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Journal of Clinical Oncology, Vol 22, No 22 (November 15), 2004: pp. 4551-4560 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.03.058 White Matter Lesions Detected by Magnetic Resonance Imaging After Radiotherapy and High-Dose Chemotherapy in Children With Medulloblastoma or Primitive Neuroectodermal TumorFrom the Departments of Hematology-Oncology, Biostatistics and Epidemiology, Radiological Sciences, Behavioral Medicine, St Jude Children's Research Hospital; Departments of Pediatrics and Radiology, University of Tennessee, Memphis, TN; Department of Pediatrics, Baylor College of Medicine, Houston, TX; Department of Hematology-Oncology, Royal Children's Hospital, Melbourne; and the Children's Hospital at Westmead, and the University of Sydney, Sydney, Australia Address reprint requests to Maryam Fouladi, MD, Department of Hematology-Oncology, St Jude Children's Research Hospital, 332 N Lauderdale, Memphis, TN 38105-2794; e-mail: maryam.fouladi{at}stjude.org
PURPOSE: White matter lesions (WMLs) have been described as a delayed effect of cranial irradiation in children with brain tumors, or a transient subacute effect characterized by an intralesional or perilesional reaction. We report the occurrence of subacute WMLs detected by magnetic resonance imaging (MRI) in children treated for medulloblastoma or primitive neuroectodermal tumor (PNET) and document the associated clinical, radiologic, and neurocognitive findings.
PATIENTS AND METHODS: Among 134 patients with medulloblastoma or supratentorial PNET treated prospectively with risk-adjusted craniospinal irradiation and conformal boost to the tumor bed, followed by four high-dose chemotherapy (HDC) cycles with stem-cell rescue, 22 developed WMLs on T1-weighted imaging with and without contrast and/or T2-weighted imaging on MRI. Patients had RESULTS: Twenty-two patients developed WMLs at a median of 7.8 months after starting therapy (range, 1.9 to 13.0 months). Lesions were predominantly in the pons (n = 8) and cerebellum (n = 6). Sixteen patients (73%) had WML resolution at a median of 6.2 months (range, 1.68 to 23.5 months) after onset; two patients developed necrosis and atrophy. Three developed persistent neurologic deficits. Cumulative incidence of WMLs at 1 year was 15% ± 3%. Patients with WMLs had a significant decline in estimated IQ (–2.5 per year; P = .03) and math (–4.5 per year; P = .003) scores. CONCLUSION: WMLs in medulloblastoma or PNET patients treated with conformal radiotherapy and HDC are typically transient and asymptomatic, and may mimic early tumor recurrence. A minority of patients with WMLs develop permanent neurologic deficits and imaging changes. Overall, the presence of WMLs is associated with greater neurocognitive decline.
White matter changes in the brain are a well-described phenomenon in children after therapy for acute lymphoblastic leukemia.1-5 Factors that predispose to these changes in patients with leukemia include higher radiation dose,6 younger age,4 use of intrathecal chemotherapy,1,7 and length of time since completion of therapy.3 White matter changes occurring particularly after irradiation have been described in patients treated for brain tumors. Subacute effects of irradiation include intralesional and perilesional white matter reactions seen on magnetic resonance imaging (MRI) as an abnormal signal on T1- and T2-weighted images or fluid-attenuated inversion recovery images, with or without focal enhancement. Late effects of irradiation include diffuse white matter changes varying from scattered focal white matter lesions (WMLs) to confluent lesions involving much of the periventricular or hemispheric white matter,8 diffuse cerebral atrophy, radiation-induced vasculopathy, mineralizing microangiopathy,9,10 and focal areas of frank radiation necrosis.11 Postirradiation CNS sequelae can often be correlated with total radiation dose, fractionation, volume of brain irradiated, age at the time of treatment, and presence of associated antineoplastic or radiosensitizing agents.12,13 The detection of typically transient WMLs occurring subacutely in a small number of children during routine neuroimaging studies on a recent multi-institutional study for patients with medulloblastoma or primitive neuroectodermal tumor (PNET) led us to a broader investigation of this heretofore unreported phenomenon. Because the pattern of abnormal enhancement can closely mimic that of recurrent tumor, such findings present a major diagnostic challenge, and can have profound implications for therapy and prognosis. Here we report the occurrence of WMLs in a series of children who have been prospectively evaluated while undergoing therapy for medulloblastomas or PNET. The clinical, radiologic, and neurocognitive findings are detailed to further characterize this phenomenon.
Between October 1996 and August 2002, 135 patients with previously untreated medulloblastoma or supratentorial PNET were enrolled onto a multi-institutional study, which was approved by the institutional review boards of the participating institutions. Patients older than 3 years and younger than 21 years of age at the time of diagnosis were eligible for the study. Disease was staged as high risk or average risk using postsurgical tumor volume and a modification of the Chang staging system. Average-risk disease was defined as absence of metastatic disease as confirmed by gadolinium (Gd) -enhanced magnetic resonance imaging of the head and spine, and by the absence of tumor cells in the cytologic examination of lumbar CSF; absence of bony metastasis as confirmed by a bone scan; and gross total resection with  1.5 cm2 residual disease as confirmed by immediate postoperative MRI. High-risk disease was defined as the presence of metastatic disease documented by Gd-enhanced MRI of the head and spine, by the presence of malignant cells in the lumbar spinal fluid, or presence of bony metastasis on a bone scan; and presence of more than 1.5 cm2 residual disease as confirmed by postoperative Gd-MRI. Patients with supratentorial PNET were enrolled onto the average-risk arm of the protocol unless they had high-risk features as defined above. All patients underwent an attempt at maximal surgical resection of the tumor. Between October of 1996 and October 2000, patients with high-risk disease were initially treated with a 6-week phase II window of topotecan therapy. All high-risk patients received craniospinal irradiation (CSI; 36 Gy, M0-1; 39.6 Gy, M2-3) and three-dimensional conformal boost to the tumor bed (total dose, 55.8 Gy) and, when appropriate, local sites of metastases (total dose, 50.4 Gy). The median duration of radiation therapy was 6 weeks. After a 6-week rest period, patients received four cycles of high-dose chemotherapy, each followed by stem-cell rescue. After January 2000, all patients also received amifostine before the cisplatin infusion, and 3 hours into the infusion, to evaluate the role of amifostine as an otoprotectant (Table 1).
After surgical resection, patients with average-risk disease received CSI (23.4 Gy) with three-dimensional conformal boost to the posterior fossa (cumulative dose, 36 Gy) and the tumor bed (55.8 Gy), followed by the same schedule of high-dose chemotherapy, and stem-cell rescue, as outlined in Table 1. All patients underwent serial neuroimaging and clinical assessment at regular intervals. One hundred thirty-five patients were enrolled onto this study until August 2002. One patient was declared ineligible. Of the 134 patients who had follow-up of at least 12 months after protocol enrollment, 127 patients could be used in the selection of age- and risk-group matched controls. Informed consent was obtained from patients, parents, or guardians, as appropriate, at the time of protocol enrollment. MRI series included T1, T2, proton density, and fluid-attenuated inversion recovery images that were acquired on all patients. Serial MRIs were reviewed in the 134 eligible patients by a neuroradiologist (J.L., F.L.) and a neuro-oncologist (M.F.). Evidence of WMLs on MRI was reported from the date of first detection to the time of resolution. WMLs were defined as follows: grade 1, abnormal signal intensity on T2-weighted images; grade 2, increased signal intensity on T2-weighted images and contrast enhancement on T1; grade 3, evidence of hemorrhage; grade 4, encephalomalacia or focal necrosis. The time of onset, the size of T2 component and/or enhancement on T1 were recorded and correlated with changes in clinical symptoms, neurologic signs, and serial neuropsychologic examinations. Neurocognitive assessments included an abbreviated intelligence quotient (IQ) test and tests of academic achievement. All participants were given the Information (fund of factual knowledge), Similarities (verbal reasoning), and Block Design (nonverbal reasoning) subtests from either the Wechsler Intelligence Scale for Children III or the Wechsler Adult Intelligence Scale-Revised.14,15 The screening process was used to provide age-corrected estimates of IQ with a normative mean score of 100 and standard deviation of 15. This abbreviated version has been found to correlate highly with traditional full-scale IQ, and has been used successfully to study brain volume and its correlation with intellectual development.16 The academic achievement of patients was assessed using the Wechsler Individual Achievement Test (WIAT).17 The WIAT is a standardized test of academic achievement, individually administered with acceptable reliability and validity, with an age-corrected normative mean of 100 and a standard deviation of 15. The screening WIAT used here, which included the Basic Reading (word recognition), Spelling, and Mathematics Reasoning subsets only, takes approximately 30 minutes to administer.
Statistical Analyses
Factors analyzed for their effect on the occurrence of WMLs were age at enrollment, risk group, total cyclophosphamide dose, number of grade 3 or 4 infections or hypotension, and number of grade 3 or 4 nonhematologic toxicities. Because protocol scheduled scans were not obtained for patients who were taken off protocol, we analyzed this problem using a competing risk type of analysis. Time at risk for development of WMLs began from the date of enrollment onto the protocol until a WML was observed, the patient was taken off treatment, or the patient died. In the cumulative incidence analysis, we estimated the cumulative incidence of time to onset of the WMLs. The analysis took the timing of the event and timing of competing events (time taken off study and death) into consideration. Given that we estimated occurrence over time, we divided the factors into fixed factors (M stage, diagnosis, risk group, and age) or time-dependent factors (cumulative cyclophosphamide dose, number of grade 3 or 4 infections, and number of grade 3 or 4 nonhematologic toxicities). We used a PHREG procedure in SAS statistical software (SAS Institute, Cary, NC) when the explanatory variable was time dependent.
Neurocognitive Statistical Analysis Of the 127 patients used in the cumulative incidence analysis, 114 patients had at least one neurocognitive examination, yielding 21 patient cases and 93 age- and risk-matched controls. The MIXED procedure in the SAS software was used to build random coefficient models to compare the decline in IQ and achievement scores between patients with WMLs and those without WMLs. In each of these models, we tested the slopes against each other to detect any significant differences in decline between these two groups of patients, as well as against a slope of zero. A slope of zero represents no IQ or achievement score decline in each of these two groups of patients over time.
WMLs and Clinical Correlations Among the 127 patients included in the analyses of 134 eligible patients in this study, 22 patients were identified to have symptomatic or asymptomatic WMLs. The distribution of demographic and clinical characteristics of patients with WMLs is summarized in Table 2. Table 3 summarizes the radiographic characteristics of the 22 patients with WMLs. Overall, the WMLs were first observed at a median of 7.8 months after the start of therapy (range, 1.9 to 13.0 months). At the time of onset of WMLs radiographically, seven patients had grade 1 lesions and 15 patients had grade 2 lesions on MRI. The greatest unidimensional measurement of the T2 abnormality at the time of initial detection ranged from 5 to 15 mm (median, 6 mm) and the enhancing abnormality ranged from 3 to 10 mm in size (median, 5 mm). The predominant locations of WMLs included the pons (n = 8), cerebellum (n = 6), centrum semiovale (n = 2), midbrain (n = 2), medulla (n = 1), periventricular (n = 1), frontoparietal (n = 1), occipital (n = 1), and temporal (n = 1) lobes.
Sixteen patients (73%) had resolution of their WMLs at a median of 6.2 months (range, 1.7 to 23.5 months) after onset; two patients (patients 7 and 19) developed progressive disease and continued to have evidence of WMLs distinct from their tumor recurrence at the time of their last scan on study; one patient (patient 5) developed necrosis at the site of the lesion; one patient (patient 13) developed focal atrophy; and two patients (patients 10 and 22) continued to show stable WMLs at the time of their last MRI scan, 31 and 19 months, respectively, after initial detection. Nineteen patients had no symptoms or signs associated with WMLs; three patients (14%) developed neurologic signs and symptoms. The MRI abnormalities were observed at a median interval of 2 months (range, 1.4 to 2.7 months) before the development of symptoms; onset of WMLs occurred at 4.8 months (range, 1.8 to 4.8 months) after the start of therapy. Patient 5 developed worsening ataxia, dysmetria, cranial nerve V, VI, VII, XI, and XII palsies, and went on to develop palatal myoclonus. The neurologic deficits did not resolve over time and the MRI findings of T2 changes with enhancement on T1-weighted imaging in the medulla developed into a necrotic area, which remains stable on the most recent scan, 5 years after onset (Figs 1A, 1B, 1C, and 1D). Patient 7 developed lethargy and encephalopathic symptoms 1.3 months after diffuse periventricular cerebral T2 changes with focal enhancing areas were noted on MRI. The radiographic changes did not resolve. The patient developed radiographically confirmed progressive disease (distinct from the areas of WMLs) 6 months after WMLs were first noted on MRI and died shortly thereafter. At autopsy, extensive leptomeningeal medulloblastoma was found along with mild diffuse oligodendrogliosis, and demyelination in the periventricular region corresponded in distribution to the T2 changes identified on MRI.
Patient 13 was found to have mild T2 changes in the pons on MRI at 4.8 months after enrollment onto the study. Two months after detection of the lesion, he presented with acute clinical deterioration consisting of quadriparesis, bilateral cranial nerve V and VII palsies, and central hypoventilation, at which time MRI revealed marked worsening of T2 changes and additional enhancement in the pons. He required prolonged mechanical ventilation and tracheostomy. At his most recent follow-up, 18 months after the detection of the WMLs, he continued to require intermittent ventilatory support at night with slight improvement of his general neurologic function. His MRI demonstrated development of atrophic changes in the pons, corresponding to the areas of previous WMLs. Among the 19 (86%) asymptomatic patients, WMLs were observed initially at a median of 8.2 months (range, 4.1 to 13.0 months) from the start of therapy and resolved at a median of 6.2 months from the date of onset (range, 1.7 to 23.5 months). Figures 2A and 2B and Figures 3A and 3B demonstrate the occurrence of such typical transient WMLs in patients 8 and 9, respectively.
The cumulative incidence of observation of WMLs in the entire cohort is 15% ± 3% at 1 year (Fig 4A) and 17.5% ± 3% at 2 years from enrollment onto the protocol. Three patients developed WMLs later than 1 year from the time of enrollment. There was no difference in cumulative incidence of WMLs by risk group (P = .78; Fig 4B), age (P = .42), cumulative dose of cyclophosphamide (P = .99), number of grade 3 or 4 episodes of infections or hypotension (P = .58), grade 3 or 4 nonhematologic toxicities (P = .55), or diagnosis (medulloblastoma v others; P = .750). Finally, there was no difference in cumulative incidence between patients who were M0 or M1, and those who were M2 or M3 (P = .23).
Neurocognitive Correlates of WMLs As described previously, 114 of 127 patients were used in the longitudinal neurocognitive analysis, yielding 21 patient cases (one patient with supratentorial PNET was excluded) and 93 age- and risk-matched controls. The IQ decline was significant (mean, –2.46 points/yr; P = .03) for patients with WMLs, but not significant for those without WMLs (mean, –0.35 points/yr). Similar to IQ, declines in math were significant for the patients with WMLs (mean, –4.49 points/yr; P = .003) but not for patients without WMLs (mean, –0.44 points/yr). The decline in spelling scores was significant for those with (mean, –4.31 points/yr; P = .0001) and without WMLs (mean, –2.86 points/yr; P = .002). Similarly, reading scores declined significantly for those with (mean, –3.59; P < .0001) and without WMLs (mean, –2.42 points/yr; P = .003; Figs 5A to 5D).
CNS reactions to cancer therapy have been documented after irradiation, cytotoxic chemotherapy, and combined therapeutic regimens. The temporal relationship to radiation therapy often defines the nature and duration of CNS changes: post-therapy effects occurring within 2 to 6 months (subacute effects) have typically affected the white matter and are often transitory; CNS changes occurring beyond 12 months (late effects) tend to be more significant both anatomically and clinically, as well as more durable.13 Delayed effects of cranial irradiation, including focal radiation necrosis, atrophy, diffuse leukoencephalopathy, and vasculopathy, are well defined in adults and children with brain tumors, including low- or high-grade glial neoplasms18,19 and, less frequently, embryonal tumors. Russo et al12 reported delayed white matter changes affecting the periventricular region in 33% of patients 1.4 and 4.5 years after treatment for standard- and high-risk medulloblastoma treated with hyperfractionated radiotherapy. Dietrich et al8 retrospectively reported the development of white matter changes occurring longer than 5 years after therapy in 44 children treated for a variety of malignant brain tumors including PNET and medulloblastoma. Sixty-four percent had evidence of white matter changes, with circumscribed WMLs present in 30%, atrophy present in 16%, and a combination of the two present in 18% of patients. Patients with medulloblastoma developed significantly fewer delayed WMLs. Diffuse white matter injury has also been described after moderate-dose cranial irradiation in conjunction with methotrexate.1 In patients with CNS tumors, the relationship of cytotoxic chemotherapy (eg, platinating agents) to postirradiation changes has been suggested in the literature, with little documentation of the impact of high-dose alkylating agents.20 Histopathologically, late effects of irradiation range from diffuse white matter pallor and reactive astrocytosis to discrete foci of noninflammatory necrosis and reactive gliosis.13 The pathologic mechanism for injury is believed to be damage to cerebral blood vessels. Known subacute effects of cranial irradiation include the somnolence syndrome as well as intralesional and perilesional reactions (eg, in diffuse intrinsic brainstem glioma) occurring up to 6 to 12 months after irradiation. Both of these effects are believed to be secondary to transient demyelination. The current report describes the previously unreported finding and incidence of early-onset, often transient WMLs in a prospectively defined cohort of children with embryonal CNS tumors treated on a combined postoperative irradiation and high-dose chemotherapy regimen. The time of observation of these lesions is consistent with the subacute postirradiation interval, and the subsequent resolution in 73% of patient cases seems to be consistent with the pathologic transient white matter demyelination invoked earlier to explain subacute radiation injury.13 Histologically proven white matter changes, gliosis, arteriovenous malformations, and inflammation presenting as new, enhancing lesions on MRI can be mistaken easily for recurrent tumor.12,21-24 There is grave potential for error in assuming that such new lesions detected by MRI in a previously treated patient represent recurrent disease. In our series, one of the two patients with WMLs, who eventually died as a result of progressive tumor, underwent an autopsy. Autopsy confirmed the presence of progressive leptomeningeal disease but also demonstrated distinct areas of white matter changes consisting of mild diffuse oligodendrogliosis, and demyelination periventricularly, with no evidence of inflammation, consistent with the distribution of T2 changes noted on MRI. Although we previously reported that subtle loss of normal white matter in children treated for medulloblastoma or PNET can be quantified and associated with decreased attentional abilities, declining IQ, and academic achievement,25-28 no studies have reported the impact of subacute, often transient, white matter changes on intellectual outcome in children with brain tumors. In this study, patients with WMLs have significantly greater decline in IQ and math scores compared with those without WMLs. The greater cognitive declines reported in patients with WMLs are unexpected in view of the often transient and discrete nature of these changes. Although this reported association may represent a correlative and not a causative relationship, we attempted to control for the effects of such key variables as age, tumor location, and risk group. None of these factors had an impact on neurocognitive outcome. Another explanation for the more pronounced neurocognitive decline in patients with WMLs may be that, despite resolution of imaging changes in the majority of patients over time, subtle underlying pathologic damage (such as the oligodendrogliosis and demyelination noted at autopsy in patient 7) may persist indefinitely and lead to the neurocognitive decline. Finally, the roles of conformal radiotherapy29,30 as well as high-dose chemotherapy31 must be considered, given that such white matter changes have not been reported in patients with medulloblastoma treated with conventional posterior fossa irradiation and chemotherapy. In fact, Grill et al31 implicated the role of high-dose busulfan plus thiotepa treatment in the development of similar white matter changes occurring within 2 years after therapy in younger patients treated for recurrent medulloblastoma. Although the distribution of WMLs in the present series was widespread, the majority occurred in the posterior fossa (in particular, the cerebellum) which has been classically associated with motor control. Recent studies in adults and children, however, have established the clear role of the cerebellum in higher cognitive function, with focal cerebellar or posterior fossa injuries leading to deficits in executive32-34 and visual-spatial function,35-38 expressive language,36,39,40 verbal memory,36 learning, attention, and behavioral41 and reaction times.42 In conclusion, this is the first study to report the occurrence as well as the clinical and neurocognitive impact of WMLs detected by MRI detected subacutely in children with medulloblastoma or PNET treated with conformal radiotherapy and high-dose chemotherapy. Careful monitoring of these patients is warranted, given that these changes tend to be misinterpreted as tumor recurrence. Although these lesions are typically transient and asymptomatic, a minority of patients develop associated signs and symptoms that lead to permanent neurologic deficits and imaging changes. Furthermore, patients with WMLs have significantly lower IQ, math, spelling, and reading scores than expected, and tend to have greater neurocognitive deficits than patients who do not develop WMLs.
The authors indicated no potential conflicts of interest.
We thank Jana Freeman for helping with the collection of the data, Dana Wallace for assisting with the statistical analysis, and Patsy Burnside for typing the manuscript.
Supported in part by Center of Research Excellence support grant no. CA21765, American Lebanese Syrian Associated Charities (ALSAC). Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
12 months of follow-up. Neurocognitive assessments included intelligence quotient (IQ) tests and tests of academic achievement. 
