Late morbidity and mortality after autologous blood or marrow transplantation for lymphoma in children, adolescents and young adults-a BMTSS report.

We determined the risk of late morbidity and mortality after autologous blood or marrow transplantation (BMT) for lymphoma performed before age 40. The cohort included autologous BMT recipients who had survived ≥2 years after transplantation (N = 583 [HL = 59.9%; NHL = 40.1%]) and a comparison cohort (N = 1070). Participants self-reported sociodemographics and chronic health conditions. A severity score (grade 3 [severe], 4 [life threatening] or 5 [fatal]) was assigned to the conditions using CTCAE v5.0. Logistic regression estimated the odds of grade 3-4 conditions in survivors vs. comparison subjects. Proportional subdistribution hazards models identified predictors of grade 3-5 conditions among BMT recipients. Median age at BMT was 30.0 years (range: 2.0-40.0) and median follow-up was 9.8 years (2.0-32.1). Survivors were at a 3-fold higher adjusted odds for grade 3-4 conditions (95% CI = 2.3-4.1) vs. comparison subjects. Factors associated with grade 3-5 conditions among BMT recipients included age at BMT (>30 years: adjusted hazard ratio [aHR] = 2.31; 95% CI = 1.27-4.19; reference: ≤21 years), pre-BMT radiation (aHR = 1.52; 95% CI = 1.13-2.03; reference: non-irradiated), and year of BMT (≥2000: aHR = 0.54; 95% CI = 0.34-0.85; reference: <1990). The 25 years cumulative incidence of relapse-related and non-relapse-related mortality was 18.2% and 25.9%, respectively. The high risk for late morbidity and mortality after autologous BMT for lymphoma performed at age <40 calls for long-term anticipatory risk-based follow-up.

Educational attainment in survivors of childhood cancer in Denmark, Finland, and Sweden.

BACKGROUND: Survivors of childhood cancer may face difficulties at school. We investigated whether childhood cancer affects attainment of upper secondary education, in a register-based cohort study from Denmark, Finland, and Sweden, where we limit bias from selection and participation. METHODS: From the national cancer registers, we identified all long-term survivors of childhood cancer diagnosed aged 0-14 years in 1971-2005 (n = 7629), compared them to matched population comparisons (n = 35,411) and siblings (n = 6114), using odds ratios (OR) and 95% confidence intervals (CI). RESULTS: Overall, 6127 survivors (80%) had attained upper secondary education by age 25, compared to 84% among comparison groups. Elevated OR for not attaining this level were mainly confined to survivors of central nervous system (CNS) tumours (ORSurv_PopComp2.05, 95%CI: 1.83-2.29). Other risk groups were survivors who had spent more time in hospital around cancer diagnosis and those who had hospital contacts in early adulthood, particularly psychiatric. Survivors of all cancer types were less likely to have attained upper secondary education without delay. CONCLUSIONS: Although survivors of childhood cancer experienced delays in their education, many had caught up by age 25. Except for survivors of CNS tumours, survivors attained upper secondary education to almost the same extent as their peers.

Severe, life-threatening, and fatal chronic health conditions after allogeneic blood or marrow transplantation in childhood.

BACKGROUND: A comprehensive assessment of morbidity after allogeneic bone marrow transplantation (BMT) performed in childhood remains understudied. METHODS: Seven hundred eighty-nine allogeneic BMT recipients who had survived ≥2 years after BMT performed between 1974 and 2014 at age <22 years and 690 siblings completed a 255-item survey self-reporting sociodemographics and chronic health conditions. A severity score (grade 3 [severe], 4 [life-threatening], or 5 [fatal]) was assigned to the conditions using Common Terminology Criteria for Adverse Events, version 5.0. For the BMT cohort, the cumulative incidence of chronic health conditions was calculated as a function of time from BMT. Proportional subdistribution hazards models were used to determine predictors of grade 3-5 conditions. Logistic regression was used to estimate the risk of grade 3-4 conditions in BMT recipients who were alive at the time of this study compared with siblings. RESULTS: The median age at transplantation was 11.3 years (range, 0.4-22.0 years), and the median length of follow-up was 11.7 years (range, 2.0-45.3 years). The most prevalent primary diagnoses were acute lymphoblastic leukemia (30.7%), and acute myeloid leukemia/myelodysplastic syndrome (26.9%). At age 35 years, the cumulative incidence of a grade 3-4 condition was 53.8% (95% CI, 46.7%-60.3%). The adjusted odds ratio of a grade 3-4 condition was 15.1 in survivors (95% CI, 9.5-24.0) compared with siblings. The risk of a grade 3-5 condition increased with age at BMT (hazard ratio [HR], 1.03; 95% CI, 1.01-1.05) and was higher among females (HR, 1.27; 95% CI, 1.02-1.59), patients who received total body irradiation (HR, 1.71; 95% CI, 1.27-2.31), and those reporting chronic graft-versus-host disease (HR, 1.38; 95% CI, 1.09-1.74). CONCLUSIONS: Two-year survivors of allogeneic BMT in childhood have an increased risk of grade 3-4 chronic health conditions compared with siblings, suggesting the need for long-term follow-up.

Long-Term Risk of Hospitalization for Somatic Diseases Among Survivors of Childhood Acute Lymphoblastic Leukemia.

BACKGROUND: Survivors of childhood acute lymphoblastic leukemia (ALL) may be at increased long-term risk of hospitalization for somatic diseases. However, large population-based cohort studies with risk estimates for survivors successfully cured without experiencing a relapse or requiring hematopoietic stem cell transplantation (HSCT) are lacking. METHODS: Danish and Swedish patients diagnosed with ALL before age 20 years in 1982-2008 were identified in the national cancer registries. Five-year survivors and matched population comparisons without childhood cancer were followed for hospitalization for 120 somatic disease categories in the national hospital registries from 5 years postdiagnosis until 2017, and disease-specific hospitalization rate ratios (RR) were calculated. The mean cumulative count method was used to estimate the mean number of multiple and recurrent disease-specific hospitalizations per individual. RESULTS: A total of 2024 5-year survivors and 9797 population comparisons were included. The overall hospitalization rate was more than twice as high compared with comparisons (RR = 2.30, 95% confidence interval [CI] = 2.09 to 2.52). At 30 years postdiagnosis, the mean cumulative hospitalization count was 1.69 (95% CI = 1.47 to 1.90) per survivor and 0.80 (95% CI = 0.73 to 0.86) per comparison. In the subcohort without relapse or HSCT (n = 1709), the RR was 1.41 (95% CI = 1.27 to 1.58). CONCLUSIONS: Survivors of childhood ALL were at increased long-term risk for disease-specific hospitalizations; however, in survivors without relapse or HSCT, the rate was only modestly higher than in population comparisons without a childhood cancer. The absolute mean numbers of multiple and recurrent hospitalizations were generally low.

Psychiatric disorders in childhood cancer survivors in Denmark, Finland, and Sweden: a register-based cohort study from the SALiCCS research programme.

BACKGROUND: A childhood cancer diagnosis and treatment-induced somatic late effects can affect the long-term mental health of survivors. We aimed to explore whether childhood cancer survivors are at higher risk of psychiatric disorders later in life than their siblings and the general population. METHODS: In this register-based cohort study (part of the Socioeconomic Consequences in Adult Life after Childhood Cancer [SALiCCS] research programme), we included 5-year survivors of childhood cancer diagnosed before 20 years of age between Jan 1, 1974 and Dec 31, 2011, in Denmark, Finland, and Sweden. In Denmark and Sweden, 94·7% of individuals were born in a Nordic country (ie, Denmark, Finland, Iceland, Norway, or Sweden); similar information was not available in Finland. Data on ethnicity were not collected. Survivors were compared with their siblings and randomly selected individuals from the general population who were matched to the survivors by year of birth, sex, and geographical region. We followed up our study population from 5 years after the childhood cancer diagnosis or corresponding calendar date for matched individuals (the index date) until Aug 11, 2017, and assessed information on hospital contacts for any and specific psychiatric disorders. For siblings, the index date was defined as 5 years from the date on which they were of the same age as their sibling survivor when diagnosed with cancer. FINDINGS: The study population included 18 621 childhood cancer survivors (9934 [53·3%] males and 8687 [46·7%] females), 24 775 siblings (12 594 [50·8%] males and 12 181 [49·2%] females), and 88 630 matched individuals (47 300 [53·4%] males and 41 330 [46·6%] females). The cumulative incidence proportion of having had a psychiatric hospital contact by 30 years of age between Jan 1, 1979, and Aug 11, 2017, was 15·9% (95% CI 15·3-16·5) for childhood cancer survivors, 14·0% (13·5-14·5) for siblings, and 12·7% (12·4-12·9) for matched individuals. Despite a small absolute difference, survivors were at higher relative risk of any psychiatric hospital contact than their siblings (1·39, 1·31-1·48) and matched individuals (hazard ratio 1·34, 95% CI 1·28-1·39). The higher risk persisted at the age of 50 years. Survivors had a higher burden of recurrent psychiatric hospital contacts and had more hospital contacts for different psychiatric disorders than their siblings and the matched individuals. INTERPRETATION: Childhood cancer survivors are at higher long-term risk of psychiatric disorders than their siblings and matched individuals from the general population. To improve mental health and the overall quality of life after childhood cancer, survivorship care should include a focus on early signs of mental health problems, especially among high-risk groups of survivors. FUNDING: NordForsk, Aarhus University, Swedish Childhood Cancer Foundation, Danish Health Foundation, and Swiss National Science Foundation.

Somatic Disease in Survivors of Childhood Malignant Bone Tumors in the Nordic Countries.

Survivors of malignant bone tumors in childhood are at risk of long-term adverse health effects. We comprehensively reviewed cases of somatic diseases that required a hospital contact in survivors of osteosarcoma and Ewing sarcoma. In a population-based cohort study, 620 five-year survivors of osteosarcoma (n = 440) or Ewing sarcoma (n = 180), diagnosed before the age of 20 years in Denmark, Finland, Iceland, and Sweden during 1943-2008, were followed in the national hospital registers. Overall rates of hospital contacts for any somatic disease and for 12 main diagnostic groups and 120 specific disease categories were compared with those in a matched comparison cohort (n = 3049) randomly selected from the national population registers. The rate of hospital contact for any somatic disease was 80% higher in survivors of malignant bone tumors than in comparisons and remained elevated up to 30 years after diagnosis. The rate of hospital contacts was higher after Ewing sarcoma (rate ratio (RR) 2.24; 95% confidence interval (CI) 1.76-2.85) than after osteosarcoma (RR 1.67; 95% CI 1.41-1.98). Elevated rates were observed for 11 main diagnostic groups, including infections, second malignant neoplasms, and diseases of the skin, bones, and circulatory, digestive, endocrine, and urinary systems. Survivors of malignant bone tumors in childhood are at increased risk of somatic diseases many years after diagnosis. This comprehensive study contributes new insight into the risk of late effects in survivors of osteosarcoma and Ewing sarcoma, which is an essential basis for optimal patient counseling and follow-up care.

Skeletal adverse events in childhood cancer survivors: An Adult Life after Childhood Cancer in Scandinavia cohort study.

The dynamic growth of the skeleton during childhood and adolescence renders it vulnerable to adverse effects of cancer treatment. The lifetime risk and patterns of skeletal morbidity have not been described in a population-based cohort of childhood cancer survivors. A cohort of 26 334 1-year cancer survivors diagnosed before 20 years of age was identified from the national cancer registries of Denmark, Finland, Iceland and Sweden as well as a cohort of 127 531 age- and sex-matched comparison subjects randomly selected from the national population registries in each country. The two cohorts were linked with data from the national hospital registries and the observed numbers of first-time hospital admissions for adverse skeletal outcomes among childhood cancer survivors were compared to the expected numbers derived from the comparison cohort. In total, 1987 childhood cancer survivors had at least one hospital admission with a skeletal adverse event as discharge diagnosis, yielding a rate ratio (RR) of 1.35 (95% confidence interval, 1.29-1.42). Among the survivors, we observed an increased risk for osteonecrosis with a RR of 25.9 (15.0-44.5), osteoporosis, RR 4.53 (3.28-6.27), fractures, RR 1.27 (1.20-1.34), osteochondropathies, RR 1.57 (1.28-1.92) and osteoarthrosis, RR 1.48 (1.28-1.72). The hospitalization risk for any skeletal adverse event was higher among survivors up to the age of 60 years, but the lifetime pattern was different for each type of skeletal adverse event. Understanding the different lifetime patterns and identification of high-risk groups is crucial for developing strategies to optimize skeletal health in childhood cancer survivors.

Disease-specific hospitalizations among 5-year survivors of Wilms tumor: A Nordic population-based cohort study.

BACKGROUND: With modern therapy, over 90% of Wilms tumor patients can expect to become long-term survivors, and focus on morbidity and late effects become increasingly important. We provide a novel evaluation and insight to subsequent hospitalizations in 5-year survivors of Wilms tumor. METHODS: As part of the Adult Life after Childhood Cancer in Scandinavia (ALiCCS) study, we identified 5-year survivors of Wilms tumor. Based on stratified random sampling, we constructed a population comparison cohort. Outcomes of interest were overall hospitalizations; hospitalizations for specific organ systems and disease-specific categories. Standardized hospitalization rate ratios (SHRR) and absolute excess risks (AER) were calculated. RESULTS: We included 913, 5-year survivors of Wilms tumor and 152 231 population comparisons. Survivors of Wilms tumor had an increased overall risk of being hospitalized (SHRR 1.8; 95% confidence interval (CI) 1.7-2.0). The hospitalization risk was increased within all major organ systems: urinary and genital organs (SHRR 2.5; 95% CI 2.1-3.0), endocrine (SHRR 2.5; 95% CI 1.9-3.3), cardiovascular (SHRR 2.2; 95% CI 1.7-2.9), and gastrointestinal (SHRR 1.5; 95% CI 1.3-1.8). Risks for specific diseases are reported in the study. CONCLUSIONS: Survivors of Wilms tumor had higher risks than population comparisons for a wide range of diseases, with the highest risks seen for urinary, endocrine, and cardiovascular disorders. Five to 20 years after the Wilms tumor diagnosis, 43% of survivors had been hospitalized at least once versus 29% of population comparisons. The overall AER was 2.3, which translates into 0.2 extra hospitalizations in 10 years for every Wilms tumor survivor.

Risk of late health effects after soft-tissue sarcomas in childhood - a population-based cohort study within the Adult Life after Childhood Cancer in Scandinavia research programme.

BACKGROUND: In the 1960s only 1/3 of children with soft-tissue sarcomas survived, however with improved treatments survival today has reached 70%. Given the previous poor survival and the rarity of soft-tissue sarcomas, the risk of somatic late effects in a large cohort of Nordic soft-tissue sarcoma survivors has not yet been assessed. METHODS: In this population-based cohort study we identified 985 five-year soft-tissue sarcoma survivors in Nordic nationwide cancer registries and late effects in national hospital registries covering the period 1964-2012. Information on tumour site and radiotherapy was available for Danish and Finnish survivors (N = 531). Using disease-specific rates of first-time hospital contacts for somatic diseases in survivors and in 4,830 matched comparisons we calculated relative rates (RR) and rate differences (RD). RESULTS: Survivors had a RR of 1.5 (95% CI 1.4-1.7) and an absolute RD of 23.5 (17.7-29.2) for a first hospital contact per 1,000 person-years. The highest risks in both relative and absolute terms were of endocrine disorders (RR = 2.5; RD = 7.6), and diseases of the nervous system (RR = 1.9; RD = 6.6), digestive organs (RR = 1.7; RD = 5.4) and urinary system (RR = 1.7; RD = 5.6). By tumour site, excess risk was lower after extremity tumours. Irradiated survivors had a 2.6 (1.2-5.9) times higher risk than non-irradiated. CONCLUSIONS: Soft-tissue sarcoma survivors have an increased risk of somatic late effects in 5 out of 10 main diagnostic groups of diseases, and the risk remains increased up to 40 years after cancer diagnosis. Risks were slightly lower for those treated for tumours in the extremities, and radiotherapy increased the risk by more than two-fold.

Neurologic disorders in long-term survivors of neuroblastoma - a population-based cohort study within the Adult Life after Childhood Cancer in Scandinavia (ALiCCS) research program.

Background: Neuroblastoma is the commonest extracranial solid tumor of childhood, yet rare, and with poor survival before 1990, especially for high-risk disease; thus, information on late effects is sparse. With great advances in cancer treatment, survival has reached 80% in the Nordic countries. The aim of the study was to investigate the risk of developing neurologic disorders after neuroblastoma.Material and methods: Through population-based cancer registries of four Nordic countries we identified 654 5-year survivors of neuroblastoma (diagnosed 1959-2008) and 133,668 matched population comparisons. We grouped neurologic diagnoses from national hospital registries into 11 main diagnostic categories and 56 disease-specific sub-categories and calculated relative risks (RRs), absolute excess risks (AERs), cumulative incidence and mean cumulative count (MCC). Information on cancer treatment was available for 49% of survivors.Results: A hospital contact for a neurologic disorder was observed in 181 survivors 5 years or more from cancer diagnosis with 59 expected, yielding a RR of 3.1 (95% CI 2.7-3.6) and an AER of 16 per 1,000 person-years (95% CI 12-19). The most frequent disorders included epilepsy, paralytic syndromes, diseases of the eyes and ears and hearing loss. The cumulative incidence of any neurologic disorder was 31% in survivors 20 years after cancer diagnosis with a MCC of 0.5 unique diagnoses. All risks were highest in survivors of high-risk neuroblastoma.Conclusion: Neuroblastoma survivors represent a population with a high risk of developing neurologic disorders. Our results should contribute to improving health care planning and underscores the need for systematic follow-up care of this vulnerable group of survivors.

Long-Term Risk of Hospitalization Among Five-Year Survivors of Childhood Leukemia in the Nordic Countries.

BACKGROUND: Adverse effects from childhood leukemia treatment may persist or present years after cure from cancer. We provide a comprehensive evaluation of subsequent hospitalization in five-year survivors of childhood acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), and chronic myeloid leukemia (CML). METHODS: In the Adult Life after Childhood Cancer in Scandinavia Study, we identified 4003 five-year survivors diagnosed with childhood leukemia 1970-2008 in Denmark, Sweden, Iceland, and Finland. Survivors and 129 828 population comparisons were followed for first-time nonpsychiatric hospitalizations for 120 disease categories in the hospital registries. Standardized hospitalization rate ratios and absolute excess rates were calculated. All statistical tests were two-sided. RESULTS: Survivors of ALL (n = 3391), AML (n = 389), and CML (n = 92) had an increased overall hospitalization rate compared with population comparisons. The rate ratio for any hospitalization was 1.95 (95% confidence interval [CI] = 1.83 to 2.07) in ALL, 3.09 (95% CI = 2.53 to 3.65) in AML, and 4.51 (95% CI = 3.03 to 6.00) in CML survivors and remained increased even 20 years from leukemia diagnosis. Corresponding absolute excess rates per 1000 person-years were 28.48 (95% CI = 24.96 to 32.00), 62.75 (95% CI = 46.00 to 79.50), and 105.31 (95% CI = 60.90 to 149.72). CONCLUSION: Leukemia survivors have an increased rate of hospitalization for medical conditions. We provide novel insight into the relative and absolute rate of hospitalization for 120 disease categories in survivors of ALL, AML, and CML, which are likely to be informative for both survivors and healthcare providers.

Neurologic disorders in 4858 survivors of central nervous system tumors in childhood-an Adult Life after Childhood Cancer in Scandinavia (ALiCCS) study.

Background: A comprehensive overview of neurologic complications among survivors of central nervous system (CNS) tumors in childhood is lacking. We aimed to investigate the risk for these disorders in a large, population-based study with outcome measures from nationwide hospital registries. Methods: We identified 4858 five-year survivors with diagnoses of CNS tumor in childhood in Denmark, Iceland, Finland, and Sweden in 1943-2007, and 166658 matched population comparison subjects. Inpatient discharge diagnoses of neurologic disorders were used to calculate relative risks (RRs) and absolute excess risks (AERs). Results: A neurologic disorder was verified in 1309 survivors, while 92.4 were expected, yielding an overall RR of 14.2 (95% confidence interval [CI]: 13.3-15.1) and an AER of 20 hospitalizations per 1000 persons per year. The risks remained increased more than 20 years after diagnosis (RR: 6.3, 95% CI: 5.6-7.2; AER: 11, 9-12). The most frequent diagnoses were epilepsy (affecting 14.1% of all survivors) followed by hydrocephalus (9.5%) and paralytic syndromes (4.2%), with RRs of 28.7 (95% CI: 26.0-31.6), 243 (95% CI: 190-311), and 40.3 (95% CI: 33.1-49.2), respectively. Of these outcomes, 30%-40% were diagnosed prior to or synchronously with the CNS tumor. The survivors had highly increased RRs for infectious diseases of the CNS, disorders of cranial nerves, and degenerative diseases of the nervous system. Conclusions: Survivors of childhood CNS tumors are at markedly increased risk for neurologic disorders throughout their lives. Health care professionals must be aware of survivors who might benefit from preventive interventions and intensive follow-up.

Late Mortality after Allogeneic Bone Marrow Transplantation in Childhood for Bone Marrow Failure Syndromes and Severe Aplastic Anemia.

Children with bone marrow failure syndromes and severe aplastic anemia (SAA) are treated with allogeneic blood or marrow transplantation (BMT). However, there is a paucity of studies examining late mortality risk after allogeneic BMT performed in childhood for bone marrow failure syndromes and SAA and evaluating how this risk differs between these diseases. We investigated cause-specific late mortality in 2-year survivors of allogeneic BMT for bone marrow failure syndromes and SAA performed before age 22years between 1974 and 2010 at 2 US transplantation centers. Vital status information was collected from medical records, the National Death Index, and Accurint databases. Overall survival was calculated using Kaplan-Meier techniques. The standardized mortality ratio (SMR) was calculated using age- sex-, and calendar-specific mortality rates from the Centers for Disease Control and Prevention. Among the 2-year survivors of bone marrow failure syndromes (n = 120) and SAA (n = 147), there were 15 and 19 deaths, respectively, yielding an overall survival of 86.4% for bone marrow failure syndromes and 93.1% for SAA at 15years post-BMT. Compared with the general population, patients with bone marrow failure syndromes were at a higher risk for premature death (SMR, 22.7; 95% CI, 13.1 to 36.2) compared with those with SAA (SMR, 4.5; 95% CI, 2.8 to 7.0) (P < .0001). The elevated relative risk persisted at ≥15years after BMT for both diseases. The hazard of all-cause late mortality was 2.9-fold (95% CI, 1.1 to 7.3) higher in patients with bone marrow failure syndromes compared with those with SAA. The high late mortality risk in recipients of allogeneic BMT in childhood for bone marrow failure syndromes calls for intensified life-long follow-up.

Assessment of Late Mortality Risk After Allogeneic Blood or Marrow Transplantation Performed in Childhood.

Importance: Allogeneic blood or marrow transplantation (BMT) is a curative option for malignant and nonmalignant diseases of childhood. However, little is known about trends in cause-specific late mortality in this population during the past 3 decades. Objectives: To examine cause-specific late mortality among individuals who have lived 2 years or more after allogeneic BMT performed in childhood and whether rates of late mortality have changed over time. Design, Setting, and Participants: A retrospective cohort study was conducted of individuals who lived 2 years or more after undergoing allogeneic BMT performed in childhood between January 1, 1974, and December 31, 2010. The end of follow-up was December 31, 2016. Exposure: Allogeneic BMT performed in childhood. Main Outcomes and Measures: All-cause mortality, relapse-related mortality, and non-relapse-related mortality. Data on vital status and causes of death were collected using medical records, the National Death Index Plus Program, and Accurint databases. Results: Among 1388 individuals (559 females and 829 males) who lived 2 years or more after allogeneic BMT performed in childhood, the median age at transplantation was 14.6 years (range, 0-21 years). In this cohort, there was a total of 295 deaths, yielding an overall survival rate of 79.3% at 20 years after BMT. The leading causes of death were infection and/or chronic graft-vs-host disease (121 of 244 [49.6%]), primary disease (60 of 244 [24.6%]), and subsequent malignant neoplasms (45 of 244 [18.4%]). Overall, the cohort had a 14.4-fold increased risk for death (95% CI, 12.8-16.1) compared with the general population (292 deaths observed; 20.3 deaths expected). Relative mortality remained elevated at 25 years or more after BMT (standardized mortality ratio, 2.9; 95% CI, 2.0-4.1). The absolute excess risk for death from any cause was 12.0 per 1000 person-years (95% CI, 10.5-13.5). The cumulative incidence of non-relapse-related mortality exceeded that of relapse-related mortality throughout follow-up. The 10-year cumulative incidence of late mortality decreased over time (before 1990, 18.9%; 1990-1999, 12.8%; 2000-2010, 10.9%; P = .002); this decrease remained statistically significant after adjusting for demographic and clinical factors (referent group: <1990; 1990-1999: hazard ratio, 0.64; 95% CI, 0.47-0.89; P = .007; 2000-2010: hazard ratio, 0.49; 95% CI, 0.31-0.76; P = .002; P < .001 for trend). Conclusions and Relevance: Late mortality among children undergoing allogeneic BMT has decreased during the past 3 decades. However, these patients remain at an elevated risk of late mortality even 25 years or more after transplantation when compared with the general population, necessitating lifelong follow-up.

Somatic late effects in 5-year survivors of neuroblastoma: a population-based cohort study within the Adult Life after Childhood Cancer in Scandinavia study.

Because of the rarity of neuroblastoma and poor survival until the 1990s, information on late effects in neuroblastoma survivors is sparse. We comprehensively reviewed the long-term risk for somatic disease in neuroblastoma survivors. We identified 721 5-year survivors of neuroblastoma in Nordic population-based cancer registries and identified late effects in national hospital registries covering the period 1977-2012. Detailed treatment information was available for 46% of the survivors. The disease-specific rates of hospitalization of survivors and of 152,231 randomly selected population comparisons were used to calculate standardized hospitalization rate ratios (SHRRs) and absolute excess risks (AERs). During 5,500 person-years of follow-up, 501 5-year survivors had a first hospital contact yielding a SHRR of 2.3 (95% CI 2.1-2.6) and a corresponding AER of 52 (95% CI 44-60) per 1,000 person-years. The highest relative risks were for diseases of blood and blood-forming organs (SHRR 3.8; 95% CI 2.7-5.4), endocrine diseases (3.6 [3.1-4.2]), circulatory system diseases (3.1 [2.5-3.8]), and diseases of the nervous system (3.0 [2.6-3.3]). Approximately 60% of the excess new hospitalizations of survivors were for diseases of the nervous system, urinary system, endocrine system, and bone and soft tissue. The relative risks and AERs were highest for the survivors most intensively treated. Survivors of neuroblastoma have a highly increased long-term risk for somatic late effects in all the main disease groups as compared to background levels. Our results are useful for counseling survivors and should contribute to improving health care planning in post-therapy clinics.

Late mortality after autologous blood or marrow transplantation in childhood: a Blood or Marrow Transplant Survivor Study-2 report.

Autologous blood or marrow transplantation (BMT) is a curative option for several types of childhood cancer. However, there is little information regarding the risk of late mortality. We examined all-cause mortality, relapse-related mortality (RRM), and nonrelapse-related mortality (NRM) in 2-year survivors of autologous BMT performed before age 22 between 1980 and 2010 at 1 of 2 US transplant centers. Vital status information was collected using medical records, National Death Index, and Accurint databases. Overall survival was calculated using Kaplan-Meier techniques. Cumulative incidence of mortality used competing risk methods. Standardized mortality ratio (SMR) was calculated using age-, sex-, and calendar-specific mortality rates from Centers for Disease Control and Prevention. Cox regression analysis was used to determine predictors of all-cause late mortality. Among the 345 2-year survivors, 103 deaths were observed, yielding an overall survival of 70.3% 15 years post-BMT. The leading causes of death included primary disease (50.0%), subsequent neoplasm (21.4%), and infection (18.2%). Overall, the cohort was at a 22-fold increased risk of late mortality (SMR, 21.8; 95% CI, 17.9-26.3), compared with the general population. Mortality rates remained elevated among the 10-year survivors (SMR, 20.6; 95% CI, 9.9-37.2) but approached those of the general population ≥15 years post-BMT. The 10-year cumulative incidence of RRM (14.3%) exceeded that of NRM (10.4%). The 10-year cumulative mortality rate declined over time (<1990, 35.1%; 1990-1999, 25.6%; 2000-2010, 21.8%; P = .05). In conclusion, childhood autologous BMT recipients have an increased risk of late mortality, compared with the general population. The late mortality rates have declined over the past 3 decades.

Measuring childhood cancer late effects: evidence of a healthy survivor effect.

INTRODUCTION: Given considerable focus on health outcomes among childhood cancer survivors, we aimed to explore whether survivor bias is apparent during long-term follow-up of childhood cancer survivors. METHODS: We identified all 1-year survivors of cancer diagnosed before 20 years of age in Denmark, Finland, Iceland, and Sweden. From the general population, we randomly sampled a comparison cohort. Study individuals were followed for hospitalizations for diseases of the gastroenterological tract, endocrine system, cardiovascular system, or urinary tract from the start of the cancer registries to 2010. We estimated cumulative incidence with death as competing risk and used threshold regression to compare the hazards of the diseases of interest at ages 20, 40, 60, and 75 years. RESULTS: Our study included 27,007 one-year survivors of childhood cancer and 165,620 individuals from the general population. The cumulative incidence of all four outcomes was higher for childhood cancer survivors during early adulthood, but for three outcomes, the cumulative incidence was higher for the general population after age 55 years. The hazard ratios (HRs) decreased for all outcomes with increasing age, and for two of the outcomes, the hazards were higher for the general population at older ages (endocrine diseases: age-specific HRs = 3.0, 1.4, 1.0, 0.87; Cardiovascular diseases: age-specific HRs = 4.1, 1.4, 0.97, 0.84). CONCLUSIONS: Our findings provide empirical evidence that survivor bias attenuates measures of association when comparing survivors with the general population. The design and analysis of studies among childhood cancer survivors, particularly as this population attains older ages, should account for survivor bias to avoid misinterpreting estimates of disease burden.

Long-term inpatient disease burden in the Adult Life after Childhood Cancer in Scandinavia (ALiCCS) study: A cohort study of 21,297 childhood cancer survivors.

BACKGROUND: Survivors of childhood cancer are at increased risk for a wide range of late effects. However, no large population-based studies have included the whole range of somatic diagnoses including subgroup diagnoses and all main types of childhood cancers. Therefore, we aimed to provide the most detailed overview of the long-term risk of hospitalisation in survivors of childhood cancer. METHODS AND FINDINGS: From the national cancer registers of Denmark, Finland, Iceland, and Sweden, we identified 21,297 5-year survivors of childhood cancer diagnosed with cancer before the age of 20 years in the periods 1943-2008 in Denmark, 1971-2008 in Finland, 1955-2008 in Iceland, and 1958-2008 in Sweden. We randomly selected 152,231 population comparison individuals matched by age, sex, year, and country (or municipality in Sweden) from the national population registers. Using a cohort design, study participants were followed in the national hospital registers in Denmark, 1977-2010; Finland, 1975-2012; Iceland, 1999-2008; and Sweden, 1968-2009. Disease-specific hospitalisation rates in survivors and comparison individuals were used to calculate survivors' standardised hospitalisation rate ratios (RRs), absolute excess risks (AERs), and standardised bed day ratios (SBDRs) based on length of stay in hospital. We adjusted for sex, age, and year by indirect standardisation. During 336,554 person-years of follow-up (mean: 16 years; range: 0-42 years), childhood cancer survivors experienced 21,325 first hospitalisations for diseases in one or more of 120 disease categories (cancer recurrence not included), when 10,999 were expected, yielding an overall RR of 1.94 (95% confidence interval [95% CI] 1.91-1.97). The AER was 3,068 (2,980-3,156) per 100,000 person-years, meaning that for each additional year of follow-up, an average of 3 of 100 survivors were hospitalised for a new excess disease beyond the background rates. Approximately 50% of the excess hospitalisations were for diseases of the nervous system (19.1% of all excess hospitalisations), endocrine system (11.1%), digestive organs (10.5%), and respiratory system (10.0%). Survivors of all types of childhood cancer were at increased, persistent risk for subsequent hospitalisation, the highest risks being those of survivors of neuroblastoma (RR: 2.6 [2.4-2.8]; n = 876), hepatic tumours (RR: 2.5 [2.0-3.1]; n = 92), central nervous system tumours (RR: 2.4 [2.3-2.5]; n = 6,175), and Hodgkin lymphoma (RR: 2.4 [2.3-2.5]; n = 2,027). Survivors spent on average five times as many days in hospital as comparison individuals (SBDR: 4.96 [4.94-4.98]; n = 422,218). The analyses of bed days in hospital included new primary cancers and recurrences. Of the total 422,218 days survivors spent in hospital, 47% (197,596 bed days) were for new primary cancers and recurrences. Our study is likely to underestimate the absolute overall disease burden experienced by survivors, as less severe late effects are missed if they are treated sufficiently in the outpatient setting or in the primary health care system. CONCLUSIONS: Childhood cancer survivors were at increased long-term risk for diseases requiring inpatient treatment even decades after their initial cancer. Health care providers who do not work in the area of late effects, especially those in primary health care, should be aware of this highly challenged group of patients in order to avoid or postpone hospitalisations by prevention, early detection, and appropriate treatments.