Recurrent Glioblastoma: From Molecular Landscape to New Treatment Perspectives

SIMPLE SUMMARY: Glioblastoma is the most common and aggressive malignant primary brain cancer in adults. The prognosis remains poor following standard-of-care treatment with surgery, radiotherapy and chemotherapy, with a median overall survival of about 15 months. Theoretically, all glioblastoma patients relapse. Once tumors progress after first-line therapy, treatment options are limited and management of recurrent glioblastoma remains challenging. In recent years, new treatments have been tested on recurrent glioblastoma patients. These include immunotherapy, antiangiogenic treatment, targeted therapy and combination regimens. Here, we review these treatment approaches and provide an overview on the molecular characteristics of recurrent glioblastoma. ABSTRACT: Glioblastoma is the most frequent and aggressive form among malignant central nervous system primary tumors in adults. Standard treatment for newly diagnosed glioblastoma consists in maximal safe resection, if feasible, followed by radiochemotherapy and adjuvant chemotherapy with temozolomide; despite this multimodal treatment, virtually all glioblastomas relapse. Once tumors progress after first-line therapy, treatment options are limited and management of recurrent glioblastoma remains challenging. Loco-regional therapy with re-surgery or re-irradiation may be evaluated in selected cases, while traditional systemic therapy with nitrosoureas and temozolomide rechallenge showed limited efficacy. In recent years, new clinical trials using, for example, regorafenib or a combination of tyrosine kinase inhibitors and immunotherapy were performed with promising results. In particular, molecular targeted therapy could show efficacy in selected patients with specific gene mutations. Nonetheless, some molecular characteristics and genetic alterations could change during tumor progression, thus affecting the efficacy of precision medicine. We therefore reviewed the molecular and genomic landscape of recurrent glioblastoma, the strategy for clinical management and the major phase I-III clinical trials analyzing recent drugs and combination regimens in these patients.