Post-Operative Accelerated-Hypofractionated Chemoradiation With Volumetric Modulated Arc Therapy and Simultaneous Integrated Boost in Glioblastoma: A Phase I Study (ISIDE-BT-2)

Abstract

BackgroundGlioblastoma Multiforme (GBM) is the most common primary brain cancer and one of the most lethal tumors. Theoretically, modern radiotherapy (RT) techniques allow dose-escalation due to the reduced irradiation of healthy tissues. This study aimed to define the adjuvant maximum tolerated dose (MTD) using volumetric modulated arc RT with simultaneous integrated boost (VMAT-SIB) plus standard dose temozolomide (TMZ) in GBM.MethodsA Phase I clinical trial was performed in operated GBM patients using VMAT-SIB technique with progressively increased total dose. RT was delivered in 25 fractions (5 weeks) to two planning target volumes (PTVs) defined by adding a 5-mm margin to the clinical target volumes (CTVs). The CTV1 was the tumor bed plus the MRI enhancing residual lesion with 10-mm margin. The CTV2 was the CTV1 plus 20-mm margin. Only PTV1 dose was escalated (planned dose levels: 72.5, 75, 77.5, 80, 82.5, 85 Gy), while PTV2 dose remained unchanged (45 Gy/1.8 Gy). Concurrent and sequential TMZ was prescribed according to the EORTC/NCIC protocol. Dose-limiting toxicities (DLTs) were defined as any G ≥ 3 non-hematological acute toxicity or any G ≥ 4 acute hematological toxicities (RTOG scale) or any G ≥ 2 late toxicities (RTOG-EORTC scale).ResultsThirty-seven patients (M/F: 21/16; median age: 59 years; median follow-up: 12 months) were enrolled and treated as follows: 6 patients (72.5 Gy), 10 patients (75 Gy), 10 patients (77.5 Gy), 9 patients (80 Gy), 2 patients (82.5 Gy), and 0 patients (85 Gy). Eleven patients (29.7%) had G1-2 acute neurological toxicity, while 3 patients (8.1%) showed G ≥ 3 acute neurological toxicities at 77.5 Gy, 80 Gy, and 82.5 Gy levels, respectively. Since two DLTs (G3 neurological: 1 patient and G5 hematological toxicity: 1 patient) were observed at 82.5 Gy level, the trial was closed and the 80 Gy dose-level was defined as the MTD. Two asymptomatic histologically proven radionecrosis were recorded.ConclusionsAccording to the results of this Phase I trial, 80 Gy in 25 fractions accelerated hypofractionated RT is the MTD using VMAT-SIB plus standard dose TMZ in resected GBM.

Dose–Volume Constraints fOr oRganS At risk In Radiotherapy (CORSAIR): An “All-in-One” Multicenter–Multidisciplinary Practical Summary

“…For example, Table 1 reports 72 Gy as the D max value for the brain. Instead, some studies based on intensity-modulated RT or volumetric-modulated arc therapy showed the brain’s tolerability of doses up to 80 Gy [ 94 , 95 ]. Furthermore, many indications have rather low levels of evidence and have to be simply considered as “expert opinions".…”

Recurrence Patterns after Radiotherapy for Glioblastoma with [(11)C]methionine Positron Emission Tomography-Guided Irradiation for Target Volume Optimization

“…A recent prospective phase I study determined the maximum tolerated dose (MTD) of adjuvant volumetric modulated arc RT with a simultaneous integrated boost (VMAT-SIB) and standard dose temozolomide (TMZ) in GBM. In this trial, the MTD was 80 Gy in 25 fractions (3.2 Gy/fraction) [30]. However, when compared to historical controls and published MRI-based dose-escalation studies, no improvement in progression-free survival or overall survival was observed but there was a trend toward increased hematological and neurological toxicity.…”

Clinical Outcomes of Moderately Hypofractionated Concurrent Chemoradiotherapy for Newly Diagnosed Glioblastoma

“…Apart from ConvRT explored in the Stupp regimen, 27 HypoRT with simultaneous integrated boost offers tolerable outcomes in patients with GBM receiving concomitant temozolomide. 4 5 6 7 8 9 A recent phase II study of 89 patients treated with 60 Gy in 20 fractions (50 Gy to low-risk areas) demonstrated tolerable toxicity. 4 They also showed comparable outcomes to those of ConvRT with median PFS and OS of 13.1 and 15.2 months, respectively.…”

“…With the advent of intensity-modulated RT (IMRT) with simultaneous integrated boost, moderately hypofractionated RT (HypoRT), rather than traditional conventionally fractionated RT (ConvRT, mostly 60 Gy in 30 fractions), has been explored as a treatment option for GBM in multiple series. 4 , 5 , 6 , 7 , 8 , 9 …”