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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
Abstract
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.
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 × 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.
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.
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 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.
Children diagnosed with high-risk ALL at SickKids from 1983 to 1996 were treated uniformly with a chemotherapy regimen adapted from the approach of the Berlin-Frankfurt-Münster (BFM) study group4 (Table 1). Children were classified as high-risk if they had one or more of the following risk factors at presentation: 1 to 2 or more than 10 years old at diagnosis, WBC count greater than 50,000/mm3 (50 × 109/L), L2 morphology of blast cells, lymphoma syndrome, or evidence of either CNS or testicular disease.21
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.
The neurocognitive battery was designed to elicit information about the domains most sensitive to the late effects of treatment for childhood ALL: intelligence, academic achievement, attention, and memory. Patients underwent neurocognitive examination in one half-day session for the purpose of this study or, if available, data were abstracted from previous clinical or research files. The neurocognitive battery, including the number of patients who completed each test, is shown in Table 2.
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 χ2 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.
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).
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.
All comparisons were adjusted for age at diagnosis. Mean scores (and SDs) for each group on each measure are displayed in Table 5. The chemotherapy-only group performed better than the CRT group on 17 of 18 measures. Eight of these comparisons were significant at the P ≤ .003 level. Children treated with chemotherapy only performed significantly better than those treated with CRT on the four indexes of the Wechsler Intelligence Scales, tests of delayed visual memory, general memory, attention/concentration, and reading comprehension. Although not meeting the P ≤ .003 criterion, a trend toward better outcome was observed for the chemotherapy-only group on tests of immediate visual and verbal recall, single-word reading, decoding of nonwords, spelling and arithmetic (.05 > P > .003). The groups did not differ on the test of visual attention.
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.
Conception and design: Brenda J. Spiegler, Mark L. Greenberg, Sheila Weitzman, Paul C. Nathan
Administrative support: Brenda J. Spiegler, Kimberly Kennedy
Provision of study materials or patients: Brenda J. Spiegler, Mark L. Greenberg, Sheila Weitzman
Collection and assembly of data: Brenda J. Spiegler, Kimberly Kennedy, Ronnen Maze, Paul C. Nathan
Data analysis and interpretation: Brenda J. Spiegler, Mark L. Greenberg, Sheila Weitzman, Paul C. Nathan
Manuscript writing: Brenda J. Spiegler, Johann K. Hitzler, Paul C. Nathan
Final approval of manuscript: Brenda J. Spiegler, Kimberly Kennedy, Ronnen Maze, Mark L. Greenberg, Sheila Weitzman, Johann K. Hitzler, Paul C. Nathan
Fig 1. Flow chart of patients treated for high-risk acute lymphoblastic leukemia (ALL) at a single institution who were eligible and ineligible for this neurocognitive outcomes study. Explanations for ineligibility and nonenrollment are provided.
|
| Phase | Drug | Dose |
|---|---|---|
| Induction (4 weeks) | Vincristine | 1.5 mg/m2/d IV days 0, 7, 14, 21 |
| Daunomycin | 25 mg/m2 IV days 0, 7, 14, 21 | |
| l-asparaginase | 6,000 U/m2 IM every Monday/Wednesday/Friday × 9 doses | |
| Prednisone | 60 mg/m2 PO days 1-27 | |
| Cytarabine | 30 mg if < 2 years old; 50 mg if 2-3 years old; 70 mg if > 3 years old IT day 0 | |
| MTX | 8 mg if < 2 years old; 10 mg if 2-3 years old; 12 mg if > 3 years old IT days 14, 28 | |
| CNS Intensification (5 weeks) | Cyclophosphamide | 1,000 mg/m2 IV days 0, 14 |
| Cytarabine | 75 mg/m2 IV days 1-4, 8-11, 15-18, 22-25 | |
| 6-mercaptopurine | 60 mg/m2 PO days 0-27 | |
| MTX | 8 mg if < 2 years old; 10 mg if 2-3 years old; 12 mg if > 3 years old IT days 1, 8, 15, 22 | |
| Radiotherapy* | 18 Gy cranial radiation day 0 (administered during CNS intensification) | |
| High-dose or very-high dose MTX† (6 weeks) | MTX† | HD-MTX: 8,000 mg/m2 IV days 0, 14, 28 (with leucovorin 100 mg/m2 IV over 1 hour starting 36 hours after MTX followed by 12 mg/m2 IV every 3 hours × 6 and then every 6 hours IV/PO until plasma MTX level < 0.08 μmol/L) |
| OR | ||
| VHD-MTX: 33,600 mg/m2 IV days 0, 14, 28 (with leucovorin 200 mg/m2 IV over 1 hour starting 36 hours after MTX followed by 12 mg/m2 IV every 3 hours × 6 and then every 6 hours IV/PO until plasma MTX level < 0.08 μmol/L) | ||
| Vincristine† | 1.5 mg/m2/d IV days 0, 14, 28 | |
| 6-mercaptopurine† | HD-MTX group: 60 mg/m2 PO days 0-35 (reduce dose to 25 mg/m2 when serum MTX level > 0.08 μmol/L) | |
| OR | ||
| VHD-MTX group: 25 mg/m2 PO days 0-35 | ||
| Cytarabine† | 30 mg if < 2 years old; 50 mg if 2-3 years old; 70 mg if > 3 years old IT days 4, 18, 32 (HD-MTX) or days 7, 14, 21 (VHD-MTX) | |
| Interim maintenance (8 weeks) | MTX | 75 mg/m2 IV days 0, 4, 28, 42 |
| 6-mercaptopurine | 60 mg/m2 PO days 0-41 | |
| Reinduction and reintensification (7 weeks) | Vincristine | 1.5 mg/m2/d IV days 0, 7, 14, 21 |
| Adriamycin | 25 mg/m2 IV days 0, 7, 14, 21 | |
| l-asparaginase | 10,000 U/m2 IM days 1, 4, 7, 10 | |
| Dexamethasone | 10 mg/m2 PO days 0-27 | |
| Cyclophosphamide | 1000 mg/m2 IV day 35 | |
| 6-thioguanine | 60 mg/m2 PO days 36-49 | |
| Cytarabine | 75 mg/m2 IV days 36-39, 43-46 | |
| MTX | 8 mg if < 2 years old; 10 mg if 2-3 years old; 12 mg if > 3 years old IT days 39, 46 | |
| Maintenance (12 weeks)‡ | Vincristine | 1.5 mg/m2 IV days 0, 28, 56 |
| Prednisone | 40 mg/m2 PO days 0-4, 28-32, 56-60 | |
| 6-mercaptopurine | 75 mg/m2 PO days 0-83 | |
| MTX | 75 mg/m2 IV days 14, 28, 42, 56, 70 | |
| MTX | 8 mg if < 2 years old; 10 mg if 2-3 years old; 12 mg if > 3 years old IT day 0 |
Abbreviations: IV, intravenously; PO, orally; IM, intramuscularly; IT, intrathecally; MTX, methotrexate; HD, high dose; VHD, very high dose.
*Cranial radiation group only.
†High-dose or very-high dose methotrexate groups only.
‡Maintenance cycles repeated for total of 3 years of therapy.
|
| Test | Age Range | Functions Assessed | No. of Patients Completing Assessment |
|---|---|---|---|
| Wechsler Intelligence Scale for Children-III30 | 6 years-16 years, 11 months | Verbal comprehension | 72 |
| Perceptual reasoning | 72 | ||
| Freedom from distractibility | 72 | ||
| Processing speed | 72 | ||
| Wechsler Adult Intelligence Scale-III31 | 16 years and older | Verbal comprehension | 6 |
| Perceptual organization | 6 | ||
| Working memory | 6 | ||
| Processing speed | 6 | ||
| Wide Range Achievement Test, 3rd Edition32 | 5 years-adult | Word reading | 77 |
| Spelling | 77 | ||
| Written arithmetic | 77 | ||
| Woodcock Reading Mastery Test–Revised33 | 5 years-adult | Reading decoding | 72 |
| Reading comprehension | 75 | ||
| Gordon Diagnostic System34 | 4 years-16 years, 11 months | Response modulation | 66 |
| Sustained attention | 69 | ||
| Distractibility | 69 | ||
| Children's Memory Scale35 | 5 years-16 years, 11 months | General memory index | 64 |
| Immediate verbal memory | 64 | ||
| Delayed verbal memory | 64 | ||
| Immediate visual memory | 64 | ||
| Delayed visual memory | 64 | ||
| Attention/concentration | 64 | ||
| Wechsler Memory Scale-III36 | 16 years and older | Auditory immediate memory | 7 |
| Auditory delayed memory | 7 | ||
| Visual immediate memory | 7 | ||
| Visual delayed memory | 7 | ||
| Working memory | 7 |
|
| Tested | Not Tested | P | |||||
|---|---|---|---|---|---|---|---|
| No. | % | No. | % | ||||
| Total | 79 | 41 | |||||
| Sex | |||||||
| Male | 37 | 47 | 19 | 46 | .96 | ||
| Female | 42 | 53 | 22 | 54 | |||
| Age at diagnosis, years | |||||||
| Mean | 2.83 | 3.05 | .30 | ||||
| SD | 1.07 | 1.19 | |||||
| WBC count, ×109/L | |||||||
| Mean | 47.7 | 61.3 | .34 | ||||
| SD | 72.9 | 75.6 | |||||
| Treatment group | |||||||
| 8 g | 32 | 63 | 19 | 37 | .01 | ||
| 33.6 g | 22 | 92 | 2 | 8 | |||
| CRT | 25 | 56 | 20 | 44 | |||
Abbreviations: SD, standard deviation; CRT, cranial radiation therapy.
|
| Whole Group | HD-MTX | VHD-MTX | CRT | P* | |
|---|---|---|---|---|---|
| No. of patients | 79 | 32 | 22 | 25 | |
| Sex | .70 | ||||
| Male | 37 | 14 | 12 | 11 | |
| Female | 42 | 18 | 10 | 14 | |
| Age at diagnosis, years | < .001 | ||||
| Mean | 2.8 | 2.9 | 1.9 | 3.5 | |
| SD | 1.1 | 1.0 | 0.6 | 0.9 | |
| Range | 1.0-5.0 | 1.4-4.9 | 1.0-3.4 | 1.9-5.0 | |
| Time since diagnosis, years | |||||
| Mean | 10.5 | 9.0 | 11.8 | 11.2 | < .001 |
| SD | 2.7 | 1.9 | 3.2 | 2.3 | |
| Range | 5.1-20.6 | 5.1-13.5 | 5.5-20.6 | 7.4-15.5 | |
| Age at testing, years | |||||
| Mean | 13.3 | 11.9 | 13.8 | 14.7 | < .001 |
| SD | 2.7 | 2.0 | 3.2 | 2.1 | |
| Range | 6.8-22.1 | 8.9-16.1 | 6.8-22.1 | 10.7-19.1 |
Abbreviations: MTX, methotrexate; HD, high dose; VHD, very high dose; CRT, cranial radiation therapy; SD, standard deviation.
*Analysis of variance used for continuous variables and χ2 for categorical variables.
|
| Population Norm | Chemotherapy* (n = 54) | CRT (n = 25) | P† | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Mean | SD | Mean | SD | Mean | SD | |||||
| Intelligence | ||||||||||
| Verbal comprehension | 100 | 15 | 99.5 | 10.27 | 89.8 | 10.4 | .0003 | |||
| Perceptual organization | 100 | 15 | 102.9 | 14.4 | 88.7 | 14.5 | .0002 | |||
| Freedom from distractibility | 100 | 15 | 98.4 | 13.0 | 88.2 | 10.6 | .0011 | |||
| Processing speed | 100 | 15 | 104.9 | 14.1 | 90.8 | 14.8 | .0001 | |||
| Attention | ||||||||||
| Delay | 0.0 | 1.0 | −.74 | 1.4 | −.60 | 1.2 | .73 | |||
| Vigilance | 0.0 | 1.0 | −.31 | 1.4 | −.41 | 1.3 | .78 | |||
| Distractibility | 0.0 | 1.0 | −.17 | 1.6 | −.18 | 1.1 | .98 | |||
| Memory | ||||||||||
| Visual immediate | 100 | 15 | 100.7 | 13.1 | 93.3 | 10.8 | .03 | |||
| Visual delay | 100 | 15 | 103.0 | 10.5 | 90.4 | 12.4 | .0001 | |||
| Verbal immediate | 100 | 15 | 100.0 | 14.4 | 91.2 | 10.1 | .017 | |||
| Verbal delay | 100 | 15 | 101.1 | 14.7 | 94.4 | 9.0 | .065 | |||
| Attention/concentration | 100 | 15 | 101.6 | 13.3 | 90.2 | 14.2 | .0026 | |||
| General memory index | 100 | 15 | 102.8 | 15.1 | 88.2 | 12.3 | .0011 | |||
| Academics | ||||||||||
| Single-word reading | 100 | 15 | 102.9 | 9.7 | 95.3 | 14.8 | .009 | |||
| Reading decoding | 100 | 15 | 102.2 | 8.0 | 95.6 | 13.0 | .009 | |||
| Reading comprehension | 100 | 15 | 101.3 | 9.9 | 89.2 | 11.8 | < .0001 | |||
| Spelling | 100 | 15 | 101.9 | 12.5 | 94.3 | 13.2 | .0172 | |||
| Arithmetic | 100 | 15 | 96.4 | 14.5 | 89.5 | 11.9 | .047 | |||
Abbreviations: CRT, cranial radiation therapy; SD, standard deviation.
*Combined high-dose and very high-dose methotrexate groups.
†Adjusted for age at diagnosis.
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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.
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