David L. Winter

Long-term cause-specific mortality among survivors of childhood cancer.

CONTEXT Survivors of childhood cancer are at increased risk of premature mortality compared with the general population, but little is known about the long-term risks of specific causes of death, particularly beyond 25 years from diagnosis at ages when background mortality in the general population starts to increase substantially. OBJECTIVE To investigate long-term cause-specific mortality among 5-year survivors of childhood cancer in a large-scale population-based cohort. DESIGN, SETTING, AND PATIENTS British Childhood Cancer Survivor Study, a population-based cohort of 17,981 5-year survivors of childhood cancer diagnosed with cancer before age 15 years between 1940 and 1991 in Britain and followed up until the end of 2006. MAIN OUTCOME MEASURES Cause-specific standardized mortality ratios (SMRs) and absolute excess risks (AERs). RESULTS Overall, 3049 deaths were observed, which was 11 times the number expected (SMR, 10.7; 95% confidence interval [CI], 10.3-11.1). The SMR declined with follow-up but was still 3-fold higher than expected (95% CI, 2.5-3.9) 45 years from diagnosis. The AER for deaths from recurrence declined from 97 extra deaths (95% CI, 92-101) per 10,000 person-years at 5 to 14 years from diagnosis, to 8 extra deaths (95% CI, 3-22) beyond 45 years from diagnosis. In contrast, during the same periods of follow-up, the AER for deaths from second primary cancers and circulatory causes increased from 8 extra deaths (95% CI, 7-10) and 2 extra deaths (95% CI, 2-3) to 58 extra deaths (95% CI, 38-90) and 29 extra deaths (95% CI, 16-56), respectively. Beyond 45 years from diagnosis, recurrence accounted for 7% of the excess number of deaths observed while second primary cancers and circulatory deaths together accounted for 77%. CONCLUSION Among a cohort of British survivors of childhood cancer, excess mortality from second primary cancers and circulatory diseases continued to occur beyond 25 years from diagnosis.

Long-term Risks of Subsequent Primary Neoplasms Among Survivors of Childhood Cancer

CONTEXT Survivors of childhood cancer are at excess risk of developing subsequent primary neoplasms but the long-term risks are uncertain. OBJECTIVES To investigate long-term risks of subsequent primary neoplasms in survivors of childhood cancer, to identify the types that contribute most to long-term excess risk, and to identify subgroups of survivors at substantially increased risk of particular subsequent primary neoplasms that may require specific interventions. DESIGN, SETTING, AND PARTICIPANTS British Childhood Cancer Survivor Study--a population-based cohort of 17,981 5-year survivors of childhood cancer diagnosed with cancer at younger than 15 years between 1940 and 1991 in Great Britain, followed up through December 2006. MAIN OUTCOME MEASURES Standardized incidence ratios (SIRs), absolute excess risks (AERs), and cumulative incidence of subsequent primary neoplasms. RESULTS After a median follow-up time of 24.3 years (mean = 25.6 years), 1354 subsequent primary neoplasms were ascertained; the most frequently observed being central nervous system (n = 344), nonmelanoma skin cancer (n = 278), digestive (n = 105), genitourinary (n = 100), breast (n = 97), and bone (n = 94). The overall SIR was 4 times more than expected (SIR, 3.9; 95% confidence interval [CI], 3.6-4.2; AER, 16.8 per 10,000 person-years). The AER at older than 40 years was highest for digestive and genitourinary subsequent primary neoplasms (AER, 5.9 [95% CI, 2.5-9.3]; and AER, 6.0 [95%CI, 2.3-9.6] per 10,000 person-years, respectively); 36% of the total AER was attributable to these 2 subsequent primary neoplasm sites. The cumulative incidence of colorectal cancer for survivors treated with direct abdominopelvic irradiation was 1.4% (95% CI, 0.7%-2.6%) by age 50 years, comparable with the 1.2% risk in individuals with at least 2 first-degree relatives affected by colorectal cancer. CONCLUSION Among a cohort of British childhood cancer survivors, the greatest excess risk associated with subsequent primary neoplasms at older than 40 years was for digestive and genitourinary neoplasms.

The British Childhood Cancer Survivor Study: Objectives, methods, population structure, response rates and initial descriptive information.

In Britain 75% of individuals diagnosed with childhood cancer survive at least 5 years. The British Childhood Cancer Survivor Study was established to determine the risks of adverse health and social outcomes among survivors. To be eligible individuals were diagnosed with childhood cancer in Britain between 1940 and 1991 and survived at least 5 years. The entire cohort of 17,981 form the basis of population‐based studies of late mortality and the risks/causes of second malignant neoplasms using national registration systems.

Long-term population-based risks of second malignant neoplasms after childhood cancer in Britain

In a population-based, retrospective cohort study of 16 541 3-year survivors of childhood cancer treated in Britain up to the end of 1987, 278 second malignant neoplasms (SMNs) were identified against 39.4 expected giving a standardised incidence ratio (SIR) of 6.2. The overall cumulative risk of an SMN by 25 years from 3-year survival from childhood cancer was 4.2%. Analysis of the cohort of nonretinoblastoma childhood cancers combined revealed a significant decline in SIR of SMN with increasing duration of follow-up. There was a greater risk of developing a SMN, particularly secondary acute myeloid leukaemia, in those diagnosed with childhood cancer from 1980 onwards. However, on multivariate modeling, this was not an independent risk factor. There was significant heterogeneity (P<0.001) in SIR of SMN across different treatment groups, the greatest risk observed in the group exposed to both radiotherapy and chemotherapy. The risks of SMN observed were comparable with those in other population-based studies. While the decline in SIR with duration of follow-up and the small excess numbers of cancers observed over later decades after diagnosis are reassuring, the high excess risk, particularly of leukaemia, associated with recent more intense therapy is of concern.

Health-status of adult survivors of childhood cancer: a large-scale population-based study from the British Childhood Cancer Survivor Study.

The purpose of this study was to investigate the effect of childhood cancer and its treatment on self‐reported health‐status in 10,189 adult survivors of childhood cancer in Britain. Age‐ and sex‐adjusted scores on the SF‐36 Mental and Physical Component Summary scales (MCS, PCS, respectively) were compared between survivors and UK norms, and between subgroups of survivors, by multiple regression. Survivors had comparable scores to UK‐norms on the MCS scale (difference (D) = −0.1, 99% CI: −0.5, 0.3). The difference in scores between survivors and UK‐norms on the PCS scale varied by age (pheterogeneity < 0.001). Young survivors (16–19 years) scored similarly to UK‐norms (D = 0.5, (−1.1, 2.2), whereas the age groups of 25 and older scored statistically and clinically significantly below UK‐norms (all p‐values < 0.0001), with Ds ranging between −2.3 (−3.5, −1.2) and −3.7 (−5.0, −2.4). Survivors of central nervous system (CNS) and bone tumors scored significantly (p‐value at all ages <0.003) below UK‐norms on the PCS scale. Specifically, these survivors were substantially more limited in specific daily activities such as, for example, walking a mile (40, 63%, respectively) when compared to UK‐norms (16%). In conclusion, childhood cancer survivors rate their mental health broadly similarly to those in the general population. Survivors of CNS and bone tumors report their physical health‐status to be importantly below population norms. Although self‐reported physical health is at least as good as in the general population among young survivors, this study suggests that perceived physical health declines more rapidly over time than in the general population.

Population-Based Risks of CNS Tumors in Survivors of Childhood Cancer: The British Childhood Cancer Survivor Study

PURPOSE CNS tumors are the most common second primary neoplasm (SPN) observed after childhood cancer in Britain, but the relationship of risk to doses of previous radiotherapy and chemotherapy is uncertain. METHODS The British Childhood Cancer Survivor Study is a national, population-based, cohort study of 17,980 individuals surviving at least 5 years after diagnosis of childhood cancer. Linkage to national, population-based cancer registries identified 247 SPNs of the CNS. Cohort and nested case-control studies were undertaken. RESULTS There were 137 meningiomas, 73 gliomas, and 37 other CNS neoplasms included in the analysis. The risk of meningioma increased strongly, linearly, and independently with each of dose of radiation to meningeal tissue and dose of intrathecal methotrexate. Those whose meningeal tissue received 0.01 to 9.99, 10.00 to 19.99, 20.00 to 29.99, 30.00 to 39.99 and≥40 Gy had risks that were two-fold, eight-fold, 52-fold, 568-fold, and 479-fold, respectively, the risks experienced by those whose meningeal tissue was unexposed. The risk of meningioma among individuals receiving 1 to 39,40 to 69, and at least 70 mg/m2 of intrathecal methotrexate was 15-fold, 11-fold, and 36-fold, respectively, the risk experienced by those unexposed. The standardized incidence ratio for gliomas was 10.8 (95% CI, 8.5 to 13.6). The risk of glioma/primitive neuroectodermal tumors increased linearly with dose of radiation, and those who had CNS tissue exposed to at least 40 Gy experienced a risk four-fold that experienced by those who had CNS tissue unexposed. CONCLUSION The largest-ever study, to our knowledge, of CNS tumors in survivors of childhood cancer indicates that the risk of meningioma increases rapidly with increased dose of radiation to meningeal tissue and with increased dose of intrathecal methotrexate.

Pregnancy Outcomes among Adult Survivors of Childhood Cancer in the British Childhood Cancer Survivor Study

Purpose: We used data from the first large-scale overwhelmingly population-based study (a) to quantify the risk of adverse pregnancy outcomes in survivors of childhood cancer in relation to cancer type and treatment and (b) to assess live birth rates relative to the general population. Methods: A questionnaire, including questions inquiring about pregnancy outcomes, was completed by 10,483 survivors. A total of 7,300 pregnancies were reported. Odds ratios (OR) for live birth, miscarriage, termination, stillbirth, premature birth, and low birth weight were calculated for different types of childhood cancer and by whether initial treatment involved chemotherapy and abdominal or brain irradiation. For females, the observed number of live births was compared with that expected based on the general population of England and Wales. Results: Female survivors exposed to abdominal irradiation had a significantly increased OR of delivering preterm [OR, 3.2; 95% confidence interval (95% CI), 2.1-4.7] and producing offspring with a low birth weight (OR, 1.9; 95% CI, 1.1-3.2). An increased OR of miscarriage was also associated with abdominal radiotherapy (OR, 1.4; 95% CI, 1.0-1.9). The number of live births observed from all female survivors was two thirds of that expected (O/E, 0.64; 95% CI, 0.62-0.66) and lowest among survivors treated with brain (O/E, 0.52; 95% CI, 0.48-0.56) and abdominal radiotherapy (O/E, 0.55; 95% CI, 0.50-0.61). Conclusion: Female survivors of childhood cancer treated with abdominal radiotherapy are at 3-fold increased risk of delivering preterm, 2-fold increased risk of low birth weight, and a small increased risk of miscarriage. Overall, female survivors produce considerably fewer offspring than expected, particularly those treated with abdominal or brain radiotherapy. (Cancer Epidemiol Biomarkers Prev 2009;18(8):2239–47)

Risk of thyroid cancer in survivors of childhood cancer: results from the British Childhood Cancer Survivor Study.

Second primary neoplasms (SPNs) are a recognised late effect of treatment for childhood cancer. Thyroid SPNs can develop after exposure to low‐dose radiation, due to the radio‐sensitivity of the thyroid gland. The British Childhood Cancer Survivor Study (BCCSS) was set up to directly monitor the late effects of treatment, including risk of SPNs, in childhood cancer survivors and includes 17,980 5‐year survivors. We carried out a cohort analysis to determine the risk of thyroid SPNs in the BCCSS, and estimated risk using standardised incidence ratios (SIRs), relative risk (RR) using multivariate Poisson regression and cumulative incidence curves. There were 340,202 person years at risk subsequent to a 5‐year survival, median follow‐up 17.4 years per survivor. We identified 50 thyroid SPNs including 31 (62%) papillary carcinomas, 15 (30%) follicular carcinomas and 4 (8%) other types. 88% of thyroid SPNs developed after exposure to radiotherapy in or around the thyroid gland. SIR overall was 18.0 (95% confidence interval 13.4–23.8). Risk of thyroid cancer was highest after Hodgkins disease: RR 3.3 (1.1–10.1) and Non Hodgkins Lymphoma: RR 3.4 (1.1–10.7) relative to leukaemia (RR 1.0) (p < 0.001). Survivors treated with radiotherapy in childhood had a RR of 4.6 (1.4–15.1) relative to survivors not treated with radiotherapy (RR 1.0), p = 0003. In conclusion, the risk of thyroid cancer in childhood cancer survivors is relatively high in this cohort of childhood cancer survivors. These results will be of use in counselling survivors of childhood cancer exposed to radiation in or around the thyroid area.

Long‐term population‐based marriage rates among adult survivors of childhood cancer in Britain

The objectives of this study were to assess the number of adult survivors of childhood cancer who ever married and the factors influencing marriage, compare observed marriages to those expected from the general population, and assess age at marriage and influencing factors. The data is based on the British Childhood Cancer Survivor Study (BCCSS), which is a population‐based cohort of 18,119 individuals who were diagnosed with childhood cancer between 1940 and 91 and survived at least 5 years. Fourteen thousand five hundred thirty‐nine were alive, aged at least 16 years and eligible to receive a postal questionnaire, which ascertained marriage status. Thirty‐four percent of 9,954 survivors had married. Survivors with the following characteristics: males, CNS neoplasm, received radiotherapy, diagnosed with mental retardation, registered blind, low social functioning score (calculated from SF‐36 health status measure), and achieved the highest level of educational attainment, were less likely to have married than the complementary survivor groups. The deficits in the proportion ever married compared to the general population were mostly between 9 and 18% among males and 7–10% among females. The largest ever married deficits were among male CNS neoplasm survivors aged 30 years or over (29–38%). Age at first marriage among survivors was related to: sex, childhood cancer type, age at diagnosis, chemotherapy, radiotherapy, mental retardation, and level of educational attainment. Regular follow‐up for these survivors should address not just physical late‐effects of the childhood cancer and treatment, but also psychosocial needs throughout the lifespan of the survivors to help them achieve life events as they occur in the general population.

The use of the SF-36 questionnaire in adult survivors of childhood cancer: evaluation of data quality, score reliability, and scaling assumptions

BackgroundThe SF-36 has been used in a number of previous studies that have investigated the health status of childhood cancer survivors, but it never has been evaluated regarding data quality, scaling assumptions, and reliability in this population. As health status among childhood cancer survivors is being increasingly investigated, it is important that the measurement instruments are reliable, validated and appropriate for use in this population. The aim of this paper was to determine whether the SF-36 questionnaire is a valid and reliable instrument in assessing self-perceived health status of adult survivors of childhood cancer.MethodsWe examined the SF-36 to see how it performed with respect to (1) data completeness, (2) distribution of the scale scores, (3) item-internal consistency, (4) item-discriminant validity, (5) internal consistency, and (6) scaling assumptions. For this investigation we used SF-36 data from a population-based study of 10,189 adult survivors of childhood cancer.ResultsOverall, missing values ranged per item from 0.5 to 2.9 percent. Ceiling effects were found to be highest in the role limitation-physical (76.7%) and role limitation-emotional (76.5%) scales. All correlations between items and their hypothesised scales exceeded the suggested standard of 0.40 for satisfactory item-consistency. Across all scales, the Cronbachs alpha coefficient of reliability was found to be higher than the suggested value of 0.70.Consistent across all cancer groups, the physical health related scale scores correlated strongly with the Physical Component Summary (PCS) scale scores and weakly with the Mental Component Summary (MCS) scale scores. Also, the mental health and role limitation-emotional scales correlated strongly with the MCS scale score and weakly with the PCS scale score. Moderate to strong correlations with both summary scores were found for the general health perception, energy/vitality, and social functioning scales.ConclusionThe findings presented in this paper provide support for the validity and reliability of the SF-36 when used in long-term survivors of childhood cancer. These findings should encourage other researchers and health care practitioners to use the SF-36 when assessing health status in this population, although it should be recognised that ceiling effects can occur.