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Preliminary Results From a Phase II Trial of Conformal Radiation Therapy and Evaluation of Radiation-Related CNS Effects for Pediatric Patients With Localized Ependymoma

From the Division of Radiation Oncology, Department of Biostatistics, Division of Behavioral Medicine, St Jude Children's Research Hospital; Semmes-Murphey Neurologic and Spine Institute; and Division of Pediatric Neurosurgery, University of Tennessee, College of Medicine, Memphis, TN; and Division of Pediatric Endocrinology, University of California San Francisco, San Francisco, CA

Address reprint requests to Thomas E. Merchant, DO, PhD, Division of Radiation Oncology, St Jude Children's Research Hospital, 332 N Lauderdale St, Memphis, TN 38105-2794; e-mail: thomas.merchant{at}stjude.org

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
PURPOSE: We conducted a phase II trial of conformal radiation therapy (CRT) for localized childhood ependymoma to determine whether the irradiated volume could be reduced to decrease CNS-related side effects without diminishing the rate of disease control.

PATIENTS AND METHODS: Between July 1997 and January 2003, 88 pediatric patients (median age, 2.85 ± 4.5 years) received CRT in which doses (59.4 Gy to 73 patients or 54.0 Gy after gross-total resection to 15 patients younger than 18 months) were administered to the gross tumor volume and a margin of 10 mm. Patients were categorized according to extent of resection (underwent gross total resection, n = 74; near-total resection, n = 6; subtotal resection, n = 8), prior chemotherapy (n = 16), tumor grade (anaplastic, n = 35), and tumor location (infratentorial, n = 68). An age-appropriate neurocognitive battery was administered before and serially after CRT.

RESULTS: The median length of follow-up was 38.2 months (± 16.4 months); the 3-year progression-free survival estimate was 74.7% ± 5.7%. Local failure occurred in eight patients, distant failure in eight patients, and both in four patients. The cumulative incidence of local failure as a component of failure at 3 years was 14.8% ± 4.0%. Mean scores on all neurocognitive outcomes were stable and within normal limits, with more than half the cohort tested at or beyond 24 months.

CONCLUSION: Limited-volume irradiation achieves high rates of disease control in pediatric patients with ependymoma and results in stable neurocognitive outcomes.

	INTRODUCTION

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Ependymoma is a rare brain tumor that occurs in very young children: fewer than 150 cases per year occur in the United States among persons younger than 14 years.¹ Surgery and postoperative radiation therapy are essential to the successful management of ependymoma, but those who receive radiation therapy are at risk of side effects that negatively affect cognitive, endocrine, and neurologic function.² The specter of radiation-related side effects, which is most ominous for those who are very young at the time of treatment, has motivated investigators to test strategies to delay or avoid the use of radiation in young children. However, cooperative group trials testing the use of chemotherapy to delay irradiation have met with limited success, reporting results inferior to those achieved for patients treated with immediate postoperative radiation therapy.^3-5

Conformal radiation therapy (CRT) is a spectrum of radiation treatment planning and delivery techniques developed to focus radiation and limit the highest doses to the volume at risk of recurrence while sparing normal tissues. These techniques incorporate three-dimensional imaging (computed tomography and magnetic resonance imaging) into the planning process and use sophisticated software to delineate and display the treatment volume and important normal tissue structures for selective targeting and optimization of dosimetry. Initially developed for the treatment of adults with prostate and head and neck cancer, CRT has been successful in reducing side effects and improving tumor control^6,7 and holds the promise of reducing radiation-related treatment effects in children with brain tumors, although no long-term clinical trials have yet been reported. The successful application of CRT to ependymoma in children may improve outcomes by reducing side effects and thereby permit the reintroduction of radiation therapy as a treatment option for very young children. Nevertheless, guidelines for the use of CRT will be needed to ensure that the appropriate volume receives the prescription dose and that disease control is not compromised.

We designed and conducted a phase II trial to test the hypothesis that irradiation of a smaller-than-conventional treatment volume reduces side effects without affecting the rate of tumor control or local pattern of failure. We selected an anatomically confined margin of 10 mm around the tumor, tumor bed, or both as the clinical target volume for a prospective phase II trial. These guidelines were used prospectively to treat 88 pediatric patients with ependymoma, the largest trial to date for such patients. The neurocognitive function of these patients was evaluated before and after CRT in a comprehensive manner that has not been previously reported in the literature.

	PATIENTS AND METHODS

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Patients
From July 1997 through January 2003, 88 pediatric patients with intracranial ependymoma were enrolled onto a phase II trial approved by the institutional review board. Criteria for enrollment included age between 1 and 21 years at the time of irradiation; histologic confirmation of intracranial ependymoma; no evidence of dissemination; no prior irradiation; no ongoing chemotherapy; adequate performance status; and written informed consent. The protocol was amended to allow enrollment of patients as old as 25 years; only one patient older than 21 years entered the study. Sixteen patients received chemotherapy before irradiation; most received multiagent chemotherapy including cyclophosphamide, cisplatin or carboplatin, etoposide, and vincristine.

Extent of Resection Definitions
All patients underwent resection before radiation therapy. Gross-total resection was defined as resection after which the only tumor cells that remained were visible with the use of the operating microscope; patients for whom this type of resection was achieved had no evidence of disease on postoperative neuroimaging. Near-total resection was defined as resection after which only residual tumor < 5-mm thick was visible on postoperative neuroimaging. Subtotal resection was defined as resection that left behind residual tumor > 5-mm thick on postoperative neuroimaging. Further surgery was systematically applied to maximize the extent of resection before irradiation.

CRT
Target volume definitions and planning and treatment parameters have been previously described.⁸ The gross tumor volume (GTV) contained the tumor bed, residual tumor, or both. The clinical target volume (CTV) contained the GTV with an added margin of 10 mm, which was included so that subclinical microscopic disease beyond the GTV could be treated. The CTV was anatomically confined; that is, it was limited by normal tissue structures through which tumor extension was unlikely. The planning target volume included the CTV surrounded by an additional margin of 3 to 5 mm expanded in three dimensions to account for uncertainty in patient positioning and image registration. Conventional fractionation (1.8 Gy per day) was used to treat all patients, and the prescribed dose was 59.4 Gy. Exceptions included children younger than 18 months and three children older than 18 months who received 54.0 Gy after gross-total resection.

Neurocognitive Testing
Neurocognitive testing was performed before (baseline) and 6, 12, 24, 36, 48, and 60 months after the start of CRT. Baseline testing was delayed slightly if the institution of CRT was given logistic priority. Age-appropriate tests included those for cognitive development (Bayley Scale of Infant Development–II,⁹ Wechsler Preschool and Primary Scales of Intelligence–Revised,¹⁰ Wechsler Intelligence Scale for Children–III,¹¹ and Wechsler Adult Intelligence Scale III¹²), verbal memory and recall (California Verbal Learning Test: Child and Adult versions^13,14), academic achievement (Wechsler Individual Achievement Test,¹⁵) activities of daily living (Vineland Adaptive Behavior Scale Survey¹⁶), and visual-auditory paired associate learning (Visual-Auditory Learning Test¹⁷). All tests have well-documented reliability and validity and result in age-corrected standard scores. The testing regimen was based on patient age. When more than one instrument was age-appropriate for a patient, the selection of instrument reflected the desire to maintain consistency in the use of consecutive instruments and to conduct at least two evaluations by using the same instrument. Clinical judgment was used to select the instrument with which the child was expected to achieve the most valid performance.

Statistical Methods
Progression-free survival (PFS) was measured from the initiation of radiation therapy to the neuroimaging documented time of tumor recurrence, where tumor recurrence included local-only failure, distant-only failure, or simultaneous local and distant failure. One patient who died of reasons unrelated to radiation therapy was censored at the date of death in the estimate of PFS. The rate of local failure was monitored by using group sequential boundaries obtained according to the sequential conditional probability ratio tests.¹⁸ Patients were followed every 3 months for 2 years and every 6 months thereafter. PFS was estimated by using the Kaplan-Meier method.¹⁹ Estimates based on categoric clinical variables were compared by using the log-rank test,²⁰ and estimates based on continuous clinical variables were compared by using Cox regression analysis.²¹ Variables for which P < .10 in the univariate analysis were included in a Cox regression model.²¹ Local control was estimated using cumulative incidence methods,²² with distant tumor recurrence and death (one patient whose death was not attributed to disease progression or radiation therapy) as competing risks. The longitudinal trends in neurocognitive outcomes were estimated by using linear mixed models with random coefficients.²³ SAS software was used for all analyses.²⁴ Data analyses were performed by the biostatistical coauthors.

	RESULTS

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Clinical and treatment characteristics of the study patients are presented in Table 1. To identify similarities and differences among the patients, we categorized them according to age (younger than 3 years or 3 years) for comparison. Older patients were more likely to have supratentorial tumors (P = .012), and the younger patients were more likely to have hydrocephalus (P = .014) and require CSF shunting (P = .057). Larger proportions of the younger patients received preirradiation chemotherapy and had anaplastic tumors at diagnosis. However, these proportions were not significantly different from those of the older patients.

View larger version (12K): [in this window] [in a new window]   Fig 1. Event-free survival estimates for patients treated with postoperative conformal radiation therapy.

View larger version (13K): [in this window] [in a new window]   Fig 2. Estimated mean intelligence quotient (IQ) before and after conformal radiation therapy.

View larger version (20K): [in this window] [in a new window]   Fig 4. Mean Vineland Adaptive Behavior Scale scores before and after conformal radiation therapy.

	DISCUSSION

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Of the 20 patients who experienced recurrence or progression, none had marginal failures; however, the relatively large proportion of patients experiencing relapse with disease in the neuraxis but not at the primary site after treatment was both disappointing and informative. This proportion was higher than the expected proportion, which is based on lower rates reported in some series,³¹ and may indicate that the overall pattern of failure changed as a result of the high rate of local tumor control and gross-total resection.³⁰

The improved rate of disease control in this study may be attributable to factors that include the high proportion of cases in which gross-total resection was done, systematic targeting with three-dimensional imaging, and the relatively high prescribed total dose. Gross-total resection was performed in 84% of cases, near-total resection in 7%, and subtotal resection in 9%; the average volume of residual disease was only 1.2 cm³. The percentage of cases in which gross-total resection was conducted in this study was higher than the national average, which has ranged from 40% to 60%.^32,33

We evaluated CNS effects in a rigorous, consistent manner, using widely accepted tests to identify the effects of radiation on cognitive, endocrine, and neurologic function. The most encouraging finding from this study was the level of function and lack of treatment-related effects in a young and vulnerable group of children treated with high-dose irradiation. Only a limited comparison of neurocognitive effects can be made between patients from this study and those treated conventionally, because prospective data from a similarly well-characterized group of pediatric patients with ependymoma are not available. After correcting for other factors responsible for neurocognitive function in pediatric patients with CNS tumors, other investigators found that the dose and volume of irradiation seem to play a role in altering neurocognitive status or intellectual outcome. In a study that included 59 pediatric patients with medulloblastoma and 37 with posterior fossa ependymoma (including 14 patients younger than 3 years at the time ependymoma was diagnosed), 90% of those with ependymoma, which was treated with irradiation to the posterior fossa, maintained an IQ greater than 90 at 5 to 10 years after treatment.³⁴ In the group with medulloblastoma, which was treated with craniospinal irradiation and a boost to the posterior fossa, only 20% of patients had an IQ greater than 90 at 5 years, and the proportion decreased to 10% at 10 years. In a separate publication, a review of multiple studies compared the IQ of pediatric patients treated postoperatively with craniospinal irradiation, focal irradiation of the primary site, or no irradiation.³⁵ Patients who received craniospinal irradiation had significantly lower IQs than those who did not receive such treatment; however, those treated with focal irradiation had IQ values comparable to those who received no irradiation. These results support efforts to reduce the volume of irradiation. Much of the fear instilled in those who treat young children with brain tumors may be derived from reports about children with medulloblastoma for whom a persistent and early decline in intellectual outcome is anticipated after craniospinal irradiation.³⁶ Perhaps the most direct comparison of the present neurocognitive outcomes can be made with the results from the study of Grill et al,³⁷ who reported a mean IQ of 85.3 (standard deviation, ± 13.6) for 12 long-term survivors of ependymoma treated with conventional posterior fossa irradiation at age 5 years. Spiegler et al³⁸ recently reported on four patients with ependymoma and 30 with medulloblastoma in a study that was meant to show change over time and the onset of stability for IQ measured after radiation therapy. Because of the small number of serial evaluations, their modeling was limited to 17 patients evaluated within 6 months from diagnosis and followed for a median of 3.3 years. They found that patients evaluated early in their treatment course experienced a steep decline with eventual leveling in the pattern of a quadratic function.

Our study is unique because it includes children younger than 3 years at the time of irradiation. The age of 3 years has been used to define those who are at greatest risk of the effects of irradiation and for whom trials have been designed in an effort to delay or avoid irradiation. Age at the time of diagnosis has also been described as an important prognostic factor. In the present study, 13 of the 48 patients younger than 3 years experienced disease progression. Children in this age group in earlier studies had a worse prognosis than older patients, possibly because of more aggressive tumor biology, reluctance to give postoperative radiation therapy, or use of lower doses of radiation.^{29,39, 40} The first infant study by the Pediatric Oncology Group attempted to delay radiation therapy by using postoperative chemotherapy and showed a significant difference in outcome based on age.^3,41 The 5-year PFS estimate was 12.7% ± 8% for the 31 patients between the ages of 0 and 23 months treated with chemotherapy for 2 years, whereas the 17 patients who were 24 to 36 months old treated with chemotherapy for 1 year had an estimate of 54.8% ± 15%. The age-related differences remained even when the analysis was limited to those without metastases who had undergone gross-total resection: the 5-year PFS estimates were 37.5% ± 17% for the eight patients who were 0 to 23 months of age and 87.5% ± 12% for the eight patients who were 24 to 36 months old. Their findings suggested that the poor survival estimates frequently reported for young children were probably related to the delay in the administration of radiation therapy, although tumor location and extent of resection were important cofactors.

Preirradiation chemotherapy was shown to marginally effect PFS by univariate statistics in this report. The PFS after radiation therapy has been shown to be shorter for those treated with chemotherapy compared with those not treated with chemotherapy.^42,43 In the prospective Pediatric Oncology Group study,³ those who received chemotherapy for 2 years had a worse PFS when compared with those who received chemotherapy for 1 year; however, because the Pediatric Oncology Group study did not have a radiation control arm, the effect seemed to be age-related. In our study, we had a sufficient number of young patients who did and did not receive chemotherapy so that we were able to perform univariate and multivariate analyses to show that age was not a factor and that preirradiation chemotherapy affects PFS by univariate statistics. The marginal significance of this result leads us to believe that the 7-week course of chemotherapy for incompletely resected patients on the current Children's Oncology Group study will not compromise PFS.

The French Society of Pediatric Oncology conducted a study to determine whether postoperative chemotherapy and additional surgery at the completion of chemotherapy or time of progression could replace radiation therapy as treatment for ependymoma in 73 children younger than 5 years.⁵ PFS estimates at 2 and 4 years were 33% and 22%, respectively; 50% of patients experienced relapse during the planned chemotherapy course. Radiation therapy was ultimately delivered to 39 patients (53%), but nearly 72% of patients with relapsed disease required further surgery and irradiation. At the time of their report, 34 patients (47%) had avoided irradiation, but only 11 were without evidence of disease and remained at high risk of progression.

The median age of patients enrolled on the present study was 2.85 years, and their outcome has raised further questions about the necessity of chemotherapy and of efforts to delay or avoid irradiation. On the basis of our findings, the use of radiation therapy for pediatric patients of all ages (1 to 21 years) has been adopted by investigators from the Children's Oncology Group. The current national trial for pediatric patients with localized ependymoma uses the targeting guidelines from this study and seeks to increase the proportion of cases in which gross-total resection is achieved, through the use of second surgery (Children's Oncology Group ACNS0121).

	Authors' Disclosures of Potential Conflicts of Interest

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The authors indicated no potential conflicts of interest.

View larger version (19K): [in this window] [in a new window]   Fig 3. Mean Wechsler Individual Achievement Test (WIAT) scores before and after conformal radiation therapy. CVLT-C, California Verbal Learning Test: Child; VAL, visual-auditory learning test.

	NOTES

Authors' disclosures of potential conflicts of interest are found at the end of this article.

	REFERENCES

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Submitted November 24, 2003; accepted May 8, 2004.

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