The RIST Strategy: Molecular-Based Multimodal Treatment Regimens in Pediatric Oncology

Despite the success story of childhood oncology, the outcome of several pediatric diseases like stage IV neuroblastoma (NB), glioblastoma multiforme (GBM) and relapsed/refractory solid tumors remains dismal. Over the last decade our molecular understanding of the pathophysiology of cancer led to the development of multiple new substances that specifically target pivotal pathogenetic oncological pathways. Nevertheless only a few diseases profited from this research and most established therapeutic regimens rely further on conventional chemotherapy.

We developed a multimodal molecular-based therapy regimen that consists of a combination of kinase inhibitors with the mTOR inhibitor rapamycin, irinotecan and temozolomide. The drugs were combined in a metronomic design and we treated 10 patients, 8 with relapsed/refractory neuroblastoma (NB) and 2 with glioblastoma multiforme (GBM) in a multicentre compassionate use program. All 8 patients with refractory NB achieved a second and/or third remission by imaging and NB-specific parameters with a median duration of 8 months. The patients with GBM were MGMT negative and only partially resected or non-resectable before the start of the RIST therapy. Both are currently in remission for a median of 25 months (24 and 26 months). The treatment was outpatient-based and well tolerated. The observed adverse events were mild and consisted of nausea, vomiting and diarrhea. A relevant myelosupression with transfusion-dependant anemia and/or thrombocytopenia was observed infrequently. The molecular-based metronomic study design induced a remarkably sustained remission. Its applicability in an outpatient setting combined with a mild toxicity profile is convincing and seems worthy for a prospective evaluation.