© 2005 Foundation for Promotion of Cancer Research
Radiation Treatment for Medulloblastoma: a Review of 64 Cases at a Single Institute
1 Department of Radiation Oncology, Cancer Hospital (Institute), Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China and 2 Department of Radiation Oncology, St Jude Children's Research Hospital, Memphis, TN, USA
For reprints and all correspondence: Yueping Liu, Department of Radiation Oncology, Cancer Hospital (Institute), Chinese Academy of Medical Sciences, PO Box 2258, Beijing 100021, PR China. E-mail: wanyx{at}public.bta.net.cn
Received October 20, 2004; accepted January 2, 2005
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Abstract |
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Background: Although the optimal treatment mode for medulloblastoma is frequently discussed, results based on large series of cases, especially those treated in Asia, have rarely been reported. Our purpose was to evaluate the efficacy of postoperative radiation therapy, and to identify prognostic factors, in a relatively large cohort of patients with limited-stage medulloblastoma treated at a single institute in China.
Methods: Between January 1996 and April 2001, 69 patients with Chang stage M0/M1 medulloblastoma were referred to our hospital for radiation therapy after total or subtotal resection of the primary tumor. All patients received 30 Gy to the craniospinal axis followed by a 20–25 Gy boost to the posterior fossa (median fraction, 1.8 Gy).
Results: Sixty-four patients were followed for a median period of 38.5 months. The rates of 3-year and 5-year overall survival were 68.8% and 55.7%, respectively; corresponding disease-free survival were 57.8% and 51.4%, respectively. Patients who had received radiation treatment within 25 days after resection had a greater probability of 3-year survival (81.5% versus 59.5%; P = 0.11) and 3-year disease-free survival (74.1% versus 46.0%; P = 0.03) than patients who began radiation treatment later. No relationship was found between survival and age, sex or tumor size.
Conclusions: This regimen was comparatively ineffective in preventing recurrence of postoperative medulloblastoma; however, we found that the interval between surgery and radiation is a significant prognostic factor for disease-free survival.
Key Words: craniospinal axis irradiation • medulloblastoma • prognostic factors • survival
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INTRODUCTION |
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TOPAbstractINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONReferences |
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Medulloblastoma is classically identified as a primitive neuroectodermal tumor arising in the cerebellum, which comprises 20–30% of brain tumors and about 40% of all posterior fossa tumors in children (1). The peak age at presentation is 5–10 years (2,3). Surgical resection followed by craniospinal irradiation (CSI) has been the mainstay of medulloblastoma therapy for many years (4). The standard radiation regimen has comprised a dose of 36 Gy to the entire craniospinal axis followed by a boost to the whole posterior fossa, for a total dose of 55 Gy (2,5). In recent years, thanks to cis-platinum-based chemotherapy added to the therapy regimen for medulloblastoma, the survival for high-risk disease has been improved (6) and the radiation dose of neuraxis for average-risk disease has been decreased without compromising survival (5). The recently reported 5-year survival estimates for patients with medulloblastoma range from 60 to 80% (3,7–14). Prognostic factors include Chang's M stage (Table 1) (8,15), extent of resection (2,11,12,16), total dose of radiation (11,16–18) and use of supplemental chemotherapy (19,20). The prognostic value of age, sex and tumor size remains controversial (8,12,15,17,21).
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Although there are many recent reports on medulloblastoma, data from large patient cohorts, especially those in Asia, are lacking. We retrospectively analyzed the results of postoperative radiotherapy for patients with limited-stage medulloblastoma treated at a single institute in China, and examined possible prognostic factors.
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SUBJECTS AND METHODS |
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PATIENTS
Between January 1996 and April 2001, 69 patients with medulloblastoma were referred to the Cancer Hospital, Chinese Academy of Medical Sciences, for radiotherapy after undergoing tumor resection. All cases were ruled out of gross nodule seeding in the subarachnoid space or hematogenous metastasis by craniospinal magnetic resonance imaging (MRI) before surgery, and routine checks including chest X-ray, ultrasonography and blood biochemistry were carried out. Cytological examination of cerebrospinal fluid and primary tumor bed evaluation after surgery were not complete. Thus, these patients belonged to Chang stage M0 or M1. Patients' ages ranged from 4 to 35 years (median, 11 years), and there were 40 male patients (M:F ratio, 1.67:1). Tumor size was measured during surgery. Five patients were lost to follow-up and were excluded from the analysis.
TREATMENT
All patients had undergone total or near-total resection of the primary tumor elsewhere (58 with total resection and six with subtotal resection under the naked eye). Emergent ventriculoperitoneal shunting was carried out in four patients before operating on the primary tumor. Three patients received postoperative ventriculoperitoneal shunting due to craniospinal fluid blockade after tumor resection. The same radiation technique was used for all patients. Patients were placed in a prone position, with the head and neck immobilized by use of a plastic mask. Bilateral opposite fields and 6–8 MV X-rays were used to irradiate the brain and posterior fossa. Spinal irradiation utilized electrons, 6–8 MV X photons, or mixed rays. The energy of electrons was selected according to the depth of the spinal cord. Two to three fields were established according to spine length, with the fourth sacral aperture used as the inferior limit of the spinal fields. If X-rays were used, a 0.5–1.5 cm gap was left between the brain field and spinal field or between the upper and lower spinal fields, corresponding to the depth of the spine. The whole-brain and spinal irradiation fields were usually partitioned immediately inferior to the fourth cervical vertebra. Each week, the gaps between fields were moved in the superior or inferior direction, a distance equivalent to the width of the gap. The standard regimen used for this patient population during the study period comprised a 30-Gy dose to the craniospinal axis, followed by a 20–25-Gy boost dose delivered to the posterior fossa. Doses were fractionated at 100–200 cGy per day (median fraction, 180 cGy). Median overall treatment time was 42 days (from 35 to 65 days). Chemotherapy was not used as initial treatment for this group of patients.
OUTCOME AND STATISTICAL ANALYSIS
All patients were followed for a median term of 38.5 months (range, 5 to 71 months) at intervals of 3–6 months for the first 2 years and 6–12 months thereafter. Relapse was identified by MRI or computed tomography (CT) imaging evidence of tumor recurrence. We calculated the probability of survival and disease-free survival after the end of the radiation therapy by the Kaplan–Meier method, and we compared these probabilities across groups by using the log rank test. The differences in patient characteristics and treatment between the early and delayed radiation groups were compared through crosstabs and independent-samples T test. (SPSS 10.0 software).
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RESULTS |
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For the group as a whole, the 3-year and 5-year survival rates were 68.8% and 55.7%, respectively, and the 3-year and 5-year disease-free survival rates were 57.8% and 51.4%, respectively (Fig. 1). Twenty-seven patients (42.2%) experienced recurrence within 3 years after irradiation. Disease recurred in the central nervous system (CNS) in 20 patients. After recurrence, 11 patients received a second course of local irradiation or stereotactic radiotherapy, seven received chemotherapy, five were treated with local radiation plus chemotherapy (chemotherapy regimens included various drug combinations based on cisplatin, vincristine, lomustine, methotrexate, adriamycin and procarbazine) and four received no additional antitumor therapy.
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We analyzed survival according to the interval between tumor resection and radiation (range, 13–60 days; median, 27 days). Radiotherapy was delayed because of surgical complications in some patients (infection in one patient; craniospinal fluid blockade in three patients) and by delays in the availability of radiotherapy in other cases. Radiation began within 25 days after surgery for 27 patients and after the 25th day for 37 patients. These two groups were comparable in age, tumor size and treatment; however, the group who waited longer for radiotherapy had a higher proportion of male patients (Table 2). The 3-year overall survival rate differed appreciably between these two groups (81.5% for radiotherapy within 25 days versus 59.5% for radiotherapy later; P = 0.11), and the rate of 3-year disease-free survival differed significantly (74.1% versus 46.0%; P = 0.03) (Fig. 2).
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In addition, we compared the survival of patients who were >10 years of age (n = 34) versus
10 years of age (n = 30) at the time of radiotherapy. The overall survival rates of these two groups were similar (70.6% versus 66.7%, respectively; P = 0.88). We then examined the effect of sex on survival. The 3-year survival rate was 67.5% for males and 70.8% for females (P = 0.49). We next analyzed survival according to tumor volume. Primary tumor volume calculated from the surgeons' measurements ranged from 9 cm3 to 294 cm3 (median, 80 cm3). When patients were divided into two groups according to tumor volume 
90 cm3 (n = 23) or <90 cm3 (n = 41), their 3-year survival rates were 65.2% and 70.7%, respectively (P = 0.37). The most common acute toxic effect of radiotherapy was hematological toxicity. Leukocytopenia (leukocyte count <4000/µl) was observed in 92.2% of patients, and 64.0% of patients had grade 2 or 3 hematological toxicity as defined by the NCI-CTC toxicity criteria (version 2.0).
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DISCUSSION |
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Medulloblastoma is a relatively radiosensitive and curable tumor (2). A 5-year survival rate of 60–80% can be achieved by using combined surgery and radiotherapy with or without chemotherapy (3,7–14). With combined therapy, Kortmann and colleagues (15) achieved 70% 3-year disease-free survival in 137 medulloblastoma patients, and Prados et al. (22) reported 3-year disease-free survival of 63% and 5-year survival of 69% in patients with average-risk medulloblastoma (risk classification is listed in Table 1). The 3-year and 5-year survival rates of 68.8% and 55.7%, and 3-year and 5-year disease-free survival rates of 57.8% and 51.4% obtained in our study group were less satisfactory. The patients in this study were a combination of average-risk and high-risk groups of medulloblastomas, and the relatively low dose of CSI (30 Gy) given in the absence of adjuvant chemotherapy could explain the possible reasons. The standard dose of CSI for average-risk medulloblastoma was, at one time, 36 Gy (2,5). Although the dose was subsequently reduced because of long-term toxicity and the risk of secondary tumors, a lower dose of CSI was found to be associated with inferior outcome in the absence of adjuvant chemotherapy. In a cooperative study by the Children's Cancer Group and Paediatric Oncology Group (23), 126 average-risk patients were randomized to receive either standard-dose (36 Gy in 20 fractions) or reduced-dose (23.4 Gy in 13 fractions) neuraxis irradiation. Both groups received a total dose of 54 Gy irradiation to the posterior fossa. The event-free survival rates at 5-years were 67% in the standard-dose group and 52% in the reduced-dose group (P = 0.08). Whereas reduced-dose radiotherapy was established later when combined with chemotherapy in patients with average-risk disease, in a Children's Cancer Group study (5), 65 children between 3 and 10 years of age with nondisseminated medulloblastoma were treated with postoperative, reduced-dose CSI therapy (23.4 Gy) and 55.8 Gy of local radiation therapy. Adjuvant vincristine chemotherapy was administered during radiotherapy, and lomustine, vincristine and cisplatin chemotherapy was administered after radiation. Progression-free survival was 86 ± 4% at 3 years and 79 ± 7% at 5 years. These overall survival rates compared favorably with those obtained in studies using standard-dose radiation therapy alone (
60% at 5 years). For high-risk medulloblastoma, survival has been improved in the recent years after standard-dose radiotherapy combined with adjuvant chemotherapy (6,24,25). Considering the low-dose CSI and level of risk case-enrollment, the treatment of medulloblastoma in this study was insufficient, resulting in a high treatment failure. Paulino et al. (26) reported that protracted duration of radiotherapy would dwarf the progress-free survival rate in medulloblastoma. When we investigated the effect of radiotherapy delay, we found that the interval between surgery and radiotherapy affected both the probability of 3-year overall survival and 3-year disease-free survival. Radiation begun within 25 days after surgery carried a favorable result, especially for disease-free survival. In an analysis of adult patients with medulloblastoma who underwent identical postoperative radiotherapy, Abacioglu et al. (27) also found the interval between surgery and the start of radiotherapy to be significantly prognostic of disease-free survival. The 5-year disease-free survival rates were 85% for patients who waited 3–6 weeks and 75% for patients waiting more than 6 weeks before beginning radiotherapy. These findings suggest that radiotherapy for medulloblastoma should begin as soon as possible after the surgical wound has healed.
The prognostic importance of age and sex in patients with medulloblastoma has always been controversial (8,12,14,15,17,21,28). We found no significant difference in survival between patients >10 years and 10 years of age, or between male and female patients. Bouffet et al. (17), Aragones et al. (21) and Silverman and Simpson (28) also concluded that age and sex are not prognostic factors in patients with medulloblastoma. Although very young children (2 years) do have a worse prognosis than older ones, this discrepancy may reflect inadequate treatment of the very young (low-dose irradiation without proper chemotherapy). With optimal treatment, the difference might be less substantial.
The survival difference between tumor size of 90 cm3 and <90 cm3 was not statistically significant in this study. Reports from other authors also suggested prognosis of Chang's T stage to be less important than Chang's M stage (8,29).
In conclusion, we have shown that a delay of radiotherapy after surgery adversely affects the outcome of patients with medulloblastoma. Age, sex, and tumor size are not prognostic factors when modern therapy is given.
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Acknowledgments |
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The authors would like to acknowledge Mr Shengjie Wu from St Jude Children's Research Hospital (USA) and Junxin Wu from Cancer Hospital, Chinese Academy of Medical Sciences for their assistance in biostatistical analysis of our data, and we would like to thank Sharon Naron, MPA, ELS, from St Jude Children's Research Hospital for editorial review.
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References |
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