|Year : 2006 | Volume
| Issue : 2 | Page : 49-55
Medulloblastoma in children: Birmingham experience
Anil Sivasankaran, Spyros Sgouros, Richard Walsh, Anthony Hockley
Birmingham Children's Hospital, Birmingham, United Kingdom
67, Persiaran Blm 2, Bandar Laguna Merbok, 08000, Sungai Petan, Kedah, Malaysia
Source of Support: None, Conflict of Interest: None
| Abstract|| |
A retrospective review of 41 children diagnosed with medulloblastoma in Birmingham (United Kingdom) between 1992-2002 presented. The age of the patients ranged from 2 weeks to 14.1 years (mean 5.89 years) and the mean follow-up was 3.8 years. Children less than 3 years of age fared worse than those over 3 years. The 5-year survival with total and subtotal tumor excision was 61.3 and 40% respectively. Those children who received radiotherapy following surgery had an improved survival of 68% at 5 years as compared to 18% in those who did not receive irradiation. With regards to chemotherapy, the 5-year survival rates were 57% in those who received it and 52% in those who did not. The overall survival was 62% at 5 years for those patients who had postoperative combined radiotherapy and chemotherapy and only 48% for the rest, who received no adjuvant therapy. Age of the patient has a definite influence on overall survival. We found significant statistical difference in survival between patients with total tumor resection and those with subtotal resection. The 5-year survival rate was not directly affected by tumor location, hydrocephalus or ventriculo-peritoneal shunting. Postoperative irradiation and chemotherapy are clearly associated with improved survival.
Keywords: Medulloblastoma, primitive neuroectodermal tomour.
|How to cite this article:|
Sivasankaran A, Sgouros S, Walsh R, Hockley A. Medulloblastoma in children: Birmingham experience. J Pediatr Neurosci 2006;1:49-55
Medulloblastoma is the second commonest posterior fossa tumor in children and represents 15-25% of central nervous system tumors in the population under 20 years of age.,, It is a malignant invasive embryonal tumor with inherent tendency to metastasize via the cerebrospinal fluid (CSF). Patients with this tumor usually present in the first decade of life and 70% are diagnosed when they are less than 8 years old. Also known as primitive neuroectodermal tumors (PNETs), medulloblastomas are located in the midline of or within the cerebellar hemispheres.
Management consists of perioperative corticosteroids, surgery, radiotherapy and chemotherapy., Craniospinal irradiation is administered to children over 3 years of age. Younger children and those who are considered to be at poorer risk receive adjuvant chemotherapy. This has led to an improved survival, with a 5-year survival rate now around 50-70%, as opposed to 2-11% in the 1960s and 1970s., In children less than 2 years of age, the mortality is 100% in 2-3 years. Once there is recurrence, prognosis is very dismal and the patients usually die within a year. Complications of therapy, primarily of radiotherapy, include growth and thyroid deficiencies. Deficits in psychosocial and neuropsychosocial functioning (i.e., intelligence, short-term memory and academic skills) have also been reported.,,,
This paper reviews the outcome in pediatric patients with medulloblastoma diagnosed and treated at the Birmingham Childrens Hospital, Birmingham, United Kingdom between 1992-2002.
| Materials and Methods|| |
Charts were made for all children diagnosed with medulloblastoma from the medical records department at the Birmingham Children's Hospital, Birmingham, United Kingdom 1992. Each chart was reviewed and the following data were obtained: age, sex, date of birth, symptom and signs, length of symptoms before diagnosis, diagnostic imaging tool, extent of surgery (gross total vs. subtotal resection) and presence or absence of hydrocephalus and/or a ventriculo-peritoneal shunt. The extent of tumor resection was determined by the surgeon's impression and findings of the postoperative imaging. If the surgeon had noted that more than 90% of the tumor had been removed or if there was a residual tumor (<1.5 cm) on postoperative scan, the patient was judged to have undergone a subtotal resection. Radiation and chemotherapy protocols, follow-up neuroimaging, metastatic work-up, endocrine status and neuropsychological functions were reviewed. The length of survival, time of relapse and time of death were noted. Outcomes were based on the following factors: sex, tumor location, tumor metastasis, total vs. subtotal resection, treatment with radiation and /or chemotherapy, development of hydrocephalus, presence of ventriculo-peritoneal (VP) shunt and histopathology of the tumor.
Statistical analysis was done with the 'SPSS 8.0 for Windows' program. Means and standard deviations were calculated. In addition, Kaplan-Meirs curves were constructed to compare survival with different factors.
| Results|| |
Between 1992 and December 2002, 41 children between the ages of 2 weeks and 14.1 years (mean 5.8, median 6.0, range 2 weeks - 14.1) were diagnosed with medulloblastomas. There were 23 boys and 18 girls.
Vomiting was the commonest presenting symptom (85%), followed by headaches in 70%. Difficulty with balance was present in 52% of patients. The commonest signs on physical examination were papilledema (67%), ataxia (52%) and dysmetria (33%). Patients were diagnosed between 3 days and 24 months (mean 3.7 ± 5.4 months) after the onset of symptoms. Brain CT was the primary mode for imaging of the tumor. (Thirty-five patients were diagnosed using CT.) MRI has been used for better delineation of the tumor. Altogether, only six neurosurgeons were involved in the management of these cases.
Tumor location and surgery
In 50% of children, tumor was present in both the cerebellar hemisphere and the vermis, while 39% had tumor only in the midline and 11% had tumor solely in the cerebellar hemisphere at the time of diagnosis. Patients were started on intravenous dexamethasone soon after diagnosis. All patients underwent a midline suboccipital craniotomy. Total resection of the tumor was performed in 31 patients (61%), subtotal in 9 (33%) and 1 patient had no surgical intervention. Although hydrocephalus was present in 58% of the patients at the time of diagnosis, only 40% eventually required a CSF shunting procedure. Eight patients had shunt insertion prior to tumor resection and the remaining 8 had shunt insertion during or after the resection of tumor. Only 2 patients had repeat surgery for tumor recurrence. Histopathological diagnosis confirmed the type of tumor in all cases. The tumors were described as desmoplastic (2 patients), neuroblastic (7 patients), astrocytic (2 patients), desmoplastic and neuroblastic (1 patient), neuroblastic and astrocytic (1 patient), melanotic and glioblastomous (1 patient), mixed neuroblastic, astrocytic and desmoplastic (2 patients). The remaining 25 reports mentioned PNET or medulloblastoma only as the histopathological diagnosis. Four patients had postoperative metastases with grave prognosis.
Radiotherapy was completed at the oncological center at Birmingham Children's Hospital, Birmingham. Thirty patients (67%) received radiation to the craniospinal axis with a boost to the posterior fossa. The remaining patients were below 3 years of age. Radiation therapy consisted of 3,000-4,000 cGy administered to the craniospinal axis (fractionated), with a boost of 500-2,000 cGy to the posterior fossa.
Chemotherapy was administered at the oncology unit, Birmingham Children's Hospital, Birmingham. Twenty-two patients (55%) received the SIOP trial (carboplatin, vincristine, cyclophosphamide, etoposide). Since 1991 most of the patients were treated with vincristine, cyclophosphamide, etoposide, cisplatin or carboplatin. In seven patients, chemotherapy was not completed owing to lack of tolerance or withdrawal of treatment or because the patient died.
Patients were followed up for a mean of 3-8 years (0 to 11.3 years). Patients were seen frequently in the neuro-oncology and neurosurgery clinics over the first few years for repeat CT or MRI to detect tumor regrowth or recurrence. No patient was lost to follow-up.
The neuropsychological outcome of these children was examined. Cerebellar syndrome (comprising of diplopia, gait ataxia, dysmetria, dysdiadochokinesia and mutism) was seen in 10 patients. Pseudomeningocele was seen in 3 patients, hemorrhage in 3 patients (2 intracerebellar and 1 intraventricular) and hydrocephalus in 6 patients.
Septicemia was the main complication in patients receiving chemotherapy (5 patients). Endocrinological disturbances were seen in 10 patients post-radiotherapy. Growth hormone deficiency was seen in all of them and only one was hypothyroid. Chronic hepatic dysfunction was seen in 6 of them.
Recurrence and survival
Nineteen patients died between 0 weeks and 11.3 years after diagnosis (means±SD 3-83±3.11 years). This includes three children who had postoperative MRI free of tumor-developed recurrences and died within 1 to 11 months after recurrence. All patients who had recurrences or metastatic lesions during follow-up died. Metastases were found in the spinal cord, brainstem or meninges.
The 1-year survival rate was 83% [Figure - 1]. The mean and median survival time was 6.44 and 9.0 years respectively. The male and female ratio was 1.25:1 and the gender ratio for deaths was 2:1. No significant difference was found between male and female survival rates or between different locations of tumor in the cerebellum (cerebellar hemisphere or vermis or both). Only two patients with hemispheric involvement died. Presence of hydrocephalus or a ventriculo-peritoneal (VP) shunt did not make a difference in terms of survival, nor was there any patient identified with abdominal metastasis as a result of the VP shunt.
Children who had gross total resection of the tumor appeared to have fared better, with a mean survival time of 7.4 years; whereas those with subtotal resection had a mean survival time of 4.24 years. Only 1 patient was not subjected to surgery and his mean survival time was 2 months. Overall, the survival analysis showed a 61.29% survival for 31 patients who underwent gross total resection. The overall survival was 53.66% [Figure - 2].
Thirty patients received radiotherapy and the mean survival time in this subgroup was 7.90 years, while a mean survival time of 1.35 years was noted in the remaining 11 children who did not receive such treatment. The survival analysis showed 66.67% survival in these 30 patients and only 18.18% survival in the rest, who had no radiotherapy [Figure - 3].
The 22 patients who received chemotherapy showed a mean survival time of 6.79 years (median 9.00); and the remaining 19, who were not treated with chemotherapy, showed a mean survival time of 4.94 years. The survival analysis showed 54.55% survival for those who received chemotherapy and 52.63% for those who did not [Figure - 4].
When survival analysis was done on 17 patients who received both these modalities of treatment, radiotherapy (DXT) and chemotherapy (CXT), following surgery, the mean survival time was 7.29 (median 9.00) compared to 4.80 years (median 2.80) for the remaining 24 cases, who received none of these therapies. The overall survival was 58.82% for these 17 patients compared to 50% for the remaining 24 patients [Figure - 5].
The 25 patients who underwent gross total surgical resection followed by radiotherapy to tumor bed and craniospinal axis showed a mean survival time of 8.15 years, while the remaining patients who underwent subtotal resection followed by radiotherapy had a mean survival time of 7.20 years. The 6 patients who had gross total surgical resection with no radiotherapy had a mean survival time 2.10 years. Those 4 patients who underwent subtotal resection with no radiotherapy had a mean survival of 0.55 years. Only one patient, with no treatment, showed a mean survival of 0.02 years. The overall survival analysis showed the following [Figure - 6]:
1. Gross total surgery + DXT 68% survival
2. Subtotal surgery + DXT 60% survival
3. Gross total surgery alone 33% survival
4. Subtotal surgery alone 18% survival
From the above analysis, it's quite clear that multimodality treatment regimes help in the overall prognosis of the disease.
| Discussion|| |
Over a period of 9 years, 41 children were diagnosed and treated for medulloblastoma at the Birmingham Children's Hospital, a tertiary referral center for children in United Kingdom. The age of the patients at initial diagnosis varied widely - from 2 weeks to 14.1 years. All children were less than 15 years of age and 28 of them were above 3 years. Although some authors have shown that girls have a better outcome than boys, our results failed to indicate any sex-related difference. Vassilyadi et al had similar results. However, there is a small proportional increase in incidence of male preponderance to the tumor.
We only had 13 children who were less than 3 years of age; 7 of them died within 2 years of diagnosis. The 5-year survival for this subgroup was less than 20% compared to 62% for the rest. Others have reported survival rates of <12%, 38%, 40% and 50% in similar groups. While some studies indicate that younger age at diagnosis is associated with a poor prognosis,,, a review by Giordana et al. concluded that the prognostic role of age is uncertain, because several studies have found no age-related difference in survival.
Our 1-year survival rate of 83% is comparable to the rates reported in other series., In the long term, we have had excellent survival results - 62% at 5 years. This is also comparable to other survival reports, which range from 50-70%.,,,,, The most common presenting symptoms reported in the past have been vomiting, headache, ataxia and cranial nerve deficits., Our patients had similar presentation. Children below 3 years were diagnosed earlier than the others. This may be because their tumors were more aggressive (7 of 13 died). It has been reported in the past that the shorter the duration of symptoms, the more advanced the disease., In this group of patients, the mean time of diagnosis after onset of symptoms was 3 months. This was longer than previously reported periods, anywhere in the range of 6 weeks to 3 months.,,
Tumor location within the posterior fossa has been reported to have prognostic value. Laterally placed (hemispheric) medulloblastomas have been reported to have more favorable rates of freedom from relapse.,, In our series and in the series by Vassilyadi et al and Modha et al, there was no difference in survival with respect to different locations of tumor in the posterior fossa. Medulloblastomas with desmoplastic features have been reported to result in a more favorable length of survival.,,, This may be because of the nodular nature and accessible location of these tumors in the cerebellar hemisphere that make their removal relatively simpler and easier. Other studies show no difference in survival outcomes with respect to different histological types of this tumor., Unfortunately we did not have sufficient data to compare survival rates with respect to various histopathological types of medulloblastomas.
In the pediatric population, the extent of surgical resection has been found to influence survival rates.,,,,, Resection of 90% or greater of the tumor is associated with improved survival at least in children older than 3 years without evidence of tumor dissemination., Some studies have indicated that even a residual tumor of less than 1.5 cm 3 size is associated with good prognosis., Although others have suggested that the extent of tumor resection is not a reliable prognostic factor,, we found a significant difference in survival outcomes between patients who had a gross total tumor resection as compared to those who had subtotal resection and a trend towards better survival was apparent in the total resection group [Figure - 2]. Contrary to a high mortality of 14% reported in the literature, we did not experience any death in our series. The 5-year survival rates have been reported as 59-75% for total removal and 35-49% for subtotal resection in the previous series,,,,, whereas the corresponding figures in our study were 62 and 33%.
Approximately 34% of our patients underwent shunting, which was comparable to other reviews of 25-40%.,, There is no clear view in the literature on the prognosis in medulloblastomas associated with hydrocephalus and/or the presence of a CSF diversion shunt. VP shunting was recognized as a poor prognostic factor in several studies, including the one from the Memorial Sloan-Kettering Cancer Center. However, our results clearly indicate that hydrocephalus on admission and/or presence of a ventriculo-peritoneal shunt did not make a difference in overall survival, which was supported by other studies., In addition, none of our shunted patients developed abdominal metastasis, supporting data that indicated that shunting does not increase the rate of metastasis.
Craniospinal irradiation has provided the single greatest improvement in survival of children with medulloblastoma. Radiation significantly reduces recurrence and metastasis. In this series, seven children under the age of 3 years and a majority of the rest received radiation treatment in conventional dosage. There have been several reports about treatment with low doses of radiation, but so far there have not been any randomized controlled trials comparing low versus high doses. There have been case series showing that when adjuvant chemotherapy was associated with low-dose radiotherapy, the rate of failure of treatment did not increase and the 5-year survival rates were similar to those who received conventional doses. In one study, the posterior fossa boost did not influence prognosis.
Since the mid-1980s, chemotherapy has been given to younger children (<3 years) with extensive tumor invasion or incomplete resection to prevent recurrence. Chemotherapy apparently improves prognosis in this age group, to the point where irradiation may be postponed until the child is older. Studies done at the M. D. Anderson Cancer Center with MOPP (mechlorethamine, vincristine, procarbazine, prednisolone); and by the Pediatric Oncology Group with vincristine, cyclophosphamide, etoposide and cisplatin; have shown improved survival in children below 3 years of age. Another study by the Children's Cancer Group has also indicated that chemotherapy significantly increases the tumor-free time. In all three studies, radiation treatment was either postponed until the child was older than 3 years or was not given at all. While chemotherapy delayed relapse in a series reviewed by Belza et al, it did not demonstrate a long-term survival advantage for patients. However, other authors believe that no significant benefits can be derived from chemotherapy prior to radiation in children with nondisseminated disease.,,, Presently MOPP is the most effective regimen in children less than 3 years of age. Although the optimal regimen in older children remains unclear, Packer et al. have shown very good survival rates with vincristine, CCNU and cisplatin. In the study carried out by Modha et al, vincristine, cyclophosphamide, etoposide and cisplatin (POG9031); or ifosfamide, carboplatin and etoposide; have been used, which showed no better prognosis as proven by the Memorial Sloan-Kettering Cancer Center study by Merchant et al. In their study, children who had chemotherapy had a worse outcome than those who did not. This may be because these children were more affected with the disease and had worse tumor characteristics. In our series, 22 children received chemotherapy and showed overall survival of 54.5%. The survival in the remaining 19 patients who did not receive chemotherapy was 52.6%. When the mean survival time was considered, there was an increased survival by 29 months for those who received chemotherapy as compared to those who did not, making this treatment modality significant.
There was no patient lost to follow-up in this series. These patients were carefully followed up in the neurosurgery, endocrinology and oncology clinics regularly and transferred to an adult institution once they were old enough. Surveillance neuroimaging was frequently performed. Recent report suggests that this may not be necessary and scanning should be done only if the patient becomes symptomatic.,,
Collin's law predicts that a relapse will occur within the time determined by the patient's age at diagnosis plus 9 months. In our series, this was true for the 2 patients (5%) who had recurrence. Cervoni and Cantore had a 77% recurrence rate, while Modha et al. had a 28% recurrence rate that also followed Collin's law. Brown et al, who obtained data from Childhood Brain Tumor Consortium, reported that only 38 children with medulloblastoma were found not to have followed Collin's law prior to 1995. Children less than 3 years of age have been reported to have a higher rate of both recurrence (100% vs. 65%) and metastasis (44% vs. 28%) than those older than 3 years. In our series, 10 out of 13 children under 3 years of age died as a result of recurrence of the primary tumor or metastases. This study confirms previous reports that relapse invariably leads to death. In addition, we found that all children who developed metastases fared worse than the others. Only 2 children developed metastases to other organ system (lymphatics). A recurrence-free period of 8 years was considered to be a cure in this disease in a retrospective review of 77 patients at Stafford University Medical Center. In our series, the incidence of recurrence was dramatically reduced after 5 years, with all deaths occurring within the first 3 years of diagnosis. In the other series reviewed, the rate of 10 years' survival was reported to be lower than that of 5 years' survival.,,,,
In this study, 9 patients were found to be GH deficient and they were treated with growth hormone supplements. A retrospective review of 38 children with PNET followed over 4 years showed that the average growth velocity was below the mean for age and sex. This study looked at the growth velocity standard deviation scores (GVSDS) of children who received radiation versus those who received both chemotherapy and radiotherapy. Significantly reduced GVSDS were found in both groups relative to a normative sample. In addition, those who received chemotherapy and radiation had significantly lower GVSDS than those who received radiation alone. Chemotherapy probably potentiates the effects of radiation on growth in such a way that children surviving chemotherapy grow poorly regardless of the chemotherapeutic regimen. The estimated minimum dose of craniospinal radiotherapy that causes GH deficiency is 18-20 Gy., At least 24 Gy is needed to treat the craniospinal axis., Radiation also reduces spinal growth., The higher the radiation dose, the worse is the spinal growth. Similarly, the younger the child, the more adverse the effect radiation has on spinal growth. In addition, there is a linear association between age at irradiation and age at onset of puberty (i.e., the younger the patient at the time of radiotherapy, the earlier puberty would set in), decreasing the time available for GH treatment. Impaired GH response to insulin-induced hypoglycemia has also been reported.
Radiotherapy has been associated with impairment in neurocognitive functions., Other factors may also be implicated, including tumor size, hydrocephalus, chemotherapy; and perioperative factors, such as obtundation.,, Cognitive deficits have been related to the destruction of oligodendrocytes and endothelial cells, diffuse multifocal white matter hyperintensities and calcifications in the cortical gray matter and basal ganglia. Impaired academic achievement and poor psychosocial functioning have been found in this population. In addition, difficulty with perceptual motor coordination, sequencing and memory have also been reported in survivors of medulloblastoma.,,, Children may obtain lower scores on age.,, Younger age at diagnosis is also related to a decrease in intelligence over time and there is progressive degradation of I.Q. over the years.,, Lower doses of radiation are associated with less intellectual impairment.
| Conclusion|| |
The 1-year survival rate of 83% and the 5-year survival rate of 62% are comparable to outcomes reported by other centers. Children less than 3 years of age fared worse than those over 3 years. Gender did not influence survival. Statistical difference in survival was found between patients who had total resection and those who had subtotal resection. There was no significant influence on survival by tumor location, hydrocephalus or ventriculo-peritoneal shunting. Postoperative radiotherapy clearly showed a significant survival and so did chemotherapy. The recurrence rate followed Collin's law and recurrence led to death within 12 months. However, any child with no recurrence by 5 years after diagnosis had a very good probability of survival.
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[Figure - 1], [Figure - 2], [Figure - 3], [Figure - 4], [Figure - 5], [Figure - 6]
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