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ORIGINAL ARTICLE
Year : 2020  |  Volume : 16  |  Issue : 6  |  Page : 1488-1494

Perfusion magnetic resonance imaging in contouring of glioblastoma patients: Preliminary experience from a single institution


1 Department of Radiation Oncology, Fortis Memorial Research Institute, Gurgaon, Haryana, India
2 Department of Radiology, Fortis Memorial Research Institute, Gurgaon, Haryana, India
3 Department of Neurosurgery, Fortis Memorial Research Institute, Gurgaon, Haryana, India

Date of Submission23-Dec-2019
Date of Decision07-Apr-2020
Date of Acceptance06-May-2020
Date of Web Publication18-Dec-2020

Correspondence Address:
Anusheel Munshi
Manipal Hospitals, Dwarka, New Delhi
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_1151_19

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 > Abstract 


Purpose: T1-contrast and T2-flair images of magnetic resonance imaging (MRI) are commonly fused with computed tomography (CT) and used for delineation of postoperative residual tumor and bed after surgery in patients with glioblastoma multiforme (GBM). Our prospective study was aimed to see the feasibility of incorporating perfusion MRI in delineation of brain tumor for radiotherapy planning and its implication on treatment volumes.
Methods: Twenty-four patients with histopathologically proven GBM were included in the study. All patients underwent radiotherapy planning with a contrast CT scan. In addition to radiotherapy (RT) planning protocol, T1-perfusion MRI was also done in all patients in the same sitting. Perfusion imaging was processed on the in-house-developed JAVA-based software. The images of CT and MRI were sent to the iPlan planning system (Brainlab AG, GmbH) using a Digital Imaging and Communications in Medicine - Radiation Therapy (DICOM-RT) protocol. A structure of gross tumor volume (GTV)-perfusion (GTV-P) was delineated based only on the MRI perfusion images. Subsequently, GTV-P and GTV were fused together to make GTV-summated (GTV-S). Using existing guidelines, GTV-S was expanded to form clinical target volume-summated (CTV-S) and planning target volume-summated (PTV-S). The increment in each of the summated volumes as compared to baseline volume was noted. The common overlap volume (GTVO) between GTV and GTV-P was calculated using intersection theory (GTV n GTV-P = GTVO [Overlap]).
Results: Mean ± standard deviation (cc) for GTV, GTV-P, and GTVO was 46.3 ± 33.4 cc (range: 5.2 cc–108.0 cc), 26.0 ± 26.2 (range: 6.6 cc–10.3.0 cc), and 17.5 ± 22.3 cc (range: 10.0 cc–92 cc), respectively. Median volume (cc) for GTV, GTV-P, and GTVO was 40.8 cc, 17.2 cc, and 8.0 cc, respectively. Mean absolute and relative increments from GTV to that of GTV-S were 8.5 ± 8.2 cc and 27.2 ± 30.9%, respectively. Average CTV volume (cc) was 230.4 ± 115.3 (range: 80.8 cc–442.0 cc). Mean and median CTV-S volumes were 262.0 ± 126.3 cc (range: 80.8 cc–483.0 cc) and 221.0 cc, respectively. The increment in the mean CTV volume (with respect to CTV created from GTV-S) was 15.2 ± 15.9%. Mean and median PTV volumes created on the summated CTV were 287.1 ± 134.0 cc (range: 118.9 cc–576.0 cc) and 258.0 cc, respectively. Absolute and relative increments in PTV volume, while incorporating the perfusion volume, were 31.3 ± 28.9 cc and 12.5 ± 13.3%, respectively. Out of the total of 24 patients, perfusion scanning did not do any increment in GTV in five patients.
Conclusions: Our study is the first to present the feasibility and the outcome of contouring on perfusion imaging and its overlay on regular MRI images. The implications of this on long-term outcome and control rates of glioblastoma patients need to be seen in future studies.

Keywords: Contouring, glioblastoma, perfusion magnetic resonance imaging


How to cite this article:
Munshi A, Ganesh T, Gupta RK, Vaishya S, Patir R, Sarkar B, Khataniar N, Bansal K, Rastogi K, Mohanti BK. Perfusion magnetic resonance imaging in contouring of glioblastoma patients: Preliminary experience from a single institution. J Can Res Ther 2020;16:1488-94

How to cite this URL:
Munshi A, Ganesh T, Gupta RK, Vaishya S, Patir R, Sarkar B, Khataniar N, Bansal K, Rastogi K, Mohanti BK. Perfusion magnetic resonance imaging in contouring of glioblastoma patients: Preliminary experience from a single institution. J Can Res Ther [serial online] 2020 [cited 2021 Oct 27];16:1488-94. Available from: https://www.cancerjournal.net/text.asp?2020/16/6/1488/303889




 > Introduction Top


Glioblastoma multiforme (GBM) is one of the most aggressive tumors of the central nervous system.[1],[2] These tumors generally have aggressive course and poor overall survival.[2],[3] The combination regimen of concurrent postoperative radiotherapy along with temozolomide has shown some improvement in the outcome of GBM patients.[4] A Phase II large randomized trial proved a small but significant survival benefit of 2.5 months compared to radiotherapy alone (median survival: 14.6 vs. 12.1 months)[4],[5] when it was administered concurrently with radiotherapy and continued beyond as adjuvant.

From the early practice of whole-brain radiotherapy in 1980, the tailored three dimensional (3D) where only the tumor bed and residual tumor is treated with an appropriate margin has become the norm.[6] Various guidelines and articles have been published on contouring the 3D volume of high-grade gliomas (HGGs).[6],[7] All of these have stressed on using T1-contrast and T2-fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI) for delineation of postoperative residual tumor and the postoperative bed.[6],[7] Perfusion-weighted imaging can be used for measuring angiogenesis/neoangiogenesis in gliomas.[8],[9] T1-based dynamic contrast-enhanced (DCE) perfusion imaging (DCE-MRI) is an emerging modality in workup of brain tumors.[10] The DCE-MRI technique measures a combination of hemodynamic and pharmacokinetic perfusion parameters. By these indices, the neuroradiologist is provided a quantitative measurement of the integrity of the blood–brain barrier (BBB) and tissue perfusion. These methods account for the leakage to correctly estimate the cerebral blood volume (CBV) in cases of a disrupted BBB.[10],[11] T1-based perfusion imaging is routinely used in the evaluation of gliomas as part of the preoperative diagnostic workup as well as for the follow-up study. This measurement of relative CBV (rCBV) is known to demonstrate the enhancing as well as nonenhancing high-grade components of the glioma which may not be visible on the basis of enhancement. Our prospective study was aimed to extend this diagnostic neuroradiologic approach in a pilot study to see the feasibility of incorporating perfusion MRI in delineation of brain tumor for radiotherapy planning and its implication on treatment volumes.


 > Methods Top


A sum of 24 patients with pathologically confirmed GBM who were operated at our institute or referred from outside for treatment was included in the study. The simulation process of patients included making a thermoplastic mask, followed by planning computed tomography (CT) and planning brain MRI. A thermoplastic mask was devised for every patient. All the patients were subjected to radiotherapy planning with a contrast CT using 1-mm slice thickness on a 64-slice CT scanner (Philips, TruFlight Select, The Netherlands). MRI was performed on a 3T system (Philips HealthTech, The Netherlands) with an 8-element receive-only head coil. In addition to radiotherapy (RT) planning protocol, T1-perfusion MRI was also done in all patients in the same sitting. The imaging protocol has been given in the Supplementary File S1.

Perfusion data were processed on the in-house-developed JAVA-based software, and the float files obtained from the output for cerebral blood volume were converted to grayscale DICOM format using MatLab, v. 14a, MathWorks, Natick, MA. The images of CT and MRI were sent to the iPlan planning system (Brainlab AG, GmbH) for radiation therapy dosimetry and planning purpose using a DICOM-RT protocol as part of the study. In all patients, the T1-postcontrast, T2-FLAIR, and perfusion images were fused to the planning CT image set. An experienced radiation oncologist subsequently contoured the target and the organs at risk in CT-MR-fused image data set in the iPlan system. After contouring, the images were sent to the Monaco (V5.01) treatment planning system (Elekta CMS, Sunnyvale, CA) without altering the isocenter information. As per the hospital protocol and established international guidelines, gross tumor volume (GTV), clinical target volume (CTV), and planning target volume (PTV) were contoured.[6] These were considered as baseline for comparison against the study volumes [Figure 1].
Figure 1: Contouring on contrast and perfusion images

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For the purpose of the study, a structure of GTV-perfusion (GTVPer) was delineated based only on the MRI perfusion images. The contouring physician was blinded to the contrast images of MRI at the time of perfusion-based contouring. Subsequently, GTVPer and GTV were fused together to make GTV-summated (GTVSum). Using existing guidelines, GTVSum was expanded to form CTVSum and PTVSum. The increment in each of the summated volumes as compared to baseline volume was noted. The common overlap volume (GTVOvr) between GTV and GTVPer was calculated using intersection theory (GTV n GTV-P = GTVOvr).

All the patients underwent routine treatment planning/contouring for their actual treatment. The changes in the contour due to perfusion information were not taken into account for actual treatment planning and delivery.


 > Results Top


[Table 1] gives the individual data related to all the patients. The mean (±standard deviation [SD]) volume (cc) of GTV was 46.3 ± 33.4 cc. The mean (SD) volume (cc) of GTVPer was 26.0 ± 26.2 cc. [Table 2] represents the mean, SD, and median of different analyzed volume parameters. The overlap volume (GTVOvr), calculated as described above, is given in [Figure 2].
Table 1: Individual patient characteristics

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Table 2: Volumetric parameters and increments after perfusion imaging

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Figure 2: Union and overlap of gross tumor volume and gross tumor volume-perfusion volumes. GTVSum = GTV ∪ GTVPer; GTVOvr (overlap/ intersection) = GTV ∩ GTVPer

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Out of the total of 24 patients, perfusion scanning did not do any increment in GTV in 5 patients. Mean ± SD (cc) for GTV, GTVPer, and GTVOvr was 46.3 ± 33.4 cc (range: 5.2 cc–108.0 cc), 26.0 ± 26.2 (range: 6.6 cc–10.3 cc), and 17.5 ± 22.3 cc (range: 10.0 cc–92 cc), respectively. Median volume (cc) for GTV, GTVPer, and GTVOvr was 40.8 cc, 17.2 cc, and 8.0 cc, respectively. Mean absolute and relative increments from GTV to that of GTVSum were 8.5 ± 8.2 cc and 27.2 ± 30.9%, respectively. Average CTV volume (cc) was 230.4 ± 115.3 (range: 80.8 cc–442.0 cc). Mean and median CTVSum volumes were 262.0 ± 126.3 cc (range: 80.8 cc–483.0 cc) and 221.0 cc, respectively. The increment in the mean CTV volume (with respect to CTV created from GTV summated) was 15.2 ± 15.9%. Mean and median PTV volumes created on the summated CTV were 287.1 ± 134.0 cc (range: 118.9 cc–576.0 cc) and 258.0 cc, respectively. Absolute and relative increments in PTV volume, while incorporating the perfusion volume, were 31.3 ± 28.9 cc and 12.5 ± 13.3%, respectively. [Figure 3] shows the different GTV (GTV, GTVPer, GTVSum, GTVOvr, and their absolute and relative variations) for individual patients. Similarly, [Figure 4] and [Figure 5] show different CTV (CTV and CTVSum) and PTV (PTV and PTVSum) volumes and their absolute and relative variation for individual patients.
Figure 3: Different gross tumor volumes (GTV, GTVPer, GTVSum, and GTVOvr) and their increments for individual patients

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Figure 4: Different clinical target volumes and their absolute (cc) and relative (%) increment for individual patients

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Figure 5: Different planning target volume volumes and their absolute (cc) and relative (%) increment for individual patients

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 > Discussion Top


Using MRI perfusion images with the existing CT-MRI fusion sequences for volumetric radiation therapy planning, we found a mean increment in PTV of 31.3 cc in our cohort of 24 patients. The mean percentage increment in PTV was 12.5%. Our study, the first of its kind in literature, demonstrates the feasibility as well as the necessity of using MRI perfusion for delineation of target volumes in GBM. It also demonstrates that there are regions of target which show hyperperfusion but are not seen in routine MRI contrast and flair imaging. These findings can have significant implications in contouring and outcome of GBM patients.

Optimal target volume in radiation therapy for GBM is a balance between maximizing tumor control while keeping treatment-related side effects to a bare minimum. In the present day, it is standard practice to do postoperative MRI and fuse the same with the planning CT images during precision target delineation. It is also accepted that in patients with gross resection of tumor, delineation of the target should be based on the visible resection cavity plus any residual enhancing tumor on contrast-enhanced MRI. In general, the GTV should include all postoperative contrast-enhancing areas. Our study is unique since it presents advancement in tailoring the gross tumor volume, and this can have a carryover effect in delineation of the further expansion volumes. The CTV is defined as the GTV plus a margin to account for microscopic spread of disease. Typically, a 20-mm margin is taken in all directions beyond the GTV edge in all directions, with suitable editing and reduction of margins at natural anatomical barriers such as the skull, falx, and tentorium.

Dynamic susceptibility contrast (DSC)-perfusion MRI is a modern-day tool which aims to detect fluctuations and variations in microvascular kinetics by measuring rCBV. This enables it to detect critical differences in microvascular density (MVD), thereby offering a promising complement to the conventional MRI sequences. Tumor growth typically reveals increased angiogenesis and increased MVD. The passage of intravascular contrast agent through the capillary network of the brain tissue proved a unique opportunity for perfusion-weighted MRI. This measures the temporal changes of T1 or T2* signal intensity. The principle of first pass of the gadolinium injection is used by the DSC-enhanced MRI, including T2*-weighted gradient echo-planar imaging sequences. These exploit the T1-contrast phase to monitor the dynamics of tracer flow and concurrently give a reliable albeit semi-quantitative measurement of microvascular permeability. It has been shown in some studies that relative CBV and permeability can have independent prognostic values in unfavorable Grade 2 gliomas and in HGG.[12],[13] Many authors have used a cutoff of 1.75 for grading. In addition, perfusion/permeability maps have been found to have a critical role in differentiating active or recurrent glioma from postradiation necrosis.[14],[15],[16]

Previous authors have attempted to integrate information from spectroscopic MRI imaging into radiotherapy contouring. MR spectroscopic imaging (MRSI) has the potential to identify biochemical patterns in normal brain and tumor tissue, aided by the choline (Cho) and N-acetylaspartate (NAA) distributions. A study assessed volumetric 3D MRSI to delineate Cho and NAA over a large portion of the brain with an aim to assess metabolic tumor volumes (MTVs). Nineteen patients of GBM were assessed, and volumetric MRSI with effective voxel size of ~1.0 mL was taken. The authors took two important parameters, CTVs receiving 46 and 60 Gy. These two were contoured and then evaluated (CTV46 and CTV60). Volumes with high-Cho and low-NAA were used to delineate MTVCho and MTVNAA. The authors reported MRSI coverage of the brain between 70% and 76%. Importantly, the MTVNAA was almost entirely contained within the delineated portion of edema. The reported correlation between the two volumes was considered significant (r = 0.68, P = 0.001). However, in contrast to this, a median of 33% of the MTVCho was outside of the edema. It was noteworthy that for some patients, this was also outside of the CTV46 and CTV60.[17]

As HGGs usually present with increased angiogenesis, an abnormal permeability could be a surrogate marker for tumor aggressiveness, whereas perfusion could be an indicator of the volume of the disease. Therefore, it could be of special interest to exploit these T2 sequences, which are relatively rapidly acquired, adding only a few minutes of scanning time. This noninvasive tool can be used for better radiation delineation of highly active areas of the HGG. In our study, 75% of the patients had altered target volumes when perfusion imaging was incorporated in treatment planning.

It is well known that better delineation of the really active part of GBM can permit a higher rate of local control. The ongoing Spectro-Glio study (NCT01507506) study is comparing conventional arm 3D conformational radiotherapy + temozolomide versus the experimental arm of simultaneous-integrated boost with intensity-modulated radiotherapy guided by magnetic resonance spectroscopic imaging + temozolomide. The main objective of this study is to improve the overall survival of patients treated in experimental group (with simultaneous integrated boost).

In a search to define tumor activity in gliomas, radiomics-based multiparametric MRI is gaining attention to improve the diagnostic capabilities. Our present study can be considered a pilot study which has incorporated such a radiomics parameter to enhance the feasibility of radiation therapy for gliomas, which show high recurrence potential.

Our study has some drawbacks as well. It is important to resolve the current heterogeneity in reporting of perfusion MRI and have uniformity in perfusion values across centers. Spatial distortion of MRI, especially higher tesla MRI, also needs to be considered. In our study, the color images of the perfusion MRI were converted into gray-white images in our planning system. Future planning systems can develop using the color images, and this may further improve delineation in fused perfusion images.


 > Conclusion Top


Our study is the first to present the feasibility and the outcome of contouring on perfusion imaging and its overlay on regular MRI images. The implications of this on long-term outcome and control rates of glioblastoma patients need to be seen in future larger studies.

Acknowledgments

Dr. Biplab Sarkar was responsible for statistical analysis.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.


 > Supplementary File Top


Supplementary File S1: The imaging protocol included three-dimentional (3D) fluid-attenuated inversion recovery (TR/TE/T1 = 4700 ms/294 ms/1600 ms, NEX = 1, section thickness = 1 mm, matrix = 224 × 224, and flip angle = 90°); 3D T2-weighted (TR/TE = 2500 ms/251 ms, NEX = 1, section thickness = 1 mm, and matrix = 252 × 252, and flip angle = 90°), and 3D pre- and postcontrast turbo field echo (TFE) T1-weighted inversion recovery-prepared sequences (TR/TE = 7.8 ms/3.6 ms, NEX = 1, section thickness = 1 mm, flip angle = 90°, acquisition matrix = 240 × 222, FOV = 240 × 240 mm2, and reconstructed matrix = 288 × 288). The following acquisition parameters were used for T1 perfusion magnetic resonance imaging: precontrast fat-suppressed 2D T1-weighted turbo spin echo (TR/TE 360/10 ms) and fast dual spin echo proton density-weighted and T2-weighted (TR/TE1/TE2 = 3500/23.2/90 ms) sequences with 6 mm slice thickness, FOV = 240 × 240 mm2, and matrix size = 256 × 256. These images were acquired to quantify voxel-wise precontrast tissue longitudinal relaxation time T10. This was followed by 3D TFE dynamic study with acquisition parameters: TR/TE = 4.4 ms/2.1 ms, flip angle = 100°, slice thickness = 6 mm, FOV = 240 × 240 mm2, matrix size = 128 × 128, temporal resolution = 3.9 s, number of dynamics = 32, and slices = 12). At the fourth time point of the dynamic data acquisition, 0.1 mmol/kg body weight of Gd-BOPTA (Multihance, Bracco, Italy) was administered intravenously at a rate of 3.0 ml/s, followed by a 30-ml saline flush.





 
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