Survival Study in Pediatric Patients with Medulloblastoma in a General Hospital in Tehran, Iran

Brain tumours are the most common solid tumours that afflict the pediatric population^[1]. Medulloblastoma (MB) is the most common malignant brain tumour in children, constituting nearly 20% of all pediatric brain tumours^[2]. MB is a malignant tumour that frequently arises within the cerebellum. It is categorised as an embryonal neuroepithelial tumour of the cerebellum^[3]. This is a high-grade tumour that has a tendency to spread via the cerebrospinal fluid (CSF). MB is classified as grade IV in the World Health Organisation classification because of its destructive course^{[4, 5]}. This type of tumour is one of the most routine brain tumours occurring in children. MB occurs most commonly in patients between 5 and 7 years of age. This cancer accounts for 25% of all childhood brain tumors and approximately 40% of pediatric posterior fossa tumors^[6]. In the first few years after diagnosis, mortality approximates 15%; however, cure rates reach as high as 60% with current therapeutic modalities. Surgical resection followed by radiation and chemotherapy is the basis of therapy, with five-year survival rates of between 50% and 90%^[7]. This extensive range is multifactorial, owing in part to age at diagnosis, the presence of metastases at diagnosis, and a histologic variant of MB^[8]. Tumour removal followed by craniospinal irradiation and chemotherapy comprise the treatment protocol in the pediatric population. With the risk-adapted therapy approach, the five-year overall survival (OS) rate in childhood nonmetastatic patients is now greater than 80% in many institutions^{[7, 9]}. Unfortunately, the tumours have an affinity to metastasize through the subarachnoid space. Thirty-two percent of patients showed CSF spreading at diagnosis^[3]. Various factors have been studied to identify significant prognostic factors such as age and stage of disease. Therefore the differences in survival should be related to differences in tumour biology^[12]. There were few scientific research studies about the survival of pediatric patients with MB in the Islamic Republic of Iran.

Due to the small number of articles and research studies conducted in pediatric patients with MB, conducting clinical trials is difficult and data are relatively limited. We therefore performed a retrospective study of pediatric MB patients. The purpose of this study is evaluation of overall survival rates of pediatric patients with MB at one year, three years, five years, and ten years according to the cases. This study could thus help further the treatment of this group of patients, and we believe a survival study is essential to evaluate the current situation in treatment.

Most MB patients are identified between the ages of 5 and 10 years old, accounting for 25% of cases of pediatric brain tumours^[7]. Because MBs in adults are rare, few potential clinical trials have been performed so actual survival rates and prognostic factors are difficult to measure^[8]. The differences in patient outcomes could be due to metastasis, remaining tumour, adjuvant chemotherapy, tumour location, and histological subtypes^[13]. Tumour penetration of the floor of the fourth ventricle was the only independent prognostic factor in our series (p = 0.032); only a few studies have reported this finding^[14]. Wefers et al.^[15] found that type c and type d MB most often contacted both cuneate and cochlear nuclei and always infiltrated the fourth ventricle. Pediatric MB is distinct from adult MB in terms of molecular staging and clinical outcomes. Incomplete resection has been found to affect outcome in some studies^[16], but no difference in survival has been noted in others^[17]. This is because near total removal was performed in the majority of patients and new diagnostic tools are more sensitive in detecting remaining tumour. Histology might be important in MB outcomes^[18]. According to our findings, patient survival rate was quite poor. About 4.5% of the patients could not be included in adjuvant therapy due to their poor condition after surgery. Twenty-three percent of the patients experienced death or relapse within four months after surgery, and patients’ median PFS was about 5 months (Table 2). We found a similar result to Nalita et al.^[5] about MB survival in Iran. In their report, the median length of survival of patients is about 150 months. The age distribution of DNMB is bimodal, with peaks in early childhood and adulthood. Long-term follow-up is important because late relapse has been reported to be more common in childhood^[19]. In a study based on the SEER database, Smoll^[20] reported a “fork-like” Kaplan–Meier survival curve and an “age-by-follow-up interaction” only after four years. Differences in survival between adult and pediatric patients could emerge only four years after diagnosis and adults are reported to have poorer survival rates^[20]. This was confirmed in our study, especially in the high-risk group. In our cohort, 4 of 22 high-risk-group patients relapsed after four months and only one was alive without relapse at the time of follow-up. Many authors have reported no significant difference between average-risk and high-risk patients and no difference between adult and pediatric patients, but observed difference has related to the bias in information about the patients’ general condition before and after surgery. Patients whose treatment has not included adjuvant therapy had worse outcomes. Median survival of this group of patients is about four months, and only one patient in this group had survived as long as two years. However, this could be in part due to the lack of long-term follow-up. Whether chemotherapy should be administered to adult MB patients is currently under discussion^[21]. Adjuvant chemotherapy has been recommended in recent years to patients in both the average- and high-risk groups^[18]. It seems that our data also show a trend toward better OS for high-risk-group patients who received conservation chemotherapy. Call et al.^[21] recently proved that chemotherapy was related to a decreased risk of relapse in the posterior fossa in high-risk patients with classic histology (n = 25). A trend toward better OS was also noted in this small group. Friedrich et al.^[16] published the outcomes of adult MB patients treated in the HIT2000 trial. Patients treated with a reduced dose (23.4 Gy, n = 9) and maintenance chemotherapy had a similar PFS and OS to those treated with the standard dose (35.2 Gy, n = 47), with or without chemotherapy. In our study, though, patients who had chemotherapy had a relatively better survival rate than the rest of the patients, although other factors such as tumour stage were also very important. This long-term follow up study showed that the incidence of return increased markedly after two years. It should be noted that the number of patients who received adjuvant chemotherapy in our study and in previous studies is small, making it difficult to identify a significant difference. The exact value of chemotherapy in treating pediatric MB has to be studied further in prospective clinical trials. In the literature, many factors in MB can improve the survival rate, such as histology variants, metastasis, and chemotherapy. The limited number of samples in this study was a primary limitation. Histologically, the DNMB variants reported the best prognosis^[18], and LC/A variants had a poor prognosis. The majority of tumours were CMB, however, so DNMB and LC/A variants were rare. Differences in survival rates between histology variants were insignificant in this study.

In conclusion, MB patients’ survival was quite good in our hospital. However, the result has been similar to reports by other centres and in other countries. More than half of the patients survived the ten-year follow-up period without any problems; most of them had LC/A MB and CMB. These data prove that late mortality remains a significant problem in these patients. The causes of death are largely attributable to disease recurrence and secondary malignancies. Efforts to improve risk factors and appropriate therapy will help in decreasing late mortality in this population. Further prospective or retrospective clinical trials should be performed to confirm our findings.