Long-term excess mortality and morbidity following treatment of childhood cancer Ubbink, M.C.

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1 UvA-DARE (Digital Academic Repository) Long-term excess mortality and morbidity following treatment of childhood cancer Ubbink, M.C. Link to publication Citation for published version (APA): Ubbink, M. C. (2009). Long-term excess mortality and morbidity following treatment of childhood cancer General rights It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulations If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. UvA-DARE is a service provided by the library of the University of Amsterdam ( Download date: 12 Dec 2018

2 Long-Term Excess Mortality and Morbidity Following Treatment of Childhood Cancer Mathilde Cardous-Ubbink Long-Term Excess Mortality and Morbidity Following Treatment of Childhood Cancer Mathilde Cardous-Ubbink

3 Long-Term Excess Mortality and Morbidity Following Treatment of Childhood Cancer Mathilde C Cardous-Ubbink

4 The research presented in this thesis was financially supported by the Dutch Cancer Society (Koningin Wilhelmina Fonds; KWF Kankerbestrijding) and the Foundation of Paediatric Cancer Research (Stichting Kindergeneeskundig Kankeronderzoek). Financial support for publication of this thesis by the Dutch Cancer Society, Pfizer BV, Integraal Kankercentrum Amsterdam (IKA (Comprehensive Cancer Centre Amsterdam (CCAA*)), Eli Lilly Nederland BV, Genzyme Nederland and Boehringer Ingelheim bv is gratefully acknowledged. Layout: Chris Bor, Medisch Fotografie en Illustratie, AMC, Amsterdam Printed by: Drukkerij Wilco, BV Amersfoort ISBN: Photograph Cover: Mathilde Cardous-Ubbink Achter de wolken schijnt altijd de zon 2009, M.C. Cardous-Ubbink, Amersfoort No part of this thesis may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording or otherwise without permission of the author. * The CCAA is one of nine Comprehensive Cancer Centers in the Netherlands. Its area is the north-western part of the Netherlands and involves 2,800,000 inhabitants, 17 general hospitals, two university hospitals and the Netherlands Cancer Institute. The comprehensive cancer centers (CCC s) in the Netherlands have been founded to provide comprehensive and high-quality cancer care close to home for all cancer patients. The CCCA provides and coordinates a collaboration of all health care professionals and institutions involved in cancer and palliative care. The CCAA functions as a centre of knowledge and quality care that helps to improve cancer treatment, patient care and clinical research as well as prevention of cancer and decrease of cancer mortality

5 Long-Term Excess Mortality and Morbidity Following Treatment of Childhood Cancer ACADEMISCH PROEFSCHRIFT ter verkrijging van de graad van doctor aan de Universiteit van Amsterdam op gezag van de Rector Magnificus prof.dr. D.C. van den Boom ten overstaan van een door het college voor promoties ingestelde commissie, in het openbaar te verdedigen in de Agnietenkapel op vrijdag 25 september 2009, te 10:00 uur door Mathilde Claudia Ubbink geboren te Papendrecht

6 PROMOTIECOMMISSIE Promotores: Co-promotores: Overige leden: Prof. dr. H.N. Caron Prof. dr. ir. F.E. van Leeuwen Prof. dr. P.J.M. Bakker Dr. L.C.M. Kremer Prof. dr. P.M.M. Bossuyt Prof. dr. H.S.A. Heymans Prof. dr. C.C.A. Koning Prof. dr. H.J. de Koning Prof. dr. M. Offringa Prof. dr. R. Pieters Faculteit der Geneeskunde

7 CONTENTS Chapter 1 General introduction 7 Chapter 2 Medical assessment of adverse health outcomes in longterm 19 survivors of childhood cancer JAMA 2007; 297(24): Chapter 3 Risk of second malignancies in long-term survivors of 41 childhood cancer Eur J Cancer 2007; 43: Chapter 4 Long-term cause-specific mortality among five-year 59 survivors of childhood cancer Pediatr Blood Cancer 2004; 42: Chapter 5 Hypertension in long-term survivors of childhood cancer: 77 a nested case-control study Under review by Eur J Cancer Chapter 6 General discussion 93 Summary 111 Samenvatting 117 Dankwoord 125 Curriculum vitae 133

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9 1 General Introduction

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11 General Introduction GENERAL INTRODUCTION The studies described in this thesis deal with the long-term adverse effects of childhood cancer survivors. As a general introduction, this chapter begins with a short review of relevant background information. First some epidemiological aspects of paediatric oncology and the risks of long-term adverse effects are discussed. Next, some information will be given about the long-term follow-clinic in the Emma Children s Hospital/ Academic Medical Centre (EKZ/AMC), where childhood cancer survivors are regularly screened. Furthermore, some methodological considerations are described. Finally, the outline of this thesis is given. EPIDEMIOLOGICAL ASPECTS OF CHILDHOOD CANCER Incidence of childhood cancer Paediatric and adolescent cancers account for only a small proportion of the worldwide cancer burden (1). Approximately 480 children (age 0-14 years) with cancer are registered annually by the Netherlands Cancer Registry, leading to an age-standardised annual incidence rate (ASR) of per million (95% CI ) (2;3). The characteristics of malignant tumours in childhood differ greatly from those in adults, not only with regard to the affected sites but also with regard to histology. Table 1.1 shows the distribution by morphological type of cancer among children aged 0-14 years. Table 1.1: Distribution of the different childhood cancer diagnoses in children aged 0-14 years (Source: the Netherlands Cancer Registry 2006; Diagnosis Total N Boys N Girls N Leukaemia Brain/ CNS tumour Lymphoma Soft tissue tumour Nephroblastoma Bone tumour Neuroblastoma Carcinomas Other (like retinoblastoma, germ cell tumours, hepatic tumours) Total Leukaemia (predominantly acute lymphoblastic leukaemia), brain and central nervous system tumours and lymphoma are the most common cancers in children. Diagnoses of childhood cancer are not equally common in both sexes, for example leukaemias and lymphomas occur more often in boys. Figure 1.1 shows the European age-specific cancer 9

12 Chapter 1 Per million EUROPE Boys EUROPE Girls Age in years Figure 1.1: Age-specific cancer incidence among children in Europe as a whole by single year of age, separately for boys and girls, Source: ACCIS (Automated Childhood Cancer Information System (3)). incidence among children separately for boys and girls (3). The data used are form the Automated Childhood Cancer Information System (ACCIS); a collaborative project of the European cancer registries, aiming at collection, analysis, interpretation, and dissemination of data on cancer incidence and survival of children and adolescents in Europe. The ACCIS database contains data from some 80 population-based cancer registries, which cover about 50% of the European population aged 0-14 years, living in the 35 participating countries, including the Netherlands (4). It is well known that there are only small differences in childhood cancer incidence between the different European countries. The age-specific incidence curves varies between diagnostic groups (5). There is a peak in incidence in the age groups younger than 5 years of age for many of the childhood cancers (i.e. leukaemias, tumours of the central nervous system, neuroblastoma, retinoblastoma, Wilms` tumour and hepatoblastoma) and an increasing incidence with age in others (i.e. Hodgkin s lymphoma, bone tumours, thyroid cancer and melanoma) (6). Survival of childhood cancer The overall survival of childhood cancer survivors improved dramatically over the last decades. Where in the late sixties only 30% of childhood cancer patients survived five or more years; the survival is nowadays around 75% for patients aged 0-14 years (2;7-10). The improved survival rates are reflected in decreasing mortality rates of childhood cancer. Figure 1.2 shows improved survival rates for different diagnosis in Europe, based on ACCIS data (11). Unfortunately, there are no more recent European data available. 10

13 General Introduction 90 Trends in survival for children aged 0-14 years, selected sites of cancer, year survival rates (%) Leukaemia Lymphoma CNS Neoplasm Renal tumours Malignant neoplasms of the bone Soft tissue sarcoma All neoplasms year of childhood cancer diagnosis Figure 1.2: Trends in 5-year survival for children under age of 15. Source: ACCIS (Automated Childhood Cancer Information System) (11) Figure 1.3 shows the relative survival of childhood cancer in the IKA-region in the Netherlands, which is the area covering the provinces of Noord-Holland and Flevoland, according to year of diagnosis. In the most recent time period the survival is still improving. Not all regional cancer registries collect follow-up data and therefore national data are not available. However, the IKA-region is a large region in the Netherlands with reliable data. 100% 95% 90% Survival (%) 85% 80% 75% 70% 65% 60% Years after diagnosis Figure 1.3: Relative survival of childhood cancer (in children 0-14 years) in the IKA region in the Netherlands (Province of Noord-Holland and Flevoland), according to year of diagnosis (Source: 11

14 Chapter 1 As shown in the figures above, the introduction of more effective treatment modalities for childhood cancer from the 1970s onwards, has dramatically improved survival rates, implying that childhood cancer survivors are a rapidly growing group of young adults (3;12;13). Due to the excellent survival rates this yields an estimated prevalence (at June 1 st 2008) of more than 6000 childhood cancer survivors aged 0-17 years at time of diagnosis (diagnosed between 1960 and 2003) in the Netherlands. Long-term adverse effects Unfortunately, improved prognosis has been accompanied by a rising incidence of treatment-related complications. These long-term adverse effects are often referred to as early or late. Early adverse effects occur within days to weeks of treatment, of which some will become chronic. Adverse effects that occur one or more years later are usually called long-term adverse effects. Adverse effects can occur after any type of treatment, including surgery, chemotherapy and radiotherapy. The severity of the treatment complications depends on the type of cancer treated, the location of the disease, the age of the child at time of treatment, and the treatment modality and intensity of the treatment. Long-term adverse effects may manifest themselves in different ways, like (1) clinically obvious effects, (2) clinically subtle effects noticeable to the trained observer and (3) subclinical effects detectable only by laboratory screening or medical imaging techniques. Already in 1975 Meadows et al published an article of long-term adverse effects of cancer treatment in children (14). Since then numerous articles have been published of all kinds of long-term adverse effects (15-19). These effects include second neoplasms (20-22), organ dysfunction (23-26), endocrine and metabolic disorders (27-29), orthopaedic problems (30), and psychosocial and cognitive problems (31-33). These late effects may adversely affect the quality of life of survivors and predispose them to early morbidity and mortality (15;34). Recently, Oeffinger and colleagues (15) described an overview of the incidence and severity of long-term chronic health conditions in the Childhood Cancer Survivor Study in the United States (US), a multi-institutional, retrospectively ascertained cohort of adults who have survived for at least 5 years after treatment of childhood cancer. Survivors were diagnosed in one of the 26 collaborating institutions, between 1970 and 1986, and had an age less than 21 years at diagnosis. The occurrence of adverse events in this study was compared with siblings. Frequencies of chronic health problems were calculated for adult survivors and 3034 siblings. After a median follow-up of 26.6 years 62.3% had at least one chronic health condition and 27.5% had a severe or lifethreatening condition. Survivors were 3.3 times as likely as their siblings to have a chronic health condition (95% Confidence Interval (CI): ); for a severe or life-threatening condition, the risk was 8.2 (95% CI: ). Among survivors, the cumulative incidence of a chronic health condition reached 73.4% 30 years after the primary cancer diagnosis. 12

15 General Introduction Limitations of this study include the incomplete follow-up for 30 % of the survivors and the fact that the information of adverse events was based on self-reported health outcomes in questionnaires. In 2008, Mertens et al (34) reported on cause-specific late mortality among 5-year survivors of childhood cancer in the same Childhood Cancer Survivor Study cohort as described in the study by Oeffinger and collaborators. In the cohort of childhood cancer survivors, 2821 (13.8%) 5-year survivors had died by the end of the follow-up period (December 31, 2002). The cause of death was obtained for 2534 individuals, with 57.5% of deaths attributed to recurrent disease. The overall Standardised Mortality Ratio (SMR) was 8.4 (95%CI: ) compared to the US population. The absolute excess risk of death from any cause was 7.4 deaths per 1000 person-years. Increases in causespecific mortality were mainly seen for deaths due to subsequent malignancy (SMR = 15.2; 95% CI: ), cardiac causes (SMR = 7.0; 95% CI: ), and pulmonary causes (SMR = 8.8; 95% CI: ). Twenty-five years after first cancer diagnosis, the death rate due to a subsequent malignancy exceeded that due to all other causes. This study with extended follow-up indicates that excess mortality persists long after diagnosis. All anti-cancer treatment regimens can cause long-term adverse effects (35). Radiotherapy can, for example, cause second malignant neoplasms in previously irradiated fields, reduced growth of bones and muscles in the irradiated area (especially in the youngest children), vascular damage in the arteries or veins, and hearing loss. Some chemotherapeutic agents can, for example, lead to pulmonary dysfunction, reduced kidney function and infertility, and especially anthracyclines can cause cardiac dysfunction. Mobility problems are direct consequences of amputation, but infertility, pulmonary dysfunction and hypertension can also be caused by surgery. Long-term follow-up clinic Due to insight into the large number of potential long-term effects occurring in childhood cancer survivors, follow-up care is becoming more important and uniformly recognized. Early detection of (sub)clinical adverse events makes it possible to take preventive measures or to treat adverse effects. In the last decades in the United States, United Kingdom and the Nordic Countries nationwide initiatives also started to identify five-year survivors of childhood cancer (36-41). In these countries research was initiated into the magnitude of the burden from late effects in long-term survivors and identification of treatment-related risk factors. Since the 1980s more and more paediatric oncology centres have developed programs designed specifically for childhood cancer survivors (42). But only few paediatric institutions have provisions for follow-up into the adult years (43). In the Netherlands the EKZ/AMC identified their childhood cancer survivor population using the Childhood Cancer Registry of the EKZ/AMC started in Therefore, in 1996, the Emma Children s Hospital Academic Medical Center in Amsterdam established 13

16 Chapter 1 an outpatient clinic (PLEK EKZ/AMC) for the assessment of long-term adverse effects of childhood cancer treatment. Already 1080 childhood cancer survivors visited PLEK EKZ/AMC. AIM OF THE THESIS It is increasingly important to evaluate to which extent the occurrence of long-term complications affects (the quality of) the long-term survival of childhood cancer patients (44;45). Most studies in the past focused only on one type of adverse event and the majority of the studies examined late effects after one specific childhood cancer diagnosis. Our cohort is, as far as we know, one of the first cohorts worldwide determining the total burden of adverse health outcomes in a complete cohort including all childhood cancer diagnoses. Therefore, the aim of the studies described in this thesis Long-term excess mortality and morbidity following treatment of childhood cancer is to explore the frequency of and risk factors for long-term adverse effects after treatment for childhood cancer. The study population consists of survivors who had a follow-up of at least five years after diagnosis of the initial childhood cancer. Description of relevant methodology Study designs Several epidemiologic study designs are appropriate to evaluate the risk of long-term adverse effects among childhood cancer survivors. Two commonly used observational designs, cohort studies and case-control studies, have both been used in the studies described in this thesis. Three out of 4 studies were cohort studies; the fourth study was a nested case-control study within the cohort. A cohort is a group of individuals with a common characteristic, such as childhood cancer in our cohort, within a defined period. The occurrence of disease in the cohort (incidence, mortality) can be compared with a reference population, such as the general population. However, an internal comparison of disease occurrence between different subgroups within the cohort can also be made. Defining our cohort could be done efficiently and validly, because there is a hospital-based childhood cancer registry in the EKZ/AMC. The registry could be used to retrospectively define the cohort of all 5-year survivors who had been treated for childhood cancer in the past. The registry already exists from 1966 onwards and contains detailed information regarding patient characteristics, the primary diagnosis including all primary treatments, and second malignancies. The inclusion criteria of our cohort were accurately defined: - Age of childhood cancer below 18 years; - Calendar period of diagnosis between 1966 and 1996; 14

17 General Introduction - Diagnosed and treated in the EKZ/AMC in Amsterdam, the Netherlands; - Survived at least 5 year after diagnosis. Subsequently, data were extracted regarding patient, tumour and treatment characteristics, like dates of birth and diagnosis, treatment details and other risk factors for long-term adverse effects. Missing data regarding patient and treatment characteristics as well as missing follow-up data were completed by tracing the medical records or approaching patients general practitioners or other treating physicians, or by checking the most recent address at the municipal registries if patient was still alive. Finally, the cohort consisted of 1362 childhood cancer survivors, of whom 1080 visited PLEK EKZ/AMC. The median follow-up of the cohort was 17 years with a median attained age of 24 years at end of follow-up. The medical follow-up was complete for more than 94%. The advantages of our cohort are the very long-term follow-up and the high level of completeness of follow-up, and the fact that survivors underwent a medical assessment by our own physicians using standardized follow-up protocols based on previous treatments. Case-control studies are used to identify risk factors for a medical condition by comparing subjects who have the disease of interest ( cases ) with patients who do not have this disease ( controls ) (46). Ideally, cases and controls should be selected from the same source population to prevent selection bias, i.e. to be certain that when an increased risk is observed, this can be attributed to the treatment. A nested case-control study is a study design where cases and controls are derived from the same cohort ( nested ). Compared with a case-control study, a nested case-control study strongly reduces selection bias, and compared with a cohort study, a nested case-control study can reduce cost and save time. The data collection for case-control studies is less labour-intensive compared to cohort studies, because for fewer records data need to be collected. For the selected records, however, more detailed data need to be collected, which is much more efficient than detailed data collection for the full cohort. Our fourth study was a nested case-control study within the cohort of childhood cancer survivors. In our case-control study, survivors who developed hypertension are the so-called cases, whereas survivors who did not develop hypertension are selected as controls. In our nested case-control study, cases and controls are derived from the same childhood cancer cohort. Controls are matched to the cases with regard to sex, age and year of diagnosis, and Wilms - non Wilms ; in addition it was required that controls had not developed the event of interest after a follow-up duration at least as long as the interval between childhood cancer diagnosis and hypertension in the corresponding case. The matching procedure ensures a similar distribution among cases and controls of important characteristics which could distort the association between the exposure and the event of interest (confounding factors). 15

18 Chapter 1 Measures of disease occurrence In our studies several outcome measures are used, like incidence, prevalence and mortality. Incidence refers to new cases of disease occurring among previously unaffected individuals (47). The incidence rate is defined as the incidence per total number of person-years of observation among those who have not yet developed the disease. Unlike incidence measures, which focus on new events in a well- defined time span, prevalence focuses on the disease status, and may be defined as the proportion of a population that has the disease of interest at a cross-sectional point in time (48). Mortality is a specific type of incidence. OUTLINE OF THE THESIS After this general introduction (Chapter 1), chapter 2 report the results of the overall assessment of long-term adverse effects in our cohort of long-term childhood cancer survivors. In this study we assessed the total burden of adverse events in our cohort, and determined treatment-related risk factors for the development of various long-term adverse events. Childhood cancer survivors are known to be at increased risk for second malignancies. Only a few studies examined treatment-specific risk over extended followup periods. In chapter 3 we report on long-term second cancer risk in our 5-year survivors of childhood cancer and the treatment-related risk factors. Chapter 4 describes the very long-term overall and cause-specific mortality in our study cohort. In chapter 5 we report on our case-control study of hypertension. In this study we identified treatmentrelated risk factors for hypertension. Finally, in the general discussion (Chapter 6) main conclusions, methodological and theoretical reflections, implications for clinical practice and recommendations for future research are described. A summary in both English and Dutch concludes this thesis. REFERENCES (1) Parkin DM, Whelan SL, Ferlay J, Teppo L, Thomas DB. Cancer incidence in five continents. IARC Sci Publ 2002; Volume VIII. (2) Signaleringscommissie Kanker van KWF Kankerbestrijding. Kanker in Nederland; Trends, prognoses en implicaties voor zorgvraag. Drukkerij van den Boogaard; Oisterwijk, (3) Stiller CA, Marcos-Gragera R, Ardanaz E, Pannelli F, Almar ME, Canada MA et al. Geographical patterns of childhood cancer incidence in Europe, Report from the Automated Childhood Cancer Information System project. Eur J Cancer 2006; 42(13): (4) Steliarova-Foucher E, Kaatsch P, Lacour B, Pompe-Kirn V, Eser S, Miranda A et al. Quality, comparability and methods of analysis of data on childhood cancer in Europe ( ): report from the Automated Childhood Cancer Information System project. Eur J Cancer 2006; 42(13): (5) Cancer in children; clinical management. 5 ed. Oxford: Oxford University Press,

19 General Introduction (6) Principles and Practice of Pediatric Oncology. 5 ed. Lippincott Williams and Wilkins, (7) Stiller CA, Draper GJ. The epidemiology of cancer in children. In: Voûte PA, Kalifa C, Barret A, editors. Cancer in children: clinical management. Oxford University Press, 1998: (8) Terracini B, Coebergh JW, Gatta G, Magnani C, Stiller C, Verdecchia A et al. Childhood cancer survival in Europe: an overview. Eur J Cancer 2001; 37(6): (9) D Angio GJ. Introduction and Historical Perspective. In: Schwartz CL, Hobbie WL, Constine LS, Ruccione KS, editors. Survivors of Childhood Cancer. St. Louis: Mosby, 1994: 1-4. (10) Sankila R, Martos Jimenez MC, Miljus D, Pritchard-Jones K, Steliarova-Foucher E, Stiller C. Geographical comparison of cancer survival in European children ( ): report from the Automated Childhood Cancer Information System project. Eur J Cancer 2006; 42(13): (11) Magnani C, Pastore G, Coebergh JW, Viscomi S, Spix C, Steliarova-Foucher E. Trends in survival after childhood cancer in Europe, : report from the Automated Childhood Cancer Information System project (ACCIS). Eur J Cancer 2006; 42(13): (12) Lukens JN. Progress resulting from clinical trials. Solid tumors in childhood cancer. Cancer 1994; 74(9 Suppl): (13) Meadows AT, Hobbie WL. The medical consequences of cure. Cancer 1986; 58(2 Suppl): (14) Meadows AT, D Angio GJ, Evans AE, Harris CC, Miller RW, Mike V. Oncogenesis and other late effects of cancer treatment in children. Radiology 1975; 114(1): (15) Oeffinger KC, Mertens AC, Sklar CA, Kawashima T, Hudson MM, Meadows AT et al. Chronic health conditions in adult survivors of childhood cancer. N Engl J Med 2006; 355(15): (16) Marina N. Long-term survivors of childhood cancer. The medical consequences of cure. Pediatr Clin North Am 1997; 44(4): (17) Meister LA, Meadows AT. Late effects of childhood cancer therapy. Curr Probl Pediatr 1993; 23(3): (18) Schwartz CL. Late effects of treatment in long-term survivors of cancer. Cancer Treat Rev 1995; 21(4): (19) Gleeson HK, Darzy K, Shalet SM. Late endocrine, metabolic and skeletal sequelae following treatment of childhood cancer. Best Pract Res Clin Endocrinol Metab 2002; 16(2): (20) Neglia JP, Friedman DL, Yasui Y, Mertens AC, Hammond S, Stovall M et al. Second malignant neoplasms in five-year survivors of childhood cancer: childhood cancer survivor study. J Natl Cancer Inst 2001; 93(8): (21) Jenkinson HC, Hawkins MM, Stiller CA, Winter DL, Marsden HB, Stevens MC. Long-term populationbased risks of second malignant neoplasms after childhood cancer in Britain. Br J Cancer 2004; 91(11): (22) Bhatia S, Yasui Y, Robison LL, Birch JM, Bogue MK, Diller L et al. High risk of subsequent neoplasms continues with extended follow-up of childhood Hodgkin s disease: report from the Late Effects Study Group. J Clin Oncol 2003; 21(23): (23) Kremer LC, van Dalen EC, Offringa M, Ottenkamp J, Voute PA. Anthracycline-induced clinical heart failure in a cohort of 607 children: long-term follow-up study. J Clin Oncol 2001; 19(1): (24) Simbre VC, Duffy SA, Dadlani GH, Miller TL, Lipshultz SE. Cardiotoxicity of cancer chemotherapy: implications for children. Paediatr Drugs 2005; 7(3): (25) Skinner R, Pearson AD, English MW, Price L, Wyllie RA, Coulthard MG et al. Risk factors for ifosfamide nephrotoxicity in children. Lancet 1996; 348(9027): (26) Marks LB, Yu X, Vujaskovic Z, Small W, Jr., Folz R, Anscher MS. Radiation-induced lung injury. Semin Radiat Oncol 2003; 13(3): (27) Sklar CA, Constine LS. Chronic neuroendocrinological sequelae of radiation therapy. Int J Radiat Oncol Biol Phys 1995; 31(5):

20 Chapter 1 (28) van Santen HM, de Kraker J, Vulsma T. Endocrine late effects from multi-modality treatment of neuroblastoma. Eur J Cancer 2005; 41(12): (29) Gleeson HK, Shalet SM. The impact of cancer therapy on the endocrine system in survivors of childhood brain tumours. Endocr Relat Cancer 2004; 11(4): (30) Hopyan S, Tan JW, Graham HK, Torode IP. Function and upright time following limb salvage, amputation, and rotationplasty for pediatric sarcoma of bone. J Pediatr Orthop 2006; 26(3): (31) Mackie E, Hill J, Kondryn H, McNally R. Adult psychosocial outcomes in long-term survivors of acute lymphoblastic leukaemia and Wilms tumour: a controlled study. Lancet 2000; 355(9212): (32) Zebrack BJ, Gurney JG, Oeffinger K, Whitton J, Packer RJ, Mertens A et al. Psychological outcomes in long-term survivors of childhood brain cancer: a report from the childhood cancer survivor study. J Clin Oncol 2004; 22(6): (33) Mulhern RK, Merchant TE, Gajjar A, Reddick WE, Kun LE. Late neurocognitive sequelae in survivors of brain tumours in childhood. Lancet Oncol 2004; 5(7): (34) Mertens AC, Liu Q, Neglia JP, Wasilewski K, Leisenring W, Armstrong GT et al. Cause-specific late mortality among 5-year survivors of childhood cancer: the Childhood Cancer Survivor Study. J Natl Cancer Inst 2008; 100(19): (35) Jenney MEM. Late effects of cancer treatment and current protective measures. In: Voûte PA, Barrett A, Stevens MCG, Caron HN, editors. Cancer in children; clinical management. New York: Oxford University Press, 2005: (36) Nathan PC, Greenberg ML, Ness KK, Hudson MM, Mertens AC, Mahoney MC et al. Medical care in long-term survivors of childhood cancer: a report from the childhood cancer survivor study. J Clin Oncol 2008; 26(27): (37) Campbell BA, Wheeler G, Seymour JF, Ritchie D, Goroncy N. The Late Effects Clinic in action: for survivors of childhood malignancy. Acta Oncol 2007; 46(8): (38) Taylor A, Hawkins M, Griffiths A, Davies H, Douglas C, Jenney M et al. Long-term follow-up of survivors of childhood cancer in the UK. Pediatr Blood Cancer 2004; 42(2): (39) Kurt BA, Armstrong GT, Cash DK, Krasin MJ, Morris EB, Spunt SL et al. Primary care management of the childhood cancer survivor. J Pediatr 2008; 152(4): (40) Eiser C, Absolom K, Greenfield D, Snowden J, Coleman R, Hancock B et al. Follow-up care for young adult survivors of cancer: lessons from pediatrics. J Cancer Surviv 2007; 1(1): (41) Arvidson J, Soderhall S, Eksborg S, Bjork O, Kreuger A. Medical follow-up visits in adults 5-25 years after treatment for childhood acute leukaemia, lymphoma or Wilms tumour. Acta Paediatr 2006; 95(8): (42) Meadows AT. Pediatric cancer survivorship: research and clinical care. J Clin Oncol 2006; 24(32): (43) Oeffinger KC, Eshelman DA, Tomlinson GE, Buchanan GR. Programs for adult survivors of childhood cancer. J Clin Oncol 1998; 16(8): (44) Neglia JP. Late effects of treatment in children with cancer. [Review]. Semin Pediatr Surg 1993; 2: (45) Hawkins MM, Stevens MC. The long-term survivors. Br Med Bull 1996; 52(4): (46) Altman DG. Practical statistics for medical research. London: Chapman & Hall, (47) Breslow NE, Day NE. Statistical methods in cancer research. Volume I - The analysis of case-control studies. Lyon: IARC Sci.Publ., (48) Rothman KJ, Greenland S. Modern epidemiology. 2 ed. Philadelphia: Lippincott-Raven,

21 2 Medical Assessment of Adverse Health Outcomes in Long-Term Survivors of Childhood Cancer M.C. Cardous-Ubbink*, MSc (1) M.M. Geenen*, MD (1,2) L.C.M. Kremer, MD, PhD (1,3) C. van den Bos, MD, PhD (1,3) H.J.H. van der Pal, MD (1,2) R.C. Heinen, MSc (1) M.W.M. Jaspers, PhD (4) C.C.E. Koning, MD, PhD (1,5) F. Oldenburger, MD (5) N.E. Langeveld, RN, PhD(3) A.A.M. Hart, MSc (6) P.J.M. Bakker, MD, PhD (1,2) H.N. Caron, MD, PhD (1,3) F.E. van Leeuwen, PhD (1,7) The Journal of the American Medical Association 2007; 297(24): * These authors contributed equally to this manuscript (1) Late Effects Study Group and Outpatient Clinic / Polikliniek Late Effecten Kindertumoren (PLEK), (2) Department of Medical Oncology, (3) Department of Pediatric Oncology, (4) Department of Medical Informatics and (5) Department of Radiotherapy, Emma s Children s Hospital / Academic Medical Center (EKZ/AMC), Amsterdam, The Netherlands, (6) Department of Radiotherapy, (7) Department of Epidemiology, the Netherlands Cancer Institute, Amsterdam, The Netherlands

22 Chapter 2 ABSTRACT CONTEXT Improved survival of children with cancer has been accompanied by multiple treatmentrelated complications. However, most studies in survivors of childhood cancer focused on only 1 late effect. OBJECTIVE To assess the total burden of adverse health outcomes (clinical and 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 year survivors of childhood cancer treated in a single institution in the Netherlands between 1966 and All survivors were invited to a late-effects clinic for medical assessment of adverse events. Adverse events occurring before January 2004 were graded for severity in a standardized manner. MAIN OUTCOME MEASURES Treatment-specific prevalence of adverse events (according to severity) at end of followup and relative risk of high or severe burden of disease ( 2 severe or 1 life-threatening or disabling adverse events) associated with various treatments. RESULTS Medical follow-up was complete for 94.3% of survivors (median follow-up, 17.0 years). The median attained age at end of follow-up was 24.4 years. Almost 75% of survivors had 1 or more adverse events, and 24.6% had 5 or more adverse events. Furthermore, 40% of survivors had at least 1 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 15% of survivors treated with chemotherapy only, compared with 25% of survivors who had surgery only (adjusted relative risks: 2.18 [95% confidence interval: ] and 0.65 [95% confidence interval: ], respectively). A high or severe burden of adverse events was most often observed in survivors of bone tumors (64%) and least often in survivors of leukemia or Wilms tumor (12% each). CONCLUSION 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. 20

23 Medical Assessment of Adverse Health Outcomes INTRODUCTION The introduction of more effective treatments for childhood cancer has dramatically improved survival rates, implying that childhood cancer survivors are a rapidly growing group of young adults (1;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 (3;4). Late treatment sequelae will increase the incidence of chronic diseases in survivors and ultimately reduce their life expectancy. Therefore, the need for long-term follow-up of survivors of childhood cancer is uniformly recognized (5-8). Research focusing on identification and characterization of high-risk populations is an essential foundation on which to build evidence-based recommendations for long-term follow-up (6;9). Although many studies have reported on late effects of treatment in survivors of childhood cancer (10-21), most of these focused on only 1 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 s Children s Hospital/ Academic Medical Center (EKZ/AMC) in the Netherlands. While called adverse event, 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 1966 and 1996, and 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 In total, 1362 out of 2596 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 1996, 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. 21

24 Chapter 2 Of the 1362 survivors, 1078 visited the late-effects outpatient clinic between January 1, 1996 and January 1, 2004, and 107 were seen by their own pediatric or medical oncologist. Medical follow-up data of 93 survivors were obtained from other treating physicians, and 6 survivors filled out a mailed health questionnaire. We therefore obtained medical follow-up data until January 1, 2004, for 1284 (94.3%) of the 1362 survivors. Of the 78 survivors with missing medical follow-up data, 57 had died (with known cause of death) before the study started; 1.5% of all survivors were lost to follow-up. In 1185 survivors who visited the late-effects clinic or their own oncologist (87% 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 Table 2.1: Overview of Numbers of Survivors in Burden Score Groups, according to Graded Adverse Events (N=1362) [1] Burden Score No. of Survivors Severe (n=81) 41 1 No. of Adverse Events Grade 5 Grade 4 Grade 3 Grade 2 Grade High (n=220) Medium (n=573) Low (n=141) Reference Group (no Adverse Events) (n=269) Unknown Adverse Events (n=78) 78 [1] The Common Terminology Criteria for Adverse Events version 3.0 instrument distinguishes grades 1 through 5 with unique clinical descriptions of the severity for each event (grade 1, mild; grade 2, moderate; grade 3, severe; grade 4, life-threatening or disabling; grade 5, adverse event-related death). Survivors with 1 grade 1 event were classified as having a low burden; those with 1 grade 2 and/or 1 grade 3 event, a medium burden; those with 2 grade 3 events, or 1 grade 4 event and at most 1 grade 3 event, a high burden; and those with more grade 3/4 events or a grade 5 event, a severe burden. 22

25 Medical Assessment of Adverse Health Outcomes 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 1 of the authors (M.M.G.) according to the Common Terminology Criteria for Adverse Events version 3.0 (CTCAEv3.0, available at cancer.gov/forms/ctcaev3.pdf), a scoring system developed through the US National Cancer Institute by a multidisciplinary group. The CTCAEv3.0 instrument can be used to score both acute and chronic conditions in patients with cancer and distinguishes grades 1 through 5 with unique clinical descriptions of the severity for each event (grade 1, mild; grade 2, moderate; grade 3, severe; grade 4, life-threatening or disabling; grade 5, adverse event-related death). To investigate interobserver variability, 3 authors (M.M.G., C.vd.B., P.J.M.B.) graded 240 adeverse events among randomly chosen survivors based on the CTCAEv3.0 scoring. Originally, there were 40% differences between the 3 observers. Specific events not listed in the CTCAEv3.0, 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 1 or 2 psychosocial items and fatigue. There were almost no differences in grade 3 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 2.1). Survivors with 1 or more grade 1 event were classified as having a low burden; those with 1 or more grade 2 and/or 1 grade 3 event, a medium burden; those with 2 or more grade 3 events, or 1 grade 4 event and at most 1 grade 3 event, a high burden; and those with more grade 3/4 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 78 survivors with unknown adverse events were excluded from all multivariable analyses. Analyses were performed using SPSS version (SPSS Inc, Chicago, Ill) and SAS version 8.2 (SAS Institute Inc, Cary, NC). A user-written SAS macro was used to perform the study population-averaged calculations. 23

26 Chapter 2 Table 2.2: Patient Characteristics of the Emma Children s Hospital/Academic Medical Center Childhood Cancer Survivor Cohort (N=1362) Characteristic 5-year Cancer Survivors No. (%) Sex Male 745 (54.7) Female 617 (45.3) Primary Childhood Cancer Diagnosis Leukemia 335 (24.6) Lymphoma 259 (19.0) Kidney/ Wilms tumor 189 (13.9) Brain/ CNS tumor 107 (7.9) Bone tumor 116 (8.5) Soft Tissue Sarcoma 151 (11.1) Neuroblastoma 85 (6.2) Other[1] 120 (8.8) Age at Diagnosis Childhood Cancer (years) (43.8) (27.8) (22.7) (5.8) Overall Treatment Category (n=1362)[2] Chemotherapy only (± surgery) 652 (47.9) Radiotherapy only (± surgery) 93 (6.8) CT[3] & RT[4] first treatment (no recurrence) 334 (24.5) CT[3] & RT[4] including recurrence treatment 180 (13.2) Surgery alone 103 (7.6) Type of Chemotherapy (n=1166)[2] Anthracyclines (± other chemotherapy)[5] 110 (9.4) Alkylating Agents (± other chemotherapy)[6] 260 (22.3) Anthracyclines & Alkylating Agents (± other chemotherapy)[7] 452 (38.8) Other Chemotherapy only[8] 344 (29.5) Localization of Radiotherapy (n=607)[2] Head and/ or Neck (+/- extremities) 249 (41.0) Thorax and/ or Abdomen (+/- extremities) 174 (28.7) Head and/ or Neck + Thorax and/ or Abdomen (incl Craniospinal) (+/-extremities) 106 (17.5) Extremities only (incl 6 unknown RT field) 44 (7.2) TBI or MIBG only 34 (5.6) Recurrence Yes 276 (20.3) No 1086 (79.7) Survival after Diagnosis (years) (18.4) (21.9) (22.0) (19.0) ³ (18.7) 24

27 Medical Assessment of Adverse Health Outcomes Table 2.2 (continued): Patient Characteristics of the Emma Children s Hospital/Academic Medical Center Childhood Cancer Survivor Cohort (N=1362) Characteristic 5-year Cancer Survivors No. (%) Attained Age at end of follow-up (years) (15.1) (15.6) (22.0) (18.6) (16.3) ³ (12.3) Vital Status at End of Follow-up Alive 1241 (91.1) Dead[9] 121 (8.9) Abbreviations: CNS, central nervous system; MIBG, iodine-131-meta-iodobenzylguanidine; TBI, total body irradiation. [1] Includes: 45 (gonadal) germ cell tumors, 21 retinoblastoma, 13 thyroid carcinoma, 12 hepatoblastomas, 11 malignant histiocytosis, 18 miscellaneous. [2] Mutually exclusive treatment groups, based on all treatments received. [3] Chemotherapy ± Surgery. [4] Radiotherapy ± Surgery. [5] Including 22.7% cisplatin and/or carboplatin. [6] Including 25.4% cisplatin and/or carboplatin and 3.1% bleomycine. [7] Including 12.8% cisplatin and/or carboplatin and 29.4% bleomycine. [8] Including 5.5% cisplatin and/or carboplatin and 2.3% bleomycine. [9] 59.5% died due to the primary cancer; 12.4% died due to complications of the primary tumour/treatment; 28.1% died while in complete remission. RESULTS Study Population The large majority (94.3%) of our 1362 survivors was diagnosed with childhood cancer before age 15 years. At the end of follow-up the median attained age of the survivors was 24.4 years, with 1194 (88%) of survivors younger than 35 years (Table 2.2). The median follow-up time was 17.0 (interquartile range ) years. The distribution of primary childhood cancer diagnoses by treatment category is shown in Figure 2.1. As of January 1, 2004, 121 of the 1362 survivors had died, the majority (72 [59.5%]) due to the primary cancer. The overall excess risk of death (excluding death from primary cancer) was increased 5.1 fold compared with the general population.(23) Adverse Events Of the 1362 survivors, 269 (19.8%) had no adverse events and 1015 (74.5%) had 1 or more events, whereas no medical follow-up (except for cause of death) was available for the remaining 78 (5.7%) (Table 2.3). The majority of survivors with medical followup data had more than 1 event (757/1284 [59%]), and 316/1284 (24.6%) had 5 or more events. Furthermore, 473 (36.8%) of the survivors had at least 1 severe or lifethreatening or disabling disorder, and 41 (3.2%) died due to an adverse events. Among the 1015 survivors with at least 1 adverse events, a total of 3751 events were observed. Figure 2.2 gives an overview of the events most frequently observed in our 25

28 Chapter 2 cohort. Almost 22% of events were severe, life threatening or disabling, or caused death. Of those events, orthopedic disorders occurred most often (14.2%), followed by second tumors (11.9%), obesity (9.4%), fertility disorders (8.9%), psychosocial or cognitive disorders (7.9%), neurologic disorders (7.7%), and endocrine disorders (5.3%). Total Burden of Adverse Events Of all survivors with medical follow-up data. 301 (23.4%) had a high or severe burden of adverse events, defined as at least 2 severe events or 1 or more life-threatening Figure 2.1: Distribution of Primary Childhood Cancer Diagnosis by Treatment Category CNS indiactes central nervous system. 26

29 Medical Assessment of Adverse Health Outcomes Table 2.3: Adverse Events in the Emma Children s Hospital/Academic Medical Center Childhood Cancer Survivor Cohort Events Cancer Survivors No. (%) 1362 (100) Adverse Events at End of Follow-up[1] Yes 1015 (74.5) No 269 (19.8) Unknown 78 (5.7) Number of Adverse Events per Survivor[2] (20.1) (14.3) (11.2) (8.9) 5 94 (7.3) ³ (17.3) Maximum Grade of Adverse Events per Survivor[3] 1 Mild 141 (11.0) 2 Moderate 360 (28.0) 3 Severe 311 (24.2) 4 Life-threatening or disabling 162 (12.6) 5 Death 41 (3.2)[4] Burden Score of Adverse Events[5] Low 141 (11.0) Medium 573 (44.6) High 220 (17.1) Severe 81 (6.3) [1] N=1362. [2] N=1284 with medical follow-up data. In total, 3751 adverse events in 1015 survivors. [3] N=1284 with medical follow-up data. Includes 269 survivors with no registered adverse events. [4] Fifteen 5-year survivors died while their the primary cancer or recurrence was still present: infectious (6), cardiovascular (4), pulmonary (3), gastrointestinal tract (2). Of the 5-year survivors who died while in complete remission, 21 (17.4%) died of a second or third malignancy, 4 (3.3%) of cardiovascular disease, and 1 of infection. [5] N=1284 with medical follow-up data. Includes 269 survivors with no registered adverse events. Low burden: survivors with one or more grade 1 adverse event, medium burden: one or more grade 2 and/or one grade 3 adverse event, high burden: two or more grade 3 and/or one grade 4 adverse event, severe burden: more than two grade 3 and one grade 4 or two or more grade 4 or a grade 5 adverse event. or disabling event. Figure 2.3 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 (64%), while survivors of leukemia or Wilms tumor least often had a high or severe burden of events (12% each). The distribution of adverse event burden scores according to treatment is depicted in Figure 2.4. Of all patients treated with radiotherapy only, 55% had a high or severe burden of events, compared with 15% and 25% among patients treated with chemotherapy only and surgery only, respectively. 27