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Journal of Clinical Oncology, Vol 25, No 31 (November 1), 2007: pp. 4914-4921 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.10.8464 Neuropsychological Outcomes From a Randomized Trial of Triple Intrathecal Chemotherapy Compared With 18 Gy Cranial Radiation As CNS Treatment in Acute Lymphoblastic Leukemia: Findings From Dana-Farber Cancer Institute ALL Consortium Protocol 95-01
From the Division of Psychology, Department of Psychiatry, Children's Hospital; Departments of Psychiatry and Pediatrics, Harvard Medical School; Divisions of Hematology and Oncology, Department of Medicine, Children's Hospital and Departments of Pediatric Oncology, Biostatistics, and Computational Biology, Dana-Farber Cancer Institute, Boston, MA; Department of Pediatrics, Golisano Children's Hospital at Strong, University of Rochester Medical Center, Rochester, NY; Division of Pediatric Hematology/Oncology, McMaster University, Hamilton, Ontario; Departments of Pediatric Hematology/Oncology, Division of Hematology/Oncology, Hôpital Sainte Justine, Montreal; Division of Psychology, Department of Pediatric Hematology/Oncology, Centre Mère-Enfant, Quebec, Canada; and the Interamerican University, San Germán, Puerto Rico Address reprint requests to Deborah P. Waber, PhD, Department of Psychiatry, Children's Hospital, 300 Longwood Ave, Boston, MA 02115; e-mail: deborah.waber{at}childrens.harvard.edu
Purpose: We evaluated late neuropsychological toxicity in children treated for standard-risk acute lymphoblastic leukemia (ALL) who were randomly assigned to receive either cranial radiation therapy (CRT) with double intrathecal (IT) chemotherapy or intensive triple IT chemotherapy (no CRT) as CNS-directed therapy. Patients and Methods: Between 1996 and 2000, 164 children with standard-risk ALL treated on Dana-Farber Cancer Institute Consortium Protocol 95-01 were randomly assigned to receive either 18 Gy CRT delivered in twice daily fractions (0.9 Gy) with double IT therapy (methotrexate and cytarabine) or intensive triple IT drug (methotrexate, cytarabine and hydrocortisone) without CRT. Neuropsychological testing was completed at a median 6 years postdiagnosis for 79 children (CRT, n = 39; triple IT, n = 40), all of whom were in continuous complete remission. Results: Cognitive function for both groups was solidly in the average range, with no consistent group differences in basic cognitive skills. Children treated on the CRT plus double IT arm did, however, exhibit less fluent output and were less effective at modulating their behavior by parent report. Conclusion: This randomized trial revealed only subtle differences 6 years after diagnosis between children who received CNS therapy as CRT plus double IT drug or as intensive triple IT drug. In most situations where comparable therapeutic efficacy can be achieved without CRT, it is preferable to do so. Where therapeutically necessary, however, CRT at lower doses may not add risk for significant neurotoxicity.
A number of studies have compared neuropsychological outcomes among children treated for acute lymphoblastic leukemia (ALL) with or without cranial radiation therapy (CRT).1-8 Collectively, they indicate that children treated with CRT experience poorer neurocognitive outcomes, although not consistently so.9-11 Few of these studies, however, employ a randomized controlled trial design, and fewer still are relevant to modern era therapy. Because contemporary protocols typically use lower doses of CRT and more intensive forms of chemotherapy, the relevance of many of these trials to current practices is problematic. In one large study, Hill et al5 compared young adults treated as children who had been randomly assigned to either intravenous (IV) and intrathecal (IT) methotrexate (MTX; IV-MTX plus IT-MTX) or to CRT (24 Gy) plus IT-MTX. Those patients treated with CRT exhibited a higher prevalence of psychiatric and academic problems as adults. Patients treated on the two arms of the randomization did not differ in terms of event-free survival (EFS) at 12 years (37% ± 3.6%), although EFS was poor by modern standards.12 Rowland et al6 similarly demonstrated poorer neuropsychological outcomes in children randomly assigned to 24 Gy CRT or chemotherapy only. MacLean et al4 compared neurocognitive function in preschool children randomly assigned to IT-MTX alone or 18 Gy CRT plus IT-MTX. Nine months after diagnosis, the children treated with CRT generally performed more poorly. Older children treated on the same protocol, however, exhibited no differences in neurocognitive outcome.7Although overall EFS did not differ between the groups,13 older children showed greater medical benefit if therapy included CRT. There is no published report of longer-term neurocognitive follow-up for these children. To estimate potential for CRT-related neuropsychological sequelae in the context of contemporary therapy, involving more intensive chemotherapy and lower dose CRT, Dana-Farber Cancer Institute (DFCI) ALL Consortium Protocol 95-01 included a randomized comparison of 18 Gy CRT (with double IT chemotherapy) versus intensive triple IT chemotherapy (no CRT) as CNS-directed treatment for standard-risk patients. At a median of 5 years follow-up, the EFS of randomly assigned patients was not significantly different (87% ± 4% for CRT group v 84 ± 4% for chemotherapy-only group; P = .26).14 Children randomly assigned to the chemotherapy-only group experienced more CNS relapses, but only if randomized to Erwinia rather than E Coli asparaginase. This study evaluated late neuropsychological toxicity among the children who participated in the CNS therapy random assignment.
Treatment Protocols Patients were treated on DFCI ALL Protocol 95-01,14 detailed in Table 1. Patients were considered standard risk if they met all the following criteria: WBC lower than 50,000/mL; age between  1.00 and 9.99 years; absence of lymphoblasts in a cytocentrifuged CSF specimen regardless of CSF WBC count (ie, not CNS 2 or CNS 3); absence of anterior mediastinal mass; B-lineage immunophenotype (excluding mature B-cell ALL); and absence of Philadelphia chromosome (t(9,22)(q34;q11)).
Therapy for standard-risk patients on protocol 95-01 is summarized in Table 1.14 Systemic chemotherapy was identical for all standard-risk patients regardless of CNS random assignment. For CNS-directed therapy, standard-risk patients were randomly assigned to either intensive triple IT chemotherapy (methotrexate, cytarabine, and hydrocortisone) without CRT or 18 Gy CRT delivered in twice daily fractions (0.9 Gy twice daily) with double IT therapy (methotrexate and cytarabine), both dosed according to age. Dosing was the same in both treatment arms. Patients randomly assigned to intensive triple IT chemotherapy (no CRT) received four doses over 2 weeks during the CNS phase (commencing 4 weeks after diagnosis), then every 9 weeks for a total of six doses, then every 18 weeks until the completion of all treatment (total of 15 doses of IT therapy). Patients randomly assigned to CRT received four doses of IT chemotherapy over 2 weeks concurrent with CRT (commencing 4 weeks after diagnosis), then every 18 weeks until completion of all chemotherapy (total of 12 doses of IT therapy). Standard-risk girls between 2 and 9 years of age or with presenting leukocyte counts lower than 20,000/mm3 were directly assigned to intensive triple IT chemotherapy (no CRT) because such patients had been treated successfully without CRT on a prior DFCI ALL Consortium protocol.15 The neuropsychological follow-up study included only those patients who participated in the CNS random assignment.
Patient Population Two hundred seventy-two patients (55%) treated on DFCI ALL protocol 95-01 were classified as standard risk, of whom 164 participated in the random assignment. The CONSORT diagram is displayed as Figure 1. Children were recruited for the neuropsychological testing at a target of 5 years postdiagnosis (median, 6.1 years; range, 3.7 to 9.1 years). The final sample included 79 children, 40 randomly assigned to intensive triple IT therapy without radiation and 39 to 18 Gy CRT. Children randomly assigned to the two arms did not differ with respect to age, sex distribution, parent education, or primary language (Table 2). The number of children enrolled in special education at the time of testing was also comparable. Comparison of eligible patients who were tested with those who were not tested revealed no difference in sex (P > .99) or CNS therapy randomization (P > .99).
The neuropsychological follow-up study was performed after approval by local institutional human investigations committees and in accordance with an assurance filed with and approved by the Department of Health and Human Services. Informed consent was obtained from each participant or each participant's guardian, and assent was obtained from minors.
Neuropsychological Testing Table 3 lists the neuropsychological battery. It included five representative subtests of the age-appropriate Wechsler IQ test (WISC-III or WAIS-III).16,17 Two of these, vocabulary and block design, permit estimation of full-scale IQ; correlation of this dyad with full-scale IQ is 0.9.
Adaptations were made for the children from Puerto Rico and Quebec, whose primary language was Spanish and French, respectively. The most recent edition of the Wechsler Scale in their language was used, and the Wide Range Test of Memory and Learning verbal learning subtest was translated into Spanish or French. The Rapid Automatized Naming (RAN) and Rapid Alternating Sequencing (RAS) are available only in English, however. The WJIII passage comprehension was administered in the Spanish version or translated to French, and calculation was not language dependent. All other Woodcock-Johnson psychoeducational battery III measures were administered to English-speakers only. The Behavioral Assessment System for Children (BASC) questionnaire was available in all three languages, but the Behavioral Rating Inventory of Executive Function (BRIEF) was available in English only.
Statistical Methods
Table 4 displays the scores for the neuropsychological measures. There were few group differences. Children on the CRT arm performed somewhat more poorly on the Wechsler Vocabulary subtest, but better on the Wide Range Test of Memory and Learning visual memory subtest, although the statistical significance levels were marginal. More striking was the consistent difference favoring the IT therapy group on rapid naming (RAN and RAS). This difference reached statistical significance even though only 30 children completed it and there was reduced power to detect a difference. There were no statistically significant differences in performance on the achievement tests.
Figure 2 displays box plots for two tests of particular interest, estimated IQ and rapid naming. The IQ scores are comparable in terms of their medians and distributions, but there are prominent group differences for the rapid naming tests.
For the Rey-Osterrieth Complex Figure, standardized scores are provided as percentile categories. A score below the 10th percentile was deemed to indicate impaired performance for each outcome (organization, accuracy for structural and incidental elements, and errors) for the copy and recall performances. There were no reliable group differences for any of these scores (Appendix Table A1, online only). For all of the outcomes, however, more than 10% of the children scored at or below the 10th percentile, and for eight of 16 outcomes (four for each group), percentages exceeded 30%. Table 5 displays findings for the behavioral questionnaires. On the BASC, there were no group differences in either the internalizing or externalizing scale, but children treated with CRT were rated more poorly on the adaptive skills composite, most prominently on the component adaptability scale, which measures flexibility and adaptability to change. Although group differences on the BRIEF did not reach statistical significance, parents of children treated with CRT consistently endorsed more problems. Because fewer parents completed the BRIEF than the BASC, there may have been insufficient power to detect a difference, although some of the effect sizes were clinically meaningful.
This randomized trial compared outcomes for children diagnosed with standard-risk ALL whose CNS treatment included either triple IT drug (no CRT) or 18 Gy CRT (with less frequent double IT chemotherapy). Differences between the groups in basic cognitive skills and academic achievement were relatively minimal. Moreover, the prevalence of children receiving special education, a good indicator of potential clinical impact, was virtually identical for children on the two arms of the protocol. This study was powered to detect differences of approximately two thirds of a standard deviation, a medium effect size that would be of clinical significance and comparable in magnitude to effect sizes reported in nonrandomized studies comparing children treated for ALL with or without CRT.1,2,8 The magnitude of the differences demonstrated here, however, was generally smaller and often negligible. Children whose therapy included CRT did, however, exhibit behaviors implicating diminished fluency in their information processing. Rapid naming of simple stimuli was consistently slower in the CRT group. This finding is all the more striking because of our reduced power to detect differences for these variables. Since slow naming speed is more common among children with diverse learning problems,19 this finding could indicate risk in the CRT group that was not revealed by our other testing. Longer follow-up might also have revealed clearer differences. Children on the CRT arm were also rated lower on the BASC adaptive skills index; this index is comprised of adaptability, social skills and leadership. Adaptability, which measures flexibility in everyday life (eg, adjustment to new teachers or change in routine), was most prominently affected. Thus, children treated with CRT on this protocol exhibited more behavioral rigidity in their daily activities and slowed processing, although their cognitive skills were generally well preserved. Although there were no consistent group differences in cognitive skills, both groups exhibited similar patterns of strengths and weaknesses. The proportion of children exhibiting poor scores on the Rey-Osterrieth Complex Figure Test appeared to be elevated, consistent with our findings from prior cohorts,20,21 suggesting greater difficulty managing more complex and abstract material. Both groups also achieved low scores relative to their other IQ scores on digit span, a measure of verbal working memory, also consistent with our findings from prior DFCI cohorts,21-23 as well as mathematics fluency, the ability to rapidly access math facts. Thus, cognitive profiles that might predispose to academic or other functional difficulties were apparent across groups, even though the groups did not differ from each other. The performance of the children on the CRT arm is of particular interest because cognitive test scores were estimated to be solidly in the average range, with median IQ approximating the population mean of 100, at variance with reports from some other groups. In a cohort comparison study, Spiegler et al,8 for example, recently reported a mean IQ of 99 in children treated with chemotherapy only, but only 89 in children treated with CRT. One potential source of the difference could be that our IQ scores were estimates based on two subtests, whereas Spiegler et al8 administered the entire test, including measures of working memory and processing speed. However, we administered the digit span, which measures working memory, and found no group difference. Moreover, our study revealed scores consistently in the average range on subtests that are primary components of the IQ indices reported by Spiegler et al8 (eg, vocabulary subtest and the verbal comprehension index). Another potential source of the difference is the sex and age distributions of the children. We and others have found that females can be more vulnerable to the effects of leukemia therapies.22,24-26 Males were over-represented, however, in our study because of the structure of the radiation randomization on DFCI protocol 95-01. Also, early age at diagnosis and treatment can increase risk for late effects.27,28 Although the median age of diagnosis in our sample was 3 years and the majority of patients were diagnosed before age 5, our sample also included children diagnosed at older ages. Because the randomization was not stratified with respect to sex or age, the potential impact of these characteristics could not be evaluated in the context of our study. Our studies of late neurocognitive effects on cohorts treated on two prior DFCI protocols,20,23 however, also documented a mean IQ of approximately 100 among children whose treatment included CRT. These samples included equal numbers of males and females and a representative distribution of age at diagnosis. The mean IQ for children 3 years or younger at diagnosis was 98, comparable to 101 for the rest of the children.20 Differences in systemic chemotherapy between various regimens could also influence outcomes. Agents administered in conjunction with CRT can have synergistic or protective effects.22,29,30 Categoric conclusions about the toxicity of any particular treatment, such as CRT, should not be reached absent consideration of potential interactions among other agents, doses, and even timing31,32 of specific agents. Indeed, some chemotherapy-only protocols have yielded much poorer neurocognitive outcomes than those reported herein, with nearly half of children achieving IQ scores more than 1 standard deviation below the mean.33 The profile of slowed information processing and diminished adaptability is consistent with prior observations of children treated with CRT, especially children with brain tumors, in whom slowed processing is a cardinal symptom. The most likely biologic substrate for neurotoxicity, especially slow processing and attention problems, is cerebral white matter.34 Decreased white matter volume has been associated with poorer cognitive function, especially attention, in children treated for leukemia. Although loss of white matter volume is greater in children treated with 18 Gy CRT than chemotherapy alone, white matter volumes are decreased relative to sibling controls even for children treated with chemotherapy only.35 Moreover, fractional anisotropy, a measure of the organization of cerebral white matter, can predict IQ in survivors of both brain tumors and ALL, independent of CRT dose.34 Other factors, such as disease severity11 or developmental variation unrelated to the disease or its therapy, can also affect brain structure and function, potentially accounting for some of these relationships. Furthermore, certain genetic polymorphisms may confer risk for neurotoxicity,36 introducing yet another source of variability into the associations between therapy modality and neuropsychological outcomes. In summary, this randomized trial comparing children treated with triple IT chemotherapy (no CRT) or 18 Gy CRT revealed only modest group differences. Children treated with CRT exhibited slowed rate of information processing and less flexibility in their everyday life. Yet no reliable differences could be detected in cognition or academic achievement, and, as a measure of real world function, no difference in the prevalence of children receiving special education services. Both groups, moreover, showed similar cognitive profiles of strength and weakness in a number of domains, suggesting a potential effect of the disease and its treatment that is independent of whether or not CRT is a component of therapy. In most situations where comparable efficacy can be achieved without CRT, it is preferable to avoid risk for neurotoxic adverse effects. Treatment with CRT also increases the risk of second malignancy in long-term survivors of childhood ALL.37 Based on these concerns, we are utilizing triple IT chemotherapy (without CRT) as CNS treatment for all standard-risk and most high-risk patients on our current clinical trials. Patients at the highest risk of relapse, including those with T-cell phenotype, CNS-3 status at diagnosis and high levels of minimal residual disease at the end of remission induction (approximately 20% of patients), receive CRT, but at a lower dose (12 Gy). Our study demonstrates that, when therapeutically necessary, 18 Gy CRT does not appear to add risk for significant neurocognitive or neurobehavioral toxicity. This conclusion is tempered, however, by the fact that our study did not have sufficient power to detect modest differences and the 5-year follow-up interval may have been insufficient for the full picture to emerge. The considerable similarities between the groups in patterns of deficit, moreover, indicate that the potential for neurotoxicity associated with certain drug doses and combinations, even without CRT, should also continue to be carefully monitored.33
The author(s) indicated no potential conflicts of interest.
Conception and design: Deborah P. Waber, Philippe Robaey, Ivonne Romero, Stephen E. Sallan, Lewis B. Silverman Financial support: Stephen E. Sallan Provision of study materials or patients: Stephen E. Sallan, Lewis B. Silverman Collection and assembly of data: Deborah P. Waber, Jennifer Turek, Lori Catania, Philippe Robaey, Ivonne Romero, Heather Adams, Cheryl Alyman, Christine Jandet-Brunet Data analysis and interpretation: Deborah P. Waber, Jennifer Turek, Kristen Stevenson, Donna S. Neuberg Manuscript writing: Deborah P. Waber, Jennifer Turek, Kristen Stevenson, Lewis B. Silverman, Phillippe Robaey Final approval of manuscript: Deborah P. Waber, Jennifer Turek, Kristen Stevenson, Philippe Robaey, Ivonne Romero, Heather Adams, Cheryl Alyman, Christine Jandet-Brunet, Donna S. Neuberg, Stephen E. Sallan, Lewis B. Silverman
Supported by Grant No. 2 P01 CA 68484 from the National Cancer Institute, the Michael J. Garil Fund for Leukemia Research, and by Mental Retardation Center Grant No. P30-HD18655. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
10% for Age on the Rey-Osterrieth Complex Figure Test for Children
