ABSTRACT
PURPOSE: To determine the maximum tolerated dose (MTD) of fractionated intensity-modulated radiotherapy (IMRT) with temozolomide (TMZ) in patients with glioblastoma. METHODS AND MATERIALS: A Phase I clinical trial was performed. Eligible patients had surgically resected or biopsy-proven glioblastoma. Patients started TMZ (75 mg/day) during IMRT and continued for 1 year (150-200 mg/day, Days 1-5 every 28 days) or until disease progression. Clinical target volume 1 (CTV1) was the tumor bed +/- enhancing lesion with a 10-mm margin; CTV2 was the area of perifocal edema with a 20-mm margin. Planning target volume 1 (PTV1) and PTV2 were defined as the corresponding CTV plus a 5-mm margin. IMRT was delivered in 25 fractions over 5 weeks. Only the dose for PTV1 was escalated (planned dose escalation: 60 Gy, 62.5 Gy, 65 Gy) while maintaining the dose for PTV2 (45 Gy, 1.8 Gy/fraction). Dose limiting toxicities (DLT) were defined as any treatment-related nonhematological adverse effects rated as Grade >or=3 or any hematological toxicity rated as >or=4 by Radiation Therapy Oncology Group (RTOG) criteria. RESULTS: Nineteen consecutive glioblastoma were treated with step-and-shoot IMRT, planned with the inverse approach (dose to the PTV1: 7 patients, 60 Gy; 6 patients, 62.5 Gy; 6 patients, 65 Gy). Five coplanar beams were used to cover at least 95% of the target volume with the 95% isodose line. Median follow-up time was 23 months (range, 8-40 months). No patient experienced DLT. Grade 1-2 treatment-related neurologic and skin toxicity were common (11 and 19 patients, respectively). No Grade >2 late neurologic toxicities were noted. CONCLUSION: Accelerated IMRT to a dose of 65 Gy in 25 fractions is well tolerated with TMZ at a daily dose of 75 mg.
Subject(s)
Antineoplastic Agents, Alkylating/administration & dosage , Brain Neoplasms/drug therapy , Brain Neoplasms/radiotherapy , Dacarbazine/analogs & derivatives , Glioblastoma/drug therapy , Glioblastoma/radiotherapy , Radiotherapy, Intensity-Modulated/methods , Adult , Aged , Antineoplastic Agents, Alkylating/adverse effects , Brain Neoplasms/mortality , Brain Neoplasms/pathology , Dacarbazine/administration & dosage , Dacarbazine/adverse effects , Dose Fractionation, Radiation , Drug Administration Schedule , Female , Glioblastoma/mortality , Glioblastoma/pathology , Humans , Male , Maximum Tolerated Dose , Middle Aged , Prospective Studies , Temozolomide , Tumor BurdenABSTRACT
Hypertension can lead to subarachnoid hemorrhage and eventually to cerebral vasospasm. It has been suggested that the latter could be the result of oxidative stress and an inflammatory response evoked by subarachnoid hemorrhage. Because an unavoidable consequence of hemorrhage is lysis of red blood cells, we first tested the hypothesis on carotid arteries that the proinflammatory cytokine tumor necrosis factor-alpha contributes to vascular oxidative stress evoked by hemolysis. We observed that hemolysis induces a significant increase in tumor necrosis factor-alpha both in blood and in vascular tissues, where it provokes Rac-1/NADPH oxidase-mediated oxidative stress and vasoconstriction. Furthermore, we extended our observations to cerebral vessels, demonstrating that tumor necrosis factor-alpha triggered this mechanism on the basilar artery. Finally, in an in vivo model of subarachnoid hemorrhage obtained by the administration of hemolyzed blood in the cisterna magna, we demonstrated, by high-resolution ultrasound analysis, that tumor necrosis factor-alpha inhibition prevented and resolved acute cerebral vasoconstriction. Moreover, tumor necrosis factor-alpha inhibition rescued the hemolysis-induced brain injury, evaluated with the method of 2,3,5-triphenyltetrazolium chloride and by the histological analysis of pyknotic nuclei. In conclusion, our results demonstrate that tumor necrosis factor-alpha plays a crucial role in the onset of hemolysis-induced vascular injury and can be used as a novel target of the therapeutic strategy against cerebral vasospasm.
