of excess risk for stroke. There are no statistically significant (p>0.2) differences between risks by endpoint, and few indications of curvature in the dose response. There are significant modifications of relative risk by time since exposure, the magnitude of which does not vary between endpoints (p>0.2). Risk modifications are similar if analysis is restricted to those receiving radiation, although relative risks are slightly larger and the risk of stroke fails to be significant. The slopes of the dose response are generally consistent with those observed in the Japanese atomic bomb survivors and in occupationally and medically exposed groups.
There are excess risks for a variety of circulatory diseases in this dataset, with significant modification of risk by time since exposure. The consistency of the dose-response slopes with those observed in radiotherapeutically-treated groups at much higher dose, as well as in lower-dose exposed cohorts such as the Japanese atomic bomb survivors and nuclear workers implies that there may be little sparing effects of fractionation of dose or low dose-rate exposure.
PMCID: PMC3396750  PMID: 22494591
circulatory disease; ischemic heart disease; stroke; peptic ulcer; benign disease
24.  Fractures among long-term survivors of childhood cancer: A report from the Childhood Cancer Survivor Study 
Cancer  2012;118(23):5920-5928.
Although reductions in bone mineral density are well-documented among children during treatment for cancer and among childhood cancer survivors, little is known about the long-term risk of fracture. The aim of this study was to ascertain the prevalence of and risk factors for fractures among individuals participating in the Childhood Cancer Survivor Study (CCSS).
Analyses included 7414 5+ year survivors of childhood cancer diagnosed between 1970-86 who completed the 2007 CCSS follow-up questionnaire and a comparison group of 2374 siblings. Generalized linear models stratified by sex were used to compare the prevalence of reported fractures between survivors and siblings.
The median ages at follow-up among survivors and siblings were 36.2, (range: 21.2-58.8) and 38.1 years (range: 18.4-62.6), respectively with a median 22.7 years of follow-up after cancer diagnosis for survivors. Approximately 35% of survivors and 39% of siblings reported ≥1 fractures during their lifetime. The prevalence of fractures was lower among survivors than siblings, both in males (prevalence ratio=0.87, 95%CI=0.81-0.94, p<0.001) and females (prevalence ratio=0.94, 95%CI=0.86-1.04, p=0.22). In multivariable analyses, increasing age at follow-up, white race, methotrexate treatment and balance difficulties were associated with increased prevalence of fractures among female survivors (p=0.05). Among males, only smoking history and white race were associated with an increased prevalence of fracture (p<0.001).
Findings from this study indicate that the prevalence of fractures among adult survivors is not increased compared to that of siblings. Additional studies of bone health among aging female cancer survivors may be warranted.
PMCID: PMC3439597  PMID: 22605509
25.  Cancer Mortality Following Radiotherapy for Benign Gynecologic Disorders 
Radiation research  2012;178(4):266-279.
The purpose of this study is to quantify cancer mortality in relationship to organ-specific radiation dose among women irradiated for benign gynecologic disorders. Included in this study are 12,955 women treated for benign gynecologic disorders at hospitals in the Northeastern U.S. between 1925 and 1965; 9,770 women treated by radiation and 3,186 women treated by other methods. The average age at treatment was 45.9 years (range, 13–88 years), and the average follow-up period was 30.1 years (maximum, 69.9 years). Radiation doses to organs and active bone marrow were reconstructed by medical physicists using original radiotherapy records. The highest doses were received by the uterine cervix (median, 120 Gy) and uterine corpus (median, 34 Gy), followed by the bladder, rectum and colon (median, 1.7–7.2 Gy), with other abdominal organs receiving median doses ≤1 Gy and organs in the chest and head receiving doses <0.1 Gy. Standardized mortality rate ratios relative to the general U.S. population were calculated. Radiation-related risks were estimated in internal analyses using Poisson regression models. Mortality was significantly elevated among irradiated women for cancers of the uterine corpus, ovary, bladder, rectum, colon and brain, as well as for leukemia (exclusive of chronic lymphocytic leukemia) but not for cancer of the cervix, Hodgkin or non-Hodgkin lymphoma, multiple myeloma, or chronic lymphocytic leukemia. Evidence of a dose-response was seen for cancers of the ovary [excess relative risk (ERR) 0.31/Gy, P < 0.001], bladder (ERR = 0.21/Gy, P = 0.02) and rectum (ERR = 0.23/Gy, P = 0.05) and suggested for colon (ERR = 0.09/Gy, P = 0.10), but not for cancers of the uterine corpus or brain nor for non-chronic lymphocytic leukemia. Relative risks of mortality due to cancers of the stomach, pancreas, liver and kidney were close to 1.0, with no evidence of dose-response over the range of 0–1.5 Gy. Breast cancer was not significantly associated with dose to the breast or ovary. Mortality due to cancers of heavily irradiated organs remained elevated up to 40 years after irradiation. Significantly elevated radiation-related risk was seen for cancers of organs proximal to the radiation source or fields (bladder, rectum and ovary), as well as for non-chronic lymphocytic leukemia. Our results corroborate those from previous studies that suggest that cells of the uterine cervix and lymphopoietic system are relatively resistant to the carcinogenic effects of radiation. Studies of women irradiated for benign gynecologic disorders, together with studies of women treated with higher doses of radiation for uterine cancers, provide quantitative information on cancer risks associated with a broad range of pelvic radiation exposures.
PMCID: PMC3471655  PMID: 22856888

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