Concurrent temozolomide and dose-escalated intensity-modulated radiation therapy in newly diagnosed glioblastoma

Abstract

Purpose: To determine the maximum-tolerated dose (MTD) of radiation (RT) with concurrent temozolomide in patients with newly diagnosed glioblastoma (GBM), to estimate their progression-free (PFS) and overall survival (OS), and to assess the role of (11)C methionine PET (MET-PET) imaging in predicting recurrence.

Experimental design: Intensity-modulated RT (IMRT) doses of 66 to 81 Gy, assigned to patients by the time-to-event continual reassessment method, were delivered over 6 weeks with concurrent daily temozolomide (75 mg/m(2)) followed by adjuvant cyclic temozolomide (200 mg/m(2) d1-5 q28d ×6 cycles). Treatment was based on gadolinium-enhanced MRI. Pretreatment MET-PET scans were obtained for correlation with eventual sites of failure.

Results: A total of 38 patients were analyzed with a median follow-up of 54 months for patients who remain alive. Late CNS grade ≥III toxicity was observed at 78 (2 of 7 patients) and 81 Gy (1 of 9 patients). None of 22 patients receiving 75 or less Gy developed RT necrosis. Median OS and PFS were 20.1 (14.0-32.5) and 9.0 (6.0-11.7) months, respectively. Twenty-two of 32 patients with pretreatment MET-PET uptake showed uptake beyond the contrast-enhanced MRI. Patients whose treatment did not include the region of increased MET-PET uptake showed an increased risk of noncentral failure (P < 0.001).

Conclusions: Patients with GBM can safely receive standard temozolomide with 75 Gy in 30 fractions, delivered using IMRT. The median OS of 20.1 months is promising. Furthermore, MET-PET appears to predict regions of high risk of recurrence not defined by MRI, suggesting that further improvements may be possible by targeting metabolically active regions.

Figure 1

Kaplan Meier overall (solid) and progression free survival curves (dotted line) of all patients (n=39) receiving study treatment is shown above.

Figure 2

a 11C MET PET (middle panel) clearly demonstrates areas of increased metabolic uptake extending beyond the contrast-enhancing lesion on MRI (left panel) but not beyond MR FLAIR.(right panel) MR FLAIR volume also includes surrounding peritumoral edema. b Pre-treatment post gadolinium T1-weighted MRI (middle panel) has been co-registered to the pre-treatment 11CMET-PET scan (left panel) as well as the post gadolinium T1-weighted MRI at recurrence (right panel). This example shows the overlap between the area of initial increased PET uptake (yellow) and eventual area of recurrence.