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Treatment and prognosis of medulloblastoma

Treatment and prognosis of medulloblastoma
Literature review current through: Jan 2024.
This topic last updated: Dec 06, 2023.

INTRODUCTION — Medulloblastoma is the most common malignant brain tumor of childhood and occurs in the posterior fossa, predominantly in the cerebellum. Treatment consists of a combined-modality approach that includes surgery, radiation therapy (RT), and chemotherapy in most patients. Long-term survival is now achieved in approximately three-quarters of all patients with medulloblastoma, though specific risk groups have varied survival outcomes. Unfortunately, each component of therapy can cause delayed complications that have a profound effect on quality of life in survivors. Clinical trials and future research efforts are focused on attempts to decrease treatment toxicity while maintaining high cure rates in patients with medulloblastoma.

The treatment and prognosis of medulloblastoma in children and adults, as well as the delayed complications of therapy, are discussed here. The clinical presentation, diagnosis, risk stratification, histopathology, and molecular pathogenesis of medulloblastoma are discussed separately. (See "Clinical presentation, diagnosis, and risk stratification of medulloblastoma" and "Histopathology, genetics, and molecular groups of medulloblastoma".)

GENERAL PRINCIPLES — The optimal initial treatment of patients with medulloblastoma includes both general measures to alleviate increased intracranial pressure and specific therapy directed against the tumor. Based upon results from multiple cooperative group trials, the preferred approach in most patients includes a combination of maximal safe surgical resection, radiation therapy (RT) to both the tumor site and the craniospinal axis, and systemic chemotherapy. The application of this combined-modality approach to different risk groups is discussed below. (See 'Initial therapy' below.)

Increased intracranial pressure — Patients with medulloblastoma often present with increased intracranial pressure due to obstructive hydrocephalus from compression of the fourth ventricle by the expanding tumor. Placement of a cerebrospinal fluid (CSF) shunt to relieve hydrocephalus is usually deferred until after a surgical resection, if it's performed at all, since surgery alone is often sufficient to treat this complication.

Local swelling from the tumor can contribute to symptoms of increased intracranial pressure. This vasogenic tumor edema is typically temporarily relieved by treatment with glucocorticoids. The management of increased intracranial pressure is discussed separately. (See "Elevated intracranial pressure (ICP) in children: Clinical manifestations and diagnosis" and "Evaluation and management of elevated intracranial pressure in adults".)

Surgery — Maximal safe resection is a key component of the treatment of all patients with medulloblastoma. Resection confirms the diagnosis, relieves increased intracranial pressure, and assists in local control. Surgery is used to remove as much of the tumor as possible without causing serious neurologic sequelae (eg, persistent ataxia, cranial nerve deficits).

With modern surgical techniques and imaging guidance in the operating room, gross total or near-total resection is achieved in the majority of patients. Because of the potential for neurologic complications, however, total or radical resection is not always possible, and overly aggressive attempts to achieve complete resection should be avoided.

Whether gross total resection confers improved survival over near-total resection has not been tested in a randomized trial. Observational data, mostly in the era before institution of combined craniospinal radiation and multiagent chemotherapy, have suggested that extent of resection is a key prognostic factor [1-5]. However, the magnitude of this effect may be lower than previously thought, particularly when molecular group is taken into account [6,7].

Surgical resection of tumors in the midline cerebellum can be associated with posterior fossa syndrome, also called cerebellar mutism, which occurs in approximately one-quarter of patients undergoing resection of a medulloblastoma. (See 'Posterior fossa syndrome' below.)

Radiation therapy — RT is an integral component of the initial management of patients with medulloblastoma. RT is used to control residual posterior fossa disease, to treat any disease that has spread along the craniospinal axis, and to prevent recurrence along the craniospinal axis. However, toxicity to the brain and spinal cord limits the doses used. This is particularly true in very young children, for whom craniospinal radiation is avoided or delayed due to severe toxicity to the rapidly developing central nervous system (CNS).

Technique — After surgical excision, depending on the age of the child, medulloblastoma is treated with external beam RT to the craniospinal axis, with an additional boost to the primary tumor site [4,8,9]. Contemporary radiation doses vary according to risk group. (See 'Risk stratification' below.)

Contemporary RT techniques including proton RT and intensity-modulated RT (IMRT) are prioritized to limit radiation to normal tissues [10-14]. While whole brain radiation with protons is no safer than with photons, use of protons or IMRT planning for primary site boost and spine RT avoids or minimizes radiation to the medial temporal lobes, inner ear, thyroid gland, lungs, heart, and adjacent abdominal organs compared with older techniques, without sacrificing disease control [10,11,13-19].

For average-risk disease in children (≥3 years of age), the whole brain and spine are typically treated with 23.4 Gy, with primary site boost of 30.6 Gy to a total dose of 54 Gy. For advanced-stage disease, 36 Gy is administered to the whole brain and spine, with a primary site boost of 18 Gy to a total dose of 54 Gy.

The rationale for additional radiation (boost) to the tumor bed is based upon the observation that 50 to 70 percent of recurrences occur in the posterior fossa [20,21]. The field of the boost includes the tumor bed and its margins (referred to as primary site or involved field boost). Compared with a full posterior fossa boost, use of an involved field boost reduces excess radiation exposure to normal brain and retains full treatment efficacy [22]. Local failure in the posterior fossa outside the tumor bed is rare as the solitary site of failure [20,21].

Using conventional techniques, the brain and spine are treated with separate but abutting RT fields. Placement of the junction between these two fields must be done precisely. Adjusting the site where these two fields abut each other two or three times during the course of craniospinal RT is routinely done to minimize the potential of overlapping dose to the spinal cord. However, sparing the spinal cord increases the dose to the thyroid gland, mandible, pharynx, and larynx. In developing children, this may increase the risk of late hypothyroidism or mandibular hypoplasia [23].

Complications — Although higher doses of RT are associated with better tumor control [4,24], irradiation to the craniospinal axis in children is associated with a significant incidence of neurologic complications, including neurocognitive impairment. Whenever possible, RT is delayed for children younger than three years of age to permit further development of the CNS. (See 'Neurocognitive impairment' below.)

In addition to its effects on neurocognitive development, craniospinal RT can cause decreased skeletal growth, hypothyroidism, adrenal insufficiency, and hypogonadism, all of which may be minimized with lower doses of radiation and/or newer techniques. (See 'Complications of treatment' below.)

Because of the risks of serious complications, the initial management of pediatric patients with medulloblastoma has utilized adjuvant chemotherapy with decreased doses of RT in average-risk children or substituted chemotherapy for RT in the initial management of infants and young children. (See 'Average-risk disease in children ≥3 years of age' below and 'Infants and young children' below.)

Chemotherapy — Chemotherapy has an important role in the multimodality management of children with medulloblastoma in several settings:

In young children, chemotherapy is used after surgery to delay or avoid irradiating the developing brain and spinal cord. (See 'Infants and young children' below.)

In average-risk children, adjuvant chemotherapy is used following surgery and RT to decrease the incidence of recurrence and minimize craniospinal radiation exposure. (See 'Average-risk disease in children ≥3 years of age' below.)

Chemotherapy is used with RT to treat high-risk disease. (See 'High-risk disease in children ≥3 years of age' below.)

INITIAL THERAPY

Children — The combined-modality approach to the treatment of children with medulloblastoma has evolved in a stepwise fashion. Prior to use of radiation, no children survived with surgical resection alone as therapy. Radiation therapy (RT) was incorporated to reduce the rate of local recurrence in the surgical bed and along the craniospinal axis. (See 'Radiation therapy' above.)

Most often, children with medulloblastoma are treated as part of a multicenter clinical trial or institution-specific protocol. Additional information and instructions for referring a patient to an appropriate research center can be obtained from the ClinicalTrials.gov database maintained by the United States National Library of Medicine.

Risk stratification — The current approach to the treatment of children with medulloblastoma varies according to two main factors: risk for recurrence, which depends primarily on extent of disease, and risk for treatment toxicity, with children younger than the age of three being at particularly high risk for neurologic impairment from RT. Using these factors, patients are divided into the following treatment groups (algorithm 1):

Infants and children younger than three years of age, who are at high risk of severe neurologic toxicity from craniospinal RT (see 'Infants and young children' below)

Children ≥3 years of age with average-risk disease, defined as total or near-total resection at the time of surgery, no evidence of disseminated disease by brain and spine magnetic resonance imaging (MRI) and lumbar cerebrospinal fluid (CSF) analysis, and classic or nodular desmoplastic histology (see 'Average-risk disease in children ≥3 years of age' below)

Children ≥3 years of age with high-risk disease, defined as the presence of ≥1.5 cm2 of residual tumor after surgery, evidence of disseminated or metastatic disease, or large cell/anaplastic histology (see 'High-risk disease in children ≥3 years of age' below)

In addition to these factors, there is an increasing understanding that medulloblastomas are genetically heterogeneous and can be divided into at least four molecular groups, each with divergent genetics, clinical behavior, prognosis, and potentially therapeutic targets (table 1). These groups are being integrated into clinical trial design and will likely form the basis for improved risk stratification and individualized therapy in the future. (See "Histopathology, genetics, and molecular groups of medulloblastoma", section on 'Molecular groups'.)

Infants and young children — The recommended approach for infants and young children consists of multiagent chemotherapy, often paired with autologous hematopoietic stem cell rescue, as part of a clinical trial protocol. The goal of chemotherapy is to delay or obviate the need for RT, and thereby allow the nervous system an opportunity to develop further, while maximizing survival outcomes [25-34]. Use of craniospinal RT in this population results in unacceptably high rates of severe neurologic impairment in survivors. (See 'Neurocognitive impairment' below.)

Molecular groups increasingly inform clinical trial design and interpretation of clinical trial results in infants. Cross-trial comparisons remain difficult due to small numbers of patients and heterogeneity of treatment regimens. Within these limitations, three major groups are emerging from the contemporary data in infants:

Sonic hedgehog (SHH) – SHH pathway tumors make up approximately 75 percent of infant medulloblastomas. This group is largely overlapping with desmoplastic/nodular and extensive nodularity histologic variants. In these patients, the HIT-2000 trial regimen of multiagent systemic chemotherapy plus intraventricular methotrexate and risk-adapted local RT resulted in excellent five-year progression-free and overall survival of 93 and 100 percent, respectively [35].

Further analysis dividing infantile SHH tumors into two groups by deoxyribonucleic acid (DNA) methylation profiling indicates that the HIT-2000 regimen may be particularly effective in SHH-I tumors, which appear to have worse outcomes with regimens that do not include intraventricular chemotherapy [36-38]. Across several trials, patients with SHH-II tumors have had excellent outcomes with chemotherapy-only regimens with or without intraventricular methotrexate [35-37,39].

Group 3 and 4 – Group 3 and 4 tumors make up the remaining 25 percent of medulloblastomas in infants. These groups have worse outcomes compared with SHH tumors. For group 3 in particular, the five-year survival with chemotherapy remains less than 50 percent [35,36,40]. There appears to be no benefit to the inclusion of focal RT [36]. Future trials in these groups will attempt to improve upon results of systemic chemotherapy with the possible addition of pre-relapse reduced-dose craniospinal RT and/or novel agents [38].

Average-risk disease in children ≥3 years of age — Our approach to children age ≥3 years with medulloblastoma that is amenable to total or near-total resection includes surgery followed by craniospinal RT (23.4 Gy) with involved field boost (32.4 Gy), followed by adjuvant multiagent chemotherapy.

The results of this approach in this patient subset are illustrated by the Children's Oncology Group (COG) ACNS0331 trial, which enrolled 549 patients ages 3 to 21 years with average-risk medulloblastoma from 2004 to 2014 [22]. The trial was designed with a two-stage randomization to investigate two aspects of the RT portion of treatment: first, involved field versus (standard) posterior fossa RT boost in all patients; and second, reduced-dose (18 Gy) versus standard-dose (23.4 Gy) craniospinal RT in patients three to seven years of age. All patients received weekly vincristine during RT, and maintenance chemotherapy consisted of alternating regimens of cisplatin, lomustine, and vincristine (cycle A) and cyclophosphamide and vincristine (cycle B) with a cycle schedule of AABAABAAB. Of note, weekly vincristine during craniospinal RT is no longer considered universally standard for medulloblastoma, based on results of a separate trial [41].

For the entire cohort of 464 eligible and evaluable children enrolled on COG ACNS0331 and with a median follow-up of 9.3 years, the five-year event-free and overall survival rates were 81 and 85 percent, respectively [22]. An involved field RT boost resulted in similar outcomes compared with standard posterior fossa boost for both event-free survival (hazard ratio [HR] 0.97, one-sided 94% upper CI 1.35; five-year rates, 82.5 versus 80.5 percent) and overall survival (five-year rates, 84.6 versus 85.2 percent). No posterior fossa failures occurred outside the limited boost volume among children who received an involved field boost. Although it was hypothesized that narrowing the RT boost volume would lower certain toxicities, ototoxicity rates were similar between the two groups, and there were few significant differences in neurocognitive outcomes based on RT boost assignment. However, longer follow-up or a larger sample size may be needed to detect the benefit of reduced RT exposure upon neurocognitive and hearing outcomes.

For the second randomization of craniospinal dose in children three to seven years of age, the reduced (18 Gy) dose of craniospinal RT resulted in worse outcomes compared with standard dose for both event-free survival (HR 1.67, one-sided 80% CI 2.10; five-year rates, 71.4 versus 82.9 percent, p = 0.28) and overall survival (five-year rates, 77.5 versus 85.6 percent, p = 0.049) [22]. Post hoc segregation of patients into molecular groups demonstrated that the increased failure rate was limited to group 4 tumors and not to tumors of the Wingless-related integration site (Wnt) subgroup.

Clinical trials in progress have adopted a reduced craniospinal RT dose for Wnt subgroup tumors, in the range of 15 to 18 Gy. For the other standard-risk tumors in this age group outside of a clinical trial, 23.4 Gy of craniospinal RT remains the standard of care based on the inferior survival outcomes associated with reduced-dose or deferred craniospinal RT [22,42,43].

Multidrug maintenance chemotherapy after RT is also standard of care. In both COG phase III trials that have incorporated multidrug maintenance chemotherapy after completion of RT in average-risk patients [22,44], outcomes have been superior to those previously seen in trials using RT alone, even when a higher dose of RT was used [9,24]. Results are also at least as good as those seen in trials using more intensive chemotherapy regimens [45,46].

Toxicities observed in the COG trials of craniospinal RT plus multiagent chemotherapy in average-risk disease have included the following [22,47-49]:

Acute grade 3 or 4 hematologic toxicity occurred in virtually all patients during treatment.

Severe ototoxicity was seen in approximately 25 percent of patients. In a secondary analysis of one of the trials, cumulative cisplatin dose was not associated with event-free or overall survival, suggesting that lower doses of cisplatin can likely be used to help reduce ototoxicity without compromising survival outcomes [48].

Significant neurologic sequelae from surgery and RT occurred in approximately 25 percent of patients and persisted at one year in approximately one-half [49].

Secondary malignancies occurred at a rate of 4.2 percent at 10 years [47]. (See 'Secondary neoplasms' below.)

Neurocognitive assessments in ACNS0331 showed worsening intelligence quotient (IQ) and processing speed scores over time, particularly in younger children [22].

Detailed evaluation of endocrine outcomes has not been reported, but a significant frequency of such abnormalities is anticipated as seen historically.

High-risk disease in children ≥3 years of age — The optimal treatment for children with metastatic, unresectable, or anaplastic/large cell histology medulloblastoma is unknown, and there is an increased risk for recurrence and death even with multimodal treatment that includes RT and chemotherapy.

Several prospective studies have examined adding concurrent chemotherapy to RT in an attempt to improve outcomes [50-52]. However, accumulating data suggest that the use of concurrent chemotherapy during RT only increases toxicity, without meaningful survival benefit in most subgroups. The standard of care has therefore shifted to omit chemotherapy, including weekly vincristine, during delivery of craniospinal RT for medulloblastoma [41]. Post-RT multiagent chemotherapy remains standard, and the doses of RT used for high-risk disease (36 Gy craniospinal RT plus 18 Gy primary site boost) are higher compared with average-risk disease.

As an example, the COG ACNS0332 trial randomly assigned 294 children age 3 to 18 years with high-risk medulloblastoma (72 percent with metastatic disease) to receive craniospinal RT (36 Gy) and weekly vincristine with or without daily carboplatin, followed by six cycles of maintenance chemotherapy with cisplatin, cyclophosphamide, and vincristine [53]. A second randomization to examine isotretinoin maintenance therapy closed early due to futility. With a median follow-up of 6.7 years and 261 patients evaluable, the addition of carboplatin to RT and vincristine did not significantly improve five-year event-free survival (66.4 versus 59.2 percent, p = 0.11) or overall survival (77.6 versus 68.8 percent, p = 0.28) for the entire cohort enrolled. Hematologic toxicity was greater with carboplatin during RT as well as during the first cycles of maintenance chemotherapy. Ototoxicity and neurocognitive toxicity were similar between groups.

In a subgroup analysis of ACNS0332 according to molecular group, however, group 3 tumors (n = 79) appeared to benefit from concurrent carboplatin, with improved five-year event-free survival (73.2 versus 53.7 percent, p = 0.047) and a trend towards improved overall survival (82.8 versus 63.7 percent, p = 0.06) [53]. However, these results require prospective confirmation.

High-dose chemotherapy and autologous hematopoietic cell transplantation (HCT) following RT has been explored in this group of patients. In a prospective study that included 48 patients with high-risk disease treated with craniospinal RT (36 to 39.6 Gy) followed by four cycles of high-dose chemotherapy and autologous HCT, the five-year event-free survival rate was 70 percent with no treatment-related mortalities [54]. A subsequent prospective study using a more intensive chemotherapy regimen but with reduced-dose craniospinal RT (23.4 to 30.6 Gy) reported five-year event-free and overall survival rates of 70 and 74 percent, respectively, and a treatment-related mortality rate of 10 percent [55]. Larger studies and long-term follow-up are needed to determine whether the additional short- and long-term risks of high-dose chemotherapy and autologous HCT regimens outweigh the potential benefits in this patient population.

Another treatment modification being explored in patients with high-risk disease is hyperfractionated accelerated RT, which in at least two prospective studies appears to be feasible when combined with multidrug chemotherapy [51,56]. The effect upon survival of this modality has yet to be determined.

Adults — Medulloblastoma is rare in adults, and there are no randomized studies upon which to base treatment decisions, particularly in regard to the role of chemotherapy. The treatment approach (algorithm 2) is informed primarily by indirect evidence in children and lower-quality evidence in adults.

Surgery and risk stratification – As in children, maximal safe resection is recommended, and a postoperative brain MRI should be obtained within 48 hours of surgery to assess for residual disease. Staging includes a spine MRI with contrast and lumbar CSF cytology, which should be obtained either preoperatively, if safe, or two to three weeks postoperatively to maximize specificity.

In adults, average risk is generally defined as having residual tumor <1.5 cm2, negative spine MRI, negative lumbar CSF cytology, and classic or desmoplastic histology. High-risk disease includes patients with bulky residual disease (>1.5 cm2), evidence of leptomeningeal dissemination or distant metastasis (either on brain and spine MRI or as seen on lumbar CSF cytology), and large cell/anaplastic histology [57]. Molecular markers of high risk include group 4 (MYC amplification) and SHH tumors with mutant tumor protein p53 (TP53) [58].

Average-risk adults – For most average-risk adults, we suggest standard-dose craniospinal RT with primary site boost (ie, 30 to 36 Gy to neuraxis and a total of 54 Gy to the tumor bed plus a margin) followed by multiagent adjuvant chemotherapy. Standard-dose craniospinal RT alone, without adjuvant chemotherapy, is another alternative to combination therapy in older adults and those with poor functional status who may be unable to tolerate chemotherapy safely. Reduced-dose craniospinal RT (ie, 23 Gy to neuraxis) with primary site boost in combination with chemotherapy is being studied prospectively in adults (NCT01857453) [59], but efficacy data are not yet available outside of the pediatric population.

Most, but not all, retrospective studies in adults suggest that adjuvant chemotherapy is associated with improved survival compared with craniospinal RT alone, even after adjusting for potential confounders [60-64]. However, the added value of chemotherapy in average-risk adults is less clear than in children, both because the toxicity of chemotherapy is considerably higher in adults and because there is less urgency to reduce the total radiation dose in the mature versus developing nervous system. The typical chemotherapy regimen used in adults is the Packer regimen, which is a combination of cisplatin, cyclophosphamide or lomustine, and vincristine [44,57]. Weekly vincristine during RT has not been shown to improve outcomes in children, and therefore, it is not routinely given in adults [57,58].

When multiagent chemotherapy regimens are used along with RT in adults, dose modifications are required in nearly all patients, and older patients are at higher risk for toxicity and treatment-related morbidities. In a prospective single-arm trial (NOA-07) of craniospinal RT with concurrent vincristine followed by up to eight cycles of chemotherapy (cisplatin, lomustine, and vincristine), treatment was terminated or dose reduced due to toxicity in nearly 60 percent of patients by cycle four [65]. Patients >45 years of age were at increased risk for toxicity. Three-year progression-free and overall survival were 67 and 70 percent, respectively. With long-term follow-up, verbal working memory declined but health-related quality of life improved from the posttreatment baseline [66].

In a separate prospective observational multicenter study that included 70 adults (≥21 years old) with nonmetastatic medulloblastoma, treatment consisted of maximal safe resection and craniospinal RT with posterior fossa boost in all patients [67]. Forty-nine out of 70 patients also received weekly vincristine during RT followed by up to eight cycles of maintenance chemotherapy (cisplatin, lomustine, vincristine). With a median follow-up of 44 months, the four-year event-free and overall survival rates were 68 and 89 percent, respectively. In a multivariable analysis, factors associated with worse outcome included presence of residual tumor after surgery and lateral tumor location. Receiving chemotherapy did not impact survival, although treatment allocation was not randomized; chemotherapy was the recommended approach in all patients.

High-risk adults – For adults with high-risk disease, including those with positive lumbar CSF cytology, we suggest standard-dose craniospinal RT with primary site boost followed by multiagent maintenance chemotherapy. The addition of preradiation or concurrent chemotherapy during RT is also considered in younger, fit patients.

Supportive evidence for treatment in high-risk adults includes a prospective phase II trial of 26 patients with T3b-T4 tumors, metastatic disease (either on brain and spine MRI or lumbar CSF cytology), or postoperative residual tumor (>1.5 cm2) [68]. Patients were treated with two cycles of upfront chemotherapy (mainly cisplatin) followed by craniospinal RT and adjuvant chemotherapy. With a median follow-up of 7.6 years, 5-year overall survival was 73 percent.

Recurrent disease – Treatment of recurrent disease should be individualized, and there are no standard regimens. Re-resection may be beneficial for a localized brain recurrence, followed by either additional chemotherapy or focal RT. High-dose chemotherapy with autologous HCT rescue can be considered in patients who achieve a complete response with conventional chemotherapy or who have no residual disease after resection [57,69]. Limited data support the use of vismodegib in recurrent SHH pathway tumors [70]. (See 'Recurrent disease' below.)

POST-THERAPY SURVEILLANCE — Following completion of therapy and restaging, patients are seen at periodic intervals to monitor for treatment complications and disease recurrence. Our approach is to see patients every three months for the first one to two years, then every 6 to 12 months for the next 5 to 10 years, then every one to two years or as clinically indicated. At these visits, we perform a history and physical examination and obtain brain MRI to monitor for recurrence, as well as spine MRI in patients with previous spine disease and as clinically indicated.

The utility of routine screening spine MRIs is likely to be low in patients without a history of disseminated disease. In an observational study that included 89 patients with medulloblastoma followed with screening brain and spine MRIs, 990 brain MRIs and 758 spine MRIs were obtained over a median follow-up of 52 months [71]. An isolated spine recurrence was detected on five spine MRIs, with a detection rate of 7/1000 (0.7 percent).

RECURRENT DISEASE — Despite the improved prognosis for children with medulloblastoma, an estimated 20 to 30 percent will relapse following their initial treatment [72]. Relapses tend to be local in approximately one-third of patients, disseminated (brain or spine) in one-third, and both local and disseminated in the remaining third [9,44,73]. In children, most relapses occur within the first three years after diagnosis; in adults, late relapses appear to be more common, as are extraneural metastases, typically to bone or bone marrow, which is rarely seen in the pediatric population in the modern era [67,74].

The likelihood of long-term survival decreases substantially in the setting of recurrent disease after initial therapy. High-dose chemotherapy with autologous hematopoietic cell transplantation (HCT; rescue) has been studied by multiple groups in this setting [69,72,75-77]. In small series, this approach has resulted in prolonged disease-free survival in approximately 20 to 25 percent of patients that had not received prior irradiation [69,72]. High-dose chemotherapy with HCT is not effective in patients who have received prior radiation therapy (RT).

For infants and young children who relapse following surgery and chemotherapy alone, salvage therapy with craniospinal radiation can sometimes result in prolonged disease-free survival [78]. A multicenter retrospective study identified 380 patients with progressive or relapsed medulloblastoma after initial therapy that did not include craniospinal radiation, all less than six years of age at the time of initial diagnosis [79]. Treatment included craniospinal radiation and systemic chemotherapy in most patients. Among 294 patients treated with curative intent, three- and five-year postrelapse survival rates were 52 and 43 percent, respectively. On multivariable analysis in 150 patients for whom molecular subgrouping was available, factors associated with improved survival included localized relapse, sonic hedgehog (SHH) subgroup, treatment with craniospinal radiation, and age ≥36 months at initial diagnosis.

EMERGING THERAPIES — Inhibition of molecular targets involved in the pathogenesis of medulloblastoma is an area of active investigation, particularly for the sonic hedgehog (SHH) pathway tumors [80].

Smoothened (SMO) inhibitors such as vismodegib, which has been approved by the US Food and Drug Administration (FDA) for treatment of advanced basal cell carcinoma, have shown evidence of activity in some, but not all, SHH medulloblastomas [81,82]. There are ongoing efforts to understand mechanisms of acquired resistance and molecular predictors of response within the SHH group, which is genetically heterogeneous [83,84]. Trials thus far have been mixed.

In two phase II trials by the Pediatric Brain Tumor Consortium, 31 adults and 12 pediatric patients with recurrent medulloblastoma were treated with vismodegib 150 to 300 mg per day [70]. There were no responses observed in the 31 patients with non-SHH pathway tumors. Among the 12 patients with SHH tumors, four had a protocol-defined response (complete or partial response maintained for at least eight weeks). Responders to vismodegib were more likely to harbor patched 1 (PTCH1) mutations and/or loss of heterozygosity, while nonresponders were enriched in downstream molecular alterations such as SUFU and GLI2. Diffuse p53 staining, as seen in TP53-mutant SHH tumors, was also predictive of nonresponse to SMO inhibition. A separate phase I/II trial of temozolomide with or without vismodegib in 24 patients with recurrent medulloblastoma established safety of the combination but did not show an overall benefit in progression-free survival [85].

PROGNOSIS AND GENETIC RISK — With modern multimodality therapy, approximately 75 percent of all children diagnosed with medulloblastoma will survive into adulthood. Clinical and histologic factors that are associated with worse prognosis include young age (less than three years), disseminated or metastatic disease at the time of diagnosis, residual disease after resection (>1.5 cm2), large cell and anaplastic histology, and MYC amplification.

The prognosis of children with medulloblastoma is also influenced by genetic risk. The incidence of germline mutations causing genetic predisposition to cancer is significantly higher than previously thought, ranging 5 to 6 percent overall and as high as 20 percent for patients in the SHH subgroup (table 2) [86]. Testing for germline mutations is now recommended, especially for subgroups with highest risk or if the family history is consistent with increased risk of cancer. Identification of genetic risk is critical not only for appropriate genetic counseling of the patient and relatives, but also for appropriate surveillance of other cancers for which the genetic predisposition causes increased risk. (See "Histopathology, genetics, and molecular groups of medulloblastoma", section on 'Genetic predisposition'.)

The prognosis of patients with genetic predisposition is variable by specific mutation but overall appears to be worse, with 52 percent five-year progression-free survival (95% CI 40-69) and 65 percent overall survival (95% CI 52-81) in these patients [86].

Children ≥3 years – Prognostic groups have been refined through molecular stratification, as illustrated by the SJMB03 prospective trial of risk-adapted therapy in 330 children ages 3 to 21 years with newly diagnosed medulloblastoma [41]:

Sonic hedgehog (SHH) tumors – Among SHH tumors, two divergent prognostic groups emerged. A low-risk subset had a very favorable prognosis with standard therapy, with a five-year progression-free survival of 100 percent. This group was identified by absence of all of the following: metastatic disease, TP53 mutation, LC/A histology, MYC amplification, GL12 mutation, and chromosome 17p loss. In the presence of any of these factors, prognosis was much worse (five-year progression-free survival <50 percent) [41]. Patients with SHH tumors have been shown to have particularly high risk of germline mutations, most commonly SUFU, PTCH1, TP53, partner and localizer of BRCA2 (PALB2), and BRCA2 [86]. Germline mutations of TP53 are associated with a remarkably poor prognosis in SHH medulloblastoma. (See "Histopathology, genetics, and molecular groups of medulloblastoma", section on 'Li-Fraumeni syndrome (TP53)'.)

Wingless-related integration site (Wnt) tumors – All 53 children with Wnt pathway tumors were alive and progression free at five years. There were four late deaths in this group related to second malignancies or pulmonary fibrosis [41]. Going forward, clinical trials are investigating reducing therapy in this group. Children with Wnt tumors without somatic mutation of catenin beta 1 (CTNNB1) have high risk of germline adenomatous polyposis coli (APC) mutations [86]. (See "Histopathology, genetics, and molecular groups of medulloblastoma", section on 'Familial adenomatous polyposis (APC)'.)

Group 3 and 4 tumors – These tumors had overlapping biology and were analyzed based on a variety of molecular assays. Three risk groups emerged with integration of methylation analysis. The main risk factors for poor outcome were MYC amplification and metastatic disease at diagnosis; with either of these factors, five-year progression-free survival was approximately 50 percent [41]. Patients with group 3 and 4 tumors have increased risk of germline PALB2 and BRCA2 mutations [86]. (See "Histopathology, genetics, and molecular groups of medulloblastoma", section on 'Other germline mutations (BRCA2, PALB2, GPR161)'.)

Infants and children <3 years – Children younger than age three years have a poor prognosis, with an estimated five-year survival of approximately 40 to 50 percent [32,34]. This is in part due to the necessary reduction or elimination of radiation. Young children with disseminated disease at the time of diagnosis have a particularly poor prognosis, with a five-year survival of approximately 15 to 30 percent [32,34]. Germline SUFU or PTCH1 mutations occur most frequently in infants, with a median age at diagnosis of two years [86]. (See "Histopathology, genetics, and molecular groups of medulloblastoma", section on 'Nevoid basal cell carcinoma syndrome (PTCH1, SUFU)'.)

Adults – Adults with medulloblastoma have a worse prognosis compared with children, with long-term survival ranging from approximately 50 to 80 percent in most studies [87-92]. Survival may be improving with contemporary multimodality treatment, however [91]. Clinical risk factors for worse outcomes include older age (eg, >30 years), incomplete resection, and disseminated disease. Extracranial relapse and late recurrences (beyond five years) are uncommon but well described [91]. Group 4 tumors have a particularly poor prognosis in adults, with a high incidence of high-risk disease and large cell and/or anaplastic histology [93]. Adults carry the greatest risk for PALB2 and BRCA2 germline mutations [86]. (See "Histopathology, genetics, and molecular groups of medulloblastoma", section on 'Other germline mutations (BRCA2, PALB2, GPR161)'.)

COMPLICATIONS OF TREATMENT — Each component of treatment can cause delayed complications that have a profound effect on quality of life and longevity in medulloblastoma survivors, particularly those patients diagnosed and treated during childhood and adolescence [94,95]. Although the late effects of treatment on quality of life are often attributed to craniospinal radiation therapy (RT), chemotherapy has a significant role in aggravating the adverse effects of RT [9,96].

Specific long-term follow-up survivorship guidelines for childhood central nervous system (CNS) tumors have been published by the Children's Oncology Group (COG) and are available online [97].

Posterior fossa syndrome — Posterior fossa syndrome, also called cerebellar cognitive affective syndrome or cerebellar mutism, can be seen in approximately one-quarter of patients [98]. It is a distinctive postoperative complication that is caused by injury to the inferior cerebellar vermis and cerebellar outflow pathways. Symptoms may largely be caused by disrupted communication between the cerebellum and mediodorsal thalamus.

This complication is characterized by impaired language production in association with emotional lability [99-101]. The most severely affected individuals also have varying degrees of inattention or difficulty initiating movement. Other associated postoperative neurologic symptoms include cranial nerve palsies or bowel and bladder incontinence [102].

Posterior fossa syndrome can appear one to two days after surgery. Symptoms frequently improve over the course of weeks to months, although some patients may not fully recover language skills for months or years. In a prospective study of 450 children from the COG study, 24 percent had symptoms consistent with posterior fossa syndrome, and 92 percent of these were moderately to severely affected [103].

Patients with medulloblastoma with associated posterior fossa syndrome are also at increased risk of long-term neurocognitive dysfunction. In a prospective study with five years of follow-up, patients with posterior fossa syndrome had worse neurocognitive function compared with age- and treatment-matched controls at all time points [104]. Mean scores were consistently lower than controls on measures of intellectual ability, processing speed, and attention; some functions, including attention and working memory, declined over time.

Neurocognitive impairment — Neurocognitive impairment is commonly observed following multimodality treatment for medulloblastoma, particularly in young children; this can be severe. Adult survivors of childhood medulloblastoma are half as likely as their unaffected siblings to earn a college degree [105]. Risk factors for increased severity of long-term deficits include younger age, high-risk disease, and radiation dose [95,106].

Late toxicity is particularly prominent in young children [107-110]. The most commonly observed deficits are in process speed, attention, and working memory [111]. Cumulative exposure to anesthesia during therapy may also be associated with increased risk for neurocognitive impairment among survivors [112].

Limited observational data suggest that proton craniospinal RT may be associated with less neurocognitive decline compared with conventional photon delivery methods [17,18,113]. In one nonrandomized comparative study, children who received proton RT had stable scores in most domains and superior performance compared with children who received photon RT at a mean follow-up of over four years, with the exception of processing speed, which declined in both groups [18].

Neuropsychological examinations are recommended in all medulloblastoma survivors to assist with needs assessment and monitor for changes over time. They can be especially useful at times of transition into middle school, high school, and college to aid in curriculum planning, appropriate placement, and educational accommodations.

Hearing loss — Ototoxicity is a significant risk given the doses of RT used in medulloblastoma protocols, and there may be synergistic toxicity between RT and cisplatin chemotherapy. Approximately 40 to 60 percent of long-term survivors of childhood medulloblastoma experience moderate to severe hearing loss, often requiring hearing assistance devices [12,95,105]. Use of protons and intensity-modulated RT (IMRT) techniques to reduce the dose to otic structures may be associated with lower rates of significant hearing loss, although longer-term follow-up is still needed [12,16,114]. (See "Delayed complications of cranial irradiation", section on 'Ototoxicity'.)

Early detection of ototoxicity in children receiving platinum agents may minimize the risk of severe impairment in the frequencies required for speech recognition, and all children should have a baseline audiogram prior to receiving cisplatin and irradiation so that hearing changes can be followed over time. Audiograms are typically performed every one to two years in survivors to monitor for hearing loss (table 3).

Intravenous sodium thiosulfate has been studied as a preventive agent when administered with each dose of cisplatin and was approved by the US Food and Drug Administration in September 2022 to help decrease the risk of hearing loss in children receiving cisplatin for localized, nonmetastatic solid tumors [115]. Approval was based on data from two randomized trials, one in children with hepatoblastoma and one in children with a variety of solid tumors (26 out of 125 with medulloblastoma), showing that sodium thiosulfate reduced the relative incidence of cisplatin-induced hearing loss by approximately 40 percent [116-118]. Although the approval of sodium thiosulfate is applicable to children with average-risk medulloblastoma, there is not yet consensus on its role, particularly in children treated with contemporary RT techniques (protons, IMRT) that spare the cochlea. Safety and efficacy have not been established in adults or in children with disseminated or metastatic disease. Supporting data on sodium thiosulfate are reviewed in detail separately. (See "Overview of neurologic complications of platinum-based chemotherapy", section on 'Ototoxicity'.)

Rarely, a slowly progressive sensorineural hearing loss and ataxia has been reported developing years after treatment [119]. In some cases, this has been found to occur in association with a hypointense rim of iron coating the surface of the cerebellum and brainstem and has been called superficial siderosis [119].

Skeletal problems — Craniospinal RT can cause decreased vertebral height and skeletal growth, resulting in significantly decreased adult height [25]. Patients are also prone to scoliosis [120]. The vertebral effects appear to be mediated by decreased levels of growth hormone (GH) and may be partially avoided with decreased doses of radiation [121] or use of proton RT [122]. (See "Bone problems in childhood cancer patients", section on 'Altered epiphyseal growth'.)

In addition, survivors are at risk for decreased bone mineral density (BMD) and vertebral fractures [123,124]. Adequate calcium and vitamin D intake, weight-bearing exercise, and avoidance of smoking are key aspects of preventive care. Early identification and therapy of hormone deficits has the potential to preserve BMD. (See "Bone problems in childhood cancer patients", section on 'Reduced bone mineral density'.)

Endocrine abnormalities — Endocrine abnormalities are very common following RT for medulloblastoma [121,122,125,126]. Irradiation of the pituitary hypothalamic axis can result in GH, adrenocorticotrophic hormone (ACTH), and thyroid-stimulating hormone (TSH) deficiencies. In addition, irradiation of the thyroid can cause primary hypothyroidism. Hypogonadism and early puberty have also been described.

The incidence of endocrine abnormalities was illustrated by a prospective series of 88 children treated between 1996 and 2003 at St. Jude Children's Research Hospital for embryonal brain tumors, including 78 (89 percent) with medulloblastoma [125]. All patients underwent detailed endocrinologic evaluation and were followed for a minimum of one year. The following findings were noted at a median follow-up of 1.5 to 1.8 years:

GH deficiency was present in 94 percent. (See "Endocrinopathies in cancer survivors and others exposed to cytotoxic therapies during childhood".)

TSH deficiency was present in 10 percent overall and was more frequent in those receiving higher doses of radiation to the hypothalamus. (See "Acquired hypothyroidism in childhood and adolescence", section on 'Etiology'.)

Primary hypothyroidism was present in 50 percent, but was less common in average-risk patients, who received lower doses of radiation (four-year incidence 13 versus 54 percent in high-risk patients who received higher doses of irradiation). (See "Acquired hypothyroidism in childhood and adolescence", section on 'Other causes'.)

ACTH deficiency was present in 43 percent. (See "Causes of central adrenal insufficiency in children".)

Risk factors include young age at the start of RT, dose of RT to the hypothalamus and pituitary, and time elapsed since treatment [126].

Use of proton RT may reduce the risk of some, but not all, of these endocrine abnormalities. In a study that included 40 children with medulloblastoma treated with proton radiation and 37 children treated with photon radiation, proton radiation was associated with a reduced risk of hypothyroidism (23 versus 69 percent) and requirement for any endocrine replacement therapy (55 versus 78 percent), but no change in the incidence of GH deficiency (53 versus 57 percent), adrenal insufficiency (5 versus 8 percent), or precocious puberty (18 versus 16 percent), with a median follow-up of six to seven years [122]. The reduced risk of hypothyroidism is driven by lower rates of primary hypothyroidism because the thyroid gland receives less radiation with proton RT; rates of central hypothyroidism are similar [127].

Due to the high rates of endocrine dysfunction in survivors of medulloblastoma, we recommend a baseline endocrine evaluation within a year of completing therapy and annual blood work to screen for hypothyroidism, GH deficiency, and adrenal insufficiency, typically under the supervision of an endocrinologist (table 4). (See "Endocrinopathies in cancer survivors and others exposed to cytotoxic therapies during childhood".)

Infertility — Both craniospinal RT and chemotherapy pose risks for fertility impairment in survivors [128,129]. Rates of impairment and recovery of fertility are not well studied in medulloblastoma survivors, however.

In one study of 31 females with a history of childhood medulloblastoma, persistent primary ovarian dysfunction was present in approximately 20 percent of patients with a median age of 17 years at last follow-up [130]. Ovarian dysfunction requiring hormone replacement therapy was most common after high-dose chemotherapy with autologous stem cell rescue.

Infertility and pregnancy in cancer survivors are reviewed in detail separately. (See "Overview of infertility and pregnancy outcome in cancer survivors" and "Overview of cancer survivorship in adolescents and young adults", section on 'Fertility'.)

Cataracts — Low-dose radiation exposure to the lens is a risk factor for premature cataracts. In one long-term follow-up study, the cumulative incidence of cataracts in medulloblastoma survivors was 14 percent at 30 years [105].

Cerebrovascular disease — Cerebrovascular disease, including occlusive vascular disease and stroke, intracranial hemorrhage, and cavernous malformations, is an increasingly recognized long-term complication of cranial irradiation in brain tumor survivors. Children appear to be more susceptible to radiation-induced vasculopathy than adults, and receipt of chemotherapy along with radiation may also increase this risk. (See "Delayed complications of cranial irradiation", section on 'Cerebrovascular effects'.)

Secondary neoplasms — The incidence of second neoplasms (both benign and malignant) is increased in children following RT and/or chemotherapy for primary CNS malignancies [44,131-135]. These secondary tumors may be diagnosed many years after the original presentation. The most common secondary cancers are brain and thyroid [94]. The cumulative incidence may be rising in the era of multimodality therapy [95].

In the COG phase III study for average-risk children, secondary malignancies were diagnosed in 15 children at a median of 5.8 years after diagnosis, which translates to a cumulative 10-year incidence rate of 4.2 percent [47]. Tumors included seven primary CNS tumors (six malignant gliomas, one pilocytic astrocytoma), three hematologic malignancies, one basal cell carcinoma in a patient with Gorlin syndrome, and four non-CNS solid tumors.

Meningiomas are also common late-occurring tumors. In a study that tracked both benign and malignant second neoplasms among nearly 1000 medulloblastoma survivors, the cumulative incidence of second neoplasms was 9.5 percent, including 24 benign meningiomas (one-quarter of all tumors) and eight malignant gliomas [95].

Our practice is to perform annual physical and dermatologic examinations to monitor for basal cell carcinomas and annual or every-other-year brain MRI to screen for secondary CNS tumors in medulloblastoma survivors.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Primary brain tumors".)

SUMMARY AND RECOMMENDATIONS

Importance of clinical trials – Advances in molecular classification of medulloblastomas have brought significant changes in risk stratification and treatment, which are starting to be incorporated into prospective clinical trials. It is strongly recommended that all children be treated on a clinical trial that takes advantage of these important developments. Screening and testing for genetic cancer risk from germline mutations are strongly recommended. (See "Histopathology, genetics, and molecular groups of medulloblastoma", section on 'Genetic counseling and testing'.)

Surgical resection – Maximal safe resection is a key component of the treatment of all patients with medulloblastoma. Resection confirms the diagnosis, relieves increased intracranial pressure, assists in local control, and has prognostic value depending on the extent of resection. (See 'Surgery' above and 'Increased intracranial pressure' above.)

Risk stratification – Following resection, treatment recommendations are based on age at diagnosis, amount of residual disease, histology, and extent of disease (metastatic versus localized). Molecular group informs prognosis and is being integrated into ongoing and future prospective clinical trials to inform escalation and deescalation of therapy. (See 'Risk stratification' above.)

Average risk – Average risk refers to patients with complete or near-complete resection (<1.5 cm2 of residual tumor), negative lumbar cerebrospinal fluid (CSF) cytology, no evidence of distant metastases, and classic or nodular desmoplastic histology.

High risk – High risk refers to patients with ≥1.5 cm2 of residual tumor after surgery, evidence of disseminated or metastatic disease, or large cell and/or anaplastic histology.

Postoperative therapy Most often, children with medulloblastoma are treated as part of a multicenter clinical trial or institution-specific protocol. Additional information and instructions for referring a patient to an appropriate research center can be obtained from the ClinicalTrials.gov database maintained by the United States National Library of Medicine.

When clinical trial enrollment is not possible, treatment is informed by ongoing and completed Children's Oncology Group (COG) trials (algorithm 1).

Age <3 years – For children <3 years of age, who are at high risk of severe neurologic impairment from craniospinal radiation therapy (RT), we recommend combination chemotherapy, often paired with autologous hematopoietic stem cell rescue, in an effort to delay or avoid use of craniospinal RT (Grade 1B). Clinical trials in this age group are now stratifying and adapting regimens based on molecular subgroup. (See 'Infants and young children' above.)

Average risk, age 3 to 21 years – For children 3 to 21 years of age with average-risk disease, we recommend craniospinal plus primary site RT, followed by adjuvant combination chemotherapy (Grade 1B). Single-modality therapy results in lower rates of cure. (See 'Average-risk disease in children ≥3 years of age' above.)

The standard dose of craniospinal RT for this group is 23.4 Gy. The primary site is boosted with 30.6 Gy, targeting the tumor bed plus a margin.

For adjuvant chemotherapy, we use alternating regimens of cisplatin/lomustine/vincristine and cyclophosphamide/vincristine as per the COG ACNS0331 trial. Most practitioners no longer use weekly vincristine during craniospinal RT.

High risk, age 3 to 21 years – For most children 3 to 21 years with high-risk disease, we suggest craniospinal RT (36 Gy) plus primary site RT (18 Gy) without concurrent vincristine or carboplatin, followed by combination chemotherapy (Grade 2C). The use of concurrent chemotherapy during RT adds toxicity but does not improve outcomes. (See 'High-risk disease in children ≥3 years of age' above.)

Age >21 years – For most adults with medulloblastoma (algorithm 2), we suggest craniospinal plus primary site RT followed by adjuvant combination chemotherapy (Grade 2C). (See 'Adults' above.)

For adults with poor performance status or multiple comorbidities, craniospinal RT alone, without adjuvant chemotherapy, is a reasonable alternative. Pre-RT chemotherapy may be considered for adults with high-risk disease.

Complications of therapy – Delayed complications of treatment can have a profound effect on quality of life in medulloblastoma survivors. The most common long-term complications are neurocognitive impairment, hearing loss, infertility, endocrine abnormalities, cerebrovascular disease, and second malignancies. (See 'Complications of treatment' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Scott L Pomeroy, MD, PhD, who contributed to earlier versions of this topic review.

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