Phase I study of hypofractionated intensity modulated radiation therapy with concurrent and adjuvant temozolomide in patients with glioblastoma multiforme

Abstract

PurposeTo determine the safety and efficacy of hypofractionated intensity modulated radiation therapy (Hypo-IMRT) using helical tomotherapy (HT) with concurrent low dose temozolomide (TMZ) followed by adjuvant TMZ in patients with glioblastoma multiforme (GBM).Methods and materialsAdult patients with GBM and KPS > 70 were prospectively enrolled between 2005 and 2007 in this phase I study. The Fibonacci dose escalation protocol was implemented to establish a safe radiation fractionation regimen. The protocol defined radiation therapy (RT) dose level I as 54.4 Gy in 20 fractions over 4 weeks and dose level II as 60 Gy in 22 fractions over 4.5 weeks. Concurrent TMZ followed by adjuvant TMZ was given according to the Stupp regimen. The primary endpoints were feasibility and safety of Hypo-IMRT with concurrent TMZ. Secondary endpoints included progression free survival (PFS), pattern of failure, overall survival (OS) and incidence of pseudoprogression. The latter was defined as clinical or radiological suggestion of tumour progression within three months of radiation completion followed by spontaneous recovery of the patient.ResultsA total of 25 patients were prospectively enrolled with a median follow-up of 12.4 months. The median age at diagnosis was 53 years. Based on recursive partitioning analysis (RPA) criteria, 16%, 52% and 32% of the patients were RPA class III, class IV and class V, respectively. All patients completed concurrent RT and TMZ, and 19 patients (76.0%) received adjuvant TMZ. The median OS was 15.67 months (95% CI 11.56 - 20.04) and the median PFS was 6.7 months (95% CI 4.0 – 14.0). The median time between surgery and start of RT was 44 days (range of 28 to 77 days). Delaying radiation therapy by more than 6 weeks after surgery was an independent prognostic factor associated with a worse OS (4.0 vs. 16.1 months, P = 0.027). All recurrences occurred within 2 cm of the original gross tumour volume (GTV). No cases of pseudoprogression were identified in our cohort of patients. Three patients tolerated dose level I with no dose limiting toxicity and hence the remainder of the patients were treated with dose level II according to the dose escalation protocol. Grade 3–4 hematological toxicity was limited to two patients and one patient developed Grade 4 Pneumocystis jiroveci pneumonia.ConclusionHypo-IMRT using HT given with concurrent TMZ is feasible and safe. The median OS and PFS are comparable to those observed with conventional fractionation. Hypofractionated radiation therapy offers the advantage of a shorter treatment period which is imperative in this group of patients with limited life expectancy.

Dose-escalated intensity-modulated radiotherapy and irradiation of subventricular zones in relation to tumor control outcomes of patients with glioblastoma multiforme

“…The observed lack of effect with DE in the current study is consistent with several other reports that have also failed to demonstrate a dose-response in tumor control and survival beyond conventional dose-schedules in patients with GBM. 17 , 18 With the exception of the study by Tsien et al that reported a median PFS and OS of 9 and 20.1 months, respectively, with DE radiotherapy (75 Gy delivered in 30 fractions), approximately half of the patients in that study still failed centrally. 19 …”

Efficacy and Safety of Hypofractionated Radiotherapy for the Treatment of Newly Diagnosed Glioblastoma Multiforme: A Systematic Review and Meta-Analysis

“…Some studies have found that participants who received HFR plus TMZ had comparable outcomes to those who received CFR. However, some studies have found that participants who received HFR had a better survival outcomes than those who received CFR (10, 36, 44, 45). A recent meta-analysis based on retrospective studies of the treatment of elderly patients (≥65 years) with GBM, found that participants who received HFR combined with TMZ had similar PFS to participants who received CRF plus TMZ, but that those who received HFR plus TMZ had a shorter OS (46).…”

Oligodendrogliomas in pediatric and adult patients: an outcome-based study from the Surveillance, Epidemiology, and End Result database

“… 2 Although TMZ has slightly lower reported response rates compared to PCV, it has significantly improved toxicity profile with fewer than 10% of patients receiving TMZ developing a grade 3 or 4 hematologic toxicity compared to 50% of patients receiving PCV. 7 , 19 Speirs et al 20 studied 59 patients with anaplastic OG or anaplastic astrocytoma and reported superior OS with the use of radiation therapy and adjuvant TMZ among patients with 1p/19q codeletion (91% vs. 68% at 5 years, p =0.02), compared to patients without the chromosomal deletions. PFS was also improved but not statistically significant (70% vs. 46% at 5 years, p =0.10).…”