Medical Assessment of Adverse Health Outcomes in Long-term Survivors of Childhood Cancer JAMA. 2007;297:

ORIGINAL CONTRIBUTION CLINICIAN S CORNER Medical Assessment of Adverse Health Outcomes in Long-term Survivors of Childhood Cancer Maud M. Geenen, MD Mathilde C. Cardous-Ubbink, MSc Leontien C. M. Kremer, MD, PhD Cor van den Bos, MD, PhD Helena J. H. van der Pal, MD Richard C. Heinen, MSc Monique W. M. Jaspers, PhD, MSc Caro C. E. Koning, MD, PhD Foppe Oldenburger, MD Nelia E. Langeveld, PhD, RN Augustinus A. M. Hart, MSc Piet J. M. Bakker, MD, PhD Huib N. Caron, MD, PhD Flora E. van Leeuwen, PhD, MSc THE INTRODUCTION OF MORE EFfective treatments for childhood cancer has dramatically improved survival rates, implying that childhood cancer survivors comprise a rapidly growing group of young adults.,2 Unfortunately, improved prognosis has been accompanied by the occurrence of late, treatment-related complications such as second neoplasms, organ dysfunction, and psychosocial and cognitive problems.,4 Late treatment sequelae will increase the incidence of chronic diseases in survivors and ultimately re- For editorial comment see p 22. CME available online at www.jama.com Context Improved survival of children with cancer has been accompanied by multiple treatment-related complications. However, most studies in survivors of childhood cancer focused on only late effect. Objective To assess the total burden of adverse health outcomes (clinical or subclinical disorders [ adverse events ]) following childhood cancer in a large cohort of childhood cancer survivors with long-term and complete medical follow-up. Design, Setting, and Population Retrospective cohort study of five-year survivors of childhood cancer treated in a single institution in the Netherlands between 9 and 99. All survivors were invited to a late-effects clinic for medical assessment of adverse events. Adverse events occurring before January 24 were graded for severity in a standardized manner. Main Outcome Measures Treatment-specific prevalence of adverse events (according to severity) at end of follow-up and relative risk of high or severe burden of disease ( 2 severe or life-threatening or disabling adverse events) associated with various treatments. Results Medical follow-up was complete for 94.% of survivors (median followup,. years). The median attained age at end of follow-up was 24.4 years. Almost 5% of survivors had or more adverse events, and 24.% had 5 or more adverse events. Furthermore, 4% of survivors had at least severe or life-threatening or disabling adverse event. A high or severe burden of adverse events was observed in 55% of survivors who received radiotherapy only and 5% of survivors treated with chemotherapy only, compared with 25% of survivors who had surgery only (adjusted relative risks, 2. [95% confidence interval,.2 2.95] and.5 [95% confidence interval,.4.9], respectively). A high or severe burden of adverse events was most often observed in survivors of bone tumors (4%) and least often in survivors of leukemia or Wilms tumor (% each). Conclusions In young adulthood, a substantial proportion of childhood cancer survivors already has a high or severe burden of disease, particularly after radiotherapy. This underscores the need for lifelong risk-stratified medical surveillance of childhood cancer survivors. JAMA. 2;29:25-25 www.jama.com Author Affiliations: Late Effects Study Group and Outpatient Clinic/Polikliniek Late Effecten Kindertumoren (PLEK) (Drs Geenen, Kremer, van den Bos, van der Pal, Koning, Bakker, Caron, and van Leeuwen and Ms Cardous-Ubbink and Mr Heinen) and Department of Pediatric Oncology (Drs Kremer, van der Bos, Langeveld, and Caron), Emma Children s Hospital/ Academic Medical Center; Departments of Medical Oncology (Drs Geenen, van der Pal, and Bakker), Medical Informatics (Dr Jaspers), and Radiotherapy (Drs Oldenburger and Koning), Academic Medical Center; and Departments of Radiotherapy (Mr Hart) and Epidemiology (Dr van Leeuwen), the Netherlands Cancer Institute, Amsterdam, the Netherlands. Corresponding Author: Huib N. Caron, MD, PhD, Emma Children s Hospital/Academic Medical Center, PO Box 22, DD, Amsterdam, the Netherlands (h.n.caron@amc.uva.nl). 2 American Medical Association. All rights reserved. (Reprinted) JAMA, June 2, 2 Vol 29, No. 24 25 Downloaded From: on /2/2

duce their life expectancy. Therefore, the need for long-term follow-up of survivors of childhood cancer is uniformly recognized. 5- Research focusing on identification and characterization of high-risk populations is an essential foundation on which to build evidence-based recommendations for long-term followup.,9 Although many studies have reported on late effects of treatment in survivors of childhood cancer, -2 most of these focused on only late effect, had incomplete follow-up, or were performed in a survivor group of limited size. The aim of the present study was to assess the total burden of adverse health outcomes (clinical and subclinical disorders, hereafter termed adverse events ) following childhood cancer in a cohort of childhood cancer survivors treated at the Emma Children s Hospital/Academic Medical Center (EKZ/AMC) in the Netherlands. While called adverse events, these events sometimes may not be related to the childhood cancer or its treatment. After long-term and near-complete follow-up, we assessed the prevalence of adverse events based on medical information and graded all events for severity. Subsequently, we evaluated treatment-related risk factors for a high burden of disease in survivors of childhood cancer. METHODS Study Population All patients who were treated for childhood cancer in the EKZ/AMC between 9 and 99 and who survived for at least 5 years were included in the study cohort. They were identified using the Childhood Cancer Registry of the EKZ/ AMC, which was established in 9. In total, of 259 patients survived their primary malignancy for 5 years or more. Complete data concerning cancer diagnosis and therapy were extracted from the registry. Follow-up and Data Collection In 99, the EKZ/AMC started an outpatient clinic (Polikliniek Late Effecten Kindertumoren) for the assessment of late effects of childhood cancer treatment. Special attempts were made to trace and invite all 5-year survivors. Of the survivors, visited the late-effects outpatient clinic between January, 99, and January, 24, and were seen by their own pediatric or medical oncologist. Medical follow-up data of 9 survivors were obtained from other treating physicians, and survivors filled out a mailed health questionnaire. We therefore obtained medical follow-up data until January, 24, for 4 (94.%) of the survivors. Of the survivors with missing medical follow-up data, 5 had died (with known cause of death) before the study started;.5% of all survivors were lost to follow-up. Table. Overview of Numbers of Survivors in Burden Score Groups, According to Graded Adverse Events (N = )* No. of Adverse Events Burden Score No. of Survivors Grade 5 Grade 4 Grade Grade 2 Grade Severe (n = ) 4 9 2 2 2 High (n = 22) 2 22 2 54 2 2 24 2 2 2 Medium (n = 5) 95 2 54 4 5 2 5 Low (n = ) 54 2 Reference group (no adverse events) (n = 29) 29 Unknown adverse events (n = ) *The Common Terminology Criteria for Adverse Events version. instrument distinguishes grades through 5 with unique clinical descriptions of the severity of each event (grade, mild; grade 2, moderate; grade, severe; grade 4, life-threatening or disabling; grade 5, adverse event related death). Survivors with grade event were classified as having a low burden; those with grade 2 and/or grade event, a medium burden; those with 2 grade events, or grade 4 event and at most grade event, a high burden; and those with more grade /4 events or a grade 5 event, a severe burden. 2 JAMA, June 2, 2 Vol 29, No. 24 (Reprinted) 2 American Medical Association. All rights reserved. Downloaded From: on /2/2

In 5 survivors who visited the late-effects clinic or their own oncologist (% of all survivors), a full medical assessment was performed by a physician according to standardized follow-up protocols based on previous treatment modalities including medical history, physical examination, additional radiological and functional investigations, and blood analysis. Furthermore, these survivors were seen at least once by a psychologist or specialized nurse. All clinical and subclinical disorders were registered in a specially designed database. The EKZ/ AMC institutional review board reviewed and approved the collection of data used for the analyses presented. Written informed consent was obtained from all participants. Definition of Adverse Events All adverse events were graded by of the authors (M.M.G.) according to the Common Terminology Criteria for Adverse Events version. (CT- CAEv., available at http://ctep.cancer.gov/forms/ctcaev.pdf), a scoring system developed through the US National Cancer Institute by a multidisciplinary group. The CTCAEv. instrument can be used to score both acute and chronic conditions in patients with cancer and distinguishes grades through 5 with unique clinical descriptions of the severity for each event (grade, mild; grade 2, moderate; grade, severe; grade 4, lifethreatening or disabling; grade 5, adverse event related death). To investigate interobserver variability, authors (M.M.G., C.vd.B., P.J.M.B.) graded 24 adverse events among randomly chosen survivors based on the CTCAEv. scoring. Originally, there were 4% differences between the observers. Specific events not listed in CTCAEv., as well as those responsible for major inconsistencies, were discussed, and detailed coding rules were made (available on request from the authors). After these sessions, interobserver variability was assessed again, with only 5% differences observed. The remaining variation mainly concerned grade or 2 psychosocial items and fatigue. There were almost no differences in grade or higher adverse events. To evaluate the total burden of adverse events, we classified survivors into 4 different groups based on the total number of events and the grade of each (TABLE ). Survivors with or more grade event were classified as having a low burden; those with or more grade 2 and/or grade event, a medium burden; those with 2 or more grade events, or grade 4 event and at most grade event, a high burden; and those with more grade /4 events or a grade 5 event, a severe burden. Statistical Analysis The outcome of interest was the prevalence of adverse events. Multivariable logistic regression was used to evaluate treatment-related risk factors for the occurrence of any adverse event, a high or severe burden of such events, and selected events. All logistic analyses were adjusted for follow-up duration, age at diagnosis, and sex. Since the prevalence of events was high, the odds ratios from logistic regression analyses could not be interpreted as relative risks (RRs) and therefore were translated to study population averaged RRs. 22 The survivors with unknown adverse events were excluded from all multivariable analyses. Analyses were performed using SPSS version.. (SPSS Inc, Chicago, Ill) and SAS version.2 (SAS Institute Inc, Cary, NC). A user-written SAS macro was used to perform the study population averaged calculations. Table 2. Patient Characteristics of the Emma Children s Hospital/Academic Medical Center Childhood Cancer Survivor Cohort (N = ) 5-y Cancer Survivors, Characteristic No. (%) Sex Male 45 (54.) Female (45.) Primary childhood cancer diagnosis 5 (24.) 259 (9.) Kidney/Wilms tumor 9 (.9) Brain/CNS tumor (.9) Bone tumor (.5) Soft tissue sarcoma 5 (.) 5 (.2) * (.) Age at diagnosis of childhood cancer, y -4 59 (4.) 5-9 (2.) - 9 (22.) 5-9 (5.) Overall treatment category (N = ) Chemotherapy only, with/without surgery 52 (4.9) Radiotherapy only, with/without surgery 9 (.) Chemotherapy radiotherapy first treatment, no recurrence 4 (24.5) Chemotherapy radiotherapy including recurrence treatment* (.2) Surgery only (.) Type of chemotherapy (n = ) Anthracyclines with/without other chemotherapy (9.4) Alkylating agents with/without other chemotherapy 2 (22.) Anthracyclines and alkylating agents, with/without other chemotherapy 452 (.) chemotherapy only# 44 (29.5) (continued) 2 American Medical Association. All rights reserved. (Reprinted) JAMA, June 2, 2 Vol 29, No. 24 2 Downloaded From: on /2/2

RESULTS Study Population The large majority (94.%) of our survivors was diagnosed with childhood cancer before age 5 years. At the end of follow-up the median attained age of the survivors was 24.4 years, with 94 (%) of survivors younger than 5 years (TABLE 2). The median follow-up time was. (interquartile range,.-2.) years. The distribution of primary childhood cancer diagnoses by treatment category is shown in FIGURE. As of January, 24, of the survivors had died, the majority (2 [59.5%]) due to the primary cancer. The overall excess risk of death (excluding death from primary cancer) was increased 5.-fold compared with the general population. 2 Table 2. Patient Characteristics of the Emma Children s Hospital/Academic Medical Center Childhood Cancer Survivor Cohort (N = ) (cont) 5-y Cancer Survivors, Characteristic No. (%) Localization of radiotherapy (n = ) Head and/or neck, with/without extremities 249 (4.) Thorax and/or abdomen, with/without extremities, including craniospinal, 4 (2.) with or without extremities Extremities only, including unknown radiotherapy fields 44 (.2) TBI 2 (.5) MIBG (2.) Recurrence Yes 2 (2.) No (9.) Survival after diagnosis, y 5-9 25 (.4) - 29 (2.9) 5-9 (22.) 2-24 259 (9.) 25 255 (.) Age at end of follow-up, y 5-25 (5.) 5-9 2 (5.) 2-24 (22.) 25-29 254 (.) -4 222 (.) 5 (.) Vital status at end of follow-up Living 4 (9.) Died** (.9) Abbreviations: CNS, central nervous system; MIBG, iodine--meta-iodobenzylguanidine; TBI, total body irradiation. *Includes 45 gonadal germ cell tumors, 2 retinoblastoma, thyroid carcinoma, hepatoblastomas, malignant histiocytosis, miscellaneous. Mutually exclusive treatment groups, based on all treatments received. Chemotherapy with or without surgery plus radiotherapy with or without surgery. Including 22.% cisplatin and/or carboplatin. Including 25.4% cisplatin and/or carboplatin and.% bleomycin. Including.% cisplatin and/or carboplatin and 29.4% bleomycin. #Including 5.5% cisplatin and/or carboplatin and 2.% bleomycin. **59.5% Died due to the primary cancer;.4% died due to complications of the primary tumor or treatment. Adverse Events Of the survivors, 29 (9.%) had no adverse events and 5 (4.5%) had or more events, whereas no medical follow-up (except for cause of death) was available for the remaining (5.%) (TABLE ). The majority of survivors with medical follow-up data had more than event (5/4 [59%]), and / 4 (24.%) had 5 or more events. Furthermore, 4 (.%) of the survivors had at least severe or lifethreatening or disabling disorder, and 4 (.2%) died due to an adverse event. Among the 5 survivors with at least adverse event, a total of 5 events were observed. FIGURE 2 gives an overview of the events most frequently observed in our cohort. Almost 22% of events were severe, lifethreatening or disabling, or caused death. Of those events, orthopedic disorders occurred most often (.2%), followed by second tumors (.9%), obesity (9.4%), fertility disorders (.9%), psychosocial or cognitive disorders (.9%), neurologic disorders (.%), and endocrine disorders (5.%). Total Burden of Adverse Events Of all survivors with medical follow-up data, (2.4%) had a high or severe burden of adverse events, defined as at least 2 severe events or or more life-threatening or disabling event. FIGURE shows the distribution of adverse-event burden scores according to primary childhood cancer diagnosis. Survivors of bone tumors most often had a high or severe burden of events (4%), while survivors of leukemia or Wilms tumor least often had a high or severe burden of events (% each). The distribution of adverseevent burden scores according to treatment is depicted in FIGURE 4. Of all patients treated with radiotherapy only, 55% had a high or severe burden of events, compared with 5% and 25% among patients treated with chemotherapy only and surgery only, respectively. Association With Treatment Factors TABLE 4 shows treatment-specific risk factors for the development of an adverse event (excluding mild events) and a high or severe burden of disease. Survivors who received radiotherapy as part of their treatment had a significantly increased risk of an event of at least moderate severity, compared with survivors treated with surgery only, with the highest risk for survivors in the radiotherapy-only group 2 JAMA, June 2, 2 Vol 29, No. 24 (Reprinted) 2 American Medical Association. All rights reserved. Downloaded From: on /2/2

(RR,.49 [95% confidence interval {CI},.2-.4]). Survivors who received radiotherapy only were also most likely to develop a high or severe burden of events (RR, 2. [95% CI,.2-2.95] vs surgery only). Survivors treated with chemotherapy only were significantly less likely to develop a high or severe burden of events than survivors in the surgery-only group (RR,.5 [95% CI,.4-.9]). Female survivors were significantly more likely than male survivors to develop an event of at least moderate severity (RR,. [95% CI,.-.]) and also had a greater risk of a high or severe burden of disease. Similar results were obtained when we assessed the risk of developing at least severe event (grade -5 vs grade -), although RRs for radiotherapy tended to be slightly higher than in other models. Table 4 also shows the effects of specific chemotherapy and radiotherapy regimens on the development of adverse events. Treatment with anthracyclines, alkylating agents, or both did not affect the risk of a high or severe burden of events, compared with treatment without chemotherapy. Survivors who were treated with other chemotherapy carried a significantly lower risk (RR,.59 [95% CI,.45-.]), compared with treatments not involving chemotherapy. When the treatment groups (anthracyclines, alkylating agents, or both) were combined and compared with the other chemotherapy group, the RR was.5 (95% CI,.-.9). The analysis was repeated for patients treated only with chemotherapy (without radiotherapy, central nervous system surgery, or amputation of the limb, n=). When the different treatment groups (anthracyclines, alkylating agents, or both) were compared with treatment with other chemotherapy, treatment with alkylating agents carried the highest risk of developing a high or severe burden score (RR,. [95% CI,.4-.92]). All radiation areas were associated with a significantly higher risk (about 2-fold) of developing a high or severe burden of adverse events, in comparison with treatments not involving radiation. Surgery was also associated with a significant.- fold (95% CI,.4-2.5) increased risk of a high or severe burden of events. Treatment-Specific Risks of Selected Events TABLE 5 shows the treatment-specific risks of events in survivors of childhood cancer. The risk of a cardiovascular adverse event was increased in survivors treated with anthracyclines (RR,.5 [95% CI,.52-.2] vs no chemotherapy), and an even higher risk was found for survivors treated with both anthracyclines and alkylating agents (RR,.4 [95% CI,.- 5.]). The RRs for a cardiovascular or peripheral vascular event were also increased after radiotherapy to the thorax, abdomen, or both and radiotherapy to the extremities only (RRs of 2. [95% CI,.9-.29] and 2. [95% CI,.2-.5], respectively, compared with no radiotherapy). Radiotherapy involving the head and neck area was the most important risk factor for obesity (RRs from. [95% CI,.94-2.] to.9 [95% CI,.5- Figure. Distribution of Primary Childhood Cancer Diagnosis by Treatment Category Treatment Surgery Only Chemotherapy (± Surgery) Only Radiotherapy (± Surgery) Only Chemotherapy and Radiotherapy (± Surgery) for Initial Treatment Only Chemotherapy and Radiotherapy (± Surgery) for Initial and Recurrence Treatment No. of Patients 52 9 4 CNS indicates central nervous system. Cancer Diagnosis 2 2 4 4 5 5 9 9 5 9 9 2 22 5 5 2 25 5 4 45 5 25 2 2 4 2 American Medical Association. All rights reserved. (Reprinted) JAMA, June 2, 2 Vol 29, No. 24 29 Downloaded From: on /2/2

Table. Adverse Events in the Emma Children s Hospital/Academic Medical Center Childhood Cancer Survivor Cohort Cancer Survivors, Events No. (%) Adverse events at end of follow-up* Yes 5 (4.5) No 29 (9.) Unknown (5.) No. of adverse events per survivor 25 (2.) 2 (.) 4 (.2) 4 (.9) 5 94 (.) 222 (.) Maximum grade of adverse events per survivor Mild (.) 2 Moderate (2.) Severe (24.2) 4 Life-threatening or disabling (.) 5 Death 4 (.2) Burden score of adverse events Low (.) Medium 5 (44.) High 22 (.) Severe (.) *N =. n = 4 with medical follow-up data. In total, 5 adverse events in 5 survivors. n = 4 with medical follow-up data. Includes 29 survivors with no registered adverse events. Fifteen 5-year survivors died while their primary cancer or recurrence was still present: infectious (), cardiovascular (4), pulmonary (), gastrointestinal tract (2). Of the 5-year survivors who died while in complete remission, 2 (.4%) died of a second or third malignancy, 4 (.%) of cardiovascular disease, and of infection. n = 4 with follow-up data. Includes 29 survivors with no registered adverse events. Low burden: survivors with grade adverse event; medium burden: grade 2 and/or grade event; high burden: 2 grade events, or grade 4 event and at most grade event; severe burden: more grade /4 events or a grade 5 event..]). In addition, the risks for endocrine and neurologic events were significantly increased in survivors treated with radiotherapy involving the head and neck area (RRs from 4.25 [95% CI, 2.9-.9] to. [95% CI,.-.] for endocrine events and from. [95% CI, 2.2-4.2] to.2 [95% CI, 2.-4.] for neurologic events, compared with no radiotherapy). The risks of developing an endocrine or neurologic event were also increased in survivors treated with total body irradiation (RRs of 4. [95% CI,.-.] and.2 [95% CI, 2.4-5.2], respectively). The risk of developing an endocrine event was also increased in survivors treated with radioactive iodine (iodine--meta-iodobenzylguanidine [MIBG]) (RR, 5.5 [95% CI, 4.2-.]). The risk of nephrologic events was associated with chemotherapy (RR, 5. [95% CI, 2.25-.4]), especially cisplatin (data not shown). In male survivors, the risk of fertility problems was increased in survivors treated with anthracyclines, alkylating agents, or combined treatment with these agents (RRs of 5.2 [95% CI,.5-.], 9. [95% CI,.2-24.5], and. [95% CI,.-29.4], respectively, vs treatment without chemotherapy) and in survivors treated with total body irradiation (RR, 2.5 [95% CI,.-.]) (Table 5). Since the majority of female survivors used oral contraceptives, their risk of fertility problems could not be assessed. The risk of a second malignancy was elevated more than 2-fold in survivors treated with radiotherapy. The risk of fatigue was increased in female compared with male survivors (RR, 2. [95% CI,.94-.94]); radiotherapy involving the head and neck area was also a risk factor (RRs from. [95% CI,.-2.] to 2.4 [95% CI,.54-.2]). The risk of developing any psychosocial or cognitive event was increased more than 2-fold in survivors treated with radiotherapy involving the head and neck area. Similar results were found when analyses were restricted to grade -5 events (radiotherapy of the head and neck: RR,. [95% CI,.- 5.] [TABLE ]; and radiotherapy of the head and neck and the thorax and abdomen: RR, 2.55 [95% CI,..]). COMMENT After a median follow-up of years, nearly 5% of childhood cancer survivors had experienced at least adverse event, 4% at least severe or lifethreatening or disabling event, and 2.4% a high or severe burden of events. This is a high burden of disease considering the young age of our survivor population; % were younger than 5 years at end of follow-up. Treatment with radiotherapy only was associated with the highest risk of developing a high or severe burden of disease, while chemotherapy only was associated with significantly lower risk than surgery only. Unique features of our study include near-complete medical follow-up (94%), with % of survivors being seen in our specialized lateeffects clinic. In addition, all adverse events were graded for severity in a standardized manner using the CTCAEv. instrument, which represents a comprehensive, multimodality grading system for reporting acute and late effects of cancer treatment. The low interobserver variability in our study, after applying more detailed coding rules, shows that CTCAEv is a reliable method of assessing the severity of adverse events. Only a few studies have addressed the overall burden of adverse events in long-term survivors. 2,24-2 Although these studies used different methods to assess such events, they all reported at least event in more than 4% of survivors. Limitations of these reports include the small study size 24-2 and the lack of a uniform scoring system 24 or a control group. 24-2 In the United States, the Childhood Cancer Survivor Study (CCSS) addressed several of these limitations by assessing late adverse events in a well-characterized cohort of 5-year survivors (N= 9), using various methods to score events. 2,2 According to a recent study 2 that used the same scoring system (CTCAEv.) as ours did, 2.% of the survivors had at least chronic condition and 2.5% had a severe or life-threatening condition. These values are slightly lower than ours (4.5% and.%, respectively). Furthermore, the proportion of survivors with or more adverse events was 24% in the CCSS and 45% in our study. Several methodological aspects of the CCSS and our study may explain these differences. Only % of the eligible survivor population participated in the CCSS. On the one hand, incomplete follow-up may result in an overestimation of the risk of late complications, 2 JAMA, June 2, 2 Vol 29, No. 24 (Reprinted) 2 American Medical Association. All rights reserved. Downloaded From: on /2/2

since healthy survivors may be less likely to be traced and to participate. 2,29 On the other hand, survivors with severe chronic conditions may have declined participation because of their poor health status, which would lead to underestimation of risk. Furthermore, information on adverse events in the CCSS was based on selfreported conditions, which were medically confirmed only for second malignancy. This may have led to both overestimation and underestimation of the incidence and severity of various chronic health conditions. 2 By contrast, the results of our study are based on medical information; we also determined overall burden of disease, based on the number of adverse events and the severity of each. The slightly higher proportion of events in our survivor population compared with the CCSS population may be due partly to the fact that we included adverse psychosocial outcomes and that we had much more complete information on morbidity in 5-year survivors who had already died before medical assessment of adverse events. However, when we excluded psychosocial outcomes, 5.9% of our survivors still had a severe or lifethreatening condition (vs.% originally), due to the fact that most survivors with a severe or life-threatening psychosocial condition also had other such conditions. Another difference between the 2 studies is that 94% of our survivors were treated before age 5 years, whereas the CCSS also included survivors treated at ages to 2 years. Furthermore, differences in cancer diagnoses and treatment could explain some differences in adverse health outcomes between the CCSS and our study. For example, the CCSS included slightly more survivors of central nervous system tumors and leukemia and slightly fewer survivors of nephroblastoma. Also, the proportions of patients receiving any radiotherapy were different: 2.9% in the CCSS and 44.% in our study. Chemotherapy was administered to 9.% of patients in the CCSS and to 5.% of survivors in our study. These treatment differences may be explained partly by different treatment protocols used in the 2 studies and partly by less Figure 2. Overview of Most Common Adverse Events Adverse Event Category Alopecia Cardiovascular Angina Pectoris/Myocardial Infarction Cardiomyopathy Ear, Nose, and Throat Endocrine Growth Hormone Deficiency Thyroid Disorders Panhypopituitarism Fatigue Fertility Oligospermia/Azoospermia Gastroenterology Metabolic Obesity Nephrologic Hypertension Tubular Dysfunction Neurologic Seizures Motor Dysfunction/Hemiparesis Sensory Loss Ophthalmology Orthopedic Amputation/Prothesis/Rotationplasty Scoliosis/Low Back Pain Pain Psychosocial/Cognitive Problems Cognitive Problems Emotional Problems Pulmonary Second Tumors Malignant Tissue Hypoplasia Urology Miscellaneous 2 5 2 49 5 2 5 5 4 4 5 9 4 complete follow-up in the CCSS and a relatively high proportion of CCSS patients with unknown treatment data (5%). Overall 5 5 9 242 252 254 295 5 4 2 4 5 No. of Scored Adverse Events 49 No. of Scored Adverse Events Grade 9 5 9 2 25 9 5 5 4 4 42 5 2 42 9 55 4 95 Grade 2 24 2 9 9 9 5 5 42 2 42 5 5 22 52 5 2 2 2 5 5 9 Grades, 4, and 5 *Grade 2 indicates moderate fatigue or that causing some difficulty performing some activities of daily living (ADL); grade, severe fatigue interfering with ADL; grade 4, disabling fatigue. Grade 2 indicates body mass index (BMI, calculated as weight in kilograms divided by height in meters squared) of 25 to 29.9; grade, BMI of to 9.9; grade 4, BMI 4. Grade 2 indicates moderate cognitive disability interfering with work, school, or life performance but patient capable of independent living (but specialized resources on a part-time basis indicated); grade, severe cognitive disability with significant impairment of work, school, or life performance; grade 4, unable to perform ADL (full-time specialized resources or institutionalization indicated). Grade 2 indicates transient episodes of psychosis, or personality or behavioral change adversely affecting patient or family; grade, psychosis interfering with ADL; psychosis requiring medication, supervision, or restraints; personality or behavioral change requiring mental health intervention; grade 4, psychosis rendering patient harmful to others or to self; psychosis with life-threatening consequences; personality or behavioral change rendering patient harmful to others or to self; personality or behavioral change requiring hospitalization. Grade 2 indicates deformity, hypoplasia, or asymmetry that can be remediated by prosthesis or covered by clothing; grade, functionally significant deformity, hypoplasia, or asymmetry that cannot be remediated by prosthesis or covered by clothing; grade 4, disabling hypoplasia. 29 4 2 42 2 2 4 2 5 4 5 4 22 2 9 4 4 2 American Medical Association. All rights reserved. (Reprinted) JAMA, June 2, 2 Vol 29, No. 24 2 Downloaded From: on /2/2

Figure. Distribution of Adverse Events Burden Scores by Primary Childhood Cancer Diagnosis Diagnosis No. 5 259 9 5 5 None 2 9 29 2 22 Low Adverse Events Burden Medium 9 4 5 45 22 4 44 High 9 2 2 9 55 Severe 4 9 2 4 2 4 2 4 2 4 2 4 See Methods section for definitions of burden scores. CNS indicates central nervous system. Figure 4. Distribution of Adverse Events Burden Scores by Treatment Category Treatment Surgery Only Chemotherapy (± Surgery) Only Radiotherapy (± Surgery) Only Chemotherapy and Radiotherapy (± Surgery) Only No. 52 9 5 None 2 2 2 4 Low 2 4 Adverse Events Burden Medium 5 52 2 4 High 4 2 4 Severe 5 2 4 See Methods section for definitions of burden scores. Table 4. Treatment-Specific Risk Factors for Adverse Events in the Emma Children s Hospital/Academic Medical Center Childhood Cancer Survivor Cohort Risk Factor RR (95% CI)* Adverse Events Grade 2-5 vs Grade - Burden Score High/ Severe vs No/Low Sex, female vs male. (.-.). (.95-.2) Total treatment (model ) Surgery only [Reference] [Reference] Chemotherapy only. (.4-.2).5 (.4-.9) Radiotherapy only.49 (.2-.4) 2. (.2-2.95) Chemotherapy radiotherapy first treatment, no recurrence. (.-.52). (.94-.) Chemotherapy radiotherapy including recurrence treatment. (.-.5). (.24-2.4) Specific treatments (model 2) Chemotherapy None [Reference] [Reference] Anthracyclines with/without other chemotherapy.9 (.-.).9 (.-.) Alkylating agents with/without other chemotherapy. (.9-.).4 (.-.) Anthracyclines and alkylating agents with/without other chemotherapy.95 (.4-.).9 (.-.) chemotherapy only. (.-.9).59 (.45-.) Radiotherapy None [Reference] [Reference] Head and/or neck, with/without extremities.4 (.5-.) 2.4 (2.2-2.9) Thorax and/or abdomen, with/without extremities.49 (.5-.4) 2. (.-2.) Head and/or neck and thorax and/or abdomen, including craniospinal, with/without extremities.5 (.4-.) 2. (2.-.) Extremities only.4 (.-.) 2.24 (.-.) TBI, yes vs no.4 (.2-.49).2 (.9-2.) MIBG, yes vs no. (.95-.4). (.2-2.5) Surgery, yes vs no. (.9-.2). (.4-2.5) Abbreviations: CI, confidence interval; MIBG, iodine--meta-iodobenzylguanidine; RR, relative risk; TBI, total body irradiation. *Logistic regression excluded persons with lack of information on adverse events; RRs were adjusted for follow-up time and age at diagnosis (both as continuous variables). This analysis reflects same results as for medium/high/severe burden vs no/low burden. Medium burden score excluded. Mutually exclusive treatment groups, based on all treatments received. Mutually exclusive chemotherapy groups, based on all treatments received. Mutually exclusive radiotherapy groups, based on all treatments received. 2 JAMA, June 2, 2 Vol 29, No. 24 (Reprinted) 2 American Medical Association. All rights reserved. Downloaded From: on /2/2

A limitation of our study is that we could not compare the prevalence of adverse events in our survivors with that in a healthy population. Most of the specific events included in our analyses also occur in the general population, but the population prevalence of most events is unknown. Therefore we could only compare the prevalence of adverse events and the total burden of disease between treatment groups. Nonetheless, it is clear that the prevalence is strongly increased for most events graded or higher, since they rarely occur in persons younger than 5 years. 2 In the CCSS report, the risk of a grade or 4 event was increased.2-fold (95% CI,.9-9.) compared with sibling controls. 2 Our results show that radiotherapy is the most important risk factor for a high burden of adverse events. It is important to note that 4% of survivors treated with radiotherapy only were survivors of brain or central nervous system tumors and who had received high doses of cranial radiotherapy. Radiotherapy was associated with more than 2-fold increased risks of cardiovascular, endocrine, and neurologic events, second malignancies, and psychosocial and cognitive events. Previous studies that focused on radiationinduced injury also showed prominent effects on the development of these events,,,- but total burden of dis- Table 5. Treatment-Specific Risks of Selected Adverse Events in the Emma Children s Hospital/Academic Medical Center Childhood Cancer Survivor Cohort* Adverse Event, RR (95% CI) Risk Factor Cardiovascular Obesity Endocrine Neurologic Nephrologic Sex, female vs male. (.5-.) 2.9 (.5-.24). (.9-.45).5 (.-.5).5 (.-.44) Chemotherapy None [Reference] [Reference] [Reference] [Reference] [Reference] Anthracyclines with/without other chemotherapy.5 (.52-.2).4 (.-.4). (.-.). (.9-.) Alkylating agents with/without other chemotherapy 2.2 (.9-4.4).4 (.-.52).2 (.44-.9). (.42-.5) Anthracyclines and alkylating agents with/without.4 (.-5.).99 (.49-.99).52 (.4-.9). (.25-.59) 5. (2.25-.4) other chemotherapy chemotherapy only. (.59-.).25 (.-2.4). (.5-.).45 (.-.) Radiotherapy None [Reference] [Reference] [Reference] [Reference] [Reference] Head and/or neck with/without extremities.5 (.2-.4). (.94-2.) 4.25 (2.9-.9). (2.2-4.2) Thorax and/or abdomen with/without extremities 2. (.9-.29).4 (.2-.42).9 (.-2.).5 (.95-2.4) Head and/or neck and thorax and/or abdomen including craniospinal with/without extremities.5 (.9-2.54).9 (.5-.). (.-.).2 (2.-4.).2 (.92-.) Extremities only 2. (.2-.5). (.5-2.5).2 (.5-2.).2 (.9-.2) TBI, yes vs no.99 (.42-2.).4 (.52-.5) 4. (.-.).2 (2.4-5.2) Surgery, yes vs no. (.4-.).9 (.-.59).9 (.-.29). (.-2.2) 2.95 (2.2-4.) Male Fertility Adverse Events Second Malignancy Fatigue Psychosocial and Cognitive Sex, female vs male.9 (. 24-2.5) 2. (.94-.94).5 (.-.2) Chemotherapy None [Reference] [Reference] [Reference] [Reference] Anthracyclines with/without other chemotherapy 5.2 (.5-.). (.-.5).4 (.99-.42). (.9-.) Alkylating agents with/without other chemotherapy 9. (.2-24.5). (.45-.4).4 (.-2.42).9 (.-.4) Anthracyclines and alkylating agents with/without other chemotherapy. (.-29.4). (.4-.). (.5-2.). (.-.9) chemotherapy only 2.29 (.5-.). (.4-.25). (.4-2.). (.-.45) Radiotherapy None [Reference] [Reference] [Reference] [Reference] Head and/or neck with/without extremities. (.-.5) 2.4 (.52-4.). (.-2.) 2. (.4-2.) Thorax and/or abdomen with/without extremities.9 (.2-.5) 2. (.-.).9 (.4-.). (.-.52) Head and/or neck and thorax and/or abdomen, including craniospinal with/without extremities.5 (.-2.) 2.9 (.-5.2) 2.4 (.54-.2) 2.4 (.5-.) Extremities only.99 (.49-2.) 2.52 (.-5.).99 (.4-2.44).59 (.25-.) TBI, yes vs no 2.5 (.-.) 2.59 (.9-.5). (.2-4.4).9 (.4-2.) Surgery, yes vs no.5 (.49-.).9 (.-.45).9 (.-.5).9 (.9-.2) Abbreviations: CI, confidence interval; RR, relative risk; TBI, total body irradiation. *All RRs were adjusted for chemotherapy, radiotherapy, surgery, sex, follow-up time and age at diagnosis, where appropriate. Logistic regression excluded persons with lack of information on adverse events. Mutually exclusive chemotherapy groups, based on all treatments received. Mutually exclusive radiotherapy groups, based on all treatments received. Group risks for MIBG (iodine--meta-iodobenzylguanidine) are not presented because of the very small numbers of events. 2 American Medical Association. All rights reserved. (Reprinted) JAMA, June 2, 2 Vol 29, No. 24 2 Downloaded From: on /2/2

ease was not considered in these reports. A long-term mortality study in the CCSS also showed that the risk of death was increased in survivors who had received radiotherapy (RR, 2.5 [95% CI,.-.9]), 4 although to a lesser extent than in our study. 2 The recent report by Oeffinger et al 2 showed that chest irradiation combined with either bleomycin, anthracyclines, or subdiaphragmatic irradiation increased by at least -fold the risk of developing a severe or a life-threatening or disabling adverse event, compared with sibling controls. In interpreting the risk increase associated with radiotherapy, it should be considered that the median follow-up for irradiated patients is longer than that for those receiving chemotherapy. Although we adjusted for follow-up time, we cannot exclude the possibility that yet-unknown late effects of chemotherapy may emerge with longer follow-up. Treatment with chemotherapy only was associated with a much lower burden of disease than radiotherapy only but also carried a lower risk than surgery only. It is important to note that surgery in pediatric oncology is associated with important long-term sequelae, for example, due to amputation and brain surgery. Although chemotherapy was associated with a relatively low burden of disease, elevated risks were noted for cardiovascular adverse events, fertility problems in male survivors, and nephrologic events. The risk of cardiovascular events was increased following anthracyclinecontaining chemotherapy, but alkylating agents appeared to add to this effect. While the cardiotoxicity of anthracyclines has been established,,5, the role of alkylating agents is still controversial. The risk of nephrologic events was especially elevated after platinumcontaining chemotherapy. When we considered adverse events of any grade, psychosocial and cognitive events were most frequently observed. Thirteen percent of these were graded or higher, implying serious impact on daily life. Radiotherapy to the head and neck area was strongly associated with a high risk of developing psychosocial and cognitive events (RR, 2. [95% CI,.4-2.]), and this result became even more pronounced when the analysis was restricted to the Table. Treatment-Specific Risks of Psychosocial and Cognitive Adverse Events in the Emma Children s Hospital/Academic Medical Center Childhood Cancer Survivor Cohort Psychosocial and Cognitive Events, Risk Factor Grade -5 vs None, RR (95% CI) Sex, female vs male.5 (.-.) Chemotherapy* No chemotherapy [Reference] Anthracyclines with/without other chemotherapy. (.2-.) Alkylating agents with/without other chemotherapy.4 (.9-.) Anthracyclines and alkylating agents with/without. (.-.) other chemotherapy chemotherapy only. (.-.5) Radiotherapy No radiotherapy [Reference] Head and/or neck with or without extremities. (.-5.) Thorax and/or abdomen with or without extremities.9 (.2-2.2) Head and/or neck and thorax and/or abdomen, 2.55 (.-.) including craniospinal with or without extremities Extremities only TBI, yes vs no NA NA Surgery, yes vs no. (.45-.44) Abbreviations: CI, confidence interval; NA, not available; RR, relative risk; TBI, total body irradiation. *Mutually exclusive chemotherapy groups, based on all treatments received. Mutually exclusive radiotherapy groups, based on all treatments received. Group risks for MIBG (iodine--meta-iodobenzylguanidine) are not presented because of the very small numbers of events. No events in this treatment category. most serious events. Of all grade or higher events, orthopedic events were most frequent, as was also observed in the recent CCSS report. 2 In our study, survivors of bone tumors had the highest burden of disease at end of follow-up. This is partly due to the high proportion of amputations and the occurrence of peripheral vascular events following radiotherapy to the extremities. Furthermore, patients with bone tumors were often treated with anthracyclines and cisplatin, predisposing them to cardiovascular and nephrologic adverse events. studies also have reported on the high risk of late effects in survivors of bone tumors. 2,2, More than % of survivors of brain tumors had a medium, high, or severe burden score of adverse events. Neurocognitive and endocrine events have been intensively studied in patients with central nervous system tumors, and adverse outcomes are generally associated with whole-brain irradiation.,2,9,4 The increased risk of a high or severe burden of disease in survivors of irradiated brain tumors in our study is supported by CCSS data.,2 Forty-three percent of survivors of brain tumors in the CCSS study had or more endocrine disorders, and % reported a cardiovascular problem. The risk of developing an endocrine disorder was increased in patients treated with MIBG (RR, 5.5 [95% CI, 4.2-.]), mostly due to thyroid problems following treatment. One other study also reported on endocrine disorders following treatment with MIBG. 4 In conclusion, childhood cancer survivors are at increased risk of many severe health problems, resulting in a high burden of disease during young adulthood. This will inevitably affect the survivors quality of life and also will ultimately reduce their life expectancy. Therefore, we feel that risk-stratified lifelong medical surveillance of childhood cancer survivors is needed to allow early detection of adverse events that are amenable to intervention. Future studies should focus on the efficacy of follow-up programs and other 2 JAMA, June 2, 2 Vol 29, No. 24 (Reprinted) 2 American Medical Association. All rights reserved. Downloaded From: on /2/2

intervention strategies for adverse events, to further improve health outcomes in survivors of childhood cancer. Author Contributions: Drs Geenen and Cardous- Ubbink had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Geenen, Cardous-Ubbink, Kremer, van den Bos, Jaspers, Langeveld, Bakker, Caron, van Leeuwen. Acquisition of data: Geenen, Cardous-Ubbink, van den Bos, van der Pal, Heinen, Langeveld. Analysis and interpretation of data: Geenen, Cardous-Ubbink, Kremer, van den Bos, van der Pal, Heinen, Jaspers, Koning, Oldenburger, Langeveld, Hart, Bakker, Caron, van Leeuwen. Drafting of the manuscript: Geenen, Cardous-Ubbink, van Leeuwen. Critical revision of the manuscript for important intellectual content: Geenen, Cardous-Ubbink, Kremer, van den Bos, van der Pal, Heinen, Jaspers, Koning, Oldenburger, Langeveld, Hart, Bakker, Caron, van Leeuwen. Statistical analysis: Geenen, Cardous-Ubbink, Kremer, Hart, van Leeuwen. Obtained funding: Caron. Administrative, technical, or material support: Geenen, Cardous-Ubbink, Kremer, van den Bos, van der Pal, Heinen, Jaspers, Koning, Oldenburger, Langeveld, Bakker, Caron, van Leeuwen. Study supervision: Bakker, Caron, van Leeuwen. Dr Geenen and Ms Cardous-Ubbink contributed equally to the manuscript. Financial Disclosures: None reported. Funding/Support: This study was supported by the Foundation of Paediatric Cancer Research, Amsterdam, the Netherlands. Role of the Sponsor: The Foundation of Paediatric Cancer Research had no role in the design and conduct of the study; the collection, management, analysis, and interpretation of the data; or the preparation, review, or approval of the manuscript. Acknowledgment: We thank the medical staff of the Polikliniek Late Effecten Kindertumoren, Emma Children s Hospital/Academic Medical Center, Amsterdam, the Netherlands. We also thank Meriam van Overveld, MSc, Polikliniek Late Effecten Kindertumoren, and Marian Chin a Kwie, office of Dr van Leeuwen, for their uncompensated administrative support, and the general practitioners for the provision of additional and follow-up data on patients. We are indebted to the patients and to their parents for giving their permission to participate in the study. REFERENCES. Curry HL, Parkes SE, Powell JE, Mann JR. Caring for survivors of childhood cancers: the size of the problem. Eur J Cancer. 2;42:5-5. 2. Hewitt M, Weiner SL, Simone JV, eds. Childhood Cancer Survivorship: Improving Care and Quality of Life. Washington, DC: The National Academies Press; 2.. Bhatia S, Landier W. Evaluating survivors of pediatric cancer. Cancer J. 25;:4-54. 4. Wallace HB, Green DM. Late Effects of Childhood Cancer. London, England: Arnold Publishers; 24. 5. Landier W, Bhatia S, Eshelman DA, et al. 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