Julie Kelly

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.

Long term cause specific mortality among 34 489 five year survivors of childhood cancer in Great Britain: population based cohort study

Objective To determine whether modern treatments for cancer are associated with a net increased or decreased risk of death from neoplastic and non-neoplastic causes among survivors of childhood cancer. Design Population based cohort study. Setting British Childhood Cancer Survivor Study. Participants Nationwide population based cohort of 34 489 five year survivors of childhood cancer with a diagnosis from 1940 to 2006 and followed up until 28 February 2014. Main outcome measures Cause specific standardised mortality ratios and absolute excess risks are reported. Multivariable Poisson regression models were utilised to evaluate the simultaneous effect of risk factors. Likelihood ratio tests were used to test for heterogeneity or trend. Results Overall, 4475 deaths were observed, which was 9.1 (95% confidence interval 8.9 to 9.4) times that expected in the general population, corresponding to 64.2 (95% confidence interval 62.1 to 66.3) excess deaths per 10 000 person years. The number of excess deaths from all causes declined among those treated more recently; those treated during 1990-2006 experienced 30% of the excess number of deaths experienced by those treated before 1970. The corresponding percentages for the decline in excess deaths from recurrence or progression and non-neoplastic causes were 30% and 60%, respectively. Among survivors aged 50-59 years, 41% and 22% of excess deaths were attributable to subsequent primary neoplasms and circulatory conditions, respectively, whereas the corresponding percentages among those aged 60 years or more were 31% and 37%. Conclusions The net effects of changes in cancer treatments, and surveillance and management for late effects, over the period 1940 to 2006 was to reduce the excess number of deaths from both recurrence or progression and non-neoplastic causes among those treated more recently. Among survivors aged 60 years or more, the excess number of deaths from circulatory causes exceeds the excess number of deaths from subsequent primary neoplasms. The important message for the evidence based surveillance aimed at preventing excess mortality and morbidity in survivors aged 60 years or more is that circulatory disease overtakes subsequent primary neoplasms as the leading cause of excess mortality.

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.

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.

Long-term adverse outcomes in survivors of childhood bone sarcoma: the British Childhood Cancer Survivor Study

Background:With improved survival, more bone sarcoma survivors are approaching middle age making it crucial to investigate the late effects of their cancer and its treatment. We investigated the long-term risks of adverse outcomes among 5-year bone sarcoma survivors within the British Childhood Cancer Survivor Study.Methods:Cause-specific mortality and risk of subsequent primary neoplasms (SPNs) were investigated for 664 bone sarcoma survivors. Use of health services, health and marital status, alcohol and smoking habits, and educational qualifications were investigated for survivors who completed a questionnaire.Results:Survivors were seven times more likely to experience all-cause mortality than expected, and there were substantial differences in risk depending on tumour type. Beyond 25 years follow-up the risk of dying from all-causes was comparable to the general population. This is in contrast to dying before 25 years where the risk was 12.7-fold that expected. Survivors were also four times more likely to develop a SPN than expected, where the excess was restricted to 5–24 years post diagnosis. Increased health-care usage and poor health status were also found. Nonetheless, for some psychosocial outcomes survivors were better off than expected.Conclusions:Up to 25 years after 5-year survival, bone sarcoma survivors are at substantial risk of death and SPNs, but this is greatly reduced thereafter. As 95% of all excess deaths before 25 years follow-up were due to recurrences and SPNs, increased monitoring of survivors could prevent mortality. Furthermore, bone and breast SPNs should be a particular concern. Since there are variations in the magnitude of excess risk depending on the specific adverse outcome under investigation and whether the survivors were initially diagnosed with osteosarcoma or Ewing sarcoma, risks need to be assessed in relation to these factors. These findings should provide useful evidence for risk stratification and updating clinical follow-up guidelines.

Risk of Adverse Health and Social Outcomes Up to 50 Years After Wilms Tumor: The British Childhood Cancer Survivor Study

PURPOSE Survivors of Wilms tumor (WT) are at risk for adverse health and social outcomes but risks beyond 30 years from diagnosis remain uncertain. We investigated the risks of adverse outcomes among 5-year survivors of WT, in particular, those between 30 and 50 years from diagnosis. PATIENTS AND METHODS The British Childhood Cancer Survivor Study includes 1,441 5-year survivors of WT. We investigated cause-specific mortality, risk of subsequent primary neoplasms (SPNs), and, for those who completed a questionnaire, the extent of smoking and drinking, educational achievement, health status, and health service use compared with the general population. RESULTS Cumulative risk of death from all causes, excluding recurrence, increased substantially from 5.4% to 22.7% at 30 years and 50 years, respectively, after WT diagnosis-75% of excess deaths beyond 30 years from diagnosis were attributable to SPNs (50%) and cardiac diseases (25%). Digestive cancer, most frequently bowel, accounted for 41% of excess cancers beyond 30 years. CONCLUSION Between 30 and 50 years from diagnosis, survivors of WT are at a substantially increased risk of premature mortality, and 75% of excess deaths were accounted for by SPNs and cardiac diseases. Radiotherapy exposure was a risk factor for both outcomes. The proportion of patients with WT who are exposed to radiotherapy has reduced substantially in recent decades because of initiatives such as the SIOP WT 2001 clinical trial, which sought to reduce late effects; however, the majority of current survivors, who are at least 30 years from diagnosis, received radiotherapy. Surveillance of this group should focus on SPNs, in particular, bowel and breast cancers, and cardiac conditions.

Pregnancy and Labor Complications in Female Survivors of Childhood Cancer: The British Childhood Cancer Survivor Study

Abstract Background: Female survivors of childhood cancer treated with abdominal radiotherapy who manage to conceive are at risk of delivering premature and low-birthweight offspring, but little is known about whether abdominal radiotherapy may also be associated with additional complications during pregnancy and labor. We investigated the risk of developing pregnancy and labor complications among female survivors of childhood cancer in the British Childhood Cancer Survivor Study (BCCSS). Methods: Pregnancy and labor complications were identified by linking the BCCSS cohort (n = 17 980) to the Hospital Episode Statistics (HES) for England. Relative risks (RRs) of pregnancy and labor complications were calculated by site of radiotherapy treatment (none/abdominal/cranial/other) and other cancer-related factors using log-binomial regression. All statistical tests were two-sided. Results: A total of 2783 singleton pregnancies among 1712 female survivors of childhood cancer were identified in HES. Wilms tumor survivors treated with abdominal radiotherapy were at threefold risk of hypertension complicating pregnancy (relative risk = 3.29, 95% confidence interval [CI] = 2.29 to 4.71), while all survivors treated with abdominal radiotherapy were at risk of gestational diabetes mellitus (RR = 3.35, 95% CI = 1.41 to 7.93) and anemia complicating pregnancy (RR = 2.10, 95% CI = 1.27 to 3.46) compared with survivors treated without radiotherapy. Survivors treated without radiotherapy had similar risks of pregnancy and labor complications as the general population, except survivors were more likely to opt for an elective cesarean section (RR = 1.39, 95% CI = 1.16 to 1.70). Conclusions: Treatment with abdominal radiotherapy increases the risk of developing hypertension complicating pregnancy in Wilms tumor survivors, and diabetes mellitus and anemia complicating pregnancy in all survivors. These patients may require extra vigilance during pregnancy.

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 of Cerebrovascular Events in 178,962 5-Year Survivors of Cancer Diagnosed Aged 15-39 Years: The Teenage and Young Adults Cancer Survivors Study (TYACSS)

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.

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.