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.

Follicle Stimulating Hormone is an accurate predictor of azoospermia in childhood cancer survivors.

The accuracy of Follicle Stimulating Hormone as a predictor of azoospermia in adult survivors of childhood cancer is unclear, with conflicting results in the published literature. A systematic review and post hoc analysis of combined data (n = 367) were performed on all published studies containing extractable data on both serum Follicle Stimulating Hormone concentration and semen concentration in survivors of childhood cancer. PubMed and Medline databases were searched up to March 2017 by two blind investigators. Articles were included if they contained both serum FSH concentration and semen concentration, used World Health Organisation certified methods for semen analysis, and the study participants were all childhood cancer survivors. There was no evidence for either publication bias or heterogeneity for the five studies. For the combined data (n = 367) the optimal Follicle Stimulating Hormone threshold was 10.4 IU/L with specificity 81% (95% CI 76%-86%) and sensitivity 83% (95% CI 76%-89%). The AUC was 0.89 (95%CI 0.86-0.93). A range of threshold FSH values for the diagnosis of azoospermia with their associated sensitivities and specificities were calculated. This study provides strong supporting evidence for the use of serum Follicle Stimulating Hormone as a surrogate biomarker for azoospermia in adult males who have been treated for childhood cancer.

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

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.

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.

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.

Screening and management of adverse endocrine outcomes in adult survivors of childhood and adolescent cancer.

5 year survival for childhood and adolescent cancer in developed countries is now in excess of 80% and the number of survivors of cancer continues to increase worldwide. After completion of therapy, many of these survivors will face a lifelong risk of endocrine late effects. We summarise the available evidence related to the prevalence and risk factors for endocrine late effects among adult survivors of childhood and adolescent cancer. Present screening, surveillance, and treatment recommendations differ by country and region, so we also highlight the continued effort to harmonise the international guidelines for this population.

Subsequent mortality experience in five-year survivors of childhood, adolescent and young adult cancer in Scotland: a population based, retrospective cohort study.

AIM: To assess the risk of death in patients who survive at least 5 years after diagnosis of childhood, adolescent or young adult cancer. PATIENTS AND METHODS: This was a population-based retrospective cohort study using linked national cancer registry and mortality records in Scotland. The study population consisted of 5229 individuals who were diagnosed with cancer before the age of 25 years between 1981 and 2003, and who survived at least 5 years after the date of diagnosis of their primary cancer. Indirect standardisation was used to calculate mortality ratios standardised for age and sex and absolute excess risks (AERs) compared to the general Scottish population. RESULTS: During 58,358 person-years of follow-up, there were 359 deaths among the cohort of cancer survivors. The overall SMR was 6.1 (95% confidence interval (CI) 5.5-6.7) and AER 51 (45-58) per 10,000 person-years. Largely because of age- and sex-related differences in background mortality, SMRs were higher in patients diagnosed at 0-14 years (SMR 11.0, 95% CI 9.3-12.9) than 15-24 years (4.7, 4.1-5.3), and in females (9.2, 7.8-10.8) than males (4.8, 4.2-5.5). SMRs and AERs varied substantially by primary cancer and by underlying cause of death. In general, SMRs were little altered by standardisation for an area-based indicator of socio-economic deprivation. Adjusted for age and sex, the risk of death was significantly lower in five-year survivors diagnosed during 1998-2003 compared to those diagnosed during 1981-1985 (Relative hazard ratio, 0.54, 95% CI 0.36-0.81). CONCLUSION: Long-term survivors of cancer in childhood and young adulthood remain at higher risk of mortality than the general population, although the absolute risk of death is low and the excess risk has decreased over time.

Long-term follow-up of survivors of childhood cancer.

Today more than 75% of children treated for cancer will be cured, and attention is focusing on the late effects of treatments for these long-term survivors. Treatment-related morbidity is diverse, with potential effects on the endocrine system (growth, puberty, fertility, pituitary, thyroid and other disorders), cardiovascular, pulmonary and renal complications, second tumours, cognitive, education, neuropsychological and social manifestations. Multi-disciplinary long-term follow-up of these patients is essential to monitor, treat, and prevent morbidity. Depending on the nature of the treatment delivered, long-term follow-up of the survivor of childhood cancer can be individualised and delivered by a wide range of health professionals either in hospital or in primary care. In this review we describe the chronic health problems encountered by survivors and discuss the development of a long-term follow-up service for childhood cancer survivors.

Pregnancy in women who had cancer in childhood.

The majority of female cancer survivors will have normal reproductive function and would be expected to have a successful pregnancy. For the minority of young women who have received significant cytotoxic insult to the reproductive organs and yet still manage to conceive, pregnancy must be considered a high risk condition and these patients should be managed by a multidisciplinary specialist team. Female survivors of childhood cancer who are able to become pregnant carry an excess risk of preterm delivery and low birth weight baby. This restricted foetal growth and inability of the uterus to carry the foetus to term is associated with radiation-induced damage to the uterus. Chemotherapy does not appear to be associated with adverse pregnancy outcomes. However, prospective follow-up of cohorts of patients treated with contemporary therapies, frequently involving more intensive therapies are required to determine the risk. A number of large multi-centre studies, are underway and will provide new insights into pregnancy outcomes in survivors of childhood cancer.