Relapsed Glioblastoma: Treatment Strategies for Initial and Subsequent Recurrences.

OPINION STATEMENT: At the time of glioblastoma (GBM) recurrence, a sharp analysis of prognostic factors, disease characteristics, response to adjuvant treatment, and clinical conditions should be performed. A prognostic assessment could allow a careful selection between patients that could be proposed to intensified approaches or palliative setting. Participation in clinical trials aims to improve outcome, and should be encouraged due to dismal prognosis of GBM patients after recurrence. Reoperation should be proposed if the tumor is amenable to a complete resection and if prognostic factors suggest that patient could benefit from a second surgery. Second-line chemotherapy should be chosen based on MGMT status, time to disease recurrence, and toxicity profile. If enrollment into a clinical trial is not possible, a nitrosourea-based regimen is the preferred choice, carefully evaluating any previous temozolomide (TMZ)-related toxicity. In MGMT-methylated patients relapsing after TMZ completion, a rechallenge could be proposed. After second progression, the clinical advantage of subsequent lines of chemotherapy still needs to be clarified. However, based on performance status, patients' preference, and disease behavior, a third-line treatment could be considered. Available treatments include nitrosoureas, bevacizumab, or carboplatin plus etoposide. However, more effective therapeutic options are needed.