Treatment of Newly Diagnosed Childhood Medulloblastoma
Children Older Than 3 Years with Average-Risk Medulloblastoma
Standard treatment options
Children Older Than 3 Years with High-Risk Medulloblastoma
Standard treatment options
Treatment options under clinical evaluation
Children Aged 3 Years and Younger
Standard treatment options
Treatment options under clinical evaluation
Current Clinical Trials
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.
Postoperatively, children may have significant neurologic deficits caused by preoperative tumor-related brain injury, hydrocephalus, or surgery-related brain injury.[Level of evidence: 3iC] A significant number of patients with medulloblastoma will develop cerebellar mutism syndrome. Symptoms of cerebellar mutism syndrome include the following:
- Delayed onset of speech.
- Suprabulbar palsies.
- 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 for the mutism.[3,4]; [Level of evidence: 3iC] In two Children’s Cancer Group studies evaluating children with both average-risk and high-risk medulloblastoma, the syndrome has been identified in nearly 25% of patients.[4-6]; [Level of evidence: 3iiiC] Approximately 50% of patients with this syndrome manifest long-term, permanent neurologic and neurocognitive sequelae.[5,7]Radiation therapy
Radiation therapy to the primary tumor site is usually in the range of 54 Gy to 55.8 Gy. This is usually given with a 1 cm to 2 cm margin around the primary tumor site, preferably by conformal techniques. 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. Chemotherapy is routinely administered during and after radiation therapy.
For children younger than 3 years, efforts are made to omit or delay radiation, 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 neurologic/cognitive development, growth, and endocrine function have been frequently observed, especially in younger children.[8-12] The use of proton-beam therapy to reduce toxicity is under investigation.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.[13,14]; [Level of evidence: 3iiiC]Children Older Than 3 Years with Average-Risk Medulloblastoma
Standard treatment options
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.Adjuvant therapy Adjuvant radiation therapy
- The best survival results for children with medulloblastoma have been obtained when radiation therapy is initiated within 4 to 6 weeks postsurgery.[15-18]; [Level of evidence: 1iA]
- The radiation dose for patients with average-risk medulloblastoma is 54 Gy to 55 Gy to the posterior fossa or local tumor bed and 23.4 Gy to the entire neuraxis (i.e., the whole brain and spine).[15-17,20]
- With radiation therapy alone, 5-year event-free survival (EFS) rates range between 50% and 65% in those with nondisseminated disease.[16,17]
- 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.
- If chemotherapy is added after radiation therapy, 23.4 Gy of craniospinal radiation therapy has been shown to be an effective dose.[21-23] Lower doses are being evaluated.
- Although the standard boost in medulloblastoma is to the entire posterior fossa, failure data patterns suggest that radiation therapy to the tumor bed instead of the entire posterior fossa would be equally effective and may be associated with reduced toxicity.[24,25]
Chemotherapy is now a standard component of the treatment of children with average-risk medulloblastoma.
- Prospective randomized trials and single-arm trials suggest that adjuvant chemotherapy given during and after radiation therapy improves overall survival (OS) for children with average-risk medulloblastoma.[7,15-19]
- Radiation therapy and chemotherapy given during and after surgery has demonstrated 5-year EFS rates of 70% to 85%.[15-17]; [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.[21-23,27]
- 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.[15,16,27] In addition, postradiation, high-dose chemotherapy supported by peripheral stem cell rescue has resulted in similar survival rates.
- Although medulloblastoma is often sensitive to chemotherapy, preradiation chemotherapy has not been shown to improve survival compared with treatment with radiation therapy and subsequent chemotherapy. In some prospective studies, preradiation chemotherapy has been related to a poorer rate of survival.[16-19]
Standard treatment options
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:Surgery
As for those with average-risk disease, attempt at gross-total resection is considered optimal, if deemed feasible. In those with disseminated disease at diagnosis, the degree of resection has not been shown to be an independent predictor of outcome.Adjuvant therapy
In high-risk patients, numerous studies have demonstrated that multimodality therapy improves the duration of disease control and overall disease-free survival (DFS).[28,30] Studies show that approximately 50% to 65% of patients with high-risk disease will experience long-term disease control.[15,28,30-32]; [Level of evidence: 1iiA]Adjuvant radiation therapy
- In contrast to standard-risk treatment, the craniospinal radiation dose is generally 36 Gy.
- 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.
- Postradiation, high-dose, nonmyeloablative chemotherapy supported by peripheral stem cell rescue has also been utilized and has resulted in 5-year progression-free survival rates of approximately 60%.
The following is an example of a national and/or institutional clinical trial that is currently being conducted. Information about ongoing clinical trials is available from the NCI Web site.
- COG-ACNS0332 (NCT00392327) (Chemotherapy and Radiation Therapy in Treating Young Patients With Newly Diagnosed, Previously Untreated, High-Risk Medulloblastoma or Supratentorial Primitive Neuroectodermal Tumor): This COG phase III trial for children older than 3 years is evaluating the efficacy of adding carboplatin to radiation therapy with vincristine, followed by maintenance chemotherapy with conventional adjuvant chemotherapy and isotretinoin.
Standard treatment options
Five-year DFS rates for young children with medulloblastoma have ranged between 30% and 70%, with most long-term survivors successfully treated with chemotherapy alone, having nondisseminated, totally resected tumors and histologic evidence of desmoplasia.[13,34,35]
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 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 medulloblastoma or medulloblastoma with extensive nodularity (MBEN) have a higher rate of complete resection than do patients with classic medulloblastoma.[36,37]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.[13,34,35,37-39]; [Level of evidence: 2A]; [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 outcome for patients with classic or large cell/anaplastic medulloblastoma.[36,37,42-44]; [Level of evidence: 2A]
- Desmoplasia was an independent predictor of favorable EFS rates in the German HIrnTumor (HIT) 2000 multicenter trial in which 19 patients with desmoplastic medulloblastoma or MBEN had 5-year EFS rates of 90% ± 7% and OS rates of 100% ± 0%, with all patients being treated with postoperative chemotherapy alone (including intraventricular methotrexate) prior to progression.
- 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%).
- 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). In this study, patients with desmoplastic tumors did not receive radiation prior to progression.
- In contrast to children with desmoplastic medulloblastoma or MBEN treated with current intensive chemotherapy regimens, children with other histologic subtypes fare less well.
- EFS rates are below 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.[13,37]
- Outcome is particularly poor when these patients have disseminated disease, and 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.[13,34,35]
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.[14,46][Level of evidence: 2A]Treatment options under clinical evaluation
The following are examples of national and/or institutional clinical trials that are currently being conducted. Information about ongoing clinical trials is available from the NCI Web site.
- COG-ACNS0334 (NCT00336024) (Combination Chemotherapy Followed By Peripheral Stem Cell Transplant in Treating Young Patients With Newly Diagnosed Supratentorial Primitive Neuroectodermal Tumors or High-Risk Medulloblastoma): This COG trial is open for children aged 3 years or younger at diagnosis with high-risk disease, which is defined as those with disseminated and/or subtotally resected tumors, or those younger than 8 months with otherwise standard-risk disease. Patients with cortical primitive neuroectodermal tumors or pineoblastomas are also eligible.
This study is evaluating chemotherapy as given in the completed COG study COG-99703, which used multiagent chemotherapy followed by thiotepa-based, higher-dose, marrow-ablative chemotherapy and peripheral stem cell rescue, and randomly assigns patients to treatment with or without intravenous high-dose methotrexate.
- PBTC-026 (NCT00867178) (Vorinostat, Isotretinoin, and Combination Chemotherapy in Treating Young Patients Who Have Undergone Surgery for Embryonal Tumors of the Central Nervous System): The Pediatric Brain Tumor Consortium trial is investigating the addition of vorinostat and isotretinoin to the COG-99703 backbone induction chemotherapy and as maintenance therapy following completion of the consolidation high-dose chemotherapy of this regimen.
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with untreated childhood medulloblastoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.References
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