Debra L. Friedman

A theory of the value of children

This paper uses a non-standard value assumption—uncertainty reduction—to explain parenthood. We begin by reviewing the inadequacies of normative and standard rational choice explanations of shifts in fertility behavior. Then we propose a theory of the value of children based on the uncertainty-reduction assumption. Next we generate a range of hypotheses that follow both from this assumption and from a subsidiary assumption of marital solidarity enhancement. Finally, we explore the extent to which implications based on these new ideas are supported by the relevant empirical literature.

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.

Second Neoplasms in Survivors of Childhood Cancer: Findings From the Childhood Cancer Survivor Study Cohort

PURPOSE To review the reports of subsequent neoplasms (SNs) in the Childhood Cancer Survivor Study (CCSS) cohort that were made through January 1, 2006, and published before July 31, 2008, and to discuss the host-, disease-, and therapy-related risk factors associated with SNs. PATIENTS AND METHODS SNs were ascertained by survivor self-reports and subsequently confirmed by pathology findings or medical record review. Cumulative incidence of SNs and standardized incidence ratios for second malignant neoplasms (SMNs) were calculated. The impact of host-, disease-, and therapy-related risk factors was evaluated by Poisson regression. RESULTS Among 14,358 cohort members, 730 reported 802 SMNs (excluding nonmelanoma skin cancers). This represents a 2.3-fold increase in the number of SMNs over that reported in the first comprehensive analysis of SMNs in the CCSS cohort, which was done 7 years ago. In addition, 66 cases of meningioma and 1,007 cases of nonmelanoma skin cancer were diagnosed. The 30-year cumulative incidence of SMNs was 9.3% and that of nonmelanoma skin cancer was 6.9%. Risk of SNs remains elevated for more than 20 years of follow-up for all primary childhood cancer diagnoses. In multivariate analyses, risks differ by SN subtype, but include radiotherapy, age at diagnosis, sex, family history of cancer, and primary childhood cancer diagnosis. Female survivors whose primary childhood cancer diagnosis was Hodgkins lymphoma or sarcoma and who received radiotherapy are at particularly increased risk. Analyses of risk associated with radiotherapy demonstrated different dose-response curves for specific SNs. CONCLUSION Childhood cancer survivors are at a substantial and increasing risk for SNs, including nonmelanoma skin cancer and meningiomas. Health care professionals should understand the magnitude of these risks to provide individuals with appropriate counseling and follow-up.

Solid cancers after allogeneic hematopoietic cell transplantation

Transplant recipients have been reported to have an increased risk of solid cancers but most studies are small and have limited ability to evaluate the interaction of host, disease, and treatment-related factors. In the largest study to date to evaluate risk factors for solid cancers, we studied a multi-institutional cohort of 28 874 allogeneic transplant recipients with 189 solid malignancies. Overall, patients developed new solid cancers at twice the rate expected based on general population rates (observed-to-expected ratio 2.1; 95% confidence interval 1.8-2.5), with the risk increasing over time (P trend < .001); the risk reached 3-fold among patients followed for 15 years or more after transplantation. New findings showed that the risk of developing a non-squamous cell carcinoma (non-SCC) following conditioning radiation was highly dependent on age at exposure. Among patients irradiated at ages under 30 years, the relative risk of non-SCC was 9 times that of nonirradiated patients, while the comparable risk for older patients was 1.1 (P interaction < .01). Chronic graft-versus-host disease and male sex were the main determinants for risk of SCC. These data indicate that allogeneic transplant survivors, particularly those irradiated at young ages, face increased risks of solid cancers, supporting strategies to promote lifelong surveillance among these patients.

Chemoreduction and Local Ophthalmic Therapy for Intraocular Retinoblastoma

PURPOSE To study the effectiveness of combined systemic chemotherapy and local ophthalmic therapy for retinoblastoma with the goal of avoiding enucleation and external-beam radiation therapy (EBRT). PATIENTS AND METHODS This was a prospective, nonrandomized, single-arm clinical trial. Seventy-five eyes were followed in 47 children. Patients were treated with a six-cycle protocol of vincristine, etoposide, and carboplatin. Most (83%) also received ophthalmic treatment (cryotherapy, laser photocoagulation, thermotherapy, or plaque radiation therapy) during and/or after the chemotherapy. RESULTS With a median follow-up of 13 months, event-free survival was 74%, with an event defined as enucleation and/or EBRT. Six children required EBRT in seven eyes (9%); five required enucleation of one eye (7%); five required a combination of EBRT and enucleation in six eyes (8%). Reese-Ellsworth groups 1, 2, and 3 eyes had excellent results, with avoidance of EBRT or enucleation in all 39. Treatment of groups 4 and 5 was less successful, with 33% of six eyes and 53% of 30 eyes, respectively, requiring EBRT and/or enucleation. Toxicities from chemotherapy were mild and included cytopenias (89%), fever and neutropenia (28%), infection (9%), and gastrointestinal symptoms, dehydration, and vincristine neurotoxicity (40%). No patients developed a second malignancy, metastatic disease, renal disease, or ototoxicity. CONCLUSION In retinoblastoma patients with Reese-Ellsworth eye groups 1, 2, or 3, systemic chemotherapy used with local ophthalmic therapies can eliminate the need for enucleation or EBRT without significant systemic toxicity. More effective therapy is required for Reese-Ellsworth eye groups 4 and 5.

Risk of Selected Subsequent Carcinomas in Survivors of Childhood Cancer: A Report From the Childhood Cancer Survivor Study

PURPOSE To determine the risk of subsequent carcinomas other than breast, thyroid, and skin, and to identify factors that influence the risk among survivors of childhood cancer. PATIENTS AND METHODS Subsequent malignant neoplasm history was determined in 13,136 participants (surviving > or = 5 years postmalignancy, diagnosed from 1970 to 1986 at age < 21 years) of the Childhood Cancer Survivor Study to calculate standardized incidence ratios (SIRs), using Surveillance, Epidemiology, and End Results data. RESULTS In 71 individuals, 71 carcinomas were diagnosed at a median age of 27 years and a median elapsed time of 15 years in the genitourinary system (35%), head and neck area (32%), gastrointestinal tract (23%), and other sites (10%). Fifty-nine patients (83%) had received radiotherapy, and 42 (59%) developed a second malignant neoplasm in a previous radiotherapy field. Risk was significantly elevated following all childhood diagnoses except CNS neoplasms, and was highest following neuroblastoma (SIR = 24.2) and soft tissue sarcoma (SIR = 6.2). Survivors of neuroblastoma had a 329-fold increased risk of renal cell carcinomas; survivors of Hodgkins lymphoma had a 4.5-fold increased risk of gastrointestinal carcinomas. Significantly elevated risk of head and neck carcinoma occurred in survivors of soft tissue sarcoma (SIR = 22.6), neuroblastoma (SIR = 20.9), and leukemia (SIR = 20.9). CONCLUSION Young survivors of childhood cancers are at increased risk of developing subsequent carcinomas typical of later adulthood, underscoring the importance of long-term follow-up and risk-based screening. Follow-up of the cohort is ongoing to determine lifetime risk and delineate individual characteristics that contribute to risk.

Breast Cancer after Childhood Cancer: A Report from the Childhood Cancer Survivor Study

Context Adult survivors of childhood cancer are at risk for developing breast cancer and other secondary cancer. Knowing the risk factors for breast cancer in these women may help to formulate screening policies for them. Contribution Among 6068 women who survived childhood cancer, 95 developed breast cancer at a median age of 35 years. Childhood sarcoma, chest irradiation, family history of breast cancer, and personal history of thyroid disease increased the risk for breast cancer. Implications Women who survived childhood cancer and had sarcoma, chest irradiation, family history of breast cancer, or personal history of thyroid disease should consider early, vigilant screening for breast cancer. The Editors Women treated with chest radiation therapy for childhood and adolescent Hodgkin disease are at increased risk for developing breast cancer at a young age (1-12). However, case reports and preliminary studies indicate that survivors of childhood cancer other than Hodgkin disease may also be at risk for secondary breast cancer (1, 13, 14). Practitioners caring for the growing population of young female survivors of childhood cancer are challenged with assessing breast cancer risk in order to recommend screening and preventive strategies. Although recent studies have shown that the risk for radiation-induced breast cancer is directly related to dose of chest radiation, specific details of previous treatment are not always available to clinicians and may not affect screening decisions (11, 12). In addition, whether primary cancer diagnosis, previous treatment other than chest radiation, or other well-established breast cancer risk factors contribute to a childhood cancer survivors risk for breast cancer is unknown. Studies of Hodgkin disease survivors have shown that clinical examination and screening mammography can detect early-stage secondary breast cancer in young women (15-17), and although treatment options may be limited by previous therapy, early-stage secondary breast cancer is curable (16, 17). Thus, identifying specific groups of childhood cancer survivors who would benefit from early mammographic screening might reduce the morbidity and mortality of breast cancer in these young women. In this study, we analyzed a large series of women with secondary breast cancer from a cohort of childhood cancer survivors, the Childhood Cancer Survivor Study (CCSS), to describe clinical and pathologic features of breast cancer and to determine breast cancer risk relative to the general population. We hypothesized that breast cancer risk would be modified by previous treatment and factors unrelated to treatment. Thus, in this large cohort of women, we assessed the influence of primary cancer, previous treatment, family cancer history, and menstrual and reproductive history on breast cancer risk. Methods Study Sample: Childhood Cancer Survivors Study The CCSS is a follow-up study of childhood cancer survivors established in 1994. Eligibility criteria included diagnosis at an age younger than 21 years with leukemia, brain tumor, Hodgkin disease, non-Hodgkin lymphoma, renal tumor, neuroblastoma, or soft-tissue or bone sarcoma and survival of at least 5 years after diagnosis. The 20276 eligible participants received a diagnosis from 1 January 1970 to 31 December 1986 at 1 of 25 collaborating institutions (Appendix). Participants (n= 14054) completed a self-report questionnaire, providing information about their medical history, family medical history, reproductive history, and socioeconomic status. Follow-up questionnaires were sent to patients reporting second cancer diagnoses. Information on the cohort was updated in 2000. We used data available as of May 2002 for this analysis. No men in the CCSS reported breast cancer by that date; thus, this analysis was restricted to women. Detailed information on the study methods and cohort characteristics has been reported (18). The human subjects committee at each participating institution approved the CCSS protocol. Clinical Data We abstracted treatment data from medical records, including chemotherapeutic agents and dose, and radiation therapy dose, and site for primary cancer and relapses. We asked participants who self-reported breast cancer to sign a medical release to confirm the diagnosis. We confirmed all cases of breast cancer in this report and obtained the tumor size, histologic characteristics, hormone receptor status, involvement of axillary nodes, and metastatic sites from pathology records. Statistical Analysis We compared survivors who had breast cancer with those who did not have breast cancer with respect to primary cancer diagnosis, age at diagnosis, years of follow-up, and therapy for the primary cancer. We calculated standardized incidence ratios for breast cancer by using age-, sex-, and calendar-yearspecific incidence rates of the general population (Surveillance, Epidemiology, and End Results Program [SEER], National Cancer Institute, Bethesda, Maryland [19]). We considered survivors to be at risk for breast cancer from 5 years after the childhood cancer diagnosis until 1 of the following 3 events: death, breast cancer diagnosis, or completion of the CCSS questionnaire. To make the definition of incidence comparable in the calculation of the observed and expected numbers, we included only the first primary breast cancer diagnosis. We calculated cumulative incidences of breast cancer by attained age (20). We used Poisson multiple regression models for standardized incidence ratios to assess the modification of risk for developing breast cancer by several variables chosen a priori (21). We considered the following risk factors for breast cancer: age at and years since primary cancer diagnosis; age at menarche (<12 years or 12 years); age at first live birth (never, <20 years, 20 to 24 years, or 25 years), as queried in the CCSS questionnaire; history of breast cancer in first-degree female relatives (yes or no); exposure to chest radiation (yes or no); exposure to pelvic radiation (yes or no); family history of sarcoma (yes or no); history of thyroid disease (thyroid nodules, overactive or underactive thyroid, or enlarged thyroid); and exposure to an alkylating agent (alkylating agent score, measured as previously described, accounted for several drug exposures and dose) (22). The Poisson multiple regression incorporated all time-dependent factors by splitting each survivors follow-up period into several time intervals, wherein each factor was assumed constant. We initially evaluated the relative rate of developing breast cancer for each risk factor, adjusting for the exposure to chest radiation (yes or no). We then stratified the analysis by the exposure to chest radiation and assessed the modification of risk with age at and years since primary cancer diagnosis, family history of breast cancer or sarcoma, history of thyroid disease, and exposure to pelvic radiation. The years since primary cancer diagnosis variable was the baseline time factor of the model for which we obtained fitted standardized incidence ratios relative to SEER data. For other variables, we calculated relative rates by comparing standardized incidence ratios across categories of each variable. All significance tests were 2-sided. We used SAS software, version 8 (SAS Institute Inc., Cary, North Carolina), and S-PLUS software, version 6 (Insightful Corp.), for this analysis. Role of the Funding Sources The funding sources had no role in the collection, analysis, or interpretation of the data or in the decision to submit the manuscript for publication. Results Cohort Characteristics Of the 20276 survivors eligible for the CCSS cohort, 9062 were women. Of those, 6498 women participated, 6068 of whom had signed medical record release to be eligible for this analysis. Of the 6068 eligible women, 95 women had 111 confirmed cases of breast cancer. Primary cancer diagnosis and age at treatment were similar between participants and nonparticipants (Table 1). Survivors with breast cancer were older at diagnosis of primary cancer and at follow-up than those without breast cancer. As expected, a large proportion of the women with breast cancer (65 of 95 [68%] women) were Hodgkin disease survivors, and all but 2 of the 65 women were known to have received chest radiation therapy. However, 30 of 95 (32%) women with breast cancer were survivors of other childhood cancer, and 20 of 95 (21%) women did not receive chest radiation therapy. The proportion of patients exposed to alkylating agents was similar in both groups (49.5% vs. 49.2%) (Table 1). Table 1. Characteristics of Women Who Did and Did Not Develop Breast Cancer and of Eligible Nonparticipants Since the oldest survivors in this cohort were 51 years of age, all cases of breast cancer were diagnosed in relatively young women (median age at diagnosis, 35 years [range, 20 to 49 years]) (Table 2). However, 19% (18 of 95 women) of the breast cancer cases occurred in women 20 to 29 years of age and 64% (61 of 95 women) of cases occurred in women 30 to 39 years of age. Median time from childhood cancer diagnosis to breast cancer diagnosis was 19 years; however, the range extended from 6 years to 29 years after primary cancer diagnosis (Table 2). Table 2. Clinical and Pathologic Characteristics of Breast Cancer Cases Of the 111 cases of breast cancer, 21 cases were ductal carcinoma in situ (Table 2). Of those 21 cases, 19 were diagnosed in Hodgkin disease survivors and 2 in soft-tissue sarcoma survivors. Table 2 shows the distribution of histologic characteristics in the invasive cases. We determined the stage in 66 of 90 (73%) invasive cases from pathology reports (Table 2). Twenty-six (29%) cases involved axillary lymph nodes, and 5 (6%) cases involved distant metastatic disease. Estrogen receptor status was available in 37 cases, and 76% of those were positive. There was no predominant laterality. Sixteen cases (17%) were bilateral, 5 were syn

Anthracycline-Related Cardiomyopathy After Childhood Cancer: Role of Polymorphisms in Carbonyl Reductase Genes—A Report From the Children's Oncology Group

PURPOSE Carbonyl reductases (CBRs) catalyze reduction of anthracyclines to cardiotoxic alcohol metabolites. Polymorphisms in CBR1 and CBR3 influence synthesis of these metabolites. We examined whether single nucleotide polymorphisms in CBR1 (CBR1 1096G>A) and/or CBR3 (CBR3 V244M) modified the dose-dependent risk of anthracycline-related cardiomyopathy in childhood cancer survivors. PATIENTS AND METHODS One hundred seventy survivors with cardiomyopathy (patient cases) were compared with 317 survivors with no cardiomyopathy (controls; matched on cancer diagnosis, year of diagnosis, length of follow-up, and race/ethnicity) using conditional logistic regression techniques. RESULTS A dose-dependent association was observed between cumulative anthracycline exposure and cardiomyopathy risk (0 mg/m(2): reference; 1 to 100 mg/m(2): odds ratio [OR], 1.65; 101 to 150 mg/m(2): OR, 3.85; 151 to 200 mg/m(2): OR, 3.69; 201 to 250 mg/m(2): OR, 7.23; 251 to 300 mg/m(2): OR, 23.47; > 300 mg/m(2): OR, 27.59; P(trend) < .001). Among individuals carrying the variant A allele (CBR1:GA/AA and/or CBR3:GA/AA), exposure to low- to moderate-dose anthracyclines (1 to 250 mg/m(2)) did not increase the risk of cardiomyopathy. Among individuals with CBR3 V244M homozygous G genotypes (CBR3:GG), exposure to low- to moderate-dose anthracyclines increased cardiomyopathy risk when compared with individuals with CBR3:GA/AA genotypes unexposed to anthracyclines (OR, 5.48; P = .003), as well as exposed to low- to moderate-dose anthracyclines (OR, 3.30; P = .006). High-dose anthracyclines (> 250 mg/m(2)) were associated with increased cardiomyopathy risk, irrespective of CBR genotype status. CONCLUSION This study demonstrates increased anthracycline-related cardiomyopathy risk at doses as low as 101 to 150 mg/m(2). Homozygosis for G allele in CBR3 contributes to increased cardiomyopathy risk associated with low- to moderate-dose anthracyclines, such that there seems to be no safe dose for patients homozygous for the CBR3 V244M G allele. These results suggest a need for targeted intervention for those at increased risk of cardiomyopathy.

Chemoreduction plus focal therapy for retinoblastoma: factors predictive of need for treatment with external beam radiotherapy or enucleation.

PURPOSE To report the results of chemoreduction and focal therapy for retinoblastoma with determination of factors predictive of the need for treatment with external beam radiotherapy or enucleation. DESIGN Interventional case series. METHODS One-hundred three patients with retinoblastoma (158 eyes with 364 tumors) at the Ocular Oncology Service at Wills Eye Hospital of Thomas Jefferson University in conjunction with the Division of Oncology at Childrens Hospital of Philadelphia from June 1994 to August 1999 were enrolled for this prospective clinical trial. The patients received treatment for retinoblastoma with six planned cycles (one cycle per month) of chemoreduction using vincristine, etoposide, and carboplatin combined with focal treatments (cryotherapy, thermotherapy, or plaque radiotherapy). The two main outcome measures after chemoreduction and focal therapy were the need for external beam radiotherapy and the need for enucleation. The clinical features at the time of patient presentation were analyzed for impact on the main outcome measures using a series of Cox proportional hazards regressions. RESULTS Using Reese-Ellsworth (RE) staging for retinoblastoma, there were nine (6%) eyes with group I disease, 26 (16%) eyes with group II disease, 16 (10%) eyes with group III disease, 32 (20%) eyes with group IV disease, and 75 (48%) eyes with group V retinoblastoma. All eyes showed initial favorable response with tumor regression. The median follow-up was 28 months (range, 2-63 months). Failure of chemoreduction and need for treatment with external beam radiotherapy occurred in 25% of eyes at 1 year, 27% at 3 years, and no further increase at 5 years. More specifically, external beam radiotherapy was necessary at 5 years in 10% of RE groups I-IV eyes and 47% of RE group V eyes. Multivariate factors predictive of treatment with external beam radiotherapy included non-Caucasian race, male sex, and RE group V disease. Failure of chemoreduction and the need for treatment with enucleation occurred in 13% eyes at 1 year, 29% at 3 years, and 34% at 5 years. More specifically, enucleation was necessary in 15% of RE groups I-IV eyes at 5 years and in 53% of RE group V at 5 years. Multivariate factors predictive of treatment with enucleation included patient age older than 12 months, single tumor in eye, and tumor proximity to foveola within 2 mm. Overall, of the 158 eyes, 50% required external beam radiotherapy or enucleation and 50% were successfully managed without these treatments. No patient developed retinoblastoma metastasis, pinealoblastoma, or second malignant neoplasms over the 5-year follow up. CONCLUSIONS Chemoreduction offers satisfactory retinoblastoma control for RE groups I-IV eyes, with treatment failure necessitating additional external beam radiotherapy in only 10% of eyes and enucleation in 15% of eyes at 5-year follow-up. Patients with RE group V eyes require external beam radiotherapy in 47% and enucleation in 53% at 5 years.

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

Abstract 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.