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Journal of Clinical Oncology, Vol 26, No 18 (June 20), 2008: pp. 3025-3030 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.12.4149 Neuropsychological Outcome in Chemotherapy-Only–Treated Children With Acute Lymphoblastic Leukemia
From the Department of Pediatric Hematology Oncology, Beatrix Children's Hospital, University Medical Center Groningen, and Department of Clinical and Developmental Psychology, University of Groningen; Department of Pediatric Psychology, University Medical Center Utrecht, Utrecht; Department of Pediatrics, Free University Medical Center, Amsterdam; and the Dutch Childhood Oncology Group, the Hague, the Netherlands Corresponding author: Nathalie C.A.J. Jansen, MSc, Beatrix Children's Hospital Groningen, Department of Pediatric Hematology Oncology, University Medical Center Groningen, University of Groningen, P.O. Box 30 001, 9700 RB Groningen, the Netherlands; e-mail: N.C.A.Jansen{at}umcutrecht.nl
Purpose To evaluate neuropsychological functioning over time in children treated for acute lymphoblastic leukemia (ALL) with chemotherapy only. Patients and Methods Forty-nine consecutive patients (median age at first assessment, 6.8 years; range, 4.0 to 11.8 years) treated with intrathecal and systemic chemotherapy were included in a nationwide, prospective-longitudinal, sibling-controlled study. Patients and siblings completed three extensive neuropsychological assessments: at diagnosis, 3 to 6 months after completion of (2-year) treatment and 4.5 years after diagnosis. Assessments included measures of learning, memory, attention, speed, executive functioning, visual-constructive functioning, and fine-motor functioning. Multilevel analyses were applied to evaluate patients' performances over time and to compare patients to 29 siblings (median age of siblings at first assessment, 8.2 years; range, 4.5 to 12.6 years) and to normative data. Results No major differences were found in neuropsychological performance between patients and siblings, with both groups performing mainly in the normal range. The patient group as a whole, however, scored significantly lower than the siblings on complex fine-motor functioning at the last evaluation. Large practice effects were found for both patients and siblings in four of 11 tasks. Patients who uttered physical complaints (ie, pain and/or tiredness) at the first pretreatment assessment scored significantly lower than siblings on attention and speed at the last two evaluations. Conclusion Despite intensive and potentially neurotoxic treatment, no evident negative, neuropsychological late effects were found 4.5 years after diagnosis, except for effects on complex fine-motor functioning. Both the large practice effects observed and the poorer performances on sustained attention for patients with physical complaints should be reckoned with in prospective, longitudinal neuropsychological research in children.
Since the introduction of elective treatment of the CNS, the prognosis of children with acute lymphoblastic leukemia (ALL) has improved dramatically, and almost 80% will survive.1 There are, however, questions about whether a biologic cure is accompanied by unaffected mental development and a good quality of life. Early treatment protocols, including cranial irradiation (CI) in combination with intrathecal chemotherapy, have been associated with persistent cognitive impairment that results from structural brain damage.2 In the mid-1980s, chemotherapy-only protocols, therefore, were introduced as standard treatment. To date, it is still debatable whether children with ALL who are treated with chemotherapy-only experience adverse neuropsychological late effects, but deficits generally seem mild in comparison to protocols that involve CI.3-7 Intelligence, memory, and attention have been most studied. However, findings are conflicting, probably because of significant methodologic differences among studies. A recent study showed no major intelligence quotient differences between patients and siblings over time after cessation of treatment; both groups performed mainly in the normal range.8 This is the first investigation to apply a prospective, longitudinal study design that assesses a wide variety of cognitive functions in patients with ALL compared with healthy sibling controls. Moreover, by applying multilevel analyses, performances of patients with missing values can be included to reduce the risk of biased outcome.
Patients and Healthy Siblings The present study included 49 consecutive pediatric patients with ALL. Inclusion criteria were newly diagnosed children with high- or standard-risk ALL who were between 4.0 and 12.3 years old and who spoke Dutch as the primary language. Patients with initial CNS leukemia or pre-existent disorders that could interfere with normal cognitive development (eg, developmental or psychiatric disorders or Down syndrome) were excluded. Written informed consent was obtained according to each hospital's rules. Patients were treated with chemotherapy only according to the national Dutch Childhood Oncology Group–ALL-9 protocol, which included vincristine, dexamethasone, daunorubicine with high-dose methotrexate (MTX), leucovorin rescue, and triple intrathecal therapy as CNS prophylaxis.9-11 The total duration of treatment was 108 weeks (cumulative doses of cytostatic drugs and leucovorin rescue are given in the Appendix Table A1, online only). The control group consisted of 29 healthy siblings who had the same inclusion criteria as the patients with respect to age and normal cognitive development. If there was more than one sibling, the child closest in age to the patient was chosen. Of the initial 29 siblings, two refused to participate at neuropsychological assessment (NPA)–II. One sibling agreed to participate again at NPA-III; hence, a total of 28 siblings could be assessed. Demographic variables for patients and siblings are listed in Table 1. Full details of the group of children included at NPA-I are described in Jansen et al.12
Baseline evaluation (ie, NPA-I) took place shortly after diagnosis and within 2 weeks of the start of chemotherapeutic treatment.12 The second evaluation (ie, NPA-II) was carried out 3 to 6 months after cessation of therapy (ie, 2.3 to 2.6 years [median, 2.4 years] after NPA-I).8 The last follow-up (ie, NPA-III) was performed 1.8 to 2.3 years (median, 2.2 years) after NPA-II. Between NPA-I and NPA-II, the number of patients declined because of relapse of ALL or death in three patient cases, refusal of continued participation in two patients, and a switch to another treatment protocol in one patient. Between NPA-II and NPA-III, two patients relapsed, and one patient refused continued participation. Consequently, 40 of 49 patients could be assessed three times. Siblings were assessed within 4 weeks of the patients' evaluations. To optimize standardization, all participants nationwide were tested by one qualified child neuropsychologist. Patients and siblings were individually tested either at home or at the hospital. No difference in scores was found between these two sites.
Measures
Although the NPA included intelligence tests, these results are beyond the scope of this article, and results have been published previously.8 No major intelligence quotient differences were found between patients and siblings over time, and both groups performed mainly in the normal range. Practice effects (ie, an improvement in performance as a result of repeated assessments) affect the interpretation of memory tests, in particular19,20; therefore, two parallel versions were used.13 Fitting procedures were used to convert published normative data from discrete into continuous normative data (mean, 50; standard deviation, 10). Raw scores were standardized by means of these continuous normal scores to enable comparisons of standardized scores among patients of any specific age.21,22
Statistics Because of missing values, analyses were performed with multivariate multilevel analyses (MLwiN4; Institute of Education, University of London, London, England), which enable the use of all outcome measures for an individual patient over time (Table 2).23,24 The following analyses were performed: Multilevel models were constructed, in which controlling variables were tested stepwise, analogous to hierarchical regression analysis. Controlling variables were as follows: general practice effects as a consequence of repeated assessments, age and sex, age younger than 6 years versus older than 6 years at NPA-I as a dichotomous variable, and the presence of physical complaints uttered at NPA-I. If the estimation of the regression weights of one of these factors in a specific step of testing was significantly greater than zero, the factor was kept in the model. After analysis was controlled for these factors, differences between patients and siblings were tested at every NPA. After this, the interaction between the variables of patients age younger than 6 years at diagnosis was tested. For the descriptive analyses, patients and siblings were divided into five subgroups, and these were defined according to age and the analyses of the missing values. The young patient group (< 6 years at NPA-I; n = 16) was established for two reasons: young age has been considered as a risk factor for harmful neuropsychological sequelae,8,25 and young children could not complete the full test battery because of the age restrictions of most tests. They could not, therefore, profit equally from practice effects at NPA-II and NPA-III compared with older children. A variable for age younger than 6 years was included in the model, thus precluding the inability to interpret correctly the possible effects of chemotherapy at NPA-II and NPA-III. Patients older than 6 years at NPA-I who missed more than two tests because of physical complaints (including pain, sickness, and tiredness) or restrictions (such as an infusion in the dominant hand) were defined as the sick group (n = 13). It appeared that sick patients scored lower at NPA-I as a consequence of being sick. Therefore, being sick was included as a variable in the model, to preclude the inability to interpret correctly the possible effects of chemotherapy at NPA-II and NPA-III. The patient group younger than 6 years was too small to apply subanalyses for patients who uttered physical complaints at NPA-I. Patients older than 6 years at NPA-I who, because of their ages, could perform all tests, were defined as the older group (n = 20). Healthy siblings at NPA-I (n = 6) were defined as young if aged younger than 6; like the young patients, they could not complete all neuropsychological tests because of age restrictions. The older sibling group (age > 6 at NPA-I; n = 23) could be assessed fully at every NPA and had no test shift. Significance levels were established at P < .05. Data were analyzed with MLwiN (Institute of Education, University of London, London, England).26 In mulitilevel model analysis and patient-sibling comparisons, only main effects and significant confounding variables are presented. Extensive descriptions of separate multilevel analyses in the results section are beyond the scope of this article; therefore, analyses will be summarized.
Results of assessments will be presented by testing possible confounding variables (practice effects, age, sex, and sickness at NPA-I) with MLwiN analyses, additional MLwiN analyses to test possible significant differences between patients and siblings with respect to significant controlling variables and to the age of patients younger than 6 years x time interactions, and additional descriptive statistics of differences (not tested) between the five subgroups according to line charts of mean test scores.
Learning and Memory
No significant differences between patients and siblings were found after analysis was controlled for possible confounding effects. Multilevel analyses indicated no significant effects of the interaction of patients younger than 6 years x time. In the three learning and memory tasks, the pattern between NPA-I and NPA-II was analogous for all subgroups (Figs 1A to 1C). For RAVLT learning and recall, sick patients showed lower mean scores at NPA-I compared with older siblings, but their scores normalized at NPA-III. As Figure 1C suggests, CFT recall scores at NPA-III were equal for all subgroups.
Sustained Attention and Speed For both speed and accuracy, after analysis was controlled for possible confounds, no significant differences between patients and siblings were found. Multilevel analyses did not indicate significant interactions for patients younger than 6 years x time. Figures 2A and 2B show descriptive mean scores for all subgroups at all three NPAs. Results of sick patients were not given at NPA-I, as there were only three patients who could complete the test at that time. In tests of both speed and accuracy, scores of sick patients were lower at NPA-II and NPA-III compared with older siblings. For speed, young patients scored lower compared with older siblings, but scores increased at NPA-III. Older patients showed a temporary decline in accuracy from NPA-I to NPA-II, but scores increased at NPA-III.
Executive Functioning Multilevel analyses of Wisconsin Card Sorting Test (WCST) errors and perseverations indicated a significant practice effect, as scores increased over time for all subgroups (Figs 3A and 3B). For both measures, age was a significant confounding variable: older children scored higher. At NPA-II, young children scored significantly lower, but performances normalized at NPA-III. Only in the WCST errors, sick patients scored significantly lower at NPA-II, but scores normalized at NPA-III.
For both executive functioning measures, after analysis was controlled for possible confounds, no significant differences between patients and siblings and no interactions of patients younger than 6 years x time were found. Change in pattern of WCST errors between NPA-I and NPA-III is analogous for all subgroups; the lowest (ie, unfavorable outcome) mean scores were at NPA-I, and the highest (ie, favorable outcome) mean scores were at NPA-III. Sick patients scored lower at NPA-II compared with other subgroups, but scores increased strongly at NPA-III (Fig 3A). Score obtained by young patients increase strongly from NPA-II to NPA-III.
Visual-Motor and Fine-Motor Functioning For both Rey CFT copy and PP dominant hand tests, after analysis was controlled for possible confounding variables, no significant differences between patients and siblings or significant interactions between patient groups and age younger than 6 years at diagnosis were found. With PP assembly, there were significant differences between patients and siblings at NPA-III: patients scored lower. With VMI, there is a significant interaction effect between age and VMI: older patients scored lower at NPA-I than younger patients. Except for VMI, the pattern between NPA-I and NPA-II was analogous for all groups (Figs 4A to 4D). No general trend could be detected. As mentioned for CFT delayed recall, CFT copy scores were higher at NPA-II because of the use of an easier parallel version of the test. With CFT copy, a decrease in the score was seen; mean scores for all groups at NPA-III were lower compared with NPA-I. Older siblings had the lowest mean scores at NPA-III. For PP assembly, all patient subgroups showed lower mean scores at NPA-II and NPA-III compared with both sibling subgroups.
In this prospective, longitudinal study, a relatively large cohort of children with ALL who were treated with chemotherapy only was followed neuropsychologically until 4.5 years after diagnosis. In general, no major differences in neuropsychological performance were found between patients and siblings 2 years after cessation of therapy. Overall, our results are consistent with the few other published studies, which did not find evident, negative, neuropsychological late effects of chemotherapy.28-30 The patient group as a whole, however, scored significantly lower than siblings on complex fine-motor functioning at the last evaluation. This relative deterioration can be explained by a minor deficit in processing speed,31 or it can be a result of vincristine neuropathy.32 The latter explanation would, however, seem less likely, as patients scored well on a simple fine-motor task (dominant hand on the PP). Some additional results need special attention. First, the sick group scored significantly lower than siblings on the accuracy scale of sustained attention at the second and third evaluation. It is noteworthy that patients who uttered physical complaints shortly after diagnosis still performed less well on a sustained attention task 4.5 years later. We hypothesize that these patients have reduced cognitive reserve capacity. If true, the speed and attention task should be attempted at baseline; those patients who cannot complete it because of physical complaints are those who should be considered at risk for mild impairment. This finding then may apply beyond children with cancer and may be used for chronic, severely ill pediatric patients. Generally, speed and attention tasks are among the most sensitive for the detection of acquired brain damage.18 The prefrontal cortex is important in the development of attention, and this brain area is not fully developed until adulthood. It might, therefore, be more sensitive for the detection of neuropsychological sequelae in children. Moreover, the applied BV test could be a sensitive task for children with less cognitive reserve capacity because of its tedious nature. Other studies also found (subtle) late effects within the domain of attention and speed of information processing31,33 or minor deficits on fine-motor functioning32; both apply to the performance on the BV test. Secondly, large practice effects were found for both patients and siblings on certain tasks, which means that patients and siblings scored higher at the third evaluation compared with the first two evaluations.34 A control for these practice effects in longitudinal research by including a healthy control group is essential. Also, two parallel forms were used for the RAVLT to minimize practice effects. As potentially negative effects of chemotherapeutic treatment on neuropsychological functioning seem to be small, differences between patients and siblings may manifest only as differences in practice effects.19,20 Also, practice effects should be taken into account in the interpretation of repeated individual assessments in clinical practice. Sick patients showed a temporary, relative decline in executive functioning shortly after cessation of therapy, but scores normalized at the last evaluation. It is likely that some patients need time to recover; therefore, conclusions should not been drawn too soon after completion of treatment. Our study underscores the merit of analyzing missing values at the first pretreatment and at any other assessment. Unlike the more traditional repeated measurement models, data of patients with missing values can also be included in multilevel techniques. The exclusion of these patients would have biased our results, as they were found to be at risk for mild attention impairment. Despite the application of strict methodology, our study has (insurmountable) limitations.35 First, patients with incomplete data on some tests at the first pretreatment assessment (sick patients) generally had lower baseline scores on tests that they did complete than patients who had a complete data set. This could lead to underestimation of the deterioration of scores over time, had it been possible to test all patients fully. Second, numbers of patients included were too small for subset analysis of age. One cannot preclude a possible age effect if larger numbers of patient cases had been evaluated. Although no significant differences were found, there was a general trend, and young patients consistently scored less well. In summary, patients who undergo potentially neurotoxic treatment generally do not show evident, negative, late effects of treatment on neuropsychological functioning 4.5 years after diagnosis. We cannot, however, preclude that changes can still occur several years after cessation of treatment. Patients showed a slight decrease on complex fine-motor functioning compared with healthy siblings. Moreover, patients who could not been tested fully at diagnosis are at risk of slightly lower attention functioning. Additional research should address the pathogenesis of these attention deficits in specific patients who are prone to negative sequelae.
The authors indicated no potential conflicts of interest.
Conception and design: Annette Kingma, Willem A. Kamps Financial support: Nathalie C.A.J. Jansen Administrative support: Nathalie C.A.J. Jansen, Annette Kingma Provision of study materials or patients: Nathalie C.A.J. Jansen, Annette Kingma, Anjo J.P. Veerman Collection and assembly of data: Nathalie C.A.J. Jansen, Arnout Schuitema Data analysis and interpretation: Nathalie C.A.J. Jansen, Annette Kingma, Arnout Schuitema, Anke Bouma, Willem A. Kamps Manuscript writing: Nathalie C.A.J. Jansen, Annette Kingma, Arnout Schuitema, Anke Bouma, Anjo J.P. Veerman, Willem A. Kamps Final approval of manuscript: Nathalie C.A.J. Jansen, Annette Kingma, Arnout Schuitema, Anke Bouma, Anjo J.P. Veerman, Willem A. Kamps
This study is a collaborative multicenter investigation that is coordinated by the Pediatric Oncology Center, Groningen University Hospital. The following centers participated in the study: the University Medical Center Utrecht, Utrecht; St Radboud University Medical Center, Department of Pediatrics, Nijmegen; Vrije Universiteit University Medical Center, Department of Pediatrics; and University Medical Center, Emma Children's Hospital, Amsterdam; and University Medical Center, Willem-Alexander Children and Youth Center, Leiden, the Netherlands.
We thank the children and their families for their contribution to this study. We thank Wendy Post, PhD, for her statistical advice and G. Sinnema for his cooperation while completing this report.
Supported in part by Grant No. RUG 1998-1737 from the Dutch Cancer Society. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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London, England, Institute of Education, 1998 28. Raymond-Speden E, Tripp G, Lawrence B, et al: Intellectual, neuropsychological, and academic functioning in long-term survivors of leukemia. J Pediatr Psychol 25:59-68, 2000 29. Rodgers J, Marckus R, Kearns P, et al: Attentional ability among survivors of leukaemia treated without cranial irradiation. Arch Dis Child 88:147-150, 2003 30. Spiegler BJ, Kennedy K, Maze R, et al: Comparison of long-term neurocognitive outcomes in young children with acute lymphoblastic leukemia treated with cranial radiation or high-dose or very high-dose intravenous methrotrexate. J Clin Oncol 24:3858-3864, 2006 31. Mennes M, Stiers P, Vandenbussche E, et al: Attention and information processing in survivors of childhood acute lymphoblastic leukemia treated with chemotherapy only. Pediatr Blood Cancer 44:478-486, 2005[Medline] 32. Gidding CE, Kellie SJ, Kamps WA, et al: Vincristine revised. Crit Rev Oncol Hematol 29:267-287, 1999[Medline] 33. 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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
