Glioblastoma multiforme (GBM) is the most frequent malignant primary brain tumor in adult patients. Prognosis remains poor with a median survival of 14.6 months following treatment with surgery, external beam radiotherapy (RT), and chemotherapy . Although adjuvant RT increases overall survival, whatever the age or Karnofsky/OMS status of the patient, more than 90% of failures occur within the irradiated volumes . This suggests that the dose conventionally delivered is not sufficient. Therefore, there is interest in increasing the dose to specific and more aggressive parts of the tumor while sparing normal tissue, using new technologies such as intensity-modulated radiation therapy (IMRT) [3, 4].
As conventional MRI morphological sequences are insufficient to determine the potential target for a dose escalation  other types of imaging are needed, such as metabolic imaging [6, 7]. The modality of proton magnetic resonance spectroscopy imaging (MRSI) is a relevant tool to define new targets as it can characterize the biochemical, metabolic and pathological changes in brain tissues [8–11] with the analysis of 3D-multi-voxel array within the MRI lesions and the surrounding normal tissue. MRSI data have been correlated with histopathology and can assess the residual disease after surgical resection in high-grade gliomas . In addition, MRSI parameters were also found to be predictive of survival [13, 14].
The most common observation in glioblastoma is the peak corresponding to the choline-containing compounds (Cho) which increases with membrane proliferation, thus reflecting tumor presence and aggressiveness . For relative quantification of MR spectroscopic data, the ratio of Cho over N-acetyl-aspartate (NAA, a neurotransmitter only found in normal functioning neurons), is used . The volumes corresponding to MRSI abnormalities and contrast enhancement (CE) were found to predict relapse patterns [17, 18], in concordance with our results obtained from a prospective trial . MRSI (index of Cho/NAA ≥ 2) could predict the extent of anatomical and metabolic relapse after radio-chemotherapy in patients with glioblastoma . Therefore, these volumes represent potential radioresistant areas on which subvolume boosting  or dose painting by contours  is possible.
There are two main issues for the integration of MRSI into a RT treatment planning system (TPS). Firstly, MRSI images obtained from MRI scanners are MR spectroscopic maps overlaid on corresponding anatomical MR images. These images do not conform to DICOM standards,they are not compatible (contrarily to conventional MR images) for automatic image fusion with the planning CT scans. Secondly, the escalation in radiation dose from simultaneous integrated boost (SIB) should be carefully evaluated, in particular for organs at risk (OAR).
We performed this study in order to prepare a multi-institutional phase III prospective clinical trial of glioblastoma dose painting guided by MRSI. This trial will compare two RT treatments in concomitance with temozolomide: one delivering 60 Gy on conventional target volume and the other delivering 60 Gy on conventional target volume and a SIB of 72 Gy on a new target volume specific to MRSI.
In this paper, we propose an integration method of metabolic maps into TPS, overcoming the absence of DICOM 3.0 standard for MRSI, to guide the simultaneous integrated boost. We then compare dosimetry plans of standard 60-Gy treatment in 3D conformational radiotherapy (60-Gy 3D-CRT), 60-Gy in IMRT and the treatment with the dose escalation of 72 Gy in SIB-IMRT. The method that we described in this article can be used for future prospective trials integrating MR spectroscopy in radiotherapy planning treatments.