Childhood Medulloblastoma and Other Central Nervous System Embryonal Tumors Treatment (PDQ®)–Health Professional Version - National Cancer Institute

Childhood Medulloblastoma and Other Central Nervous System Embryonal Tumors Treatment (PDQ®)–Health Professional Version

Childhood Medulloblastoma

Hereditary Cancer Predisposition Syndromes Associated With Medulloblastoma

Medulloblastoma can arise in the setting of hereditary cancer predisposition syndromes in approximately 5% of patients.[1,2] A large study of over 1,000 patients demonstrated germline mutations in approximately 5% of all patients diagnosed with medulloblastoma. Germline mutations were identified in APC, BRCA2, PALB2, PTCH1, SUFU, and TP53.[2]

Syndromes known to be associated with medulloblastoma include the following:

Turcot syndrome (related to germline mutations in APC),[3] exclusive to the WNT-activated subtype.[2]
Rubinstein-Taybi syndrome (related to germline mutations in CREBBP).[4-6]
Gorlin syndrome (also known as basal cell nevus syndrome or nevoid basal cell carcinoma syndrome, associated with germline PTCH1 and SUFU mutations).[7-11] The risk of developing medulloblastoma in patients with Gorlin syndrome appears to be higher in those with SUFU mutations than in those with PTCH1 germline mutations. In one study, 2 of 115 individuals (1.7%) with Gorlin syndrome and a PTCH1 mutation developed a pathology-proven medulloblastoma, compared with 3 of 9 individuals (33%) from three families with SUFU-related Gorlin syndrome. Each of the SUFU-related patients developed medulloblastoma before age 3 years.[11]
Li-Fraumeni syndrome (related to germline mutations in TP53).[12,13] In one analysis, all germline TP53 mutations were restricted to the sonic hedgehog (SHH)–activated subtype.[2]
Fanconi anemia (related to BRCA2 mutations).[14-17]

Sometimes medulloblastoma may be the initial manifestation of the presence of germline mutations in these predisposition genes. Germline testing should be considered in the following circumstances:

APC mutation testing in patients with WNT-activated medulloblastoma in the absence of a somatic beta-catenin mutation.
SUFU, PTCH1, TP53, PALB2, and BRCA2 mutation testing in patients with SHH-activated medulloblastoma. Patients with desmoplastic tumors with extensive nodularity should be carefully evaluated for stigmata of Gorlin syndrome.[7] One report observed that medulloblastoma with extensive nodularity (MBEN) was associated with Gorlin syndrome in 5 of 12 cases.[7] Gorlin syndrome, also called nevoid basal cell carcinoma syndrome, is an autosomal dominant disorder in which those affected are predisposed to develop basal cell carcinomas later in life, especially in skin in the radiation portal. The syndrome can be diagnosed early in life by detection of characteristic dermatological and skeletal features such as keratocysts of the jaw, bifid or fused ribs, macrocephaly, and calcifications of the falx.[7]
PALB2 and BRCA2 mutation testing in patients with a family history of BRCA-associated cancers or homologous recombination repair deficiency.

Clinical Presentation

By definition, medulloblastomas must arise in the posterior fossa.[18,19] In approximately 80% of children, medulloblastomas arise in the region of the fourth ventricle. Most of the early symptomatology is related to blockage of cerebrospinal fluid (CSF) and resultant accumulation of CSF in the brain, termed hydrocephalus. Children with medulloblastoma are usually diagnosed within 2 to 3 months of the onset of symptoms. Medulloblastoma commonly presents with the following signs and symptoms:[20]

Relatively abrupt onset of headaches, especially in the morning on waking.
Nausea and/or vomiting.
Lethargy.
Ataxia, including truncal unsteadiness.
Some degree of nystagmus.
Papilledema.

Twenty percent of patients with medulloblastoma will not have hydrocephalus at the time of diagnosis and are more likely to present initially with cerebellar deficits. For example, more laterally positioned medulloblastomas of the cerebellum may not result in hydrocephalus and, because of their location, are more likely to result in lateralizing cerebellar dysfunction (appendicular ataxia) manifested by unilateral dysmetria, unsteadiness, and weakness of the sixth and seventh nerves on the same side as the tumor. Later, as the tumor grows toward the midline and blocks CSF, the more classical symptoms associated with hydrocephalus become evident.

Cranial nerve findings are less common, except for unilateral or bilateral sixth nerve palsies, which are usually related to hydrocephalus.[20] At times, medulloblastomas will present explosively, with the acute onset of lethargy and unconsciousness resulting from hemorrhage within the tumor.

In infants, the presentation of medulloblastoma is more variable and may include the following:

Nonspecific lethargy.
Psychomotor delays.
Loss of developmental milestones.
Feeding difficulties.

On examination, there may be bulging of the anterior fontanel due to increased intracranial pressure and abnormal eye movements, including eyes that are deviated downward (the so-called sun setting sign) because of loss of upgaze secondary to compression of the tectum of the midbrain.

Cellular and Molecular Classification

The following four histologic types of medulloblastoma are recognized by the World Health Organization (WHO) classification:[19]

Medulloblastoma, classic.
Medulloblastoma, desmoplastic/nodular.
MBEN.
Medulloblastoma, large cell/anaplastic.

Significant attention has been focused on medulloblastomas that display anaplastic features, including increased nuclear size, marked cytological pleomorphism, numerous mitoses, and apoptotic bodies.[21,22] Using the criteria of anaplasia is subjective because most medulloblastomas have some degree of anaplasia. Foci of anaplasia may appear in tumors with histologic features of both classic and large cell medulloblastomas, and there is significant overlap between the anaplastic and large cell variants, which are frequently termed large cell/anaplastic medulloblastoma.[21,22] One convention is to consider medulloblastomas as anaplastic when anaplasia is diffuse (variably defined as anaplasia occurring in 50% to 80% of the tumor).

The incidence of medulloblastoma with the desmoplastic/nodular histologic variant, which most commonly arises in a cerebellar hemisphere, is higher in infants, is less common in children, and increases again in adolescents and adults. The desmoplastic/nodular histologic variant is different from MBEN; the nodular variant has an expanded lobular architecture. The MBEN subtype occurs almost exclusively in infants and carries an excellent prognosis.[7,23]

Molecular subtypes of medulloblastoma

Multiple medulloblastoma subtypes have been identified by integrative molecular analysis.[24-39] Since 2012, the general consensus is that medulloblastoma can be molecularly separated into at least four core subtypes, including WNT-activated, sonic hedgehog (SHH)–activated, group 3, and group 4 medulloblastoma. However, different regions of the same tumor are likely to have other disparate genetic mutations, adding to the complexity of devising effective molecularly targeted therapy.[40] These subtypes remain stable across primary and metastatic components.[41,42]

The 2016 World Health Organization (WHO) classification has endorsed this consensus by adding the following categories for genetically defined medulloblastoma:[19]

Medulloblastoma, WNT-activated.
Medulloblastoma, SHH-activated and TP53-mutant.
Medulloblastoma, SHH-activated and TP53–wild-type.
Medulloblastoma, non-WNT/non-SHH.

Further subclassification within these subgroups is possible, which will provide even more prognostic information.[42-44]

Medulloblastoma, WNT-activated

WNT tumors are medulloblastomas with aberrations in the WNT signaling pathway and represent approximately 10% of all medulloblastomas.[43] WNT medulloblastomas show a WNT signaling gene expression signature and beta-catenin nuclear staining by immunohistochemistry.[45] They are usually histologically classified as classic medulloblastoma tumors and rarely have a large cell/anaplastic appearance. WNT medulloblastomas generally occur in older patients (median age, 10 years) and are infrequently metastasized at diagnosis.

CTNNB1 mutations are observed in 85% to 90% of WNT medulloblastoma cases, with APC mutations detected in many of the cases that lack CTNNB1 mutations. Patients with WNT medulloblastoma whose tumors have APC mutations often have Turcot syndrome (i.e., germline APC mutations).[44] In addition to CTNNB1 mutations, WNT medulloblastoma tumors show 6q loss (monosomy 6) in 80% to 90% of cases. While monosomy 6 is observed in most medulloblastoma patients younger than 18 years at diagnosis, it appears to be much less common (approximately 25% of cases) in patients older than 18 years.[43,45]

The WNT subset is primarily observed in older children, adolescents, and adults and does not show a male predominance. The subset is believed to have brain stem origin, from the embryonal rhombic lip region.[46] WNT medulloblastomas are associated with a very good outcome in children, especially in individuals whose tumors have beta-catenin nuclear staining and proven 6q loss and/or CTNNB1 mutations.[39,47,48]

Medulloblastoma, SHH-activated and TP53-mutant and medulloblastoma, SHH-activated and TP53-wildtype

SHH tumors are medulloblastomas with aberrations in the SHH pathway and represent approximately 25% of medulloblastoma cases.[43] SHH medulloblastomas are characterized by chromosome 9q deletions; desmoplastic/nodular histology; and mutations in SHH pathway genes, including PTCH1, PTCH2, SMO, SUFU, and GLI2.[45]

SHH medulloblastomas show a bimodal age distribution and are observed primarily in children younger than 3 years and in older adolescence/adulthood. The tumors are believed to emanate from the external granular layer of the cerebellum. The heterogeneity in age at presentation maps to distinctive subsets identified by further molecular characterization, as follows:

The subset of medulloblastoma most common in children aged 3 to 16 years is enriched for MYCN and GLI2 amplifications, with TP53 mutations commonly co-occurring with one of these amplifications.[42,43] PTCH1 mutations occur in this subtype and are mutually exclusive with TP53 mutations (often germline), while SMO and SUFU mutations are rare.[42,49]
Two SHH subtypes that occur primarily in children younger than 3 years have been described.[43] One of these subtypes is more frequently metastatic, with more frequent focal amplifications.[50] The second of these subtypes is enriched for the medulloblastoma with extensive nodularity (MBEN) histology. SHH pathway mutations in children younger than 3 years with medulloblastoma include PTCH1 and SUFU mutations.[42] SUFU mutations are rarely observed in older children and adults, and they are commonly germline events.[49]
A second report that used DNA methylation arrays also identified two subtypes of SHH medulloblastoma in young children.[50] One of the subtypes contained all of the cases with SMO mutations, and it was associated with a favorable prognosis. The other subtype had most of the SUFU mutations, and it was associated with a much lower progression-free survival (PFS) rate. PTCH1 mutations were present in both subtypes.
A fourth SHH subtype includes most of the adult cases of SHH medulloblastoma.[43] This subtype is enriched for TERT promoter mutations, which are observed in approximately 90% of cases. PTCH1 and SMO mutations are observed in adults with SHH medulloblastoma, with the latter being virtually restricted to the adult subtype.

The outcome for patients with nonmetastatic SHH medulloblastoma is relatively favorable for children younger than 3 years and for adults.[43] Young children with the MBEN histology have a particularly favorable prognosis.[7,23,51-53] Patients with SHH medulloblastoma at greatest risk of treatment failure are children older than 3 years whose tumors have TP53 mutations, often with co-occurring GLI2 or MYCN amplification and large cell/anaplastic histology.[43,49,54]

Patients with unfavorable molecular findings have an unfavorable prognosis, with fewer than 50% of patients surviving after conventional treatment.[49,54-57]

The 2016 WHO classification identifies SHH medulloblastoma with a TP53 mutation as a distinctive entity (medulloblastoma, SHH-activated and TP53-mutant).[19] Approximately 25% of SHH-activated medulloblastoma cases have TP53 mutations, with a high percentage of these cases also showing a TP53 germline mutation (9 of 20 in one study). These patients are commonly between the ages of 5 years and 18 years and have a worse outcome (overall survival at 5 years, <50%).[57] The tumors often show large cell anaplastic histology.[57]

Medulloblastoma, non–WNT/non–SHH-activated

The WHO classification combines group 3 and group 4 medulloblastoma cases into a single entity, partly on the basis of the absence of immediate clinical impact for this distinction. Group 3 medulloblastoma represents approximately 25% of medulloblastoma cases, while group 4 medulloblastoma represents approximately 40% of medulloblastoma cases.[43,45] Both group 3 and group 4 medulloblastoma patients are predominantly male.[33,42] Group 3 and group 4 medulloblastomas can be further subdivided on the basis of characteristics such as gene expression and DNA methylation profiles, but the optimal approach to their subdivision is not established.[43,44]

Various genomic alterations are observed in group 3 and group 4 medulloblastomas; however, no single alteration occurs in more than 10% to 20% of cases. Genomic alterations include the following:

MYC amplification was the most common distinctive alteration reported for group 3 medulloblastoma, occurring in approximately 15% of cases.[38,44]
The most common distinctive genomic alteration described for group 4 medulloblastoma (observed in approximately 15% of cases) was activation of PRDM6 by enhancer hijacking, resulting from the tandem duplication of the adjacent SNCAIP gene.[44]
Other genomic alterations were observed in both group 3 and group 4 cases, including MYCN amplification and structural variants leading to GFI1 or GFI1B overexpression through enhancer hijacking.
Isochromosome 17q (i17q) is the most common cytogenetic abnormality and is observed in a high percentage of group 4 cases as well as in group 3 cases, but it is rarely observed in WNT and SHH medulloblastoma.[38,44] Prognosis for group 3 and group 4 patients does not appear to be affected by the presence of i17q.[58]

Group 3 patients with MYC amplification or MYC overexpression have a poor prognosis,[42] with fewer than 50% of these patients surviving 5 years after diagnosis.[43] This poor prognosis is especially true in children younger than 4 years at diagnosis.[55] However, patients with group 3 medulloblastoma without MYC amplification who are older than 3 years have a prognosis similar to that of most patients with non-WNT medulloblastoma, with a 5-year PFS rate higher than 70%.[56,58]

Group 4 medulloblastomas occur throughout infancy and childhood and into adulthood. The prognosis for group 4 medulloblastoma patients is similar to that for patients with other non-WNT medulloblastomas and may be affected by additional factors such as the presence of metastatic disease, chromosome 11q loss, and chromosome 17p loss.[37,38,43,54] One study found that group 4 patients with either chromosome 11 loss or gain of chromosome 17 were low risk, regardless of metastases. In cases lacking both of these cytogenetic features, metastasis at presentation differentiated between high and intermediate risk.[54]

For group 3 and group 4 standard-risk patients (i.e., without MYC amplification or metastatic disease), the gain or loss of whole chromosomes appears to connote a favorable prognosis. This finding was derived from the data of 91 patients with non-WNT/non-SHH medulloblastoma enrolled in the SIOP-PNET-4 (NCT01351870) clinical trial and was confirmed in an independent group of 70 children with non-WNT/non-SHH medulloblastoma treated between 1990 and 2014.[58] Chromosomal abnormalities include the following:

The gain/loss of one or more whole chromosomes was associated with a 5-year event-free survival (EFS) of 93%, compared with an EFS of 64% for no whole chromosome gains/losses.
The most common chromosomal gains/losses are gain of chromosome 7 and loss of chromosomes 8 and 11.
The optimally performing prognosis discriminator was determined to be the occurrence of two or more of the following aberrations: chromosome 7 gain, chromosome 8 loss, and chromosome 11 loss. Approximately 40% of group 3 and group 4 standard-risk patients had two or more of these chromosomal aberrations and had a 5-year EFS of 100%, compared with an EFS of 68% for patients with fewer than two aberrations.
In an independent cohort, the prognostic significance of two or more gains/losses versus zero or one gain/loss of chromosomes 7, 8, and 11 was confirmed (5-year EFS, 95% for patients with two or more vs. 59% for patients with one or fewer).

The classification of medulloblastoma into the four major subtypes will likely be altered in the future.[43,44,59,60] Further subdivision within subgroups based on molecular characteristics is likely as each of the subgroups is further molecularly dissected, although there is no consensus regarding an alternative classification.[37,45,49]

Whether the classification for adults with medulloblastoma has a predictive ability similar to that for children is unknown.[38,55] In one study of adult medulloblastoma, MYC oncogene amplifications were rarely observed, and tumors with 6q deletion and WNT activation (as identified by nuclear beta-catenin staining) did not share the excellent prognosis seen in pediatric medulloblastomas, although another study did confirm an excellent prognosis for WNT-activated tumors in adults.[38,55]

Staging Evaluation

Historically, staging was based on an intraoperative evaluation of both the size and extent of the tumor, coupled with postoperative neuroimaging of the brain and spine and cytological evaluation of CSF (the Chang system). Intraoperative evaluation of the extent of the tumor has been supplanted by neuraxis imaging before diagnosis and postoperative imaging to determine the amount of primary site residual disease. The following tests and procedures are now used for staging:

Magnetic resonance imaging (MRI) of the brain and spine (often done preoperatively).
Postoperative MRI of the brain to determine the amount of residual disease.
Lumbar CSF analysis.[61-63]

The tumor extent is defined as:

M0: No dissemination.
M1: CSF-positive cytology only.
M2: Gross nodular seeding in cerebellar-cerebral subarachnoid space and/or lateral or third ventricle.
M3: Gross nodular seeding in spinal subarachnoid space.
M4: Extraneural metastasis.

Postoperative degree of residual disease is designated as:

Gross-total resection/near-total resection: No or minimal (≤1.5 cm2) evidence of residual disease after resection.
Subtotal resection: Residual disease after diagnosis (>1.5 cm2 of measurable residual disease).
Biopsy: No tumor resection; only a sample of tumor tissue is removed.

Since the 1990s, prospective studies have been performed using this staging system to separate patients into average-risk and high-risk medulloblastoma subgroups.[62-64]

The presence of diffuse (>50% of the pathologic specimen) histologic anaplasia has been incorporated as an addition to staging systems. If diffuse anaplasia is found, patients with otherwise average-risk disease are upstaged to high-risk disease.

Risk Stratification

Risk stratification is based on neuroradiographic evaluation for disseminated disease, CSF cytological examination, postoperative neuroimaging evaluation for the amount of residual disease, and patient age. (Refer to the Staging Evaluation section of this summary for more information.) Patients older than 3 years with medulloblastoma have been stratified into the following two risk groups:

Average risk: Children older than 3 years with tumors that are totally resected or near-totally resected (≤1.5 cm2 of residual disease) and who have no metastatic disease.[62]
High risk: Children older than 3 years with metastatic disease and/or subtotal resection (>1.5 cm2 of residual disease).[62] Metastatic disease includes neuroradiographic evidence of disseminated disease, positive cytology in lumbar or ventricular CSF obtained more than 14 days after surgery, or extraneural disease.[62] Children with tumors showing diffuse anaplasia and who otherwise would have been considered average risk are assigned to the high-risk group.[22,32]

For younger children, in some studies for those younger than 3 years and for others younger than 4 or 5 years, similar separation into average-risk (no dissemination and ≤1.5 cm2 of residual disease) or high-risk (disseminated disease and/or >1.5 cm2 of residual disease) groups has been employed. Histologic findings of desmoplasia have also been used to connote a more favorable risk subgrouping, especially for the MBEN subgroup.[65,66]

Assigning a risk group on the basis of the extent of resection and disease at diagnosis may not predict treatment outcome. Molecular genetics and histologic factors may be more informative, although they must be evaluated in the context of patient age, the extent of disease at the time of diagnosis, and treatment received.[37,67] The risk characterizations of molecular subdivisions are changing and are becoming integrated into risk stratification schema to assign treatment in North American prospective studies (e.g., NCT01878617 and NCT02724579).[59]

Treatment Option Overview for Childhood Medulloblastoma

Table 3 describes the standard treatment options for newly diagnosed and recurrent childhood medulloblastoma.

Table 3. Standard Treatment Options for Childhood Medulloblastoma

Treatment Group		Standard Treatment Options
Newly diagnosed childhood medulloblastoma	Children aged 3 years and younger	Surgery
	Children aged 3 years and younger	Adjuvant chemotherapy
	Children older than 3 years with average-risk medulloblastoma	Surgery
		Adjuvant radiation therapy
		Adjuvant chemotherapy
	Children older than 3 years with high-risk medulloblastoma	Surgery
		Adjuvant radiation therapy
		Adjuvant chemotherapy
Recurrent childhood medulloblastoma		There are no standard treatment options. (Refer to the Treatment of Recurrent Childhood Medulloblastoma and Other CNS Embryonal Tumors section of this summary for more information.)

Surgery

Surgery is considered a standard part of treatment for histologic confirmation of tumor type and as a means to improve outcome. Total or near-total resections are considered optimal, if they can be performed safely.[68,69]

Postoperatively, children may have significant neurologic deficits caused by preoperative tumor-related brain injury, hydrocephalus, or surgery-related brain injury.[70][Level of evidence: 3iC] A significant number of patients with medulloblastoma will develop cerebellar mutism syndrome (also known as posterior fossa syndrome). Symptoms of cerebellar mutism syndrome include the following:

Delayed onset of speech.
Suprabulbar palsies.
Ataxia.
Hypotonia.
Emotional lability.

The etiology of cerebellar mutism syndrome remains unclear, although cerebellar vermian damage and/or disruption of cerebellar-cortical tracts has been postulated as the possible cause of the mutism.[71,72]; [73][Level of evidence: 3iC] In two Children’s Cancer Group studies that evaluated children with both average-risk and high-risk medulloblastoma, the syndrome was identified in nearly 25% of patients.[72-74]; [75][Level of evidence: 3iiiC] Approximately 50% of patients with this syndrome manifest long-term, permanent neurologic and neurocognitive sequelae.[73,75]

Radiation therapy

Radiation therapy to the primary tumor site is usually in the range of 54 Gy to 55.8 Gy. In most instances, this is given with a margin of 1 cm to 2 cm around the primary tumor site, preferably by conformal techniques. Reducing boost volumes for the whole posterior fossa and to the tumor bed plus margins did not compromise outcomes in average-risk patients in the Children's Oncology Group (COG) ACNS0331 (NCT00085735) study.[76][Level of evidence: 1iiA] For all medulloblastomas in children older than 3 or 4 years at diagnosis, craniospinal radiation therapy is given at doses ranging between 23.4 Gy and 36 Gy, depending on risk factors such as extent of disease at diagnosis. A prospective phase II toxicity study of proton radiation therapy [77] and a retrospective efficacy report of protons versus photons for medulloblastoma [78] demonstrated equivalent outcomes for progression-free survival (PFS), overall survival (OS), patterns of relapse, and delayed toxic effects. The comparative outcomes of these treatment technologies are under investigation.

Chemotherapy is usually administered during and after radiation therapy.

For children younger than 3 years, efforts are made to omit or delay radiation therapy, given the profound impact of radiation at this age. Children of all ages are susceptible to the adverse effects of radiation on brain development. Debilitating effects on neurocognitive development, growth, and endocrine function have been frequently observed, especially in younger children.[79-83]

Chemotherapy

Chemotherapy, usually given during and after radiation therapy, is a standard component of treatment for older children with medulloblastoma and other embryonal tumors. Chemotherapy can be used to delay and sometimes obviate the need for radiation therapy in 20% to 40% of children younger than 3 to 4 years with nondisseminated medulloblastoma.[84,85]; [83][Level of evidence: 3iiiC]

Treatment of Childhood Medulloblastoma

Treatment of children aged 3 years and younger

Five-year disease-free survival (DFS) rates for young children with medulloblastoma have ranged between 30% and 70%. Most long-term survivors have been successfully treated with chemotherapy alone, and have nondisseminated, totally resected tumors with histologic evidence of desmoplasia.[65,84,86]; [87][Level of evidence: 2A]

The treatment of children younger than 3 to 4 years with newly diagnosed medulloblastoma continues to evolve. Therapeutic approaches have attempted to delay and, in some cases, avoid the use of craniospinal radiation therapy because of its deleterious effects on the immature nervous system. Results have been variable, and comparison across studies has been difficult because of differences in the drug regimens used and the utilization of craniospinal and local boost radiation therapy at the end of chemotherapy or when children reached age 3 years in some studies.

Standard treatment options for children aged 3 years and younger with newly diagnosed medulloblastoma include the following:

Surgery

If deemed feasible, complete surgical resection of the tumor is the optimal treatment. Surgical resectability is associated with histology, as patients with desmoplastic/nodular medulloblastoma or MBEN have a higher rate of complete resection than do patients with classic medulloblastoma.[52,53]

Adjuvant chemotherapy

Therapies for younger children with medulloblastoma have included the use of multiagent chemotherapeutic approaches, including drugs such as cyclophosphamide, etoposide, cisplatin, and vincristine, with or without concomitant high-dose intravenous methotrexate and/or intrathecal methotrexate or mafosfamide, and/or intraventricular methotrexate.[53,65,84,86,88,89]; [90][Level of evidence: 2A]; [91][Level of evidence: 2B]

Several studies have observed that the histologic finding of desmoplasia, seen in patients with desmoplastic medulloblastoma or MBEN, connotes a significantly better prognosis compared with outcomes for patients with classic or large cell/anaplastic medulloblastoma.[7,23,51-53]; [66][Level of evidence: 2A]

Evidence (adjuvant chemotherapy):

In the German Hirntumor (HIT) 2000 multicenter trial, desmoplasia was an independent predictor of favorable EFS.[53]
- Nineteen patients with desmoplastic medulloblastoma or MBEN had 5-year EFS rates of 90% (± 7%) and OS rates of 100% (± 0%). All patients were treated with postoperative chemotherapy alone (including intraventricular methotrexate) before progression.[65]
- By contrast, EFS and OS rates for children with classic medulloblastoma in the HIT 2000 trial were significantly lower (EFS, 30% ± 11%; OS, 68% ± 10%).[53]
The COG clinical trial CCG-9921 also observed a favorable outcome for children with desmoplastic medulloblastoma (including MBEN), with an EFS of 77% (± 9%) and an OS of 85% (± 8%) for the desmoplastic group compared with an EFS of 17% (± 5%) and OS of 29% (± 6%) for patients in the nondesmoplastic group (P < .0001 for both EFS and OS comparisons).[84] In this study, patients with desmoplastic tumors did not receive radiation therapy before progression.
Compared with children with desmoplastic medulloblastoma or MBEN treated with current intensive chemotherapy regimens, children with other histologic subtypes fare less well.
- EFS rates are less than 40% despite the use of intensive chemotherapy supplemented with methotrexate (intravenous, intrathecal, and intraventricular) and the use of high-dose chemotherapeutic regimens supported with stem cell rescue.[53,84,92]
- Outcome is particularly poor when these patients have disseminated disease. There is no consensus on when and how much radiation therapy should be given and at what age radiation therapy should be instituted in patients with disseminated disease.[65,84,86,92]
Another treatment option for children younger than 3 years at diagnosis is chemotherapy followed by autologous stem cell rescue. Results of trials utilizing higher-dose, marrow-ablative chemotherapeutic regimens supported by stem cell rescue have also demonstrated that a subgroup of patients with medulloblastoma who are younger than 3 years at the time of diagnosis can be treated with chemotherapy alone.[85,87,93][Level of evidence: 2A] However, in some studies, radiation to the primary tumor site and/or craniospinal axis has been added after chemotherapy, making assessment of the efficacy of chemotherapy more difficult.[92]

Treatment of children older than 3 years with average-risk medulloblastoma

Standard treatment options for children older than 3 years with newly diagnosed average-risk medulloblastoma include the following:

Surgery

If deemed feasible, total or near-total removal of the tumor is considered optimal.[68]

Adjuvant radiation therapy

Radiation therapy is usually initiated after surgery with or without concurrent chemotherapy.[94-96] The best survival results for children with medulloblastoma have been obtained when radiation therapy is initiated within 4 to 6 weeks postsurgery.[95-97]; [98,99][Level of evidence: 1iA]

The radiation dose for patients with average-risk medulloblastoma is 54 Gy to the posterior fossa or local tumor bed and 23.4 Gy to the entire neuraxis (i.e., the whole brain and spine), termed craniospinal irradiation.[94-96,100]

Evidence (adjuvant radiation therapy):

With radiation therapy alone, using a craniospinal radiation dose of 35 Gy with a boost to the posterior fossa of 55 Gy, 5-year EFS rates range between 50% and 65% in those with nondisseminated disease.[64,95]
The minimal dose of craniospinal radiation needed for disease control is unknown. Attempts to lower the dose of craniospinal radiation therapy to 23.4 Gy without chemotherapy have resulted in an increased incidence of isolated leptomeningeal relapse.[100]
Lower doses of craniospinal radiation were evaluated in a COG study (NCT00085735). Children aged 3 to 7 years were randomly assigned to receive a craniospinal radiation dose of either 18 Gy or 23.4 Gy, as well as a limited target volume boost to the tumor bed.[76][Level of evidence: 1iiA]
- Preliminary results revealed that 18 Gy of craniospinal irradiation was inferior to 23.4 Gy of craniospinal irradiation (5-year EFS of 82.6% ± 4.2% and OS of 85.8% for patients who received 23.4 Gy vs. EFS of 71.9% ± 4.9% and OS of 77.9% ± 4.9% for patients who received 18 Gy).
Analysis according to molecular subgroups is pending. Craniospinal radiation dose reduction to 18 Gy is currently being investigated in WNT medulloblastoma patients (NCT02724579), the molecular subgroup with the best prognosis.
The SIOP-PNET-4 (NCT01351870) study compared daily radiation therapy (1.8 Gy fractions with 23.4 Gy to the neuraxis and a 30 Gy boost to the posterior fossa) with twice-per-day radiation (1 Gy fractions with 36 Gy and a 24-Gy boost to the posterior fossa). [101]
- With a median follow-up of 7.8 years, the 10-year OS was not significantly different between the two radiation groups.
- Long-term side effects were not reported in this study.
If chemotherapy is added after radiation therapy, 23.4 Gy of craniospinal radiation therapy has been shown to be an effective dose.[99,101-103] Lower doses are being evaluated.
Although the standard boost in medulloblastoma is to the entire posterior fossa, failure data patterns reveal that radiation therapy to the tumor bed instead of the entire posterior fossa is equally effective and may be associated with reduced toxicity.[104,105]; [76][Level of evidence: 1iiA]

Adjuvant chemotherapy

Chemotherapy is now a standard component of the treatment of children with average-risk medulloblastoma.

Evidence (adjuvant chemotherapy):

Prospective randomized trials and single-arm trials suggest that adjuvant chemotherapy given during and after radiation therapy improves OS for children with average-risk medulloblastoma.[75,94-98]
- Radiation therapy and chemotherapy given during and after surgery has demonstrated 5-year EFS rates of 70% to 85%.[94-96]; [106][Level of evidence: 2A]
A lower radiation dose of 23.4 Gy to the neuraxis when coupled with chemotherapy has been shown to result in disease control in up to 85% of patients and may decrease the severity of long-term neurocognitive sequelae.[99,102,103,107]
A variety of chemotherapeutic regimens have been successfully used, including the combination of cisplatin, lomustine, and vincristine or the combination of cisplatin, cyclophosphamide, and vincristine.[94,95,107,108] These therapies have increased 5-year and 10-year EFS and OS rates and have likely decreased the incidence of late relapse. However, long-term survivors treated with multimodality therapy are at a high risk of late effects such as hearing loss, cardiac complications, and secondary neoplasms.[109]
In addition, postradiation high-dose cyclophosphamide supported by peripheral stem cell rescue, but with reduced cumulative doses of vincristine and cisplatin, has resulted in similar survival rates.[48]
Although medulloblastoma is often sensitive to chemotherapy, preradiation chemotherapy has not been shown to improve survival in average-risk medulloblastoma patients compared with treatment with radiation therapy and subsequent chemotherapy. In some prospective studies, preradiation chemotherapy has been related to a poorer rate of survival.[95-98]

Treatment of children older than 3 years with high-risk medulloblastoma

Standard treatment options for children older than 3 years who are newly diagnosed with medulloblastoma and have metastatic disease or have had a subtotal resection include the following:

In high-risk patients, numerous studies have demonstrated that multimodality therapy improves the duration of disease control and overall DFS.[48,110] Studies show that approximately 50% to 70% of patients with high-risk disease, including those with metastatic disease, will experience long-term disease control.[48,94,110-112]; [113][Level of evidence: 1iiA]; [114][Level of evidence: 2A]; [115][Level of evidence: 1iiA]

Surgery

As for those with average-risk disease, attempt at gross-total resection is considered optimal, if deemed feasible.[64,68]

Adjuvant radiation therapy

In contrast to standard-risk treatment, the craniospinal radiation dose is generally 36 Gy.

Adjuvant chemotherapy

Evidence (adjuvant chemotherapy):

The drugs that have been found to be useful in children with average-risk disease are the same drugs that have been used extensively in children with high-risk disease, including cisplatin, lomustine, cyclophosphamide, etoposide, and vincristine.[113] These therapies have increased 5-year and 10-year EFS and OS rates and have likely decreased the incidence of late relapse. However, long-term survivors treated with multimodality therapy are at a high risk of late effects such as hearing loss, cardiac complications, and secondary neoplasms.[109]
Postradiation high-dose nonmyeloablative chemotherapy supported by peripheral stem cell rescue, but with reduced cumulative doses of vincristine and cisplatin, has also been utilized and has resulted in 5-year PFS rates of approximately 60%.[48]

Treatment options under clinical evaluation for childhood medulloblastoma

Early-phase therapeutic trials may be available for selected patients. These trials may be available via the COG , the Pediatric Brain Tumor Consortium , or other entities. Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.

The following is an example of a national and/or institutional clinical trial that is currently being conducted:

COG-ACNS1422 (NCT02724579) (Reduced Craniospinal Radiation Therapy and Chemotherapy in Treating Younger Patients With Newly Diagnosed WNT-Driven Medulloblastoma): This phase II trial studies the effectiveness of reduced doses of radiation therapy to the brain and spine (craniospinal) and chemotherapy for patients with the newly diagnosed type of brain tumor called WNT/Wingless (WNT)–driven medulloblastoma. Studies using chemotherapy and radiation therapy are shown to be effective in treating patients with WNT-driven medulloblastoma.

References

Zhang J, Walsh MF, Wu G, et al.: Germline Mutations in Predisposition Genes in Pediatric Cancer. N Engl J Med 373 (24): 2336-46, 2015. [PUBMED Abstract]
Waszak SM, Northcott PA, Buchhalter I, et al.: Spectrum and prevalence of genetic predisposition in medulloblastoma: a retrospective genetic study and prospective validation in a clinical trial cohort. Lancet Oncol 19 (6): 785-798, 2018. [PUBMED Abstract]
Hamilton SR, Liu B, Parsons RE, et al.: The molecular basis of Turcot's syndrome. N Engl J Med 332 (13): 839-47, 1995. [PUBMED Abstract]
Taylor MD, Mainprize TG, Rutka JT, et al.: Medulloblastoma in a child with Rubenstein-Taybi Syndrome: case report and review of the literature. Pediatr Neurosurg 35 (5): 235-8, 2001. [PUBMED Abstract]
Miller RW, Rubinstein JH: Tumors in Rubinstein-Taybi syndrome. Am J Med Genet 56 (1): 112-5, 1995. [PUBMED Abstract]
Bourdeaut F, Miquel C, Richer W, et al.: Rubinstein-Taybi syndrome predisposing to non-WNT, non-SHH, group 3 medulloblastoma. Pediatr Blood Cancer 61 (2): 383-6, 2014. [PUBMED Abstract]
Garrè ML, Cama A, Bagnasco F, et al.: Medulloblastoma variants: age-dependent occurrence and relation to Gorlin syndrome--a new clinical perspective. Clin Cancer Res 15 (7): 2463-71, 2009. [PUBMED Abstract]
Pastorino L, Ghiorzo P, Nasti S, et al.: Identification of a SUFU germline mutation in a family with Gorlin syndrome. Am J Med Genet A 149A (7): 1539-43, 2009. [PUBMED Abstract]
Brugières L, Remenieras A, Pierron G, et al.: High frequency of germline SUFU mutations in children with desmoplastic/nodular medulloblastoma younger than 3 years of age. J Clin Oncol 30 (17): 2087-93, 2012. [PUBMED Abstract]
Evans DG, Farndon PA, Burnell LD, et al.: The incidence of Gorlin syndrome in 173 consecutive cases of medulloblastoma. Br J Cancer 64 (5): 959-61, 1991. [PUBMED Abstract]
Smith MJ, Beetz C, Williams SG, et al.: Germline mutations in SUFU cause Gorlin syndrome-associated childhood medulloblastoma and redefine the risk associated with PTCH1 mutations. J Clin Oncol 32 (36): 4155-61, 2014. [PUBMED Abstract]
Li FP, Fraumeni JF: Rhabdomyosarcoma in children: epidemiologic study and identification of a familial cancer syndrome. J Natl Cancer Inst 43 (6): 1365-73, 1969. [PUBMED Abstract]
Pearson AD, Craft AW, Ratcliffe JM, et al.: Two families with the Li-Fraumeni cancer family syndrome. J Med Genet 19 (5): 362-5, 1982. [PUBMED Abstract]
de Chadarévian JP, Vekemans M, Bernstein M: Fanconi's anemia, medulloblastoma, Wilms' tumor, horseshoe kidney, and gonadal dysgenesis. Arch Pathol Lab Med 109 (4): 367-9, 1985. [PUBMED Abstract]
Offit K, Levran O, Mullaney B, et al.: Shared genetic susceptibility to breast cancer, brain tumors, and Fanconi anemia. J Natl Cancer Inst 95 (20): 1548-51, 2003. [PUBMED Abstract]
Dewire MD, Ellison DW, Patay Z, et al.: Fanconi anemia and biallelic BRCA2 mutation diagnosed in a young child with an embryonal CNS tumor. Pediatr Blood Cancer 53 (6): 1140-2, 2009. [PUBMED Abstract]
Reid S, Renwick A, Seal S, et al.: Biallelic BRCA2 mutations are associated with multiple malignancies in childhood including familial Wilms tumour. J Med Genet 42 (2): 147-51, 2005. [PUBMED Abstract]
Rorke LB: The cerebellar medulloblastoma and its relationship to primitive neuroectodermal tumors. J Neuropathol Exp Neurol 42 (1): 1-15, 1983. [PUBMED Abstract]
Louis DN, Perry A, Reifenberger G, et al.: The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathol 131 (6): 803-20, 2016. [PUBMED Abstract]
Ramaswamy V, Remke M, Shih D, et al.: Duration of the pre-diagnostic interval in medulloblastoma is subgroup dependent. Pediatr Blood Cancer 61 (7): 1190-4, 2014. [PUBMED Abstract]
McManamy CS, Lamont JM, Taylor RE, et al.: Morphophenotypic variation predicts clinical behavior in childhood non-desmoplastic medulloblastomas. J Neuropathol Exp Neurol 62 (6): 627-32, 2003. [PUBMED Abstract]
Eberhart CG, Kratz J, Wang Y, et al.: Histopathological and molecular prognostic markers in medulloblastoma: c-myc, N-myc, TrkC, and anaplasia. J Neuropathol Exp Neurol 63 (5): 441-9, 2004. [PUBMED Abstract]
Giangaspero F, Perilongo G, Fondelli MP, et al.: Medulloblastoma with extensive nodularity: a variant with favorable prognosis. J Neurosurg 91 (6): 971-7, 1999. [PUBMED Abstract]
Onvani S, Etame AB, Smith CA, et al.: Genetics of medulloblastoma: clues for novel therapies. Expert Rev Neurother 10 (5): 811-23, 2010. [PUBMED Abstract]
Dubuc AM, Northcott PA, Mack S, et al.: The genetics of pediatric brain tumors. Curr Neurol Neurosci Rep 10 (3): 215-23, 2010. [PUBMED Abstract]
Thompson MC, Fuller C, Hogg TL, et al.: Genomics identifies medulloblastoma subgroups that are enriched for specific genetic alterations. J Clin Oncol 24 (12): 1924-31, 2006. [PUBMED Abstract]
Kool M, Koster J, Bunt J, et al.: Integrated genomics identifies five medulloblastoma subtypes with distinct genetic profiles, pathway signatures and clinicopathological features. PLoS One 3 (8): e3088, 2008. [PUBMED Abstract]
Tabori U, Baskin B, Shago M, et al.: Universal poor survival in children with medulloblastoma harboring somatic TP53 mutations. J Clin Oncol 28 (8): 1345-50, 2010. [PUBMED Abstract]
Pfister S, Remke M, Benner A, et al.: Outcome prediction in pediatric medulloblastoma based on DNA copy-number aberrations of chromosomes 6q and 17q and the MYC and MYCN loci. J Clin Oncol 27 (10): 1627-36, 2009. [PUBMED Abstract]
Ellison DW, Onilude OE, Lindsey JC, et al.: beta-Catenin status predicts a favorable outcome in childhood medulloblastoma: the United Kingdom Children's Cancer Study Group Brain Tumour Committee. J Clin Oncol 23 (31): 7951-7, 2005. [PUBMED Abstract]
Polkinghorn WR, Tarbell NJ: Medulloblastoma: tumorigenesis, current clinical paradigm, and efforts to improve risk stratification. Nat Clin Pract Oncol 4 (5): 295-304, 2007. [PUBMED Abstract]
Giangaspero F, Wellek S, Masuoka J, et al.: Stratification of medulloblastoma on the basis of histopathological grading. Acta Neuropathol 112 (1): 5-12, 2006. [PUBMED Abstract]
Northcott PA, Korshunov A, Witt H, et al.: Medulloblastoma comprises four distinct molecular variants. J Clin Oncol 29 (11): 1408-14, 2011. [PUBMED Abstract]
Pomeroy SL, Tamayo P, Gaasenbeek M, et al.: Prediction of central nervous system embryonal tumour outcome based on gene expression. Nature 415 (6870): 436-42, 2002. [PUBMED Abstract]
Jones DT, Jäger N, Kool M, et al.: Dissecting the genomic complexity underlying medulloblastoma. Nature 488 (7409): 100-5, 2012. [PUBMED Abstract]
Peyrl A, Chocholous M, Kieran MW, et al.: Antiangiogenic metronomic therapy for children with recurrent embryonal brain tumors. Pediatr Blood Cancer 59 (3): 511-7, 2012. [PUBMED Abstract]
Taylor MD, Northcott PA, Korshunov A, et al.: Molecular subgroups of medulloblastoma: the current consensus. Acta Neuropathol 123 (4): 465-72, 2012. [PUBMED Abstract]
Kool M, Korshunov A, Remke M, et al.: Molecular subgroups of medulloblastoma: an international meta-analysis of transcriptome, genetic aberrations, and clinical data of WNT, SHH, Group 3, and Group 4 medulloblastomas. Acta Neuropathol 123 (4): 473-84, 2012. [PUBMED Abstract]
Pietsch T, Schmidt R, Remke M, et al.: Prognostic significance of clinical, histopathological, and molecular characteristics of medulloblastomas in the prospective HIT2000 multicenter clinical trial cohort. Acta Neuropathol 128 (1): 137-49, 2014. [PUBMED Abstract]
Morrissy AS, Cavalli FMG, Remke M, et al.: Spatial heterogeneity in medulloblastoma. Nat Genet 49 (5): 780-788, 2017. [PUBMED Abstract]
Wang X, Dubuc AM, Ramaswamy V, et al.: Medulloblastoma subgroups remain stable across primary and metastatic compartments. Acta Neuropathol 129 (3): 449-57, 2015. [PUBMED Abstract]
Schwalbe EC, Lindsey JC, Nakjang S, et al.: Novel molecular subgroups for clinical classification and outcome prediction in childhood medulloblastoma: a cohort study. Lancet Oncol 18 (7): 958-971, 2017. [PUBMED Abstract]
Cavalli FMG, Remke M, Rampasek L, et al.: Intertumoral Heterogeneity within Medulloblastoma Subgroups. Cancer Cell 31 (6): 737-754.e6, 2017. [PUBMED Abstract]
Northcott PA, Buchhalter I, Morrissy AS, et al.: The whole-genome landscape of medulloblastoma subtypes. Nature 547 (7663): 311-317, 2017. [PUBMED Abstract]
Northcott PA, Jones DT, Kool M, et al.: Medulloblastomics: the end of the beginning. Nat Rev Cancer 12 (12): 818-34, 2012. [PUBMED Abstract]
Gibson P, Tong Y, Robinson G, et al.: Subtypes of medulloblastoma have distinct developmental origins. Nature 468 (7327): 1095-9, 2010. [PUBMED Abstract]
Ellison DW, Dalton J, Kocak M, et al.: Medulloblastoma: clinicopathological correlates of SHH, WNT, and non-SHH/WNT molecular subgroups. Acta Neuropathol 121 (3): 381-96, 2011. [PUBMED Abstract]
Gajjar A, Chintagumpala M, Ashley D, et al.: Risk-adapted craniospinal radiotherapy followed by high-dose chemotherapy and stem-cell rescue in children with newly diagnosed medulloblastoma (St Jude Medulloblastoma-96): long-term results from a prospective, multicentre trial. Lancet Oncol 7 (10): 813-20, 2006. [PUBMED Abstract]
Kool M, Jones DT, Jäger N, et al.: Genome sequencing of SHH medulloblastoma predicts genotype-related response to smoothened inhibition. Cancer Cell 25 (3): 393-405, 2014. [PUBMED Abstract]
Robinson GW, Rudneva VA, Buchhalter I, et al.: Risk-adapted therapy for young children with medulloblastoma (SJYC07): therapeutic and molecular outcomes from a multicentre, phase 2 trial. Lancet Oncol 19 (6): 768-784, 2018. [PUBMED Abstract]
Leary SE, Zhou T, Holmes E, et al.: Histology predicts a favorable outcome in young children with desmoplastic medulloblastoma: a report from the children's oncology group. Cancer 117 (14): 3262-7, 2011. [PUBMED Abstract]
Rutkowski S, von Hoff K, Emser A, et al.: Survival and prognostic factors of early childhood medulloblastoma: an international meta-analysis. J Clin Oncol 28 (33): 4961-8, 2010. [PUBMED Abstract]
von Bueren AO, von Hoff K, Pietsch T, et al.: Treatment of young children with localized medulloblastoma by chemotherapy alone: results of the prospective, multicenter trial HIT 2000 confirming the prognostic impact of histology. Neuro Oncol 13 (6): 669-79, 2011. [PUBMED Abstract]
Shih DJ, Northcott PA, Remke M, et al.: Cytogenetic prognostication within medulloblastoma subgroups. J Clin Oncol 32 (9): 886-96, 2014. [PUBMED Abstract]
Cho YJ, Tsherniak A, Tamayo P, et al.: Integrative genomic analysis of medulloblastoma identifies a molecular subgroup that drives poor clinical outcome. J Clin Oncol 29 (11): 1424-30, 2011. [PUBMED Abstract]
Schwalbe EC, Williamson D, Lindsey JC, et al.: DNA methylation profiling of medulloblastoma allows robust subclassification and improved outcome prediction using formalin-fixed biopsies. Acta Neuropathol 125 (3): 359-71, 2013. [PUBMED Abstract]
Zhukova N, Ramaswamy V, Remke M, et al.: Subgroup-specific prognostic implications of TP53 mutation in medulloblastoma. J Clin Oncol 31 (23): 2927-35, 2013. [PUBMED Abstract]
Goschzik T, Schwalbe EC, Hicks D, et al.: Prognostic effect of whole chromosomal aberration signatures in standard-risk, non-WNT/non-SHH medulloblastoma: a retrospective, molecular analysis of the HIT-SIOP PNET 4 trial. Lancet Oncol 19 (12): 1602-1616, 2018. [PUBMED Abstract]
Gottardo NG, Hansford JR, McGlade JP, et al.: Medulloblastoma Down Under 2013: a report from the third annual meeting of the International Medulloblastoma Working Group. Acta Neuropathol 127 (2): 189-201, 2014. [PUBMED Abstract]
Louis DN, Perry A, Burger P, et al.: International Society Of Neuropathology--Haarlem consensus guidelines for nervous system tumor classification and grading. Brain Pathol 24 (5): 429-35, 2014. [PUBMED Abstract]
Fouladi M, Gajjar A, Boyett JM, et al.: Comparison of CSF cytology and spinal magnetic resonance imaging in the detection of leptomeningeal disease in pediatric medulloblastoma or primitive neuroectodermal tumor. J Clin Oncol 17 (10): 3234-7, 1999. [PUBMED Abstract]
Zeltzer PM, Boyett JM, Finlay JL, et al.: Metastasis stage, adjuvant treatment, and residual tumor are prognostic factors for medulloblastoma in children: conclusions from the Children's Cancer Group 921 randomized phase III study. J Clin Oncol 17 (3): 832-45, 1999. [PUBMED Abstract]
Yao MS, Mehta MP, Boyett JM, et al.: The effect of M-stage on patterns of failure in posterior fossa primitive neuroectodermal tumors treated on CCG-921: a phase III study in a high-risk patient population. Int J Radiat Oncol Biol Phys 38 (3): 469-76, 1997. [PUBMED Abstract]
Taylor RE, Bailey CC, Robinson K, et al.: Results of a randomized study of preradiation chemotherapy versus radiotherapy alone for nonmetastatic medulloblastoma: The International Society of Paediatric Oncology/United Kingdom Children's Cancer Study Group PNET-3 Study. J Clin Oncol 21 (8): 1581-91, 2003. [PUBMED Abstract]
Rutkowski S, Bode U, Deinlein F, et al.: Treatment of early childhood medulloblastoma by postoperative chemotherapy alone. N Engl J Med 352 (10): 978-86, 2005. [PUBMED Abstract]
Rutkowski S, Gerber NU, von Hoff K, et al.: Treatment of early childhood medulloblastoma by postoperative chemotherapy and deferred radiotherapy. Neuro Oncol 11 (2): 201-10, 2009. [PUBMED Abstract]
Ramaswamy V, Remke M, Adamski J, et al.: Medulloblastoma subgroup-specific outcomes in irradiated children: who are the true high-risk patients? Neuro Oncol 18 (2): 291-7, 2016. [PUBMED Abstract]
Albright AL, Wisoff JH, Zeltzer PM, et al.: Effects of medulloblastoma resections on outcome in children: a report from the Children's Cancer Group. Neurosurgery 38 (2): 265-71, 1996. [PUBMED Abstract]
Thompson EM, Hielscher T, Bouffet E, et al.: Prognostic value of medulloblastoma extent of resection after accounting for molecular subgroup: a retrospective integrated clinical and molecular analysis. Lancet Oncol 17 (4): 484-95, 2016. [PUBMED Abstract]
Stargatt R, Rosenfeld JV, Maixner W, et al.: Multiple factors contribute to neuropsychological outcome in children with posterior fossa tumors. Dev Neuropsychol 32 (2): 729-48, 2007. [PUBMED Abstract]
Pollack IF, Polinko P, Albright AL, et al.: Mutism and pseudobulbar symptoms after resection of posterior fossa tumors in children: incidence and pathophysiology. Neurosurgery 37 (5): 885-93, 1995. [PUBMED Abstract]
Robertson PL, Muraszko KM, Holmes EJ, et al.: Incidence and severity of postoperative cerebellar mutism syndrome in children with medulloblastoma: a prospective study by the Children's Oncology Group. J Neurosurg 105 (6): 444-51, 2006. [PUBMED Abstract]
Wells EM, Khademian ZP, Walsh KS, et al.: Postoperative cerebellar mutism syndrome following treatment of medulloblastoma: neuroradiographic features and origin. J Neurosurg Pediatr 5 (4): 329-34, 2010. [PUBMED Abstract]
Gudrunardottir T, Sehested A, Juhler M, et al.: Cerebellar mutism: review of the literature. Childs Nerv Syst 27 (3): 355-63, 2011. [PUBMED Abstract]
Wolfe-Christensen C, Mullins LL, Scott JG, et al.: Persistent psychosocial problems in children who develop posterior fossa syndrome after medulloblastoma resection. Pediatr Blood Cancer 49 (5): 723-6, 2007. [PUBMED Abstract]
Michalski JM, Janss A, Vezina G, et al.: Results of COG ACNS0331: a phase III trial of involved-field radiotherapy (IFRT) and low dose craniospinal irradiation (LD-CSI) with chemotherapy in average-risk medulloblastoma: a report from the Children's Oncology Group. [Abstract] Int J Radiat Oncol Biol Phys 96 (5): A-LBA-2, 937-8, 2016. Also available online Exit Disclaimer. Last accessed May 06, 2019.
Yock TI, Yeap BY, Ebb DH, et al.: Long-term toxic effects of proton radiotherapy for paediatric medulloblastoma: a phase 2 single-arm study. Lancet Oncol 17 (3): 287-98, 2016. [PUBMED Abstract]
Eaton BR, Esiashvili N, Kim S, et al.: Clinical Outcomes Among Children With Standard-Risk Medulloblastoma Treated With Proton and Photon Radiation Therapy: A Comparison of Disease Control and Overall Survival. Int J Radiat Oncol Biol Phys 94 (1): 133-8, 2016. [PUBMED Abstract]
Ris MD, Packer R, Goldwein J, et al.: Intellectual outcome after reduced-dose radiation therapy plus adjuvant chemotherapy for medulloblastoma: a Children's Cancer Group study. J Clin Oncol 19 (15): 3470-6, 2001. [PUBMED Abstract]
Packer RJ, Sutton LN, Atkins TE, et al.: A prospective study of cognitive function in children receiving whole-brain radiotherapy and chemotherapy: 2-year results. J Neurosurg 70 (5): 707-13, 1989. [PUBMED Abstract]
Johnson DL, McCabe MA, Nicholson HS, et al.: Quality of long-term survival in young children with medulloblastoma. J Neurosurg 80 (6): 1004-10, 1994. [PUBMED Abstract]
Walter AW, Mulhern RK, Gajjar A, et al.: Survival and neurodevelopmental outcome of young children with medulloblastoma at St Jude Children's Research Hospital. J Clin Oncol 17 (12): 3720-8, 1999. [PUBMED Abstract]
Laughton SJ, Merchant TE, Sklar CA, et al.: Endocrine outcomes for children with embryonal brain tumors after risk-adapted craniospinal and conformal primary-site irradiation and high-dose chemotherapy with stem-cell rescue on the SJMB-96 trial. J Clin Oncol 26 (7): 1112-8, 2008. [PUBMED Abstract]
Geyer JR, Sposto R, Jennings M, et al.: Multiagent chemotherapy and deferred radiotherapy in infants with malignant brain tumors: a report from the Children's Cancer Group. J Clin Oncol 23 (30): 7621-31, 2005. [PUBMED Abstract]
Chi SN, Gardner SL, Levy AS, et al.: Feasibility and response to induction chemotherapy intensified with high-dose methotrexate for young children with newly diagnosed high-risk disseminated medulloblastoma. J Clin Oncol 22 (24): 4881-7, 2004. [PUBMED Abstract]
Grill J, Sainte-Rose C, Jouvet A, et al.: Treatment of medulloblastoma with postoperative chemotherapy alone: an SFOP prospective trial in young children. Lancet Oncol 6 (8): 573-80, 2005. [PUBMED Abstract]
Cohen BH, Geyer JR, Miller DC, et al.: Pilot Study of Intensive Chemotherapy With Peripheral Hematopoietic Cell Support for Children Less Than 3 Years of Age With Malignant Brain Tumors, the CCG-99703 Phase I/II Study. A Report From the Children's Oncology Group. Pediatr Neurol 53 (1): 31-46, 2015. [PUBMED Abstract]
Duffner PK, Horowitz ME, Krischer JP, et al.: Postoperative chemotherapy and delayed radiation in children less than three years of age with malignant brain tumors. N Engl J Med 328 (24): 1725-31, 1993. [PUBMED Abstract]
Ater JL, van Eys J, Woo SY, et al.: MOPP chemotherapy without irradiation as primary postsurgical therapy for brain tumors in infants and young children. J Neurooncol 32 (3): 243-52, 1997. [PUBMED Abstract]
Grundy RG, Wilne SH, Robinson KJ, et al.: Primary postoperative chemotherapy without radiotherapy for treatment of brain tumours other than ependymoma in children under 3 years: results of the first UKCCSG/SIOP CNS 9204 trial. Eur J Cancer 46 (1): 120-33, 2010. [PUBMED Abstract]
Blaney SM, Kocak M, Gajjar A, et al.: Pilot study of systemic and intrathecal mafosfamide followed by conformal radiation for infants with intracranial central nervous system tumors: a pediatric brain tumor consortium study (PBTC-001). J Neurooncol 109 (3): 565-71, 2012. [PUBMED Abstract]
Lafay-Cousin L, Smith A, Chi SN, et al.: Clinical, Pathological, and Molecular Characterization of Infant Medulloblastomas Treated with Sequential High-Dose Chemotherapy. Pediatr Blood Cancer 63 (9): 1527-34, 2016. [PUBMED Abstract]
Dhall G, Grodman H, Ji L, et al.: Outcome of children less than three years old at diagnosis with non-metastatic medulloblastoma treated with chemotherapy on the "Head Start" I and II protocols. Pediatr Blood Cancer 50 (6): 1169-75, 2008. [PUBMED Abstract]
Packer RJ, Sutton LN, Elterman R, et al.: Outcome for children with medulloblastoma treated with radiation and cisplatin, CCNU, and vincristine chemotherapy. J Neurosurg 81 (5): 690-8, 1994. [PUBMED Abstract]
Bailey CC, Gnekow A, Wellek S, et al.: Prospective randomised trial of chemotherapy given before radiotherapy in childhood medulloblastoma. International Society of Paediatric Oncology (SIOP) and the (German) Society of Paediatric Oncology (GPO): SIOP II. Med Pediatr Oncol 25 (3): 166-78, 1995. [PUBMED Abstract]
Kortmann RD, Kühl J, Timmermann B, et al.: Postoperative neoadjuvant chemotherapy before radiotherapy as compared to immediate radiotherapy followed by maintenance chemotherapy in the treatment of medulloblastoma in childhood: results of the German prospective randomized trial HIT '91. Int J Radiat Oncol Biol Phys 46 (2): 269-79, 2000. [PUBMED Abstract]
Taylor RE, Bailey CC, Robinson KJ, et al.: Impact of radiotherapy parameters on outcome in the International Society of Paediatric Oncology/United Kingdom Children's Cancer Study Group PNET-3 study of preradiotherapy chemotherapy for M0-M1 medulloblastoma. Int J Radiat Oncol Biol Phys 58 (4): 1184-93, 2004. [PUBMED Abstract]
von Hoff K, Hinkes B, Gerber NU, et al.: Long-term outcome and clinical prognostic factors in children with medulloblastoma treated in the prospective randomised multicentre trial HIT'91. Eur J Cancer 45 (7): 1209-17, 2009. [PUBMED Abstract]
Packer RJ, Gajjar A, Vezina G, et al.: Phase III study of craniospinal radiation therapy followed by adjuvant chemotherapy for newly diagnosed average-risk medulloblastoma. J Clin Oncol 24 (25): 4202-8, 2006. [PUBMED Abstract]
Thomas PR, Deutsch M, Kepner JL, et al.: Low-stage medulloblastoma: final analysis of trial comparing standard-dose with reduced-dose neuraxis irradiation. J Clin Oncol 18 (16): 3004-11, 2000. [PUBMED Abstract]
Sabel M, Fleischhack G, Tippelt S, et al.: Relapse patterns and outcome after relapse in standard risk medulloblastoma: a report from the HIT-SIOP-PNET4 study. J Neurooncol 129 (3): 515-524, 2016. [PUBMED Abstract]
Oyharcabal-Bourden V, Kalifa C, Gentet JC, et al.: Standard-risk medulloblastoma treated by adjuvant chemotherapy followed by reduced-dose craniospinal radiation therapy: a French Society of Pediatric Oncology Study. J Clin Oncol 23 (21): 4726-34, 2005. [PUBMED Abstract]
Merchant TE, Kun LE, Krasin MJ, et al.: Multi-institution prospective trial of reduced-dose craniospinal irradiation (23.4 Gy) followed by conformal posterior fossa (36 Gy) and primary site irradiation (55.8 Gy) and dose-intensive chemotherapy for average-risk medulloblastoma. Int J Radiat Oncol Biol Phys 70 (3): 782-7, 2008. [PUBMED Abstract]
Fukunaga-Johnson N, Sandler HM, Marsh R, et al.: The use of 3D conformal radiotherapy (3D CRT) to spare the cochlea in patients with medulloblastoma. Int J Radiat Oncol Biol Phys 41 (1): 77-82, 1998. [PUBMED Abstract]
Huang E, Teh BS, Strother DR, et al.: Intensity-modulated radiation therapy for pediatric medulloblastoma: early report on the reduction of ototoxicity. Int J Radiat Oncol Biol Phys 52 (3): 599-605, 2002. [PUBMED Abstract]
Carrie C, Grill J, Figarella-Branger D, et al.: Online quality control, hyperfractionated radiotherapy alone and reduced boost volume for standard risk medulloblastoma: long-term results of MSFOP 98. J Clin Oncol 27 (11): 1879-83, 2009. [PUBMED Abstract]
Packer RJ, Goldwein J, Nicholson HS, et al.: Treatment of children with medulloblastomas with reduced-dose craniospinal radiation therapy and adjuvant chemotherapy: A Children's Cancer Group Study. J Clin Oncol 17 (7): 2127-36, 1999. [PUBMED Abstract]
Nageswara Rao AA, Wallace DJ, Billups C, et al.: Cumulative cisplatin dose is not associated with event-free or overall survival in children with newly diagnosed average-risk medulloblastoma treated with cisplatin based adjuvant chemotherapy: report from the Children's Oncology Group. Pediatr Blood Cancer 61 (1): 102-6, 2014. [PUBMED Abstract]
Salloum R, Chen Y, Yasui Y, et al.: Late Morbidity and Mortality Among Medulloblastoma Survivors Diagnosed Across Three Decades: A Report From the Childhood Cancer Survivor Study. J Clin Oncol 37 (9): 731-740, 2019. [PUBMED Abstract]
Verlooy J, Mosseri V, Bracard S, et al.: Treatment of high risk medulloblastomas in children above the age of 3 years: a SFOP study. Eur J Cancer 42 (17): 3004-14, 2006. [PUBMED Abstract]
Gandola L, Massimino M, Cefalo G, et al.: Hyperfractionated accelerated radiotherapy in the Milan strategy for metastatic medulloblastoma. J Clin Oncol 27 (4): 566-71, 2009. [PUBMED Abstract]
Evans AE, Jenkin RD, Sposto R, et al.: The treatment of medulloblastoma. Results of a prospective randomized trial of radiation therapy with and without CCNU, vincristine, and prednisone. J Neurosurg 72 (4): 572-82, 1990. [PUBMED Abstract]
Jakacki RI, Burger PC, Zhou T, et al.: Outcome of children with metastatic medulloblastoma treated with carboplatin during craniospinal radiotherapy: a Children's Oncology Group Phase I/II study. J Clin Oncol 30 (21): 2648-53, 2012. [PUBMED Abstract]
von Bueren AO, Kortmann RD, von Hoff K, et al.: Treatment of Children and Adolescents With Metastatic Medulloblastoma and Prognostic Relevance of Clinical and Biologic Parameters. J Clin Oncol 34 (34): 4151-4160, 2016. [PUBMED Abstract]
Tarbell NJ, Friedman H, Polkinghorn WR, et al.: High-risk medulloblastoma: a pediatric oncology group randomized trial of chemotherapy before or after radiation therapy (POG 9031). J Clin Oncol 31 (23): 2936-41, 2013. [PUBMED Abstract]