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Journal of Clinical Oncology, Vol 24, No 24 (August 20), 2006: pp. 3858-3864 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.05.9055 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 Methotrexate
From the Department of Paediatrics, Division of Haematology/Oncology; and the Department of Psychology, The Hospital for Sick Children, The University of Toronto, Toronto, Ontario, Canada Address reprint requests to Brenda J. Spiegler, PhD, The Hospital for Sick Children, 555 University Avenue, Toronto, ON, M5G 1X8, Canada; e-mail: brenda.spiegler{at}sickkids.ca
PURPOSE: Cranial radiation therapy (CRT) is associated with neurocognitive morbidity in survivors of childhood acute lymphoblastic leukemia (ALL). For most patients, CRT has been replaced with intensified systemic and intrathecal chemotherapy, often including methotrexate (MTX). The impact of chemotherapy-only protocols on neurocognitive outcomes is unclear, and the importance of systemic MTX dose has not been established. PATIENTS AND METHODS: Seventy nine of 120 eligible children diagnosed with high-risk ALL between the ages of 1.0 and 4.9 years participated in this retrospective cohort study. All patients were treated on a uniform chemotherapy protocol with one of three modalities of CNS prophylaxis, depending on their treatment era. In addition to intrathecal therapy, CNS-directed therapy consisted of CRT (18 Gy in 10 fractions) in 25 patients, high-dose intravenous (IV) MTX (8 g/m2 x 3 doses) in 32 patients and very high-dose IV MTX (33.6 g/m2 x 3 doses) in 22 patients. Participants completed tests of intelligence, academic achievement, attention, and memory. RESULTS: Neurocognitive assessment was conducted at least 5 years after diagnosis (mean, 10.5 years, standard deviation, 2.7 years). No difference was detected on any neurocognitive measure between children treated with high-dose or very high-dose IV MTX. The combined MTX groups scored near the population mean on 17/18 measures. Children treated with CRT performed more poorly than the MTX group on most measures. CONCLUSION: Treatment strategies for young children with ALL that avoid CRT are associated with good long-term neurocognitive outcomes. In this cohort, the dose of IV MTX did not influence these outcomes.
CNS-directed therapy is an essential component of treatment in childhood acute lymphoblastic leukemia (ALL). Available therapies include craniospinal or cranial radiation (CRT), high-dose intravenous methotrexate (IV MTX), intrathecal methotrexate (IT MTX), triple intrathecal chemotherapy, or a combination of these modalities.1 With current regimens, nearly 80% of children diagnosed with ALL will enjoy a 5-year event-free survival.2-4 However, survival often comes at a cost, because elements of CNS-directed therapy have long-term effects on endocrine5 and neurocognitive function6,7 and increase the risk of second malignancies.8-10 CRT in particular has been shown to have detrimental effects on neurocognitive development, especially in young children in whom general intelligence (intelligence quotient), processing speed, and attention are affected most commonly.11,12 Decrements in intelligence quotient often progress as survival time increases.13 Total radiation dose and female sex appear to be additional risk factors for poor neurocognitive outcomes after CRT.14,15 Efforts to minimize the toxicity of treatment while maintaining long-term survival include reducing the dose and field of CRT, or replacing CRT with intensified intrathecal and/or IV chemotherapy, particularly in the treatment of B-precursor ALL. However, the literature describing neurocognitive outcomes after chemotherapy alone is inconsistent, both with respect to the presence of neurocognitive late effects and the nature and severity of these late effects. Although some investigators have shown similar declines in intelligence and academic achievement scores after treatment with CRT or chemotherapy alone,16,17 most studies suggest that children treated with IV MTX and IT MTX fare better than children treated with CRT and IT MTX.12,18,19 Declines in one or more aspects of cognitive functioning are reported after treatment with chemotherapy alone in approximately two thirds of studies.20 Interpretation of these findings is complicated by differences in the agents, frequency, and dose of CNS-directed chemotherapy and reliance on different outcome measures. In this study, we examine long-term neurocognitive outcomes in a cohort of survivors of high-risk ALL diagnosed between 1.0 and 4.9 years of age who were treated on a common chemotherapy protocol with one of three forms of CNS-directed therapy. This cohort provides a unique opportunity to directly compare neurocognitive outcomes after therapy with and without CRT, and with one of two levels of high-dose IV MTX (HD-MTX), without the confounding effects of differences in the chemotherapy backbone that have limited other studies.
Patients Patients diagnosed with high-risk ALL between the ages of 1.0 and 4.9 years who were treated on the Hospital for Sick Children's (SickKids; Toronto, Canada) high-risk ALL protocol and who were alive in first remission at least 5 years from diagnosis were eligible to participate in this study of neurocognitive outcomes. Patients were considered ineligible if they had CNS disease at diagnosis, Down syndrome, any relapse or second malignancy, or had undergone hematopoietic stem-cell transplantation. Neurocognitive data were collected either specifically for this study or extracted from clinical or prior research files. The study was approved by the institution's research ethics board. Patients (or their parents) who underwent neurocognitive assessment specifically for this study provided written informed consent, but the research ethics board waived consent for the use of historical data.
Treatment Protocol
Although all patients were treated with the same systemic therapy, three different strategies were used for CNS-directed therapy (Table 1). Patients received either CRT (18 Gy in 10 fractions) or three courses of high-dose IV MTX (8 g/m2/dose) or very high-dose IV MTX (VHD-MTX: 33.6 g/m2/dose), each infused over 24 hours at 2-week intervals. Patients who received CRT were administered chemotherapy, including oral 6-mercaptopurine, concurrently. An identical regimen of IT chemotherapy was used in the CRT and MTX groups except for the addition of three doses of IT cytarabine in the MTX groups, which were not administered concurrently with either the IT or IV MTX. Patients treated with VHD-MTX received a higher initial dose of leucovorin (200 mg/m2) than those treated with HD-MTX (100 mg/m2), but the leucovorin rescue protocols were otherwise identical. In both cases, leucovorin was initiated 36 hours after the start of the MTX infusion and continued until the plasma MTX level was less than 0.08 µmol/L. Assignment to a specific CNS-prophylaxis modality was not random, but depended on the treatment era. From 1983 to 1989, children younger than 2 years of age received VHD-MTX and those older than 2 received CRT. Between 1989 and 1991 children younger than 5 years of age received VHD-MTX, and from 1991 to 1996 children younger than 5 years of age received HD-MTX.
Neurocognitive Testing
Statistical Analysis Individual test scores were converted to standard scores (based on age-related means and standard deviations [SDs] from test standardization norms). For the Wechsler Intelligence Scales, Wide Range Achievement Test, Woodcock Reading Mastery Test-Revised, and Children's Memory Scale, standard scores have a mean of 100 and a SD of 15. Either the Children’s Memory Scale or the Wechsler Memory Scale-III was administered to assess memory, depending on the patient's age, and immediate and delayed verbal and visual memory composite scores were derived from the analogous indices from these two tools. Age-adjusted z-scores were calculated for the three subtests of the Gordon Diagnostic System.
Summary data were generated for all patient and test variables. Demographic variables were compared among the three treatment groups using either the All statistical analyses were performed using SAS version 8.2 (Cary, NC). Since all analyses involved multiple statistical comparisons, we conservatively considered only P values of .003 or less as statistically significant.
Between 1983 and 1996, 156 children ages 1.0 to 4.9 years at diagnosis were treated on the high-risk ALL protocol. Of these, 120 satisfied the eligibility criteria for this study, and neurocognitive data were obtained from 79 (66%), either by specific recruitment for this study (n = 32) or by abstraction of test scores from prior research or clinical assessments (n = 47). Reasons for ineligibility or lack of participation are shown in Figure 1. The 79 participants did not differ from the 41 eligible nonparticipants in the distribution of sex, age or WBC count at diagnosis. They did differ in the distribution of method of CNS-directed therapy because the vast majority of those treated with VHD-MTX participated in the study (Table 3). Of the 79 participants, 32 received HD-MTX, 22 received VHD-MTX, and 25 received CRT.
Table 4 displays sex, age at diagnosis and neurocognitive evaluation, and length of follow-up. Forty-seven percent of the cohort was male, with no significant differences in sex distribution between groups. The mean age at diagnosis for the entire group was 2.8 years (SD, 1.1 year) with a mean interval of 10.5 years (SD, 2.7 years) to neurocognitive assessment. The groups differed in age at diagnosis (P < .001). Those treated with CRT were oldest, whereas those treated with VHD-MTX were youngest. The groups also differed with respect to age at neurocognitive testing (P < .001) because patients treated with HD-MTX were younger at testing than those treated with either CRT (P < .001) or VHD-MTX (P < .02). The differences in age at testing were related to a significant difference between groups in length of follow-up. Although all groups were followed for many years after diagnosis, the mean length of follow-up for the HD-MTX group was shorter than for either of the other two groups (P < .001 comparing HD-MTX with VHD-MTX; P = .003 comparing HD-MTX with CRT).
Comparison of Patients Treated With HD-MTX Versus VHD-MTX After adjustment for age at diagnosis and time since diagnosis, the two chemotherapy groups did not differ significantly on any neurocognitive measure. Therefore, they were combined into a larger chemotherapy-only group (n = 54) for comparison with the CRT group.
Comparison of Patients Treated With CRT Versus Chemotherapy Only
Comparison of Patients Treated With CRT or Chemotherapy Only to Population-Normative Data Mean scores for the CRT group were significantly lower than population means for eight of 18 measures, including three of the four Wechsler index scores, visual delayed memory, verbal immediate memory, general memory, arithmetic and reading comprehension. Differences in processing speed (P < .006), visual immediate memory (P < .01), verbal delayed memory (P < 0 .01), and attention/concentration (P < .007) met standard levels of significance (P < .01) but did not meet our requirement of P  .003. The CRT group did not differ from the population mean on measures of visual attention, single-word reading, reading decoding, or spelling. In contrast, the chemotherapy-only group did not differ significantly from the population mean on 17 of 18 measures. The exception to this pattern was the Delay subtest of the Gordon Diagnostic System (Gordon Diagnostic Systems Inc, DeWitt, NY; P = .0007), a measure of impulsivity, reflecting difficulty with self-restraint, or holding back from responding for a short interval.
This study describes long-term neurocognitive outcomes after treatment of ALL in young children with a uniform chemotherapy backbone and one of three forms of CNS-directed therapy. At a mean of 10.5 years after diagnosis, survivors treated with CRT scored nearly one SD lower than either survivors who were treated without CRT or the population means on tests of intelligence, academic achievement, attention, and memory. This degree of difference is both statistically and clinically significant, because children with generalized deficits of this order often require special accommodations to their academic programming. These findings are consistent with most other reports in the literature that demonstrate the deleterious effects of CRT on the developing brain,11,13,18,22,23 particularly in young children. A minority of published reports fail to document deficits in intelligence test scores after CRT24 or demonstrate comparable deficits among those treated with CRT or chemotherapy only.16 Given the complexity of different ALL treatment protocols, it is likely that the doses and combinations of other chemotherapeutic agents may modulate the neurocognitive impact of CRT, but these synergies are poorly understood. The length of follow-up in this study ranges from 5 to 20 years, which is one of the longest follow-up periods reported in the literature. These results represent stable long-term outcomes in a large and representative cohort of children treated for ALL early in life. How patients who experience the late effects of CRT will cope with the neurocognitive challenges of aging, in the context of reduced cognitive reserve capacity, is an important topic for further study.25 The impact of HD-MTX on long-term neurocognitive development is a topic of current debate. In our cohort, the combination of IT chemotherapy and HD-MTX or VHD-MTX did not result in poorer cognitive, academic or neurocognitive outcomes when compared with population norms, despite the young age at which the cohort underwent therapy. Outcomes were comparable to population norms on 17 of 18 measures, including most tests of memory and attention, functions most commonly affected by chemotherapy for ALL.20 Our results are in keeping with those of Kingma et al,26 who reported that children treated with IT and HD-MTX did not demonstrate major cognitive impairment compared with healthy controls at a mean of 7 years after diagnosis. Patients in the current study demonstrated equivalent neurocognitive function after three doses of either of 8 g/m2 or 33.6 g/m2 of IV MTX. Limited data exist regarding the impact of the dose of IV MTX on neurocognitive outcomes. IV MTX dose effects were reported for a group of 36 Dutch children ages 4.5 to 18 years at an average of nearly 5 years from completion of therapy. Survivors varied in their exposure to IT therapy (triple intrathecal chemotherapy or IT MTX) and IV MTX dose (ranging from 2 g/m2/dose to 5 g/m2/dose). Subtle deficits in attention and visual-motor control were found when survivors were compared with a control population, with deficits detected predominantly among those children who received higher doses of IV MTX.27,28 The severity of the attentional impairment was related to higher doses of IV MTX, younger age at diagnosis and female sex. The severity of the visual-motor impairment was related to female sex and a shorter time from treatment, with some suggestion that cumulative dose of IV MTX had a more severe effect in girls than boys. The investigators did not provide information about the leucovorin rescue protocol and indeed, most published studies of HD-MTX therapy have not considered the role of the leucovorin rescue in preventing CNS sequelae. In our study, patients treated with VHD-MTX received a higher initial leucovorin dose than those treated with HD-MTX, although subsequent dosing and the target plasma MTX levels were identical. It is unclear whether the absence of a difference in neurocognitive outcomes between these two chemotherapy-only groups is attributable to this difference in the leucovorin rescue protocol, or if neurocognitive outcomes after HD-MTX are, in fact, independent of MTX dose. The results presented here should be interpreted in the context of several limitations. First, we lacked a matched comparison group and baseline neurocognitive data. Although we are able to compare outcomes between the three treatment groups and with published population norms, we cannot be certain that treatment with chemotherapy alone has no adverse impact on neurocognitive outcome. Some studies have shown that siblings of children diagnosed with ALL score above population means on tests of intelligence.22,29 It is conceivable that our cohort may have had above-average neurocognitive function before diagnosis and that the average results observed in the chemotherapy-only arms might reflect deterioration from a higher baseline level. Similarly, we may have underestimated the deterioration in the CRT group. Second, study patients were not assigned randomly to CNS prophylaxis modality, but rather, treatment was based on the era of diagnosis. We have no reason to suspect that this would have led to systematic differences between groups on most baseline factors and we have adjusted our analyses for identified differences between the groups (eg, age at diagnosis, time since diagnosis). Third, although socioeconomic status (SES) is associated with cognitive status in large groups of children, SES data were not available for our patient group. We have no reason to hypothesize systematic differences between groups, but could not test this directly. Fourth, eligible patients who did not participate in this study did not differ significantly from the participants with regard to the measured demographic and clinical variables, suggesting that our sample is representative of the population of young children treated for high-risk ALL. However, we cannot exclude the possibility that nonparticipants differed from the tested sample. If, for example, the 18 subjects who declined participation did so because they were not experiencing difficulty, then current results might overestimate cognitive morbidity in the tested group. Conversely, if those who declined participation did so because they were having significant difficulties and did not want to be reminded of them, the opposite effect would hold. Finally, this study focused on children younger than 5 years, a group considered to be particularly vulnerable to the impact of CRT. The pattern of neurocognitive outcomes observed here may not be evident in children treated at older ages. In conclusion, we used a broad battery of neurocognitive tests to study a large cohort of young children treated with a homogenous chemotherapy backbone and one of three forms of CNS-directed therapy. Our results confirm the deleterious effect of 18 Gy CRT on the developing brains of young children. In contrast, treatment with high-dose IV MTX combined with intrathecal chemotherapy appears to be relatively benign in its effect on intellectual, academic and neurocognitive outcomes. Our data suggest that the impact of IV MTX on neurocognitive outcomes is not related to dose although the effect of MTX may be mitigated by the leucovorin rescue regimen employed. Future studies should report not only type and dose of agents employed, but also details about the leucovorin rescue protocol.
The authors indicated no potential conflicts of interest.
We are grateful for funding from the Hospital for Sick Children Leukemia/Lymphoma Group. Dr Mark Greenberg holds the Pediatric Oncology Group of Ontario Chair in Childhood Cancer Control at The University of Toronto.
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Howard SC, Pui CH: Endocrine complications in pediatric patients with acute lymphoblastic leukemia. Blood Rev 16: 225-243, 2002[CrossRef][Medline] 6. Mulhern RK, Palmer SL: Neurocognitive late effects in pediatric cancer. Curr Probl Cancer 27: 177-197, 2003[CrossRef][Medline] 7. Moore BD 3rd: Neurocognitive outcomes in survivors of childhood cancer. J Pediatr Psychol 30: 51-63, 2005 8. Pui CH, Cheng C, Leung W, et al: Extended follow-up of long-term survivors of childhood acute lymphoblastic leukemia. N Engl J Med 349: 640-649, 2003 9. Bhatia S, Sather HN, Pabustan OB, et al: Low incidence of second neoplasms among children diagnosed with acute lymphoblastic leukemia after 1983. Blood 99: 4257-4264, 2002 10. Neglia JP, Meadows AT, Robison LL, et al: Second neoplasms after acute lymphoblastic leukemia in childhood. N Engl J Med 325: 1330-1336, 1991[Abstract] 11. Langer T, Martus P, Ottensmeier H, et al: CNS late-effects after ALL therapy in childhood. Part III: Neuropsychological performance in long-term survivors of childhood ALL: Impairments of concentration, attention, and memory. Med Pediatr Oncol 38: 320-328, 2002[CrossRef][Medline] 12. Rowland J, Glidewell OJ, Sibley RH, Tull, Berman, et al: Effects of different forms of central nervous system prophylaxis on neuropsychologic function in childhood leukemia. J Clin Oncol 2: 1327-1335, 1984[Medline] 13. Jankovic M, Brouwers P, Valsecchi MG, et al: Association of 1800 cGy cranial irradiation with intellectual function in children with acute lymphoblastic leukaemia. Lancet 344: 224-227, 1994[CrossRef][Medline] 14. Robison LL, Nesbit ME, Sather HN, et al: Factors associated with IQ scores in long-term survivors of childhood acute lymphoblastic leukemia. Am J Ped Hemat Onc 6: 115-121, 1984 15. Waber DP, Urion DK, Tarbell NJ, et al: Late effects of central nervous system treatment of acute lymphoblastic leukemia in childhood are sex-dependent. Dev Med Child Neurol 32: 238-248, 1990[Medline] 16. Ochs J, Mulhern R, Fairclough D, et al: Comparison of neuropsychologic functioning and clinical indicators of neurotoxicity in long-term survivors of childhood leukemia given cranial radiation or parenteral methotrexate: A prospective study. J Clin Oncol 9: 145-151, 1991 17. Mulhern RK, Wasserman AL, DF, et al: Memory function in disease-free survivors of childhood acute lymphocytic leukemia given CNS prophylaxis with or without 1,800 cGy cranial irradiation. J Clin Oncol 6: 315-320, 1988[Abstract] 18. Van Dongen-Melman JEWM, De Groot A, Van Dongen JJM, et al: Cranial irradiation is the major cause of learning problems in children treated for leukemia and lymphoma: A comparative study. Leukemia 11: 1197-1200, 1997[CrossRef][Medline] 19. Butler RW, Hill JM, Steinherz PG, et al: Neuropsychologic effects of cranial irradiation, intrathecal methotrexate, and systemic methotrexate in childhood cancer. J Clin Oncol 12: 2621-2629, 1994 20. Moleski M: Neuropsychological, neuroanatomical, and neurophysiological consequences of CNS chemotherapy for Acute Lymphoblastic Leukemia. Archives of Clinical Neuropsychology 15: 603-630, 2000[CrossRef][Medline] 21. Steinherz PG, Gaynon PS, Breneman JC, et al: Treatment of patients with acute lymphoblastic leukemia with bulky extramedullary disease and T-cell phenotype or other poor prognostic features: Randomized controlled trial from the Children's Cancer Group. Cancer 82: 600-612, 1998[CrossRef][Medline] 22. Giralt J, Ortega JJ, Olive T, et al: Long-term neuropsychologic sequelae of childhood leukemia: Comparison of two CNS prophylactic regimes. Int J Radiation Oncology 24: 49-53, 1992 23. Anderson VA, Godber T, Smibert E, et al: Cognitive and academic outcome following cranial irradiation and chemotherapy in children: A longitudinal study. Br J Cancer 82: 255-262, 2000[CrossRef][Medline] 24. Waber DP, Shapiro BL, Carpentieri SC, et al: Excellent therapeutic efficacy and minimal late neurotoxicity in children treated with 18 grays of cranial radiation therapy for high risk acute lymphoblastic leukemia: A 7-year follow-up of the Dana-Farber Cancer Institute Consortium Protocol 87-01. Cancer 92: 15-22, 2001[CrossRef][Medline] 25. Dennis M, Spiegler BJ, Hetherington R: New survivors for the new millennium: Cognitive risk and reserve in adults with childhood brain insults. Brain Cogn 42: 102-105, 2000[CrossRef][Medline] 26. Kingma A, Van Dommelen RI, Mooyaart EL, et al: No major cognitive impairment in young children with acute lymphoblastic leukemia using chemotherapy only: A prospective longitudinal study. J Pediatr Hematol Oncol 24: 106-114, 2002[CrossRef][Medline] 27. Buizer AI, de Sonneville LM, van den Heuvel-Eibrink MM, et al: Chemotherapy and attentional dysfunction in survivors of childhood acute lymphoblastic leukemia: Effect of treatment intensity. Pediatr Blood Cancer 45: 281-290, 2005[CrossRef][Medline] 28. Buizer AI, De Sonneville LMJ, Van Den Heuvel-Eibrink MM, et al: Visuomotor control in survivors of childhood acute lymphoblastic leukemia treated with chemotherapy only. JINS 11: 554-565, 2005[Medline] 29. Moss HA, Nannis ED, Poplack DG: The effects of prophylactic treatment of the central nervous system on the intellectual functioning of children with acute lymphocytic leukemia. Am J Med 71: 47-52, 1981[CrossRef][Medline] 30. Wechsler D: Manual for the Wechsler Intelligence Scale for Children (ed 3). San Antonio, TX, The Psychological Corporation, 1991 31. Wechsler D: The Wechsler Adult Intelligence Scale-III: Administration and Scoring Manual. San Antonio, TX, The Psychological Corporation, 1997 32. Wilkinson GS: The Wide Range Achievement Test. Wilmington, DE, Wide Range, Inc., 1993 33. Woodcock RW: Woodcock Reading Mastery Tests-Revised Examiner's Manual, American Guidance Service, 1998 34. Gordon M: The Gordon Diagnostic System. DeWitt, NY, Gordon System, 1991 35. Cohen M: Children's Memory Scale. San Antonio, TX, The Psychological Corporation, 1997 36. Wechsler D: Wechsler Memory Scale-III. San Antonio, TX, The Psychological Corporation, 1997 Submitted February 7, 2006; accepted June 16, 2006. Related Correspondence
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 test or analysis of variance depending on whether the variables were categoric or continuous. Subsequently, the following statistical analyses were performed: (1) long-term neurocognitive outcomes were compared between patients treated with HD-MTX and VHD-MTX using multivariate linear regression, with the analyses adjusted for age at diagnosis and time since diagnosis, which differed significantly between the two groups. (2) Neurocognitive outcomes were compared between patients treated with CRT and those treated with IV MTX (combined HD-MTX and VHD-MTX groups) using multivariate linear regression with the analyses adjusted for age at diagnosis, which differed significantly between the two groups. There was no significant interaction between sex and treatment modality for any outcome and therefore a sex by treatment interaction term was not included in our analysis. (3) Test results in each treatment group (CRT, IV MTX) were compared with population norms using a 1-sample t test. 
