Carbon ion radiotherapy boost in the treatment of glioblastoma: a randomized phase I/III clinical trial

BACKGROUND: Glioblastoma (GBM) is a highly virulent tumor of the central nervous system, with a median survival < 15 months. Clearly, an improvement in treatment outcomes is needed. However, the emergence of these malignancies within the delicate brain parenchyma and their infiltrative growth pattern severely limit the use of aggressive local therapies. The particle therapy represents a new promising therapeutic approach to circumvent these prohibitive conditions with improved treatment efficacy. METHODS AND DESIGN: Patients with newly diagnosed malignant gliomas will have their tumor tissue samples submitted for the analysis of the status of O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation. In Phase I, the patients will undergo an induction carbon ion radiotherapy (CIRT) boost followed by 60 GyE of proton irradiation with concurrent temozolomide (TMZ) at 75 mg/m(2). To determine the maximal dose of safe induction boost, the tolerance, and acute toxicity rates in a dose-escalation manner from 9 to 18 GyE in three fractions will be used. In Phase III, GBM-only patients will be randomized to receive either 60 GyE (2 GyE per fraction) of proton irradiation with concurrent TMZ (control arm) or a CIRT boost (dose determined in Phase I of this trial) followed by 60 GyE of proton irradiation with concurrent TMZ. The primary endpoints are overall survival (OS) and toxicity rates (acute and long-term). Secondary endpoints are progression-free survival (PFS), and tumor response (based upon assessment with C-methionine/fluoro-ethyl-tyrosine positron emission tomography [MET/FET PET] or magnetic resonance imaging [MRI] and detection of serologic immune markers). We hypothesize that the induction CIRT boost will result in a greater initial tumor-killing ability and prime the tumor microenvironment for enhanced immunologic tumor clearance, resulting in an expected 33% improvement in OS rates. DISCUSSION: The prognosis of GBM remains grim. The mechanism underpinning the poor prognosis of this malignancy is its chronic state of tumor hypoxia, which promotes both immunosuppression/immunologic evasion and radio-resistance. The unique physical and biological properties of CIRT are expected to overcome these microenvironmental limitations to confer an improved tumor-killing ability and anti-tumor immune response, which could result in an improvement in OS with minimal toxicity. Trial registration number This trial has been registered with the China Clinical Trials Registry, and was allocated the number ChiCTR-OID-17013702.