Intracellular pH measured by ³¹ P-MR-spectroscopy might predict site of progression in recurrent glioblastoma under antiangiogenic therapy

Purpose: In solid tumors, changes in the expression/activity of plasma membrane ion transporters facilitate proton efflux and enable tumor cells to maintain a higher intracellular pH (pH_i ), while the microenvironment (pH_e ) is commonly more acidic. This supports various tumor-promoting mechanisms. We propose that these changes in pH take place before a magnetic resonance imaging (MRI)-detectable brain tumor recurrence occurs.

Materials and methods: We enrolled 66 patients with recurrent glioblastoma, treated with bevacizumab. Patients received a baseline and 8-week follow-up MRI including ¹ H/³¹ P MRSI (spectroscopy) on a 3T clinical scanner, until progressive disease according to Response Assessment in Neuro-Oncology (RANO) criteria occurred. Fourteen patients showed a distant or diffuse tumor recurrence (subsequent tumor) during treatment and were therefore selected for further evaluation. At the site of the subsequent tumor, an area of interest for MRSI voxel selection was retrospectively defined on radiographically unaffected baseline MRI sequences.

Results: Before treatment, pH_i in the area of interest (subsequent tumor) was significantly higher than pH_i of the contralateral normal-appearing tissue (control; P < 0.001). It decreased at the time of best response (P = 0.06), followed by a significant increase at progression (P = 0.03; baseline mean: 7.06, median: 7.068, SD: 0.032; best response mean: 7.044, median: 7.036, SD: 0.025; progression mean: 7.08, median: 7.095, SD 0.035). Until progression, the subsequent tumor was not detectable on standard MRI sequences. The area of existing tumor responded similar, but changes were not significant (decrease P = 0.22; increase P = 0.28).

Conclusion: Elevated pH_i in radiographically unaffected tissue at baseline might precede MRI-detectable progression in patients with recurrent glioblastoma treated with bevacizumab.

Level of evidence: 2 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2017;46:1200-1208.