Phase II Study of Erlotinib Plus Temozolomide During and After Radiation Therapy in Patients With Newly Diagnosed Glioblastoma Multiforme or Gliosarcoma

Abstract

A B S T R A C T PurposeThis open-label, prospective, single-arm, phase II study combined erlotinib with radiation therapy (XRT) and temozolomide to treat glioblastoma multiforme (GBM) and gliosarcoma. The objectives were to determine efficacy of this treatment as measured by survival and to explore the relationship between molecular markers and treatment response. Patients and MethodsSixty-five eligible adults with newly diagnosed GBM or gliosarcoma were enrolled. We intended to treat patients not currently treated with enzyme-inducing antiepileptic drugs (EIAEDs) with 100 mg/d of erlotinib during XRT and 150 mg/d after XRT. Patients receiving EIAEDs were to receive 200 mg/d of erlotinib during XRT and 300 mg/d after XRT. After XRT, the erlotinib dose was escalated until patients developed tolerable grade 2 rash or until the maximum allowed dose was reached. All patients received temozolomide during and after XRT. Molecular markers of epidermal growth factor receptor (EGFR), EGFRvIII, phosphatase and tensin homolog (PTEN), and methylation status of the promotor region of the MGMT gene were analyzed from tumor tissue. Survival was compared with outcomes from two historical phase II trials. ResultsMedian survival was 19.3 months in the current study and 14.1 months in the combined historical control studies, with a hazard ratio for survival (treated/control) of 0.64 (95% CI, 0.45 to 0.91). Treatment was well tolerated. There was a strong positive correlation between MGMT promotor methylation and survival, as well as an association between MGMT promotor-methylated tumors and PTEN positivity shown by immunohistochemistry with improved survival. ConclusionPatients treated with the combination of erlotinib and temozolomide during and following radiotherapy had better survival than historical controls. Additional studies are warranted.

Shikonin and its derivatives inhibit the epidermal growth factor receptor signaling and synergistically kill glioblastoma cells in combination with erlotinib

“…11 A recent study reported that a subset of GBM patients with MGMT promoter methylation and PTEN positivity showed significantly longer survival with the treatment of erlotinib in combination with radiotherapy and temozolomide. 13 However, most studies have shown very modest or no significant survival benefit from TKIs due to the recurrent problem of resistance caused by mutations in EGFR or tumor heterogeneity. 9,14 Shikonin, a natural naphthoquinone, isolated from the roots of the Chinese herb Lithospermum erythrorhizon, shows strong cytotoxic effects on various cancer cell lines, including multidrug-resistant cell lines and preferentially inhibits cell proliferation by inhibiting EGFR-signaling in human epidermoid carcinoma.…”

Radiotherapy followed by adjuvant temozolomide with or without neoadjuvant ACNU-CDDP chemotherapy in newly diagnosed glioblastomas: a prospective randomized controlled multicenter phase III trial

“…However, with the standardized treatment protocol for glioblastoma, use of temozolomide only slightly improved survival outcome. Thus, treatments that include the combination of temozolomide with other drugs need to be tested [11][12][13][14]. The idea for this study originated from the hypothesis that a treatment that combined the existing effective protocol (ACNU-CDDP neoadjuvant chemotherapy followed by radiotherapy) with adjuvant use of the newer drug (temozolomide) would result in synergistic effects [5,7].…”

Biomarker Discovery, Validation and Clinical Application for Patients Diagnosed with Glioma

“…In fact, no significant activity of erlotinib was observed. In another study of 65 patients, erlotinib efficacy was assessed in combination with temozolomide (Prados et al 2009). Again no association with EGFRvIII and PTEN and response was measured, however in this study, MGMT promoter methylation was associated with better response.…”