ORIGINAL PAPER

Pediatric low-grade glioma survivors experience high qualityof life

Lindy Musial-Bright & Louisa Panteli &Pablo Hernáiz Driever

Received: 24 January 2011 /Accepted: 15 April 2011 /Published online: 3 May 2011# Springer-Verlag 2011

AbstractPurpose The purpose of this study was to determine pediatriclow-grade glioma survivors" quality of life and late morbidityincluding motor, sensory, and cognitive deficits.Methods We surveyed 49 survivors and their parents(KINDL questionnaire).Results Despite tumor and treatment-associated morbidity,survivors (25 boys and 24 girls, median age at diagnosis7.8 years), but not their parents, rated their total quality oflife higher than their peers. Although all survivors hadsome late morbidity, half of them were able to conduct theirdaily lives without restriction.Conclusion These results reflect survivors" effective copingmechanisms and underscore the difficulties of assessingquality of life in pediatric populations.

Keywords Low-grade glioma . Childhood cancersurvivors . Quality of life . Disability

Introduction

Children in Germany are diagnosed with brain tumors at ayearly rate of 3 per 100,000, approximately one third ofwhom suffer from low-grade gliomas (LGG) [1]. Modernevent-free survival rates for low-grade glioma patients aregreater than 90% after successful radical resection [2, 3].

Adjuvant chemotherapy and radiation therapy are usuallyreserved for treatment of tumors not amenable to surgeryand for partially resected tumors at high risk of progression[3, 4]. Though radiation therapy can be curative, it is oftenused to halt disease progression and prolong the period ofdisease-free survival [3, 5]. Chemotherapy has gainedacceptance as a means of postponing or replacing radiationtherapy in very young children as well as in children withneurofibromatosis type 1 (NF1) [3, 4, 6–8]. Prognosticfactors (such as age, presence of NF1, tumor resectability)and treatment-related risks are included in the developmentof current treatment plans like the multicenter randomizedSIOP-LGG trial.

Despite the improved management and survival ofpediatric low-grade glioma, roughly 80% of all survivorsexperience some morbidity. This includes motor, sensory,audio, visual and cognitive deficits, endocrine deficiencies,and epilepsy [9–16]. Tumor location plays a large role inthe development of some late effects, such as epilepsy insurvivors of supratentorial tumors [11]. Young NF1 patientswith optic pathway gliomas may present with or developvisual problems [3, 17, 18]. A high incidence of dience-phalic syndrome, i.e., endocrinological deficiencies requir-ing the substitution of hormones, has been observed inLGG patients with supratentorial midline tumors [11, 19,20]. Cognitive deficits, such as a significant decline inoverall intelligence, are observed in patients after surgeryalone but are seen more frequently following radiationtherapy [14, 16, 21–25].

In addition to the traditional outcome targets, likesurvival and monitoring of late treatment-related morbidity,quality of life evaluation is gaining recognition andimportance in therapeutic decision-making—largely due to

L. Musial-Bright : L. Panteli : P. Hernáiz Driever (*)Department of Pediatric Oncology and Hematology,Charité-Universitätsmedizin Berlin,Augustenburger Platz 1,13353 Berlin, Germanye-mail: Pablo.hernaiz@charite.de

Childs Nerv Syst (2011) 27:1895–1902DOI 10.1007/s00381-011-1467-0

improvement in survival rates of pediatric brain tumorpatients and the development of age-appropriate measures[10]. The results of quality of life evaluation may helponcologists tailor treatment plans as well as the psychosocialsupport to maximize efficacy and minimize the occurrence ofdeficits that patients feel limit their autonomy, academicaspirations, their ability to make close friends, and, ultimately,their satisfaction in life [26–29]. The definition of quality oflife, by general consensus, is derived from the WHOdefinition of health and includes, but is not restricted to,the following: physical, social, mental, and emotionalaspects of health and the ability to actively participate indaily life [16, 30–33].

Many studies have examined either the quality of life ofadult survivors of LGG [20, 34–38] or the survivors of allpediatric brain tumors [39–41]. Few, however, have lookedat the isolated quality of life of pediatric LGG survivors[16, 26, 42, 43]. Pediatric LGG survivors have been shownto have better quality of life than pediatric medulloblastomapatients [10], for whom psychological screening, testing,and counseling are often a fixed component of follow-upcare [44].

Despite having a good prognosis, LGG survivors canalso suffer from late morbidity [9, 11, 21, 24, 26]. Wepostulated that the quality of life of LGG survivors treatedat our institution would be lower than that of the referencepediatric population regardless of which treatment theyreceived, whether surgery alone or in combination withadjuvant therapies. Furthermore, we investigated whethertheir QoL was influenced by self- or proxy perspective, age,gender, and disability score.

Patients and methods

Eligibility

Patients with low-grade gliomas confirmed by histology orneuroimaging who were between 4 and 17 years old at thetime of QoL assessment and seen for follow-up care at ourinstitution between November 2003 and November 2004were eligible for inclusion in this study. Of the 82 LGGsurvivors seen during the study period, 49 patients (59.8%)and their families completed a survey. The surveys werefilled out either in the clinic during the patient"s follow-upvisit or at home following the visit and returned by mail.

Quality of life assessment

We assessed the patients" quality of life using the revisedKINDL questionnaire, a measure designed and developedfor German-speaking children—pediatric patients andtheir healthy peers. The KINDL was selected as the best

questionnaire for this patient population, due to the easeand practicality of its administration, its suitability to therelevant cultural context, and the published evidence of itspsychometric properties (internal consistency, factorial,convergent and discriminant validity and sensitivity) [33,45, 46].

The KINDL is a 24-item questionnaire consisting of sixsubscales with four Likert-scaled questions per subscale.The six subscales assess the child"s perception of his or herphysical well-being, emotional well-being, self-esteem,friends, family, and ability to function in an everydaysetting, such as school. There is an additional six-question“disease” module for patients with chronic and/or life-endangering illnesses; its discriminant validity and sensi-tivity have been demonstrated in pediatric populations [47].The KINDL package consists of age-appropriate question-naires for self- and proxy evaluation, which takeapproximately 10 min to fill out [48]. Three versions ofthe self-evaluation exist for children ages 4–7, 8–12, and13–18 years, which were developed relative to thelanguage and cognitive skills of these age groups [49].The questionnaire for the youngest group was uniformlyconducted as an interview. Because younger children (ages4–7 years old) may not be as knowledgeable about theirown health problems or able to adequately communicatethat knowledge, the proxy evaluation, completed by one orboth parents, is longer and more comprehensive forparents of children in this age group.

Health status and disability

The patients" medical records from our outpatient clinic weresystematically reviewed with a uniform protocol by oneinvestigator (LP). She recorded data about patients" age,gender, tumor histology and localization, treatment, andcurrent disease status (Table 1). Further data were collectedabout disability status and late sequelae such as hearing loss,ataxia, hydrocephalus, epilepsy, as well as neurological,cognitive, endocrinological, and visual deficits (Table 2).Neurological and endocrinological information was notavailable for two patients. Patients" impairments and dis-abilities were rated according to the modified Rankin scaleby one of the authors (PHD, Table 3) [50, 51].

Statistical analysis

Parametric t tests and nonparametric Wilcoxon and Mann–Whitney tests were used to assess patients" quality of life.Kolmogorov–Smirnov tests were conducted to determinenormality. Correlations between patient characteristics,disabilities, and quality of life were investigated withSpearman"s correlation coefficient. All statistical analyseswere performed using SPSS.

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Results

LGG survivors" self-evaluation of quality of life

The low-grade glioma survivors who participated in thisstudy rated their total quality of life higher than thereference population of healthy peers (p<0.05) [49]. Aslight, though significant, difference was seen betweenpatients" self-rated and parents" proxy-rated total quality oflife (p<0.01). No significant differences were observedbetween the survivors" parent-evaluated quality of life andthe parent-evaluated published norms. Due to the samplesize, correlations between patients" quality of life and

subgroups" treatment, histology, tumor localization, anddisease status could not be investigated.

Thirty-three patients age 11–17 years old wereincluded in the self-evaluated quality of life analysiscompared with published norms for this age group(Fig. 1) [49]. They rated their total quality of life, physicalwell-being, and self-esteem significantly higher than theirhealthy peers (p<0.05). Aside from scoring higher onoverall quality of life, patients rated their quality of life onthe friends subscale higher than their parents (p<0.01).Conversely, parents rated their children"s self-esteemhigher than the patients themselves (p<0.05, Fig. 2).

Proxy evaluation of quality of life of LGG survivors

Single sample t tests of the 49 proxy evaluations(conducted by 26 mothers, 20 fathers, 1 joint evaluation,and 3 non-parental guardians) revealed that patients"emotional well-being and self-esteem were rated lowercompared with healthy peers. No significant differences inthe total quality of life were observed between the twogroups. Additionally, there were no significant differencesobserved for the total quality of life or any subscalebetween the mothers" and fathers" reports.

Disease status, gender, age, and quality of life

Thirty-one percent of low-grade glioma survivors and 37%of their parents did not fill out the disease module of theKINDL survey. The filter question for this module was,“Are you/is your child staying in the hospital now or doyou/does your child have a long term illness?.” Due to the

Table 1 Patient and treatment characteristics (n=49 unless other-wise stated)

Gender

Male 25

Female 24

Age at diagnosis (in years), median (range) 7.8 (0.8–15.9)

Follow-up (in months), mean (range) 51.8 (4–169)

Neurofibromatosis type 1, no. (%) 7 (14.3%)

Histology, no. (%)

Pilocytic astrocytoma 38 (78%)

Ganglioglioma (I/II) 3

Chordoma 2

Pleomorphic xanthoastrocytoma (I/II) 1

Meningeoma 1

Neurinoma I 1

Pinealoma 1

Tectal glioma 1

Ependymoma 1

Tumor localization, no. (%)

Posterior fossa 18 (36.8%)

Optic pathway 8

Multifocal 8

Cerebrum 7

Spinal canal 4

Diencephalon 2

Mesencephalon 2

Primary treatment, no. (%)

Tumor resection 29 (59.2%)

Tumor resection and chemotherapy 10

Wait and see 6

Tumor resection and radiation therapy 3

Primary chemotherapy 1

Response to therapy, no. (%)

Complete remission 19 (38.8%)

Partial remission 9

Stable disease 16

Progressive disease 5

Table 2 Late effects and Rankin disability scores

Hormone deficiencies (n=47), no. (%)

Cortisol 3 (6.4%)

Insulin-like growth factor 3 (6.4%)

Thyroid hormone 3 (6.4%)

Ataxia (n=47), no. (%) 12 (25.5%)

Gross motor deficits (n=47), no. (%)

Hemiparesis 3 (6.4%)

Monoparesis of the arm 2 (4.3%)

Chronic headache (n=47), no. (%) 13 (27.7%)

Epilepsy (n=47), no. (%) 4 (8.5%)

Modified Rankin disability grade, no. (%)

0 0

1 25 (51.0%)

2 8 (16.3%)

3 9 (18.4%)

4 7 (14.4%)

5 0

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extent of the missing data, the disease module was excludedfrom the statistical analysis.

Girls rated their total quality life and social quality of life(friends domain) significantly lower than the boys in thissample—a tendency also found in the reference population[49]. There were no significant differences between theboys" and girls" age at diagnosis.

Older age of patients at diagnosis was associated with higherself-evaluated scores in the physical well-being, emotionalwell-being, self-esteem, and family domains (r>0.4, p<0.01).Lower scores in the school domain of the parents"evaluation were associated with older age of patient atdiagnosis (r=−0.37, p<0.01). Patient age at the time ofassessment correlated similarly with the patients" self-reported physical well-being, psychological well-being,self-esteem, and family domains (r>0.4, p<0.01).

Disability and quality of life

All patients had some lasting symptoms of disease;however, despite these symptoms, roughly half of thepatients were able to conduct their daily lives withoutrestriction (modified Rankin grade 1). Patients with supra-tentorial tumors had higher mean disability scores than

those with infratentorial tumors (p<0.05); however, greaterdisability was not associated with reduced self-reported totalquality of life. Greater disability was weakly butsignificantly correlated with lower scores on the proxy-evaluated total quality of life (r=−0.32, p<0.05). Disabilityalso correlated with lower scores on the friends subscale(r>−0.3, p<0.05) in both the self- and proxy reports.

Discussion

Despite the presence of impairments and disabilities, thesurvivors of childhood LGG, but not their parents, ratedtheir overall quality of life higher than that of the referencepediatric population.

Conventional wisdom holds that of all patients withpediatric brain tumors, survivors of low-grade glioma,which often may be cured surgically, have the bestoutcomes in terms of late effects and long-term morbidity[6, 19, 52–55]. By extension, it was surmised and has beensubstantiated that LGG patients would also have higherquality of life than survivors of other CNS malignancies[10]. Due to the positive outcomes, clinical studies havebeen slow to focus on the isolated quality of life of LGG

Table 3 Modified Rankin disability scale

Grade Description

0 No symptoms

1 No significant disability despite symptoms—able to carry out all usual duties and activities

2 Slight disability—unable to carry out all previous activities but able to look after own affairs without assistance

3 Moderate disability—requiring some help, but able to walk without assistance

4 Moderately severe disability—unable to walk without assistance and unable to attend to own bodily needs without assistance

5 Severe disability—bedridden, incontinent, and requiring constant nursing care and attention

Fig. 1 Self-evaluated quality oflife of patients ages 11–17. LGGpatients" self-evaluated qualityof life compared to publishednorms, n=33. Phys physicalwell-being, Emo emotional well-being, Self self-esteem, Famfamily. Upwards arrows indicatehigher scores than referencepopulation, significance p<0.05

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population. In the past decade, studies of adult low-gradeglioma patients have indicated that LGG patients, especial-ly those who received radiation therapy, report lowerquality of life or reduced affective status [20, 35, 36, 38,56–58].

Since 2002, three studies have examined pediatric LGGpatients" quality of life. In 2002 Pompoli et al. examinedcerebellar astrocytoma survivors" quality of life andfunctional status (as measured by the Karnofsky Perfor-mance Scale). The 20 patients who were included in thissingle-institution study were treated by surgery alone andreported a lower quality of life than healthy controlsmatched for gender and age. The Karnofsky PerformanceScale, a measure of functional status commonly used inadult glioma studies, was shown to be poorly correlatedwith the patients" perceived quality of life [43]. The averageage of the patients at the time of diagnosis was similar toour study, but patients" average age at the time ofassessment was 27 years, i.e., almost 20 years older thanour patients" mean follow-up age [43].

In another study, Aarsen et al. reported on the functionaloutcome and self- and proxy-evaluated quality of life of 38LGG patients treated in the Netherlands. As in our study,LGG patients with tumors of different histological typesand localization were included in the single-institutionstudy. The average age at diagnosis was similar, but theaverage follow-up period was 3 years longer. Treatmentincluded surgical resection (primary therapy for 63% ofpatients), primary chemotherapy aswell as combined surgical,irradiation, and/or chemotherapy. Sixty-one percent of thepatients had impairments (e.g., epilepsy, hormone deficien-cies, and motor, visual, sensory, and auditory deficits).Unlike the findings in our study, the Aarsen groupreported reduced quality of life for all domains of theTACQOL questionnaire, except in the emotions domain.However, as seen in our study, patients with supra-

tentorial tumors had more impairments and more severedisabilities. They also found that supratentorial andinfratentorial tumor localization was not correlated withself-reported quality of life [42].

A third single-institution study by Zuzak et al. foundhigh self-reported quality of life among LGG survivors,who rated their physical health even higher than that ofhealthy controls—a finding also observed in our study. Allthe patients in the Swiss study had cerebellar astrocytomasthat were treated by surgery only, which carries a goodprognosis [59]. The patients" age at diagnosis and the lengthof the follow-up period were equivalent to the Aarsen et al.study. Forty-three percent of the 21 participants hadneurological deficits. In contrast to our study, agreementwas found between the self- and proxy-evaluated quality oflife [16].

All four LGG quality of life studies to date havelimitations inherent to cross-sectional, single-institutionstudies. Small sample sizes, of which ours is the largest,decrease the generalizability of the results, reduce thepower of the statistical analysis, and increase the chancethat differences and correlations within the data may fail toreach a level of significance. The cross-sectional studydesign is susceptible to distorting factors such as theparticipant"s mood at the time of assessment, his or herpresent ability to recount previous events, and, in the caseof an interview, social desirability [60]. Cross-sectionalstudies also preclude the observation of changes in asubject"s quality of life over time and the comparison ofthe present quality of life to an intraindividual baseline.Furthermore, each of the studies described above employeddifferent tools for quality of life assessment, which limit theresults" comparability. Only the Pompili et al. studyinvestigated possible confounding factors such as socio-economic status and life status, however the control groupwas not matched accordingly. Proficiency in the local

Fig. 2 Low-grade glioma survi-vors" proxy- and self-evaluatedquality of life. Boxplot compar-ison of patients" self- and proxy-evaluated quality of life, n=49.P proxy, S self, Phy physicalwell-being, Emo emotional well-being, Self self-esteem, Famfamily. Double daggers indicatep<0.05, asterisk indicatesp<0.01

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language was not an inclusion criterion for any of thestudies [57].

Conclusive interpretation of our results is problematicconsidering the inconsistent—and sometimes contradictory—findings of the few LGG studies to date. Several factors mustbe considered in accounting for these discrepancies: thedifferences in the study populations and methodologies werediscussed above, but closer analysis provides insight into theproblems unique to pediatric populations and to quality of liferesearch in general.

Eiser and Morse outline three principle problems withquality of life assessment in children. Children mayfundamentally view the cause, nature, and treatment ofdiseases differently than adults do. They can also have adifferent understanding and interpretation of what specificquestions in the psychometric inventories mean. Further-more, on a cognitive level, they might not be equally ableas adults to use rating scales or answer complex questions[31].

To counterbalance these considerations, many studiesrely on proxy-reported quality of life in addition to self-reports. However, if both the child and the parent reportreduced overall quality of life or reductions in the samedomains, may one assume that both the child and parent aredescribing the same phenomena? If, as is the case in ourstudy, patients" self-reports differ from the parents" reportsin multiple domains, may one assume that they aredescribing different phenomena? Perhaps the phenomenaare the same and the differences observed reflect thepatients" and their parents" different means of approachingthem, such as coping mechanisms, maladjustment, resil-ience, disappointment, hopefulness, or projection [61]. Forinstance, Aarsen et al. found age at follow-up to benegatively correlated with physical, motor, cognitive, andsocial quality of life domains. This was attributed to theprogressive nature of the late effects of cancer treatment,which became apparent during the long follow-up period aspatients “grew into deficit” [42]. In contrast, a positivecorrelation was found between our patients" age at follow-up and self-reported, but not proxy-reported, physical well-being, psychological well-being, self-esteem, and familysatisfaction domains. Perhaps this can be attributed to thehigh rate of late sequelae having not yet reached a level ofseverity in the 4-year follow-up period that would lead torelevant declines in patients" perception of their quality oflife. However, the increases observed may reflect patients"successful coping mechanisms as described in the literature[60, 62].

Despite the presence of symptoms and impairments andthe use of a health-related quality-of-life inventory withproven psychometric properties in both healthy andchronically ill pediatric populations, the findings of Zuzaket al. and our study seem counterintuitive. Models that

regard one"s perception of health and quality of life asconstant and only the objective health status as a variablemay be inadequately able to explain the paradoxical resultsoften seen in cancer patients [63–65].

Response shift is a theoretical model describing theprocess, by which a person"s self-evaluated quality of lifechanges over time, and it presents certain challenges totraditional quality of life research. Response shift describesthe recalibration of one"s internal standards, changes inone"s values, and redefinition of one"s concept of “quality oflife” [61, 63–69]. As children adapt to their cancer-relatedimpairments, these become increasingly difficult to assesswith quality of life inventories.

Although we were able to report such high quality of lifeamong survivors of childhood low-grade glioma, werecommend that present methodological tools be revisedto detect the changes in a patient"s concept of self andhealth over time. Longitudinal assessment of self- andproxy-reported quality of life and addition of “then test”properties (repeated measurement of “How I felt then…how I feel now”) should be integrated into current qualityof life measures before incorporating quality of lifeassessment into clinical endpoint studies.

References

1. Kaatsch P, Rickert CH, Kühl J, Schüz J, Michaelis J (2001)Population-based epidemiologic data on brain tumors in Germanchildren. Cancer 92:3155–3164

2. Gajjar A, Sanford R, Heideman R, Jenkins J, Walter A, Li Y,Langston J, Muhlbauer M, Boyett J, Kun L (1997) Low-gradeastrocytoma: a decade of experience at St. Jude Children"sResearch Hospital. J Clin Oncol 15:2792–2799

3. Reddy AT, Packer RJ (1999) Chemotherapy for low-gradegliomas. Childs Nerv Syst 15:506–513

4. Gnekow AK, Kortmann R-D, Pietsch T, Emser A (2004) Lowgrade chiasmatic-hypothalamic glioma-carboplatin and vincristinchemotherapy effectively defers radiotherapy within a compre-hensive treatment strategy—report from the multicenter treatmentstudy for children and adolescents with a low grade glioma—HIT-LGG 1996—of the Society of Pediatric Oncology and Hematol-ogy (GPOH). Klin Pädiatr 216:331–342

5. Kortmann R-D, Timmermann B, Taylor RE, Scarzello G,Plasswilm L, Paulsen F, Jeremic B, Gnekow AK, Dieckmann K,Kay S, Bamberg M (2003) Current and future strategies inradiotherapy of childhood low-grade glioma of the brain.Strahlenther Onkol 179:509–520

6. Anderson DM, Rennie KM, Ziegler RS, Neglia JP, Robison LR,Gurney JG (2001) Medical and neurocognitive late effects amongsurvivors of childhood central nervous system tumors. Cancer92:2709–2719

7. Hernáiz Driever P, von Hornstein S, Pietsch T, Kortmann R,Warmuth-Metz M, Emser A, Gnekow A (2010) Natural historyand management of low-grade glioma in NF-1 children. JNeurooncol 100:199–207

8. Rutkowski S, Gnekow A, Fleischhack G, Wagner S, CalaminusG, Wolff J, Müller H, Sörensen N, Faldum A, Tatagiba M, Pietsch

1900 Childs Nerv Syst (2011) 27:1895–1902

T, Warmuth-Metz M, Kortmann R (2006) Hirntumoren beiKindern und Jugendlichen. Onkologe 12:533–545

9. Benesch M, Lackner H, Sovinz P, Suppan E, Schwinger W, EderH-G, Dornbusch HJ, Moser A, Triebl-Roth K, Urban C (2006)Late sequela after treatment of childhood low-grade gliomas: aretrospective analysis of 69 long-term survivors treated between1983 and 2003. J Neurooncol 78:199–205

10. Bhat SR, Goodwin TL, Burwinkle TM, Lansdale MF, Dahl GV,Huhn SL, Gibbs IC, Donaldson SS, Rosenblum RK, Varni JW,Fisher PG (2005) Profile of daily life in children with braintumors: an assessment of health-related quality of life. J ClinOncol 23:5493–5500

11. Kortmann R-D, Timmermann B, Taylor RE, Scarzello G,Plasswilm L, Paulsen F, Jeremic B, Gnekow AK, Dieckmann K,Kay S, Bamberg M (2003) Current and future strategies inradiotherapy of childhood low-grade glioma of the brain.Strahlenther Onkol 179:585–597

12. Musial-Bright L, Fengler R, Henze G, Hernáiz Driever P (2010)Carboplatin and ototoxicity: hearing loss rates among survivors ofchildhood medulloblastoma. Childs Nerv Syst 27(3):407–413

13. Rueckriegel SM, Blankenburg F, Henze G, Baqué H, Driever PH(2009) Loss of fine motor function correlates with ataxia anddecline of cognition in cerebellar tumor survivors. Pediatr BloodCancer 53:424–431

14. Stargatt R, Rosenfeld JV, Maixner W, Ashley D (2007) Multiplefactors contribute to neuropsychological outcome in children withposterior fossa tumors. Dev Neuropsychol 32:729

15. Steinlin M, Imfeld S, Zulauf P, Boltshauser E, Lövblad K-O,Ridolfi Lüthy A, Perrig W, Kaufmann F (2003) Neuropsycholog-ical long-term sequelae after posterior fossa tumour resectionduring childhood. Brain 126:1998–2008

16. Zuzak T, Poretti A, Drexel B, Zehnder D, Boltshauser E, GrotzerM (2008) Outcome of children with low-grade cerebellarastrocytoma: long-term complications and quality of life. ChildsNerv Syst 24(12):1447–1455

17. Listernick R, Charrow J, Gutmann DH (1999) Intracranial gliomasin neurofibromatosis type 1. Am J Med Genet 89:38–44

18. Listernick R, Louis DN, Packer RJ, Gutmann DH (1997) Opticpathway gliomas in children with neurofibromatosis 1: consensusstatement from the NF1 Optic Pathway Glioma Task Force. AnnNeurol 41:143–149

19. Gurney JG, Kadan-Lottick NS, Packer RJ, Neglia JP, Sklar CA,Punyko JA, Stovall M, Yasui Y, Nicholson HS, Wolden S, McNeilDE, Mertens AC, Robison LL (2003) Endocrine and cardiovas-cular late effects among adult survivors of childhood brain tumors.Cancer 97:663–673

20. Taphoorn MJ, Schiphorst AK, Snoek FJ, Lindeboom J, WolbersJG, Karim AB, Huijgens PC, Heimans JJ (1994) Cognitivefunctions and quality of life in patients with low-grade gliomas:the impact of radiotherapy. Ann Neurol 36:48–54

21. Beebe DW, Ris MD, Armstrong FD, Fontanesi J, Mulhern R,Holmes E, Wisoff JH (2005) Cognitive and adaptive outcome inlow-grade pediatric cerebellar astrocytomas: evidence of dimin-ished cognitive and adaptive functioning in National CollaborativeResearch Studies (CCG 9891/POG 9130). J Clin Oncol 23:5198–5204

22. Cappelli C, Grill J, Raquin M, Pierre-Kahn A, Lellouch-TubianaA, Terrier-Lacombe M-J, Habrand J-L, Couanet D, Brauner R,Rodriguez D, Hartmann O, Kalifa C (1998) Long term follow upof 69 patients treated for optic pathway tumours before thechemotherapy era. Arch Dis Child 79:334–338

23. Fouladi M, Gilger E, Kocak M, Wallace D, Buchanan G, ReevesC, Robbins N, Merchant T, Kun LE, Khan R, Gajjar A, MulhernR (2005) Intellectual and functional outcome of children 3 yearsold or younger who have CNS malignancies. J Clin Oncol23:7152–7160

24. Merchant TE, Conklin HM, Wu S, Lustig RH, Xiong X (2009)Late effects of conformal radiation therapy for pediatric patientswith low-grade glioma: prospective evaluation of cognitive,endocrine, and hearing deficits. J Clin Oncol 27:3691–3697

25. Pollack IF, Claassen D, al-Shboul Q, Janosky JE, Deutsch M(1995) Low-grade gliomas of the cerebral hemispheres inchildren: an analysis of 71 cases. J Neurosurg 82:536–547

26. Aarsen FK, Paquier PF, Arts W-F, Van Veelen M-L, Michiels E,Lequin M, Catsman-Berrevoets CE (2009) Cognitive deficits andpredictors 3 years after diagnosis of a pilocytic astrocytoma inchildhood. J Clin Oncol 27:3526–3532

27. Calaminus G, Kiebert G (1999) Studies on health-related qualityof life in childhood cancer in the European setting: an overview.Int J Cancer Suppl 12:83–86

28. Calaminus G, Langer T, Willich N, Beck JD (2000) Lebensqua-lität und Spätfolgen bei Kindern und Jugendlichen mit Krebserk-rankungen. Onkologe 6:868–877

29. Ness KK, Mertens AC, Hudson MM, Wall MM, Leisenring WM,Oeffinger KC, Sklar CA, Robison LL, Gurney JG (2005)Limitations on physical performance and daily activities amonglong-term survivors of childhood cancer. Ann Intern Med143:639–647

30. Bullinger M, Hasford J (1991) Evaluating quality-of-life measuresfor clinical trials in Germany. Control Clin Trials 12:91S–105S

31. Eiser C, Morse R (2001) A review of measures of quality of lifefor children with chronic illness. Arch Dis Child 84:205–211

32. Pukrop R, Möller H-J, Saß H, Sauer H, Klosterkötter J, CzernikA, Krausz M, Stieglitz R-D, Lambert M, Matthies H, Schaub A,Woschnik M, Wulfinghoff F, Steinmeyer EM (1999) Daskonstrukt lebensqualität: metaanalytische validierung und dieentwicklung eines modularen erhebungssystems. Nervenarzt70:41–53

33. Ravens-Sieberer U, Bullinger M (1998) Assessing health-relatedquality of life in chronically ill children with the German KINDL:first psychometric and content analytical results. Qual Life Res7:399–407

34. Heimans JJ, Taphoorn MJB (2002) Impact of brain tumourtreatment on quality of life. J Neurol 249:955–960

35. Kiebert GM, Curran D, Aaronson NK, Bolla M, Menten J,Rutten EHJM, Nordman E, Silvestre ME, Pierart M, KarimABMF (1998) Quality of life after radiation therapy of cerebrallow-grade gliomas of the adult: results of a randomised phaseIII trial on dose response (EORTC trial 22844). Eur J Cancer34:1902–1909

36. Klein M, Heimans JJ, Aaronson NK, van der Ploeg HM, Grit J,Muller M, Postma TJ, Mooij JJ, Boerman RH, Beute GN,Ossenkoppele GJ, van Imhoff GW, Dekker AW, Jolles J, SlotmanBJ, Struikmans H, Taphoorn MJB (2002) Effect of radiotherapyand other treatment-related factors on mid-term to long-termcognitive sequelae in low-grade gliomas: a comparative study.Lancet 360:1361–1368

37. North CA, North RB, Epstein JA, Piantadosi S, Wharam MD(1990) Low-grade cerebral astrocytomas: survival and quality oflife after radiation therapy. Cancer 66:6–14

38. Reijneveld JC, Sitskoorn MM, Klein M, Nuyen J, Taphoorn MJB(2001) Cognitive status and quality of life in patients withsuspected versus proven low-grade gliomas. Neurology 56:618–623

39. Cardarelli C, Cereda C, Masiero L, Viscardi E, Faggin R, LaverdaA, Bisogno G, Perilongo G (2006) Evaluation of health status andhealth-related quality of life in a cohort of Italian childrenfollowing treatment for a primary brain tumor. Pediatr BloodCancer 46:637–644

40. Hudson MM, Mertens AC, Yasui Y, Hobbie W, Chen H, GurneyJG, Yeazel M, Recklitis CJ, Marina N, Robison LR, Oeffinger KC(2003) Health status of adult long-term survivors of childhood

Childs Nerv Syst (2011) 27:1895–1902 1901

cancer: a report from the childhood cancer survivor study. JAMA290:1583–1592

41. Maunsell E, Pogany L, Barrera M, Shaw AK, Speechley KN(2006) Quality of life among long-term adolescent and adultsurvivors of childhood cancer. J Clin Oncol 24:2527–2535

42. Aarsen FK, Paquier PF, Reddingius RE, Streng IC, Arts W-FM,Evera-Preesman M, Catsman-Berrevoets CE (2006) Functionaloutcome after low-grade astrocytoma treatment in childhood.Cancer 106:396–402

43. Pompili A, Caperle M, Pace A, Ramazzotti V, Raus L, Jandolo B,Occhipinti E (2002) Quality-of-life assessment in patients whohad been surgically treated for cerebellar pilocytic astrocytoma inchildhood. J Neurosurg 96:229–234

44. Rutkowski S, Fleischhack G (2008) Medulloblastome, primitivneuroektodermale Tumoren und Ependymome. Monatsschr Kind-erheilkd 156:1187–1193

45. Ravens-Sieberer U, Görtler E, Bullinger M (2000) SubjektiveGesundheit und Gesundheitsverhalten von Kindern und Jugend-lichen–Eine Befragung Hamburger Schüler im Rahmen der schu-lärztliche Untersuchung. Gesundheitswesen 62:148–155

46. Ravens-Sieberer U, Redegeld M, Bauer C-P, Mayer H, StachowR, Kiosz D, van Egmond-Fröhlich B, Rempis R, Kraft D,Bullinger M (2005) Lebensqualität chronisch kranker Kinderund Jugendlicher in der Rehabilitation. Z Med Psychol 14(1):5–12

47. Cieza A, Ravens-Sieberer U (2000) Lebensqualität und Gesund-heitsökonomie in der Medizin: Konzepte, Methoden, Anwendung.Ecomed, Landsberg

48. Rajmil L, Herdman M, Fernandez de Sanmamed M-J, Detmar S,Bruil J, Ravens-Sieberer U, Bullinger M, Simeoni M-C, AuquierP (2004) Generic health-related quality of life instruments inchildren and adolescents: a qualitative analysis of content. JAdolesc Health 34:37–45

49. Ravens-Sieberer U, Ellert U, Erhart M (2007) Gesundheitsbezo-gene Lebensqualität von Kindern und Jugendlichen in Deutsch-land. Bundesgesundheitsbl 50:810–818

50. Rankin J (1957) Cerebral vascular accidents in patients over theage of 60. II. Prognosis. Scott Med J 2:200–215

51. van Swieten JC, Koudstaal PJ, Visser MC, Schouten HJ, van GijnJ (1988) Interobserver agreement for the assessment of handicapin stroke patients. Stroke 19:604–607

52. Hirsch JF, Renier D, Czernichow P, Benveniste L, Pierre-Kahn A(1979) Medulloblastoma in childhood. Survival and functionalresults. Acta Neurochir 48:1–15

53. LeBaron S, Zeltzer PM, Zeltzer LK, Scott SE, Marlin AE (1988)Assessment of quality of survival in children with medulloblas-toma and cerebellar astrocytoma. Cancer 62:1215–1222

54. Mulhern RK, Merchant TE, Gajjar A, Reddick WE, Kun LE(2004) Late neurocognitive sequelae in survivors of brain tumoursin childhood. Lancet Oncol 5:399–408

55. Riva D, Pantaleoni C, Milani N, Belani FF (1989) Impairment ofneuropsychological functions in children with medulloblastomasand astrocytomas in the posterior fossa. Childs Nerv Syst 5:107–110

56. Klein M, Engelberts NHJ, van der Ploeg HM, van der AaronsonNK, Baaijen H, Vandertop WP, Muller M, Postma TJ, Heimans JJ,Kasteleijn-Nolst Trenité DG (2003) Epilepsy in low-gradegliomas: the impact on cognitive function and quality of life.Ann Neurol 54:514–520

57. Taphoorn MJ, Heimans JJ, Snoek FJ, Lindeboom J, Oosterink B,Wolbers JG, Karim AB (1992) Assessment of quality of life inpatients treated for low-grade glioma: a preliminary report. JNeurol Neurosurg Psychiatry 55:372–376

58. Weitzner MA, Meyers CA (1997) Cognitive functioning andquality of life in malignant glioma patients: a review of theliterature. Psychooncology 6:169–177

59. Maher CO, Raffel C (2004) Neurosurgical treatment of braintumors in children. Pediatr Clin North Am 51:327–357

60. Zebrack BJ, Chesler MA (2002) Quality of life in childhoodcancer survivors. Psychooncology 11:132–141

61. Addington-Hall J, Kalra L (2001) Who should measure quality oflife? BMJ 322:1417–1420

62. Woodgate RL, Degner LF (2003) Expectations and beliefs aboutchildren"s cancer symptoms: perspectives of children with cancerand their families. Oncol Nurs Forum 30:479–491

63. Carr AJ, Gibson B, Robinson PG (2001) Is quality of lifedetermined by expectations or experience? BMJ 322:1240–1243

64. Daig I, Lehmann A (2007) Verfahren zur Messung der Lebensqua-lität. Procedures to measure quality of life. Z Med Psychol 16:5–23

65. Sprangers MAG, Tempelaar R, van den Heuvel WJA, de HaesHCJM (2002) Explaining quality of life with crisis theory.Psychooncology 11:419–426

66. Breetvelt IS, Van Dam FS (1991) Underreporting by cancerpatients: the case of response-shift. Soc Sci Med 32:981–987

67. Lynn Snow A, Cook KF, Lin P-S, Morgan RO, Magaziner J(2005) Proxies and other external raters: methodological consid-erations. Health Serv Res 40:1676–1693

68. Sprangers MA (1996) Response-shift bias: a challenge to theassessment of patients" quality of life in cancer clinical trials.Cancer Treat Rev 22(A):55–62

69. Sprangers MA, Schwartz CE (1999) The challenge of responseshift for quality-of-life-based clinical oncology research. AnnOncol 10:747–749

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