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In long-term follow-up studies on recurrent events, the observation patterns may not be consistent over time. During some observation periods, subjects may be monitored continuously so that each event occurence time is known. While during the other observation periods, subjects may be monitored discretely so that only the number of events in each period is known. This results in mixed recurrent-event and panel-count data. In these data, there is dependence among within-subject events. Furthermore, if the data are collected from multiple centers, then there is another level of dependence among within-center subjects. Literature exists for clustered recurrent-event data, but not for clustered mixed recurrent-event and panel-count data. Ignoring the cluster effect may lead to less efficient analysis. In this paper, we present a marginal modeling approach to take into account the cluster effect and provide asymptotic distributions of the resulting regression parameters. Our simulation study demonstrates that this approach works well for practical situations. It was applied to a study comparing the hospitalization rates between childhood cancer survivors and healthy controls, with data collected from 26 medical institutions across North America during more than 20 years of follow-up. [ABSTRACT FROM AUTHOR]

Since the 1960s, paediatric oncologists have gradually become better organised in large study groups and participation in clinical trials is today considered as the standard of care, with most children with cancer in Europe and North America being enrolled on available treatment protocols. Chemotherapy is nowadays the main element of therapy, but irradiation is still required for some patients. With the advent of multimodality therapy and supportive care, five-year cancer survival exceeds 80 % in most European and North American countries today. The substantial improvements in survival led to a constantly growing population of childhood cancer survivors. Concerns regarding the risk of late effects of the intensive cancer treatment at a young age, together with increasing numbers of survivors, have directed attention towards survivorship research. Survivors of childhood cancer are at longstanding risk of various severe somatic and mental health conditions attributable to the cancer and its treatment, as well as adverse social and socioeconomic consequences, and diminished psychological well-being and quality of life. It is, however, important to stress that some survivors have no or very mild adverse health conditions. Nevertheless, joint efforts are warranted for the care and long-term follow-up of childhood cancer patients. With this article, we provide a comprehensive overview of improvements in survival and treatment modalities over time, as well as the related somatic and mental late effects, and social and socioeconomic difficulties that these children might encounter later in life., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Childhood cancer survivors exposed to abdominal radiation (abdRT) are at increased risk for diabetes mellitus, but the association between risk and radiation dose and volume is unclear., Methods: Participants included 20 762 5-year survivors of childhood cancer (4568 exposed to abdRT) and 4853 siblings. For abdRT, we estimated maximum dose to abdomen; mean doses for whole pancreas, pancreatic head, body, tail; and percent pancreas volume receiving no less than 10, 20, and 30 Gy. Relative risks (RRs) were estimated with a Poisson model using generalized estimating equations, adjusted for attained age. All statistical tests were two-sided., Results: Survivors exposed to abdRT (median age = 31.6 years, range = 10.2-58.3 years) were 2.92-fold more likely than siblings (95% confidence interval [CI] = 2.02 to 4.23) and 1.60-times more likely than survivors not exposed to abdRT (95%CI = 1.24 to 2.05) to develop diabetes. Among survivors treated with abdRT, greater attained age (RRper 10 years = 2.11, 95% CI = 1.70 to 2.62), higher body mass index (RRBMI 30+ = 5.00, 95% CI = 3.19 to 7.83 with referenceBMI 18.5-24.9), and increasing pancreatic tail dose were associated with increased diabetes risk in a multivariable model; an interaction was identified between younger age at cancer diagnosis and pancreatic tail dose with much higher diabetes risk associated with increasing pancreatic tail dose among those diagnosed at the youngest ages (P < .001). Radiation dose and volume to other regions of the pancreas were not statistically significantly associated with risk., Conclusions: Among survivors treated with abdRT, diabetes risk was associated with higher pancreatic tail dose, especially at younger ages. Targeted interventions are needed to improve cardiometabolic health among those at highest risk., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose: Therapeutic radiation in childhood cancer has decreased over time with a concomitant increase in chemotherapy. Limited data exist on chemotherapy-associated subsequent malignant neoplasm (SMN) risk., Patients and Methods: SMNs occurring > 5 years from diagnosis, excluding nonmelanoma skin cancers, were evaluated in survivors diagnosed when they were < 21 years old, from 1970 to 1999 in the Childhood Cancer Survivor Study (median age at diagnosis, 7.0 years; median age at last follow-up, 31.8 years). Thirty-year SMN cumulative incidence and standardized incidence ratios (SIRs) were estimated by treatment: chemotherapy-only (n = 7,448), chemotherapy plus radiation (n = 10,485), radiation only (n = 2,063), or neither (n = 2,158). Multivariable models were used to assess chemotherapy-associated SMN risk, including dose-response relationships., Results: Of 1,498 SMNs among 1,344 survivors, 229 occurred among 206 survivors treated with chemotherapy only. Thirty-year SMN cumulative incidence was 3.9%, 9.0%, 10.8%, and 3.4% for the chemotherapy-only, chemotherapy plus radiation, radiation-only, or neither-treatment groups, respectively. Chemotherapy-only survivors had a 2.8-fold increased SMN risk compared with the general population (95% CI, 2.5 to 3.2), with SIRs increased for subsequent leukemia/lymphoma (1.9; 95% CI, 1.3 to 2.7), breast cancer (4.6; 95% CI, 3.5 to 6.0), soft-tissue sarcoma (3.4; 95% CI, 1.9 to 5.7), thyroid cancer (3.8; 95% CI, 2.7 to 5.1), and melanoma (2.3; 95% CI, 1.5 to 3.5). SMN rate was associated with > 750 mg/m 2 platinum (relative rate [RR] 2.7; 95% CI, 1.1 to 6.5), and a dose response was observed between alkylating agents and SMN rate (RR, 1.2/5,000 mg/m 2 ; 95% CI, 1.1 to 1.3). A linear dose response was also demonstrated between anthracyclines and breast cancer rate (RR, 1.3/100 mg/m 2 ; 95% CI, 1.2 to 1.6)., Conclusion: Childhood cancer survivors treated with chemotherapy only, particularly higher cumulative doses of platinum and alkylating agents, face increased SMN risk. Linear dose responses were seen between alkylating agents and SMN rates and between anthracyclines and breast cancer rates. Limiting cumulative doses and consideration of alternate chemotherapies may reduce SMN risk.

Background: Although paediatric astrocytoma has an excellent 5-year survival rate, survivors remain at risk for morbidity and late mortality. This study aimed to estimate the risk of late mortality, chronic conditions, poor health status and social impairment in ageing paediatric astrocytoma survivors., Methods: We longitudinally evaluated 1182 5-year astrocytoma survivors diagnosed between 1970 and 1986 and 4023 siblings enrolled in a retrospective cohort study. Kaplan-Meier estimates of late mortality and cumulative incidence of serious chronic conditions were estimated. Cox regression models provided hazard ratios (HRs) with 95% confidence intervals (CIs) for development of chronic conditions, and generalised linear models provided relative risks (RRs) of the poor health status and social outcomes., Results: At 30 years from diagnosis, cumulative late mortality was 22.1% (CI 20.0-24.3%), primarily due to disease progression or recurrence. Compared with siblings, survivors were at increased risk of serious chronic conditions (HR 4.6, CI 3.8-5.5). Survivors reported higher rates of poor general health (RR 3.3, CI 2.8-3.8), poor mental health (RR 1.9, CI 1.7-2.1), functional impairment (RR 9.0, CI 7.7-10.5) and activity limitation (RR 3.6, CI 3.1-4.2) and lower rates of college graduation (RR 0.75, CI 0.69-0.82), marriage (RR 0.62, CI 0.58-0.66), employment (RR 0.75, CI 0.72-0.79) and household income ≥$40,000 (RR 0.68, CI 0.64-0.73). Even survivors without radiation exposure had elevated risk of chronic conditions, poor health status and social impairment compared with siblings., Conclusions: Survivors of paediatric astrocytoma are at high risk for long-term complications of their disease and its treatment. They require lifelong monitoring for late effects., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Purpose We aimed to predict individual risk of ischemic heart disease and stroke in 5-year survivors of childhood cancer. Patients and Methods Participants in the Childhood Cancer Survivor Study (CCSS; n = 13,060) were observed through age 50 years for the development of ischemic heart disease and stroke. Siblings (n = 4,023) established the baseline population risk. Piecewise exponential models with backward selection estimated the relationships between potential predictors and each outcome. The St Jude Lifetime Cohort Study (n = 1,842) and the Emma Children's Hospital cohort (n = 1,362) were used to validate the CCSS models. Results Ischemic heart disease and stroke occurred in 265 and 295 CCSS participants, respectively. Risk scores based on a standard prediction model that included sex, chemotherapy, and radiotherapy (cranial, neck, and chest) exposures achieved an area under the curve and concordance statistic of 0.70 and 0.70 for ischemic heart disease and 0.63 and 0.66 for stroke, respectively. Validation cohort area under the curve and concordance statistics ranged from 0.66 to 0.67 for ischemic heart disease and 0.68 to 0.72 for stroke. Risk scores were collapsed to form statistically distinct low-, moderate-, and high-risk groups. The cumulative incidences at age 50 years among CCSS low-risk groups were < 5%, compared with approximately 20% for high-risk groups ( P < .001); cumulative incidence was only 1% for siblings ( P < .001 v low-risk survivors). Conclusion Information available to clinicians soon after completion of childhood cancer therapy can predict individual risk for subsequent ischemic heart disease and stroke with reasonable accuracy and discrimination through age 50 years. These models provide a framework on which to base future screening strategies and interventions.

Purpose: Little is known about the breast cancer risk among childhood cancer survivors who did not receive chest radiotherapy. We sought to determine the magnitude of risk and associated risk factors for breast cancer among these women., Patients and Methods: We evaluated cumulative breast cancer risk in 3,768 female childhood cancer survivors without a history of chest radiotherapy who were participants in the Childhood Cancer Survivor Study., Results: With median follow up of 25.5 years (range, 8 to 39 years), 47 women developed breast cancer at a median age of 38.0 years (range, 22 to 47 years) and median of 24.0 years (range, 10 to 34 years) from primary cancer to breast cancer. A four-fold increased breast cancer risk (standardized incidence ratio [SIR] = 4.0; 95% CI, 3.0 to 5.3) was observed when compared with the general population. Risk was highest among sarcoma and leukemia survivors (SIR = 5.3; 95% CI, 3.6 to 7.8 and SIR = 4.1; 95% CI, 2.4 to 6.9, respectively). By the age of 45 years, the cumulative incidence of breast cancer in sarcoma and leukemia survivors was 5.8% (95% CI, 3.7 to 8.4) and 6.3% (95% CI, 3.0 to 11.3), respectively. No other primary cancer diagnosis was associated with an elevated risk. Alkylators and anthracyclines were associated with an increased breast cancer risk in a dose-dependent manner (P values from test for trend were both < .01)., Conclusions: Women not exposed to chest radiotherapy who survive childhood sarcoma or leukemia have an increased risk of breast cancer at a young age. The data suggest high-dose alkylator and anthracycline chemotherapy increase the risk of breast cancer. This may suggest a possible underlying gene-environment interaction that warrants further study., (© 2015 by American Society of Clinical Oncology.)

Purpose: To create clinically useful models that incorporate readily available demographic and cancer treatment characteristics to predict individual risk of heart failure among 5-year survivors of childhood cancer., Patients and Methods: Survivors in the Childhood Cancer Survivor Study (CCSS) free of significant cardiovascular disease 5 years after cancer diagnosis (n = 13,060) were observed through age 40 years for the development of heart failure (ie, requiring medications or heart transplantation or leading to death). Siblings (n = 4,023) established the baseline population risk. An additional 3,421 survivors from Emma Children's Hospital (Amsterdam, the Netherlands), the National Wilms Tumor Study, and the St Jude Lifetime Cohort Study were used to validate the CCSS prediction models., Results: Heart failure occurred in 285 CCSS participants. Risk scores based on selected exposures (sex, age at cancer diagnosis, and anthracycline and chest radiotherapy doses) achieved an area under the curve of 0.74 and concordance statistic of 0.76 at or through age 40 years. Validation cohort estimates ranged from 0.68 to 0.82. Risk scores were collapsed to form statistically distinct low-, moderate-, and high-risk groups, corresponding to cumulative incidences of heart failure at age 40 years of 0.5% (95% CI, 0.2% to 0.8%), 2.4% (95% CI, 1.8% to 3.0%), and 11.7% (95% CI, 8.8% to 14.5%), respectively. In comparison, siblings had a cumulative incidence of 0.3% (95% CI, 0.1% to 0.5%)., Conclusion: Using information available to clinicians soon after completion of childhood cancer therapy, individual risk for subsequent heart failure can be predicted with reasonable accuracy and discrimination. These validated models provide a framework on which to base future screening strategies and interventions., (© 2014 by American Society of Clinical Oncology.)

Second primary malignancies and premature death are a concern for patients surviving treatment for childhood lymphomas. We assessed mortality and second malignant neoplasms (SMNs) among 1082 5-year survivors of non-Hodgkin lymphoma (NHL) in the Childhood Cancer Survivor Study, a multi-institutional North American retrospective cohort study of cancer survivors diagnosed from 1970 to 1986. Standardized mortality ratios (SMRs) and standardized incidence ratios (SIRs) were calculated using US population rates. Relative risks for death and solid tumor SMNs were calculated based on demographic, clinical, and treatment characteristics using Poisson regression models. There were 87 observed deaths (SMR = 4.2; 95% CI, 1.8-4.1) with elevated rates of death from solid tumors, leukemia, cardiac disease, and pneumonia. Risk for death remained elevated beyond 20 years after NHL. Risk factors for death from causes other than NHL included female sex (rate ratio [RR] = 3.4) and cardiac radiation therapy exposure (RR = 1.9). There were 27 solid tumor SMNs (SIR = 3.9; 95% CI, 2.6-5.7) with 3% cumulative incidence between 5 and 20 years after NHL diagnosis. Risk factors were female sex (RR = 3.1), mediastinal NHL disease (RR = 5.2), and breast irradiation (RR = 4.3). Survivors of childhood NHL, particularly those treated with chest RT, are at continued increased risk of early mortality and solid tumor SMNs.

Purpose: To evaluate and compare psychological distress in long-term survivors of solid tumors diagnosed in childhood and their siblings, and to identify significant correlates of psychological distress., Procedure: Adult survivors (2,778) of solid tumors diagnosed in childhood and 2,925 siblings completed a long-term follow-up questionnaire assessing symptoms associated with depression, somatization, and anxiety, as well as demographic, health, and medical information., Results: Overall, a large majority of siblings and survivors reported few, if any, symptoms of psychological distress. In the aggregate, solid tumor cancer survivors reported significantly higher levels of global distress as measured by the Brief Symptom Inventory (BSI-18), as well as higher levels of somatization and anxiety, when compared to siblings. However, when compared to population norms, both survivors and siblings reported lower levels of global and dimensional distress. Female gender, lower educational and income attainment, perceived poor health status and reports of current health problems all were associated with reporting psychological distress symptoms for both survivors and siblings. Among survivors, having a limb amputation was associated with reporting fewer symptoms of global and dimensional distress., Conclusion: Poor health status, low levels of income, education, and employment appear to be predictors of distress for survivors of solid tumors. Thus, interventions that promote health and facilitate educational advancement, income attainment and social interaction to minimize isolation and maximize social support may reduce psychological distress and promote quality of life for childhood cancer survivors.

Purpose: Nonmelanoma skin cancer (NMSC) has become the most common type of cancer in many populations throughout the world. Ultraviolet and ionizing radiation are known risk factors. Because NMSCs are rarely lethal and most cancer registries do not routinely report data regarding these cancers, they have received little attention in studies evaluating long-term effects of cancer therapy. This article reports on the occurrence of secondary NMSC as a long-term effect of cancer therapy in survivors of childhood cancer., Patients and Methods: The Childhood Cancer Survivor Study (CCSS) is a cohort study of 5-year survivors of childhood and adolescent cancer from 25 participating institutions in North America. NMSC patients were defined by a history of basal cell or squamous cell carcinoma of the skin after primary malignancy treatment. Demographic and treatment data were collected and analyzed., Results: Among the 13,132 eligible CCSS participants, 213 have reported NMSC; 99 patients (46%) have had multiple occurrences. Median age of occurrence was 31 years (range, 7 to 46 years). Location of NMSC included head and neck (43%), back (24%), chest (22%), abdomen and pelvis (5%), extremity (3%), and unknown (4%). Ninety percent of patients had previously received radiation therapy (RT); 90% of tumors occurred within the RT field. RT was associated with a 6.3-fold increase in risk (95% CI, 3.5- to 11.3-fold)., Conclusion: Long-term survivors of childhood and adolescent cancer who were treated with RT are at highest risk for developing NMSC. Educational efforts need to be directed to this population to facilitate early diagnosis of NMSC and reduction in sun exposure.

Purpose: To evaluate and compare psychological outcomes in long-term survivors of pediatric brain cancer and siblings of childhood cancer survivors, and to identify significant correlates of psychological distress., Methods: One thousand one hundred one adult survivors of childhood brain cancer and 2,817 siblings completed a long-term follow-up questionnaire allowing assessment of symptoms associated with depression, somatization, and anxiety, as well as demographic, health, and medical information., Results: A large majority of siblings and survivors report few, if any, symptoms of psychological distress. The prevalence of distress approximating clinically significant levels for both survivors (11%) and siblings (5%) reflects rates found in the general population. Yet when accounting for significant sociodemographic, socioeconomic, and health-status variables, survivors of childhood brain cancer, in the aggregate, appear to report significantly higher global distress and depression scores than do siblings. As in the general population, higher levels of distress among survivors and siblings were associated with female sex, low household income, lower educational attainment, being unmarried, not being employed in the past 12 months, and poor physical health status. No diagnostic or treatment-related variables were directly and significantly associated with increases in distress symptoms for survivors of childhood brain cancer., Conclusion: Cancer treatment does not appear to contribute directly to increased psychological distress. Instead, distress appears to be associated with diminished social functioning that may be related to cancer type or treatment. Implementation and evaluation of supportive interventions that enhance survivors' social and vocational skills should be considered.