A Phase 2 Trial of Neoadjuvant Temozolomide (TMZ) Followed By Accelerated Hypofractionated Radiation Therapy (AHRT) and TMZ Followed By Adjuvant TMZ in Patients with Newly Diagnosed Glioblastoma (GBM): Long Term Survival and Toxicity Analysis

Abstract

Purpose: Encouraging results were observed on analysis of a phase II of neoadjuvant temozolomide (TMZ) followed by AHRT and TMZ followed by adjuvant TMZ in patients with newly diagnosed GBM. Here, we report long term outcomes. Fifty patients were accrued: age >18 years, histologically-proven GBM, KPS ≥ 60 and adequate hematologic, renal, and hepatic functions. Three to 4 weeks post-surgery patients started neoadjuvant TMZ for 2 weeks, followed by concomitant AHRT and TMZ followed by adjuvant TMZ. GTV was surgical cavity and/or postoperative contrast-enhancing lesion on MRI. PTV60 included GTV plus 0.5 cm and PTV 40 included GTV plus 2.0 cm. PTV60 received 60 Gy in 20 fractions, while PTV40 received 40 Gy. From March 2009 and July 2013, 50 patients were accrued with a median age of 60 years. MGMT gene promoter was methylated in 21 patients and unmethylated in 27. Gross total and partial resection were performed in 46, and biopsy in 4 patients. With a median follow up of 71 months for patients at risk, median OS is 22 months with PFS of 13.2 months. At 3 and 5 years, actuarial OS was 34% and 23%, respectively. Methylated MGMT gene promoter patients have OS of 57% and 40.9% at 3 and 5 years, respectively compared to 18.5% and 11.1% for unmethylated MGMT. Eleven patients had reoperation for suspected recurrence, 5 were found to have radiation effects with no evidence of recurrence. The actuarial freedom from necrosis is 82.5% at 78 months, with a plateau after 32.9 months. One patient had a grade 5 hematological toxicity without evidence of disease recurrence at time of death. Another patient developed a grade 4 hepatotoxicity which reversed back to normal after discontinuation of TMZ. As of the date of this report, 10 patients are alive at present with ECOG status of 0 in 4, ECOG 1 in 2, ECOG 2 in 3, and ECOG 3 in one patient. Of the 10 patients 7 are not receiving corticosteroids, while 3 are receiving dexamethasone doses varying between 0.5 mg and 4 mg QD. With a longer follow up, the initially observed OS was further confirmed, and compares favorably to OS reported by large clinical trials. The long-term toxicity continues to be monitored closely, especially for this special group of patients with long survival. Laboratory, in-vitro and in-vivo, experiments are currently underway to further understand the molecular basis of the interactions of neoadjuvant TMZ and AHRT. Future plans are to conduct a phase III randomized clinical trial to compare the current approach versus the standard Stupp’s regimen.