A phase II study of surgical excision, temozolomide, radiotherapy, and anti-EGFR radioimmunotherapy (EXTRA) as adjuvant therapy in high-grade gliomas

Abstract

Despite evolution in surgical technique, radiotherapy technology, and targeted systemic therapies, prognosis for patients with high-grade gliomas remains poor. Standard treatment consisting of surgery, adjuvant chemoradiation, and chemotherapy has marginally improved survival in these patients. A recent novel approach has been the addition of adjuvant radioimmunotherapy with 125I-labeled anti-epidermal growth factor receptor monoclonal antibody 425 (125I-epidermal growth factor receptor (EGFR) monoclonal antibody (MAb) 425), which demonstrated safety and efficacy in patients with glioblastoma. Many institutions choose to treat grade 3 gliomas in an identical fashion to grade 4 tumors. In this phase II clinical trial, we tested the efficacy of adjuvant radioimmunotherapy in patients with pathologic diagnosis of high-grade glioma comprising either glioblastoma (GBM) or astrocytoma with anaplastic foci (AAF). Patients with newly diagnosed high-grade gliomas were eligible. Adjuvant radiotherapy was delivered with a median dose of 60 Gy after surgery. 125I-EGFR MAb 425 was given by three weekly intravenous injections of 1.85 GBq of radiolabeled 125I-EGFR MAb 425 following surgery and adjuvant radiation. When administered, temozolomide was given concominantly (75 mg/m2/day, 35–42 days) with radiotherapy followed by 6 cycles of adjuvant temozolomide (TMZ) (150–200 mg/m2/day × 5 days, every 28 days q28d). Median survival was the primary endpoint. We compared survival in three treatment groups: patients who underwent surgery followed by radiation (CTL), patients who underwent surgery and radiation followed by radioimmunotherapy (RIT), and patients who underwent RIT with the additional of temozolomide (RIT + TMZ). Between 1988 and 2008, a total of 390 patients with high-grade glioma underwent treatment at Hahnemann University Hospital with a median age of 48 years. Median survival in months was 7.3, 39.7, and 79.4 in the CTL, RIT, and RIT + TMZ arms, respectively. Multivariate analysis, which controlled for age and extent of surgery, demonstrated a persistent survival benefit of RIT. Combined results are reported as well as subgroup analysis of GBM and AAF patients. Adjuvant 125I-EGFR MAb 425 radioimmunotherapy is a safe and effective treatment for patients with high-grade glioma and warrants further study with a randomized trial.