paediatrics Brussels 17

Conformal RT for Pediatric Ependymoma

imaging. Subtotal resection was defined as resection that left behind residual tumor 5-mm thick on postoperative neuroim- aging. Further surgery was systematically applied to maximize the extent of resection before irradiation. CRT Target volume definitions and planning and treatment pa- rameters have been previously described. 8 The gross tumor vol- ume (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 plan- ning 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. Con- ventional 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 Intelli- gence Scale III 12 ), verbal memory and recall (California Verbal Learning Test: Child and Adult versions 13,14 ), academic achieve- ment (Wechsler Individual Achievement Test, 15 ) activities of daily living (Vineland Adaptive Behavior Scale Survey 16 ), and visual- auditory paired associate learning (Visual-Auditory Learning Test 17 ). 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 instru- ments and to conduct at least two evaluations by using the same instrument. Clinical judgment was used to select the instru- ment with which the child was expected to achieve the most valid performance. Statistical Methods Progression-free survival (PFS) was measured from the initi- ation 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 esti- mates 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 meth- ods, 22 with distant tumor recurrence and death (one patient

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 optimi- zation 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 tu- mor 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 chil- dren 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 ependy- moma, the largest trial to date for such patients. The neu- rocognitive function of these patients was evaluated before and after CRT in a comprehensivemanner that has not been previously reported in the literature. 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 enroll- ment included age between 1 and 21 years at the time of irradia- tion; histologic confirmation of intracranial ependymoma; no evidence of dissemination; no prior irradiation; no ongoing che- motherapy; adequate performance status; and written informed consent. The protocol was amended to allow enrollment of pa- tients as old as 25 years; only one patient older than 21 years entered the study. Sixteen patients received chemotherapy be- fore irradiation; most received multiagent chemotherapy in- cluding 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 operat- ing microscope; patients for whom this type of resection was achieved had no evidence of disease on postoperative neuroimag- ing. Near-total resection was defined as resection after which only residual tumor 5-mm thick was visible on postoperative neuro- PATIENTS AND METHODS

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