Clinical Investigation
Outcome and Prognostic Factors of Radiation Therapy for Medulloblastoma

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Purpose

To investigate treatment outcome and prognostic factors after radiation therapy in patients with medulloblastomas (MB).

Methods and Materials

Sixty-six patients with histologically confirmed MB were treated at the University Hospital of Heidelberg between 1985 and 2009. Forty-two patients (64%) were pediatric (≤18 years), and 24 patients (36%) were adults. Tumor resection was performed in all patients and was complete in 47%. All patients underwent postoperative craniospinal irradiation (CSI) delivering a median craniospinal dose of 35.5 Gy with additional boosts to the posterior fossa up to 54.0 Gy. Forty-seven patients received chemotherapy, including 21 in whom chemotherapy was administered before CSI. Statistical analysis was performed using the log-rank test and the Kaplan-Meier method.

Results

Median follow-up was 93 months. Overall survival (OS) and local and distant progression-free survival (LPFS and DPFS) were 73%, 62%, and 77% at 60 months. Both local and distant recurrence predisposed for significantly reduced OS. Macroscopic complete tumor resection, desmoplastic histology and early initiation of postoperative radiation therapy within 28 days were associated with improved outcome. The addition of chemotherapy did not improve survival rates. Toxicity was moderate.

Conclusions

Complete resection of MB followed by CSI yields long survival rates in both children and adults. Delayed initiation of CSI is associated with poor outcome. Desmoplastic histology is associated with improved survival. The role of chemotherapy, especially in the adult population, must be further investigated in clinical studies.

Introduction

Medulloblastomas (MB) are the most common infratentorial malignant brain tumors with an incidence rate of 0.5 in 100.000, typically arising in childhood at age 5–9 years 1, 2. They are thought to originate from the neuroepithelial lining of the upper fourth ventricle, differentiating them from ependymomas, which represent the second most common infratentorial brain tumor in children and typically arise from the floor of the fourth ventricle. Today, most patients are treated within uniform concepts. Treatment typically consists of neurosurgical resection to the most feasible extent followed by postoperative craniospinal irradiation (CSI). In pediatric patients, CSI is performed in conjunction with concomitant and adjuvant chemotherapy (3). Also in adults, there is a strong trend towards combined treatments in analogy to pediatric patients. However, several reports have identified numerous factors of potential risk affecting treatment response and outcome of MB patients. These include tumor-intrinsic features such as histology or genetic aberrations but also epidemiological aspects such as patient age and sex, and treatment-related factors such as extent of neurosurgical resection 3, 4, 5, 6. Most studies that identified these parameters had included pediatric patients between ages 3 and 21 years. However, about 20% of all MB patients are younger than 3 years, and another 20% are diagnosed in adolescence and adulthood, when treatment response and outcome are known to differ significantly from the results of large pediatric trials 6, 7. Several characteristic clinical, histological, and molecular features of MB in young children and adult patients were described possibly explaining the differences observed in treatment results 5, 8, 9. However, apart from omission of postoperative CSI in very young children, no age- or histology-adapted therapy stratification has yet been established.

Some typical age-dependent differences between adult and pediatric MB patients were identified 3, 5, 8, 10: adult MB patients predominately present with disease patterns of beneficial prognosis such as lateral tumor location and diagnosis of a desmoplastic histological subtype 11, 12, 13, 14, 15. Nonetheless, outcome in adults is not superior to outcome in children, challenging the role of site- or histology-adapted treatment stratification. On the contrary, very young children with desmoplastic MB, in whom CSI is known to cause severe neurological toxicity, are now considered curable by postoperative chemotherapy alone 6, 16. This has lead to approaches in young children that omit CSI to spare treatment-related chronic toxicity still with excellent outcome (6). The treatment of adults, in whom chemotherapy was not administered as routinely as in children, is currently being investigated in a clinical trial that conveys the promising results of chemotherapy within pediatric protocols onto the adult population (NOA-07-trial, http://www.neuroonkologie.de). Intensified chemotherapy in the management of MB has repeatedly challenged the role of CSI and consecutively led to dose reduction and even omission in very young children 17, 18. However, for all other patients, the benefit of postoperative CSI implementation according to quality-assurance standards appears undisputed (3).

This study was initiated to summarize our institutional experiences in CSI of MB patients and to analyze prognostic factors that affect treatment results and outcome.

Section snippets

Patients and Methods

Between 1985 and 2009, 66 patients with MB were treated at the university hospital in Heidelberg, Germany. All data were collected retrospectively and in accordance with institutional ethical policies. Median follow-up time was 93 months (range, 5–269 months).

Toxicity

Both acute and late toxicities were moderate in our cohort (Table 1). The addition of chemotherapy was associated with slightly enhanced acute side effects, causing treatment delay or interruptions due to hematological toxicity in 15% of patients opposed to 6% in RT alone. Medication-refractory nausea causing treatment delay was diagnosed in 11% of irradiated patients and in 13% when chemotherapy was added. Also, side effects such as chronic neuropathy (0% vs. 29%), skin ulcerations (11% vs.

Discussion

In this study, we analyzed treatment outcome and prognostic factors in 66 MB patients treated with postoperative RT. We identified complete resection, desmoplastic histology variant, and early initiation of radiotherapy after surgery to be associated with improved outcome, and postoperative tumor residues, classic histology, and long intervals between surgery and adjuvant radiotherapy were associated with worse outcome. Patient age did not affect outcome (≤18 years vs. >18 years).

The role of

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  • Cited by (0)

    This work was supported by the Medical Faculty of the University of Heidelberg.

    Conflicts of interest: none.

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