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APediatr Blood Cancer 2005;00:1–5

HRQOL Implications of Treatment With Dexamethasone forChildren With Acute Lymphoblastic Leukemia (ALL)

Christine Eiser, PhD,1* Helena Davies, MD,2 Meriel Jenney, MD,3

Chris Stride, PhD,4 and Adam Glaser, MD5

BACKGROUND

Over 80% of children diagnosed with acute lympho-blastic leukemia (ALL) are expected to achieve long-termsurvival [1]. These survival rates have been achieved inpart through establishment of national and internationaltrials, allowing more rapid accumulation of data andexpertise compared with treatment in single centers [2].However, there is evidence of late physical and psycho-logical effects in some children, highlighting the impor-tance of balancing the risks and benefits of treatment [3].

Glucocorticoid steroids are a standard component oftherapy, and have been linked with mood, behavior, andbody shape changes in both adults [4] and children [5].Negative effects have been reported for both prednisoneand dexamethasone. Evidence suggests superior penetra-tion of dexamethasone into the CNS, with the result thatmany current trials involve replacement of prednisonewith dexamethasone [6]. Dexamethasone has been linkedwith reduced incidence of CNS disease [7] and improvedsurvival rates [8].

Published equivalency tables suggest dexamethasone isapproximately seven times more potent than prednisone[8]. Comparison of children treated on dexamethasone aspart of the Dana–Farber protocol 91-01 with historical

controls treated with prednisone on 87-01 showed thatthose on dexamethasone therapy scored lower onstandardized tests of cognitive function. These effectswere independent of cranial irradiation or methotrexate

Background. Dexamethasone is increasinglyused as the steroid of choice in trials for standardrisk children with acute lymphoblastic leukemia(ALL). Improvements in event-free survival (EFS)has been attributed to lower CNS relapse rates,However, there are concerns that dexametha-sone may be more toxic than previous conven-tional therapy with prednisone. Such toxicityraises questions about the implications forchild neuropsychological function and HRQOL.Patients participating in the UK ALL 99/01 trialwere randomized to receive dexamethasoneor prednisone as their steroid in induction andmaintenance chemotherapy. We compared theHRQOL and behavior in children randomizedto receive both these agents. Procedure. Stan-dardized questionnaires to assess parent andchild HRQOL at 3–6 months after diagnosis (T1)and 1 year later (T2) completed by mothers infamily homes. Forty-five mothers of a child withALL (32 male, 13 female; average age at T1,7 years 3 months; at T2, 8 years 3 months)

completed HRQOL questionnaires. Results. Forthe total group, child HRQOL scores improvedand behavior problems decreased significantlyfrom T1 to T2. Comparison of HRQOL scoresbetween the 17 children randomized to dexa-methasone and 28 children randomized to pre-dnisone showed no significant differences. Therate of improvement in HRQOL from T1 to T2did not differ between children randomized todexamethasone or prednisone. Conclusions.Dexamethasone is increasingly used in the treat-ment of ALL and has been linked with improvedsurvival rates. Long-term use of dexamethasoneraises questions about neuropsychologic toxi-city. Although HRQOL increased significantlyover the year for all children, the extent of thisincrease did not differ by chemotherapy. Theseresults should contribute to lessened concernsabout use of dexamethasone in the treatment ofALL. Pediatr Blood Cancer 2005;00:1–5.ß 2005 Wiley-Liss, Inc.

Key words: ALL; dexamethasone; HRQOL; prednisone

PBC/04-0305(20432)

ß 2005 Wiley-Liss, Inc.DOI 10.1002/pbc.20432Published online 00 Month 2005 in Wiley InterScience(www.interscience.wiley.com)

——————1Cancer Research UK Professor of Child Health Psychology, Child and

Family Research Group, Department of Psychology, University of

Sheffield, Western Bank, Sheffield, United Kingdom

2Consultant in Medical Education/Late Effects, Sheffield Children’s

NHS Trust, Western Bank, Sheffield, United Kingdom

3Consultant Paediatric Oncologist, Llandough Hospital, Penlan Road,

Penarth, South Glamorgan, United Kingdom

4Statistician, Institute of Work Psychology, University of Sheffield,

Western Bank, Sheffield, United Kingdom

5Consultant Paediatric Oncologist, Department of Paediatric

Oncology, Children’s Day Hospital, St. James University Hospital,

Leeds, United Kingdom

Grant sponsor: Cancer Research-UK; Grant numbers: CP 1019/0101,

CP 1019/0104.

*Correspondence to: Christine Eiser, Cancer ResearchQ1UK Professor

of Child Health Psychology, Child and Family Research Group,

Department of Psychology, University of Sheffield, Western Bank,

Sheffield, S10 2TP. E-mail: c.eiser@shef.ac.uk

Received 14 October 2004; Accepted 17 January 2005

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Atherapy [9]. However, the dexamethasone patients wereyounger on diagnosis and fewer of their parents had acollege level education. Further study is therefore neededto determine the impact on children’s learning, behaviorand health-related quality of life (HRQOL) of routine useof the more cytotoxic dexamethasone. Such information isessential to providing optimal support to families whosechildren are undergoing treatment for ALL.

Caring for a child undergoing treatment for cancer has apotentially negative effect on other members of the family[10]. Parents are under considerable distress followingdiagnosis, but this may be aggravated where children showbehavior problems in clinic or at home. For this reason weinvestigated mothers’ own well-being, on the assumptionthat mothers whose child showed more behavior problemswould themselves report lower HRQOL.

We report herein measurements of HRQOL andbehavior of children treated as part of the MRC UKALL99 (modified 2001) trial who were randomized initially toreceive either prednisone or dexamethasone. Mothersrated their child’s HRQOL [11] and behavior twice; at3 months after diagnosis (T1) and again 1 year later (T2).In addition, mothers were asked to complete the SF-36[12] as an indicator of their own HRQOL on both oc-casions. Thus, we aim to describe any differences in childor mother QOL depending on treatment. Based on pre-vious literature, we predicted more adverse impact onHRQOL for those randomized to dexamethasone.

METHOD

Sample and Procedure

Multi-Centre Research Ethics Committee approval wasobtained. English-speaking families of children aged 3–18 years treated according to national protocols (UKALL99) at five cancer centers in the UK over a 2 year periodwere eligible. Exclusions were: children with advanceddisease, cognitive or neurological impairment prior todiagnosis, or other complicating conditions (e.g., Down’ssyndrome). Fifty-two of 84 families (62%) participated.Data from six families were subsequently excluded as theydid not satisfactorily complete questionnaires. One familycompleted time 1 data only.

Our sample, therefore, included 45 mothers of a childwith ALL (32 males, 13 females). Demographic informa-tion is shown in Table I. Mothers were approached by aresearch nurse during routine clinic visits and given verbal

and written information about the study. Those who agreedto take part were then contacted by research staff. Ques-tionnaires were completed in the family home.

Measures

Child HRQOL and behavior. The PedsQLTM4.0[11]is a 23-item generic questionnaire, yielding separateHRQOL ratings of the child’s physical, social and emo-tional function. A fourth subscale, school function, wasnot completed by many parents as their child was notattending school. Each item is rated on a 5 point scale interms of how much of a problem has been experienced inthe last 4 weeks. There were parallel forms for child andadult but given the age of the sample we used parent ratingsonly. Scores are reversed so that higher scores are indi-cative of higher HRQOL.

Child difficulties. Mothers’ perceptions of theirchild’s mood and behavior were assessed using a 9-itemscale based on descriptions given by mothers in previousstudies. Ratings were made on 7-point scales (not at all—extremely) as follows: (clingy, angry, tired, frightened,active physically (reverse-scored), withdrawn, clumsy,moody, and extent of difficulties learning). Ratings wereaveraged to yield a single score (range 1–9) with higherscores indicating more problems. The scale has goodinternal reliability (a¼ 0.79) and discriminant validity[13].

Mothers’ HRQOL. The SF-36 scale [11] was includ-ed as a measure of mothers’ own well-being. This includesa single-item measure of change in health, plus eightsubscales, with varying numbers of items and responseformats, defined as physical functioning, role limitation byphysical problems, role limitation by emotional problems,social functioning, mental health, energy/vitality, pain,and general health perception.

RESULTS

For the total group we compared children’s HRQOLand behavior (measured by the 3 PedsQLTM4 subscalesand the Child Difficulties scale) and mothers’ ownHRQOL (the 8 SF-36 subscales) at T2 in relation to boththe T1 data and population norms [11,14]. The formercomparisons were made using a paired-samples t-test,though due to the small sample size, results were checkedusing the non-parametric equivalent (Wilcoxon test). Dif-ferences between T2 data and population norms were

TABLE I. Mean (and Standard Deviations) and Median for the Total Sample

Total (N¼ 45) Dexamethasone (N¼ 17) Prednisone (N¼ 28)

Child’s age at time 1 (years) Mean¼ 7.2 (3.8), median¼ 5.8 Mean¼ 7.2 (4.2), median¼ 5.5 Mean¼ 7.2 (3.6), median¼ 6.2

Child’s gender (% male) 71% 76% 68%

Child’s age on diagnosis (years) Mean¼ 6.3 (3.8), median¼ 5.0 Mean¼ 6.1 (3.9), median¼ 4.5 Mean¼ 6.5 (3.7), median¼ 5.5

Mother’s age at time 1 (years) Mean¼ 36.4 (6.2), median¼ 36.0 Mean¼ 38.3 (7.8), median¼ 36.5 Mean¼ 35.2 (4.8), median¼ 35.5

2 Eiser et al.

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Aassessed using a 1-sample t-test. We subsequentlycompared the HRQOL scores and the change in HRQOLbetween the 17 children randomized to receive de-xamethasone and 28 children randomized to receiveprednisone. A 2-way ANOVA was used, with one between-groups factor (treatment) and one within-groups factor(time); the main effect of treatment represented thedifference in HRQOL between the treatment groups, andthe extent of this interaction with time indicated the extentto which change in HRQOL between T1 and T2 differedbetween the treatment groups.

Changes in HRQOL From T1 to T2

As shown in Table II, the mean PedsQLTM4 scores forthe children increased significantly from T1 to T2 forsubscales assessing physical and emotional functioning.There was no significant change for the social functioningsubscale. Mean scores on the Child Difficulties scaledecreased significantly from T1 to T2.

There was also an increase from T1 to T2 in mothers’own self-reported HRQOL for 5 of the 8 SF-36 subscales;there were no changes in physical function, pain, andgeneral health. Both child and mother HRQOL scoreswere significantly below population norms on bothassessments

Changes in HRQOL Related to Dexamethasoneor Prednisone

No significant differences in PedsQLTM4 scores werefound depending on dexamethasone or prednisone. Formothers the only significant differences occurred on thedimensions of pain, energy, and social functioning. In allcases, mothers of children on dexamethasone reportedhigher HRQOL than mothers of children on prednisone.

There were no differences in the rate of change in HRQOLbetween groups with time (see Table III). This means thatfor the measures of HRQOL that increased significantly,the extent of this increase did not differ significantly bytype of treatment.

CONCLUSIONS

The continuing goal of treatment is to improve currentsurvival rates while preserving HRQOL as far as possible.Based on standardized measures we have shown thatHRQOL is very compromised for both children and theirmothers in the 3–6 months after diagnosis after diagnosis,and also 1 year later, regardless of the specific treatmentprotocol.

However, we found no evidence that children’sHRQOL or behavior was worse on dexamethasone com-pared with prednisone according to mothers’ report. Thesefindings should ameliorate concerns about the use ofdexamethasone in treatment of ALL.

We argued that mothers’ own HRQOL might be adver-sely affected if treatment with dexamethasone compro-mised children’s HRQOL more than treatment withprednisone. Based on a generic measure [12], we werenot able to identify differences in mothers’ own HRQOLdepending on the child’s treatment. This may reflect thefact that mothers did not rate HRQOL to be lower forchildren on dexamethasone. This was unexpected and mayreflect the fact that all children, regardless of specifictreatment, showed difficult behavior compared withbefore the diagnosis or simply that the measure we usedlacked sensitivity for our purposes. Mothers often com-mented that they were unable to say whether the child’sbehavior was worse on prednisone or dexamethasone,because they had no experience of the other. Our data

TABLE II. Comparison of Time 2 HRQOL Scores with Time 1 and Norm HRQOL Scores

Measure Na Study, T1 Study, T2 Norm

Effect sizec,

T2 versus T1

Effect size c,

T2 versus norm

Child

Physical functioning 44 37.4b 52.7 81.4b 0.78 1.90

Emotional functioning 44 47.2b 56.3 78.0b 0.48 0.39

Social functioning 42 67.6 69.2 85.4b 0.08 0.21

Child difficulties 41 3.73b 3.23 NA 0.44 NA

Parents

Physical function 37 90.5 89.7 89.5 0.05 0.06

Social functioning 41 57.3b 70.7 86.9b 0.44 1.44

Role limitation by physical problems 40 63.8b 79.4 84.6 0.47 1.29

Role limitation by emotional problems 37 43.2b 63.1 80.6b 0.41 0.50

Mental health 40 52.8b 61.2 72.0b 0.42 1.08

Energy/vitality 39 41.0b 52.8 58.6b 0.56 0.88

Pain 41 79.7 78.6 79.9 0.04 0.01

General health perception 41 71.4 67.7 75.0b 0.16 0.18

aMatched cases, times 1 and 2.bIndicates significant difference between respective score and time 2 score at P< 0.05 level, 2-tailed test.cCohen d statistic (d& 0.2, small effect; d& 0.5, medium effect; d& 0.8, large effect).

HRQOL and Dexamethasone in ALL 3

Author Proof

Asuggest it was treatment generally rather than specificallythat determined HRQOL at least in the first year afterdiagnosis.

Limitations of the study may be related to our choice ofHRQOL measure. There is a growing body of literaturedescribing both generic and disease-specific measures ofHRQOL for work with children, but little evidence thatthey all measure the same underlying concept. Given thecurrent state of knowledge about measuring HRQOL inchildren, it is not clear that similar results would neces-sarily be obtained using a different measure. In addition,we relied on mothers’ reports about their child’s HRQOL.It is likely that mothers were highly distressed about theirchild’s illness, and this was reflected in very negativeperceptions of the child’s HRQOL. There is substantialevidence that mothers tend to report their child’s HRQOLto be worse than children themselves [15]. For this reason,it would be important to obtain children’s own ratings ifpossible. Although we had intended to do this, we foundchildren were often too young or unwell.

In addition, this was an opportunistic study. We wouldhave required 40 children in each arm of the trial in order todetect a large effect size, such as a between-group differ-ence of 15 or more for the physical functioning scale(which results in Cohen’s d� 0.8 given the samplestandard deviation¼ 19), with statistical power of 95%.

In fact, the differences between the two groups ob-served on the child HRQOL scales were all considerablysmaller than this, being of approximately 5 U or less(d� 0.2). The implications of this are twofold. First, inorder to detect small differences of this order, we wouldneed to recruit a much larger number of children, whichwould only be possible by including assessment ofHRQOL in a national study. Second, given the small

differences between the two groups, we need to questionhow far differences of this size are of practical interestregarding a child’s behavior or HRQOL.

Third, more children in our study were treated withprednisone compared with dexamethasone. This may bean artifact of the small sample size, but also children wouldhave been treated on prednisone where families refusedrandomization. (According to parents’ reports, threerefused randomization).

Our findings relate to a relatively short period of follow-up. Waber et al. [9] reported deficits in learning andmemory for children treated on dexamethasone comparedwith prednisone, but all had completed therapy at thetime of assessment. If the effects of dexamethasone arecumulative over time, it would be important to re-assessHRQOL, including cognitive function, after completion ofchemotherapy.

While further exploration of the effect of dexametha-sone can be undertaken, comparison with the effects ofprednisone will not be possible in the UK, since dexa-methasone has been prescribed for all children with ALLsince June 2002. However, given the very compromisedHRQOL for the group as a whole, continued surveillanceis vital in order to optimize the care of these children. Inthis regard, it is important to note that HRQOL assessmentis now an important and welcome addition to evaluation ofon-going ALL trials.

ACKNOWLEDGMENTS

We would like to thank Yvonne Vance for help withdata collection and Linda Phelan, Liz Whiles, HeatherRake, and Janet Powell for recruiting patients to thisstudy.

TABLE III. Differences in HRQOL and Change in HRQOL Between Treatment Groups

Measure N

Time 1 mean Time 2 mean

F-Stats, sigf, and effect sizec between

subject and interaction terms

Dex Pred Dex Pred Treatment Treatmentbtime

Child

Physical functioning 44 38.3 36.9 55.3 51.1 F¼ 0.19, etasq¼ 0.007 F¼ 0.29, etasq¼ 0.004

Emotional functioning 44 49.8 45.7 60.3 53.9 F¼ 1.02, etasq¼ 0.024 F¼ 0.16, etasq¼ 0.004

Social functioning 42 67.9 67.5 69.3 69.1 F< 0.01, etasq¼ 0.001 F< 0.01, etasq¼ 0.001

Child difficulties 41 3.5 3.8 2.9 3.4 F¼ 1.80, etasq¼ 0.044 F¼ 0.39, etasq¼ 0.010

Parents

Physical function 37 91.9 89.8 90.0 89.6 F¼ 0.09, etasq¼ 0.002 F¼ 0.09, etasq¼ 0.003

Social functioning 41 66.7 51.9 85.0 62.5 F¼ 5.09a, etasq¼ 0.115 F¼ 0.61, etasq¼ 0.005

Role limitation by physical problems 40 61.7 65.0 90.0 73.0 F¼ 0.38, etasq¼ 0.010 F¼ 3.22, etasq¼ 0.078

Role limitation by emotional problems 37 41.0 44.4 66.7 61.1 F¼ 0.01, etasq¼ 0.001 F¼ 0.27, etasq¼ 0.008

Mental health 40 59.1 49.4 65.7 58.8 F¼ 2.48, etasq¼ 0.061 F¼ 0.13, etasq¼ 0.004

Energy/vitality 39 51.1 35.4 58.9 49.4 F¼ 4.78a, etasq¼ 0.114 F¼ 0.69, etasq¼ 0.008

Pain 41 93.3 71.8 91.1 71.4 F¼ 9.11a, etasq¼ 0.189 F¼ 0.69, etasq¼ 0.002

General health perception 41 74.4 69.7 75.5 63.3 F¼ 1.52, etasq¼ 0.037 F¼ 2.81, etasq¼ 0.067

aIndicates significant effect at P< 0.05 level, 2-tailed test.bAssess by independent groups t-test on time 2 data only.cPartial eta-squared.

4 Eiser et al.

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Q1: Au please check the name of the corresponding author and

address.

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HRQOL and Dexamethasone in ALL 5

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Softproofing for advanced Adobe Acrobat Users - NOTES toolNOTE: ACROBAT READER FROM THE INTERNET DOES NOT CONTAIN THE NOTES TOOL USED IN THIS PROCEDURE.

Acrobat annotation tools can be very useful for indicating changes to the PDF proof of your article.By using Acrobat annotation tools, a full digital pathway can be maintained for your page proofs.

The NOTES annotation tool can be used with either Adobe Acrobat 3.0x or Adobe Acrobat 4.0.Other annotation tools are also available in Acrobat 4.0, but this instruction sheet will concentrateon how to use the NOTES tool. Acrobat Reader, the free Internet download software from Adobe,DOES NOT contain the NOTES tool. In order to softproof using the NOTES tool you must havethe full software suite Adobe Acrobat Exchange 3.0x or Adobe Acrobat 4.0 installed on your com-puter.

Steps for Softproofing using Adobe Acrobat NOTES tool:

1. Open the PDF page proof of your article using either Adobe Acrobat Exchange 3.0x or AdobeAcrobat 4.0. Proof your article on-screen or print a copy for markup of changes.

2. Go to File/Preferences/Annotations (in Acrobat 4.0) or File/Preferences/Notes (in Acrobat 3.0)and enter your name into the “default user” or “author” field. Also, set the font size at 9 or 10point.

3. When you have decided on the corrections to your article, select the NOTES tool from theAcrobat toolbox and click in the margin next to the text to be changed.

4. Enter your corrections into the NOTES text box window. Be sure to clearly indicate where thecorrection is to be placed and what text it will effect. If necessary to avoid confusion, you canuse your TEXT SELECTION tool to copy the text to be corrected and paste it into the NOTEStext box window. At this point, you can type the corrections directly into the NOTES textbox window. DO NOT correct the text by typing directly on the PDF page.

5. Go through your entire article using the NOTES tool as described in Step 4.

6. When you have completed the corrections to your article, go to File/Export/Annotations (inAcrobat 4.0) or File/Export/Notes (in Acrobat 3.0). Save your NOTES file to a place on yourharddrive where you can easily locate it. Name your NOTES file with the article numberassigned to your article in the original softproofing e-mail message.

7. When closing your article PDF be sure NOT to save changes to original file.

8. To make changes to a NOTES file you have exported, simply re-open the original PDFproof file, go to File/Import/Notes and import the NOTES file you saved. Make changes and re-export NOTES file keeping the same file name.

9. When complete, attach your NOTES file to a reply e-mail message. Be sure to include yourname, the date, and the title of the journal your article will be printed in.