Magnetic resonance spectroscopy as an early indicator of response to anti-angiogenic therapy in patients with recurrent glioblastoma: RTOG 0625/ACRIN 6677

Abstract

Background: The prognosis for patients with recurrent glioblastoma remains poor. The purpose of this study was to assess the potential role of MR spectroscopy as an early indicator of response to anti-angiogenic therapy.

Methods: Thirteen patients with recurrent glioblastoma were enrolled in RTOG 0625/ACRIN 6677, a prospective multicenter trial in which bevacizumab was used in combination with either temozolomide or irinotecan. Patients were scanned prior to treatment and at specific timepoints during the treatment regimen. Postcontrast T1-weighted MRI was used to assess 6-month progression-free survival. Spectra from the enhancing tumor and peritumoral regions were defined on the postcontrast T1-weighted images. Changes in the concentration ratios of n-acetylaspartate/creatine (NAA/Cr), choline-containing compounds (Cho)/Cr, and NAA/Cho were quantified in comparison with pretreatment values.

Results: NAA/Cho levels increased and Cho/Cr levels decreased within enhancing tumor at 2 weeks relative to pretreatment levels (P = .048 and P = .016, respectively), suggesting a possible antitumor effect of bevacizumab with cytotoxic chemotherapy. Nine of the 13 patients were alive and progression free at 6 months. Analysis of receiver operating characteristic curves for NAA/Cho changes in tumor at 8 weeks revealed higher levels in patients progression free at 6 months (area under the curve = 0.85), suggesting that NAA/Cho is associated with treatment response. Similar results were observed for receiver operating characteristic curve analyses against 1-year survival. In addition, decreased Cho/Cr and increased NAA/Cr and NAA/Cho in tumor periphery at 16 weeks posttreatment were associated with both 6-month progression-free survival and 1-year survival.

Conclusion: Changes in NAA and Cho by MR spectroscopy may potentially be useful as imaging biomarkers in assessing response to anti-angiogenic treatment.

Keywords: Cho; NAA; anti-angiogenic therapy; bevacizumab; glioblastoma; magnetic resonance spectroscopy.

Fig. 1.

(A) The 3 regions of interest were defined on the corresponding T1-weighted postcontrast images: (grey voxels) enhancing tumor, (black voxels) peritumoral tissue, and (white voxels) normal tissue on the contralateral side of tumor. (B) Typical MRS spectra were obtained from (left) the enhancing tumor and from (right) contralateral normal tissue. Tumor tissue is characterized by elevated Cho and decreased NAA.

Fig. 2.

Changes in (A) NAA/Cho levels and (B) Cho/Cr levels in enhancing tumor relative to baseline levels. NAA/Cho levels significantly increase at 2 wk posttreatment (P = .048), and Cho/Cr significantly decreases at 2 wk posttreatment (P = .016) indicated by asterisks.

Fig. 3.

(A) Changes in NAA/Cho, Cho/Cr, and NAA/Cr from baseline in tumor voxels grouped by PFS-6 survivors (PFS >6 mo) and non–PFS-6 survivors (PFS ≤ 6 mo). (B) Changes in NAA/Cho, Cho/Cr, and NAA/Cr from baseline in peritumoral voxels grouped by PFS-6 survivors (PFS >6 mo) and non–PFS-6 survivors (PFS ≤ 6 mo). Error bars represent SEs of the mean. Numbers of patients are noted on the bottom.