Comparison of Different Radiation Treatment Strategies for High-Risk Medulloblastoma in Children (Ages 3–21)

Medulloblastoma is a malignant brain tumor that primarily occurs in children and adolescents. The high-risk form of medulloblastoma refers to a variant of this cancer characterized by certain features associated with an increased risk of recurrence and poorer treatment outcomes. A medulloblastoma is considered high-risk if, for example, tumor metastases (metastases), certain aggressive cell types (large-cell/anaplastic) have been identified, significant tumor residue remains after surgery, or specific genetic alterations such as MYC or MYCN alterations or an SHH variant with a TP53 mutation are present. This risk classification is important because it determines how intensive the treatment must be. High-risk patients require intensive treatment consisting of chemotherapy, radiation therapy, and surgery. The need for more intensive therapy, particularly radiation therapy, can be associated with serious long-term effects, such as impaired cognitive development or growth disorders.

The goal of the SIOP-HRMB study is to evaluate two new treatment approaches compared to standard therapy, with a view to determining whether they can improve patients’ chances of survival while simultaneously reducing potential long-term side effects.

The study is conducted in two phases. In Phase 1, all patients first receive induction chemotherapy consisting of carboplatin and etoposide for a period of six weeks following surgery. Afterward, one of three radiation therapy strategies is selected at random (randomization): radiation therapy at the standard dose, a so-called hyperfractionated accelerated radiation therapy (HART), in which doses are administered twice daily over a shorter treatment period, or standard-dose radiation therapy in combination with high-dose chemotherapy using the active ingredient thiotepa. In the high-dose chemotherapy arm, stem cells are additionally collected from the patients’ blood beforehand and reinfused after the intensive chemotherapy to support the recovery of the bone marrow and thus blood production.

Only patients who have also participated in Phase 1 are eligible to participate in Phase 2 of the study. Two variants of maintenance chemotherapy are now being investigated. Patients are again randomly assigned to one of these groups. Patients will receive either the currently standard chemotherapy combination of cisplatin, vincristine, and lomustine alternated with cyclophosphamide and vincristine, or, alternatively, the drug temozolomide. The four drugs in the combination chemotherapy have different mechanisms of action—but complement each other in their anti-cancer effects. This combination has proven to be very effective for high-risk medulloblastoma, but is associated with health risks. Temozolomide is a drug already used to treat brain tumors in adults. It has not yet been approved for use in children. It belongs to the class of chemotherapeutic agents and works by inhibiting DNA synthesis, thereby preventing cancer cells from multiplying further. Monotherapy with temozolomide could represent a gentler alternative for patients because it is significantly better tolerated. It causes fewer side effects and, compared to standard chemotherapy, can be administered as a tablet. This new chemotherapy approach could therefore not only be associated with fewer side effects but also be potentially just as effective or even superior.

Children, adolescents, and young adults between the ages of 3 and 21 who have been newly diagnosed with high-risk medulloblastoma are eligible to participate. No prior tumor treatment may have been administered—except, in exceptional cases, a short course of chemotherapy with carboplatin and etoposide if treatment had to be started urgently. Individuals with a hereditary genetic mutation associated with an increased risk of cancer are not eligible to participate. Patients with very large residual tumors after surgery (without other high-risk characteristics) or very advanced metastasis (M4) are also ineligible to participate. Patients with tumors in the brainstem region are likewise excluded.