Risks of adverse obstetric outcomes among female survivors of adolescent and young adult cancer in England (TYACSS): a population-based, retrospective cohort study.

BACKGROUND: There are limited data on the risks of obstetric complications among survivors of adolescent and young adult cancer with most previous studies only reporting risks for all types of cancers combined. The aim of this study was to quantify deficits in birth rates and risks of obstetric complications for female survivors of 17 specific types of adolescent and young adult cancer. METHODS: The Teenage and Young Adult Cancer Survivor Study (TYACSS)-a retrospective, population-based cohort of 200 945 5-year survivors of cancer diagnosed at age 15-39 years from England and Wales-was linked to the English Hospital Episode Statistics (HES) database from April 1, 1997, to March 31, 2022. The cohort included 17 different types of adolescent and young adult cancers. We ascertained 27 specific obstetric complications through HES among 96 947 women in the TYACSS cohort. Observed and expected numbers for births and obstetric complications were compared between the study cohort and the general population of England to identify survivors of adolescent and young adult cancer at a heighted risk of birth deficits and obstetric complications relative to the general population. FINDINGS: Between April 1, 1997, and March 31, 2022, 21 437 births were observed among 13 886 female survivors of adolescent and young adult cancer from England, which was lower than expected (observed-to-expected ratio: 0·68, 95% CI 0·67-0·69). Other survivors of genitourinary, cervical, and breast cancer had under 50% of expected births. Focusing on more common (observed ≥100) obstetric complications that were at least moderately in excess (observed-to-expected ratio ≥1·25), survivors of cervical cancer were at risk of malpresentation of fetus, obstructed labour, amniotic fluid and membranes disorders, premature rupture of membranes, preterm birth, placental disorders including placenta praevia, and antepartum haemorrhage. Survivors of leukaemia were at risk of preterm delivery, obstructed labour, postpartum haemorrhage, and retained placenta. Survivors of all other specific cancers had no more than two obstetric complications that exceeded an observed-to-expected ratio of 1·25 or greater. INTERPRETATION: Survivors of cervical cancer and leukaemia are at risk of several serious obstetric complications; therefore, any pregnancy should be considered high-risk and would benefit from obstetrician-led antenatal care. Despite observing deficits in birth rates across all 17 different types of adolescent and young adult cancer, we provide reassurance for almost all survivors of adolescent and young adult cancer concerning their risk of almost all obstetric complications. Our results provide evidence for the development of clinical guidelines relating to counselling and surveillance of obstetrical risk for female survivors of adolescent and young adult cancer. FUNDING: Children with Cancer UK, The Brain Tumour Charity, and Academy of Medical Sciences.

Risk of subsequent gliomas and meningiomas among 69,460 5-year survivors of childhood and adolescent cancer in Europe: the PanCareSurFup study.

BACKGROUND: Childhood cancer survivors are at risk of subsequent gliomas and meningiomas, but the risks beyond age 40 years are uncertain. We quantified these risks in the largest ever cohort. METHODS: Using data from 69,460 5-year childhood cancer survivors (diagnosed 1940-2008), across Europe, standardized incidence ratios (SIRs) and cumulative incidence were calculated. RESULTS: In total, 279 glioma and 761 meningioma were identified. CNS tumour (SIR: 16.2, 95% CI: 13.7, 19.2) and leukaemia (SIR: 11.2, 95% CI: 8.8, 14.2) survivors were at greatest risk of glioma. The SIR for CNS tumour survivors was still 4.3-fold after age 50 (95% CI: 1.9, 9.6), and for leukaemia survivors still 10.2-fold after age 40 (95% CI: 4.9, 21.4). Following cranial radiotherapy (CRT), the cumulative incidence of a glioma in CNS tumour survivors was 2.7%, 3.7% and 5.0% by ages 40, 50 and 60, respectively, whilst for leukaemia this was 1.2% and 1.7% by ages 40 and 50. The cumulative incidence of a meningioma after CRT in CNS tumour survivors doubled from 5.9% to 12.5% between ages 40 and 60, and in leukaemia survivors increased from 5.8% to 10.2% between ages 40 and 50. DISCUSSION: Clinicians following up survivors should be aware that the substantial risks of meningioma and glioma following CRT are sustained beyond age 40 and be vigilant for symptoms.

Risk of subsequent primary lymphoma in a cohort of 69,460 five-year survivors of childhood and adolescent cancer in Europe: The PanCareSurFup study.

BACKGROUND: Survivors of Hodgkin lymphoma (HL) are at risk of developing non-Hodgkin lymphoma (NHL) after treatment; however, the risks of developing subsequent primary lymphomas (SPLs), including HL and NHL, after different types of childhood cancer are unknown. The authors quantified the risk of SPLs using the largest cohort of childhood cancer survivors worldwide. METHODS: The Pan-European Network for Care of Survivors After Childhood and Adolescent Cancer (PanCare) Survivor Care and Follow-Up Studies (PanCareSurFup) cohort includes 69,460 five-year survivors of childhood cancer, diagnosed during 1940 through 2008, from 12 European countries. Risks of SPLs were quantified by standardized incidence ratios (SIRs) and relative risks (RRs) using multivariable Poisson regression. RESULTS: Overall, 140 SPLs, including 104 NHLs and 36 HLs, were identified. Survivors were at 60% increased risk of an SPL compared with the general population (SIR, 1.6; 95% confidence interval [CI], 1.4-1.9). Survivors were twice as likely to develop NHL (SIR, 2.3; 95% CI, 1.9-2.8), with the greatest risks among survivors of HL (SIR, 7.1; 95% CI, 5.1-10.0), Wilms tumor (SIR, 3.1; 95% CI, 1.7-5.7), leukemia (SIR, 2.8; 95% CI, 1.8-4.4), and bone sarcoma (SIR, 2.7; 95% CI, 1.4-5.4). Treatment with chemotherapy for any cancer doubled the RR of NHL (RR, 2.1; 95% CI, 1.2-3.9), but treatment with radiotherapy did not (RR, 1.2; 95% CI, 0.7-2.0). Survivors were at similar risk of developing a subsequent HL as the general population (SIR, 1.1; 95% CI, 0.8-1.5). CONCLUSIONS: In addition to HL, the authors show here for the first time that survivors of Wilms tumor, leukemia, and bone sarcoma are at risk of NHL. Survivors and health care professionals should be aware of the risk of NHL in these survivors and in any survivors treated with chemotherapy.

Risk of subsequent primary oral cancer in a cohort of 69,460 5-year survivors of childhood and adolescent cancer in Europe: the PanCareSurFup study.

BACKGROUND: Survivors of childhood cancer are at risk of subsequent primary malignant neoplasms (SPNs), but the risk for rarer types of SPNs, such as oral cancer, is uncertain. Previous studies included few oral SPNs, hence large-scale cohorts are required to identify groups at risks. METHODS: The PanCareSurFup cohort includes 69,460 5-year survivors of childhood cancer across Europe. Risks of oral SPNs were defined by standardised incidence ratios (SIRs), absolute excess risks and cumulative incidence. RESULTS: One hundred and forty-five oral SPNs (64 salivary gland, 38 tongue, 20 pharynx, 2 lip, and 21 other) were ascertained among 143 survivors. Survivors were at 5-fold risk of an oral SPN (95% CI: 4.4-5.6). Survivors of leukaemia were at greatest risk (SIR = 19.2; 95% CI: 14.6-25.2) followed by bone sarcoma (SIR = 6.4, 95% CI: 3.7-11.0), Hodgkin lymphoma (SIR = 6.2, 95% CI: 3.9-9.9) and soft-tissue sarcoma (SIR = 5.0, 95% CI: 3.0-8.5). Survivors treated with radiotherapy were at 33-fold risk of salivary gland SPNs (95% CI: 25.3-44.5), particularly Hodgkin lymphoma (SIR = 66.2, 95% CI: 43.6-100.5) and leukaemia (SIR = 50.5, 95% CI: 36.1-70.7) survivors. Survivors treated with chemotherapy had a substantially increased risk of a tongue SPN (SIR = 15.9, 95% CI: 10.6-23.7). CONCLUSIONS: Previous radiotherapy increases the risk of salivary gland SPNs considerably, while chemotherapy increases the risk of tongue SPNs substantially. Awareness of these risks among both health-care professionals and survivors could play a crucial role in detecting oral SPNs early.

Risk of cerebrovascular disease among 13 457 five-year survivors of childhood cancer: A population-based cohort study.

Survivors of childhood cancer treated with cranial irradiation are at risk of cerebrovascular disease (CVD), but the risks beyond age 50 are unknown. In all, 13457 survivors of childhood cancer included in the population-based British Childhood Cancer Survivor Study cohort were linked to Hospital Episode Statistics data for England. Risk of CVD related hospitalisation was quantified by standardised hospitalisation ratios (SHRs), absolute excess risks and cumulative incidence. Overall, 315 (2.3%) survivors had been hospitalised at least once for CVD with a 4-fold risk compared to that expected (95% confidence interval [CI]: 3.7-4.3). Survivors of a central nervous system (CNS) tumour and leukaemia treated with cranial irradiation were at greatest risk of CVD (SHR = 15.6, 95% CI: 14.0-17.4; SHR = 5.4; 95% CI: 4.5-6.5, respectively). Beyond age 60, on average, 3.1% of CNS tumour survivors treated with cranial irradiation were hospitalised annually for CVD (0.4% general population). Cumulative incidence of CVD increased from 16.0% at age 50 to 26.0% at age 65 (general population: 1.4-4.2%). In conclusion, among CNS tumour survivors treated with cranial irradiation, the risk of CVD continues to increase substantially beyond age 50 up to at least age 65. Such survivors should be: counselled regarding this risk; regularly monitored for hypertension, dyslipidaemia and diabetes; advised on life-style risk behaviours. Future research should include the recall for counselling and brain MRI to identify subgroups that could benefit from pharmacological or surgical intervention and establishment of a case-control study to comprehensively determine risk-factors for CVD.

Risk of digestive cancers in a cohort of 69 460 five-year survivors of childhood cancer in Europe: the PanCareSurFup study.

BACKGROUND: Survivors of childhood cancer are at risk of subsequent primary neoplasms (SPNs), but the risk of developing specific digestive SPNs beyond age 40 years remains uncertain. We investigated risks of specific digestive SPNs within the largest available cohort worldwide. METHODS: The PanCareSurFup cohort includes 69 460 five-year survivors of childhood cancer from 12 countries in Europe. Risks of digestive SPNs were quantified using standardised incidence ratios (SIRs), absolute excess risks and cumulative incidence. RESULTS: 427 digestive SPNs (214 colorectal, 62 liver, 48 stomach, 44 pancreas, 59 other) were diagnosed in 413 survivors. Wilms tumour (WT) and Hodgkin lymphoma (HL) survivors were at greatest risk (SIR 12.1; 95% CI 9.6 to 15.1; SIR 7.3; 95% CI 5.9 to 9.0, respectively). The cumulative incidence increased the most steeply with increasing age for WT survivors, reaching 7.4% by age 55% and 9.6% by age 60 years (1.0% expected based on general population rates). Regarding colorectal SPNs, WT and HL survivors were at greatest risk; both seven times that expected. By age 55 years, 2.3% of both WT (95% CI 1.4 to 3.9) and HL (95% CI 1.6 to 3.2) survivors had developed a colorectal SPN-comparable to the risk among members of the general population with at least two first-degree relatives affected. CONCLUSIONS: Colonoscopy surveillance before age 55 is recommended in many European countries for individuals with a family history of colorectal cancer, but not for WT and HL survivors despite a comparable risk profile. Clinically, serious consideration should be given to the implementation of colonoscopy surveillance while further evaluation of its benefits, harms and cost-effectiveness in WT and HL survivors is undertaken.

Risk of subsequent primary neoplasms in survivors of adolescent and young adult cancer (Teenage and Young Adult Cancer Survivor Study): a population-based, cohort study.

BACKGROUND: Few studies have investigated the risks of subsequent primary neoplasms after adolescent and young adult (AYA) cancer. We investigated the risks of specific subsequent primary neoplasms after each of 16 types of AYA cancer. METHODS: The Teenage and Young Adult Cancer Survivor Study is a population-based cohort of 200 945 survivors of cancer diagnosed when aged 15-39 years in England and Wales from Jan 1, 1971, to Dec 31, 2006. The cohort was established using cancer registrations from the Office for National Statistics and the Welsh Cancer registry. Follow-up was from 5-year survival until the first occurrence of death, emigration, or study end date (Dec 31, 2012). In this analysis, we focus on the risk of specific subsequent primary neoplasms after 16 types of AYA cancer: breast; cervical; testicular; Hodgkin lymphoma (female); Hodgkin lymphoma (male); melanoma; CNS (intracranial); colorectal; non-Hodgkin lymphoma; thyroid; soft-tissue sarcoma; ovarian; bladder; other female genital; leukaemia; and head and neck cancer. We report absolute excess risks (AERs; per 10 000 person-years) and cumulative incidence of specific types of subsequent primary neoplasm after each type of AYA cancer. FINDINGS: During the 2 631 326 person-years of follow-up (median follow-up 16·8 years, IQR 10·5-25·2), 12 321 subsequent primary neoplasms were diagnosed in 11 565 survivors, most frequently among survivors of breast cancer, cervical cancer, testicular cancer, and Hodgkin lymphoma. AERs of any subsequent primary neoplasms were 19·5 per 10 000 person-years (95% CI 17·4-21·5) in survivors of breast cancer, 10·2 (8·0-12·4) in survivors of cervical cancer, 18·9 (16·6-21·1) in survivors of testicular cancer, 55·7 (50·4-61·1) in female survivors of Hodgkin lymphoma, and 29·9 (26·3-33·6) in male survivors of Hodgkin lymphoma. The cumulative incidence of all subsequent primary neoplasms 35 years after diagnosis was 11·9% (95% CI 11·3-12·6) in survivors of breast cancer, 15·8% (14·8-16·7) in survivors of cervical cancer, 20·2% (18·9-21·5) in survivors of testicular cancer, 26·6% (24·7-28·6) in female survivors of Hodgkin lymphoma, and 16·5% (15·2-18·0) in male survivors of Hodgkin lymphoma. In patients who had survived at least 30 years from diagnosis of cervical cancer, testicular cancer, Hodgkin lymphoma in women, breast cancer, and Hodgkin lymphoma in men, we identified a small number of specific subsequent primary neoplasms that account for 82%, 61%, 58%, 45%, and 41% of the total excess number of neoplasms, respectively. Lung cancer accounted for a notable proportion of the excess number of neoplasms across all AYA groups investigated. INTERPRETATION: Our finding that a small number of specific subsequent primary neoplasms account for a large percentage of the total excess number of neoplasms in long-term survivors of cervical, breast, and testicular cancer, and Hodgkin lymphoma provides an evidence base to inform priorities for clinical long-term follow-up. The prominence of lung cancer after each of these AYA cancers indicates the need for further work aimed at preventing and reducing the burden of this cancer in future survivors of AYA cancer. FUNDING: Cancer Research UK, National Institute for Health Research, Academy of Medical Sciences, and Children with Cancer UK.

Population-Based Long-Term Cardiac-Specific Mortality Among 34 489 Five-Year Survivors of Childhood Cancer in Great Britain.

BACKGROUND: Increased risks of cardiac morbidity and mortality among childhood cancer survivors have been described previously. However, little is known about the very long-term risks of cardiac mortality and whether the risk has decreased among those more recently diagnosed. We investigated the risk of long-term cardiac mortality among survivors within the recently extended British Childhood Cancer Survivor Study. METHODS: The British Childhood Cancer Survivor Study is a population-based cohort of 34 489 five-year survivors of childhood cancer diagnosed from 1940 to 2006 and followed up until February 28, 2014, and is the largest cohort to date to assess late cardiac mortality. Standardized mortality ratios and absolute excess risks were used to quantify cardiac mortality excess risk. Multivariable Poisson regression models were used to evaluate the simultaneous effect of risk factors. Likelihood ratio tests were used to test for heterogeneity and trends. RESULTS: Overall, 181 cardiac deaths were observed, which was 3.4 times that expected. Survivors were 2.5 times and 5.9 times more at risk of ischemic heart disease and cardiomyopathy/heart failure death, respectively, than expected. Among those >60 years of age, subsequent primary neoplasms, cardiac disease, and other circulatory conditions accounted for 31%, 22%, and 15% of all excess deaths, respectively, providing clear focus for preventive interventions. The risk of both overall cardiac and cardiomyopathy/heart failure mortality was greatest among those diagnosed from 1980 to 1989. Specifically, for cardiomyopathy/heart failure deaths, survivors diagnosed from 1980 to 1989 had 28.9 times the excess number of deaths observed for survivors diagnosed either before 1970 or from 1990 on. CONCLUSIONS: Excess cardiac mortality among 5-year survivors of childhood cancer remains increased beyond 50 years of age and has clear messages in terms of prevention strategies. However, the fact that the risk was greatest in those diagnosed from 1980 to 1989 suggests that initiatives to reduce cardiotoxicity among those treated more recently may be having a measurable impact.

Risk of Cerebrovascular Events in 178 962 Five-Year Survivors of Cancer Diagnosed at 15 to 39 Years of Age: The TYACSS (Teenage and Young Adult Cancer Survivor Study).

BACKGROUND: Survivors of teenage and young adult cancer are at risk of cerebrovascular events, but the magnitude of and extent to which this risk varies by cancer type, decade of diagnosis, age at diagnosis, and attained age remains uncertain. This is the largest-ever cohort study to evaluate the risks of hospitalization for a cerebrovascular event among long-term survivors of teenage and young adult cancer. METHODS: The population-based TYACSS (Teenage and Young Adult Cancer Survivor Study) (N=178,962) was linked to Hospital Episode Statistics data for England to investigate the risks of hospitalization for a cerebrovascular event among 5-year survivors of cancer diagnosed when 15 to 39 years of age. Observed numbers of first hospitalizations for cerebrovascular events were compared with that expected from the general population using standardized hospitalization ratios (SHRs) and absolute excess risks per 10 000 person-years. Cumulative incidence was calculated with death considered a competing risk. RESULTS: Overall, 2782 cancer survivors were hospitalized for a cerebrovascular event-40% higher than expected (SHR=1.4, 95% confidence interval, 1.3-1.4). Survivors of central nervous system (CNS) tumors (SHR=4.6, 95% confidence interval, 4.3-5.0), head and neck tumors (SHR=2.6, 95% confidence interval, 2.2-3.1), and leukemia (SHR=2.5, 95% confidence interval, 1.9-3.1) were at greatest risk. Males had significantly higher absolute excess risks than females (absolute excess risks =7 versus 3), especially among head and neck tumor survivors (absolute excess risks =30 versus 11). By 60 years of age, 9%, 6%, and 5% of CNS tumor, head and neck tumor, and leukemia survivors, respectively, had been hospitalized for a cerebrovascular event. Beyond 60 years of age, every year, 0.4% of CNS tumor survivors were hospitalized for a cerebral infarction (versus 0.1% expected), whereas at any age, every year, 0.2% of head and neck tumor survivors were hospitalized for a cerebral infarction (versus 0.06% expected). CONCLUSIONS: Survivors of a CNS tumor, head and neck tumor, and leukemia are particularly at risk of hospitalization for a cerebrovascular event. The excess risk of cerebral infarction among CNS tumor survivors increases with attained age. For head and neck tumor survivors, this excess risk remains high across all ages. These groups of survivors, particularly males, should be considered for surveillance of cerebrovascular risk factors and potential pharmacological interventions for cerebral infarction prevention.

Respiratory mortality of childhood, adolescent and young adult cancer survivors.

BACKGROUND: Exposure to radiation and/or chemotherapy during cancer treatment can compromise respiratory function. We investigated the risk of long-term respiratory mortality among 5-year cancer survivors diagnosed before age 40 years using the British Childhood Cancer Survivor Study (BCCSS) and Teenage and Young Adult Cancer Survivor Study (TYACSS). METHODS: The BCCSS comprises 34 489 cancer survivors diagnosed before 15 years from 1940 to 2006 in Great Britain. The TYACSS includes 200 945 cancer survivors diagnosed between 15 years and 39 years from 1971 to 2006 in England and Wales. Standardised mortality ratios and absolute excess risks were used. FINDINGS: Overall, 164 and 1079 respiratory deaths were observed in the BCCSS and TYACSS cohorts respectively, which was 6.8 (95% CI 5.8 to 7.9) and 1.7 (95% CI 1.6 to 1.8) times that expected, but the risks varied substantially by type of respiratory death. Greatest excess numbers of deaths were experienced after central nervous system (CNS) tumours in the BCCSS and after lung cancer, leukaemia, head and neck cancer and CNS tumours in the TYACSS. The excess number of respiratory deaths increased with increasing attained age, with seven (95% CI 2.4 to 11.3) excess deaths observed among those aged 50+ years in the BCCSS and three (95% CI 1.4 to 4.2) excess deaths observed among those aged 60+ years in the TYACSS. It was reassuring to see a decline in the excess number of respiratory deaths among those diagnosed more recently in both cohorts. CONCLUSIONS: Prior to this study, there was almost nothing known about the risks of respiratory death after cancer diagnosed in young adulthood, and this study addresses this gap. These new findings will be useful for both survivors and those involved in their clinical management and follow-up.

The PanCareSurFup cohort of 83,333 five-year survivors of childhood cancer: a cohort from 12 European countries.

Childhood cancer survivors face risks from a variety of late effects, including cardiac events, second cancers, and late mortality. The aim of the pan-European PanCare Childhood and Adolescent Cancer Survivor Care and Follow-Up Studies (PanCareSurFup) Consortium was to collect data on incidence and risk factors for these late effects among childhood cancer survivors in Europe. This paper describes the methodology of the data collection for the overall PanCareSurFup cohort and the outcome-related cohorts. In PanCareSurFup 13 data providers from 12 countries delivered data to the data centre in Mainz. Data providers used a single variable list that covered all three outcomes. After validity and plausibility checks data was provided to the outcome-specific working groups. In total, we collected data on 115,596 patients diagnosed with cancer from 1940 to 2011, of whom 83,333 had survived 5 years or more. Due to the eligibility criteria and other requirements different numbers of survivors were eligible for the analysis of each of the outcomes. Thus, 1014 patients with at least one cardiac event were identified from a cohort of 39,152 5-year survivors; for second cancers 3995 survivors developed at least one second cancer from a cohort of 71,494 individuals, and from the late mortality cohort of 79,441 who had survived at least 5 years, 9247 died subsequently. Through the close cooperation of many European countries and the establishment of one central data collection and harmonising centre, the project succeeded in generating the largest cohort of children with cancer to date.

Cardiac Mortality Among 200 000 Five-Year Survivors of Cancer Diagnosed at 15 to 39 Years of Age: The Teenage and Young Adult Cancer Survivor Study.

BACKGROUND: Survivors of teenage and young adult cancer are acknowledged as understudied. Little is known about their long-term adverse health risks, particularly of cardiac disease that is increased in other cancer populations where cardiotoxic treatments have been used. METHODS: The Teenage and Young Adult Cancer Survivor Study cohort comprises 200 945 5-year survivors of cancer diagnosed at 15 to 39 years of age in England and Wales from 1971 to 2006, and followed to 2014. Standardized mortality ratios, absolute excess risks, and cumulative risks were calculated. RESULTS: Two thousand sixteen survivors died of cardiac disease. For all cancers combined, the standardized mortality ratios for all cardiac diseases combined was greatest for individuals diagnosed at 15 to 19 years of age (4.2; 95% confidence interval, 3.4-5.2) decreasing to 1.2 (95% confidence interval, 1.1-1.3) for individuals aged 35 to 39 years (2P for trend <0.0001). Similar patterns were observed for both standardized mortality ratios and absolute excess risks for ischemic heart disease, valvular heart disease, and cardiomyopathy. Survivors of Hodgkin lymphoma, acute myeloid leukaemia, genitourinary cancers other than bladder cancer, non-Hodgkin lymphoma, lung cancer, leukaemia other than acute myeloid, central nervous system tumour, cervical cancer, and breast cancer experienced 3.8, 2.7, 2.0, 1.7, 1.7, 1.6, 1.4, 1.3 and 1.2 times the number of cardiac deaths expected from the general population, respectively. Among survivors of Hodgkin lymphoma aged over 60 years, almost 30% of the total excess number of deaths observed were due to heart disease. CONCLUSIONS: This study of over 200 000 cancer survivors shows that age at cancer diagnosis was critical in determining subsequent cardiac mortality risk. For the first time, risk estimates of cardiac death after each cancer diagnosed between the ages of 15 and 39 years have been derived from a large population-based cohort with prolonged follow-up. The evidence here provides an initial basis for developing evidence-based follow-up guidelines.

Employment status and occupational level of adult survivors of childhood cancer in Great Britain: The British childhood cancer survivor study.

The British Childhood Cancer Survivor Study (BCCSS) provides the first detailed investigation of employment and occupation to be undertaken in a large population-based cohort. Previous studies have been limited by design issues such as using small numbers of survivors with specific diagnoses, and involved limited assessment of employment status and occupational level. The BCCSS includes 17,981 5-year survivors of childhood cancer. Employment status and occupational level were ascertained by questionnaire from eligible survivors (n = 14,836). Multivariate logistic regression was used to explore factors associated with employment and occupation, and to compare survivors to their demographic peers in the general population. Employment status was available for 10,257 survivors. Gender, current age, cancer type, radiotherapy, age at diagnosis and epilepsy were consistently associated with being: employed; unable to work; in managerial or non-manual occupations. Overall, survivors were less likely to be working than expected (OR (99% CI): 0.89 (0.81-0.98)), and this deficit was greatest for irradiated CNS neoplasm survivors (0.34 (0.28-0.41)). Compared to the general population, survivors were fivefold more likely to be unable to work due to illness/disability; the excess was 15-fold among CNS neoplasm survivors treated with radiotherapy. Overall survivors were less likely to be in managerial occupations than expected (0.85 (0.77-0.94)). However, bone sarcoma survivors were more likely to be in these occupations than expected (1.37 (1.01-1.85)) and also similarly for non-manual occupations (1.90 (1.37-2.62)). Survivors of retinoblastoma (1.55 (1.20-2.01)) and 'other' neoplasm group (1.62 (1.30-2.03)) were also more likely to be in non-manual occupations than expected.

Risk stratification of childhood cancer survivors necessary for evidence-based clinical long-term follow-up.

BACKGROUND: Reorganisation of clinical follow-up care in England was proposed by the National Cancer Survivorship Initiative (NCSI), based on cancer type and treatment, ranging from Level 1 (supported self-management) to Level 3 (consultant-led care). The objective of this study was to provide an investigation of the risks of serious adverse health-outcomes associated with NCSI Levels of clinical care using a large population-based cohort of childhood cancer survivors. METHODS: The British Childhood Cancer Survivor Study (BCCSS) was used to investigate risks of specific causes of death, subsequent primary neoplasms (SPNs) and non-fatal non-neoplastic outcomes by NCSI Level. RESULTS: Cumulative (excess) risks of specified adverse outcomes by 45 years from diagnosis among non-leukaemic survivors assigned to NCSI Levels 1, 2 and 3 were for: SPNs-5% (two-fold expected), 14% (four-fold expected) and 21% (eight-fold expected); non-neoplastic death-2% (two-fold expected), 4% (three-fold expected) and 8% (seven-fold expected); non-fatal non-neoplastic condition-14%, 27% and 40%, respectively. Consequently overall cumulative risks of any adverse health outcome were 21%, 45% and 69%, respectively. CONCLUSIONS: Despite its simplicity the risk stratification tool provides clear and strong discrimination between survivors assigned to different NCSI Levels in terms of long-term cumulative and excess risks of serious adverse outcomes.

Aspects of mental health dysfunction among survivors of childhood cancer.

BACKGROUND: Some previous studies have reported that survivors of childhood cancer are at an increased risk of developing long-term mental health morbidity, whilst others have reported that this is not the case. Therefore, we analysed 5-year survivors of childhood cancer using the British Childhood Cancer Survivor Study (BCCSS) to determine the risks of aspects of long-term mental health dysfunction. PROCEDURE: Within the BCCSS, 10 488 survivors completed a questionnaire that ascertained mental health-related information via 10 questions from the Short Form-36 survey. Internal analyses were conducted using multivariable logistic regression to determine risk factors for mental health dysfunction. External analyses were undertaken using direct standardisation to compare mental health dysfunction in survivors with UK norms. RESULTS: This study has shown that overall, childhood cancer survivors had a significantly higher prevalence of mental health dysfunction for 6/10 questions analysed compared to UK norms. Central nervous system (CNS) and bone sarcoma survivors reported the greatest dysfunction, compared to expected, with significant excess dysfunction in 10 and 6 questions, respectively; the excess ranged from 4.4-22.3% in CNS survivors and 6.9-15.9% in bone sarcoma survivors. Compared to expected, excess mental health dysfunction increased with attained age; this increase was greatest for reporting 'limitations in social activities due to health', where the excess rose from 4.5% to 12.8% in those aged 16-24 and 45+, respectively. Within the internal analyses, higher levels of educational attainment and socio-economic classification were protective against mental health dysfunction. CONCLUSIONS: Based upon the findings of this large population-based study, childhood cancer survivors report significantly higher levels of mental health dysfunction than those in the general population, where deficits were observed particularly among CNS and bone sarcoma survivors. Limitations were also observed to increase with age, and thus it is important to emphasise the need for mental health evaluation and services across the entire lifespan. There is evidence that low educational attainment and being unemployed or having never worked adversely impacts long-term mental health. These findings provide an evidence base for risk stratification and planning interventions.

Cumulative Absolute Risk of Subsequent Colorectal Cancer After Abdominopelvic Radiotherapy Among Childhood Cancer Survivors: A PanCareSurFup Study.

PURPOSE: Childhood cancer survivors are at the risk of developing subsequent colorectal cancers (CRCs), but the absolute risks by treatment modality are uncertain. We quantified the absolute risks by radiotherapy treatment characteristics using clinically accessible data from a Pan-European wide case-control study nested within a large cohort of childhood cancer survivors: the PanCareSurFup Study. METHODS: Odds ratios (ORs) from a case-control study comprising 143 CRC cases and 143 controls nested within a cohort of 69,460 survivors were calculated. These, together with standardized incidence ratios for CRC for this cohort and European general population CRC incidence rates and survivors' mortality rates, were used to estimate cumulative absolute risks (CARs) by attained age for different categories of radiation to the abdominopelvic area. RESULTS: Overall, survivors treated with abdominopelvic radiotherapy treatment (ART) were three times more likely to develop a subsequent CRC than those who did not receive ART (OR, 3.1 [95% CI, 1.4 to 6.6]). For male survivors treated with ART, the CAR was 0.27% (95% CI, 0.17 to 0.59) by age 40 years, 1.08% (95% CI, 0.69 to 2.34) by age 50 years (0.27% expected in the general population), and 3.7% (95% CI, 2.36 to 7.80) by age 60 years (0.95% expected). For female survivors treated with ART, the CAR was 0.29% (95% CI, 0.18 to 0.62) by age 40 years, 1.03% (95% CI, 0.65 to 2.22) by age 50 years (0.27% expected), and 3.0% (95% CI, 1.91 to 6.37) by age 60 years (0.82% expected). CONCLUSION: We demonstrated that by age 40 years survivors of childhood cancer treated with ART already have a similar risk of CRC as those age 50 years in the general population for whom population-based CRC screening begins in many countries. This information should be used in the development of survivorship guidelines for the risk stratification of survivors concerning CRC risk.

Radiation Doses Received by Major Organs at Risk in Children and Young Adolescents Treated for Cancer with External Beam Radiation Therapy: A Large-scale Study from 12 European Countries.

PURPOSE: Childhood cancer survivors, in particular those treated with radiation therapy, are at high risk of long-term iatrogenic events. The prediction of risk of such events is mainly based on the knowledge of the radiation dose received to healthy organs and tissues during treatment of childhood cancer diagnosed decades ago. We aimed to set up a standardized organ dose table to help former patients and clinicians in charge of long-term follow-up clinics. METHODS AND MATERIALS: We performed whole body dosimetric reconstruction for 2646 patients from 12 European countries treated between 1941 and 2006 (median, 1976). Most plannings were 2- or 3-dimensional. A total of 46% of patients were treated using Cobalt 60, and 41%, using a linear accelerator. The median prescribed dose was 27.2 Gy (IQ1-IQ3, 17.6-40.0 Gy). A patient-specific voxel-based anthropomorphic phantom with more than 200 anatomic structures or substructures delineated as a surrogate of each subject's anatomy was used. The radiation therapy was simulated with a treatment planning system based on available treatment information. The radiation dose received by any organ of the body was estimated by extending the treatment planning system dose calculation to the whole body, by type and localization of childhood cancer. RESULTS: The integral dose and normal tissue doses to most of the 23 considered organs increased between the 1950s and 1970s and decreased or plateaued thereafter. Whatever the organ considered, the type of childhood cancer explained most of the variability in organ dose. The country of treatment explained only a small part of the variability. CONCLUSIONS: The detailed dose estimates provide very useful information for former patients or clinicians who have only limited knowledge about radiation therapy protocols or techniques, but who know the type and site of childhood cancer, sex, age, and year of treatment. This will allow better prediction of the long-term risk of iatrogenic events and better referral to long-term follow-up clinics.

Risk Factors for Heart Failure Among Pan-European Childhood Cancer Survivors: A PanCareSurFup and ProCardio Cohort and Nested Case-Control Study.

PURPOSE: Heart failure (HF) is a potentially life-threatening complication of treatment for childhood cancer. We evaluated the risk and risk factors for HF in a large European study of long-term survivors. Little is known of the effects of low doses of treatment, which is needed to improve current treatment protocols and surveillance guidelines. METHODS: This study includes the PanCareSurFup and ProCardio cohort of ≥ 5-year childhood cancer survivors diagnosed between 1940 and 2009 in seven European countries (N = 42,361). We calculated the cumulative incidence of HF and conducted a nested case-control study to evaluate detailed treatment-related risk factors. RESULTS: The cumulative incidence of HF was 2% (95% CI, 1.7 to 2.2) by age 50 years. The case-control study (n = 1,000) showed that survivors who received a mean heart radiation therapy (RT) dose of 5 to < 15 Gy have an increased risk of HF (odds ratio, 5.5; 95% CI, 2.5 to 12.3), when compared with no heart RT. The risk associated with doses 5 to < 15 Gy increased with exposure of a larger heart volume. In addition, the HF risk increased in a linear fashion with higher mean heart RT doses. Regarding total cumulative anthracycline dose, survivors who received ≥ 100 mg/m2 had a substantially increased risk of HF and survivors treated with a lower dose showed no significantly increased risk of HF. The dose-response relationship appeared quadratic with higher anthracycline doses. CONCLUSION: Survivors who received a mean heart RT dose of ≥ 5 Gy have an increased risk of HF. The risk associated with RT increases with larger volumes exposed. Survivors treated with < 100 mg/m2 total cumulative anthracycline dose have no significantly increased risk of HF. These new findings might have consequences for new treatment protocols for children with cancer and for cardiomyopathy surveillance guidelines.

Risk Factors for Primary Bone Cancer After Childhood Cancer: A PanCare Childhood and Adolescent Cancer Survivor Care and Follow-Up Studies Nested Case-Control Study.

PURPOSE: Radiation to the bone and exposure to alkylating agents increases the risk of bone cancer among survivors of childhood cancer, but there is uncertainty regarding the risks of bone tissue radiation doses below 10 Gy and the dose-response relationship for specific types of chemotherapy. METHODS: Twelve European countries contributed 228 cases and 228 matched controls to a nested case-control study within a cohort of 69,460 5-year survivors of childhood cancer. Odds ratios (ORs) of developing bone cancer for different levels of cumulative radiation exposure and cumulative doses of specific types of chemotherapy were calculated. Excess ORs were calculated to investigate the shape and extent of any dose-response relationship. RESULTS: The OR associated with bone tissue exposed to 1-4 Gy was 4.8-fold (95% CI, 1.2 to 19.6) and to 5-9 Gy was 9.6-fold (95% CI, 2.4 to 37.4) compared with unexposed bone tissue. The OR increased linearly with increasing dose of radiation (Ptrend < .001) up to 78-fold (95% CI, 9.2 to 669.9) for doses of ≥40 Gy. For cumulative alkylating agent doses of 10,000-19,999 and ≥20,000 mg/m2, the radiation-adjusted ORs were 7.1 (95% CI, 2.2 to 22.8) and 8.3 (95% CI, 2.8 to 24.4), respectively, with independent contributions from each of procarbazine, ifosfamide, and cyclophosphamide. Other cytotoxics were not associated with bone cancer. CONCLUSION: To our knowledge, we demonstrate-for the first time-that the risk of bone cancer is increased 5- to 10-fold after exposure of bone tissue to cumulative radiation doses of 1-9 Gy. Alkylating agents exceeding 10,000 mg/m2 increase the risk 7- to 8-fold, particularly following procarbazine, ifosfamide, and cyclophosphamide. These substantially elevated risks should be used to develop/update clinical follow-up guidelines and survivorship care plans.

Hypothyroidism following childhood cancer therapy-an under diagnosed complication.

To determine the prevalence of hypothyroidism amongst most adult survivors of childhood cancer in Britain using the British Childhood Cancer Survivor Study (BCCSS). The BCCSS is a population based cohort of individuals diagnosed with childhood cancer between 1940 and 1991 and who survived at least 5 years from diagnosis (n = 17,981). 10483, 71% of those survivors aged at least 16 years, returned a completed questionnaire, which asked if hypothyroidism had been diagnosed. Of the whole cohort, 7.7% reported hypothyroidism with the highest risk among patients treated for Hodgkin's disease (HD) (19.9%), CNS neoplasms (15.3%), Non-Hodgkin's lymphoma (6.2%) and leukaemia (5.2%). Survivors were more likely to develop hypothyroidism if they had received radiotherapy for HD (p = 0.0001) or a CNS neoplasm (p < 0.00005) but not leukaemia (p = 0.3). In these three patient groups, the frequency of hypothyroidism was similar in men and women. Survivors of irradiated CNS tumours reported a prevalence of hypothyroidism, which was substantially lower if discharged to primary care compared with being on hospital follow-up and which declined substantially with increased follow-up in both primary care (p = 0.004) and hospital follow-up (p = 0.023) settings. Hypothyroidism is a common finding amongst adult survivors of childhood malignancy. The substantial differences in reported hypothyroidism prevalence after irradiated CNS neoplasms suggests substantial under-diagnosis, which increased with increased follow-up, and which increased among those followed-up in primary care compared with hospital settings.