Katherine E. Henson

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.

Can Observational Data Replace Randomized Trials

TO THE EDITOR: The increasing complexity and cost of conducting randomized trials have stimulated interest in using observational data sets to evaluate cancer treatments. Determining the causal effect of treatments from observational data is, however, challenging because more aggressive treatments are selectively prescribed for patients with adverse disease characteristics or favorable comorbidity profiles. Associations may, therefore, arise between treatments and outcomes that are the result of confounding and are not causal. Relatively little is known about the extent of such confounding or the degree to which it can be removed through stratification by prognostic variables. Breast cancer is one of the commonest conditions for which radiotherapy is prescribed. We have therefore used it to examine this issue. We analyzed data on women registered between 1990 and 2008 in the SEER public-use data set. Women were excluded if they were younger than 20 or older than 80 years when diagnosed, had previous cancer, unknown cancer laterality, bilateral cancer, or unknown radiotherapy status. Each woman entered the study on the date of her breast cancer diagnosis and left on the earliest of the following events: death, loss to follow-up, turning age 85 years, or January 1, 2009. Two analyses were conducted. In the first, deaths and person-years were stratified by five basic variables; the second stratification also included all available prognostic variables. Mortality ratios were estimated by maximum likelihood using Poisson regression. Calculations were performed using STATAversion 12 (STATA, College Station, TX). Information was also collated from the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) meta-analyses of randomized trials of radiotherapy versus not. Analyses were stratified by trial, individual follow-up year, age at randomization, and nodal status. After breast-conserving surgery, with only basic variables in the stratification, radiotherapy was associated with reduced mortality for all the causes examined (Appendix Table A1, online only). Stratifying for all available prognostic variables changed the estimates, but all remained significantly below one. Notably, the rate ratio for mortality from all causes except breast cancer (0.69) was lower than that for breast cancer (0.74). After mastectomy in node-positive disease, with only basic variables in the stratification, radiotherapy was associated with increased breast cancer mortality and all-cause mortality, and decreased mortality from all causes except breast cancer. Stratifying for prognostic variables changed the death rate ratios for breast cancer from 1.35 to 0.89 and all causes of death from 1.21 to 0.85, but the rate ratio for mortality from all causes except breast cancer (0.74) was still lower than that for breast cancer (0.89). Estimates of the effects of radiotherapy in the EBCTCG meta-analyses of randomized trials were then compared with the corresponding death rate ratios in the SEER data stratified by all available variables (basic and prognostic; Fig 1). After breastconserving surgery, the breast cancer death rate ratio in the EBCTCG data was 0.83 for all women and did not differ significantly between pN0 (node-negative disease) and pN1 (node-positive disease; P5 .76), whereas in the SEER data the corresponding death rate ratio for all women was lower (0.74 v 0.83; P 5 .04), and differed significantly between pN0 and pN1 (0.84 v 0.73; P 5 .008). After mastectomy, the breast cancer death rate ratio in the EBCTCG data was 0.85, similar to that after breast-conserving surgery, and it did not differ significantly according to the number of positive nodes (P for heterogeneity 5 .53). In contrast, in the SEER data, there was substantial heterogeneity in the breast cancer death rate ratios according to the number of positive nodes (P for heterogeneity , .001). In women with one to three positive nodes, postmastectomy radiotherapy was associated with significantly increased breast cancer mortality in the SEER data (1.10; 95%CI, 1.02 to 1.18) and significantly decreased breast cancer mortality in the EBCTCG data (0.80; 95% CI, 0.67 to 0.95). For mortality from all causes except breast cancer, there were also major qualitative differences between the EBCTCG and SEER data. In the EBCTCGdata, radiotherapywas associatedwith significantly higher rates of mortality from all causes except breast cancer, including from heart disease and from lung cancer. In the SEER data, radiotherapy was associated with significantly lower rates of mortality from all causes except breast cancer, including from heart disease. SEER is one of the largest, most detailed data sets. If we had used these SEER analyses to draw conclusions about the causal effects of radiotherapy, we would have concluded that radiotherapy after breastconserving surgery is more effective in node-positive than in nodenegative disease, and that radiotherapy after mastectomy in women with one to three positive nodes causes death from breast cancer. We would have also concluded that radiotherapy prevents mortality from all causes except breast cancer, including from heart disease and from accidents and violence (Appendix Table A1). These results contradict those of the randomized trials. We conclude, as have others, that nonrandomized comparisons are liable to provide misleading estimates of treatment effects. Therefore, they need careful justification every time they are used.

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.

Cardiac Mortality Among 200 000 Five-Year Survivors of Cancer Diagnosed at 15 to 39 Years of AgeClinical Perspective: 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.

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.

Risk of Cerebrovascular Events in 178 962 Five-Year Survivors of Cancer Diagnosed at 15 to 39 Years of AgeClinical Perspective

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.

Risk of Cerebrovascular Events in 178 962 Five-Year Survivors of Cancer Diagnosed at 15 to 39 Years of AgeClinical Perspective: 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.

Cardiac Mortality Among 200 000 Five-Year Survivors of Cancer Diagnosed at 15 to 39 Years of AgeClinical Perspective

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.