Medulloblastoma is the most common primary malignant brain tumor in children and is one of the most malignant neuroepithelial tumors of the central nervous system. It has reached an incidence rate that is second only to astrocytoma among all pediatric CNS tumors. It is a malignant tumor that seriously threatens the life and quality of life of children. In recent years, research on the pathogenesis and treatment of childhood medulloblastoma has progressed rapidly, and the survival rate of patients has improved dramatically, with 5-year survival rates of up to 80-90% or even more often reported abroad, and long-term survival can be achieved in a significant proportion of cases. The previous impression about the poor prognosis of the disease has been completely changed. On the other hand, with the common application of postoperative radiotherapy, the issue of how to deal with the immediate and long-term complications after radiotherapy has also received increasing attention. In this article, we focus on radiotherapy, chemotherapy, and prognosis to review new advances and new perspectives in the treatment of pediatric medulloblastoma in recent years.
Medulloblastoma grows in the cerebellum and quadrigeminal ventricles and is second only to astrocytoma in incidence. The peak age of onset is around 7 years. Medulloblastoma has a high tendency to metastasize to the leptomeninges and is particularly common in younger children.
Medulloblastoma (MB) is the most common primary malignant brain tumor in children and is one of the most malignant neuroepithelial tumors of the central nervous system. It is a type of primitive neuroectodermal tumor (PNETS) and is classified as grade IV in the WHO classification of neurological tumors.
PNETS is a type of embryonal tumor of the nervous system, which is extremely malignant, originates from embryonic remnant cells, and can occur anywhere in the brain tissue. PNETS in the cerebellum is called medulloblastoma, so medulloblastoma is also called primitive neuroepithelial tumor of the cerebellum; similar structures in the brain and spinal cord are collectively referred to as PNETS. MB originates from embryonic remnant tissue. One possibility is that it originates from the outer granule cell layer of the cerebellar embryo, which gradually disappears about six months after birth. The other may originate from primitive cells in the proliferation centers of the ventricular canal of the posterior medullary sails, and these cells may persist for several years after birth.
MB is a tumor that is sensitive to both radiotherapy and chemotherapy. Standard postoperative treatment includes radiotherapy and chemotherapy.
The prognosis of children with MB has improved significantly in recent years, with a 5-year survival rate of 90% being achieved in some children with early MB. The improvement in treatment outcome is mainly attributed to three aspects.
(1) improvements in surgical techniques.
(2) the use of radiotherapy, especially whole brain and whole spinal cord radiotherapy.
(3) the increased awareness of the role of chemotherapy in the treatment of MB in children in recent years.
The current difficulties in the treatment of medulloblastoma are mainly two.
(1) how to deal with the long-term complications such as cognitive impairment and growth retardation caused by conventional doses of radiotherapy in children.
(2) How to reduce the side effects of radiotherapy and at the same time improve the survival rate of pediatric medulloblastoma patients of low age.
1. Grading, staging and clinical prognostic factors of MB
The usual international grading method is to divide pediatric MB into high-risk and low-risk groups. The grading is mainly based on.
(1) the presence or absence of subarachnoid metastases (2) the age of the patient (3) the size of postoperative residuals.
Table 1. Grading of MB in children
Low-risk group, high-risk group
Age at first diagnosis ＞3 years ≤3 years
M0 stage
Postoperative residual <1.5 cm2 >1.5 cm2
Studies have proven that the presence of subarachnoid metastasis and the patient’s age are definite prognostic factors. In recent years, more and more scholars believe that postoperative residuals do not affect the prognosis of patients, on the grounds that MB has no obvious pathological boundaries and “total resection” in the strict sense is not possible, while a small amount of postoperative residuals can be completely killed by postoperative adjuvant radiotherapy.
In fact, the most commonly used method for grading MB in children is the Chang’s staging system for MB in the posterior cranial recess.
Table 2. Chang’s posterior cranial recess MB staging system
Tumor in situ
T1 tumor <3 cm in diameter; limited to the earthworm, parietal four ventricles, or partially invading the cerebellar hemisphere
T2 tumor ≥3 cm in diameter; further invasion of adjacent structures or partial filling of the four ventricles
T3a tumor invades more than two adjacent structures or completely fills the four ventricles (extends to the aqueduct, posterior median foramen or both foramina) and is accompanied by significant hydrocephalus
T3b tumor originates from the base of the four ventricles and fills the four ventricles
T4 tumor extends further through the aqueduct into the third ventricle or down into the upper cervical medulla
Presence of disseminated metastases
M0 No evidence of subarachnoid metastasis
M1 cytology of cerebrospinal fluid reveals tumor cells
M2 Nodal metastases found in the subarachnoid space of the brain or in the three lateral ventricles
M3 Nodal metastases found in the spinal subarachnoid space
M4 extra-neurological metastasis
The definition of M staging relies on neuroimaging and CSF cytology. Ideally, the assessment should be done preoperatively, i.e., both imaging and CSF cytology should be done preoperatively. This is because postoperative neuroimaging and CSF cytology components will inevitably be affected by the procedure. If MRI or CSF cytology cannot be completed preoperatively, then both should be performed at least 10-14 days after surgery to avoid artificial effects of the procedure. This is because in many cases tumor cells can already be detected by lumbar puncture CSF at intracerebroventricular CSF (-).
The prognosis is usually considered good for patients with stage M0 and poor for patients with stages M1-4. The same conclusion was reached by Zeltzer and Kortmann.
2. Biological prognostic factors
Recent advances in the study of molecular and cellular tumor biology have led to a new understanding of the mechanisms underlying the development of MB. Several researchers have found that there is a correlation between the degree of tumor cell apoptosis at the onset of MB and the prognosis of patients. Several researchers have used a deoxyribonucleic acid translocase end marker to detect the degree of apoptosis in tumor specimens from 43 children with MB. The authors found that tumor specimens with a high apoptotic index (i.e., average number of apoptotic cells per high-powered field of view) always corresponded to a good prognosis for the child, and that this biological index had an independent effect on prognosis, independent of clinical grade (high- or low-risk population).
A research group found that expression of TrkC, a high-affinity neurotrophic factor receptor, in children with MB always resulted in a good prognosis. Although the exact role of neurotrophic factors in tumor growth is unknown, it is hypothesized that TrkC mediates apoptosis through neurotrophic factor-3 activation, which in turn inhibits tumor growth.
Grotzer analyzed the expression of TrkC in formalin-fixed tumor specimens from 87 children with PNETS. Using one-way ANOVA, TrkC expression was found to be the single most biologically important prognostic factor, and a new tumor risk grading method for PNETS was proposed: (1) high risk group: low TrkC expression level; clinical stage ≥M1 (2) intermediate risk group: low TrkC expression level; clinical stage ≥M0 (3) low risk group: high TrkC expression level; regardless of the early or late M stage.
Certain neuropeptides also play a role in the normal development of the cerebellum and the growth of tumors. The neuropeptide growth inhibitor SS-14 is a regulator of cerebellar growth and development. A study has demonstrated the expression of SS-14 in cerebellar medulloblastoma. This finding suggests that SS-14 may play a role in the differentiation and proliferation of tumor cells. In addition, the expression of intestinal vasoactive peptide (VIP) receptor has also been found in MB, and studies have demonstrated that VIP can inhibit the proliferation of MB tumor cell lines.
3.Radiotherapy
Radiotherapy, especially whole brain and whole spinal cord radiotherapy, is the first choice of treatment for children with MB after surgery. Some foreigners call whole brain and whole spinal cord radiotherapy the “gold standard” of MB treatment.
Helseth summarized 111 cases of posterior cranial recess MB in children between 1960 and 1997. The 5-year survival rate for MB was 0 between 1960 and 1973, when radiotherapy was not available, and jumped to 53% after 1974, when radiotherapy was introduced into the routine treatment of MB. Thirty-four of these patients have survived 13.5 years. Helseth also noted that the side effects of radiation therapy were as prominent as its therapeutic effects. Sixty-one percent of the children in this group had radiation-related sequelae: growth retardation and cognitive, learning and social impairment. Radiotherapy is like a “double-edged sword”. On the one hand, it brings a breakthrough in the treatment of MB, but on the other hand, it is a difficult task to reduce various long-term complications after radiotherapy.
Less than 10% of children can survive recurrence-free after 5 years after local radiotherapy of the lesion alone. In contrast, more than 50% of children treated with whole brain whole spinal cord radiation + local radiotherapy can achieve recurrence-free survival at 5 years. This demonstrates the importance of whole-brain, whole-spinal cord radiotherapy in the treatment of children with MB.
The current conventional whole-brain whole-spinal cord radiation therapy is 3600 cGy (at a dose split of 150-180 cGy per day). The localized lesion or posterior cranial recess should be treated with 5400 cGy or more, which means that a supplemental amount of 1800 cGy is given to the primary lesion area.
In radiotherapy for pediatric MB, there are two main hot spots of recent research.
(1) whether the occurrence of long-term complications such as cognitive impairment can be reduced by reducing the amount of whole-brain, whole-spinal cord radiotherapy in a low-risk pediatric population without affecting overall survival.
(2) Whether the side effects of radiotherapy can be reduced by a highly segmented radiotherapy approach.
Deutsch conducted a prospective randomized controlled study in order to investigate the feasibility of reducing the dose of postoperative radiotherapy in children with stage M0 MB. He randomized 126 patients with stage T1-3a M0 MB between the ages of 3 and 21 years between 1986 and 1990 into two groups. The first group was given the conventional 3600 cGy (in 13 fractions) and the second group was given 2340 cGy (in 13 fractions), and the trial was terminated at 16 months because the recurrence and dissemination metastasis rates were found to be much higher in the second group than in the first group at the 16th month stage analysis. a similar randomized controlled trial was performed by Thomas and the same conclusion was obtained. The overall recurrence and metastasis rates at year 5 were higher in the low-dose whole-brain, whole-spinal cord group than in the control group. 8-year disease-free survival rates were 52% and 67% in the experimental and control groups, respectively.
To investigate the therapeutic value of low-dose whole-brain whole-spinal cord radiotherapy + adjuvant chemotherapy in children with MB, Packer performed low-dose whole-brain whole-spinal cord radiotherapy (23.4Gy) + conventional amount of local radiotherapy (55.8 Gy) in 65 children with MB aged 3-10 years. Chemotherapy with vincristine, CCNU and cisplatin was administered during and after radiotherapy. The 5-year recurrence-free survival rate in this group was 79%, which is clearly higher than the 60% survival rate reported in the literature for pediatric MB. Packer concluded that the use of low-dose whole-brain, whole-spinal cord radiotherapy + adjuvant chemotherapy in children with stage M0 MB is an effective approach that reduces radiotherapy injury while ensuring patient survival.
However, this approach is not applicable in children in the high-risk group.
To investigate the feasibility of low-dose radiotherapy in the treatment of MB in children in the high-risk group, Prodas performed low-dose whole-brain, whole-spinal cord radiotherapy + chemotherapy in 34 patients with PNETS between 1984 and 1992. Of these, 27 were MB, 5 were pineoblastoma, and 2 were supratentorial PNETS. Among the 27 children with MB, 12 were in stage M0 and 15 were in stage M1 or higher. The 5-year disease-free survival and survival rates after treatment were 52% and 73% in stage M0; 20% and 40% in stage M1 and above, respectively. The authors concluded that the use of low-dose whole-brain, whole-spinal cord radiotherapy in the high-risk group of children with MB did not improve the prognosis of patients, but instead only increased the risk of recurrence and disseminated metastases. The analysis of the reasons for the poor outcome was directly related to the inadequate dose of whole-brain, whole-spinal cord radiotherapy.
Hyper-segmentation radiotherapy is another attempt made in recent years to reduce the long-term complications of radiotherapy.
Prados used hyperfractionated radiotherapy (72 Gy for the primary foci and 30 Gy for the neuraxis) in the treatment of 39 children with newly diagnosed PNETS. The resulting 5-year survival rate for children in the low-risk group was 69%, with disseminated metastases found outside the primary lesion in 44% of cases. This group of cases does not suggest that hyper-segmentation radiotherapy significantly improves the prognosis of children with MB.
Allen used a hyper-segmented radiotherapy regimen supplemented with chemotherapy in 23 children with PNETS over 3 years of age treated between 1989 and 1995. Of these, 19 were MB, 15 were M0 stage (all children with M0 stage were T3b-T4) and 4 were M1 stage or older. All patients were treated surgically, and radiotherapy was started within 4 weeks after surgery, giving a split dose of 1 Gy twice daily (36 Gy for neuraxis and 72 Gy for localization of the lesion). As a result, the 15 children with M0 stage achieved a 95 % recurrence-free survival rate of 6.5 years. This group of cases seems to have obtained good treatment results, but due to the small number of cases in this group, it is not yet convincing.
The exact feasibility of hyper-segmentation radiotherapy has yet to be further explored because of the lack of international randomized double-blind trials; long-term clinical observation is still needed to determine whether this protocol can indeed reduce the occurrence of long-term complications such as neuroendocrine dysfunction and mental retardation.
Recently, the stereotactic technique has been applied to the treatment of MB. It is believed that the radiation dose can be focused on the tumor bed as much as possible while minimizing the radiation damage to the normal brain tissue around the tumor bed, especially the hearing damage caused by the irradiation of the cochlea. However, the long-term efficacy of this radiotherapy method needs to be further investigated.
4.Chemotherapy
In the 1970s and 1980s, studies on the therapeutic effect of chemotherapy in children with high-risk MB have demonstrated that radiotherapy followed by chemotherapy in children with high-risk MB can significantly improve the prognosis of the children. To further confirm the role of chemotherapy in the treatment of children with MB and to investigate the responsiveness of chemotherapy in the low-risk group, Packer treated a group of children with MB with conventional radiotherapy plus chemotherapy, followed by chemotherapy with vincristine and chemotherapy with CCNU plus cisplatin after radiotherapy. As a result, 63 children in the high-risk group had a 5-year disease-free survival rate of 85% and the low-risk group had a disease-free survival rate of 90%, compared with 50% in the group of children with MB treated without chemotherapy during the same period. This shows that the role of chemotherapy in the treatment of MB in children is very positive.
Since both radiotherapy and chemotherapy are definitive and effective treatments in the management of pediatric MB. Then, in the implementation of postoperative adjuvant therapy in children with MB, is it better to treat with radiotherapy first or is it more beneficial to patients to treat with chemotherapy first and then radiotherapy?
Recently, some scholars have proposed a so-called “neoadjuvant chemotherapy” approach, that is, chemotherapy before radiotherapy. This approach is based on the idea that
(1) Children tolerate chemotherapy better because their bone marrow reserves have not been destroyed at the time of chemotherapy initiation.
(2) Although both radiotherapy and chemotherapy with cisplatin are ototoxic, the sequence of chemotherapy followed by radiotherapy and radiotherapy followed by chemotherapy will reduce the degree of ototoxicity.
(3) This approach would reduce postoperative residuals and thus improve the therapeutic effect of radiotherapy. However, it turns out that this hypothetical view is not entirely correct.
The tolerance of children to chemotherapy-induced myelosuppression is improved, but the severe myelosuppression caused by chemotherapy itself delays the timing of radiotherapy or forces a longer course of radiotherapy, which obviously does not facilitate the standard treatment of MB and thus affects the treatment outcome.
The Children’s Cancer Group (USA) compared the effectiveness of two treatment regimens in children with MB. One used an “eight drugs in one day” chemotherapy regimen, applied before and after radiation therapy. The other regimen used radiotherapy followed by chemotherapy with vincristine, CCNU and prednisone. The resulting 5-year disease-free survival rates were 45% and 63% in the pre-radiotherapy and post-radiotherapy chemotherapy groups, respectively. Similar conclusions were obtained in two recent clinical trials conducted in Germany and the United States, respectively.
In summary, the current findings favor a treatment regimen of radiotherapy followed by chemotherapy.
The treatment outcome of MB in children in the high-risk group has been unsatisfactory. Although high 85% 5-year survival rates have been reported, such survival rates cannot be achieved in most case groups. Improved survival in children in the high-risk group depends on increased doses of radiotherapy and chemotherapy, which inevitably accentuate radiotherapy complications. Recent research in this area has focused on how to improve patient survival by increasing the drug intensity of chemotherapy agents or increasing the drug dose. As for the resulting severe bone marrow suppression, some scholars have proposed the use of bone marrow transplantation to maintain the normal course of chemotherapy.
The prognosis for pediatric MB cases that relapse after radiation therapy is extremely poor, with most children dying within 18 months of relapse. Conventional chemotherapy is unable to control disease progression. Studies have found that high-dose chemotherapy with bone marrow transplantation will result in long-term control in 30-40% of relapsed cases.
5. Treatment of younger children
The most difficult treatment of pediatric MB is the treatment of younger children with MB under the age of 3. Children under the age of 3 with MB are at higher risk of relapse and are more likely to develop long-term complications after treatment. The presence of disseminated metastases at the time of initial diagnosis in younger children with MB may contribute to their poor prognosis.
Rivera analyzed the survival rate of 49 children with MB under 3 years of age, and the overall survival rate after surgery + radiotherapy or chemotherapy was 38%. In children with stage M0 it was 40%; in children with stage M1 and above it was 32%. The recurrence rate after treatment is high in younger children with MB, and Kalifa reported a high recurrence rate of 77% in a group of 35 younger children with MB. The time of recurrence in younger children with MB was mostly 6-9 months after surgery.
Because of the poor tolerance of infants and children to radiotherapy, the common treatment regimen is to give 15-25% less than the conventional dose of whole brain, whole spinal cord and posterior cranial recess radiotherapy. However, this approach often causes a significant increase in the recurrence rate, and adjuvant chemotherapy does not compensate for the reduced therapeutic effect of inadequate radiation therapy.
Attempts have also been made to replace radiotherapy with chemotherapy before the child reaches 3 years of age and to start regular radiotherapy after the child reaches 3 years of age to avoid radiation damage during the “susceptible period” of infancy and childhood. However, the conclusions of several clinical trials based on this approach are inconsistent, and it seems that the feasibility of this approach needs to be further investigated.
Furthermore, it has been demonstrated that some postoperative chemotherapy followed by radiotherapy after 3 years of age or simply postoperative chemotherapy alone cannot achieve the survival rates achieved by conventional postoperative radiotherapy. This is another aspect that proves that radiotherapy also has a non-negligible role in the treatment of the younger group of children.
Current research in the treatment of younger children with MB is focused on intensive chemotherapy intrathecal chemotherapy.