International Study on Improving the Prognosis for High-Risk Neuroblastoma in Children and Adolescents by Optimizing the Individual Phases of Treatment

A neuroblastoma is a malignant tumor of the nervous system that most commonly affects young children. It arises from immature nerve cells that normally develop into functioning nerve cells or adrenal cells during development. In neuroblastoma, however, these cells develop abnormally, which can lead to uncontrolled cell growth and the formation of a tumor. The tumor is usually found in the abdomen, primarily in the adrenal gland, but also along the spine, in the chest, or in the neck. Symptoms depend heavily on the tumor’s location. Neuroblastomas can follow very different courses: Some disappear on their own, while others grow rapidly and form tumor metastases in the bones, bone marrow, lymph nodes, or liver. Treatment for patients with neuroblastoma is based on their individual clinical situation and the likelihood of the disease returning (recurrence). Patients are therefore assigned to a specific risk or treatment group at the start of treatment. Current treatment guidelines call for classification into three therapy groups: low-risk group, intermediate-risk group, and high-risk group. Different treatment plans apply to each of these therapy groups. This approach allows for treatment that is individually tailored to each patient and adapted to their specific risk. High-risk neuroblastomas are characterized by specific genetic alterations, such as MYCN amplification. Most patients with neuroblastoma are treated as part of clinical trials, meaning that many different, trial-specific treatment regimens are used. However, neuroblastoma is usually treated with a combination of induction chemotherapy and, possibly, surgery and/or radiation therapy. For induction chemotherapy in high-risk neuroblastoma, two treatment regimens are typically considered: RAPID COJEC and GPOH Standard. They differ in duration, intensity, and type of medication. RAPID COJEC is shorter and very intensive, with few rest periods. GPOH is longer but may be better tolerated. Consolidation therapy usually follows, consisting of high-dose chemotherapy with busulfan-melphalan (Bu-Mel) and a stem cell transplant. In most cases, this is followed by maintenance therapy with immunotherapeutics to reduce the risk of relapse. The goal is to completely remove the tumor or keep it under control permanently—with as few side effects as possible.

The goal of this Phase 3 study is to further improve the treatment of children and adolescents with high-risk neuroblastoma and to increase survival rates, while at the same time reducing the side effects of therapy. Specifically, the study will investigate, across three consecutive treatment phases, which combination of chemotherapy is most effective at the start (induction), whether single- or double-dose high-dose therapy (consolidation) yields better long-term outcomes, and what radiation dose is appropriate afterward to prevent relapses. In addition, the study will evaluate how effective modern immunotherapies are in preventing relapses. Assignment to the individual treatment groups is done randomly (randomized). In the first treatment phase, known as induction therapy, patients receive either the short, intensive chemotherapy regimen called RAPID COJEC or the slightly longer GPOH regimen. Both groups also receive immunotherapy with dinutuximab beta. The goal of this phase is to shrink the tumor as much as possible.

In the second phase, known as consolidation therapy, the study will determine which form of high-dose chemotherapy is more effective at destroying any remaining tumor cells after surgery. This involves administering either a single high-dose regimen of busulfan and melphalan (Bu-Mel) or a more intensive double-high-dose regimen (Tandem-HDC) consisting of Bu-Mel plus thiotepa. This is followed by a stem cell transplant in both groups.

In the third phase of treatment, radiation therapy, the study investigates whether a higher radiation dose offers benefits. This phase applies only to children who still have visible tumor remaining after chemotherapy and surgery. The study compares standard radiation therapy at 21.6 Gray (Gy) with high-dose radiation therapy totaling 36 Gy (including an additional radiation dose—known as a “boost”—to the tumor area). In addition, all patients will receive follow-up maintenance therapy with the antibody dinutuximab beta. Assignment to the groups for the different treatment phases is based on age, stage, MYCN status, and response to previous treatments as part of the study. The primary endpoint of the study is event-free survival (EFS) at one year—that is, the time after treatment without, for example, disease recurrence, disease progression, or death due to the disease.

Children, adolescents, and young adults up to age 21 with newly diagnosed high-risk neuroblastoma, as defined by the INRG, are eligible to participate. High-risk neuroblastoma is diagnosed based on specific criteria that take into account the patient’s age, disease stage, and biological characteristics of the tumor. The main criteria are stage M (metastatic neuroblastoma) in children older than 12 months, stage Ms (metastatic neuroblastoma with bone marrow involvement) in children aged 12–18 months regardless of MYCN status, or stage L2, M, or Ms with MYCN amplification. In Germany, patients under 18 months of age with Stage M without MYCN amplification are not enrolled in the HR-NBL2 study. Participation is possible immediately before the start of treatment or up to 3 weeks after the first cycle of chemotherapy with carboplatin and etoposide.