Chemotherapy for Medulloblastomas in Children

Treatment

The first major role of chemotherapy in treating medulloblastoma was the discovery that adjuvant chemotherapy after gross total resection and radiation resulted in improved survival rates and allowed for the delivery of a lower dose of craniospinal radiation in those without metastatic disease (36). This discovery contributed to the subsequent stratification of these tumors into Standard-Risk Medulloblastoma and High-Risk Medulloblastoma Protocols.

• Standard-risk medulloblastoma: Standard-risk medulloblastomas have less than a 1.5-cm2 measurable residual after surgical resection , no metastases on staging MRI of the spine, and no tumor cells seen in CSF obtained via lumbar puncture.
• High-risk medulloblastoma: High-risk medulloblastomas have greater than a 1.5- cm2 residual tumor at the primary site after surgical resection, or metastases on staging as seen either on MRI or in the CSF. More recently, anaplastic or large-cell pathology has been considered to identify a high-risk tumor.

Infants with medulloblastomas

Tactics have been explored to minimize the toxic effects of craniospinal radiation on the developing brain, particularly in children under the age of 3 years, by maximizing chemotherapy induction and following this with either single or triple submyeloablative consolidation chemotherapy in the treatment of medulloblastoma.

• Head Start: In the Head Start studies, it has been identified that minimal residual disease at the end of induction is imperative to avoid radiation in the long term. Intrathecal methotrexate has been an important alternative component of chemotherapy to avoid radiation. The success of the infant protocols has led to development of an open COG protocol comparing the use of methotrexate or not during induction followed by triple submyeloablative therapy ACNS 0334.
• EFS varies with histology: Three-year EFS rates for patients with tumors with desmoplastic histology after gross total resection with this approach are between 80 and 100%. The EFS rate is approximately 50% for patients with tumors with classical histology, and 30–50% for those with anaplastic subtype following a gross total resection and absence of metastases at diagnosis.
• Less intensive chemotherapy not as successful: A less successful approach has been posterior fossa radiation and submyeloablative therapy following failure of less intense chemotherapy, or posterior fossa radiation following resection followed by less intense adjuvant chemotherapy.
• Plans to broaden ages for treatment: The future plan is to treat older patients who at the time of their diagnosis are up to 5 years of age with this type of approach to avoid long-term morbidity associated with radiation. In addition, protocols are in development considering no radiation for any desmoplastic pathway medulloblastomas, and reduced chemotherapy for WNT signaling pathway medulloblastomas.

Adjuvant Therapy

• Radiation unless child < 3 years old: Chemotherapy is typically used in conjunction with radiation except in younger children, for whom protocols have been developed to avoid radiation.

Complications

• Bone marrow suppression: Bone marrow suppression is standard after chemotherapy. Generally, the nadir is around 7–10 days, except after treatment with nitrosoureas (4–5 weeks) and temozolomide (21–28 days). Severity depends on intensity of dosing, age, previous chemotherapy and craniospinal radiation exposure.
• Gastrointestinal distress: Nausea and vomiting are usually well controlled with ondansetron or aprepitant for more resistant cases. Additional agents may be required, such as dimenhydrinate or nabilone. Constipation is usually well addressed with regular PEG 3350.
• Ototoxicity: High frequency hearing loss is expected with cisplatin therapy. This toxicity is exacerbated when followed by high-dose carboplatin.
• Urological: See details below.
• Neurological: See details below.

Outcome

• Steadily improving: While there is variation in outcome based on the age of the child and histology of the tumor, survival is now the expected outcome for most children who are diagnosed with medulloblastomas.